(12) Patent Application Publication (10) Pub. No.: US 2015/0290211 A1 BOSSE Et Al

Home , Acetoxyketobemidone, Allylnorpethidine, Azaprocin, Chloromorphide, DADLE, Dermorphin

US 20150290211A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0290211 A1 BOSSE et al. (43) Pub. Date: Oct. 15, 2015

(54) PHARMACEUTICAL COMPOSITIONS cation No. 62/091,793, filed on Dec. 15, 2014, provi sional application No. 62/093,093, filed on Dec. 17, (71) Applicant: LOCL Pharma, Inc., Georgetown, DE 2014, provisional application No. 62/104,429, filed on (US) Jan. 16, 2015. (72) Inventors: Paul BOSSE, Jupiter, FL (US); John Publication Classification AMELING, Jupiter, FL (US); Bernard SCHACHTEL, Jupiter, FL (US); (51) Int. Cl. William KOZAREK, Jensen Beach, FL A63/545 (2006.01) (US) A63/67 (2006.01) 21) Appl. No.: 14/683,886 A613 L/485 (2006.01) (21) Appl. No.: 9 (52) U.S. Cl. 1-1. CPC ...... A6 IK3I/5415 (2013.01); A61 K3I/485 (22) Filed: Apr. 10, 2015 (2013.01); A61 K3I/I67 (2013.01) Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/977,845, filed on Apr. 10, 2014, provisional application No. 62/020,597, Provided herein are methods and compositions for effective filed on Jul. 3, 2014, provisional application No. pain treatment, which also reduce or eliminate adverse 62/029,776, filed on Jul. 28, 2014, provisional appli effects. US 2015/0290211 A1

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Friabilator Apparatus for Friability Measurements

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Tablet Orientations in Hardless Measurements

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Capsule-Shaped

Figure 4 Patent Application Publication Oct. 15, 2015 Sheet 7 of 27 US 2015/0290211 A1

HC Disso APAP PMZ Thickness || Hardness Friability 5 1O 15 5 10 15 5 10 15 kp % % 6.14 22.2 O.OO 63 76 83 73 82 85 98 || 101 || 101 6.24 17.5 O.05 64 || 8 || 87 78 || 9 || 96 80 86 86 6.26 18.0 65 77 85 78 85 89 95 98 100 6,37 160 O.13 42 637 16.5 0.10 AO 6.43 15. 0.13 43

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Friability Vs Hardness

Friability

Hardness (kp} — Power (Series)

Figure 6 Patent Application Publication Oct. 15, 2015 Sheet 9 of 27 US 2015/0290211 A1

Friability Vs Thickness

Friability g

88: 8.33 8.33 3.88: 8.8 3.33 3.383 3.38 Thickness (mm) - Expon. (Series)

Figure 7 Patent Application Publication Oct. 15, 2015 Sheet 10 of 27 US 2015/0290211 A1

Hardness (kp)

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Patent Application Publication Oct. 15, 2015 Sheet 11 of 27 US 2015/0290211 A1

Dissolution %

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Dissolution %

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Figure 10 Patent Application Publication Oct. 15, 2015 Sheet 13 of 27 US 2015/0290211 A1

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HC Dissolution Vs Thickness

Dissolution %

Thickness (nm)

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APAP Dissolution Vs Thickness 3:38

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Figure 13 Patent Application Publication Oct. 15, 2015 Sheet 16 of 27 US 2015/0290211 A1

PMZ Dissolution Vs Thickness

Dissolution %

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s Patent Application Publication Oct. 15, 2015 Sheet 18 of 27 US 2015/0290211 A1

Figure 16A. Acetaminophen 4. 5 4. 3.

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Patent Application Publication Oct. 15, 2015 Sheet 24 of 27 US 2015/0290211 A1

Mean and Standard Deviation Patent Application Publication Oct. 15, 2015 Sheet 25 of 27 US 2015/0290211 A1

Percent of Patients Patent Application Publication Oct. 15, 2015 Sheet 26 of 27 US 2015/0290211 A1

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US 2015/0290211 A1 Oct. 15, 2015

PHARMACEUTICAL COMPOSITIONS cation during the initial 6 hours or initial 24 hours post administration. In some instances, the rescue medication is a CROSS-REFERENCE Supplemental antiemetic. In some instances, the rescue medi 0001. This application claims the benefit of U.S. Provi cation is a Supplemental analgesic. In some instances, the sional Application No. 61/977,845, filed on Apr. 10, 2014, Subject is administered the pharmaceutical composition U.S. Provisional Application No. 62/020,597, filed on Jul. 3, every four to six hours. In some instances, the Subject is 2014, U.S. Provisional Application No. 62/029,776, filed on administered the pharmaceutical composition two to six Jul. 28, 2014, U.S. Provisional Application No. 62/091,793, times over the first 24 hours. In some instances, the Subject is filed on Dec. 15, 2014, U.S. Provisional Application No. administered the pharmaceutical composition one to six 62/093,093, filed on Dec. 17, 2014, and U.S. Provisional times after the first 24 hours. In some instances, the Subject is Application No. 62/104,429, filed on Jan. 16, 2015, all of administered the pharmaceutical composition no more than which are incorporated herein by reference in their entirety. six times every 24 hours. In some instances, the Subject is administered the pharmaceutical composition periodically INCORPORATION BY REFERENCE over 1-28 days. In some instances, the Subject is administered 0002 All publications, patents, and patent applications the pharmaceutical composition periodically over 1-21 days. disclosed herein are incorporated by reference to the same In some instances, the Subject is administered the pharmaceu extent as if each individual publication, patent, or patent tical composition periodically over 1-14 days. In some application was specifically and individually indicated to be instances, the Subject is administered the pharmaceutical incorporated by reference. In the event of a conflict between composition periodically over 1-7 days. In some instances, a term disclosed herein and a term in an incorporated refer the Subject is administered the pharmaceutical composition ence, the term herein controls. periodically over 1-5 days. In some instances, the Subject is administered the pharmaceutical composition periodically BACKGROUND over 1-3 days. In some instances, the Subject is administered the pharmaceutical composition periodically over 1-2 days. 0003. Available pain medications can have adverse In some instances, the Subject is administered the pharmaceu effects, such as nausea, vomiting, constipation, and skin tical composition periodically over 24 hours. In some rashes and sedation. As a result of Such adverse effects, many instances, the administration is oral administration. In some Subjects are unable to tolerate recommended dosages needed instances, administration of the pharmaceutical composition for effective pain relief because of adverse effects. Accord begins from 0 to 6 hours before surgery. In some instances, ingly, there remains a need for effective therapeutics with administration of the pharmaceutical composition begins reduced adverse effects. from 0 to 6 hours after Surgery. In some instances, the admin istration is from 0 to 6 hours after an injury. In some instances, BRIEF SUMMARY the Subject is a post-operative Subject. In some instances, the 0004. The present disclosure provides methods and com Subject is a postoperative subject. In some instances, the positions for effective pain treatment. Subject is a post-discharge Subject. In some instances, the pain 0005. In some aspects, a method is provided for providing is moderate to severe pain. In some instances the pain is pain increased pain relief in a subject in need thereof, comprising from an operation or post-operative pain. In some instances, administering to the Subject a pharmaceutical composition the pain is acute pain. In some instances, the pain is chronic that comprises, an effective amount of an opioid analgesic to pain. In some instances, the pain is severe. In some instances, treat pain and an effective amount of a non-opioid analgesic to the pain is moderate. In some instances, the pain is moderate treat pain, and an effective amount of an antiemetic to to severe. In some instances, the Subject has one or more increase the subject’s pain relief from that provided by the conditions or diseases. In some instances, the one or more opioid analgesic and the non-opioid analgesic. In some conditions or diseases comprise cancer, Surgical procedure, instances, the method provides the Subject a decrease in pain acute physical injury, chronic physical injury, bone fracture, intensity. In some instances, the method provides the Subject crush injury, spinal cord injury, inflammatory disease, non a decrease in pain duration. In some instances, the pain inten inflammatory neuropathic condition, photophobia, or any sity is reduced by more than 30% following first administra combination thereof. In some instances, the pharmaceutical tion of the pharmaceutical composition. In some instances, composition does not cause increased sedation in comparison the method further comprises a relative reduction in the risk to a pharmaceutical composition with the same amount of the of vomiting of at least 50% for the 24 hours or more following opioid analgesic, in the absence of the antiemetic. In some administration of the pharmaceutical composition. In some instances, the pharmaceutical composition is a Solid dosage instances, the Subject is nausea-prone. In some instances, the form. In some instances, the Solid dosage form comprises a Subject is Susceptible to opioid induced nausea or Vomiting first layer comprising the effective amount of the antiemetic (OINV). In some instances, the subject has increased pain formulated for immediate-release. In some instances, the relief compared to a Subject administered a pharmaceutical Solid dosage form comprises a second layer comprising the composition that comprises the opioid analgesic and the non effective amount of the opioid analgesic formulated for con opioid analgesic without the antiemetic. In some instances, trolled-release and an effective amount of a non-opioid anal the subject has increased pain relief during the initial 6 hours gesic formulated for controlled-release. In some instances, post administration. In some instances, the method further the solid dosage form is a tablet, particle or capsule. In some comprises reducing or preventing opioid induced nausea or instances, the tablet is a bi-layer tablet. In some instances, the vomiting (OINV) in a subject. In some instances, the subject tablet is a multi-layer tablet. In some instances, the antiemetic experiences a reduced need for a rescue medication during the is promethazine or a pharmaceutically acceptable salt initial 6 hours or initial 24 hours post-administration. In some thereof. In some instances, the opioid is hydrocodone or a instances, the Subject experiences no need for a rescue medi pharmaceutically acceptable salt thereof. In some instances, US 2015/0290211 A1 Oct. 15, 2015

the opioid is oxycodone or a pharmaceutically acceptable salt corresponding standard-release antiemetic. In some thereof. In some instances, the non-opioid analgesic is instances, the immediate-release antiemetic has an about acetaminophen or a pharmaceutically acceptable salt thereof. 20-200% greater absorption in the 90 minutes than a corre In some instances, the pharmaceutical composition com sponding standard-release antiemetic. In some instances, the prises from about 6.5 mg to about 8.5 mg of hydrocodone, immediate-release antiemetic has an about 20-200% greater oxycodone, or a pharmaceutically acceptable salt thereof and absorption in the first hour than a corresponding standard from about 12.5 mg to about 25 mg of promethazine or a release antiemetic. In some instances, the immediate-release pharmaceutically acceptable salt thereof. In some instances, antiemetic has an about 20-100% greater absorption in the the pharmaceutical composition comprises from about 6.5 first hour than a corresponding standard-release antiemetic. mg to about 8.5 mg of hydrocodone, oxycodone, or a phar In some instances, the immediate-release antiemetic has an maceutically acceptable salt thereof, from about 12.5 mg to about 60% greater absorption in the first hour than a corre about 25 mg of promethazine or a pharmaceutically accept sponding standard-release antiemetic. In some instances, the able salt thereof and from about 290 to about 360 mg of the immediate-release antiemetic has an about 20-60% greater acetaminophen or a pharmaceutically acceptable salt thereof. absorption in the first 45 minutes than a corresponding stan In some instances, the non-opioid analgesic is present in an dard-release antiemetic. In some instances, the immediate amount of about 200 mg to about 600 mg, about 200 mg to release antiemetic has an about 40% greater absorption in the about 1000 mg, about 200 mg to about 325 mg, about 325 mg first 45 minutes than a corresponding standard-release anti to about 330 mg, about 330 mg to about 335 mg, about 335 emetic. In some instances, the immediate-release antiemetic mg to about 340 mg, about 340 mg to about 345 mg, about has an about 20-60% greater absorption in the first30 minutes 345 mg to about 350 mg, about 325 mg to about 350 mg. than a corresponding standard-release antiemetic. In some about 350 mg to about 400 mg, about 400 mg to about 1000 instances, the immediate-release antiemetic has an about mg, or any combination thereof. In some instances, the phar 40% greater absorption in the first 30 minutes than a corre maceutical composition comprises 12.5 mg of promethazine, sponding standard-release antiemetic. In some instances, the or a pharmaceutically acceptable salt thereof, about 7.5 mg of immediate-release antiemetic is promethazine or a pharma the hydrocodone or a pharmaceutically acceptable salt ceutically acceptable salt thereof. In some instances, the thereof, and about 325 mg of the acetaminophen or a phar immediate-release antiemetic is promethazine hydrochlo maceutically acceptable Salt thereof. In some instances, the ride. pharmaceutical composition comprises about 12.5 mg of 0006. In some aspects, a method is provided for providing promethazine hydrochloride, about 7.5 mg of hydrocodone increased pain relief in a subject in need thereof, comprising bitartrate and about 325 mg of acetaminophen. In some administering to the Subject a pharmaceutical composition instances, the Subject is human. In some instances, the phar that comprises, an effective amount of an opioid analgesic to maceutical composition further comprises one or more treat pain and an effective amount of an antiemetic to increase excipients. In some instances, the one or more excipients the subject’s pain relief from that provided by the opioid comprise an antioxidant agent, a binder, a coating material, a analgesic. In some instances, the method provides the Subject colorant agent, a diluent, a disintegrant, a disperant, an emul a decrease in pain intensity. In some instances, the method Sifying agent, a flavoring agent, a glidant, a lubricant, a pH provides the Subject a decrease in pain duration. In some modifying agent, a plasticizer, a preservative agent, a solubi instances, the pain intensity is reduced by more than 30% lizing agent, a stabilizer, a Surfactant, a Sweetening agent, a following first administration of the pharmaceutical compo thickening agent, a pharmaceutically inert material, or any sition. In some instances, the method further comprises a combination thereof. In some instances, the immediate-re relative reduction in the risk of vomiting of at least 50% for lease antiemetic has a Tmax that is about 3-6 hours. In some the 24 hours or more following administration of the pharma instances, the immediate-release antiemetic has a Tmax that ceutical composition. In some instances, the Subject is nau is about 20-100 minutes shorter thana Tmax of a correspond sea-prone. In some instances, the Subject is susceptible to ing standard-release antiemetic. In some instances, the imme opioid induced nausea or vomiting (OINV). In some diate-release antiemetic has a Tmax that is about 3-5 hours, instances, the Subject has increased pain relief compared to a wherein the Subject is fasted. In some instances, the immedi Subject administered a pharmaceutical composition that com ate-release antiemetic has a Tmax of about 4 hours. In some prises the opioid analgesic and the non-opioid analgesic with instances, the immediate-release antiemetic has a Tmax that out the antiemetic. In some instances, the Subject has is about 20-80 minutes shorter than a Tmax of a correspond increased pain relief during the initial 6 hours post adminis ing standard-release antiemetic, wherein the Subject is fasted. tration. In some instances, the method further comprises In some instances, the immediate-release antiemetic has a reducing or preventing opioid induced nausea or vomiting Tmax that is about 50 minutes shorter than a Tmax of a (OINV) in a subject. In some instances, the subject experi corresponding standard-release antiemetic. In some ences a reduced need for a rescue medication during the initial instances, the immediate-release antiemetic has a Tmax that 6 hours or initial 24 hours post-administration. In some is about 4-6 hours, wherein the subject is fed. In some instances, the Subject experiences no need for a rescue medi instances, the immediate-release antiemetic has a Tmax of cation during the initial 6 hours or initial 24 hours post about 5 hours. In some instances, the immediate-release anti administration. In some instances, the rescue medication is a emetic has a Tmax that is about 40-100 minutes shorter than Supplemental antiemetic. In some instances, the rescue medi a Tmax of a corresponding standard-release antiemetic, cation is a Supplemental analgesic. In some instances, the wherein the Subject is fed. In some instances, the immediate Subject is administered the pharmaceutical composition release antiemetic has a Tmax that is about 70 minutes shorter every four to six hours. In some instances, the Subject is than a Tmax of a corresponding standard-release antiemetic. administered the pharmaceutical composition two to six In some instances, the immediate-release antiemetic has an times over the first 24 hours. In some instances, the Subject is about 20-200% greater absorption in the two hours than a administered the pharmaceutical composition one to six US 2015/0290211 A1 Oct. 15, 2015

times after the first 24 hours. In some instances, the Subject is mg to about 8.5 mg of hydrocodone, oxycodone, or a phar administered the pharmaceutical composition no more than maceutically acceptable salt thereof, from about 12.5 mg to six times every 24 hours. In some instances, the Subject is about 25 mg of promethazine or a pharmaceutically accept administered the pharmaceutical composition periodically able salt thereof and from about 290 to about 360 mg of the over 1-28 days. In some instances, the Subject is administered acetaminophen or a pharmaceutically acceptable salt thereof. the pharmaceutical composition periodically over 1-21 days. In some instances, the non-opioid analgesic is present in an In some instances, the Subject is administered the pharmaceu amount of about 200 mg to about 600 mg, about 200 mg to tical composition periodically over 1-14 days. In some about 1000 mg, about 200 mg to about 325 mg, about 325 mg instances, the Subject is administered the pharmaceutical to about 330 mg, about 330 mg to about 335 mg, about 335 composition periodically over 1-7 days. In some instances, mg to about 340 mg, about 340 mg to about 345 mg, about the Subject is administered the pharmaceutical composition 345 mg to about 350 mg, about 325 mg to about 350 mg. periodically over 1-5 days. In some instances, the Subject is about 350 mg to about 400 mg, about 400 mg to about 1000 administered the pharmaceutical composition periodically mg, or any combination thereof. In some instances, the phar over 1-3 days. In some instances, the Subject is administered maceutical composition comprises 12.5 mg of promethazine, the pharmaceutical composition periodically over 1-2 days. or a pharmaceutically acceptable salt thereof, about 7.5 mg of In some instances, the Subject is administered the pharmaceu the hydrocodone or a pharmaceutically acceptable salt tical composition periodically over 24 hours. In some thereof, and about 325 mg of the acetaminophen or a phar instances, the administration is oral administration. In some maceutically acceptable Salt thereof. In some instances, the instances, administration of the pharmaceutical composition pharmaceutical composition comprises about 12.5 mg of begins from 0 to 6 hours before Surgery. In some instances, promethazine hydrochloride, about 7.5 mg of hydrocodone administration of the pharmaceutical composition begins bitartrate and about 325 mg of acetaminophen. In some from 0 to 6 hours after Surgery. In some instances, the admin instances, the Subject is human. In some instances, the phar istration is from 0 to 6 hours after an injury. In some instances, maceutical composition further comprises one or more the Subject is a post-operative Subject. In some instances, the excipients. In some instances, the one or more excipients Subject is a postoperative subject. In some instances, the comprise an antioxidant agent, a binder, a coating material, a Subject is a post-discharge Subject. In some instances, the pain colorant agent, a diluent, a disintegrant, a disperant, an emul is moderate to severe pain. In some instances the pain is pain Sifying agent, a flavoring agent, a glidant, a lubricant, a pH from an operation or post-operative pain. In some instances, modifying agent, a plasticizer, a preservative agent, a solubi the pain is acute pain. In some instances, the pain is chronic lizing agent, a stabilizer, a surfactant, a Sweetening agent, a pain. In some instances, the pain is severe. In some instances, thickening agent, a pharmaceutically inert material, or any the pain is moderate. In some instances, the pain is moderate combination thereof. In some instances, the immediate-re to severe. In some instances, the Subject has one or more lease antiemetic has a Tmax that is about 3-6 hours. In some conditions or diseases. In some instances, the one or more instances, the immediate-release antiemetic has a Tmax that conditions or diseases comprise cancer, Surgical procedure, is about 20-100 minutes shorter thana Tmax of a correspond acute physical injury, chronic physical injury, bone fracture, ing standard-release antiemetic. In some instances, the imme crush injury, spinal cord injury, inflammatory disease, non diate-release antiemetic has a Tmax that is about 3-5 hours, inflammatory neuropathic condition, photophobia, or any wherein the Subject is fasted. In some instances, the immedi combination thereof. In some instances, the pharmaceutical ate-release antiemetic has a Tmax of about 4 hours. In some composition does not cause increased sedation in comparison instances, the immediate-release antiemetic has a Tmax that to a pharmaceutical composition with the same amount of the is about 20-80 minutes shorter than a Tmax of a correspond opioid analgesic, in the absence of the antiemetic. In some ing standard-release antiemetic, wherein the Subject is fasted. instances, the pharmaceutical composition is a solid dosage In some instances, the immediate-release antiemetic has a form. In some instances, the Solid dosage form comprises a Tmax that is about 50 minutes shorter than a Tmax of a first layer comprising the effective amount of the antiemetic corresponding standard-release antiemetic. In some formulated for immediate-release. In some instances, the instances, the immediate-release antiemetic has a Tmax that Solid dosage form comprises a second layer comprising the is about 4-6 hours, wherein the subject is fed. In some effective amount of the opioid analgesic formulated for con instances, the immediate-release antiemetic has a Tmax of trolled-release and an effective amount of a non-opioid anal about 5 hours. In some instances, the immediate-release anti gesic formulated for controlled-release. In some instances, emetic has a Tmax that is about 40-100 minutes shorter than the solid dosage form is a tablet, particle or capsule. In some a Tmax of a corresponding standard-release antiemetic, instances, the tablet is a bi-layer tablet. In some instances, the wherein the Subject is fed. In some instances, the immediate tablet is a multi-layer tablet. In some instances, the antiemetic release antiemetic has a Tmax that is about 70 minutes shorter is promethazine or a pharmaceutically acceptable salt than a Tmax of a corresponding standard-release antiemetic. thereof. In some instances, the opioid is hydrocodone or a In some instances, the immediate-release antiemetic has an pharmaceutically acceptable salt thereof. In some instances, about 20-200% greater absorption in the two hours than a the opioid is oxycodone or a pharmaceutically acceptable salt corresponding standard-release antiemetic. In some thereof. In some instances, the non-opioid analgesic is instances, the immediate-release antiemetic has an about acetaminophen or a pharmaceutically acceptable salt thereof. 20-200% greater absorption in the 90 minutes than a corre In some instances, the pharmaceutical composition com sponding standard-release antiemetic. In some instances, the prises from about 6.5 mg to about 8.5 mg of hydrocodone, immediate-release antiemetic has an about 20-200% greater oxycodone, or a pharmaceutically acceptable salt thereof and absorption in the first hour than a corresponding standard from about 12.5 mg to about 25 mg of promethazine or a release antiemetic. In some instances, the immediate-release pharmaceutically acceptable salt thereof. In some instances, antiemetic has an about 20-100% greater absorption in the the pharmaceutical composition comprises from about 6.5 first hour than a corresponding standard-release antiemetic. US 2015/0290211 A1 Oct. 15, 2015

In some instances, the immediate-release antiemetic has an In some instances, the Subject is administered the pharmaceu about 60% greater absorption in the first hour than a corre tical composition periodically over 1-14 days. In some sponding standard-release antiemetic. In some instances, the instances, the Subject is administered the pharmaceutical immediate-release antiemetic has an about 20-60% greater composition periodically over 1-7 days. In some instances, absorption in the first 45 minutes than a corresponding stan the Subject is administered the pharmaceutical composition dard-release antiemetic. In some instances, the immediate periodically over 1-5 days. In some instances, the Subject is release antiemetic has an about 40% greater absorption in the administered the pharmaceutical composition periodically first 45 minutes than a corresponding standard-release anti over 1-3 days. In some instances, the Subject is administered emetic. In some instances, the immediate-release antiemetic the pharmaceutical composition periodically over 1-2 days. has an about 20-60% greater absorption in the first30 minutes In some instances, the Subject is administered the pharmaceu than a corresponding standard-release antiemetic. In some tical composition periodically over 24 hours. In some instances, the immediate-release antiemetic has an about instances, the administration is oral administration. In some 40% greater absorption in the first 30 minutes than a corre instances, administration of the pharmaceutical composition sponding standard-release antiemetic. In some instances, the begins from 0 to 6 hours before Surgery. In some instances, immediate-release antiemetic is promethazine or a pharma administration of the pharmaceutical composition begins ceutically acceptable salt thereof. In some instances, the from 0 to 6 hours after Surgery. In some instances, the admin immediate-release antiemetic is promethazine hydrochlo istration is from 0 to 6 hours after an injury. In some instances, ride. the Subject is a post-operative Subject. In some instances, the 0007. In some aspects, a method is provided for providing Subject is a postoperative subject. In some instances, the increased pain relief in a subject in need thereof, comprising Subject is a post-discharge Subject. In some instances, the pain administering to the Subject a pharmaceutical composition is moderate to severe pain. In some instances the pain is pain that comprises, an effective amount of an opioid analgesic from an operation or post-operative pain. In some instances, formulated for controlled-release to treat pain and an effec the pain is acute pain. In some instances, the pain is chronic tive amount of a non-opioid analgesic formulated for con pain. In some instances, the pain is severe. In some instances, trolled-release to treat pain; and an effective amount of an the pain is moderate. In some instances, the pain is moderate antiemetic formulated for immediate-release to increase the to severe. In some instances, the Subject has one or more subject’s pain relief from that provided by the opioid analge conditions or diseases. In some instances, the one or more sic and the non-opioid analgesic. In some instances, the conditions or diseases comprise cancer, Surgical procedure, method provides the subject a decrease in pain intensity. In acute physical injury, chronic physical injury, bone fracture, Some instances, the method provides the Subject a decrease in crush injury, spinal cord injury, inflammatory disease, non pain duration. In some instances, the pain intensity is reduced inflammatory neuropathic condition, photophobia, or any by more than 30% following first administration of the phar combination thereof. In some instances, the pharmaceutical maceutical composition. In some instances, the method fur composition does not cause increased sedation in comparison ther comprises a relative reduction in the risk of Vomiting of to a pharmaceutical composition with the same amount of the at least 50% for the 24 hours or more following administra opioid analgesic, in the absence of the antiemetic. In some tion of the pharmaceutical composition. In some instances, instances, the pharmaceutical composition is a Solid dosage the Subject is nausea-prone. In some instances, the Subject is form. In some instances, the Solid dosage form comprises a susceptible to opioid induced nausea or vomiting (OINV). In first layer comprising the effective amount of the antiemetic Some instances, the Subject has increased pain relief com formulated for immediate-release. In some instances, the pared to a subject administered a pharmaceutical composition Solid dosage form comprises a second layer comprising the that comprises the opioid analgesic and the non-opioid anal effective amount of the opioid analgesic formulated for con gesic without the antiemetic. In some instances, the Subject trolled-release and an effective amount of a non-opioid anal has increased pain relief during the initial 6 hours post admin gesic formulated for controlled-release. In some instances, istration. In some instances, the method further comprises the solid dosage form is a tablet, particle or capsule. In some reducing or preventing opioid induced nausea or vomiting instances, the tablet is a bi-layer tablet. In some instances, the (OINV) in a subject. In some instances, the subject experi tablet is a multi-layer tablet. In some instances, the antiemetic ences a reduced need for a rescue medication during the initial is promethazine or a pharmaceutically acceptable salt 6 hours or initial 24 hours post-administration. In some thereof. In some instances, the opioid is hydrocodone or a instances, the Subject experiences no need for a rescue medi pharmaceutically acceptable salt thereof. In some instances, cation during the initial 6 hours or initial 24 hours post the opioid is oxycodone or a pharmaceutically acceptable salt administration. In some instances, the rescue medication is a thereof. In some instances, the non-opioid analgesic is Supplemental antiemetic. In some instances, the rescue medi acetaminophen or a pharmaceutically acceptable salt thereof. cation is a Supplemental analgesic. In some instances, the In some instances, the pharmaceutical composition com Subject is administered the pharmaceutical composition prises from about 6.5 mg to about 8.5 mg of hydrocodone, every four to six hours. In some instances, the Subject is oxycodone, or a pharmaceutically acceptable salt thereof and administered the pharmaceutical composition two to six from about 12.5 mg to about 25 mg of promethazine or a times over the first 24 hours. In some instances, the Subject is pharmaceutically acceptable salt thereof. In some instances, administered the pharmaceutical composition one to six the pharmaceutical composition comprises from about 6.5 times after the first 24 hours. In some instances, the Subject is mg to about 8.5 mg of hydrocodone, oxycodone, or a phar administered the pharmaceutical composition no more than maceutically acceptable salt thereof, from about 12.5 mg to six times every 24 hours. In some instances, the Subject is about 25 mg of promethazine or a pharmaceutically accept administered the pharmaceutical composition periodically able salt thereof and from about 290 to about 360 mg of the over 1-28 days. In some instances, the Subject is administered acetaminophen or a pharmaceutically acceptable salt thereof. the pharmaceutical composition periodically over 1-21 days. In some instances, the non-opioid analgesic is present in an US 2015/0290211 A1 Oct. 15, 2015

amount of about 200 mg to about 600 mg, about 200 mg to release antiemetic has an about 40% greater absorption in the about 1000 mg, about 200 mg to about 325 mg, about 325 mg first 45 minutes than a corresponding standard-release anti to about 330 mg, about 330 mg to about 335 mg, about 335 emetic. In some instances, the immediate-release antiemetic mg to about 340 mg, about 340 mg to about 345 mg, about has an about 20-60% greater absorption in the first30 minutes 345 mg to about 350 mg, about 325 mg to about 350 mg. than a corresponding standard-release antiemetic. In some about 350 mg to about 400 mg, about 400 mg to about 1000 instances, the immediate-release antiemetic has an about mg, or any combination thereof. In some instances, the phar 40% greater absorption in the first 30 minutes than a corre maceutical composition comprises 12.5 mg of promethazine, sponding standard-release antiemetic. In some instances, the or a pharmaceutically acceptable salt thereof, about 7.5 mg of immediate-release antiemetic is promethazine or a pharma the hydrocodone or a pharmaceutically acceptable salt ceutically acceptable salt thereof. In some instances, the thereof, and about 325 mg of the acetaminophen or a phar immediate-release antiemetic is promethazine hydrochlo maceutically acceptable Salt thereof. In some instances, the ride. pharmaceutical composition comprises about 12.5 mg of 0008. In some aspects, a method is provided for providing promethazine hydrochloride, about 7.5 mg of hydrocodone increased pain relief in a Subject in need thereof, comprising bitartrate and about 325 mg of acetaminophen. In some administering to the Subject a pharmaceutical composition instances, the Subject is human. In some instances, the phar that comprises, an effective amount of an opioid analgesic maceutical composition further comprises one or more formulated for controlled-release to treat pain and an effec excipients. In some instances, the one or more excipients tive amount of an antiemetic formulated for immediate-re comprise an antioxidant agent, a binder, a coating material, a lease to increase the subjects pain relief from that provided colorant agent, a diluent, a disintegrant, a disperant, an emul by the opioid analgesic. In some instances, the method pro Sifying agent, a flavoring agent, a glidant, a lubricant, a pH vides the Subject a decrease in pain intensity. In some modifying agent, a plasticizer, a preservative agent, a solubi instances, the method provides the Subject a decrease in pain lizing agent, a stabilizer, a Surfactant, a Sweetening agent, a duration. In some instances, the pain intensity is reduced by thickening agent, a pharmaceutically inert material, or any more than 30% following first administration of the pharma combination thereof. In some instances, the immediate-re ceutical composition. In some instances, the method further lease antiemetic has a Tmax that is about 3-6 hours. In some comprises a relative reduction in the risk of Vomiting of at instances, the immediate-release antiemetic has a Tmax that least 50% for the 24 hours or more following administration is about 20-100 minutes shorter thana Tmax of a correspond of the pharmaceutical composition. In some instances, the ing standard-release antiemetic. In some instances, the imme subject is nausea-prone. In some instances, the subject is diate-release antiemetic has a Tmax that is about 3-5 hours, susceptible to opioid induced nausea or vomiting (OINV). In wherein the Subject is fasted. In some instances, the immedi Some instances, the Subject has increased pain relief com ate-release antiemetic has a Tmax of about 4 hours. In some pared to a Subject administered a pharmaceutical composition instances, the immediate-release antiemetic has a Tmax that that comprises the opioid analgesic and the non-opioid anal is about 20-80 minutes shorter than a Tmax of a correspond gesic without the antiemetic. In some instances, the Subject ing standard-release antiemetic, wherein the Subject is fasted. has increased pain relief during the initial 6 hours post admin In some instances, the immediate-release antiemetic has a istration. In some instances, the method further comprises Tmax that is about 50 minutes shorter than a Tmax of a reducing or preventing opioid induced nausea or vomiting corresponding standard-release antiemetic. In some (OINV) in a subject. In some instances, the subject experi instances, the immediate-release antiemetic has a Tmax that ences a reduced need for a rescue medication during the initial is about 4-6 hours, wherein the subject is fed. In some 6 hours or initial 24 hours post-administration. In some instances, the immediate-release antiemetic has a Tmax of instances, the Subject experiences no need for a rescue medi about 5 hours. In some instances, the immediate-release anti cation during the initial 6 hours or initial 24 hours post emetic has a Tmax that is about 40-100 minutes shorter than administration. In some instances, the rescue medication is a a Tmax of a corresponding standard-release antiemetic, Supplemental antiemetic. In some instances, the rescue medi wherein the Subject is fed. In some instances, the immediate cation is a Supplemental analgesic. In some instances, the release antiemetic has a Tmax that is about 70 minutes shorter Subject is administered the pharmaceutical composition than a Tmax of a corresponding standard-release antiemetic. every four to six hours. In some instances, the Subject is In some instances, the immediate-release antiemetic has an administered the pharmaceutical composition two to six about 20-200% greater absorption in the two hours than a times over the first 24 hours. In some instances, the Subject is corresponding standard-release antiemetic. In some administered the pharmaceutical composition one to six instances, the immediate-release antiemetic has an about times after the first 24 hours. In some instances, the Subject is 20-200% greater absorption in the 90 minutes than a corre administered the pharmaceutical composition no more than sponding standard-release antiemetic. In some instances, the six times every 24 hours. In some instances, the Subject is immediate-release antiemetic has an about 20-200% greater administered the pharmaceutical composition periodically absorption in the first hour than a corresponding standard over 1-28 days. In some instances, the Subject is administered release antiemetic. In some instances, the immediate-release the pharmaceutical composition periodically over 1-21 days. antiemetic has an about 20-100% greater absorption in the In some instances, the Subject is administered the pharmaceu first hour than a corresponding standard-release antiemetic. tical composition periodically over 1-14 days. In some In some instances, the immediate-release antiemetic has an instances, the Subject is administered the pharmaceutical about 60% greater absorption in the first hour than a corre composition periodically over 1-7 days. In some instances, sponding standard-release antiemetic. In some instances, the the Subject is administered the pharmaceutical composition immediate-release antiemetic has an about 20-60% greater periodically over 1-5 days. In some instances, the Subject is absorption in the first 45 minutes than a corresponding stan administered the pharmaceutical composition periodically dard-release antiemetic. In some instances, the immediate over 1-3 days. In some instances, the Subject is administered US 2015/0290211 A1 Oct. 15, 2015 the pharmaceutical composition periodically over 1-2 days. or a pharmaceutically acceptable salt thereof, about 7.5 mg of In some instances, the Subject is administered the pharmaceu the hydrocodone or a pharmaceutically acceptable salt tical composition periodically over 24 hours. In some thereof, and about 325 mg of the acetaminophen or a phar instances, the administration is oral administration. In some maceutically acceptable Salt thereof. In some instances, the instances, administration of the pharmaceutical composition pharmaceutical composition comprises about 12.5 mg of begins from 0 to 6 hours before Surgery. In some instances, promethazine hydrochloride, about 7.5 mg of hydrocodone administration of the pharmaceutical composition begins bitartrate and about 325 mg of acetaminophen. In some from 0 to 6 hours after Surgery. In some instances, the admin instances, the Subject is human. In some instances, the phar istration is from 0 to 6 hours after an injury. In some instances, maceutical composition further comprises one or more the Subject is a post-operative Subject. In some instances, the excipients. In some instances, the one or more excipients Subject is a postoperative subject. In some instances, the comprise an antioxidant agent, a binder, a coating material, a Subject is a post-discharge Subject. In some instances, the pain colorant agent, a diluent, a disintegrant, a disperant, an emul is moderate to severe pain. In some instances the pain is pain Sifying agent, a flavoring agent, a glidant, a lubricant, a pH from an operation or post-operative pain. In some instances, modifying agent, a plasticizer, a preservative agent, a solubi the pain is acute pain. In some instances, the pain is chronic lizing agent, a stabilizer, a Surfactant, a Sweetening agent, a pain. In some instances, the pain is severe. In some instances, thickening agent, a pharmaceutically inert material, or any the pain is moderate. In some instances, the pain is moderate combination thereof. In some instances, the immediate-re to severe. In some instances, the Subject has one or more lease antiemetic has a Tmax that is about 3-6 hours. In some conditions or diseases. In some instances, the one or more instances, the immediate-release antiemetic has a Tmax that conditions or diseases comprise cancer, Surgical procedure, is about 20-100 minutes shorter thana Tmax of a correspond acute physical injury, chronic physical injury, bone fracture, ing standard-release antiemetic. In some instances, the imme crush injury, spinal cord injury, inflammatory disease, non diate-release antiemetic has a Tmax that is about 3-5 hours, inflammatory neuropathic condition, photophobia, or any wherein the Subject is fasted. In some instances, the immedi combination thereof. In some instances, the pharmaceutical ate-release antiemetic has a Tmax of about 4 hours. In some composition does not cause increased sedation in comparison instances, the immediate-release antiemetic has a Tmax that to a pharmaceutical composition with the same amount of the is about 20-80 minutes shorter than a Tmax of a correspond opioid analgesic, in the absence of the antiemetic. In some ing standard-release antiemetic, wherein the Subject is fasted. instances, the pharmaceutical composition is a solid dosage In some instances, the immediate-release antiemetic has a form. In some instances, the solid dosage form comprises a Tmax that is about 50 minutes shorter than a Timax of a first layer comprising the effective amount of the antiemetic corresponding standard-release antiemetic. In some formulated for immediate-release. In some instances, the instances, the immediate-release antiemetic has a Tmax that Solid dosage form comprises a second layer comprising the is about 4-6 hours, wherein the subject is fed. In some effective amount of the opioid analgesic formulated for con instances, the immediate-release antiemetic has a Tmax of trolled-release and an effective amount of a non-opioid anal about 5 hours. In some instances, the immediate-release anti gesic formulated for controlled-release. In some instances, emetic has a Tmax that is about 40-100 minutes shorter than the solid dosage form is a tablet, particle or capsule. In some a Tmax of a corresponding standard-release antiemetic, instances, the tablet is a bi-layer tablet. In some instances, the wherein the Subject is fed. In some instances, the immediate tablet is a multi-layer tablet. In some instances, the antiemetic release antiemetic has a Tmax that is about 70 minutes shorter is promethazine or a pharmaceutically acceptable salt than a Tmax of a corresponding standard-release antiemetic. thereof. In some instances, the opioid is hydrocodone or a In some instances, the immediate-release antiemetic has an pharmaceutically acceptable salt thereof. In some instances, about 20-200% greater absorption in the two hours than a the opioid is oxycodone or a pharmaceutically acceptable salt corresponding standard-release antiemetic. In some thereof. In some instances, the non-opioid analgesic is instances, the immediate-release antiemetic has an about acetaminophen or a pharmaceutically acceptable salt thereof. 20-200% greater absorption in the 90 minutes than a corre In some instances, the pharmaceutical composition com sponding standard-release antiemetic. In some instances, the prises from about 6.5 mg to about 8.5 mg of hydrocodone, immediate-release antiemetic has an about 20-200% greater oxycodone, or a pharmaceutically acceptable salt thereof and absorption in the first hour than a corresponding standard from about 12.5 mg to about 25 mg of promethazine or a release antiemetic. In some instances, the immediate-release pharmaceutically acceptable salt thereof. In some instances, antiemetic has an about 20-100% greater absorption in the the pharmaceutical composition comprises from about 6.5 first hour than a corresponding standard-release antiemetic. mg to about 8.5 mg of hydrocodone, oxycodone, or a phar In some instances, the immediate-release antiemetic has an maceutically acceptable salt thereof, from about 12.5 mg to about 60% greater absorption in the first hour than a corre about 25 mg of promethazine or a pharmaceutically accept sponding standard-release antiemetic. In some instances, the able salt thereof and from about 290 to about 360 mg of the immediate-release antiemetic has an about 20-60% greater acetaminophen or a pharmaceutically acceptable salt thereof. absorption in the first 45 minutes than a corresponding stan In some instances, the non-opioid analgesic is present in an dard-release antiemetic. In some instances, the immediate amount of about 200 mg to about 600 mg, about 200 mg to release antiemetic has an about 40% greater absorption in the about 1000 mg, about 200 mg to about 325 mg, about 325 mg first 45 minutes than a corresponding standard-release anti to about 330 mg, about 330 mg to about 335 mg, about 335 emetic. In some instances, the immediate-release antiemetic mg to about 340 mg, about 340 mg to about 345 mg, about has an about 20-60% greater absorption in the first30 minutes 345 mg to about 350 mg, about 325 mg to about 350 mg. than a corresponding standard-release antiemetic. In some about 350 mg to about 400 mg, about 400 mg to about 1000 instances, the immediate-release antiemetic has an about mg, or any combination thereof. In some instances, the phar 40% greater absorption in the first 30 minutes than a corre maceutical composition comprises 12.5 mg of promethazine, sponding standard-release antiemetic. In some instances, the US 2015/0290211 A1 Oct. 15, 2015 immediate-release antiemetic is promethazine or a pharma instances, the Subject is administered the pharmaceutical ceutically acceptable salt thereof. In some instances, the composition periodically over 1-2 days. In some instances, immediate-release antiemetic is promethazine hydrochlo the Subject is administered the pharmaceutical composition ride. periodically over 24 hours. In some instances, the adminis 0009. In some aspects, a method is provided for providing tration is oral administration. In some instances, administra increased pain relief and reducing or preventing opioid tion of the pharmaceutical composition begins from 0 to 6 induced nausea or vomiting (OINV) in a subject in need hours before Surgery. In some instances, administration of the thereof, comprising administering to the Subject a pharma pharmaceutical composition begins from 0 to 6 hours after ceutical composition that comprises, an effective amount of Surgery. In some instances, the administration is from 0 to 6 an opioid analgesic formulated for controlled-release to treat hours after an injury. In some instances, the Subject is a pain and an effective amount of a non-opioid analgesic for post-operative Subject. In some instances, the Subject is a mulated for controlled-release to treat pain, and an effective postoperative Subject. In some instances, the Subject is a amount of an antiemetic formulated for immediate-release to post-discharge Subject. In some instances, the pain is moder increase the subject’s pain relief from that provided by the ate to severe pain. In some instances the pain is pain from an opioid analgesic and the non-opioid analgesic, and to reduce operation or post-operative pain. In some instances, the pain or prevent OINV. In some instances, the subject has reduced is acute pain. In some instances, the pain is chronic pain. In intensity of nausea. In some instances, the Subject has Some instances, the pain is severe. In some instances, the pain reduced intensity of nausea in the 6 hours following initial is moderate. In some instances, the pain is moderate to severe. administration of the pharmaceutical composition. In some In some instances, the Subject has one or more conditions or instances, the Subject has reduced intensity of nausea in the 24 diseases. In some instances, the one or more conditions or hours following initial administration of the pharmaceutical diseases comprise cancer, Surgical procedure, acute physical composition. In some instances, reducing nausea or vomiting injury, chronic physical injury, bone fracture, crush injury, in a subject includes reducing the frequency of vomiting over spinal cord injury, inflammatory disease, non-inflammatory 24 hours or more following administration of the pharmaceu neuropathic condition, photophobia, or any combination tical composition. In some instances, the method further com thereof. In some instances, the pharmaceutical composition prises a relative reduction in the risk of Vomiting of at least does not cause increased sedation in comparison to a phar 50% for the 24 hours or more following administration of the maceutical composition with the same amount of the opioid pharmaceutical composition. In some instances, reducing analgesic, in the absence of the antiemetic. In some instances, nausea or vomiting in the subject is in comparison to a subject the pharmaceutical composition is a solid dosage form. In administered a pharmaceutical composition that comprises Some instances, the Solid dosage form comprises a first layer the opioid analgesic and the non-opioid analgesic without the comprising the effective amount of the antiemetic formulated antiemetic. In some instances, the method further comprises for immediate-release. In some instances, the solid dosage reducing the frequency of Vomiting in the initial 24 hours form comprises a second layer comprising the effective following administration of the pharmaceutical composition. amount of the opioid analgesic formulated for controlled In some instances, reducing nausea or Vomiting in a subject release and an effective amount of a non-opioid analgesic includes reducing the occurrence of nausea. In some formulated for controlled-release. In some instances, the instances, the Subject is administered doses of the pharma Solid dosage form is a tablet, particle or capsule. In some ceutical composition more than once over 24 hours or longer. instances, the tablet is a bi-layer tablet. In some instances, the In some instances, the Subject experiences a reduced need for tablet is a multi-layer tablet. In some instances, the antiemetic a rescue medication during the initial 6 hours or initial 24 is promethazine or a pharmaceutically acceptable salt hours post-administration. In some instances, the Subject thereof. In some instances, the opioid is hydrocodone or a experiences no need for a rescue medication during the initial pharmaceutically acceptable salt thereof. In some instances, 6 hours or initial 24 hours post-administration. In some the opioid is oxycodone or a pharmaceutically acceptable salt instances, the rescue medication is a Supplemental anti thereof. In some instances, the non-opioid analgesic is emetic. In some instances, the rescue medication is a Supple acetaminophen or a pharmaceutically acceptable salt thereof. mental analgesic. In some instances, the Subject is adminis In some instances, the pharmaceutical composition com tered the pharmaceutical composition every four to six hours. prises from about 6.5 mg to about 8.5 mg of hydrocodone, In some instances, the Subject is administered the pharmaceu oxycodone, or a pharmaceutically acceptable salt thereof and tical composition two to six times over the first 24 hours. In from about 12.5 mg to about 25 mg of promethazine or a Some instances, the Subject is administered the pharmaceuti pharmaceutically acceptable salt thereof. In some instances, cal composition one to six times after the first 24 hours. In the pharmaceutical composition comprises from about 6.5 Some instances, the Subject is administered the pharmaceuti mg to about 8.5 mg of hydrocodone, oxycodone, or a phar cal composition no more than six times every 24 hours. In maceutically acceptable salt thereof, from about 12.5 mg to Some instances, the Subject is administered the pharmaceuti about 25 mg of promethazine or a pharmaceutically accept cal composition periodically over 1-28 days. In some able salt thereof and from about 290 to about 360 mg of the instances, the Subject is administered the pharmaceutical acetaminophen or a pharmaceutically acceptable salt thereof. composition periodically over 1-21 days. In some instances, In some instances, the non-opioid analgesic is present in an the Subject is administered the pharmaceutical composition amount of about 200 mg to about 600 mg, about 200 mg to periodically over 1-14 days. In some instances, the Subject is about 1000 mg, about 200 mg to about 325 mg, about 325 mg administered the pharmaceutical composition periodically to about 330 mg, about 330 mg to about 335 mg, about 335 over 1-7 days. In some instances, the Subject is administered mg to about 340 mg, about 340 mg to about 345 mg, about the pharmaceutical composition periodically over 1-5 days. 345 mg to about 350 mg, about 325 mg to about 350 mg. In some instances, the Subject is administered the pharmaceu about 350 mg to about 400 mg, about 400 mg to about 1000 tical composition periodically over 1-3 days. In some mg, or any combination thereof. In some instances, the phar US 2015/0290211 A1 Oct. 15, 2015

maceutical composition comprises 12.5 mg of promethazine, sponding standard-release antiemetic. In some instances, the or a pharmaceutically acceptable salt thereof, about 7.5 mg of immediate-release antiemetic is promethazine or a pharma the hydrocodone or a pharmaceutically acceptable salt ceutically acceptable salt thereof. In some instances, the thereof, and about 325 mg of the acetaminophen or a phar immediate-release antiemetic is promethazine hydrochlo maceutically acceptable Salt thereof. In some instances, the ride. pharmaceutical composition comprises about 12.5 mg of 0010. In some aspects, a method is provided for providing promethazine hydrochloride, about 7.5 mg of hydrocodone increased pain relief and reducing or preventing opioid bitartrate and about 325 mg of acetaminophen. In some induced nausea or vomiting (OINV) in a subject in need instances, the Subject is human. In some instances, the phar thereof, comprising administering to the Subject a pharma maceutical composition further comprises one or more ceutical composition that comprises, an effective amount of excipients. In some instances, the one or more excipients an opioid analgesic formulated for controlled-release to treat comprise an antioxidant agent, a binder, a coating material, a pain and an effective amount of an antiemetic formulated for colorant agent, a diluent, a disintegrant, a disperant, an emul immediate-release to increase the subject’s pain relief from Sifying agent, a flavoring agent, a glidant, a lubricant, a pH that provided by the opioid analgesic and to reduce or prevent modifying agent, a plasticizer, a preservative agent, a solubi OINV. In some instances, the subject has reduced intensity of lizing agent, a stabilizer, a Surfactant, a Sweetening agent, a nausea. In some instances, the Subject has reduced intensity thickening agent, a pharmaceutically inert material, or any of nausea in the 6 hours following initial administration of the combination thereof. In some instances, the immediate-re pharmaceutical composition. In some instances, the Subject lease antiemetic has a Tmax that is about 3-6 hours. In some has reduced intensity of nausea in the 24 hours following instances, the immediate-release antiemetic has a Tmax that initial administration of the pharmaceutical composition. In is about 20-100 minutes shorter thana Tmax of a correspond Some instances, reducing nausea or vomiting in a subject ing standard-release antiemetic. In some instances, the imme includes reducing the frequency of vomiting over 24 hours or diate-release antiemetic has a Tmax that is about 3-5 hours, more following administration of the pharmaceutical compo wherein the Subject is fasted. In some instances, the immedi sition. In some instances, the method further comprises a ate-release antiemetic has a Tmax of about 4 hours. In some relative reduction in the risk of vomiting of at least 50% for instances, the immediate-release antiemetic has a Tmax that the 24 hours or more following administration of the pharma is about 20-80 minutes shorter than a Tmax of a correspond ceutical composition. In some instances, reducing nausea or ing standard-release antiemetic, wherein the Subject is fasted. Vomiting in the Subject is in comparison to a Subject admin In some instances, the immediate-release antiemetic has a istered a pharmaceutical composition that comprises the Tmax that is about 50 minutes shorter than a Tmax of a opioid analgesic and the non-opioid analgesic without the corresponding standard-release antiemetic. In some antiemetic. In some instances, the method further comprises instances, the immediate-release antiemetic has a Tmax that reducing the frequency of Vomiting in the initial 24 hours is about 4-6 hours, wherein the subject is fed. In some following administration of the pharmaceutical composition. instances, the immediate-release antiemetic has a Tmax of In some instances, reducing nausea or Vomiting in a subject about 5 hours. In some instances, the immediate-release anti includes reducing the occurrence of nausea. In some emetic has a Tmax that is about 40-100 minutes shorter than instances, the Subject is administered doses of the pharma a Tmax of a corresponding standard-release antiemetic, ceutical composition more than once over 24 hours or longer. wherein the Subject is fed. In some instances, the immediate In some instances, the Subject experiences a reduced need for release antiemetic has a Tmax that is about 70 minutes shorter a rescue medication during the initial 6 hours or initial 24 than a Tmax of a corresponding standard-release antiemetic. hours post-administration. In some instances, the Subject In some instances, the immediate-release antiemetic has an experiences no need for a rescue medication during the initial about 20-200% greater absorption in the two hours than a 6 hours or initial 24 hours post-administration. In some corresponding standard-release antiemetic. In some instances, the rescue medication is a Supplemental anti instances, the immediate-release antiemetic has an about emetic. In some instances, the rescue medication is a Supple 20-200% greater absorption in the 90 minutes than a corre mental analgesic. In some instances, the Subject is adminis sponding standard-release antiemetic. In some instances, the tered the pharmaceutical composition every four to six hours. immediate-release antiemetic has an about 20-200% greater In some instances, the Subject is administered the pharmaceu absorption in the first hour than a corresponding standard tical composition two to six times over the first 24 hours. In release antiemetic. In some instances, the immediate-release Some instances, the Subject is administered the pharmaceuti antiemetic has an about 20-100% greater absorption in the cal composition one to six times after the first 24 hours. In first hour than a corresponding standard-release antiemetic. Some instances, the Subject is administered the pharmaceuti In some instances, the immediate-release antiemetic has an cal composition no more than six times every 24 hours. In about 60% greater absorption in the first hour than a corre Some instances, the Subject is administered the pharmaceuti sponding standard-release antiemetic. In some instances, the cal composition periodically over 1-28 days. In some immediate-release antiemetic has an about 20-60% greater instances, the Subject is administered the pharmaceutical absorption in the first 45 minutes than a corresponding stan composition periodically over 1-21 days. In some instances, dard-release antiemetic. In some instances, the immediate the Subject is administered the pharmaceutical composition release antiemetic has an about 40% greater absorption in the periodically over 1-14 days. In some instances, the Subject is first 45 minutes than a corresponding standard-release anti administered the pharmaceutical composition periodically emetic. In some instances, the immediate-release antiemetic over 1-7 days. In some instances, the Subject is administered has an about 20-60% greater absorption in the first30 minutes the pharmaceutical composition periodically over 1-5 days. than a corresponding standard-release antiemetic. In some In some instances, the Subject is administered the pharmaceu instances, the immediate-release antiemetic has an about tical composition periodically over 1-3 days. In some 40% greater absorption in the first 30 minutes than a corre instances, the Subject is administered the pharmaceutical US 2015/0290211 A1 Oct. 15, 2015 composition periodically over 1-2 days. In some instances, or a pharmaceutically acceptable salt thereof, about 7.5 mg of the Subject is administered the pharmaceutical composition the hydrocodone or a pharmaceutically acceptable salt periodically over 24 hours. In some instances, the adminis thereof, and about 325 mg of the acetaminophen or a phar tration is oral administration. In some instances, administra maceutically acceptable Salt thereof. In some instances, the tion of the pharmaceutical composition begins from 0 to 6 pharmaceutical composition comprises about 12.5 mg of hours before Surgery. In some instances, administration of the promethazine hydrochloride, about 7.5 mg of hydrocodone pharmaceutical composition begins from 0 to 6 hours after bitartrate and about 325 mg of acetaminophen. In some Surgery. In some instances, the administration is from 0 to 6 instances, the Subject is human. In some instances, the phar hours after an injury. In some instances, the Subject is a maceutical composition further comprises one or more post-operative Subject. In some instances, the Subject is a excipients. In some instances, the one or more excipients postoperative Subject. In some instances, the Subject is a comprise an antioxidant agent, a binder, a coating material, a post-discharge Subject. In some instances, the pain is moder colorant agent, a diluent, a disintegrant, a disperant, an emul ate to severe pain. In some instances the pain is pain from an Sifying agent, a flavoring agent, a glidant, a lubricant, a pH operation or post-operative pain. In some instances, the pain modifying agent, a plasticizer, a preservative agent, a solubi is acute pain. In some instances, the pain is chronic pain. In lizing agent, a stabilizer, a Surfactant, a Sweetening agent, a Some instances, the pain is severe. In some instances, the pain thickening agent, a pharmaceutically inert material, or any is moderate. In some instances, the pain is moderate to severe. combination thereof. In some instances, the immediate-re In some instances, the Subject has one or more conditions or lease antiemetic has a Tmax that is about 3-6 hours. In some diseases. In some instances, the one or more conditions or instances, the immediate-release antiemetic has a Tmax that diseases comprise cancer, Surgical procedure, acute physical is about 20-100 minutes shorter thana Tmax of a correspond injury, chronic physical injury, bone fracture, crush injury, ing standard-release antiemetic. In some instances, the imme spinal cord injury, inflammatory disease, non-inflammatory diate-release antiemetic has a Tmax that is about 3-5 hours, neuropathic condition, photophobia, or any combination wherein the Subject is fasted. In some instances, the immedi thereof. In some instances, the pharmaceutical composition ate-release antiemetic has a Tmax of about 4 hours. In some does not cause increased sedation in comparison to a phar instances, the immediate-release antiemetic has a Tmax that maceutical composition with the same amount of the opioid is about 20-80 minutes shorter than a Tmax of a correspond analgesic, in the absence of the antiemetic. In some instances, ing standard-release antiemetic, wherein the Subject is fasted. the pharmaceutical composition is a solid dosage form. In In some instances, the immediate-release antiemetic has a some instances, the solid dosage form comprises a first layer Tmax that is about 50 minutes shorter than a Timax of a comprising the effective amount of the antiemetic formulated corresponding standard-release antiemetic. In some for immediate-release. In some instances, the Solid dosage instances, the immediate-release antiemetic has a Tmax that form comprises a second layer comprising the effective is about 4-6 hours, wherein the subject is fed. In some amount of the opioid analgesic formulated for controlled instances, the immediate-release antiemetic has a Tmax of release and an effective amount of a non-opioid analgesic about 5 hours. In some instances, the immediate-release anti formulated for controlled-release. In some instances, the emetic has a Tmax that is about 40-100 minutes shorter than Solid dosage form is a tablet, particle or capsule. In some a Tmax of a corresponding standard-release antiemetic, instances, the tablet is a bi-layer tablet. In some instances, the wherein the Subject is fed. In some instances, the immediate tablet is a multi-layer tablet. In some instances, the antiemetic release antiemetic has a Tmax that is about 70 minutes shorter is promethazine or a pharmaceutically acceptable salt than a Tmax of a corresponding standard-release antiemetic. thereof. In some instances, the opioid is hydrocodone or a In some instances, the immediate-release antiemetic has an pharmaceutically acceptable salt thereof. In some instances, about 20-200% greater absorption in the two hours than a the opioid is oxycodone or a pharmaceutically acceptable salt corresponding standard-release antiemetic. In some thereof. In some instances, the non-opioid analgesic is instances, the immediate-release antiemetic has an about acetaminophen or a pharmaceutically acceptable salt thereof. 20-200% greater absorption in the 90 minutes than a corre In some instances, the pharmaceutical composition com sponding standard-release antiemetic. In some instances, the prises from about 6.5 mg to about 8.5 mg of hydrocodone, immediate-release antiemetic has an about 20-200% greater oxycodone, or a pharmaceutically acceptable salt thereof and absorption in the first hour than a corresponding standard from about 12.5 mg to about 25 mg of promethazine or a release antiemetic. In some instances, the immediate-release pharmaceutically acceptable salt thereof. In some instances, antiemetic has an about 20-100% greater absorption in the the pharmaceutical composition comprises from about 6.5 first hour than a corresponding standard-release antiemetic. mg to about 8.5 mg of hydrocodone, oxycodone, or a phar In some instances, the immediate-release antiemetic has an maceutically acceptable salt thereof, from about 12.5 mg to about 60% greater absorption in the first hour than a corre about 25 mg of promethazine or a pharmaceutically accept sponding standard-release antiemetic. In some instances, the able salt thereof and from about 290 to about 360 mg of the immediate-release antiemetic has an about 20-60% greater acetaminophen or a pharmaceutically acceptable salt thereof. absorption in the first 45 minutes than a corresponding stan In some instances, the non-opioid analgesic is present in an dard-release antiemetic. In some instances, the immediate amount of about 200 mg to about 600 mg, about 200 mg to release antiemetic has an about 40% greater absorption in the about 1000 mg, about 200 mg to about 325 mg, about 325 mg first 45 minutes than a corresponding standard-release anti to about 330 mg, about 330 mg to about 335 mg, about 335 emetic. In some instances, the immediate-release antiemetic mg to about 340 mg, about 340 mg to about 345 mg, about has an about 20-60% greater absorption in the first30 minutes 345 mg to about 350 mg, about 325 mg to about 350 mg. than a corresponding standard-release antiemetic. In some about 350 mg to about 400 mg, about 400 mg to about 1000 instances, the immediate-release antiemetic has an about mg, or any combination thereof. In some instances, the phar 40% greater absorption in the first 30 minutes than a corre maceutical composition comprises 12.5 mg of promethazine, sponding standard-release antiemetic. In some instances, the US 2015/0290211 A1 Oct. 15, 2015 immediate-release antiemetic is promethazine or a pharma the pharmaceutical composition periodically over 24 hours. ceutically acceptable salt thereof. In some instances, the In some instances, the administration is oral administration. immediate-release antiemetic is promethazine hydrochlo In some instances, administration of the pharmaceutical com ride. position begins from 0 to 6 hours before Surgery. In some 0011. In some aspects, a method is provided for treating instances, administration of the pharmaceutical composition pain and reducing or preventing opioid induced nausea or begins from 0 to 6 hours after Surgery. In some instances, the vomiting (OINV) due to periodic administration of an opioid administration is from 0 to 6 hours after an injury. In some for 24 hours or more in a Subject in need thereof, comprising instances, the Subject is a post-operative Subject. In some periodically administering to the Subject over 24 hours or instances, the Subject is a postoperative subject. In some more a pharmaceutical composition that comprises an effec instances, the Subject is a post-discharge Subject. In some tive amount of an antiemetic formulated for immediate-re instances, the pain is moderate to severe pain. In some lease to reduce or preventing OINV, an effective amount of an instances the pain is pain from an operation or post-operative opioid analgesic formulated for controlled-release to treat pain. In some instances, the pain is acute pain. In some pain and an effective amount of a non-opioid analgesic for instances, the pain is chronic pain. In some instances, the pain mulated for controlled-release to treat pain, wherein the sub is severe. In some instances, the pain is moderate. In some jects pain is treated and the subjects reduced or prevented instances, the pain is moderate to severe. In some instances, OINV is maintained for the 24 hours or more. In some the Subject has one or more conditions or diseases. In some instances, the Subject in need thereof is prone to nausea or instances, the one or more conditions or diseases comprise Vomiting. In some instances, the Subject has previously expe cancer, Surgical procedure, acute physical injury, chronic rienced nausea or vomiting after administration of a pharma physical injury, bone fracture, crush injury, spinal cord injury, ceutical composition that comprises an opioid without an inflammatory disease, non-inflammatory neuropathic condi antiemetic. In some instances, the Subject has previously tion, photophobia, or any combination thereof. In some experienced or is experiencing nausea or vomiting after Sur instances, the pharmaceutical composition does not cause gery. In some instances, the reduced or prevented OINV is a increased sedation in comparison to a pharmaceutical com reduction or prevention in the incidence of nausea or vomit position with the same amount of the opioid analgesic, in the ing for the 24 hours or more. In some instances, the reduced absence of the antiemetic. In some instances, the pharmaceu or prevented OINV is a reduction or prevention in the severity tical composition is a Solid dosage form. In some instances, of nausea or vomiting for the 24 hours or more. In some the Solid dosage form comprises a first layer comprising the instances, the subject's reduced or prevented OINV is in effective amount of the antiemetic formulated for immediate comparison to a Subject administered an pharmaceutical release. In some instances, the Solid dosage form comprises a composition that comprises the opioid analgesic and the non second layer comprising the effective amount of the opioid opioid analgesic without the antiemetic. In some instances, analgesic formulated for controlled-release and an effective the method further comprises a relative risk reduction of amount of a non-opioid analgesic formulated for controlled OINV of at least 50% for the 24 hours or more. In some release. In some instances, the Solid dosage form is a tablet, instances, the method further comprises a relative risk reduc particle or capsule. In some instances, the tablet is a bi-layer tion of OINV of at least 60% for the 24 hours or more. In some tablet. In some instances, the tablet is a multi-layer tablet. In instances, the Subject experiences a reduced need for a rescue Some instances, the antiemetic is promethazine or a pharma medication during the initial 6 hours or initial 24 hours post ceutically acceptable salt thereof. In some instances, the administration. In some instances, the Subject experiences no opioid is hydrocodone or a pharmaceutically acceptable salt need for a rescue medication during the initial 6 hours or thereof. In some instances, the opioid is oxycodone or a initial 24 hours post-administration. In some instances, the pharmaceutically acceptable salt thereof. In some instances, rescue medication is a Supplemental antiemetic. In some the non-opioid analgesic is acetaminophen or a pharmaceu instances, the rescue medication is a Supplemental analgesic. tically acceptable salt thereof. In some instances, the pharma In some instances, the Subject is administered the pharmaceu ceutical composition comprises from about 6.5 mg to about tical composition every four to six hours. In some instances, 8.5 mg of hydrocodone, oxycodone, or a pharmaceutically the Subject is administered the pharmaceutical composition acceptable salt thereof and from about 12.5 mg to about 25 two to six times over the first 24 hours. In some instances, the mg of promethazine or a pharmaceutically acceptable salt Subject is administered the pharmaceutical composition one thereof. In some instances, the pharmaceutical composition to six times after the first 24 hours. In some instances, the comprises from about 6.5 mg to about 8.5 mg of hydroc Subject is administered the pharmaceutical composition no odone, oxycodone, or a pharmaceutically acceptable salt more than six times every 24 hours. In some instances, the thereof, from about 12.5 mg to about 25 mg of promethazine Subject is administered the pharmaceutical composition peri or a pharmaceutically acceptable salt thereof and from about odically over 1-28 days. In some instances, the Subject is 290 to about 360 mg of the acetaminophen or a pharmaceu administered the pharmaceutical composition periodically tically acceptable salt thereof. In some instances, the non over 1-21 days. In some instances, the Subject is administered opioid analgesic is present in an amount of about 200 mg to the pharmaceutical composition periodically over 1-14 days. about 600 mg, about 200 mg to about 1000 mg, about 200 mg In some instances, the Subject is administered the pharmaceu to about 325 mg, about 325 mg to about 330 mg, about 330 tical composition periodically over 1-7 days. In some mg to about 335 mg, about 335 mg to about 340 mg, about instances, the Subject is administered the pharmaceutical 340 mg to about 345 mg, about 345 mg to about 350 mg. composition periodically over 1-5 days. In some instances, about 325 mg to about 350 mg, about 350 mg to about 400 the Subject is administered the pharmaceutical composition mg, about 400 mg to about 1000 mg, or any combination periodically over 1-3 days. In some instances, the Subject is thereof. In some instances, the pharmaceutical composition administered the pharmaceutical composition periodically comprises 12.5 mg of promethazine, or a pharmaceutically over 1-2 days. In some instances, the Subject is administered acceptable salt thereof, about 7.5 mg of the hydrocodone or a US 2015/0290211 A1 Oct. 15, 2015

pharmaceutically acceptable salt thereof, and about 325 mg thereof. In some instances, the immediate-release antiemetic of the acetaminophen or a pharmaceutically acceptable salt is promethazine hydrochloride. thereof. In some instances, the pharmaceutical composition 0012. In some aspects, a method of treating pain and comprises about 12.5 mg of promethazine hydrochloride, reducing or preventing opioid induced nausea or vomiting about 7.5 mg of hydrocodone bitartrate and about 325 mg of (OINV) due to periodic administration of an opioid for 24 acetaminophen. In some instances, the Subject is human. In hours or more in a subject in need thereof, comprising peri Some instances, the pharmaceutical composition further com odically administering to the Subject over 24 hours or more a prises one or more excipients. In some instances, the one or pharmaceutical composition that comprises an effective more excipients comprise an antioxidant agent, a binder, a amount of an antiemetic formulated for immediate-release to coating material, a colorant agent, a diluent, a disintegrant, a reduce or preventing OINV. an effective amount of an opioid disperant, an emulsifying agent, a flavoring agent, a glidant, a analgesic formulated for controlled-release to treat pain, lubricant, a pH modifying agent, a plasticizer, a preservative wherein the subject’s pain is treated and the subjects reduced agent, a solubilizing agent, a stabilizer, a Surfactant, a Sweet or prevented OINV is maintained for the 24 hours or more. In ening agent, a thickening agent, a pharmaceutically inert Some instances, the Subject in need thereof is prone to nausea material, or any combination thereof. In some instances, the or vomiting. In some instances, the Subject is has previously immediate-release antiemetic has a Tmax that is about 3-6 experienced nausea or vomiting after administration of a hours. In some instances, the immediate-release antiemetic pharmaceutical composition that comprises an opioid with has a Tmax that is about 20-100 minutes shorter thana Tmax out an antiemetic. In some instances, the Subject has previ of a corresponding standard-release antiemetic. In some ously experienced or is experiencing nausea or vomiting after instances, the immediate-release antiemetic has a Tmax that surgery. In some instances, the reduced or prevented OINV is is about 3-5 hours, wherein the subject is fasted. In some a reduction or prevention in the incidence of nausea or Vom instances, the immediate-release antiemetic has a Tmax of iting for the 24 hours or more. In some instances, the reduced about 4 hours. In some instances, the immediate-release anti or prevented OINV is a reduction or prevention in the severity emetic has a Tmax that is about 20-80 minutes shorter than a of nausea or vomiting for the 24 hours or more. In some Tmax of a corresponding standard-release antiemetic, instances, the subjects reduced or prevented OINV is in wherein the Subject is fasted. In some instances, the immedi comparison to a Subject administered an pharmaceutical ate-release antiemetic has a Tmax that is about 50 minutes composition that comprises the opioid analgesic and the non shorter than a Tmax of a corresponding standard-release anti opioid analgesic without the antiemetic. In some instances, emetic. In some instances, the immediate-release antiemetic the method further comprises a relative risk reduction of has a Tmax that is about 4-6 hours, wherein the subject is fed. OINV of at least 50% for the 24 hours or more. In some In some instances, the immediate-release antiemetic has a instances, the method further comprises a relative risk reduc Tmax of about 5 hours. In some instances, the immediate tion of OINV of at least 60% for the 24 hours or more. In some release antiemetic has a Tmax that is about 40-100 minutes instances, the Subject experiences a reduced need for a rescue shorter than a Tmax of a corresponding standard-release anti medication during the initial 6 hours or initial 24 hours post emetic, wherein the Subject is fed. In some instances, the administration. In some instances, the Subject experiences no immediate-release antiemetic has a Tmax that is about 70 need for a rescue medication during the initial 6 hours or minutes shorter than a Tmax of a corresponding standard initial 24 hours post-administration. In some instances, the release antiemetic. In some instances, the immediate-release rescue medication is a Supplemental antiemetic. In some antiemetic has an about 20-200% greater absorption in the instances, the rescue medication is a Supplemental analgesic. two hours than a corresponding standard-release antiemetic. In some instances, the Subject is administered the pharmaceu In some instances, the immediate-release antiemetic has an tical composition every four to six hours. In some instances, about 20-200% greater absorption in the 90 minutes than a the Subject is administered the pharmaceutical composition corresponding standard-release antiemetic. In some two to six times over the first 24 hours. In some instances, the instances, the immediate-release antiemetic has an about Subject is administered the pharmaceutical composition one 20-200% greater absorption in the first hour than a corre to six times after the first 24 hours. In some instances, the sponding standard-release antiemetic. In some instances, the Subject is administered the pharmaceutical composition no immediate-release antiemetic has an about 20-100% greater more than six times every 24 hours. In some instances, the absorption in the first hour than a corresponding standard Subject is administered the pharmaceutical composition peri release antiemetic. In some instances, the immediate-release odically over 1-28 days. In some instances, the Subject is antiemetic has an about 60% greater absorption in the first administered the pharmaceutical composition periodically hour than a corresponding standard-release antiemetic. In over 1-21 days. In some instances, the Subject is administered Some instances, the immediate-release antiemetic has an the pharmaceutical composition periodically over 1-14 days. about 20-60% greater absorption in the first 45 minutes than In some instances, the Subject is administered the pharmaceu a corresponding standard-release antiemetic. In some tical composition periodically over 1-7 days. In some instances, the immediate-release antiemetic has an about instances, the Subject is administered the pharmaceutical 40% greater absorption in the first 45 minutes than a corre composition periodically over 1-5 days. In some instances, sponding standard-release antiemetic. In some instances, the the Subject is administered the pharmaceutical composition immediate-release antiemetic has an about 20-60% greater periodically over 1-3 days. In some instances, the Subject is absorption in the first 30 minutes than a corresponding stan administered the pharmaceutical composition periodically dard-release antiemetic. In some instances, the immediate over 1-2 days. In some instances, the Subject is administered release antiemetic has an about 40% greater absorption in the the pharmaceutical composition periodically over 24 hours. first 30 minutes than a corresponding standard-release anti In some instances, the administration is oral administration. emetic. In some instances, the immediate-release antiemetic In some instances, administration of the pharmaceutical com is promethazine or a pharmaceutically acceptable salt position begins from 0 to 6 hours before Surgery. In some US 2015/0290211 A1 Oct. 15, 2015 instances, administration of the pharmaceutical composition about 7.5 mg of hydrocodone bitartrate and about 325 mg of begins from 0 to 6 hours after Surgery. In some instances, the acetaminophen. In some instances, the Subject is human. In administration is from 0 to 6 hours after an injury. In some Some instances, the pharmaceutical composition further com instances, the Subject is a post-operative Subject. In some prises one or more excipients. In some instances, the one or instances, the Subject is a postoperative Subject. In some more excipients comprise an antioxidant agent, a binder, a instances, the Subject is a post-discharge subject. In some coating material, a colorant agent, a diluent, a disintegrant, a instances, the pain is moderate to severe pain. In some disperant, an emulsifying agent, a flavoring agent, a glidant, a instances the pain is pain from an operation or post-operative lubricant, a pH modifying agent, a plasticizer, a preservative pain. In some instances, the pain is acute pain. In some agent, a solubilizing agent, a stabilizer, a Surfactant, a Sweet instances, the pain is chronic pain. In some instances, the pain ening agent, a thickening agent, a pharmaceutically inert is severe. In some instances, the pain is moderate. In some material, or any combination thereof. In some instances, the instances, the pain is moderate to severe. In some instances, immediate-release antiemetic has a Tmax that is about 3-6 the Subject has one or more conditions or diseases. In some hours. In some instances, the immediate-release antiemetic instances, the one or more conditions or diseases comprise has a Tmax that is about 20-100 minutes shorter thana Tmax cancer, Surgical procedure, acute physical injury, chronic of a corresponding standard-release antiemetic. In some physical injury, bone fracture, crush injury, spinal cord injury, instances, the immediate-release antiemetic has a Tmax that inflammatory disease, non-inflammatory neuropathic condi is about 3-5 hours, wherein the subject is fasted. In some tion, photophobia, or any combination thereof. In some instances, the immediate-release antiemetic has a Tmax of instances, the pharmaceutical composition does not cause about 4 hours. In some instances, the immediate-release anti increased sedation in comparison to a pharmaceutical com emetic has a Tmax that is about 20-80 minutes shorter than a position with the same amount of the opioid analgesic, in the Tmax of a corresponding standard-release antiemetic, absence of the antiemetic. In some instances, the pharmaceu wherein the Subject is fasted. In some instances, the immedi tical composition is a Solid dosage form. In some instances, ate-release antiemetic has a Tmax that is about 50 minutes the Solid dosage form comprises a first layer comprising the shorter than a Tmax of a corresponding standard-release anti effective amount of the antiemetic formulated for immediate emetic. In some instances, the immediate-release antiemetic release. In some instances, the Solid dosage form comprises a has a Tmax that is about 4-6 hours, wherein the subject is fed. second layer comprising the effective amount of the opioid In some instances, the immediate-release antiemetic has a analgesic formulated for controlled-release and an effective Tmax of about 5 hours. In some instances, the immediate amount of a non-opioid analgesic formulated for controlled release antiemetic has a Tmax that is about 40-100 minutes release. In some instances, the Solid dosage form is a tablet, shorter than a Tmax of a corresponding standard-release anti particle or capsule. In some instances, the tablet is a bi-layer emetic, wherein the Subject is fed. In some instances, the tablet. In some instances, the tablet is a multi-layer tablet. In immediate-release antiemetic has a Tmax that is about 70 Some instances, the antiemetic is promethazine or a pharma minutes shorter than a Tmax of a corresponding standard ceutically acceptable salt thereof. In some instances, the release antiemetic. In some instances, the immediate-release opioid is hydrocodone or a pharmaceutically acceptable salt antiemetic has an about 20-200% greater absorption in the thereof. In some instances, the opioid is oxycodone or a two hours than a corresponding standard-release antiemetic. pharmaceutically acceptable salt thereof. In some instances, In some instances, the immediate-release antiemetic has an the non-opioid analgesic is acetaminophen or a pharmaceu about 20-200% greater absorption in the 90 minutes than a tically acceptable salt thereof. In some instances, the pharma corresponding standard-release antiemetic. In some ceutical composition comprises from about 6.5 mg to about instances, the immediate-release antiemetic has an about 8.5 mg of hydrocodone, oxycodone, or a pharmaceutically 20-200% greater absorption in the first hour than a corre acceptable salt thereof and from about 12.5 mg to about 25 sponding standard-release antiemetic. In some instances, the mg of promethazine or a pharmaceutically acceptable salt immediate-release antiemetic has an about 20-100% greater thereof. In some instances, the pharmaceutical composition absorption in the first hour than a corresponding standard comprises from about 6.5 mg to about 8.5 mg of hydroc release antiemetic. In some instances, the immediate-release odone, oxycodone, or a pharmaceutically acceptable salt antiemetic has an about 60% greater absorption in the first thereof, from about 12.5 mg to about 25 mg of promethazine hour than a corresponding standard-release antiemetic. In or a pharmaceutically acceptable salt thereof and from about Some instances, the immediate-release antiemetic has an 290 to about 360 mg of the acetaminophen or a pharmaceu about 20-60% greater absorption in the first 45 minutes than tically acceptable salt thereof. In some instances, the non a corresponding standard-release antiemetic. In some opioid analgesic is present in an amount of about 200 mg to instances, the immediate-release antiemetic has an about about 600 mg, about 200 mg to about 1000 mg, about 200 mg 40% greater absorption in the first 45 minutes than a corre to about 325 mg, about 325 mg to about 330 mg, about 330 sponding standard-release antiemetic. In some instances, the mg to about 335 mg, about 335 mg to about 340 mg, about immediate-release antiemetic has an about 20-60% greater 340 mg to about 345 mg, about 345 mg to about 350 mg. absorption in the first 30 minutes than a corresponding stan about 325 mg to about 350 mg, about 350 mg to about 400 dard-release antiemetic. In some instances, the immediate mg, about 400 mg to about 1000 mg, or any combination release antiemetic has an about 40% greater absorption in the thereof. In some instances, the pharmaceutical composition first 30 minutes than a corresponding standard-release anti comprises 12.5 mg of promethazine, or a pharmaceutically emetic. In some instances, the immediate-release antiemetic acceptable salt thereof, about 7.5 mg of the hydrocodone or a is promethazine or a pharmaceutically acceptable salt pharmaceutically acceptable salt thereof, and about 325 mg thereof. In some instances, the immediate-release antiemetic of the acetaminophen or a pharmaceutically acceptable salt is promethazine hydrochloride. thereof. In some instances, the pharmaceutical composition 0013. In some aspects, a tablet is provided, the table com comprises about 12.5 mg of promethazine hydrochloride, prising an effective amount of one or more opioid analgesics US 2015/0290211 A1 Oct. 15, 2015 and one or more antiemetics, and a pharmaceutically accept thioproperazine, tropisetron, droperidol, haloperidol. able carrier or vehicle, wherein the tablet has a friability of prochloperazine, metoclopramide, diphenhydramine, can about 0.9% or less. In some instances, the tablet comprises an nabis, midazolam, lorazepam, hyoscine, dexamethasone, immediate release layer and a controlled release layer. In emetrol, propofol, or a pharmaceutically acceptable salt of Some instances, the tablet is a bi-layer tablet. In some any one of the foregoing, or any combination thereof. In some instances, the tablet is a two layer tablet. In some instances, instances, the one or more antiemetics is promethazine or a the two layer tablet comprises an immediate release layer and pharmaceutically acceptable salt thereof. In some instances, a controlled release layer. In some instances, the controlled the immediate release layer comprises the promethazine or a release layer comprises the one or more opioid analgesics. In pharmaceutically acceptable salt thereof. In some instances, Some instances, the immediate release layer comprises the the one or more opioid analgesics is hydrocodone or a phar one or more antiemetics. In some instances, the immediate maceutically acceptable salt thereof and the one or more release layer and the controlled release layer comprise the one antiemetics is promethazine or a pharmaceutically acceptable or more antiemetics. In some instances, the one or more salt thereof. In some instances, the tablet comprises from opioid analgesics has a dissolution rate of at least 33% in about 6.5 mg to about 8.5 mg of the hydrocodone or a phar about 5 minutes or less. In some instances, the one or more maceutically acceptable salt thereof and from about 11 mg to opioid analgesics has a dissolution rate of at least 68% in about 14 mg of the promethazine or a pharmaceutically about 10 minutes or less. In some instances, the one or more acceptable salt thereof. In some instances, the promethazine opioid analgesics has a dissolution rate of at least 79% in ora pharmaceutically acceptable salt thereofhas a dissolution about 15 minutes or less. In some instances, the one or more rate of at least 80% in about 5 minutes or less. In some antiemetics has a dissolution rate of at least 80% in about 5 instances, the promethazine or a pharmaceutically acceptable minutes or less. In some instances, the one or more antiemet salt thereof has a dissolution rate of at least 86% in about 10 ics has a dissolution rate of at least 86% in about 10 minutes minutes or less. In some instances, the promethazine or a or less. In some instances, the one or more antiemetics has a pharmaceutically acceptable salt thereof has a dissolution dissolution rate of at least 88% in about 15 minutes or less. In rate of at least 88% in about 15 minutes or less. In some Some instances, the one or more opioid analgesics comprise instances, the table further comprises one or more non-opioid hydrocodone, oxycodone, oripavine, dihydromorphine, analgesics comprising acetaminophen, acetylsalicylic acid, hydromorphinol, nicomorphine, dipropanoylmorphine, amoxiprin, benorilate, choline magnesium salicylate, diacetyldihydromorphine, desomorphine, methyldesorphine, diflunisal, faislamine, methyl salicylate, magnesium salicy heterocodeine, benzylmorphine, dihydroheterocodeine, late, diclofenac, aceclofenac, acemetacin, bromfenac, etod myrophine, pentamorphone, etorphine, acetyldihydroco olac, indometacin, nabumetone, Sulindac, tolmetin, ibupro deine, nicocodeine, nicodicodeine, alphamethylfentanyl. fen, carprofen, fenbuprofen, flubiprofen, ketaprofen, carfentanil, parafluorofentanyl, thiofentanyl, anileridine, ketorolac, loxoprofen, naproxen, Suprofen, mefenamic acid, benzethidine, difenoxin, diphenoxylate, etoxeridine, furethi meclofenamic acid, piroXicam, lomoxicam, meloxicam, dine, morpheridine, pheneridine, phenoperidine, piminodine, tenoxicam, phenylbutaZone, azapropaZone, metamizole, allylprodine, loperamide, dextropropoxyphene, dihydroetor oxyphenbutaZone, SulfinpraZone, Valdecoxib, celecoxib, phine, acetorphine, levophenacylmorphan, phenomorphan, rofecoxib, lidocaine, mexiletine, amitriptyline, carbam drotebanol, dipipanone, normethadone, phenadoxone, dime aZepine, gabapentin, pregabalin, amoxapine, clomipramine, pheptanol, levacetylmethadol, dextromoramide, diethylthi desipramine, doSulepin, doxepin, imipramine, iprindole, ambutene, dimethylthiambutene, ethylmethylthiambutene, lofepramine, nortriptyline, opipramol, protryptyline, trimi dextropropoxyphene, dimenoxadol, tilidine, ethoheptazine, pramine, orphenadrine, cyclobenzaprine, Scopolamine, atro proheptazine, piritramide, etonitaZene, tapentadol, tramadol, pine, gabapentin, tetrahydrocannabinol, ketamine, amanta or a pharmaceutically acceptable salt of any one of the fore dine, dextromethorphan, dextrorphan, ibogaine, going, or any combination thereof. In some instances, the one phencyclidine, riluzole, tiletamine, memantine, dizocilpine, or more opioid analgesics is hydrocodone or a pharmaceuti patiganel, remacimide, clonidine, or a pharmaceutically cally acceptable salt thereof. In some instances, the controlled acceptable salt of any one of the foregoing, or any combina release layer comprises the hydrocodone or a pharmaceuti tion thereof. In some instances, the one or more non-opioid cally acceptable salt thereof. In some instances, the hydroc analgesics is acetaminophen or a pharmaceutically accept odone or a pharmaceutically acceptable salt thereof has a able salt thereof. In some instances, the controlled release dissolution rate of at least 33% in about 5 minutes or less. In layer comprises the one or more non-opioid analgesics. In Some instances, the hydrocodone or a pharmaceutically Some instances, the controlled release layer comprises the acceptable salt thereofhas a dissolution rate of at least 68% in acetaminophen or a pharmaceutically acceptable salt thereof. about 10 minutes or less. In some instances, the hydrocodone In some instances, the non-opioid analgesics has a dissolution ora pharmaceutically acceptable salt thereofhas a dissolution rate of at least 69% in about 5 minutes or less. In some rate of at least 79% in about 15 minutes or less. In some instances, one of the non-opioid analgesics has a dissolution instances, the one or more antiemetics comprise promethaZ rate of at least 81% in about 10 minutes or less. In some ine, aprepitant, dronabinol, perphenazine, palonosetron, tri instances, one of the non-opioid analgesics has a dissolution methyobenzamide, metoclopromide, domperidone, prochlo rate of at least 85% in about 15 minutes or less. In some rperazine, chlorpromazine, trimethobenzamide, instances, the acetaminophen or a pharmaceutically accept ondansetron, granisetron, hydroxy Zine, acetylleucine mono able salt thereofhas a dissolution rate of at least 69% in about ethanolamine, alizapride, azasetron, benzquinamide, biet 5 minutes or less. In some instances, the acetaminophen or a anautine, bromopride, buclizine, clebopride, cyclizine, pharmaceutically acceptable salt thereof has a dissolution dimenhydrinate, diphenidol, dolasetron, meclizine, methal rate of at least 81% in about 10 minutes or less. In some latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco instances, the acetaminophen or a pharmaceutically accept polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, able salt thereofhas a dissolution rate of at least 85% in about US 2015/0290211 A1 Oct. 15, 2015

15 minutes or less. In some instances, the pharmaceutically mm. In some instances, the tablet has a thickness that is about acceptable carrier comprises microcrystalline cellulose, 7 mm. In some instances, the tablet has a hardness that is from Sodium carboxymethyl cellulose, sodium starch glycolate, about 10 kp to about 19 kp. In some instances, the tablet has corn starch, colloidal silica, Sodium laurel Sulphate, magne a hardness that is from about 16 kp to about 19 kp. In some sium Stearate, croScarmellose Sodium, crospovidone, or com instances, the tablet has a hardness that is about 17 kp. In binations thereof. In some instances, the pharmaceutically Some instances, the tablet has a hardness that is about 18 kp. acceptable carrier comprises silicified microcrystalline cellu In some instances, the friability is about 0.2% or less, the lose, croscarmellose sodium, magnesium Stearate, or combi hardness is about 8 to about 22 kp, the dissolution rate of the nations thereof. In some instances, the dissolution rate of the hydrocodone or a pharmaceutically acceptable salt thereof is hydrocodone or a pharmaceutically acceptable salt thereof is about 33 to about 72% within about 5 minutes or less, the about 33% to about 72% in about 5 minutes or less. In some dissolution rate of the acetaminophen or a pharmaceutically instances, the dissolution rate of the hydrocodone or a phar acceptable salt thereof is about 55 to about 80% within about maceutically acceptable salt thereof is about 35% to about 5 minutes or less, and the dissolution rate of the promethazine 60% in about 5 minutes or less. In some instances, the disso or a pharmaceutically acceptable salt thereof is about 65 to lution rate of the hydrocodone or a pharmaceutically accept about 100% within about 5 minutes or less. In some instances, able salt thereof is about 65 to about 86% in about 10 minutes the friability is about 0.2% or less, the hardness is about 8 to or less. In some instances, the dissolution rate of the hydro about 22 kp, the dissolution rate of the hydrocodone or a codone or a pharmaceutically acceptable salt thereof is about pharmaceutically acceptable salt thereof is about 65 to about 78 to about 95% in about 15 minutes or less. In some 86% within about 10 minutes or less, the dissolution rate of instances, the one or more antiemetics comprises promethaZ the acetaminophen or a pharmaceutically acceptable salt ine, aprepitant, dronabinol, perphenazine, palonosetron, tri thereof is about 65 to about 100% within about 10 minutes or methyobenzamide, metoclopromide, domperidone, prochlo less, and the dissolution rate of the promethazine or a phar rperazine, chlorpromazine, trimethobenzamide, maceutically acceptable salt thereof is about 78 to about ondansetron, granisetron, hydroxy Zine, acetylleucine mono 100% within about 10 minutes or less. In some instances, the ethanolamine, alizapride, azasetron, benzquinamide, biet friability is about 0.2% or less, the hardness is about 8 to about anautine, bromopride, buclizine, clebopride, cyclizine, 22 kp, the dissolution rate of the hydrocodone or a pharma dimenhydrinate, diphenidol, dolasetron, meclizine, methal ceutically acceptable salt thereof is about 78 to about 95% latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco within about 15 minutes or less, the dissolution rate of the polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, acetaminophen or a pharmaceutically acceptable salt thereof thioproperazine, tropisetron, droperidol, haloperidol. is about 75 to about 100% within about 15 minutes or less, and prochloperazine, metoclopramide, diphenhydramine, can the dissolution rate of the promethazine or a pharmaceutically nabis, midazolam, lorazepam, hyoscine, dexamethasone, acceptable salt thereof is about 86 to about 100% within about emetrol, propofol, or a pharmaceutically acceptable salt of 15 minutes or less. In some instances, the friability is about any one of the foregoing, or any combination thereof. In some 0.05% to about 0.2%, the hardness is about 12 to about 20kp, instances, the promethazine or a pharmaceutically acceptable the dissolution rate of the hydrocodone or a pharmaceutically salt thereof, wherein the dissolution rate of the promethazine acceptable salt thereof is about 35 to about 60% within about or a pharmaceutically acceptable salt thereof is about 65 to 5 minutes or less, the dissolution rate of the acetaminophen or about 100% in about 5 minutes or less. In some instances, the a pharmaceutically acceptable salt thereof is about 55 to promethazine or a pharmaceutically acceptable salt thereof, about 80% within about 5 minutes or less, and the dissolution wherein the dissolution rate of the promethazine or a phar rate of the promethazine or a pharmaceutically acceptable salt maceutically acceptable salt thereof is about 80 to about thereof is about 80 to about 100% within about 5 minutes or 100% in about 5 minutes or less. In some instances, the less. In some instances, the friability is about 0.05% to about promethazine or a pharmaceutically acceptable salt thereof, 0.2%, the hardness is about 12 to about 20kp, the dissolution wherein the dissolution rate of the promethazine or a phar rate of the hydrocodone or a pharmaceutically acceptable salt maceutically acceptable salt thereof is about 78 to about thereof is about 65 to about 86% within about 10 minutes or 100% in about 10 minutes or less. In some instances, the less, the dissolution rate of the acetaminophen or a pharma promethazine or a pharmaceutically acceptable salt thereof, ceutically acceptable salt thereof is about 65 to about 100% wherein the dissolution rate of the promethazine or a phar within about 10 minutes or less, and the dissolution rate of the maceutically acceptable salt thereof is about 86 to about promethazine or a pharmaceutically acceptable salt thereof is 100% in about 15 minutes or less. In some instances, the about 78 to about 100% within about 10 minutes or less. In tablet further comprises one or more non-opioid analgesics some instances, the friability is about 0.05% to about 0.2%, comprising acetaminophen or a pharmaceutically acceptable the hardness is about 12 to about 20kp, the dissolution rate of salt thereof. In some instances, the dissolution rate of the the hydrocodone or a pharmaceutically acceptable salt acetaminophen or a pharmaceutically acceptable salt thereof thereof is about 78 to about 95% within about 15 minutes or is about 55 to about 80% in about 5 minutes or less. In some less, the dissolution rate of the acetaminophen or a pharma instances, the dissolution rate of the acetaminophen or a ceutically acceptable salt thereof is about 75 to about 100% pharmaceutically acceptable salt thereof is about 65 to about within about 15 minutes or less, and the dissolution rate of the 100% in about 10 minutes or less. In some instances, the promethazine or a pharmaceutically acceptable salt thereof is dissolution rate of the acetaminophen or a pharmaceutically about 86 to about 100% within about 15 minutes or less. In acceptable salt thereof is about 74 to about 100% in about 15 some instances, the friability is about 0.05% to about 0.14%, minutes or less. In some instances, the tablet has a thickness the hardness is about 10 to about 19 kp, the dissolution rate of that is from about 5 mm to about 8 mm. In some instances, the the hydrocodone or a pharmaceutically acceptable salt tablet has a thickness that is from about 6 mm to about 7 mm. thereof is about 40 to about 65% within about 5 minutes or In some instances, the tablet has a thickness that is about 6 less, the dissolution rate of the acetaminophen or a pharma US 2015/0290211 A1 Oct. 15, 2015 ceutically acceptable salt thereof is about 55 to about 80% instances, the Subject is a post-operative Subject. In some within about 5 minutes or less, and the dissolution rate of the instances, the Subject is a postoperative subject. In some promethazine or a pharmaceutically acceptable salt thereof is instances, the Subject is a post-discharge Subject. In some about 80 to about 100% within about 5 minutes or less. In instances, the pain is moderate to severe pain. In some some instances, the friability is about 0.05% to about 0.14%, instances, the pain is from an operation or post-operative the hardness is about 10 to about 19 kp, the dissolution rate of pain. In some instances, the pain is acute pain. In some the hydrocodone or a pharmaceutically acceptable salt instances, the pain is chronic pain. In some instances, the pain thereof is about 40 to about 52% within about 5 minutes or is severe. In some instances, the pain is moderate. In some less, the dissolution rate of the acetaminophen or a pharma instances, the pain is moderate to severe. ceutically acceptable salt thereof is about 55 to about 80% 0015. In some aspects, a tablet is provided, the table com within about 5 minutes or less, and the dissolution rate of the prising an effective amount of one or more opioid analgesics promethazine or a pharmaceutically acceptable salt thereof is and one or more antiemetics, and a pharmaceutically accept about 80 to about 100% within about 5 minutes or less. In able carrier or vehicle, wherein the tablet has a friability of some instances, the friability is about 0.05% to about 0.14%, about 0.4% or less. In some instances, the tablet comprises an the hardness is about 18 kp, the dissolution rate of the hydro immediate release layer and a controlled release layer. In codone or a pharmaceutically acceptable salt thereof is about Some instances, the tablet is a bi-layer tablet. In some 40 to about 52% within about 5 minutes or less, the dissolu instances, the tablet is a two layer tablet. In some instances, tion rate of the acetaminophen or a pharmaceutically accept the two layer tablet comprises an immediate release layer and able Salt thereof is about 55 to about 80% within about 5 a controlled release layer. In some instances, the controlled minutes or less, and the dissolution rate of the promethazine release layer comprises the one or more opioid analgesics. In or a pharmaceutically acceptable salt thereof is about 80 to Some instances, the immediate release layer comprises the about 100% within about 5 minutes or less. In some instances, one or more antiemetics. In some instances, the immediate the tablet remains stable at ambient conditions for at least 24 release layer and the controlled release layer comprise the one months. In some instances, the tablet remains stable at ambi or more antiemetics. In some instances, the one or more ent conditions for at least 48 months. In some instances, the opioid analgesics has a dissolution rate of at least 33% in tablet remains stable at high temperature for at least 6 months. about 5 minutes or less. In some instances, the one or more In some instances, the tablet provides an effective amount of opioid analgesics has a dissolution rate of at least 68% in at least one opioid analgesic or antiemetic to a Subject in need about 10 minutes or less. In some instances, the one or more thereof for about 4 to about 8 hours following oral adminis opioid analgesics has a dissolution rate of at least 79% in tration. In some instances, the tablet provides an effective about 15 minutes or less. In some instances, the one or more amount of at least one opioid analgesic or antiemetic to a antiemetics has a dissolution rate of at least 80% in about 5 subject in need thereof for about 4 to about 6 hours following minutes or less. In some instances, the one or more antiemet oral administration. In some instances, the tablet provides an ics has a dissolution rate of at least 86% in about 10 minutes effective amount of at least one opioid analgesic orantiemetic or less. In some instances, the one or more antiemetics has a to a subject in need thereof for about 4 hours following oral dissolution rate of at least 88% in about 15 minutes or less. In administration. In some instances, the tablet provides an Some instances, the one or more opioid analgesics comprise effective amount of at least one opioid analgesic orantiemetic hydrocodone, oxycodone, oripavine, dihydromorphine, to a subject in need thereof for about 6 hours following oral hydromorphinol, nicomorphine, dipropanoylmorphine, administration. In some instances, the friability is measured diacetyldihydromorphine, desomorphine, methyldesorphine, with a standard method according to the United States Phar heterocodeine, benzylmorphine, dihydroheterocodeine, macopeia and the National Formulary (USP-NF). In some myrophine, pentamorphone, etorphine, acetyldihydroco instances, the friability is measured with a standard method deine, nicocodeine, nicodicodeine, alphamethylfentanyl. according to the General Chapter 1216 Tablet Friability sec carfentanil, parafluorofentanyl, thiofentanyl, anileridine, tion of the USP-NF. In some instances, the friability is mea benzethidine, difenoxin, diphenoxylate, etoxeridine, furethi Sured in a friabilator. In some instances, the friability is mea dine, morpheridine, pheneridine, phenoperidine, piminodine, sured when a horizontal axis of the friabilator rotates at 25+1 allylprodine, loperamide, dextropropoxyphene, dihydroetor rpm. In some instances, the dissolution rate is measured with phine, acetorphine, levophenacylmorphan, phenomorphan, a standard method according to the United States Pharma drotebanol, dipipanone, normethadone, phenadoxone, dime copeia and the National Formulary (USP-NF). In some pheptanol, levacetylmethadol, dextromoramide, diethylthi instances, the dissolution rate is measured with a standard ambutene, dimethylthiambutene, ethylmethylthiambutene, method according to the General Methods 711 Dissolution dextropropoxyphene, dimenoxadol, tilidine, ethoheptazine, Standards section of the USP-NF. In some instances, the proheptazine, piritramide, etonitaZene, tapentadol, tramadol, dissolution rate is measured with a USP rotating paddle appa or a pharmaceutically acceptable salt of any one of the fore ratus. In some instances, the apparatus is VK-8000 or equiva going, or any combination thereof. In some instances, the one lent. In some instances, the hardness is measured using a or more opioid analgesics is hydrocodone or a pharmaceuti hardness testing apparatus. In some instances, the hardness cally acceptable salt thereof. In some instances, the controlled testing apparatus is Key Model HT300, Model HT500, or release layer comprises the hydrocodone or a pharmaceuti Pharma Test PTS/301. cally acceptable salt thereof. In some instances, the hydroc 0014. In some aspects, a method is provided for treating odone or a pharmaceutically acceptable salt thereof has a pain, the method comprising administering the tablet to a dissolution rate of at least 33% in about 5 minutes or less. In Subject in need thereof. In some instances, the one or more Some instances, the hydrocodone or a pharmaceutically antiemetics reduce or prevent a symptom experienced by the acceptable salt thereofhas a dissolution rate of at least 68% in Subject caused by the one or more opioid analgesics. In some about 10 minutes or less. In some instances, the hydrocodone instances, the symptom is nausea or vomiting. In some ora pharmaceutically acceptable salt thereofhas a dissolution US 2015/0290211 A1 Oct. 15, 2015

rate of at least 79% in about 15 minutes or less. In some instances, one of the non-opioid analgesics has a dissolution instances, the one or more antiemetics comprise promethaZ rate of at least 81% in about 10 minutes or less. In some ine, aprepitant, dronabinol, perphenazine, palonosetron, tri instances, one of the non-opioid analgesics has a dissolution methyobenzamide, metoclopromide, domperidone, prochlo rate of at least 85% in about 15 minutes or less. In some rperazine, chlorpromazine, trimethobenzamide, instances, the acetaminophen or a pharmaceutically accept ondansetron, granisetron, hydroxy Zine, acetylleucine mono able salt thereofhas a dissolution rate of at least 69% in about ethanolamine, alizapride, azasetron, benzquinamide, biet 5 minutes or less. In some instances, the acetaminophen or a anautine, bromopride, buclizine, clebopride, cyclizine, pharmaceutically acceptable salt thereof has a dissolution dimenhydrinate, diphenidol, dolasetron, meclizine, methal rate of at least 81% in about 10 minutes or less. In some latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco instances, the acetaminophen or a pharmaceutically accept polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, able salt thereofhas a dissolution rate of at least 85% in about thioproperazine, tropisetron, droperidol, haloperidol. 15 minutes or less. In some instances, the pharmaceutically prochloperazine, metoclopramide, diphenhydramine, can acceptable carrier comprises microcrystalline cellulose, nabis, midazolam, lorazepam, hyoscine, dexamethasone, Sodium carboxymethyl cellulose, sodium starch glycolate, emetrol, propofol, or a pharmaceutically acceptable salt of corn starch, colloidal silica, Sodium laurel Sulphate, magne any one of the foregoing, or any combination thereof. In some sium Stearate, croScarmellose sodium, crospovidone, or com instances, the one or more antiemetics is promethazine or a binations thereof. In some instances, the pharmaceutically pharmaceutically acceptable salt thereof. In some instances, acceptable carrier comprises silicified microcrystalline cellu the immediate release layer comprises the promethazine or a lose, croScarmellose sodium, magnesium Stearate, or combi pharmaceutically acceptable salt thereof. In some instances, nations thereof. In some instances, the dissolution rate of the the one or more opioid analgesics is hydrocodone or a phar hydrocodone or a pharmaceutically acceptable salt thereof is maceutically acceptable salt thereof and the one or more about 33% to about 72% in about 5 minutes or less. In some antiemetics is promethazine or a pharmaceutically acceptable instances, the dissolution rate of the hydrocodone or a phar salt thereof. In some instances, the tablet comprises from maceutically acceptable salt thereof is about 35% to about about 6.5 mg to about 8.5 mg of the hydrocodone or a phar 60% in about 5 minutes or less. In some instances, the disso maceutically acceptable salt thereof and from about 11 mg to lution rate of the hydrocodone or a pharmaceutically accept about 14 mg of the promethazine or a pharmaceutically able salt thereof is about 65 to about 86% in about 10 minutes acceptable salt thereof. In some instances, the promethazine or less. In some instances, the dissolution rate of the hydro or a pharmaceutically acceptable salt thereofhas a dissolution codone or a pharmaceutically acceptable salt thereof is about rate of at least 80% in about 5 minutes or less. In some 78 to about 95% in about 15 minutes or less. In some instances, the promethazine or a pharmaceutically acceptable instances, the one or more antiemetics comprises promethaZ salt thereofhas a dissolution rate of at least 86% in about 10 ine, aprepitant, dronabinol, perphenazine, palonosetron, tri minutes or less. In some instances, the promethazine or a methyobenzamide, metoclopromide, domperidone, prochlo pharmaceutically acceptable salt thereof has a dissolution rperazine, chlorpromazine, trimethobenzamide, rate of at least 88% in about 15 minutes or less. In some ondansetron, granisetron, hydroxy Zine, acetylleucine mono instances, the table further comprises one or more non-opioid ethanolamine, alizapride, aZasetron, benzquinamide, biet analgesics comprising acetaminophen, acetylsalicylic acid, anautine, bromopride, buclizine, clebopride, cyclizine, amoxiprin, benorilate, choline magnesium salicylate, dimenhydrinate, diphenidol, dolasetron, meclizine, methal diflunisal, faislamine, methyl salicylate, magnesium salicy latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco late, diclofenac, aceclofenac, acemetacin, bromfenac, etod polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, olac, indometacin, nabumetone, Sulindac, tolmetin, ibupro thioproperazine, tropisetron, droperidol, haloperidol. fen, carprofen, fenbuprofen, flubiprofen, ketaprofen, prochloperazine, metoclopramide, diphenhydramine, can ketorolac, loxoprofen, naproxen, Suprofen, mefenamic acid, nabis, midazolam, lorazepam, hyoscine, dexamethasone, meclofenamic acid, piroXicam, lomoxicam, meloxicam, emetrol, propofol, or a pharmaceutically acceptable salt of tenoxicam, phenylbutaZone, azapropaZone, metamizole, any one of the foregoing, or any combination thereof. In some oxyphenbutaZone, SulfinpraZone, Valdecoxib, celecoxib, instances, the promethazine or a pharmaceutically acceptable rofecoxib, lidocaine, mexiletine, amitriptyline, carbam salt thereof, wherein the dissolution rate of the promethazine aZepine, gabapentin, pregabalin, amoxapine, clomipramine, or a pharmaceutically acceptable salt thereof is about 65 to desipramine, do Sulepin, doxepin, imipramine, iprindole, about 100% in about 5 minutes or less. In some instances, the lofepramine, nortriptyline, opipramol, protryptyline, trimi promethazine or a pharmaceutically acceptable salt thereof, pramine, orphenadrine, cyclobenzaprine, Scopolamine, atro wherein the dissolution rate of the promethazine or a phar pine, gabapentin, tetrahydrocannabinol, ketamine, amanta maceutically acceptable salt thereof is about 80 to about dine, dextromethorphan, dextrorphan, ibogaine, 100% in about 5 minutes or less. In some instances, the phencyclidine, riluzole, tiletamine, memantine, dizocilpine, promethazine or a pharmaceutically acceptable salt thereof, patiganel, remacimide, clonidine, or a pharmaceutically wherein the dissolution rate of the promethazine or a phar acceptable salt of any one of the foregoing, or any combina maceutically acceptable salt thereof is about 78 to about tion thereof. In some instances, the one or more non-opioid 100% in about 10 minutes or less. In some instances, the analgesics is acetaminophen or a pharmaceutically accept promethazine or a pharmaceutically acceptable salt thereof, able salt thereof. In some instances, the controlled release wherein the dissolution rate of the promethazine or a phar layer comprises the one or more non-opioid analgesics. In maceutically acceptable salt thereof is about 86 to about Some instances, the controlled release layer comprises the 100% in about 15 minutes or less. In some instances, the acetaminophen or a pharmaceutically acceptable salt thereof. tablet further comprises one or more non-opioid analgesics In some instances, the non-opioid analgesics has a dissolution comprising acetaminophen or a pharmaceutically acceptable rate of at least 69% in about 5 minutes or less. In some salt thereof. In some instances, the dissolution rate of the US 2015/0290211 A1 Oct. 15, 2015

acetaminophen or a pharmaceutically acceptable salt thereof thereof is about 78 to about 95% within about 15 minutes or is about 55 to about 80% in about 5 minutes or less. In some less, the dissolution rate of the acetaminophen or a pharma instances, the dissolution rate of the acetaminophen or a ceutically acceptable salt thereof is about 75 to about 100% pharmaceutically acceptable salt thereof is about 65 to about within about 15 minutes or less, and the dissolution rate of the 100% in about 10 minutes or less. In some instances, the promethazine or a pharmaceutically acceptable salt thereof is dissolution rate of the acetaminophen or a pharmaceutically about 86 to about 100% within about 15 minutes or less. In acceptable salt thereof is about 74 to about 100% in about 15 some instances, the friability is about 0.05% to about 0.14%, minutes or less. In some instances, the tablet has a thickness the hardness is about 10 to about 19 kp, the dissolution rate of that is from about 5 mm to about 8 mm. In some instances, the the hydrocodone or a pharmaceutically acceptable salt tablet has a thickness that is from about 6 mm to about 7 mm. thereof is about 40 to about 65% within about 5 minutes or In some instances, the tablet has a thickness that is about 6 less, the dissolution rate of the acetaminophen or a pharma mm. In some instances, the tablet has a thickness that is about ceutically acceptable salt thereof is about 55 to about 80% 7 mm. In some instances, the tablet has a hardness that is from within about 5 minutes or less, and the dissolution rate of the about 10 kp to about 19 kp. In some instances, the tablet has promethazine or a pharmaceutically acceptable salt thereof is a hardness that is from about 16 kp to about 19 kp. In some about 80 to about 100% within about 5 minutes or less. In instances, the tablet has a hardness that is about 17 kp. In some instances, the friability is about 0.05% to about 0.14%, Some instances, the tablet has a hardness that is about 18 kp. the hardness is about 10 to about 19 kp, the dissolution rate of In some instances, the friability is about 0.2% or less, the the hydrocodone or a pharmaceutically acceptable salt hardness is about 8 to about 22 kp, the dissolution rate of the thereof is about 40 to about 52% within about 5 minutes or hydrocodone or a pharmaceutically acceptable salt thereof is less, the dissolution rate of the acetaminophen or a pharma about 33 to about 72% within about 5 minutes or less, the ceutically acceptable salt thereof is about 55 to about 80% dissolution rate of the acetaminophen or a pharmaceutically within about 5 minutes or less, and the dissolution rate of the acceptable salt thereof is about 55 to about 80% within about promethazine or a pharmaceutically acceptable salt thereof is 5 minutes or less, and the dissolution rate of the promethazine about 80 to about 100% within about 5 minutes or less. In or a pharmaceutically acceptable salt thereof is about 65 to some instances, the friability is about 0.05% to about 0.14%, about 100% within about 5 minutes or less. In some instances, the hardness is about 18 kp, the dissolution rate of the hydro the friability is about 0.2% or less, the hardness is about 8 to codone or a pharmaceutically acceptable salt thereof is about about 22 kp, the dissolution rate of the hydrocodone or a 40 to about 52% within about 5 minutes or less, the dissolu pharmaceutically acceptable salt thereof is about 65 to about tion rate of the acetaminophen or a pharmaceutically accept 86% within about 10 minutes or less, the dissolution rate of able Salt thereof is about 55 to about 80% within about 5 the acetaminophen or a pharmaceutically acceptable salt minutes or less, and the dissolution rate of the promethazine thereof is about 65 to about 100% within about 10 minutes or or a pharmaceutically acceptable salt thereof is about 80 to less, and the dissolution rate of the promethazine or a phar about 100% within about 5 minutes or less. In some instances, maceutically acceptable salt thereof is about 78 to about the tablet remains stable at ambient conditions for at least 24 100% within about 10 minutes or less. In some instances, the months. In some instances, the tablet remains stable at ambi friability is about 0.2% or less, the hardness is about 8 to about ent conditions for at least 48 months. In some instances, the 22 kp, the dissolution rate of the hydrocodone or a pharma tablet remains stable at high temperature for at least 6 months. ceutically acceptable salt thereof is about 78 to about 95% In some instances, the tablet provides an effective amount of within about 15 minutes or less, the dissolution rate of the at least one opioid analgesic or antiemetic to a Subject in need acetaminophen or a pharmaceutically acceptable salt thereof thereof for about 4 to about 8 hours following oral adminis is about 75 to about 100% within about 15 minutes or less, and tration. In some instances, the tablet provides an effective the dissolution rate of the promethazine or a pharmaceutically amount of at least one opioid analgesic or antiemetic to a acceptable salt thereof is about 86 to about 100% within about subject in need thereof for about 4 to about 6 hours following 15 minutes or less. In some instances, the friability is about oral administration. In some instances, the tablet provides an 0.05% to about 0.2%, the hardness is about 12 to about 20kp, effective amount of at least one opioid analgesic orantiemetic the dissolution rate of the hydrocodone or a pharmaceutically to a subject in need thereof for about 4 hours following oral acceptable salt thereof is about 35 to about 60% within about administration. In some instances, the tablet provides an 5 minutes or less, the dissolution rate of the acetaminophen or effective amount of at least one opioid analgesic orantiemetic a pharmaceutically acceptable salt thereof is about 55 to to a subject in need thereof for about 6 hours following oral about 80% within about 5 minutes or less, and the dissolution administration. In some instances, the friability is measured rate of the promethazine or a pharmaceutically acceptable salt with a standard method according to the United States Phar thereof is about 80 to about 100% within about 5 minutes or macopeia and the National Formulary (USP-NF). In some less. In some instances, the friability is about 0.05% to about instances, the friability is measured with a standard method 0.2%, the hardness is about 12 to about 20 kp, the dissolution according to the General Chapter 1216 Tablet Friability sec rate of the hydrocodone or a pharmaceutically acceptable salt tion of the USP-NF. In some instances, the friability is mea thereof is about 65 to about 86% within about 10 minutes or Sured in a friabilator. In some instances, the friability is mea less, the dissolution rate of the acetaminophen or a pharma sured when a horizontal axis of the friabilator rotates at 25+1 ceutically acceptable salt thereof is about 65 to about 100% rpm. In some instances, the dissolution rate is measured with within about 10 minutes or less, and the dissolution rate of the a standard method according to the United States Pharma promethazine or a pharmaceutically acceptable salt thereof is copeia and the National Formulary (USP-NF). In some about 78 to about 100% within about 10 minutes or less. In instances, the dissolution rate is measured with a standard some instances, the friability is about 0.05% to about 0.2%, method according to the General Methods 711 Dissolution the hardness is about 12 to about 20kp, the dissolution rate of Standards section of the USP-NF. In some instances, the the hydrocodone or a pharmaceutically acceptable salt dissolution rate is measured with a USP rotating paddle appa US 2015/0290211 A1 Oct. 15, 2015

ratus. In some instances, the apparatus is VK-8000 or equiva going, or any combination thereof. In some instances, the one lent. In some instances, the hardness is measured using a or more opioid analgesics is hydrocodone or a pharmaceuti hardness testing apparatus. In some instances, the hardness cally acceptable salt thereof. In some instances, the controlled testing apparatus is Key Model HT300, Model HT500, or release layer comprises the hydrocodone or a pharmaceuti Pharma Test PTS/301. cally acceptable salt thereof. In some instances, the hydroc 0016. In some aspects, a method is provided for treating odone or a pharmaceutically acceptable salt thereof has a pain, the method comprising administering the tablet to a dissolution rate of at least 33% in about 5 minutes or less. In Subject in need thereof. In some instances, the one or more Some instances, the hydrocodone or a pharmaceutically antiemetics reduce or prevent a symptom experienced by the acceptable salt thereofhas a dissolution rate of at least 68% in Subject caused by the one or more opioid analgesics. In some about 10 minutes or less. In some instances, the hydrocodone instances, the symptom is nausea or vomiting. In some ora pharmaceutically acceptable salt thereofhas a dissolution instances, the Subject is a post-operative Subject. In some rate of at least 79% in about 15 minutes or less. In some instances, the Subject is a postoperative Subject. In some instances, the one or more antiemetics comprise promethaz instances, the Subject is a post-discharge subject. In some ine, aprepitant, dronabinol, perphenazine, palonosetron, tri instances, the pain is moderate to severe pain. In some methyobenzamide, metoclopromide, domperidone, prochlo instances, the pain is from an operation or post-operative rperazine, chlorpromazine, trimethobenzamide, pain. In some instances, the pain is acute pain. In some ondansetron, granisetron, hydroxy Zine, acetylleucine mono instances, the pain is chronic pain. In some instances, the pain ethanolamine, alizapride, aZasetron, benzquinamide, biet is severe. In some instances, the pain is moderate. In some anautine, bromopride, buclizine, clebopride, cyclizine, instances, the pain is moderate to severe. dimenhydrinate, diphenidol, dolasetron, meclizine, methal 0017. In some aspects, a tablet is provided, the table com latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco prising an effective amount of one or more opioid analgesics polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, and one or more antiemetics, and a pharmaceutically accept thioproperazine, tropisetron, droperidol, haloperidol. able carrier or vehicle, wherein the tablet has a friability of prochloperazine, metoclopramide, diphenhydramine, can about 0.1% or less. In some instances, the tablet comprises an nabis, midazolam, lorazepam, hyoscine, dexamethasone, immediate release layer and a controlled release layer. In emetrol, propofol, or a pharmaceutically acceptable salt of Some instances, the tablet is a bi-layer tablet. In some any one of the foregoing, or any combination thereof. In some instances, the tablet is a two layer tablet. In some instances, instances, the one or more antiemetics is promethazine or a the two layer tablet comprises an immediate release layer and pharmaceutically acceptable salt thereof. In some instances, a controlled release layer. In some instances, the controlled the immediate release layer comprises the promethazine or a release layer comprises the one or more opioid analgesics. In pharmaceutically acceptable salt thereof. In some instances, Some instances, the immediate release layer comprises the the one or more opioid analgesics is hydrocodone or a phar one or more antiemetics. In some instances, the immediate maceutically acceptable salt thereof and the one or more release layer and the controlled release layer comprise the one antiemetics is promethazine or a pharmaceutically acceptable or more antiemetics. In some instances, the one or more salt thereof. In some instances, the tablet comprises from opioid analgesics has a dissolution rate of at least 33% in about 6.5 mg to about 8.5 mg of the hydrocodone or a phar about 5 minutes or less. In some instances, the one or more maceutically acceptable salt thereof and from about 11 mg to opioid analgesics has a dissolution rate of at least 68% in about 14 mg of the promethazine or a pharmaceutically about 10 minutes or less. In some instances, the one or more acceptable salt thereof. In some instances, the promethazine opioid analgesics has a dissolution rate of at least 79% in ora pharmaceutically acceptable salt thereofhas a dissolution about 15 minutes or less. In some instances, the one or more rate of at least 80% in about 5 minutes or less. In some antiemetics has a dissolution rate of at least 80% in about 5 instances, the promethazine or a pharmaceutically acceptable minutes or less. In some instances, the one or more antiemet salt thereof has a dissolution rate of at least 86% in about 10 ics has a dissolution rate of at least 86% in about 10 minutes minutes or less. In some instances, the promethazine or a or less. In some instances, the one or more antiemetics has a pharmaceutically acceptable salt thereof has a dissolution dissolution rate of at least 88% in about 15 minutes or less. In rate of at least 88% in about 15 minutes or less. In some Some instances, the one or more opioid analgesics comprise instances, the table further comprises one or more non-opioid hydrocodone, oxycodone, oripavine, dihydromorphine, analgesics comprising acetaminophen, acetylsalicylic acid, hydromorphinol, nicomorphine, dipropanoylmorphine, amoxiprin, benorilate, choline magnesium salicylate, diacetyldihydromorphine, desomorphine, methyldesorphine, diflunisal, faislamine, methyl salicylate, magnesium salicy heterocodeine, benzylmorphine, dihydroheterocodeine, late, diclofenac, aceclofenac, acemetacin, bromfenac, etod myrophine, pentamorphone, etorphine, acetyldihydroco olac, indometacin, nabumetone, Sulindac, tolmetin, ibupro deine, nicocodeine, nicodicodeine, alphamethylfentanyl. fen, carprofen, fenbuprofen, flubiprofen, ketaprofen, carfentanil, parafluorofentanyl, thiofentanyl, anileridine, ketorolac, loxoprofen, naproxen, Suprofen, mefenamic acid, benzethidine, difenoxin, diphenoxylate, etoxeridine, furethi meclofenamic acid, piroXicam, lomoxicam, meloxicam, dine, morpheridine, pheneridine, phenoperidine, piminodine, tenoxicam, phenylbutaZone, azapropaZone, metamizole, allylprodine, loperamide, dextropropoxyphene, dihydroetor oxyphenbutaZone, SulfinpraZone, Valdecoxib, celecoxib, phine, acetorphine, levophenacylmorphan, phenomorphan, rofecoxib, lidocaine, mexiletine, amitriptyline, carbam drotebanol, dipipanone, normethadone, phenadoxone, dime aZepine, gabapentin, pregabalin, amoxapine, clomipramine, pheptanol, levacetylmethadol, dextromoramide, diethylthi desipramine, doSulepin, doxepin, imipramine, iprindole, ambutene, dimethylthiambutene, ethylmethylthiambutene, lofepramine, nortriptyline, opipramol, protryptyline, trimi dextropropoxyphene, dimenoxadol, tilidine, ethoheptazine, pramine, orphenadrine, cyclobenzaprine, Scopolamine, atro proheptazine, piritramide, etonitaZene, tapentadol, tramadol, pine, gabapentin, tetrahydrocannabinol, ketamine, amanta or a pharmaceutically acceptable salt of any one of the fore dine, dextromethorphan, dextrorphan, ibogaine, US 2015/0290211 A1 Oct. 15, 2015 phencyclidine, riluzole, tiletamine, memantine, dizocilpine, promethazine or a pharmaceutically acceptable salt thereof, patiganel, remacimide, clonidine, or a pharmaceutically wherein the dissolution rate of the promethazine or a phar acceptable salt of any one of the foregoing, or any combina maceutically acceptable salt thereof is about 78 to about tion thereof. In some instances, the one or more non-opioid 100% in about 10 minutes or less. In some instances, the analgesics is acetaminophen or a pharmaceutically accept promethazine or a pharmaceutically acceptable salt thereof, able salt thereof. In some instances, the controlled release wherein the dissolution rate of the promethazine or a phar layer comprises the one or more non-opioid analgesics. In maceutically acceptable salt thereof is about 86 to about Some instances, the controlled release layer comprises the 100% in about 15 minutes or less. In some instances, the acetaminophen or a pharmaceutically acceptable salt thereof. tablet further comprises one or more non-opioid analgesics In some instances, the non-opioid analgesics has a dissolution comprising acetaminophen or a pharmaceutically acceptable rate of at least 69% in about 5 minutes or less. In some salt thereof. In some instances, the dissolution rate of the instances, one of the non-opioid analgesics has a dissolution acetaminophen or a pharmaceutically acceptable salt thereof rate of at least 81% in about 10 minutes or less. In some is about 55 to about 80% in about 5 minutes or less. In some instances, one of the non-opioid analgesics has a dissolution instances, the dissolution rate of the acetaminophen or a rate of at least 85% in about 15 minutes or less. In some pharmaceutically acceptable salt thereof is about 65 to about instances, the acetaminophen or a pharmaceutically accept 100% in about 10 minutes or less. In some instances, the able salt thereofhas a dissolution rate of at least 69% in about dissolution rate of the acetaminophen or a pharmaceutically 5 minutes or less. In some instances, the acetaminophen or a acceptable salt thereof is about 74 to about 100% in about 15 pharmaceutically acceptable salt thereof has a dissolution minutes or less. In some instances, the tablet has a thickness rate of at least 81% in about 10 minutes or less. In some that is from about 5 mm to about 8 mm. In some instances, the instances, the acetaminophen or a pharmaceutically accept tablet has a thickness that is from about 6 mm to about 7 mm. able salt thereofhas a dissolution rate of at least 85% in about In some instances, the tablet has a thickness that is about 6 15 minutes or less. In some instances, the pharmaceutically mm. In some instances, the tablet has a thickness that is about acceptable carrier comprises microcrystalline cellulose, 7 mm. In some instances, the tablet has a hardness that is from Sodium carboxymethyl cellulose, sodium starch glycolate, about 10 kp to about 19 kp. In some instances, the tablet has corn starch, colloidal silica, Sodium laurel Sulphate, magne a hardness that is from about 16 kp to about 19 kp. In some sium Stearate, croScarmellose Sodium, crospovidone, or com instances, the tablet has a hardness that is about 17 kp. In binations thereof. In some instances, the pharmaceutically Some instances, the tablet has a hardness that is about 18 kp. acceptable carrier comprises silicified microcrystalline cellu In some instances, the friability is about 0.2% or less, the lose, croscarmellose sodium, magnesium Stearate, or combi hardness is about 8 to about 22 kp, the dissolution rate of the nations thereof. In some instances, the dissolution rate of the hydrocodone or a pharmaceutically acceptable salt thereof is hydrocodone or a pharmaceutically acceptable salt thereof is about 33 to about 72% within about 5 minutes or less, the about 33% to about 72% in about 5 minutes or less. In some dissolution rate of the acetaminophen or a pharmaceutically instances, the dissolution rate of the hydrocodone or a phar acceptable salt thereof is about 55 to about 80% within about maceutically acceptable salt thereof is about 35% to about 5 minutes or less, and the dissolution rate of the promethazine 60% in about 5 minutes or less. In some instances, the disso or a pharmaceutically acceptable salt thereof is about 65 to lution rate of the hydrocodone or a pharmaceutically accept about 100% within about 5 minutes or less. In some instances, able salt thereof is about 65 to about 86% in about 10 minutes the friability is about 0.2% or less, the hardness is about 8 to or less. In some instances, the dissolution rate of the hydro about 22 kp, the dissolution rate of the hydrocodone or a codone or a pharmaceutically acceptable salt thereof is about pharmaceutically acceptable salt thereof is about 65 to about 78 to about 95% in about 15 minutes or less. In some 86% within about 10 minutes or less, the dissolution rate of instances, the one or more antiemetics comprises promethaZ the acetaminophen or a pharmaceutically acceptable salt ine, aprepitant, dronabinol, perphenazine, palonosetron, tri thereof is about 65 to about 100% within about 10 minutes or methyobenzamide, metoclopromide, domperidone, prochlo less, and the dissolution rate of the promethazine or a phar rperazine, chlorpromazine, trimethobenzamide, maceutically acceptable salt thereof is about 78 to about ondansetron, granisetron, hydroxy Zine, acetylleucine mono 100% within about 10 minutes or less. In some instances, the ethanolamine, alizapride, azasetron, benzquinamide, biet friability is about 0.2% or less, the hardness is about 8 to about anautine, bromopride, buclizine, clebopride, cyclizine, 22 kp, the dissolution rate of the hydrocodone or a pharma dimenhydrinate, diphenidol, dolasetron, meclizine, methal ceutically acceptable salt thereof is about 78 to about 95% latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco within about 15 minutes or less, the dissolution rate of the polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, acetaminophen or a pharmaceutically acceptable salt thereof thioproperazine, tropisetron, droperidol, haloperidol. is about 75 to about 100% within about 15 minutes or less, and prochloperazine, metoclopramide, diphenhydramine, can the dissolution rate of the promethazine or a pharmaceutically nabis, midazolam, lorazepam, hyoscine, dexamethasone, acceptable salt thereof is about 86 to about 100% within about emetrol, propofol, or a pharmaceutically acceptable salt of 15 minutes or less. In some instances, the friability is about any one of the foregoing, or any combination thereof. In some 0.05% to about 0.2%, the hardness is about 12 to about 20kp, instances, the promethazine or a pharmaceutically acceptable the dissolution rate of the hydrocodone or a pharmaceutically salt thereof, wherein the dissolution rate of the promethazine acceptable salt thereof is about 35 to about 60% within about or a pharmaceutically acceptable salt thereof is about 65 to 5 minutes or less, the dissolution rate of the acetaminophen or about 100% in about 5 minutes or less. In some instances, the a pharmaceutically acceptable salt thereof is about 55 to promethazine or a pharmaceutically acceptable salt thereof, about 80% within about 5 minutes or less, and the dissolution wherein the dissolution rate of the promethazine or a phar rate of the promethazine or a pharmaceutically acceptable salt maceutically acceptable salt thereof is about 80 to about thereof is about 80 to about 100% within about 5 minutes or 100% in about 5 minutes or less. In some instances, the less. In some instances, the friability is about 0.05% to about US 2015/0290211 A1 Oct. 15, 2015 20

0.2%, the hardness is about 12 to about 20 kp, the dissolution according to the General Chapter 1216 Tablet Friability sec rate of the hydrocodone or a pharmaceutically acceptable salt tion of the USP-NF. In some instances, the friability is mea thereof is about 65 to about 86% within about 10 minutes or Sured in a friabilator. In some instances, the friability is mea less, the dissolution rate of the acetaminophen or a pharma sured when a horizontal axis of the friabilator rotates at 25+1 ceutically acceptable salt thereof is about 65 to about 100% rpm. In some instances, the dissolution rate is measured with within about 10 minutes or less, and the dissolution rate of the a standard method according to the United States Pharma promethazine or a pharmaceutically acceptable salt thereof is copeia and the National Formulary (USP-NF). In some about 78 to about 100% within about 10 minutes or less. In instances, the dissolution rate is measured with a standard method according to the General Methods 711 Dissolution some instances, the friability is about 0.05% to about 0.2%, Standards section of the USP-NF. In some instances, the the hardness is about 12 to about 20kp, the dissolution rate of dissolution rate is measured with a USP rotating paddle appa the hydrocodone or a pharmaceutically acceptable salt ratus. In some instances, the apparatus is VK-8000 or equiva thereof is about 78 to about 95% within about 15 minutes or lent. In some instances, the hardness is measured using a less, the dissolution rate of the acetaminophen or a pharma hardness testing apparatus. In some instances, the hardness ceutically acceptable salt thereof is about 75 to about 100% testing apparatus is Key Model HT300, Model HT500, or within about 15 minutes or less, and the dissolution rate of the Pharma Test PTS/301. promethazine or a pharmaceutically acceptable salt thereof is 0018. In some aspects, a method is provided for treating about 86 to about 100% within about 15 minutes or less. In pain, the method comprising administering the tablet to a some instances, the friability is about 0.05% to about 0.14%, Subject in need thereof. In some instances, the one or more the hardness is about 10 to about 19 kp, the dissolution rate of antiemetics reduce or prevent a symptom experienced by the the hydrocodone or a pharmaceutically acceptable salt Subject caused by the one or more opioid analgesics. In some thereof is about 40 to about 65% within about 5 minutes or instances, the symptom is nausea or Vomiting. In some less, the dissolution rate of the acetaminophen or a pharma instances, the Subject is a post-operative Subject. In some ceutically acceptable salt thereof is about 55 to about 80% instances, the Subject is a postoperative subject. In some within about 5 minutes or less, and the dissolution rate of the instances, the Subject is a post-discharge Subject. In some promethazine or a pharmaceutically acceptable salt thereof is instances, the pain is moderate to severe pain. In some about 80 to about 100% within about 5 minutes or less. In instances, the pain is from an operation or post-operative some instances, the friability is about 0.05% to about 0.14%, pain. In some instances, the pain is acute pain. In some the hardness is about 10 to about 19 kp, the dissolution rate of the hydrocodone or a pharmaceutically acceptable salt instances, the pain is chronic pain. In some instances, the pain thereof is about 40 to about 52% within about 5 minutes or is severe. In some instances, the pain is moderate. In some less, the dissolution rate of the acetaminophen or a pharma instances, the pain is moderate to severe. ceutically acceptable salt thereof is about 55 to about 80% BRIEF DESCRIPTION OF THE DRAWINGS within about 5 minutes or less, and the dissolution rate of the promethazine or a pharmaceutically acceptable salt thereof is 0019 FIG. 1 illustrates an exemplary dissolution profile of about 80 to about 100% within about 5 minutes or less. In a bi-layer tablet. some instances, the friability is about 0.05% to about 0.14%, 0020 FIGS. 2A-2C illustrate one of manufacturing pro the hardness is about 18 kp, the dissolution rate of the hydro cesses for pharmaceutical composition fabrication. FIG. 2A codone or a pharmaceutically acceptable salt thereof is about shows a process of making a layer of hydrocodone bitartate 40 to about 52% within about 5 minutes or less, the dissolu and acetaminophen (APAP). FIG. 2B shows a process of tion rate of the acetaminophen or a pharmaceutically accept making a layer of promethazine HC1. FIG. 2C shows a pro able Salt thereof is about 55 to about 80% within about 5 cess of compressing two layers into a bi-layer tablet. minutes or less, and the dissolution rate of the promethazine 0021 FIG. 3 illustrates a friabilator apparatus utilized for or a pharmaceutically acceptable salt thereof is about 80 to friability measurements. about 100% within about 5 minutes or less. In some instances, 0022 FIG. 4 illustrates tabletorientations in a plunger for the tablet remains stable at ambient conditions for at least 24 hardness measurements. months. In some instances, the tablet remains stable at ambi 0023 FIG. 5 illustrates a range of values for pharmaceu ent conditions for at least 48 months. In some instances, the tical composition hardness (kp), thickness (mm), friability tablet remains stable at high temperature for at least 6 months. (%), and dissolution rates (Disso) of hydrocodone (HC), In some instances, the tablet provides an effective amount of acetaminophen (APAP), and promethazine (PMZ). at least one opioid analgesic or antiemetic to a Subject in need 0024 FIG. 6 illustrates a correlation between pharmaceu thereof for about 4 to about 8 hours following oral adminis tical composition hardness and friability. tration. In some instances, the tablet provides an effective 0025 FIG. 7 illustrates a correlation between pharmaceu amount of at least one opioid analgesic or antiemetic to a tical composition thickness and friability. subject in need thereof for about 4 to about 6 hours following 0026 FIG. 8 illustrates a correlation between pharmaceu oral administration. In some instances, the tablet provides an tical composition thickness and hardness. effective amount of at least one opioid analgesic orantiemetic 0027 FIG. 9 illustrates a correlation between pharmaceu to a subject in need thereof for about 4 hours following oral tical composition hardness and percent hydrocodone (HC) administration. In some instances, the tablet provides an dissolution within 10 and 15 minutes. effective amount of at least one opioid analgesic orantiemetic 0028 FIG. 10 illustrates a correlation between pharma to a subject in need thereof for about 6 hours following oral ceutical composition hardness and percent acetaminophen administration. In some instances, the friability is measured (APAP) dissolution within 10 and 15 minutes. with a standard method according to the United States Phar 0029 FIG. 11 illustrates a correlation between pharma macopeia and the National Formulary (USP-NF). In some ceutical composition hardness and percent promethazine instances, the friability is measured with a standard method (PMZ) dissolution within 10 and 15 minutes. US 2015/0290211 A1 Oct. 15, 2015

0030 FIG. 12 illustrates a correlation between pharma 0046. The term “subject as used herein refers to a mam ceutical composition thickness and percent hydrocodone mal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, (HC) dissolution within 10 and 15 minutes. cow, pig, or non-human primate, Such as a monkey, chimpan 0031 FIG. 13 illustrates a correlation between pharma Zee or baboon). In a particular instance the Subject is a human ceutical composition thickness and percent acetaminophen Subject. (APAP) dissolution with 10 and 15 minutes. 0047. The term “controlled-release' or “controlled 0032 FIG. 14 illustrates a correlation between pharma release' refers to release of at least one pharmaceutically ceutical composition hardness and percent promethazine active agent in a formulation or component of a formulation (PMZ) dissolution within 10 and 15 minutes. (e.g., a layer in a tablet, a particulate in a multi-particulate 0033 FIGS. 15A and 15B illustrate a linear scale of mean composition, etc.) at a time later than immediately after con plasma concentrations (ng/mL) of hydrocodone from Formu tact with a dissolution fluid or administration to a Subject. lation A and commercial hydrocodone within the first 4 hours Typically, the active agent exhibits a lag time in quantifiable (FIG.15A) and 8 hours (FIG. 15B) following administration dissolution. A controlled-release formulation or component to treatment groups A (Formulation A Fasted), B (Formu of a formulation has a slower release of the at least one lation A Fed), C (Comparator Fasted) and D (Compara pharmaceutically active agent than a pharmaceutically active tor Fed). agent in an immediate-release formulation or component of a 0034 FIGS. 16A and 16B illustrate a linear scale of mean formulation. A controlled-release formulation can begin its plasma concentrations (ug/mL) of acetaminophen from For release and continue that release over an extended period of mulation A and commercial acetaminophen within the first 4 time. A rate of release in a controlled-release formulation can hours (FIG. 16A) and 8 hours (FIG. 16B) following admin be constant, can increase or decrease overtime, can be pulsed, istration to treatment groups A (Formulation A Fasted), B can be continuous or intermittent, and the like. (Formulation A Fed), C (Comparator Fasted) and D 0048. The term “immediate-release” or “immediate (Comparator—Fed). release' refers to the release of at least one pharmaceutically 0035 FIGS. 17A and 17B illustrates a linear scale of mean active agent in a formulation or component of a formulation plasma concentrations (ng/mL) of promethazine from For (e.g., a layer in a tablet, a particulate in a multi-particulate mulation A and commercial promethazine within the first 4 composition, etc.) quickly after contact with a dissolution hours (FIG. 17A) and 8 hours (FIG. 17B) following admin fluid or administration to a subject. istration to treatment groups A (Formulation A-Fasted), B 0049. The term "supplemental antiemetic' refers to an (Formulation A Fed), C (Comparator—Fasted) and D antiemetic used as rescue medication taken after a target (Comparator—Fed). composition (e.g., an opioid analgesic) intended for treatment 0.036 FIG. 18 illustrates the mean and standard deviation of a condition, such as pain, is administered to a subject in of summed pain intensity differences (on the Categorical Pain need thereof. The term "supplemental analgesic’ refers to an Intensity Scale) over 24 hours (SPID24). analgesic used as rescue medication taken after a target com 0037 FIG. 19 illustrates a Kaplan Meier survival curve of position (e.g., an opioid analgesic) intended for treatment of time to onset of perceptible pain reduction among Subjects a condition, such as pain, is administered to a subject in need with moderate pain or greater than moderate pain relief in the thereof. first 6 hours. 0050. The present disclosure provides methods and com 0038 FIG. 20 illustrates a Kaplan Meier survival curve of positions for effective pain treatment. The term “pain” as used time to the second use of study medication from the first dose herein to all types of pain, in particular moderate to severe of study medication. pain. Pain includes neuropathic pain, post-operative pain, 0039 FIG. 21 illustrates a Kaplan Meier survival curve of chronic lowerback pain, clusterheadaches, herpes neuralgia, time to first dose of supplemental analgesic medication from phantom limb pain, central pain, dental pain, neuropathic the first dose of study medication. pain, visceral pain, Surgical pain, bone injury pain, pain dur 0040 FIG. 22 illustrates the mean and standard deviation ing labor and delivery, pain resulting from burns, post partum of Summed nausea intensity differences on the Nausea Inten pain, migraine, angina pain, genitourinary tract-related pain sity Scale (NIS) over 24 hours. including cystitis and nociceptive pain. In some instances, the 0041 FIG. 23 illustrates frequency of vomiting after the pain is chronic or acute ("chronic pain” or “acute pain'). The first dose over all 5 post-operation days. term “post-operative pain” as used herein refers to a subjects 0042 FIG. 24 illustrates the percentage of subjects using pain after Surgery. In some aspects, provided herein are meth Supplementary medication for nausea/vomiting over 5 days. ods for treating pain in a Subject, comprising administering to a subject in need thereof a pharmaceutical composition that 0043 FIG.25 illustrates a Kaplan Meier survival curve of comprises an immediate-release antiemetic and a controlled time to first dose of Supplemental medication for nausea/ release opioid analgesic, wherein the Subject experiences Vomiting from the first dose of study medication. increased pain relief compared to a Subject administered with a composition of the same opioid analgesic. In some DETAILED DESCRIPTION instances, the pharmaceutical composition that comprises an 0044) The disclosure is generally directed to compositions immediate-release antiemetic and a controlled-release opioid comprising multiple pharmaceutically active agents that are analgesic has a synergistic effect to provide increased pain useful as therapeutics that alleviate, abate or eliminate one or relief to a subject in need thereof. more conditions in a Subject in need thereof, as further 0051. In another aspect, provided herein are methods for described herein below. treating pain in a Subject, comprising administering to a Sub 0045. The term “about” means the referenced numeric ject in need thereof a pharmaceutical composition that com indication plus or minus 15% of that referenced numeric prises an immediate-release antiemetic and a controlled-re indication. lease opioid analgesic, wherein the Subject experiences US 2015/0290211 A1 Oct. 15, 2015 22 increased pain relief and decreased nausea or vomiting com of 0 to 10, where 0 is no nausea and 10 is severe nausea. In pared to a Subject administered with a composition of the Some instances, nausea can be measured by Soliciting feed same opioid analgesic. In another aspect, provided herein are back from a Subject. In some instances, nausea can be mea methods for treating pain in a Subject, comprising adminis Sured as the time from administration of the opioid analgesic tering to a subject a pharmaceutical composition that com to the time of the first episode of nausea. In some instances, prises an immediate-release antiemetic and a controlled-re nausea can be measured as the time from administration to the lease opioid analgesic, wherein the Subject experiences a time of delivery of a rescue therapy. reduced need for a Supplemental antiemetic or a Supplemental 0054. In some instances, vomiting can be measured or analgesic compared to a subject administered with a compo quantified using the Vomiting Frequency Scale (VFS). In sition of the same opioid analgesic. In another aspect, pro vided herein are methods for treating pain in a subject, com Some instances, vomiting can be measured based on a ques prising periodically administering to the Subject for one or tion, “how often did you vomit over the past hour?” where more days a pharmaceutical composition that comprises an 0 no vomiting, 1-one time to vomit, 2-two times to vomit, immediate-release antiemetic and a controlled-release opioid 3 three or more times to vomit. In some instances, vomiting analgesic, wherein the Subject experiences less frequent or can be measured by Soliciting feedback from a subject. In less intense nausea or Vomiting compared to a Subject peri Some instances, vomiting can be measured as the time from odically administered with a composition of the same opioid administration to the time of the first episode of vomiting. analgesic for one or more days. In some instances, the Subject 0055. In some instances, administration of a pharmaceu is a human. tical compound disclosed herein is repeated every 4-6 hours 0052. In some instances, the pain treated herein is chronic to a subject in need thereof. In some instances, the adminis pain. In some instances, the pain is moderate to severe. In tration is repeated every 8 hours. In some instances, the Some instances, the pain treated herein is moderate. In some administration is repeated for 1-5 days. In some instances, instances, the pain treated herein is severe. In some instances, nausea or Vomiting of a Subject is prevented or reduced within on a scale of 0 to 100 mm, where 0 mm no pain, and 100 24, 48, 72, 96, or 120 hours after the administration of a mm severe pain, moderate pain is about 50 mm to about 70 pharmaceutical composition disclosed herein to a Subject in mm, severe pain is about 70 mm to about 100 mm, and need thereof. moderate to severe pain is about 50 mm to about 100 mm. In 0056. In some instances, compositions disclosed herein Some instances, a Subject treated for pain is a post-operative comprise a controlled-release opioid analgesic. In some Subject who has undergone a recent Surgical procedure. In instances, the a controlled-release opioid analgesic comprises Some instances, a Subject the Subject treated for pain is a hydrocodone, oxycodone, oripavine, dihydromorphine, post-discharge Subject who has been recently discharged hydromorphinol, nicomorphine, dipropanoylmorphine, from a hospital or Surgical care unit. In some instances, the diacetyldihydromorphine, desomorphine, methyldesorphine, pain is caused by Surgery. In some instances, the pain is heterocodeine, benzylmorphine, dihydroheterocodeine, operative pain. In some instances, the pain continues after myrophine, pentamorphone, etorphine, acetyldihydroco Surgery is complete. In some instances the pain is post-opera deine, nicocodeine, nicodicodeine, alphamethylfentanyl. tive or post-discharge pain. In some instances, the paintreated carfentanil, parafluorofentanyl, thiofentanyl, anileridine, herein is caused by a disease or condition. In some instances, benzethidine, difenoxin, diphenoxylate, etoxeridine, furethi the one or more conditions or diseases comprise cancer, acute dine, morpheridine, pheneridine, phenoperidine, piminodine, physical injury, chronic physical injury, bone fracture, crush allylprodine, loperamide, dextropropoxyphene, dihydroetor injury, spinal cord injury, inflammatory disease, non-inflam phine, acetorphine, levophenacylmorphan, phenomorphan, matory neuropathic condition, or any combination thereof. drotebanol, dipipanone, normethadone, phenadoxone, dime 0053. In some instances, an incidence of nausea or vom pheptanol, levacetylmethadol, dextromoramide, diethylthi iting is prevented or reduced after the administration of a ambutene, dimethylthiambutene, ethylmethylthiambutene, pharmaceutical composition disclosed herein. In some dextropropoxyphene, dimenoxadol, tilidine, ethoheptazine, instances, the incidence of the nausea or vomiting is reduced proheptazine, piritramide, etonitaZene, tapentadol, tramadol, by about 10-25% or 10-50% after the administration of the a pharmaceutically acceptable salt of any one of the forego pharmaceutical composition to a Subject in need thereof, in ing, or any combination thereof. comparison to administration with the composition of the 0057. In some instances, compositions disclosed herein same opioid analgesic. In some instances, an intensity of comprise an immediate-release antiemetic. In some nausea or vomiting is reduced after the administration of the instances, the immediate-release antiemetic comprises pharmaceutical composition to a Subject in need thereof. In promethazine, aprepitant, dronabinol, perphenazine, pal Some instances, the intensity of the nausea or vomiting is onosetron, metoclopromide, domperidone, prochlorperazine, reduced from (severe to moderate) to (mild to none) after the chlorpromazine, trimethobenzamide, ondansetron, granis administration of the pharmaceutical composition to a subject etron, hydroxy Zine, acetylleucine monoethanolamine, aliza in need thereof. In some instances, the intensity of the nausea pride, aZasetron, benzquinamide, bietanautine, bromopride, or vomiting is reduced from severe to moderate, from severe buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol. to mild, or from severe to none, after the administration of the dolasetron, meclizine, methallatal, metopimazine, nabilone, pharmaceutical composition to a Subject in need thereof. In oxyperndyl, pipamazine, Scopolamine, Sulpiride, thiethylp Some instances, the intensity of the nausea or vomiting is erazine, thioproperazine, tropisetron, droperidol, haloperi reduced from moderate to mild, or from moderate to none, dol, diphenhydramine, midazolam, lorazepam, hyoscine, after the administration of the pharmaceutical composition to dexamethasone, emetrol, a pharmaceutically acceptable salt a subject in need thereof. In some instances, nausea can be of any one of the foregoing, or any combination thereof. In measured or quantified using the Nausea Intensity Scale Some instances, the immediate-release antiemetic is promet (NIS). In some instances, nausea can be measured on a scale hazine or a pharmaceutically acceptable salt thereof. US 2015/0290211 A1 Oct. 15, 2015

0058. In some instances, a controlled-release opioid anal layer tablet, a tannate tablet, an oral disintegrating tablet, an gesic comprises hydrocodone, oxycodone, or a pharmaceuti effervescent tablet, or any combination thereof. In some cally acceptable salt of any one of the foregoing, or any instances, the pharmaceutical composition is formulated as combination thereof and the immediate-release antiemetic the capsule that is a soft gelatin capsule or a hard gelatin comprises promethazine or a pharmaceutically acceptable capsule. In some instances, the capsule has micro drilled salt thereofandondansetronora pharmaceutically acceptable holes. In some instances, the capsule is formulated with an salt thereof. In some instances, a pharmaceutical composition immediate-release powder. In some instances, the capsule is comprises from about 6.5 mg to about 8.5 mg of hydroc formulated with one or more controlled-release particulates. odone, oxycodone, or a pharmaceutically acceptable salt of In some instances, the particulate is a bead, a sphere, or a any one of the foregoing, or any combination thereof and pellet. In some instances, the tablet or capsule further com from about 11 mg to about 14 mg of promethazine or a prises an inner dosage and an outer dosage, the latter being in pharmaceutically acceptable salt thereof. the form of an envelope over the former. In some instances, 0059. In some instances, a pharmaceutical composition the inner dosage and outer dosage components are separated comprises a controlled-release non-opioid analgesic and a by an enteric layer. controlled-release non-opioid analgesic. In some instances, 0062. In some instances, a pharmaceutical composition the controlled-release non-opioid analgesic comprises disclosed herein comprises one or more excipients. In some acetaminophen, acetylsalicylic acid, amoxiprin, benorilate, instances, the one or more excipients comprise an antioxidant choline magnesium salicylate, diflunisal, faislamine, methyl agent, a binder, a coating material, a colorant agent, a diluent, salicylate, magnesium salicylate, diclofenac, aceclofenac, a disintegrant, a disperant, an emulsifying agent, a flavoring acemetacin, bromfenac, etodolac, indometacin, nabumetone, agent, a glidant, a lubricant, a pH modifying agent, a plasti sulindac, tolmetin, ibuprofen, carprofen, fenbuprofen, flubi cizer, a preservative agent, a solubilizing agent, a stabilizer, a profen, ketaprofen, ketorolac, loxoprofen, naproxen, Supro Surfactant, a Sweetening agent, a thickening agent, a pharma fen, mefenamic acid, meclofenamic acid, piroxicam, lomoxi ceutically inert material, or any combination thereof. In some cam, meloxicam, tenoxicam, phenylbutaZone, azapropaZone, instances, the one or more excipients comprise the antioxi metamizole, oxyphenbutaZone, SulfinpraZone, a pharmaceu dant agent that is a flavonoid, an anthocyanidin, an anthocya tically acceptable salt of any one of the foregoing, or any nin, a proanthocyanidin, or any combination thereof. In some combination thereof. In some instances, the controlled-re instances, the one or more excipients comprise the binder that lease non-opioid analgesic is acetaminophen or a pharmaceu is hydroxypropylcellulose, methylcellulose, corn starch, tically acceptable salt thereof. In some instances, the con pregelatinized starch, hydroxypropylmethylcellulose, trolled-release non-opioid analgesic is present in an amount hydroxpropyl Starch, glucose, dextrose, Sucrose, lactose, Sor of about 200 mg to about 600 mg, about 200 mg to about 1000 bitol, polyvinyl alcohol, polyethylene glycol, acacia, traga mg, about 200 mg to about 325 mg, about 325 mg to about canth, sodium alginate, polymethacrylate, polyvinylpyrroli 330 mg, about 330 mg to about 335 mg, about 335 mg to done, povidone, dextrin, pullulane, agar, gelatin, tragacanth, about 340 mg, about 340 mg to about 345 mg, about 345 mg macrogol, or any combination thereof. In some instances, the to about 350 mg, about 325 mg to about 350 mg, about 350 one or more excipients comprise the coating material that is mg to about 400 mg, about 400 mg to about 1000 mg. or any hydroxypropylmethyl cellulose 2910, aminoalkyl methacry combination thereof. late copolymer E. polyvinylacetal diethylaminoacetate, mac 0060. In some instances, a pharmaceutical composition rogol 6000, titanium oxide, or any combination thereof. In comprises two or more immediate-release antiemetics. In Some instances, the one or more excipients comprise the Some instances, the two or more immediate-release antiemet colorant agent that is food red dye No. 2, food red dye No. 3, ics comprise promethazine or a pharmaceutically acceptable food yellow dye No. 4, food yellow dye No. 5, food blue dye salt thereofandondansetronora pharmaceutically acceptable No. 1, food blue dye No. 2, water-insoluble lake dye, beta salt thereof. In some instances, a pharmaceutical composition carotene, chlorophyll, iron oxide red, D&C Red No. 33. comprises an opioidantagonist oran abuse deterrent agent. In FD&C Red No. 3, FD&C Red No. 40, D&C Yellow No. 10, C Some instances, the opioidantagonist agent or abuse deterrent Yellow No. 6, or any combination thereof. In some instances, agent comprises nalmefene, naloxone, naltrexone, cyclaza the one or more excipients comprise the diluent that is cellu cine, levallorphan, niacin, a pharmaceutically acceptable salt lose, microcrystalline cellulose, dry starch, hydrolyzed of any one of the foregoing, or any combination thereof. In starch, corn starch, cyclodextrin, powdered Sugar, lactose, Some instances, the pharmaceutical composition further com D-mannitol, aluminum hydroxide gel, precipitated calcium prises the abuse deterrent agent that is formulated as a gel carbonate, carbonate, magnesium aluminometasilicate, diba forming agent comprising a pharmaceutically acceptable sic calcium phosphate, Sodium chloride, silicon dioxide, tita polymer. In some instances, the pharmaceutically acceptable nium dioxide, titanium oxide, dicalcium phosphate dihy polymer is capable of forming a viscous gel upon contact with drate, calcium sulfate, alumina, kaolin, talc, or any a solvent, wherein the Viscous gel resists crushing and Snort combination thereof. In some instances, the one or more ing. In some instances, the pharmaceutically acceptable poly excipients comprise the disintegrant that is alginic acid, mer comprises polyethylene oxide, polyvinyl alcohol, crosslinked polyvinylpyrrolidone, croScarmellose Sodium, hydroxypropyl methyl cellulose, carbomers, or any combina potassium starch glycolate, sodium starch glycolate, clay, tion thereof. cellulose, starch, gum, or any combination thereof. In some 0061. In some instances, a pharmaceutical composition instances, the one or more excipients comprise the emulsify disclosed herein is formulated as a tablet, capsule, or lollipop. ing agent that is gelatin, egg yolk, casein, cholesterol, acacia, In some instances, the pharmaceutical composition is formu tragacanth, chondrus, pectin, methyl cellulose, carbomer, lated with a controlled-release enteric coating. In some cetostearyl alcohol, cetyl alcohol, or any combination instances, the pharmaceutical composition is formulated as thereof. In some instances, the one or more excipients com the tablet that is a bi-layer tablet, a two layer tablet, a multi prise the flavoring agent that is natural fruit, artificial fruit, US 2015/0290211 A1 Oct. 15, 2015 24 artificial banana, artificial Strawberry, artificial pineapple, or release opioid analgesic has a Tmax that is about: 5-10 min any combination thereof. In some instances, the one or more utes, 10-20 minutes, 20-30 minutes, 30-40 minutes, 40-50 excipients comprise the lubricant that is mineral oil, magne minutes, or 50-60 minutes longer than a corresponding Tmax sium Stearate, calcium Stearate, Stearic acid, glyceryl behen of the composition of the same opioid analgesic. In some ate, polyethylene glycol, talc, or any combination thereof. In instances, the controlled-release opioid analgesic has a Tmax Some instances, the one or more excipients comprise the pH that is about: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 buffering agent that is gluconate, lactate, citrate, citric acid, minutes longer than a corresponding Tmax of the composi acetate, phosphate, potassium phosphate, sodium phosphate, tion of the same opioid analgesic. benzoate, Sodium benzoate, carbonate salt, or any combina 0064. In some instances, an immediate-release antiemetic tion thereof. In some instances, the one or more excipients has a Tmax that is about 3.5 to 4.3 hours. In some instances, comprise the plasticizer that is triethylcitrate, triacetin, mac the immediate-release antiemetic has a Tmax that is about: rogol 6000, or any combination thereof. In some instances, 3.5, 3.6, 3.7, 3.75, 3.8, 3.85, 3.9, 3.95, 4, 4.1, 4.2, or 4.3 hours. the one or more excipients comprise the preservative agent In some instances, the immediate-release antiemetic has a that is sodium benzoate, paraoxybenzoic acid ester, methyl Tmax that is about 30-120 minutes shorter than a Tmax of a paraben, ethyl paraben, butyl paraben, propyl paraben, chlo corresponding standard-release antiemetic. In some robutanol, benzyl alcohol, phenylethylalcohol, dehydroace instances, the immediate-release antiemetic has a Tmax that tic acid, Sorbic acid, benzalkonium chloride, benzethonium is about 50-100 minutes shorter thana Tmax of a correspond chloride, phenol, phenylmercuric nitrate, thimerosal, or any ing standard-release antiemetic. In some instances, the imme combination thereof. In some instances, the one or more diate-release antiemetic has a Tmax that is about 60-90 min excipients comprise the Solubilizing agent that is ethyl alco utes shorter than a Tmax of a corresponding standard-release hol, glycerin, D-mannitol, trehalose, benzyl benzoate, antiemetic. In some instances, the immediate-release anti trisaminomethane, cholesterol, triethanolamine, Sodium car emetic has a Tmax that is about: 30-40 minutes, 40-50 min bonate, Sodium citrate, sodium salicylate, Sodium acetate, utes, 50-60 minutes, 60-70 minutes, 70-80 minutes, 80-90 ethanol, isopropanol, t-butanol, phenol, cresol, benzyl alco minutes, 90-100 minutes, 100-110 minutes, or 110-120 min hol, propylene glycol, polypropylene glycol, polyethylene utes shorter than a Tmax of a corresponding standard-release glycol, or any combination thereof. In some instances, the one antiemetic in median times. In some instances, the immedi or more excipients comprise the stabilizer that is ethanol, ate-release antiemetic has a Tmax that is about: 30,35, 40, 45, glycerin, polyethylene glycol, propylene glycol, polypropy 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 105,110, 115, or lene glycol, hydroxypropylmethylcellulose, hydroxymethyl 120 minutes shorter thana Tmax of a corresponding standard cellulose, or any combination thereof. In some instances, the release antiemetic in median times. In some instances, the one or more excipients comprise the Surfactant that is poly immediate-release antiemetic has a Tmax that is about: 70, oxyl Stearate, polyoxyethylene hydrogenated castor oil, poly 71, 72,73, 74, 75, 76, 77, 78,79, or 80 minutes shorter thana oxyethylene polyoxypropylene glycol, Sorbitan sesquioleate, Tmax of a corresponding standard-release antiemetic in Sorbitan trioleate, Sorbitan monostearate, Sorbitan mono median times. palmitate, Sorbitan monolaurate, polysorbate, glyceryl 0065. In some instances, a controlled-release non-opioid monostearate, Sodium lauryl Sulfate, lauromacrogol, poloX analgesic has a Tmax that is about 0.9 to 1.1 hours. In some amer, or any combination thereof. In some instances, the one instances, the controlled-release non-opioid analgesic has a or more excipients comprise the Sweetening agent that is Tmax that is about: 0.9, 0.92, 0.94, 0.96,0.98, 1, 1.02, 1.04, Sorbitol, saccharin, acesulfame, acesulfame potassium, 1.06, 1.08, or 1.1 hours. In some instances, the controlled Sucralose, Xylitol, maltitol. Sucrose, aspartame, fructose, release non-opioid analgesic has a Tmax that is about 5-30 neotame, glycerin, sodium saccharate, glycyrrhizin dipotas minutes longer than a corresponding Tmax of the composi sium, acesulfame K, mannitol, invert Sugar, liquid Sugar, or tion of the same opioid analgesic and the same non-opioid any combination thereof. In some instances, the one or more analgesic. In some instances, the controlled-release non excipients comprise the thickening agent that is acacia, alg opioid analgesic has a Tmax that is about 10-25 minutes inic acid bentonite, carbomer, carboxymethylcellulose cal longer than of a corresponding Tmax of the composition of cium, carboxymethylcellulose sodium, cetostearyl alcohol, the same opioid analgesic and the same non-opioid analgesic. methyl cellulose, ethylcellulose, glycerin, gelatin guar gum, In some instances, the controlled-release non-opioid analge hydroxyethyl cellulose, hydroxymethyl cellulose, hydrox sics has a Tmax that is about 10-15 minutes longer than a ypropyl cellulose, hydroxypropyl methyl cellulose, malto corresponding Tmax of the composition of the same opioid dextrin, polyvinyl alcohol, povidone, propylene carbonate, analgesic and the same non-opioid analgesic. In some propylene glycol alginate, Sodium alginate, Sodium starch instances, the controlled-release non-opioid analgesic has a glycolate, starch tragacanth, Xanthan gum, or any combina Tmax that is about: 5-10 minutes, 10-15 minutes, 15-20 min tion thereof. utes, 20-25 minutes, or 25-30 minutes longer than a corre 0063. In some instances, a controlled-release opioid anal sponding Tmax of the composition of the same opioid anal gesic has a Tmax that is about 1.4-2.0 hours. In some gesic and the same non-opioid analgesic. In some instances, instances, the controlled-release opioid analgesic has a Tmax the controlled-release non-opioid analgesic has a Tmax that is that is about: 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, about: 5, 10, 15, 20, 25, or 30 minutes longer than a corre 1.9, 1.95, or 2 hours. In some instances, the controlled-release sponding Tmax of the composition of the same opioid anal opioid analgesic has a Tmax that is about 5-60 minutes longer gesic and the same non-opioid analgesic. In some instances, than a corresponding Tmax of the composition of the same the controlled-release non-opioid analgesic has a Tmax that is opioid analgesic. In some instances, the controlled-release about: 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 opioid analgesic has a Tmax that is about 10-30 minutes minutes longer than a corresponding Tmax of the composi longer than a corresponding Tmax of the composition of the tion of the same opioid analgesic and the same non-opioid same opioid analgesic. In some instances, the controlled analgesic. US 2015/0290211 A1 Oct. 15, 2015

0066. In some instances, a pharmaceutical composition (0071 Exemplary opioid peptides include adrenorphin, disclosed herein is a solid composition. In some instances, a amidorphin, casomorphin, (2R)-2-[(2S)-2-[2-(2R)-2- pharmaceutical composition disclosed herein is a liquid com (2S)-2-amino-3-(4-hydroxyphenyl)propanoyl)aminolpro position. In some instances, a pharmaceutical composition panoyl)aminoacetylamino-3-phenylpropanoylaminol-4- disclosed herein is formulated as a patch. methylpentanoic acid (DADLE), (2S)-2-amino-N-(2R)-1- 2-(2S)-1-(2-hydroxyethylamino)-1-oxo-3- Pharmaceutical Agents phenylpropan-2-yl)-methylamino-2-oxoethylamino-1- oxopropan-2-yl)-3-(4-hydroxyphenyl) propanamide Opioid Analgesics (DAMGO), dermorphin, morphiceptin, nociceptin, oct 0067. In some instances, a pharmaceutical composition as reotide, opiorphin, L-tyrosyl-N-(3-methylbutyl)amino disclosed herein comprises one or more opioid analgesics. acetyl-D-alaninamide (TRIMU 5), or a pharmaceutically Opioid analgesics include, without limitation, an opiate, an acceptable salt of any one of the foregoing, or any combina endogenous opioid, an opium alkaloid, an active opiate tion thereof. metabolite, an opioid peptide, an opioid from the morphine 0072 Exemplary semi-synthetic opioids include etor family, a semi-synthetic opioid, a synthetic opioid, and a phine, hydrocodone, hydromorphone, oxycodone, oxymor pharmaceutically acceptable salt of any one of the foregoing. phone, ethylmorphine, chloromorphide, 14-hydroxydihydro Opioid analgesics also include any combination of those codeine, acetyldihydrocodeine, nicocodeine, nicodicodeine, mentioned above. oxymorphazone, 1-iodomorphine, or a pharmaceutically 0068 Exemplary endogenous opioids include endorphins, acceptable salt of any one of the foregoing, or any combina enkephalins, dynorphins, or endomorphins Opium alkaloids, tion thereof. naturally occurring in opium, can include codeine, morphine, (0073 Exemplary synthetic opioids include: a) anilidopip thebaine, oripavine, papaveretum, or a pharmaceutically eridines including alphamethylfentanyl, 3-allylfentanyl. acceptable salt of any one of the foregoing, or any combina 3-methylfentanyl, 3-methylthiofentanyl, 4-phenylfentanyl. tion thereof. alfentanil, C.-methylacetylfentanyl, C.-methylfentanyl, C.-me 0069. Exemplary opioids from the morphine family thylthiofentanyl, B-hydroxyfentanyl, B-hydroxythiofentanyl. include: a) 2.4-dinitrophenylmorphine, 4.5-O-Epoxy-17-me B-methylfentanyl, brifentanil, carfentanil, fentanyl, lofenta thyl-6-methylenemorphinan-3-ol (6-MDDM), dihydromor nil, mirfentanil, ocfentanil, ohmefentanyl, parafluorofenta phine, hydromorphinol, N-phenethylnormorphine, 3,6,14 nyl, phenaridine, remifentanil, Sufentanil, thiofentanyl, trihydroxy-4,5C.-epoxy-17-(2-phenylethyl) morphinan trefentanil, or a pharmaceutically acceptable salt of any one (RAM-378), or a pharmaceutically acceptable salt of any one of the foregoing, or any combination thereof; b) 4-phenylpi of the foregoing, or any combination thereof; b) esters of peridines including 4-fluoromeperidine, allylnorpethidine, morphine including diacetylmorphine, nicomorphine, dipro anileridine, benzethidine, carperidine, difenoxin, diphenoxy panoylmorphine, diacetyldihydromorphine, acetylpropio late, etoxeridine, furethidine, hydroxypethidine, morpheri nylmorphine, desomorphine, methyldesorphine, dibenzoyl dine, oxpheneridine, pethidine, pheneridine, phenoperidine, morphine, dihydroheroin, or a pharmaceutically acceptable piminodine, properidine, allylprodine, 1-methyl-4-phenyl-4- salt of any one of the foregoing, or any combination thereof; propionoxypiperidine (Desmethylprodine or MPPP), 4-phe c) ethers of morphine including dihydrocodeine, ethylmor nyl-1-(2-phenylethyl)piperidin-4-yl acetate (PEPAP), C-pro phine, heterocodeine, or a pharmaceutically acceptable salt of dine, prosidol, trimeperidine, acetoxyketobemidone, any one of the foregoing, or any combination thereof; d) droxypropine, ketobemidone, methylketobemidone, propy codeine-dionine family members including (4R,4aR.7R, lketobemidone, loperamide, or a pharmaceutically accept 7aR,12bS)-9-methoxy-3-methyl-2,4,4a.7.7a, 13-hexahydro able salt of any one of the foregoing, or any combination 1H-4,12-methanobenzofuro3.2-elisoquinoline-7-yl)acetate thereof; c) diphenylpropylamine derivatives including pro (6-Monoacetylcodeine or 6-MAC), benzylmorphine, codeine poxyphene, dextroporpoxyphene, or a pharmaceutically methylbromide, dihydroheterocodeine, pholcodine, myro acceptable salt of any one of the foregoing, or any combina phine, or a pharmaceutically acceptable salt of any one of the tion thereof; d) orvinols and oripavine derivatives including foregoing, or any combination thereof, and e) morphinones dihydroetorphine, etorphine, (2R)-2-((4R.7S,7aR.12bS. and morphols including 14-cinnamoyloxycodeinone. 14R)-7,9-dimethoxy-3-methyl-1,2,3,4,7,7a-hexahydro-7, 14-ethoxymetopon, 14-methoxymetopon, 3-Hydroxy-14-(3- 4a-ethano-4,12-methanobenzofuro3.2-elisoquinolin-14 phenylpropoxy)-5-methyl-7,8-dihydro-4.5o-epoxy-17-me yl)-4-phenylbutan-2-ol (7-PET), acetorphine, thylmorphinan-6-one (14-Phenylpropoxymetopon or N-cyclopropylmethyl-7a,8a,2',3'-cyclohexano-1"Sl-hy PPOM), 7-spiroindanyloxymorphone, acetylmorphone, droxy-6, 14-endo-ethenotetrahydronororipavine (BU-48). codeinone, codoxime, thebacon, metopon, morphinone, pen norbuprenorphine, or a pharmaceutically acceptable salt of tamorphone, or a pharmaceutically acceptable salt of any one any one of the foregoing, or any combination thereof; e) of the foregoing, or any combination thereof. morphinan derivative including levorphanol, levomethor 0070) Exemplary active opiate metabolites include (2S, phan, levophenacylmorphan, norlevorphanol, phenomor 3S4S.5R.6R)-6-(4R,4aR,7S,7aR.12bS)-9-hydroxy-3-me phan, furethylnorlevorphanol, drotebanol, or a pharmaceuti thyl-2,4,4a,7,7a, 13-hexahydro-1H-4.12-methanobenzofuro cally acceptable salt of any one of the foregoing, or any 3.2-eisoquinoline-7-yl)oxy-3,4,5-trihydroxyoxane-2- combination thereof: f) allosteric modulators including can carboxylic acid (morphine-6-glucuronide or M6G). nabidiol, tetrahydrocannabinol, or a pharmaceutically 3-hydroxy-6-acetyl-(5a,6a)-7,8-Didehydro-4,5-epoxy-17 acceptable salt of any one of the foregoing, or any combina methylmorphinan (6-monoacetylmorphine or 6-MAM), nor tion thereof, g) open chain opioids including dipipanone, codeine, normorphine, morphine-N-oxide, or a pharmaceuti methadone, normethadone, phenadoxone, dimepheptanol, cally acceptable salt of any one of the foregoing, or any dextromoramide, levomoramide, racemoramide, diethylthi combination thereof. ambutene, dimethylthiambutene, ethylmethylthiambutene, US 2015/0290211 A1 Oct. 15, 2015 26 pip eridylthiambutene, pyrrolidinylthiambutene, thiam tanil, Sufentanil, tramadol, tapentadol, or a pharmaceutically butene, tipepidine, dextropropoxyphene, dimenoxadol, diox acceptable salt of any one of the foregoing, or any combina aphetyl butyrate, levopropoxyphene, norpropoxyphene, tion thereof. diampromide, phenampromide, methiodone, isoaminile, lefetamine, 6-(3,4-dihydro-1"H.2H-spiro naphthalene-1,4'- Non-Opioid Analgesics piperidin-1-yl)-4,4-diphenylhexan-3-one (R-4066), or a pharmaceutically acceptable salt of any one of the foregoing, 0075. A pharmaceutical composition disclosed herein or any combination thereof, and h) various others including comprise one or more non-opioid analgesics. Exemplary non menthol, tilidine, ethoheptazine, metheptazine, metethohep opioid analgesics can include a non-steroidal anti-inflamma tazine, proheptazine, bezitramide, piritramide, clonitaZene, tory drug (NSAID) such as a salicylate (including for etonitaZene, 7-hydroxymitragynine, akuammine, eseroline, example, amoxiprin, benorilate, choline magnesium salicy hodgkinsine, mitragynine, pericine, 4-(R)-(2S,5R)-2,5- late, diflunisal, faislamine, methyl salicylate, magnesium dimethyl-4-prop-2-enylpiperazin-1-yl)-(3-hydroxyphenyl) salicylate), an arylalkanoic acid (including, for example, methyl-N,N-diethylbenzamide (BW373U86), 4-((aS)-O- diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, ((2S.5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl) indometacin, nabumetone, Sulindac, tolmetin), a profen (in benzyl)-N,N-diethylbenzamide (DPI-221), 4-(R)-(2S,5R)- cluding, for example, ibuprofen, carprofen, fenbuprofen, flu 2,5-dimethyl-4-benzylpiperazin-1-yl)-(3-hydroxyphenyl) biprofen, ketaprofen, ketorolac, loxoprofen, naproxen, methyl-N,N-diethylbenzamide (DPI-287), (+)-3-((aR)-O- Suprofen), a fenamic acid (including, for example, mefe ((2S.5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3- namic acid, meclofenamic acid), an oxicam (including, for hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide example, piroXicam, lomoxicam, meloxicam, tenoxicam), a (DPI-3290), 4-(R)-(2S.5R)-4-allyl-2,5-dimethylpiperazin pyrazolidine derivative (including, for example, phenylbuta 1-yl)(3-methoxyphenyl)methyl-N,N-diethylbenzamide Zone, azapropaZone, metamizole, oxyphenbutaZone, or (SNC-80), 3,4-dichloro-N-(1-dimethylamino)cyclohexylm SulfinpraZone), or a pharmaceutically acceptable salt of any ethylbenzamide (AH-7921), azaprocin, bromadol, dichlo one of the foregoing, or any combination thereof. rophenyl)-1-(2S)-2-(pyrrolidin-1-ylmethyl) piperidin-1-yl) 0076. In some instances, a non-opioid analgesic includes a ethanone (BRL-52537), bromadoline, trans-4-(p- Cox-2 inhibitor. Exemplary Cox-2 inhibitors include Valde Bromophenyl)-4-(dimethylamino)-1-(2-(thiophen-2-yl) coxib, celecoxib, rofecoxib or a pharmaceutically acceptable ethyl)cyclohexanol (thiobromadol or C-8813), doxpicomine, salt of any one of the foregoing, or any combination thereof. enadoline, faxeladol, methyl 4-2-(3,4-dichlorophenyl) In some instances, the non-opioid analgesic can be a local acetyl-3-(pyrrolidin-1-ylmethyl) piperazine-1-carboxylate analgesic. Exemplary local analgesics include lidocaine, (GR-89696), herkinorin, 2-(3,4-dichlorophenyl)-N-methyl mexiletine, or a pharmaceutically acceptable salt of any one N-(1S)-1-phenyl-2-pyrrolidin-1-ylethylacetamide (ICI of the foregoing, or any combination thereof. In some 199.441), 2-(3-1-(2-(3,4-dichlorophenyl)acetyl-methy instances, the non-opioid analgesic can be an anti-depressant. lamino)-2-pyrrolidin-1-ylethylphenoxy) acetic acid (ICI Exemplary anti-depressants include amitriptyline, carbam 204,448), 2-(3,4-dichlorophenyl)-N-(2S)-1-(2,5- aZepine, gabapentin, pregabalin, amoxapine, clomipramine, dihydropyrrol-1-yl)-3-methylbutan-2-yl)-N- desipramine, doSulepin, doxepin, imipramine, iprindole, methylacetamide (LPK-26), methopholine, 8-chloro-11 lofepramine, nortriptyline, opipramol, protryptyline, trimi piperazin-1-yl-5H-dibenzob.e. 14 diazepine pramine, or a pharmaceutically acceptable salt of any one of (N-desmethylclozapine or norclozapine or NDMC), methyl the foregoing, or any combination thereof. In some instances, 8-(1-naphthylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro4. the non-opioid analgesic can be an atypical analgesic. Exem 5 dec-3-yl)acetate (NNC 63-0532), nortilidine, O-desmeth plary atypical analgesics include orphenadrine, cyclobenza yltramadol, prodilidine, 8-(1S,3aS)-2,3.3a,4,5,6- prine, Scopolamine, atropine, gabapentin, or a pharmaceuti hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro4. cally acceptable salt of any one of the foregoing, or any 5 decan-4-one (Ro64-6198), 6-(dimethylamino)methyl-3- combination thereof. In some instances, the non-opioid anal ethoxy-21-fluoro-20-oxopregna-3,5-dien-17-yl acetate (SC gesic can be a psychotropic agent. Exemplary psychotropic 17599), N,N-diethyl-4-((8-phenethyl-8-azabicyclo[3.2.1 agents include tetrahydrocannabinol or a pharmaceutically oct-3-ylidene)phenylmethyl)benzamide (RWJ-394674), acceptable salt thereof. In some instances, the non-opioid 3-(4aS, 12aR)-11-amino-2-methyl-1,3,4,5,12,12a-hexahy analgesic can be an NMDA receptor antagonist. Exemplary dropyrido 3,4-blacridin-4a(2H)-yl)phenol (SB-205,607 or NMDA receptor antagonists include ketamine, amantadine, TAN-67), tapentadol, tifluadom, tramadol, trimebutine, 2-(3. dextromethorphan, dextrorphan, ibogaine, phencyclidine, 4-dichlorophenyl)-N-methyl-N-(1R,2R)-2-pyrrolidin-1-yl riluzole, tiletamine, memantine, dizocilpine, patiganel, rem cyclohexyl)acetamide (U-50488), N-methyl-2-phenyl-N- acimide, or a pharmaceutically acceptable salt of any one of (5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro4.5 dec-8-yl) the foregoing, or any combination thereof. In some instances, acetamide (U-69593), (E)-4-chloro-N-(1-(4-nitrophenethyl) the non-opioid analgesic can be an C2-adrenoreceptor ago piperidin-2-ylidene)benzenesulfonamide (W-18), 1-1-(1- nist. Exemplary C2-adrenoreceptor agonists include cloni methylcyclooctyl)-4-piperidinyl-2-((3R)-3-piperidinyl dine or a pharmaceutically acceptable salt of any one of the 1H-benzimidazole (MCOPPEB), or a pharmaceutically foregoing, or any combination thereof. In some instances, the acceptable salt of any one of the foregoing, or any combina non-opioid analgesic is acetaminophen or a pharmaceutically tion thereof. acceptable salt thereof. 0074. In some instances, the opioid analgesic includes hydrocodone, oxycodone, propoxyphene, fentanyl. Antiemetics acetyldihydrocodeinone, diamorphine, codeine, pethidine, 0077. A pharmaceutical composition disclosed herein can alfentanil, codeine, hydromorphone, levorphanol, meperi comprise one or more antiemetics. In some instances, the dine, methadone, morphine Sulfate, oxymorphone, remifen antiemetic can be an antihistamine. Exemplary antihista US 2015/0290211 A1 Oct. 15, 2015 27 mines include promethazine, dolasetron, granisetron, dine, dimenhydrinate, diphenhydramine, emedastine, ondansetron, tropisetron, palonosetron, domperidone, dro fexofenadine, hydroxy Zine, ketotifen, levocabastine, lorata peridol, haloperidol, chlorpromazine, prochloperazine, dine, meclizine, olopatadine, phenindamine, promoathazine, metoclopramide, aliZapride, cyclizine, diphenhydramine, or a pharmaceutically acceptable salt of any one of the fore dimenhydrinate, meclizine, hydroxy Zine, cannabis, dronab going, or any combination thereof. inol, nabilone, midazolam, lorazepam, hyoscine, dexametha I0084. In other instances, exemplary antiemetics can Sone, trimethobenzamide, emetrol, or propofol, or pharma include aprepitant, dronabinol, perphenazine, palonosetron, ceutically acceptable salt of any one of the foregoing, or any trimethyobenzamide, metoclopromide, domperidone, combination thereof. prochlorperazine, promethazine, promethazine HCl, chlor 0078. In some instances, an antihistamine comprises an promazine, trimethobenzamide, ondansetron, granisetron, H1 agonist or H1 antagonist. Exemplary H1 agonists or par hydroxy Zine, acetylleucine monoethanolamine, alizapride, tial agonists include 2-(m-fluorophenyl)-histamine or a phar aZasetron, benzquinamide, bietanautine, bromopride, bucliz maceutically acceptable salt thereof. Exemplary H1 antago ine, clebopride, cyclizine, dimenhydrinate, diphenidol, dola nists can include azelastine, buclizine, carbinoxamine, setron, meclizine, methallatal, metopimazine, nabilone, cetrizine, clemastine, cyproheptadine, desloratidine, dimen oxyperndyl, pipamazine, Scopolamine, Sulpiride, tetrahydro hydrinate, diphenhydramine, emedastine, fexofenadine, cannabinol, thiethylperazine, thioproperazine, tropisetron, hydroxy Zine, ketotifen, levocabastine, olopatadine, phenin droperidol, haloperidol, prochloperazine, metoclopramide, damine, promethazine, chlorphenamine, Scopolamine, diphenhydramine, cannabis, midazolam, lorazepam, hyos mepyramine, terfenadine, astemizole, triprolidine or a phar cine, dexamethasone, emetrol, propofol, or a pharmaceuti maceutically acceptable Salt of any one of the foregoing, or cally acceptable salt of any one of the foregoing, or any any combination thereof. combination thereof. 0079 Additional exemplary antagonists include ethanola mines such as carbinoxamine, dimenhydrinate, diphenhy Barbiturate Agents dramine, doxylamine, or a pharmaceutically acceptable salt of any one of the foregoing, or any combination thereof. I0085. In some instances, a pharmaceutical composition ethylaminediamines such as pyrilamine, tripelennamine, or a disclosed herein comprises a barbiturate active agent. Exem pharmaceutically acceptable salt of any one of the foregoing, plary barbiturate agents include allobarbital, alphenal, amobarbital, aprobarbital, barbexaclone, barbital, brallobar or any combination thereof; piperazine derivatives such as bital, butabarbital, butalbital, butobarbital, butallylonal, cro dydroxyzine, cyclizine, fexofenadine, meclizine, or a phar tylbarbital, cyclobarbital, cyclopal, ethallobarbital, febar maceutically acceptable Salt of any one of the foregoing, or bamate, heptabarbital, hexethal, hexobarbital, any combination thereof alkylamines Such as bromphe mephobarbital, metharbital, methohexital, methylphenobar niramine, chlorpheniramine, or a pharmaceutically accept bital, narcobarbital, nealbarbital, pentobarbital, primidone, able salt of any one of the foregoing, or any combination probarbital, propallylonal, proxibarbal, proxibarbital, thereof, and miscellaneous antagonists such as cyprohepta reposal, secbutabarbital, secobarbital, sigmodal, talbutal, thi dine, loratadine, cetrizine, or a pharmaceutically acceptable albarbital, thiamylal, thiobarbital, thiobutabarbital, thiopen salt of any one of the foregoing, or any combination thereof. tal, valofane, vinbarbital, vinylbital, 1,3-dimethoxymethyl 0080. In some instances, an antihistamine includes an H2 5,5-diphenyl-barbituric acid (DMMDPB), agonist or H2 antagonist. Exemplary H2 agonists include 1-monomethoxymethyl 5,5-diphenylbarbituric acid dimaprit, impromidine, amthamine, or a pharmaceutically (MMMDPB), a diphenyl-barbituric acid (DPB) and their pre acceptable salt of any one of the foregoing, or any combina cursors, derivatives and analogs, or a pharmaceutically tion thereof. Exemplary H2 antagonists (useful in the treat acceptable salt of any one of the foregoing, or any combina ment of gastric acid secretion) include cimetidine, ranitidine, nizatidine, famotidine, or a pharmaceutically acceptable salt tion thereof. of any one of the foregoing, or any combination thereof. Stimulants and Irritants 0081. In some instances, an antihistamine includes an H3 agonist or H3 antagonist. Exemplary H3 agonists include 0086. In some instances, a pharmaceutical composition R-alpha-methylhistamine, imetit, immepip, or a pharmaceu disclosed herein comprises a stimulant agent. Exemplary tically acceptable salt of any one of the foregoing, or any stimulant agents include aminophylline, caffeine, dyphline, combination thereof. Exemplary H3 antagonists include thio oxitriphylline, theophhylline, amphetamine, benzphetamine, peramide, iodophenpropit, clobempropit, or a pharmaceuti dextroamphetamine, diethylpropion, mazindol, metham cally acceptable salt of any one of the foregoing, or any phetamine, methylphenidate, dexmethylphenidate, pemo combination thereof. line, Sibutramine, modafinil, atomoxetine, phendimetrizine, 0082 In some instances, an antihistamine includes an H4 phenteramine, adrafinil, phenylpropanolamine, pseudoephe agonist or H4 antagonist. In some instances, an antihistamine drine, Synephrine, amphetaminil, furfenorex, or a pharma includes an H4 agonists and H4 antagonists. Exemplary H4 ceutically acceptable salt of any one of the foregoing, or any agonists include clobenpropit, imetit, clozapine, or a pharma combination thereof. In some instances, pharmaceutical com ceutically acceptable salt of any one of the foregoing, or any positions can comprise a stimulant agent that provides an combination thereof. Exemplary H4 antagonists include thio anti-sedative effect. peramide or a pharmaceutically acceptable salt thereof. 0087. In some instances, a stimulant agent comprises an 0083. In some instances, an agent useful for preventing or amphetamine. Exemplary amphetamines include metham Suppressing an adverse effect includes an H1 antagonist. phetamine, levo amphetamine, dextroamphetamine, 3.5-me Exemplary H1 antagonists include azelastine, bromphe thyloxy amphetamine, 2,5-dimethoxy-4-methylthioamphet niramine, buclizine, carbinoxamine, cetrizine, chlorphe amine, 2,5-dimethoxy-4-ethylthioamphetamine, 2.5- niramine, clemastine, cyclizine, cyproheptadine, deslorati dimethoxy-4-(i)-propylthioamphetamine, 2,5-dimethoxy-4- US 2015/0290211 A1 Oct. 15, 2015 28 phenylthioamphetamine, 2,5-dimethoxy-4-(n)- Exemplary vasoconstrictors include isometheptene mucate, propylthioamphetamine, brolamfetamine, 2,5-dimethoxy-4- amphetamines, antihistamines, cocaine, caffeine, pseu iodoamphetamine, 2,5-dimethoxy-4-methylamphetamine, doephedrine, ergine, methylphenidate, psilocybin, stimulants 2,5-dimethoxy-4-butyl-amphetamine, 3,4-dimethyl-2.5 Such as amphakines (e.g., drugs effective to glutagatergic dimethoxyamphetamine, 2-phenylethylamine, propylam AMPA receptors and benzoylpiperidine derivatives) or a phetamine, methylphenidate, lisdexamfetamine, ethylam pharmaceutically acceptable salt of any one of the foregoing, phetamine, MDMA (3.4-methylenedioxy-N-methylamphet or any combination thereof. amine), MDEA (3.4-methylenedioxy-N-ethylamphetamine), PMA (p-methoxyamphetamine), DMA (2-(2,4-dimethoxy Anti-Platelet Agents phenyl)-1-methyl-ethylamine), benzphetamine, 4-FMP (para-fluoroamphetamine), or 4-MTA (4-methylthioamphet 0095. In some instances, a pharmaceutical composition amine), or a pharmaceutically acceptable salt of any one of disclosed herein comprises one or more anti-platelet agents. the foregoing, or any combination thereof. Exemplary anti-platelet agents include acetylsalycyclic acid, 0088. In some instances, a stimulant agent comprises a clopidogrel, ticlopidine, cilostazol, abciximab, eptifibatide, laxative. Exemplary laxatives include anthracenedione, triph tirofiban defibrotide, dipyridamole, or a pharmaceutically enylmethane, ricinoleic acid, or a pharmaceutically accept acceptable salt of any one of the foregoing, or any combina able salt of any one of the foregoing, or any combination tion thereof. thereof. 0089. In some instances, a stimulant comprises an Anti-Convulsants anthracenedione. Exemplary anthracenediones include dant 0096. In some instances, a pharmaceutical composition ron (1,8-dihydroxyanthraquinone), emodine (6-methyl-1,3, disclosed herein comprises one or more anti-convulsants. 8-trihydroxyanthraquinone), aloe emodin (1.8-Dihydroxy-3- Exemplary anti-convulsants include topiramate, divaprex, (hydroxymethyl)-9,10-anthracenedione), a Senna glycoside, phenobarbital, methlyphenobarbital, metharbital, barbex or a pharmaceutically acceptable salt of any one of the fore aclone, Stiripentol, clobazam, clonazepam, cloraZepate, diaz going, or any combination thereof. epam, midazolam, lorazepam, nitrazepam, temazepam, 0090. In some instances, a stimulant comprises a triph nimetazepam, potassium bromide, felbamate, carbam enylmethane. Exemplary triphenylmethanes include bisa azepine, oXcarbazepine, vigabatrin, progabide, tiagabine, codyl(4,4'-(pyridin-2-ylmethylene)bis(4,1-phenylene)diac gabapentin, pregabalin, ethotoin, phenytoin, mephenytoin, etate), phenolphthalein, or a pharmaceutically acceptable salt fosphenytoin, paramethadione, trimethadione, ethadione, of any one of the foregoing, or any combination thereof. beclaminde, primidone, brivaracetam, levetiracetam, sele tracetam, eth Suximide, phesuXimide, mesuXimide, acetazola Anti-Tussive Agents mide, Sulthiame, methazolamide, Zonisamide, lamotrigine, 0091. In some instances, a pharmaceutical composition pheneturide, phenacemide, valpromide, Valnoctamide, or a disclosed herein comprises an antitussive agent. Exemplary pharmaceutically acceptable salt of any one of the foregoing, antitussive agents include dextromethorphan, dextrorphan, or any combination thereof. noscapine, ethyl morphine, codeine, camphor, menthol, theo bromine, guaifenesin, dihydrocodein, hydrocodone, pholco Ergots dine, or a pharmaceutically acceptable salt of any one of the 0097. In some instances, a pharmaceutical composition foregoing, or any combination thereof. disclosed herein comprises one or more ergots. Exemplary ergots include ergotamine, methysergide, Zonisamide, or a Beta Blockers pharmaceutically acceptable salt of any one of the foregoing, 0092. In some instances, a pharmaceutical composition or any combination thereof. disclosed herein comprises one or more beta blockers. Exem plary beta blockers include acebutolol, arotinolol, atenolol. Calcitonin-Gene-Related Peptide (CGRP) Receptor betaxolol, bisoprolol, butoxamine, carvedilol, carteolol. Antagonists esmolol, carteolol, carvedilol, labetalol, levobunolol, mepin 0098. In some instances, a pharmaceutical composition dolol, metoprolol, nebivolol, nadolol, oXprenolol, penb disclosed herein comprises one or more calcitonin-gene-re utolol, propranolol, pindolol, Sotalol, timololora pharmaceu lated peptide (CGRP) receptor antagonists. Exemplary tically acceptable salt of any one of the foregoing, or any CGRP include MK-0974, CGRP8-37, BIBN 4096 BS, qui combination thereof. In one instance, the beta blocker can be nine, nitrobenzamide, 4-oxobutanamides, cyclopropane propranolol or a pharmaceutically acceptable salt thereof. derivatives, benzimidazolinyl piperidine, or a pharmaceuti cally acceptable salt of any one of the foregoing, or any Serotonin Receptor Agonists combination thereof. 0093. In some instances, a pharmaceutical composition disclosed herein comprises one or more serotonin receptor Laxatives agonists. Exemplary serotonin receptoragonists include bus 0099. In some instances, pharmaceutical compositions pirone, mescaline, psilocybin, cisapride, lysergic acid diethy disclosed herein comprise one or more laxatives. Exemplary lamide, or a pharmaceutically acceptable salt of any one of the laxatives include a bulk-producing agent, a stool softener, a foregoing, or any combination thereof. lubricant, a hydrating agent, a stimulant, an irritant, a seroto nin agonist, a chloride channel activator, or any combination Vasoconstrictors thereof. In some instances, the laxative comprises a bulk 0094. In some instances, a pharmaceutical composition producing agent. Exemplary bulk-producing agents include disclosed herein comprises one or more vasoconstrictors. polycarbophil calcium, methyl cellulose, a soluble dietary US 2015/0290211 A1 Oct. 15, 2015 29 fibre, an insoluble dietary fibre, or a pharmaceutically accept nations thereof. In some instances, one or more antioxidants able salt of any one of the foregoing, or any combination can be included in the liquid dosage form. In some instances, thereof. Exemplary soluble and insoluble dietary fibers antioxidants help provide long term stability to liquid com include bran, gamkaraya, Sterculia, psyllium husk, or combi positions, e.g., at ambient conditions for at least about one nations thereof. In some instances, the laxative comprises a month, at least about 3 months, at least about 24 months, or stool softener. Exemplary stool softeners include dioctyl cal longer, depending on the type and concentration of antioxi cium Sulfo Succinate (docusate calcium), dioctyl sodium Sul dant used and depending on other components of the storage foSuccinate (docusate Sodium, DSS), dioctyl potassium Sul microenvironment, Such as pH, buffering agent, etc. foSuccinate (docusate potassium), or a pharmaceutically 0102) Exemplary binders include celluloses such as acceptable salt of any one of the foregoing, or any combina hydroxypropylcellulose, methylcellulose, and hydroxypro tion thereof. In some instances, the laxative comprises a lubri pylmethylcellulose; starches such as corn starch, pregelati cant. An exemplary lubricant is mineral oil. In some nized starch, and hydroxpropyl Starch: Sugars such as glu instances, the laxative comprises a hydrating agent. Exem cose, dextrose, Sucrose, lactose and Sorbitol; alcohols such as plary hydrating agents include a saline laxative, a hyperos polyvinyl alcohol and polyethylene glycol, waxes and natural motic agent, or a pharmaceutically acceptable salt of any one and synthetic gums such as acacia, tragacanth, Sodium algi of the foregoing, or any combination thereof. Exemplary nate; synthetic polymers such as polymethacrylates and poly saline laxatives include Sodium chloride, Sodium bicarbon vinylpyrrolidone; and povidone, dextrin, pullulane, agar, ate, potassium chloride, Sodium Sulfate, Sodium phosphate, gelatin, tragacanth, macrogol, or combinations thereof. Bind potassium sodium tartrate, magnesium citrate, magnesium ers can impact cohesive qualities to a tablet formulation, or a hydroxide, magnesium Sulfate, or a pharmaceutically accept particle formulation in a capsule. Tablets can remain intact able salt of any one of the foregoing, or any combination after compression by including a binder in the pharmaceutical thereof. Exemplary hyperosmotic agents include Sorbitol, composition. lactulose, polyethylene glycol, glycerin, or a pharmaceuti 0103 Exemplary coating materials include hydroxypro cally acceptable salt of any one of the foregoing, or any pylmethyl cellulose 2910, aminoalkyl methacrylate copoly combination thereof. In some instances, the laxative com mer E. polyvinylacetal diethylaminoacetate, macrogol 6000, prises a stimulant or irritant. Exemplary stimulants or irritants titanium oxide, or combinations thereof. Exemplary plasti include an anthracenedione, a triphenylmethane, a castor oil, cizers include triethyl citrate, triacetin, macrogol 6000, or a ricinoleic acid, or a pharmaceutically acceptable salt of any combinations thereof. one of the foregoing, or any combination thereof. Exemplary 0104 Exemplary colorantagents include one or more syn anthracenediones include dantron (1,8-dihydroxyan thetic organic food additives (e.g., food dyes such as food red thraquinone), emodine (6-methyl-1,3,8-trihydroxyan dye Nos. 2 and 3, food yellow dye Nos. 4 and 5 and food blue thraquinone), aloe emodin (1.8-Dihydroxy-3-(hydroxym dye Nos. 1 and 2), water-insoluble lake dyes (e.g., aluminum ethyl)-9,10-anthracenedione), a Senna glycoside, or a salts of the above synthetic organic food additives, etc.), pharmaceutically acceptable salt of any one of the foregoing, natural pigments (e.g., beta-carotene, chlorophyll, iron oxide or any combination thereof. Exemplary triphenylmethanes red, etc.), or combinations thereof. Other suitable colorant include bisacodyl(4,4'-(pyridin-2-ylmethylene)bis(4,1-phe agents can include D&C Red No. 33, FD&C Red No. 3, nylene)diacetate), phenolphthalein, or a pharmaceutically FD&C Red No. 40, D&C Yellow No. 10, and CYellow No. 6, acceptable salt of any one of the foregoing, or any combina or any combination of these or the above colorants. A colorant tion thereof. In some instances, the laxative comprises a sero agent, when included in the liquid dosage form, can be pro tonin agonist. Exemplary serotonin agonists include tegas vided in an amount Sufficient to provide the pharmaceutical erod, cisapride, prucalopride, or a pharmaceutically compositions with a more aesthetic and/or distinctive appear acceptable salt of any one of the foregoing, or any combina aCC. tion thereof. In some instances, the laxative comprises a chlo 0105 Exemplary diluents include cellulose and cellulose ride channel activator. Exemplary chloride channel activators derivatives such as microcrystalline cellulose; starches Such include lubiprostone or a pharmaceutically acceptable salt as dry starch, hydrolyzed Starch, and starch derivatives Such thereof. In some instances, a pharmaceutical composition as corn starch; cyclodextrin; Sugars such as powdered Sugar disclosed herein includes an amount of a laxative effective in and Sugar alcohols such as lactose; D-mannitol; inorganic reducing or eliminating constipation in a Subject in need diluents such as aluminum hydroxide gel, precipitated cal thereof. cium carbonate, carbonate, magnesium aluminometasilicate, Excipients/Carriers/Additives dibasic calcium phosphate; and Sodium chloride, silicon dioxide, titanium dioxide, titanium oxide, dicalcium phos 0100. In some instances, a pharmaceutical composition phate dihydrate, calcium sulfate, alumina, kaolin, talc, or disclosed herein comprises one or more excipients, carriers, combinations thereof. Diluents, also terms “fillers', can or additives. Exemplary excipients, carriers, or additives can increase the bulk of a tablet so that a practical size is provided include antioxidant agents, binders, coating materials, colo for compression. rant agents, diluents, disintegrants, disperants, emulsifying 0106 Exemplary disintegrants include starches, alginic agents, flavoring agents, glidants, lubricants, pH modifying acid, crosslinked polymers such as, e.g., crosslinked polyvi agents (e.g., buffering agents), plasticizers, preservative nylpyrrolidone, croScarmellose sodium, potassium or sodium agents, solubilizing agents, stabilizers or stabilizing agents, starch glycolate, clays, celluloses, starches, gums, or combi Surfactants, Sweetening agents, thickening agents, orpharma nations thereof. Disintegrants can facilitate tablet disintegra ceutically inert materials. In some instances, excipients can tion after administration, or following contact with dissolu comprise nontoxic auxiliary Substances. tion fluid, or as measured in an in vitro dissolution study. 0101 Exemplary antioxidants can include flavonoids, 0107 Exemplary emulsifying agents include gelatin, egg anthocyanidins, anthocyanins, proanthocyanidins, or combi yolk, casein, cholesterol, acacia, tragacanth, chondrus, pec US 2015/0290211 A1 Oct. 15, 2015 30 tin, methyl cellulose, carbomer, cetostearyl alcohol, cetyl agents, or antimicrobial agents. Stabilizing agent(s) can be alcohol, or combinations thereof. Emulsifying agents can be included in the liquid dosage form. Thus, it should be under included in the liquid dosage form in an amount Sufficient to stood that certain solubilizing agents can function effectively facilitate more uniform dispersion of one or more active as a stabilizing agent. For example, propylene glycol can ingredients or other pharmaceutically acceptable excipient function as both a solubilizing agent and as a stabilizing that is not generally soluble in the liquid. agent. 0108 Exemplary glidants include silicon dioxide, talc, 0113 Exemplary surfactants include sucrose esters of dried aluminum hydroxide gel, magnesium silicate, or com fatty acids, polyoxyl Stearate, polyoxyethylene hydrogenated binations thereof. Exemplary lubricants include magnesium castor oil, polyoxyethylene polyoxypropylene glycol, Sorbi Stearate, calcium Stearate, Stearic acid, glyceryl behenate, tan sesquioleate, Sorbitan trioleate, Sorbitan monostearate, polyethylene glycol, talc, or combinations thereof. Lubri Sorbitan monopalmitate, Sorbitan monolaurate, polysorbate, cants can also facilitate tablet manufacture. glyceryl monostearate, Sodium lauryl Sulfate, lauromacrogol, 0109 Exemplary buffering agents include gluconate, lac or combinations thereof. Surfactants can also be anionic, tate, citrate, acetate, phosphate, benzoate, carbonate salts, or cationic, amphoteric, or nonionic. combinations thereof. The buffering agent can be present in 0114 Exemplary Sweetening agents include Sorbitol, sac an amount sufficient to buffer the pH of the solution and charin, acesulfame, e.g., acesulfame potassium, Sucralose, minimize degradation of the active ingredients. Some buffer Xylitol, maltitol. Sucrose, aspartame, fructose, neotame, glyc ing agents can also modulate active ingredient solubility in erin, sodium saccharate, glycyrrhizin dipotassium, the liquid dosage form. The pH can be adjusted with a com acesulfame K. mannitol, invert Sugar, or combinations bination of two or more of these buffering agents, e.g. citric thereof. In some instances, a Sweetening agent, such as one or acid and sodium benzoate. The buffering agent can be present more Sucralose-containing components or saccharin-contain as a buffersolution. In some instances, the buffering agent can ing components, can be added to the pharmaceutical compo include a phosphate. Such as a potassium phosphate or sition to modify the taste of the pharmaceutical composition. Sodium phosphate, or any combination thereof. In some instances, a viscous Sweetener Such as one or more of 0110 Exemplary preservative agents include sodium ben a Sorbitol Solution, a syrup (Sucrose solution), or high-fruc Zoate, paraoxybenzoic acid esters, methyl, ethyl, butyl, and tose corn syrup can increase viscosity and retard sedimenta propyl parabens, chlorobutanol, benzyl alcohol, phenylethy tion. In one instance, the Sweetening agent can include an lalcohol, dehydroacetic acid, Sorbic acid, benzalkonium chlo acesulfame-containing, Sucralose-containing, or saccharin ride (BKC), benzethonium chloride, phenol, phenylmercuric containing component. The Sweetening agent can include nitrate, thimerosal, or combinations thereof. Preservative glycerin, Saccharin, liquid Sugar (Sucrose Solution), or any agents can be included in the liquid dosage form. The preser combination thereof. In some instances, a Sweetening agent Vative agents can be in an amount Sufficient to extend the can be present in an amount Sufficient to minimize or mask shelf-life or storage stability, or both, of the liquid dosage any off-flavors in the taste of the active agents (e.g., opioid form. analgesic, non-opioid analgesic, antiemetic, laxative, barbi 0111 Exemplary solubilizing agents include an alcohol, turate, etc), and also to minimize or mask any other off-flavor e.g., 95% ethyl alcohol, a glycol, glycerin, D-mannitol, tre components included in the pharmaceutical composition. halose, benzyl benzoate, trisaminomethane, cholesterol, tri 0.115. In some instances, a Sweetening agent is present in ethanolamine, Sodium carbonate, Sodium citrate, sodium sali an amount of about 0.1 volume percent to 85 volume percent cylate, sodium acetate, or combinations thereof. Exemplary (v/v), based on the total volume of the solution. In one alcohols can include ethanol, isopropanol, t-butanol, phenol, example, the Sweetening agent is present in an amount of cresol, a benzyl alcohol, or any combination thereof. Exem about 5 volume percent to 70 volume percent (v/v), based on plary glycols include C2-20 alkenes functionalized with a the total Volume of the solution. Exemplary amounts of glyc glycol, including propylene glycol, polypropylene glycol, erin can include about 2 volume percent to 18 volume percent polyethylene glycol, etc., or any combination thereof. Solu (v/v), or about 5 volume percent to 10 volume percent (v/v). bilizing agents can be included in the liquid dosage form, e.g., Exemplary amounts of liquid Sugar can include about 40 in an amount Sufficient to facilitate greater or more rapid volume percent to 75 volume percent (v/v), or about 60 vol dissolution of one or more active ingredients or other excipi ume percent to 70 volume percent (v/v), based on the total ents. A solubilizing agent can be included in an amount of Volume of the solution. Certain types of thickening agent or about 1 volume percent to 20 volume percent (v/v), or about Sweetening agent can also act as a solubilizing agent or a 4 volume percent to 15 volume percent (v/v), based on the stabilizing agent, or both, or have other properties, when total volume of the solution. Exemplary amounts of solubi included as a component of a pharmaceutically acceptable lizing agent include about 7 volume percent to 12 Volume carrier. For example, a Sweetening agent Such as glycerin can percent (v/v) based on the total volume of the solution. also act as a thickening agent. An oral liquid dosage form can 0112 Exemplary stabilizing agents include one or more also contain, in addition to a Sweetening agent, a flavoring liquid excipients such as ethanol or glycerin; one or more agent, for example, one or more of natural and artificial fruit, glycols, such as polyethylene glycol, e.g., PEG-400, propy artificial banana, Strawberry, and pineapple. lene glycol, or polypropylene glycol; a cellulose-based com 0116 Exemplary thickening agents include acacia, alginic ponent, such as hydroxypropylmethylcellulose (HPMC) or acid bentonite, carbomer, carboxymethylcellulose calcium or hydroxymethylcellulose (HMC); or combinations thereof. Sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, Stabilizers can inhibit or retard drug decompositions reac glycerin, gelatin guar gum, hydroxyethyl cellulose, tions including oxidative reactions. A stabilizing agent can hydroxymethyl cellulose, hydroxypropyl cellulose, hydrox include any suitable monohydroxy phenol component or ypropyl methyl cellulose (“HPMC), any other suitable cel polyhydroxyphenol component, or any combination thereof. lulose-based component, maltodextrin, polyvinyl alcohol, Such stabilizing agents can also function as antioxidant poVidone, propylene carbonate, propylene glycol alginate, US 2015/0290211 A1 Oct. 15, 2015

Sodium alginate, sodium starch glycolate, starch tragacanth, pyl myristate, isopropyl palmitate, lactic acid, lactitol, lano and Xanthan gum, or combinations thereof. A thickening lin, lanolin (hydrous), lanolin alcohol, lauric acid, lecithin, agent or viscosity-enhancing agent can improve the mouth leucine, linoleic acid, magnesium aluminum silicate, magne feel of the liquid oral dosage form and/or to help coat the sium carbonate, magnesium oxide, magnesium trisilicate, lining of the gastrointestinal tract. maleic acid, malic acid, maltitol, maltitol Solution, maltodex 0117. In some instances, a thickening agentis present in an trin, maltol, maltose, medium-chain triglyceride, meglumine, amount of about 0.1 volume percent to 20 volume percent menthol, methionine, methylparaben, mineral oil, lanolin (v/v), based on the total volume of the solution. In one alcohol, monoethanolamine, monosodium glutamate, mono example, glycerin can be present in an amount of about 1 thioglycerol, myristic acid, myristyl alcohol, neohesperidin volume percent to 10 volume percent (v/v), based on the total dihydrochalcone, neotame, nitrogen, nitrous oxide, octyl Volume of the Solution. Exemplary amounts of thickening dodecanol, oleic acid, oleyl alcohol, olive oil, palmitic acid, agent can include from about 1 Volume percent to 12 Volume paraffin, peanut oil, pectin, pentetic acid, petrolatum, petro percent (v/v), or at an amount of about 4 volume percent to 10 latum alcohol, phenol, phenoxyethanol, phenylethyl alcohol, volume percent (v/v), based on the total volume of the solu phenylmercuric acetate, phenylmercuric borate, phenylmer tion. An exemplary amount can include about 6 to 10 volume curic nitrate, phospholipid, phosphoric acid, polacrilin potas percent (v/v). sium, poloxamer, polycarbophil, polydextrose, poly(dl-lactic 0118. In some instances, an excipient includes cellulose acid), polyethylene oxide, poly(methyl vinylether/maleic ethers such as hydroxypropylmethylcellulose (e.g., Methocel anhydride), polyoxyethylene alkyl ether, polyoxyethylene K4M) or silicified microcrystalline cellulose; polyvinylac Sorbitan fatty acid ester, polyoxyethylene Stearate, polyoxy etate-based excipients such as, e.g., Kollidon SR, and poly lglyceride, polyvinyl acetate phthalate, potassium alginate, mers and copolymers based on methacrylates and meth potassium alum, potassium benzoate, potassium bicarbonate, acrylic acid such as, e.g., Eudragit NE 30D; microcrystalline potassium chloride, potassium citrate, potassium hydroxide, cellulose, sodium carboxymethyl cellulose, Sodium starch potassium metabisulfite, potassium Sorbate, proanthocyani glycolate, corn starch, colloidal silica, Sodium laurel Sul din, propionic acid, propyl gallate, propylene carbonate, pro phate, magnesium stearate, Prosolve SMCC (HD90), cros pylene glycol, propylene glycolalginate, propylparaben, pro carmellose sodium, Crospovidone NF, Avicel PH200 or com pylparaben Sodium, pyrrolidone, raffinose, saccharin, binations thereof. saccharin sodium, safflower oil, Saponite, Sesame oil, shellac, 0119. In some instances, an excipient includes acesulfame simethicone, Sodium acetate, sodium ascorbate, Sodium ben potassium, glacial acetic acid, acetone, acetyltributyl citrate, Zoate, Sodium bicarbonate, sodium borate, Sodium carbonate, acetyltriethyl citrate, adipic acid, albumin, aliphatic polyes Sodium citrate dihydrate, Sodium cyclamate, sodium formal ter, alitame, almond oil, alpha tocopherol, aluminum dehyde Sulfoxylate, sodium hyaluronate, Sodium lactate, monostearate, aluminum oxide, aluminum phosphate adju Sodium metabisulfite, sodium phosphate (dibasic), sodium vant, ammonia, ammonium alginate, ammonium chloride, phosphate (monobasic), Sodium propionate, sodium sulfite, anthocyanidin, anthocyanin, ascorbic acid, ascorbyl palmi Sodium thiosulfate, Sorbic acid, Sorbitan fatty acid ester, Soy tate, aspartame, attapulgite, bentonite, benzalkonium chlo bean oil, Stearyl alcohol. Sucralose, Sucrose octaacetate, Sul ride, benzethonium chloride, benzoic acid, benzyl alcohol, fobutylether b-cyclodextrin, sulfur dioxide, sulfuric acid, benzyl benzoate, boric acid, bronopol, butylated hydroxya Sunflower oil, Suppository bases (hard fat), tagatose, tartaric nisole, butylated hydroxytoluene, butylene glycol, butylpara acid, tetrafluoroethane, thaumatin, thimerosal, thymol, treha ben, calcium acetate, calcium alginate, calcium chloride, cal lose, tributyl citrate, tricaprylin, triethanolamine, triolein, cium hydroxide, calcium lactate, calcium phosphate Vanillin, hydrogenated vegetable oil, Vitamine polyethylene (tribasic), calcium silicate, canola oil, carbomer, carbon diox glycol Succinate, water, wax (anionic emulsifying), wax ide, carboxymethylcellulose calcium, carboxymethylcellu (cetyl esters), wax (microcristalline), wax (nonionic emulsi lose Sodium, carrageenan, casein, castor oil, podere cellulose, fying), wax (white), wax (yellow), Xanthan gum, Xylitol, Zein, cellulose acetate, cellulose acetate phthalate, ceratonia, cer Zinc acetate, zinc stearate, food red dye No. 2, food red dye esin, cetostearyl alcohol, cetrimide, cetyl alcohol, cetylpyri No. 3, food yellow dye No. 4, food yellow dye No. 5, food dinium chloride, chitosan, chlorhexidine, chlorobutanol, blue dye No. 1, food blue dye No. 2, beta-carotene, chloro chlorocresol, chlorodifluoroethane, chlorofluorocarbon, phyll, iron oxide red, titanium dioxide, gluconate, lactate, chloroxylenol, cholesterol, chondrus, citric acid monohy paraoxybenzoic acid ester, phenylethylalcohol, dehydroace drate, coconut oil, copovidone, corn oil, cottonseed oil, tic acid, ethyl alcohol, trisaminomethane, Sodium salicylate, cresol, cyclomethicone, denatonium benzoate, dextrate, ethanol, isopropanol, t-butanol, polypropylene glycol, dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl hydroxymethylcellulose, acesulfame, Sodium saccharate, phthalate, difluoroethane, dimethicone, dimethyl ether, dim glycyrrhizin dipotassium, acesulfame K, or ethylcellulose. ethyl phthalate, dimethyl sulfoxide, dimethylacetamide, I0120 Examples of excipients include acacia, acesulfame disodium edetate, docusate Sodium, edetic acid, egg yolk, potassium, acetic acid (glacial), acetone, acetyltributyl cit erythorbic acid, erythritol, ethyl acetate, ethyl lactate, ethyl rate, acetyltriethylcitrate, adipic acid, agar, albumin, alcohol, maltol, ethyl oleate, ethyl Vanillin, ethylene glycol Stearate, alginic acid, aliphatic polyesters, alitame, almond oil, alpha ethylene vinyl acetate, ethylparaben, flavonoid, fructose, tocopherol, aluminum hydroxide adjuvant, aluminum fumaric acid, glycerin, glyceryl monooleate, glyceryl palmi monostearate, aluminum oxide, aluminum phosphate adju to Stearate, glycine, glycofurol, guar gum, hectorite, hep vant, ammonia Solution, ammonium alginate, ammonium tafluoropropane, hexetidine, hydrocarbon, hydrochloric acid, chloride, ascorbic acid, ascorbyl palmitate, aspartame, atta hydrophobic colloidal silica, hydroxyethyl cellulose, pulgite, bentonite, benzalkonium chloride, benzethonium hydroxyethylmethyl cellulose, hydroxypropyl betadex, chloride, benzoic acid, benzyl alcohol, benzylbenzoate, boric hydroxpropyl Starch, hypromellose acetate Succinate, imi acid, bronopol, butylated hydroxyanisole, butylated hydroxy durea, inulin, iron oxide, isomalt, isopropyl alcohol, isopro toluene, butylene glycol, butylparaben, calcium acetate, cal US 2015/0290211 A1 Oct. 15, 2015 32 cium alginate, calcium carbonate, calcium chloride, calcium polyoxylglycerides, polyvinyl acetate phthalate, polyvinyl hydroxide, calcium lactate, calcium phosphate (dibasic anhy alcohol, potassium alginate, potassium alum, potassium ben drous), calcium phosphate (dibasic dihydrate), calcium phos Zoate, potassium bicarbonate, potassium chloride, potassium phate (tribasic), calcium silicate, calcium Stearate, calcium citrate, potassium hydroxide, potassium metabisulfite, potas Sulfate, canola oil, carbomer, carbon dioxide, carboxymeth sium Sorbate, povidone, propionic acid, propyl gallate, pro ylcellulose calcium, carboxymethylcellulose Sodium, carra pylene carbonate, propylene glycol, propylene glycol algi geenan, castor oil, castor oil (hydrogenated), cellulose (mi nate, propylparaben, propylparaben Sodium, pyrrolidone, crocristalline), cellulose (microcrystalline and raffinose, Saccharin, Saccharin sodium, safflower oil, Sapo carboxymethylcellulose sodium), cellulose (podere), cellu nite, Sesame oil, shellac, simethicone, Sodium acetate, Sodium alginate, sodium ascorbate, sodium benzoate, sodium lose (silicified microcristalline), cellulose acetate, cellulose bicarbonate, sodium borate, sodium carbonate, Sodium chlo acetate phthalate, ceratonia, ceresin, cetostearyl alcohol, cet ride, Sodium citrate dihydrate, sodium cyclamate, sodium rimide, cetyl alcohol, cetylpyridinium chloride, chitosan, formaldehyde Sulfoxylate, Sodium hyaluronate, sodium chlorhexidine, chlorobutanol, chlorocresol, chlorodifluoroet hydroxide, sodium lactate, Sodium lauryl Sulfate, sodium hane (HCFC), chlorofluorocarbons (CFC), chloroxylenol, metabisulfite, sodium phosphate—dibasic, Sodium phos cholesterol, citric acid monohydrate, coconut oil, colloidal phate (monobasic), Sodium propionate, Sodium starch glyco silicon dioxide, colorant agents, copovidone, corn oil, corn late, sodium Stearyl fumarate, sodium sulfite, sodium thiosul starch and pregelatinized starch, cottonseed oil, cresol, cros fate, Sorbic acid, Sorbitan esters (sorbitan fatty acid esters), carmellose sodium (AC-Di-Sol), crospovidone, cyclodex Sorbitol, soybean oil, starch, starch (pregelatinized), starch trins, cyclomethicone, denatonium benzoate, dextrates, dex (sterilizable maize), Stearic acid, Stearyl alcohol. Sucralose, trin, dextrose, dibutyl phthalate, dibutyl sebacate, Sucrose. Sucrose octaacetate, Sugar (compressibile), Sugar diethanolamine, diethyl phthalate, difluoroethane (HFC), (confectioners), Sugar spheres, Sulfobutylether b-cyclodex dimethicone, dimethyl ether, dimethyl phthalate, dimethyl trin, Sulfur dioxide, Sulfuric acid, Sunflower oil. Suppository Sulfoxide, dimethylacetamide, disodium edetate, docusate bases (hard fat), tagatose, talc, tartaric acid, tetrafluoroethane Sodium, edetic acid, erythorbic acid, erythritol, ethyl acetate, (HFC), thaumatin, thimerosal, thymol, titanium dioxide, ethyl lactate, ethyl maltol, ethyl oleate, ethyl vanillin, ethyl tragacanth, trehalose, triacetin, tributyl citrate, tricaprylin, cellulose, ethylene glycol Stearates, ethylene vinyl acetate, triethanolamine, triethyl citrate, triolein, vanillin, vegetable ethylparaben, fructose, fumaric acid, gelatin, glucose (liq oil (hydrogenated), Vitamine polyethylene glycol Succinate, uid), glycerin, glyceryl behenate, glyceryl monooleate, glyc water, wax (anionic emulsifying), wax (carnauba), wax (cetyl eryl monostearate, glyceryl palmitostearate, glycine, glyco esters), wax (microcristalline), wax (nonionic emulsifying), furol, guar gum, hectorite, heptafluoropropane (HFC), wax (white), wax (yellow), Xanthan gum, Xylitol, Zein, Zinc hexetidine, hydrocarbons (HC), hydrochloric acid, hydro acetate, Zinc Stearate, or combinations thereof. Furthermore, phobic colloidal silica, hydroxyethyl cellulose, hydroxyeth dosage forms herein can comprise acceptable carriers or salts ylmethyl cellulose, hydroxypropyl betadex, hydroxypropyl known in the art, such as those described in the Handbook of cellulose, hydroxypropyl cellulose (low-substituted), Pharmaceutical Excipients, American Pharmaceutical Asso hydroxypropyl Starch, hypromellose, hypromellose acetate ciation (1986), incorporated by reference herein in its Succinate, hypromellose phthalate, imidurea, inulin, iron entirety. oxides, isomalt, isopropyl alcohol, isopropyl myristate, iso propyl palmitate, kaolin, lactic acid, lactitol, lactose (anhy Salts drous), lactose (inhalation), lactose (monohydrate), lactose (monohydrate and corn starch), lactose (monohydrate and 0121. In some instances, a pharmaceutical composition microcrystalline cellulose), lactose (monohydrate and povi disclosed herein comprises a pharmaceutically active agent done), lactose (monohydrate and powdered cellulose), lac that can be in the form of its free base, its pharmaceutically tose (spray-dried), lanolin, lanolin (hydrous), lanolin alco acceptable salt, prodrug, analog, or complex. Exemplary hols, lauric acid, lecithin, leucine, linoleic acid, macrogol 15 pharmaceutically acceptable salts include metal salts, such as hydroxy Stearate, magnesium aluminum silicate, magnesium Sodium salts, potassium salts, lithium salts; alkaline earth carbonate, magnesium oxide, magnesium silicate, magne metals. Such as calcium salts, magnesium salts; organic amine sium Stearate, magnesium trisilicate, maleic acid, malic acid, salts, such as triethylamine salts, pyridine salts, picoline salts, maltitol, maltitol Solution, maltodextrin, maltol, maltose, ethanolamine salts, triethanolamine salts, dicyclohexylamine mannitol, medium-chain triglycerides, meglumine, menthol, salts, N,N'-dibenzylethylenediamine salts; inorganic acid methionine, methylcellulose, methylparaben, mineral oil, salts such as hydrochloride salts, hydrobromide salts, sulfate mineral oil (light), mineral oil and lanolin alcohols, monoet salts, phosphate salts; organic acid salts such as formate salts, hanolamine, monosodium glutamate, monothioglycerol, acetate salts, trifluoroacetate salts, maleate salts, tartrate salts; myristic acid, myristyl alcohol, neohesperidin dihydrochal Sulfonate salts such as methanesulfonate salts, benzene cone, neotame, nitrogen, nitrous oxide, octyldodecanol, oleic Sulfonate salts, p-toluenesulfonate salts; and amino acid salts, acid, oleyl alcohol, olive oil, palmitic acid, paraffin, peanut Such as arginate salts, asparginate salts, glutamate salts, or oil, pectin, pentetic acid, petrolatum, petrolatum and lanolin combinations thereof. alcohols, phenol, phenoxyethanol, phenylethyl alcohol, phe 0122. In some instances, a pharmaceutically acceptable nylmercuric acetate, phenylmercuric borate, phenylmercuric salt includes bitaritrate, bitartrate hydrate, hydrochloride, nitrate, phospholipids, phosphoric acid, polacrilin potassium, p-toluenesulfonate, phosphate, Sulfate, trifluoroacetate, bitar poloxamer, polycarbophil, polydextrose, poly(dl-lactic acid), trato hemipentahydrate, pentafluoropropionate, hydrobro polyethylene glycol, polyethylene oxide, polymethacrylates, mide, mucate, oleate, phosphate dibasic, phosphate monoba poly(methyl vinylether/maleic anhydride), polyoxyethylene sic, acetate trihydrate, bis(heptafuorobutyrate), bis alkyl ethers, polyoxyethylene castor oil derivatives, polyoxy (pentafluoropropionate), bis(pyridine carboxylate), bis ethylene Sorbitan fatty acid esters, polyoxyethylene Stearates, (trifluoroacetate), chlorhydrate, sulfate pentahydrate, or US 2015/0290211 A1 Oct. 15, 2015

combinations thereof. In some instances, exemplary pharma “effective amount' when used in connection with an anti ceutically acceptable salts include, e.g., water-soluble and emetic agent is an amount that is effective for preventing or water-insoluble salts, such as the acetate, amsonate(4,4-di reducing or eliminating one or more adverse effects associ aminostilbene-2,2-disulfonate), benzenesulfonate, benzon ated with one or more pharmaceutically active agent dis ate, bicarbonate, bisulfate, bitartrate, borate, butyrate, cal closed herein. In some instances, an "effective amount” when cium edetate, camphorsulfonate, camsylate, carbonate, used in connection with an antiemetic agent is an amount that citrate, clavulariate, dihydrochloride, edetate, edisylate, esto is effective for increasing the subjects pain relief from that late, esylate, flunarate, fumarate, gluceptate, gluconate, provided by an opioid analgesic and/or an non-opioid anal glutamate, glycolylarsanilate, hexafluorophosphate, hexyl gesic. In some instances, an “effective amount' when used in resorcinate, hydrabamine, hydrobromide, hydrochloride, connection with an antiemetic agent is an amount that is hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, effective for preventing or reducing or eliminating one or laurate, malate, maleate, mandelate, mesylate, methylbro more adverse effects associated with one or more pharmaceu mide, methylnitrate, methylsulfate, mucate, napsylate, tically active agent disclosed herein and for increasing the nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2- Subject's pain relief from that provided by an opioid analgesic naphthoate, oleate, oxalate, palmitate, pamoate (1.1-meth and/or an non-opioid analgesic. ene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, 0.125. In some instances, the one or more pharmaceuti phosphate/diphosphate, picrate, polygalacturonate, propi cally active agent includes but is not limited to an opioid onate, p-toluenesulfonate, Salicylate, Stearate, Subacetate, analgesic and/or a non-opioid analgesic. In further instances, Succinate, Sulfate, or combinations thereof. In some such adverse effects which are reduced, prevented or elimi instances, a pharmaceutically acceptable salt includes bitar nated include but are not limited to incidence of nausea, trate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, Vomiting, or constipation. Furthermore, an “effective phosphate, Sulfate, trifluoroacetate orbitartratohemipentahy amount when used in connection with an antiemetic is an drate. amount that is effective for preventing or reducing the inci dence of nausea, vomiting, or constipation, or preventing or Effective Amount reducing adverse effects associated with an opioid analgesic 0123. An “effective amount” when used in connection (e.g., opioid-induced nausea, vomiting, or constipation). In with a pharmaceutical composition disclosed herein is an further instances, an "effective amount of an antiemetic is an amount Sufficient to produce a therapeutic result in a subject amount that is effective for preventing or reducing or elimi in need thereof. For example atherapeutic result can include, nating nausea or vomiting such as opioid-induced nausea or but is not limited to, treating or preventing pain, nausea, vomiting (OINV). An “effective amount” when used in con Vomiting, or constipation by a subject. An "effective amount nection with a stimulantagent is an amount that is effective to when used in connection with an opioid analgesic agent alone increase alertness, or lessen Soporific effects of an opioid or in combination is an amount that is effective for treating or agent, wherein the stimulant agent is present in a dosage preventing pain, wherein the opioid analgesic agent is pro formulation alone or in combination with one or more phar vided in combination with one or more pharmaceutically maceutically active agent disclosed herein. In some instances, active agents disclosed herein. In one instance, the one or the one or more pharmaceutically active agent includes but is more pharmaceutically active agent is an antiemetic. An not limited to an antiemetic agent and a barbiturate. An “effective amount' when used in connection with an anti “effective amount' when used in connection with a barbitu emetic agent is an amount that is effective for preventing or rate agent is an amount that is effective for treating or pre reducing or eliminating one or more adverse effects associ venting pain, producing a sedative effect, anesthetic effect or ated with one or more pharmaceutically active agent dis calming effect when provided alone or in combination with closed herein. In some instances, an "effective amount' when one or more pharmaceutically active agent disclosed herein. used in connection with an antiemetic agent is an amount that In some instances, the one or more pharmaceutically active is effective for increasing the subjects pain relief from that agent includes but is not limited to an opioid analgesic, a provided by an opioid analgesic and/or an non-opioid anal non-opioid analgesic, an antiemetic or combination thereof. An “effective amount' when used in connection with a opioid gesic. In some instances, an "effective amount' when used in antagonist agent is an amount that is effective for preventing connection with an antiemetic agent is an amount that is or inhibiting abuse of a dosage form comprising an opioid effective for preventing or reducing or eliminating one or analgesic agent, wherein the antagonist agent is provided in more adverse effects associated with one or more pharmaceu combination with one or more pharmaceutically active agent tically active agent disclosed herein and for increasing the disclosed herein. In some instances, the one or more pharma Subject’s pain relief from that provided by an opioid analgesic ceutically active agent includes but is not limited to an opioid and/or an non-opioid analgesic. agent, a non-opioid analgesic, a stimulant, a barbiturate, or 0124. An “effective amount” when used in connection any combination thereof. An “effective amount' when used in with a pharmaceutical composition disclosed herein is an connection with a laxative is an amount that is effective for amount Sufficient to produce a therapeutic result in a subject preventing, reducing, or eliminating constipation (e.g., in need thereof. For example atherapeutic result can include, but is not limited to, treating or preventing pain, nausea, opioid-induced constipation). An “effective amount' when in Vomiting, or constipation by a subject. An "effective amount used in connection with one or more of agents disclosed when used in connection with an opioid analgesic agent alone herein is the total amount of one or more of the agents that is or in combination is an amount that is effective for treating or useful for the treatment of pain. preventing pain, wherein the opioid analgesic agent is pro Pharmaceutical Compositions vided in combination with one or more pharmaceutically active agents disclosed herein. In one instance, the one or 0.126 In some instances, a pharmaceutically active agent more pharmaceutically active agent is an antiemetic. An disclosed herein is capable of use in a pharmaceutical com US 2015/0290211 A1 Oct. 15, 2015 34 position disclosed herein. A pharmaceutically active agent, non-opioid analgesic agent includes but is not limited to Such as an opioid analgesic agent, a non-opioid analgesic promethazine, dolasetron, granisetron, ondansetron, tro agent, an antitussive agent, an antiemetic agent, a stimulant, pisetron, palonosetron, domperidone, droperidol, haloperi or a barbituate, can be in the form of a pharmaceutically dol, chlorpromazine, prochloperazine, metoclopramide, acceptable salt of any one of the foregoing, or any combina alizapride, cyclizine, diphenhydramine, dimenhydrinate, tion thereof. In some instances, a pharmaceutical composi meclizine, hydroxyzine, cannabis, dronabinol, nabilone, tion comprises an analgesic agent (e.g., one analgesic or two, midazolam, lorazepam, hyoscine, dexamethasone, tri three or more analgesics) and an antiemetic agent (e.g., one, methobenzamide, emetrol, and propofol or a pharmaceuti two or more of an antiemetic) that reduces or eliminates an cally acceptable salt of any one of the foregoing, or any adverse effect of an analgesic agent. In some instances, a combination thereof. pharmaceutical composition disclosed herein comprises one 0.130. In some instances, a pharmaceutical composition or more pharmaceutically active agents herein, or a pharma disclosed herein comprises a non-opioid analgesic agent ceutically acceptable Salt herein, or any combination thereof. which is acetaminophen, ibuprofen, naproxen or flubiprofen, In some instances, a pharmaceutical composition comprises or a pharmaceutically acceptable salt of any one of the fore an effective amount of an opioid analgesic agent, an effective going, or any combination thereof. In one instance, the agent amount of non-opioid analgesic agent, an effective amount of is naproxen Sodium or magnesium. In one instance, the opioid an agent that reduces or eliminates an adverse effect of an analgesic agent is hydrocodone or oxycodone, or a pharma analgesic agent, or any combination thereof. ceutically acceptable salt thereof thiosemicarbazone, p-nitro 0127. In some instances, a pharmaceutical composition phenylhydraZone, o-methyloxime, semicarbazone, or bis(m- comprises an antiemetic and about 70% to about 80% of the ethylcarbamate) derivative, (each of the foregoing being an antiemetic dissolves in the stomach of a Subject in need opioid analgesic agent orderivative). Inafurther instance, the thereof after about 5 to about 10 minutes following oral opioid analgesic agent is hydrocodone bitartrate or oxyc administration. In one instance, about 100% of the antiemetic odone hydrochloride. dissolves in the stomach of a subject about 40, about 50 or 0131. In some instances, an opioid analgesic agent is tap about 60 minutes following oral administration. In one entadol or a pharmaceutically acceptable salt thereof. In one instance, the antiemetic is promethazine or a pharmaceuti instance, the opioid analgesic agent is tapentadol hydrochlo cally acceptable salt thereof. In another instance, the promet ride. In one instance, the opioid analgesic agent is tramadol or hazine Salt is promethazine hydrochloride (promethazine a pharmaceutically acceptable salt thereof. In one instance, HCl). In some instances, a pharmaceutical composition com the opioid analgesic agent is tramadol hydrochloride. In some prises an opioid analgesic and about 30% to about 40% of the instances, an opioid analgesic agent is a naturally occurring opioid analgesic dissolves in the stomach of a Subject in need opiate, such as an alkaloid occurring in the opium poppy. In thereof after about 5 to about 10 minutes following oral one instance, the naturally occurring opiate is morphine, administration. In one instance, about 100% of the opioid codeine, narcotine, papaverine, narceline, thebaine, or a phar analgesic dissolves in the stomach of a Subject in need thereof maceutically acceptable salt of any one of the foregoing, or about 40, about 50 or about 60 minutes following oral admin any combination thereof. istration. In one instance, the opioid analgesic is hydroc 0.132. In some instances, a pharmaceutical composition odone, oxycodone or a pharmaceutically acceptable salt of comprises an effective amount of each of an opioid analgesic, any one of the foregoing, or any combination thereof. In a non-opioid analgesic and an antiemetic, wherein the phar another instance, the hydrocodone salt is hydrocodone bitar maceutical composition is capable of providing an effective trate; or the oxycodone salt is oxycodone HC1. plasma concentration of the antiemetic prior to an effective 0128. In some instances, a pharmaceutical composition plasma concentration of the opioid and the non-opioid anal disclosed herein is administered to a subject in need thereofat gesic, post oral administration. For example, a pharmaceuti about every 4 to about 8 hours. In one instance, a pharmaceu cal composition comprising an effective amount of each of an tical composition disclosed herein is administered to a subject opioid analgesic, non-opioid analgesic, and an antiemetic— in need thereofat about every 4 to about 6 hours as needed. In provides an effective plasma concentration of the latter anti one instance, a pharmaceutical composition disclosed herein emetic earlier than the effective plasma concentration of an is administered to a subject in need thereofat about every 4 to analgesic. In one instance, a pharmaceutical composition about 8 hours. In one instance, a pharmaceutical composition comprises an effective amount of each of one or more phar disclosed herein is administered to a subject in need thereofat maceutically active agents disclosed herein. In one instance, about every 6 to about 8 hours as needed. In one instance, a the pharmaceutical composition is a bi-layer tablet compris pharmaceutical composition disclosed herein is administered ing a controlled-release layer and an immediate-release layer. to a subject in need thereofatabout every 4 hours, about every 0133. In some instances, a pharmaceutical composition 5 hours, about every 6 hours, about every 7 hours, or about comprises an opioid analgesic and one or more excipients. In every 8 hours. In one instance, a pharmaceutical composition Such instances, the opioid analgesic can comprise hydroc disclosed herein is administered once daily. In one instance, a odone, oxycodone, propoxyphene, fentanyl, acetyldihydro pharmaceutical composition disclosed herein is administered codeinone, diamorphine, codeine, pethidine, alfentanil, not more than 2-6 times daily. In another instance, a pharma codeine, hydromorphone, levorphanol, meperidine, metha ceutical composition disclosed herein is administered not done, morphine Sulfate, oxymorphone, remifentanil, Sufenta more than 4 times daily. nil, tapentadol, tramadol, or a pharmaceutically acceptable 0129. In some instances, an agent that reduces or elimi salt of any one of the foregoing, or any combination thereof. nates an adverse effect is an antiemetic agent. In further 0.134. In some instances, a pharmaceutical composition instances, the adverse effect reduced or eliminated is a non comprises an antiemetic and one or more excipients. In Such opioid analgesic. In some instances, an agent that reduces or instances, the antiemetic can comprise aprepitant, dronab eliminates an adverse effect of an opioid analgesic agent or a inol, perphenazine, palonosetron, trimethyobenzamide, US 2015/0290211 A1 Oct. 15, 2015

metoclopromide, domperidone, prochlorperazine, promet fluid described in Example 6 or as measured by any of the hazine, chlorpromazine, trimethobenzamide, ondansetron, dissolution methods as described herein. granisetron, hydroxy Zine, acetylleucine monoethanolamine, 0140. In some instances, from about 90 to about 100% of alizapride, azasetron, benzquinamide, bietanautine, bro a pharmaceutically active agent is capable of achieving dis mopride, buclizine, clebopride, cyclizine, dimenhydrinate, solution from the immediate-release layer at about 40, about diphenidol, dolasetron, meclizine, methallatal, metopi 50 or about 60 minutes following oral administration. In yet mazine, nabilone, oxyperndyl, pipamazine, Scopolamine, another instance, from about 90 to about 100% of a pharma Sulpiride, tetrahydrocannabinol, thiethylperazine, thioprop ceutically active agent is capable of achieving dissolution erazine, tropisetron, droperidol, haloperidol, prochlopera from the immediate-release layer at about 40, about 50 or Zine, metoclopramide, diphenhydramine, cannabis, mida about 60 minutes following contact with a dissolution fluid, Zolam, lorazepam, hyoscine, dexamethasone, emetrol, such as the dissolution fluid described in Example 6 or as propofol, or a pharmaceutically acceptable salt of any one of measured by any of the dissolution methods as described the foregoing, or any combination thereof. herein. 0135) In some instances, about 70 to about 80% of a phar 0.141. In some instances, immediate-release results in dis maceutically active agent is capable of achieving dissolution Solution of an active agent within 1-20 minutes after entering from an immediate-release layer at about 5 to about 10 min the stomach and/or intestine. In some instances, dissolution utes following oral administration. In another instance, about can be of all or less than the entire amount of the active agent. 70 to about 80% of a pharmaceutically active agent is capable For example, dissolution of 100% of an active agent (for of achieving dissolution from the immediate-release layer at example, an antiemetic) can occur in the prescribed time. In about 5 to about 10 minutes following contact with a disso Some instances, dissolution of less than all of the active agent lution fluid, such as the dissolution fluid described in can occur in about 1 to about 20 minutes (e.g., dissolution of Example 6 or as measured by any of the dissolution methods about 70%, about 75%, about 80%, about 85%, about 90%, as described herein. about 91%, about 92%, about 93%, about 94%, about 95%, 0136. In some instances, about 100% of a pharmaceuti about 96%, about 97%, about 98%, about 99%, about 99.5% cally active agent is capable of achieving dissolution from the or 99.9% of an agent). In some instances, immediate-release immediate-release layer at about 40 minutes following oral occurs when there is dissolution of an agent within 1-20 administration. In another instance, about 100% to of a phar minutes after oral administration. In another instance, imme maceutically active agent is capable of achieving dissolution diate-release results in Substantially complete dissolution from the immediate-release layer at about 40 minutes follow within about 1 hour following oral administration to a subject ing contact with a dissolution fluid, Such as the dissolution in need thereof. In one instance, a pharmaceutical composi fluid described in Example 6 or as measured by any of the tion disclosed herein can be capable of providing about 80% dissolution methods as described herein. dissolution of an antiemetic in about 5 minutes (e.g., FIG. 1). 0.137 In some instances, about 30 to about 40% of a phar In another instance, immediate-release results in complete or maceutically active agent is capable of achieving dissolution less than complete dissolution within about 1 hour following from the controlled-release layer at about 5 to about 10 min rectal administration to a subject in need thereof. utes following oral administration. In another instance, about 0142. In some instances, immediate-release is through 30% to about 40% of a pharmaceutically active agent is inhalation, Such that dissolution occurs in a Subject’s lungs, as capable of achieving dissolution from the controlled-release further described herein. Dissolution of less than all of an layer at about 5 to about 10 minutes following contact with a active includes but is not limited to dissolution of about 50%, dissolution fluid, such as the dissolution fluid described in 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.1%, Example 6 or as measured by any of the dissolution methods 99.2%, 99.35, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or as described herein. 99.99% of the active agent. Methods for measuring dissolu 0138. In some instances, controlled-release includes dis tion profiles are described herein (e.g., Example 6, infra). solution of about 40% to about 50% of an active agent by 10 0143. In some instances, a pharmaceutical composition is minutes after administration, or following contact with dis in the form of any oral dosage form disclosed herein, includ Solution fluid, or as measured in an in vitro dissolution study. ing but not limited to a pill, tablet, or capsule. In one instance, In one embodiment, controlled-release is dissolution of about the pharmaceutical composition is in the form of a bi-layer 60% of an active agent by 20 minutes after administration, or tablet having an immediate-release layer and a controlled following contact with dissolution fluid, or as measured in an release layer, wherein one or more pharmaceutically active in vitro dissolution study. In one embodiment, controlled agents are present in the immediate-release layer and one or release is dissolution of about 70% to about 80% of an active more pharmaceutically active agents are present in the con agent by 30 minutes after administration, or following contact trolled-release layer. In another instance, the immediate-re with dissolution fluid, or as measured in an in vitro dissolu lease layer comprises one or more antiemetics, and the con tion study. In one embodiment, controlled-release is dissolu trolled-release layer comprises one or more pharmaceutically tion of about 80% to about 100% of an active agent by 60 active agents disclosed herein, but which are not an anti minutes after administration, or following contact with dis emetic. In a further instance, an antiemetic is present in both Solution fluid, or as measured in an in vitro dissolution study. the immediate-release and controlled-release layer. In 0.139. In some instances, about 90% of a pharmaceutically another instance, the immediate-release layer comprises active agent is capable of achieving dissolution from the promethazine or a pharmaceutically acceptable salt thereof. controlled-release layer at about 60 minutes following oral In another instance, the promethazine salt is promethazine administration. In another instance, about 90% of a pharma HC1. In another instance, the controlled-release layer com ceutically active agent is capable of achieving dissolution prises an opioid analgesic. In a further instance, the opioid from the controlled-release layer at about 60 minutes follow analgesic is hydrocodone or oxycodone, or a pharmaceuti ing contact with a dissolution fluid, Such as the dissolution cally acceptable salt of any one of the foregoing, or any US 2015/0290211 A1 Oct. 15, 2015 36 combination thereof. In one instance, the hydrocodone salt is which reduces or eliminates an adverse effect of an opioid hydrocodone bitartrate. In another instance, the oxycodone analgesic; and (b) a controlled-release layer that comprises an salt is oxycodone HC1. In a further instance, the controlled effective amount of each of an opioid analgesic agent and a release layer further comprises one or more non-opioid anal non-opioid analgesic agent. In one instance, the multi-layer gesic. In one instance, the non-opioid analgesic is acetami tablet is a two layer tablet that comprises: (a) an immediate nophen or a pharmaceutically acceptable salt thereof. In one release layer that comprises an effective amount of an agent instance, the pharmaceutical composition is in a form that which reduces or eliminates an adverse effect of an opioid achieves a hardness of from about 5 to about 15 kiloponds and analgesic; and (b) a controlled-release layer that comprises an has a thickness of about 5, about 5.5, about 6, about 6.5, about effective amount of each of an opioid analgesic agent and a 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or 10 mm. non-opioid analgesic agent. In one instance, the pharmaceutical composition is in a form 0.148. In one instance, an agent that reduces or eliminates that achieves a hardness of from about 5 to about 30 kiloponds an adverse effect associated with administration of an opioid and has a thickness of about 5, about 5.5, about 6, about 6.5, or non-opioid analgesic agent is released in a Subject in need about 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or 10 thereof at a substantially faster rate than an opioid or non mm. In one instance, the tablet has a hardness of about 12.5 opioid analgesic in a pharmaceutical composition disclosed kiloponds. In one instance, the tablet has a hardness of about herein. For example, in one instance, a plasma concentration 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, of the agent that reduces or eliminates an adverse effect of an 27, 28, 29, or 30 kiloponds. In another instance, the tablet has opioid analgesic is achieved in about 1 to about 20 minutes a hardness of about 12.5 kiloponds. It would be understood following oral administration, as compared with a plasma that as to the kilopond and thickness measurements, incre concentration of an analgesic agent, which can be achieved in ments of 0.1 decimal points are within the scope of the dis about 30 minutes to about 8 hours following oral administra closure. tion. In some instances, the pharmaceutical compositions 0144. In some instances, a pharmaceutical composition is herein comprise an agent that reduces or eliminates an capable of providing an effective plasma concentration of an adverse effect associated with administration of an opioid antiemetic in about 1 to about 20 minutes after administration analgesic or non-opioid analgesic, where the agent provides to a subject in need thereof. In another instance, the anti an effective plasma concentration in about 1 to about 20 emetic is promethazine or a pharmaceutically acceptable salt minutes following oral administration. thereof. In a further instance, the salt is promethazine HC1. In 0149. In some instances, a pharmaceutical composition some instances, a pharmaceutical composition comprises comprises an effective amount of an opioid analgesic agent, a from about 1 to about 20% by weight of an antiemetic; from non-opioid analgesic agent, and an agent that reduces or about 10 to about 80% by weight a non-opioid analgesic; and eliminates an adverse effect associated with administration of from about 1 to about 20% by weight of an opioid analgesic. the opioid or non-opioid analgesic. An adverse effect of 0145. In some instances, a method is provided for reduc opioid or non-opioid analgesic agents includes but is not ing or eliminating an adverse effect of an analgesic agent, limited to nausea, vomiting, constipation, other gastric upset, comprising administering to a Subject in need thereof an skin rash, an allergic reaction Such as Swelling, difficulty pharmaceutical composition comprising an effective amount breathing, closing of throat, abdominal pain, unusual bleed of each of an opioid analgesic agent, a non-opioid analgesic ing or bruising, sedation, CNS depression, or respiratory agent and an agent which reduces or eliminates an adverse depression. In one instance, the adverse effect that is reduced effect of the analgesic agents. In some instances, a method is or eliminated is nausea, vomiting, constipation, or any com provided for treating or preventing pain, comprising admin bination thereof. In some instances, an agent that reduces or istering to a Subject in need thereof an effective amount of a eliminates an adverse effect associated with an opioid or a pharmaceutical composition comprising an effective amount non-opioid analgesic is an antiemetic. In some instances, an of each of an opioid analgesic, or a pharmaceutically accept opioid analgesic agent is, for example, hydrocodone, oxyc able salt thereof, a non-opioid analgesic, or a pharmaceuti odone propoxyphene, or fentanyl, or a pharmaceutically cally acceptable salt thereof, and an agent which reduces an acceptable salt of any one of the foregoing, or any combina adverse effect associated with the opioid or non-opioid anal tion thereof the non-opioid analgesic agent is, for example, gesic agent. In one instance, the agent that reduces an adverse acetaminophen, ibuprofen, ketaprofen, naproxen, or acetyl effect is an antiemetic. salicylic acid or a pharmaceutically acceptable salt of any one 0146 In some instances, an agent useful for reducing or of the foregoing, or any combination thereof, and the agent eliminating an adverse effect associated with administration useful for preventing and/or suppressing an adverse effect is, of an opioid or non-opioid analgesic agent, is promethazine, for example, an antiemetic Such as promethazine or a phar dolasetron, granisetron, ondansetron, tropisetron, pal maceutically acceptable salt thereof. In one instance, the onosetron, domperidone, droperidol, haloperidol, chlorpro pharmaceutically acceptable salt of naproxen is naproxen mazine, prochloperazine, metoclopramide, alizapride, Sodium. cyclizine, diphenhydramine, dimenhydrinate, meclizine, 0150. In some instances, an opioid analgesic agent, a non hydroxy Zine, cannabis, dronabinol, nabilone, midazolam, opioid analgesic agent and an agent that reduces or eliminates lorazepam, hyoscine, dexamethasone, trimethobenzamide, an adverse effect are formulated in a bi-layer tablet. In one emetrol, or propofol, or pharmaceutically acceptable salt of instance, an opioid analgesic agent, a non-opioid analgesic any one of the foregoing, or any combination thereof. agent and an agent that reduces or eliminates an adverse effect 0147 A pharmaceutical composition can be in any form are formulated in a two layer tablet. In one instance, the disclosed herein, such as a multi-layer tablet (e.g., a bi-layer bi-layer tablet comprises an immediate-release layer and a tablet or a two layer tablet). In one instance, the multi-layer controlled-release layer. In another instance, the immediate tablet is a bi-layer tablet that comprises: (a) an immediate release layer comprises one or more pharmaceutically active release layer that comprises an effective amount of an agent agent disclosed herein and the controlled-release layer com US 2015/0290211 A1 Oct. 15, 2015 37 prises one or more pharmaceutically active agents disclosed analgesic agent. Therefore, in one instance, after administra herein. In some instances, the immediate-release layer com tion to a subject, the antiemetic is released or an effective prises an antiemetic and the controlled-release layer com plasma concentration of an antiemetic is achieved before the prises an opioid analgesic, a barbiturate, a stimulant, or any analgesic agent is released or an effective plasma concentra combination thereof. tion of the analgesic agent is achieved. The analgesic agent 0151. In some instances, a pharmaceutical composition can be an opioid analgesic or said non-opioid analgesic. In comprises an effective amount of each of an analgesic agent, Some instances, the dosage form provides an effective plasma an antitussive agent, and an agent that reduces or eliminates concentration of the antiemetic at from about 1 to about 20 an adverse effect of the analgesic agent or the antitussive minutes after administration, such as about 1 min, 2 min, 3 agent. In some in stances, the antitussive is also an analgesic. min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, In some instances, a pharmaceutical composition comprises 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 acetaminophen, hydrocodone or oxycodone, or a pharmaceu min, 20 min, 21 min, 22 min, 23 min, 24 min, or 25 min tically acceptable salt of any one of the foregoing, or any following administration. In some instances, the dosage form combination thereof, and an antitussive agent such as dolas provides an effective plasma concentration of the opioid anal etron, domperidone, meclizine, dronabinol, a benzodiaz gesic or the non-opioid analgesic at from about 20 minutes to epine, an anticholinergic, hydrocodone or oxycodone, or a about 8 hours after administration, such as about 20 minutes, pharmaceutically acceptable salt of any one of the foregoing, 30 minutes, 40 minutes, 50 minutes, 1 hr, 1.2 hrs, 1.4 hrs, 1.6 or any combination thereof. hrs, 1.8 hrs, 2 hrs, 2.2 hrs, 2.4 hrs, 2.6 hrs, 2.8 hrs, 3 hrs, 3.2 0152. In some instances, an opioid analgesic agent is, for hrs, 3.4 hrs, 3.6 hrs, 3.8 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, or 8 hrs example, hydrocodone, or oxycodone or a pharmaceutically following administration. acceptable salt of any one of the foregoing, or any combina 0157. In some instances, a pharmaceutical composition tion thereof the non-opioid analgesic agent is, for example, comprises an effective amount of each of an opioid analgesic, acetaminophen, ibuprofen, ketoprofen, naproxen, lidocaine, a non-opioid analgesic agent, an antihistamine, anti-psy or acetylsalicylic acid, or a pharmaceutically acceptable salt chotic, anti-anxiety agent, or other CNS depressant is admin of any one of the foregoing, or any combination thereof; the istered a reduced dosage of one or lessen and adverse effect antiemetic agent is, for example a 5-HT receptor antagonist, (e.g. CNS depression). In another instance, the dosage of one a dopamine antagonist, an antihistamine, a cannabinoid, a or more of pharmaceutically active agents is adjusted accord benzodiazepine, an anticholinergic, wherein all or less than ing to the severity of the pain and the response of the Subject. all of the total amount of the antiemetic agent is formulated 0158. In one instance, a pharmaceutical composition com for immediate-release. prises: hydrocodone, oxycodone, or a pharmaceutically 0153. Another instance is directed to a method for the acceptable salt of any one of the foregoing, or any combina treatment of pain, comprising administering an effective tion thereof, in a dosage range of from about 1.0 to about 200 amount of each of an opioid analgesic agent, a non-opioid mg; acetaminophen or a pharmaceutically acceptable salt analgesic agent and an agent that reduces or eliminates an thereof in a dosage range of from about 200 to about 1000 mg: adverse effect of the opioid analgesic agent to a Subject in and, promethazine or a pharmaceutically acceptable salt need thereof. thereof in a dosage range of from about 0.5 to about 100 mg. 0154. In some instances, a method allows for use of an In one instance, a pharmaceutical composition comprises: analgesic in populations at risk of adverse effects such as oxycodone or a pharmaceutically acceptable salt thereof in a nausea, vomiting, constipation, other gastric upsets, skin dosage range of from about 10 to about 80 mg; Naltrexone or rashes, allergic reactions such as Swelling, difficulty breath a pharmaceutically acceptable salt thereof in a dosage range ing, closing of throat, abdominal pain, unusual bleeding or of from about 0.5 to about 0.75 mg; and, promethazine or a bruising, skin rashes, sedation, CNS depression, or respira pharmaceutically acceptable salt thereof in a dosage range of tory depression. from about 12.5 to about 50 mg. In one instance, a pharma 0155. In some instances, a pharmaceutical composition ceutical composition comprises: oxycodone or a pharmaceu disclosed herein comprises an effective amount of each of an tically acceptable salt thereof in a dosage range of from about opioid analgesic, an antiemetic, and an opioidantagonist, and 10 to about 80 mg; and promethazine or a pharmaceutically is capable of providing protection from a metabolic conse acceptable salt thereof in a dosage range of from about 12.5 to quence of vomiting, particularly severe Vomiting, in a subject about 50 mg. Pharmaceutical composition disclosed herein in need thereof particularly prone to adverse effects associ can beformulated using conventional technologies to provide ated with an opioid analgesic. An example of metabolic con for a controlled release over a desired dosage interval, Such as sequence of vomiting is dehydration. In a further instance, the about 4 to 8 hours, e.g., about 4 hours, 5 hours, 6 hours, 7 Subject administered a pharmaceutical composition disclosed hours, 8 hours, hours. In another instance, the pharmaceutical herein is about 55 years of age or older, about 60 years of age compositions comprise about 7.5 mg of hydrocodone or a or older, about 65 years of age or older, or about 70 years of pharmaceutically acceptable salt thereof, about 325 mg of age or older. In one instance, the pharmaceutical composition acetaminophen or a pharmaceutically acceptable salt thereof, administered to such a subject comprises an opioid analgesic and about 12.5 mg of promethazine or a pharmaceutically and one or more antiemetic agent. In one instance, the phar acceptable Salt thereof. In another instance, the pharmaceu maceutical composition comprises oxycodone, promethaZ tical compositions comprise about 5 mg of hydrocodone or a ine, and naltrexone, or a pharmaceutically acceptable salt of pharmaceutically acceptable salt thereof, about 325 mg of any one of the foregoing, or any combination thereof. acetaminophen or a pharmaceutically acceptable salt thereof, 0156. In some instances, a dosage form comprising an and about 12.5 mg of promethazine or a pharmaceutically antiemetic and an analgesic agent provides an effective acceptable Salt thereof. In another instance, the pharmaceu plasma concentration of the antiemetic at a substantially tical compositions comprise about 10 mg of hydrocodone or faster release rate as compared with the release rate for the a pharmaceutically acceptable salt thereof, about 325 mg of US 2015/0290211 A1 Oct. 15, 2015

acetaminophen or a pharmaceutically acceptable salt thereof, 939: 4,950,484; gel forms disclosed in U.S. Pat. Nos. 4,904, and about 12.5 mg or 25 mg of promethazine or a pharma 479; 6,482.435; 6,572,871:5,013,726: patches for delivery of ceutically acceptable salt thereof. In one instance, a pharma pharmaceutical compositions such as those disclosed in U.S. ceutical composition comprises about 7.5 mg of oxycodone Pat. Nos. 5,741,510; 4,624,665; 4,626,539; 4,834,978; 6,469, or a pharmaceutically acceptable salt thereof, about 325 mg 227: 5,919,479; 6,261,595; 6,303,142; 6,341,387; 6,465,006; of acetaminophen or a pharmaceutically acceptable salt 6,613.350; 6,780,426; 7,094.228; 6.756,053; capsule forms thereof, and about 12.5 mg or 25 mg of promethazine or a disclosed in U.S. Pat. Nos. 4,800,083; 4,532,126; 4,935,243: pharmaceutically acceptable salt thereof. 6.258.380; liquid forms disclosed in U.S. Pat. Nos. 4,625, 0159. In one instance, a pharmaceutical composition com 494; 4,478,822; 5,610, 184; or I.V. forms disclosed in U.S. prises an effective amount of hydrocodone or oxycodone or a Pat. Nos. 4,871,353: 4,925,444; 5,484,406; each of which is pharmaceutically acceptable salt thereof an effective amount incorporated herein by reference in its entirety. of acetaminophen or a pharmaceutically acceptable salt 0163. In some instances, a pharmaceutical composition thereof, and an effective amount of promethazine or a phar comprises an antiemetic in an amount capable of achieving a maceutically acceptable salt thereof, combined in a single, serum level C of from about 0.2 ng/mL to about 1 ng/mL oral pill, or tablet or lollipop, form having dosage levels that at a T of from about 1 to about 6 hours following oral can be safely doubled for combating severe pain. administration. In some instances, the antiemetic is promet 0160. In a one instance, all or less than the entire total hazine or a pharmaceutically acceptable salt thereof. In amount of the promethazine or a pharmaceutically acceptable another instance, the pharmaceutically acceptable salt is salt thereof is formulated for immediate-release into the sub promethazine HC1. In a further instance, the pharmaceutical jects blood stream. In a further instance, all or less than the composition is a bi-layer tablet that has an immediate-release entire amount of the hydrocodone or oxycodone, or a phar layer and a controlled-release layer. In yet a further instance, maceutically acceptable Salt of any one of the foregoing, or the controlled-release layer comprises an opioid analgesic any combination thereof is formulated for controlled-release agent or a non-opioid analgesic agent. In a further instance, into the Subject's body. In some instances, an agent is formu the immediate-release layer comprises promethazine or a lated as a dosage form (e.g., tablet, capsule, gel, lollipop), pharmaceutically acceptable salt thereof. parenteral, intraspinal infusion, inhalation, nasal spray, trans 0164. In some instances, a pharmaceutical composition dermal patch, iontophoresis transport, absorbing gel, liquid, comprises promethazine or a pharmaceutically acceptable liquid tannate, Suppositories, injection, I.V. drip, otherformu salt thereof in an amount capable of achieving a serum level lation, or any combination thereof to treat subjects. In some C of about 0.46 ng/mL at a T of about 2 to about 3 hours instances, an agent is formulated as single oral dosage form following oral administration. In some instances, the promet Such as a tablet, capsule, cachet, soft gelatin capsule, hard hazine or a pharmaceutically acceptable salt is at a dose by gelatin capsule, extended release capsule, tannate tablet, oral weight in the pharmaceutical composition of about 10 to disintegrating tablet, multi-layer tablet, effervescent tablet, about 15 mg. In another instance, the promethazine or phar bead, liquid, oral Suspension, chewable lozenge, oral solu maceutically acceptable salt is at a dose (by weight in the tion, lozenge, lollipop, oral syrup, Sterile packaged powder pharmaceutical composition) of about 12.5 mg. In a further including pharmaceutically-acceptable excipients, other oral instance, the pharmaceutical composition is in the form of a dosage forms, or any combination thereof. In some instances, bi-layer tablet that has an immediate-release layer and a con a pharmaceutical composition is a Solid composition. In some trolled-release layer. In some instances, the promethazine or instances, the pharmaceutical composition is a liquid compo a pharmaceutically acceptable salt is the only pharmaceuti sition. In some instances, the pharmaceutical composition is cally active agent in the immediate-release layer of a bi-layer formulated as a patch. In another instance, a pharmaceutical tabletherein. In one instance, the promethazine is promethaZ composition disclosed herein comprises one or more further ine HC1. In yet a further instance, the controlled-release layer agents in immediate-release, controlled-release, other release comprises an opioid analgesic agent or a non-opioid analge formulations or patterns, or any combination thereof. sic agent. In some instances, the opioid analgesic is the only 0161 In one instance, a pharmaceutical composition dis pharmaceutically active agent in the controlled-release layer closed herein comprises three active agents, such as a decon of a bi-layer tablet, non-opioid analgesic is the only pharma gestant, an antitussive, an expectorant, a mucus-thinning ceutically active agent in the controlled-release layer of a drug, an analgesic or an antiemetic. For example, in one bi-layer tablet or both the opioid analgesic and non-opioid instance one of the agents is an antitussive or a pharmaceuti analgesic are the only pharmaceutically active agents of the cally acceptable salt thereof; the other agent is a decongestant pharmaceutical composition. Such as, e.g., phenylephrine, pseudoephedrine, or a pharma 0.165 An aspect of the disclosure provides a pharmaceu ceutically acceptable salt thereof, and the other agent is an tical composition, wherein the pharmaceutical composition expectorant. One would recognize that an active agent can fit can comprise an effective amount of i) one or more opioid into more than one category (e.g., hydrocodone is an antitus analgesics wherein the one or more opioid analgesics are sive and opioid analgesic). selected from the group consisting of hydrocodone, oxyc 0162. In any of the instances disclosed herein, a pharma odone, oripavine, dihydromorphine, hydromorphinol, nico ceutical composition disclosed herein can be administered morphine, dipropanoylmorphine, diacetyldihydromorphine, using one or more different dosage forms which are further desomorphine, methyldesorphine, heterocodeine, benzyl described herein. For example, a pharmaceutical composition morphine, dihydroheterocodeine, myrophine, pentamor comprising multiple active agents can be administered in phone, etorphine, acetyldihydrocodeine, nicocodeine, Solid, semi-solid, micro-emulsion, gel, patch or liquid form. nicodicodeine, alphamethylfentanyl, carfentanil, parafluoro Such dosage forms are further described herein. Examples of fentanyl, thiofentanyl, anileridine, benzethidine, difenoxin, Such dosage forms are known, such as tablet forms disclosed diphenoxylate, etoxeridine, furethidine, morpheridine, phen in U.S. Pat. Nos. 3,048,526; 3,108,046; 4,786,505; 4,919, eridine, phenoperidine, piminodine, allylprodine, loperam US 2015/0290211 A1 Oct. 15, 2015 39 ide, dextropropoxyphene, dihydroetorphine, acetorphine, about 340 mg, about 340 mg to about 345 mg, about 345 mg levophenacylmorphan, phenomorphan, drotebanol, dipi to about 350 mg, about 325 mg to about 350 mg, about 350 panone, normethadone, phenadoxone, dimepheptanol, mg to about 400 mg, about 400 mg to about 1000 mg. or any levacetylmethadol, dextromoramide, diethylthiambutene, combination thereof. dimethylthiambutene, ethylmethylthiambutene, dextropro poxyphene, dimenoxadol, tilidine, ethoheptazine, prohep In one aspect of the disclosure, a pharmaceutical composition tazine, piritramide, etonitaZene, tapentadol, tramadol, a phar disclosed herein comprises two or more of the antiemetics. In maceutically acceptable salt of each of the foregoing, and any Some instances, the two or more of the antiemetics comprises combination thereof, and ii) one or more antiemetics; and iii) promethazine or a pharmaceutically acceptable salt thereof a pharmaceutically acceptable carrier or vehicle. and ondansetron or a pharmaceutically acceptable salt thereof. Another aspect of the disclosure provides for a phar 0166 In one aspect, the one or more antiemetics can com maceutical composition, wherein the pharmaceutical compo prise promethazine, aprepitant, dronabinol, perphenazine, sition comprises a stimulant disclosed herein. In some palonosetron, trimethyobenzamide, metoclopromide, domp instances, the stimulant comprises an amphetamine, a laxa eridone, prochlorperazine, chlorpromazine, trimethobenza tive, an agent that produces an anti-sedative effect, or a phar mide, ondansetron, granisetron, hydroxy Zine, acetylleucine maceutically acceptable salt of any one of the foregoing, or monoethanolamine, alizapride, azasetron, benzquinamide, any combination thereof. Another aspect of the disclosure bietanautine, bromopride, buclizine, clebopride, cyclizine, provides for a pharmaceutical composition, wherein the phar dimenhydrinate, diphenidol, dolasetron, meclizine, methal latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco maceutical composition comprises an opioidantagonist oran polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, abuse deterrent agent herein. Another aspect of the disclosure thioproperazine, tropisetron, droperidol, haloperidol. provides for a pharmaceutical composition, wherein the phar prochloperazine, metoclopramide, diphenhydramine, can maceutical composition comprises one or more controlled nabis, midazolam, lorazepam, hyoscine, dexamethasone, release dosage forms, one or more immediate-release forms, emetrol, propofol, or a pharmaceutically acceptable salt of or any combination thereof. any one of the foregoing, or any combination thereof. 0169. In a further aspect, the pharmaceutical composition 0167. In one aspect, the one or more antiemetics can com is formulated as a tablet, capsule, or lollipop. In some prise promethazine or a pharmaceutically acceptable salt instances, the pharmaceutical composition formulated as the thereof. In some instances, the one or more opioid analgesics tablet can be a bi-layer tablet, two layer tablet, a multi-layer can comprise hydrocodone, Oxycodone, or a pharmaceuti tablet, a tannate tablet, an oral disintegrating tablet, an effer cally acceptable salt thereof and the one or more antiemetics Vescent tablet, or any combination thereof. In some instances, can comprise promethazine or a pharmaceutically acceptable the pharmaceutical composition formulated as the capsule is salt thereofandondansetronora pharmaceutically acceptable a soft gelatin capsule or a hard gelatin capsule. In some salt thereof. instances, the capsule can have micro drilled holes. In a 0168 In some instances, a pharmaceutical composition further aspect, the tablet is a controlled-release layer and an disclosed hereincomprises from about 6.5 mg to about 8.5 mg immediate-release layer. In some instances, the tablet is a of the hydrocodone, oxycodone, or a pharmaceutically controlled-release layer comprising the one or more opioid acceptable salt of any one of the foregoing, or any combina analgesics and an immediate-release layer comprising the tion thereof and can comprise from about 11 mg to about 14 one or more antiemetics. In some instances, the one or more mg of the promethazine or a pharmaceutically acceptable salt controlled-release dosage forms comprises an enteric coat thereof. In some instances, a pharmaceutical composition ing, a particulate, a powder, a multi-layer, or any combination disclosed herein further comprises one or more non-opioid thereof. In some instances, the capsule can be formulated analgesics. In some instances, the one or more non-opioid with a controlled-release enteric coating. In some instances, analgesics comprises a non-steroidal anti-inflammatory the capsule is formulated with an immediate-release powder. agent, a cox-2 inhibitor, a local analgesic, an anti-depressant, In some instances, the tablet can be formulated with a con an atypical analgesic, a psychotropic agent, an NMDA recep trolled-release enteric coating. In some instances, the capsule tor, an alpha2-adrenoreceptor agonist, a synthetic drug hav is formulated with one or more controlled-release particu ing narcotic properties, or a pharmaceutically acceptable salt lates. In some instances, the particulate is a bead, a sphere, or of any one of the foregoing, or any combination thereof. In a pellet. In some instances, the tablet or capsule comprises an Some instances, the one or more non-opioid analgesics com inner dosage and an outer dosage, the latter being in the form prises acetaminophen, acetylsalicylic acid, amoxiprin, beno of an envelope over the former. In some instances, the inner rilate, choline magnesium salicylate, diflunisal, faislamine, dosage and outer dosage components is separated by an methyl salicylate, magnesium salicylate, diclofenac, ace enteric layer. clofenac, acemetacin, bromfenac, etodolac, indometacin, 0170 Another aspect of the disclosure provides for a phar nabumetone, Sulindac, tolmetin, ibuprofen, carprofen, fen maceutical composition, wherein the pharmaceutical compo buprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, sition comprises one or more excipients herein. In some naproxen, Suprofen, mefenamic acid, meclofenamic acid, instances, the one or more excipients can comprise an anti piroXicam, lomoxicam, meloxicam, tenoxicam, phenylbuta oxidant agent, a binder, a coating material, a colorant agent, a Zone, azapropaZone, metamizole, oxyphenbutaZone, Sulfin diluent, a disintegrant, a disperant, an emulsifying agent, a praZone, or a pharmaceutically acceptable salt of any one of flavoring agent, a glidant, a lubricant, a pH modifying agent, the foregoing, or any combination thereof. In some instances, a plasticizer, a preservative agent, a solubilizing agent, a the one or more non-opioid analgesics is present in an amount stabilizer, a Surfactant, a Sweetening agent, a thickening of about 200 mg to about 600 mg, about 200 mg to about 1000 agent, a pharmaceutically inert material, or a pharmaceuti mg, about 200 mg to about 325 mg, about 325 mg to about cally acceptable salt of any one of the foregoing, or any 330 mg, about 330 mg to about 335 mg, about 335 mg to combination thereof. US 2015/0290211 A1 Oct. 15, 2015 40

0171 Another aspect of the disclosure provides that when 110-120 minutes shorter, than a corresponding standard-re a pharmaceutical composition is administered to a mammal, lease antiemetic, e.g., in median times. In some instances, one or more opioid analgesics have a Tmax that is about when the pharmaceutical composition is administered to a 1.4-2.0 hours, e.g., about: 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, mammal, the one or more antiemetics have a Tmax that is 1.75, 1.8, 1.85, 1.9, 1.95, or 2 hours. In some instances, the about: 30,35, 40, 45, 50,55, 60, 65,70, 75,80, 85,90, 95, 100, Tmax is about 1.7 hours. Another aspect of the disclosure 105, 110, 115, or 120 minutes shorter than a corresponding provides that when a pharmaceutical composition is admin standard-release antiemetic, e.g., in median times. In some istered to a mammal, one or more opioid analgesics have a instances, when the pharmaceutical composition is adminis Tmax that is about 5-60 minutes longer, e.g., about 10-30 minutes longer or about 5-10 minutes longer, than a corre tered to a mammal, the one or more antiemetics have a Tmax sponding standard-release opioid analgesic, e.g., in mean or that is about: 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 median times. In some instances, when the pharmaceutical minutes shorter than a corresponding standard-release anti composition is administered to a mammal, the one or more emetic, e.g., in median times. In some instances, when the opioid analgesics have a Tmax that is about: 5-10 minutes, pharmaceutical composition is administered to a mammal, 10-20 minutes, 20-30 minutes, 30-40 minutes, 40-50 min the one or more antiemetics have a Tmax that is about 75 utes, or 50-60 minutes longer than a corresponding standard minutes shorter than a corresponding standard-release anti release opioid analgesic, e.g., in mean or median times. In emetic, e.g., in median times. Some instances, when the pharmaceutical composition is 0.175. Another aspect of the disclosure provides that when administered to a mammal, the one or more opioid analgesics a pharmaceutical composition is administered to a mammal, have a Tmax that is about: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, one or more antiemetics have a Tmax that is about 10-50% 55, or 60 minutes longer than a corresponding standard release opioid analgesic, e.g., in mean or median times. In shorter, e.g., about 20-40% or 25-35% shorter, than a corre Some instances, when the pharmaceutical composition is sponding standard-release antiemetic, e.g., in median or administered to a mammal, the one or more opioid analgesics mean times. In some instances, when the pharmaceutical have a Tmax that is about 9-32 minutes longer than a corre composition is administered to a mammal, the one or more sponding standard-release opioid analgesic, e.g., in mean or antiemetics have a Tmax that is about: 10-20%, 20-30%, median times. 30%-40%, or 40%-50% shorter than a corresponding stan 0172 Another aspect of the disclosure provides that when dard-release antiemetic, e.g., in median or mean times. In a pharmaceutical composition is administered to a mammal, Some instances, when the pharmaceutical composition is one or more opioid analgesics have a Tmax that is about administered to a mammal, the one or more antiemetics have 30-60% longer, e.g., about 40-50% longer, thana correspond aTmax that is about: 10%, 12%, 14%, 16%, 18%, 20%, 21%, ing standard-release opioid analgesic, e.g., in mean times. In 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, Some instances, when the pharmaceutical composition is 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 45%, or administered to a mammal, the one or more opioid analgesics 50% shorter than a corresponding standard-release anti have a Tmax that is about: 30%, 35%, 40%, 41%, 42%, 43%, emetic, e.g., in median or mean times. 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, or 60% longer 0176 Another aspect of the disclosure provides that when than a corresponding standard-release opioid analgesic, e.g., a pharmaceutical composition is administered to a mammal, in mean times. one or more non-opioid analgesics have a Tmax that is about 0173 Another aspect of the disclosure provides that when 0.9 to 1.1 hours, e.g., about: 0.9, 0.92, 0.94, 0.96,0.98, 1, 1.02, a pharmaceutical composition is administered to a mammal, 1.04, 1.06, 1.08, or 1.1 hours. In some instance, the Tmax is one or more opioid analgesics have a Tmax that is about about 1.04 hours. Another aspect of the disclosure provides 5-25% longer, e.g., about 5-15% longer, than a corresponding that when a pharmaceutical composition is administered to a standard-release opioid analgesic, e.g., in median times. In mammal, one or more non-opioid analgesics have a Tmax Some instances, when the pharmaceutical composition is that is about 5-30 minutes longer, e.g., about 10-25 minutes administered to a mammal, the one or more opioid analgesics longer or about 10-15 minutes longer, than a corresponding have a Tmax that is about: 5%, 6%, 7%, 8%, 9%, 10%, 11%, standard-release non-opioid analgesic, e.g., in mean or 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, median times. In some instances, when the pharmaceutical 22%, 23%, 24%, or 25% longer than a corresponding stan composition is administered to a mammal, the one or more dard-release opioid analgesic, e.g., in median times. Another non-opioid analgesics have a Tmax that is about: 5-10 min aspect of the disclosure provides that when a pharmaceutical utes, 10-15 minutes, 15-20 minutes, 20-25 minutes, or 25-30 composition is administered to a mammal, one or more anti minutes longer than a corresponding standard-release non emetics have a Tmax that is about 3.5 to 4.3 hours, e.g., about: opioid analgesic, e.g., in mean or median times. In some 3.5, 3.6, 3.7, 3.75, 3.8, 3.85, 3.9, 3.95, 4, 4.1, 4.2, or 4.3 hours. instances, when the pharmaceutical composition is adminis In some instances, the Tmax is about 3.87 hours. tered to a mammal, the one or more non-opioid analgesics 0.174 Another aspect of the disclosure provides that when have a Tmax that is about: 5, 10, 15, 20, 25, or 30 minutes a pharmaceutical composition is administered to a mammal, longer than a corresponding standard-release non-opioid one or more antiemetics have a Tmax that is about 30-120 analgesic, e.g., in mean or median times. In some instances, minutes shorter than a corresponding standard-release anti when the pharmaceutical composition is administered to a emetic, e.g., in median times. In some instances, when the mammal, the one or more non-opioid analgesics have a Tmax pharmaceutical composition is administered to a mammal, that is about: 6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 the one or more antiemetics have a Tmax that is about 50-100 minutes longer than a corresponding standard-release non minutes or 60-90 minutes shorter, e.g., about: 30-40 minutes, opioid analgesic, e.g., in mean or median times. In some 40-50 minutes, 50-60 minutes, 60-70 minutes, 70-80 min instances, when the pharmaceutical composition is adminis utes, 80-90 minutes, 90-100 minutes, 100-110 minutes, or tered to a mammal, the one or more non-opioid analgesics US 2015/0290211 A1 Oct. 15, 2015

have a Tmax that is about 13 minutes longer than a corre (129) and added to the blender (127) with the promethazine sponding standard-release non-opioid analgesic, e.g., in pre-blends. The contents of the blender are mixed. The blend mean or median times. is discarded into the appropriate storage container (130). The 0177. Another aspect of the disclosure provides that when accountable yield for the final promethazine blend (131) is a pharmaceutical composition is administered to a mammal, calculated and recorded. Tablet Compression is performed by one or more non-opioid analgesics have a Tmax that is about transferring the first layer of hydrocodonefacetaminophen 10-50% longer, e.g., about 10-40% or 20-30% longer, than a blend (117) into the first hopper. The press (132) is setup with corresponding standard-release non-opioid analgesic, e.g., in its respective parameters appropriately. The second layer mean or median times. In some instances, when the pharma promethazine blend (130) is transferred into the second hop ceutical composition is administered to a mammal, the one or per. The press is started to begin producing the tablets to the more non-opioid analgesics have a Tmax that is about: specified parameters. During compressing, tablets are 10-20%, 20-30%, 30%-40%, or 40%-50% longer than a cor sampled at various times for in-process testing for weight, responding standard-release non-opioid analgesic, e.g., in metal, microbiological contamination, thickness, hardness, mean or median times. In some instances, when the pharma and % friability. The accountable yield for the final blend ceutical composition is administered to a mammal, the one or (133) is calculated and recorded. At the end of the batch, the more non-opioid analgesics have a Tmax that is about: 10%, compressed tablets are deposited into an appropriate con 15%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, tainer (134) and stored. 29%, 30%, 35%, 40%, 45%, or 50% longer than a corre 0179. In some instances, friability means the ability of a sponding standard-release non-opioid analgesic, e.g., in Solid composition, such as a tablet, to be reduced to Smaller mean or median times. pieces or particles or fibers with minimal force. In some embodiments, a mean loss of tablet mass for three determi 0178. In some instances, tablets can beformed by a manu nations is not more than 1.0%. A friable tablet is one that is facturing process, see FIG. 2A-2C. For example, a blend of easily crumbled or pulverized. Friability can be measured hydrocodone bitartrate and acetaminophen is manufactured using the methods and apparatus as described in the General by passing hydrocodone bitartrate, croscarmellose Sodium, Chapters and General Methods of the Harmonization section and hypromellose (100) through a screen (101) and adding of the United States Pharmacopeia and the National Formu the contents to a clean blender (102). The contents are mixed lary (USP-NF), such as the General Chapter 1216 Tablet in the blender. The hypromellose (103) is passed through a Friability section. In some instances, friability is measured in screen (104) and added to the blender (102). The contents of a friabilator (a rotating drum), see e.g., Example 4, and results the blender are mixed. The silicified microcrystalline cellu are reported as a percent friability, i.e., percent tablet weight lose (105) is passed through a screen (106) and added to the loss after rotation. blender (102). The contents of the blender were mixed. The silicified microcrystalline cellulose (107) is passed through a 0180. In some instances, friability measurement is calcu screen (108) and added to the blender (102). The contents of lated using a friabilator, with a horizontal axis that rotates at blender are mixed. The silicified microcrystalline cellulose 25+/- 1 rpm. The drum for the friabilator comprises a syn (109) is passed through a screen (110) and added to the thetic transparent polymer with an internal diameter between blender. The contents of the blender are mixed. The blended 283 and 291 mm and a depth between 36 and 40 mm. The contents are discharged from the blender into an appropri drum comprises a curved projection with an inside radius ately labeled container (111). A clean blender is setup (112). between 75.5 and 85.5 mm, see FIG. 3. For example, tablets The hydrocodone bitartrate is added to the blend from the with a unit mass equal to or less than 650 mg, are measured previous step (111) and half of the total acetaminophen (113) using a representative sample of whole tablets corresponding is also added to the clean blender and the contents are mixed. to 6.5 g. If the tablet unit mass is greater than 650 mg, a The second half of the total acetaminophen (114) is added to representative sample often whole tablets is measured. Loose the blender and the contents are mixed. The magnesium Stear powder from the tablets is removed with the aid of air pressure ate and stearic acid are passed (115) through a screen (116) or a soft brush. An initial tablet weight is recorded. The tablets and added to the blender with the hydrocodone bitartrate/ are placed inside the friabilator drum, the drum is closed and acetaminophen blend. The contents of the blender are mixed. rotated for 100 rotations for 4 minutes. Tablets are then The blend is discharged into the appropriate container(s) removed from the drum. Any loose powder from all intact (117). The accountable yield for the final blend (118) is cal (non-broken, non-capped) tablets is removed. If any tablets culated and recorded. A blend of promethazine HCl is manu are broken or capped, the number for each category is factured by setting up a clean blender for the promethazine recorded. Pieces of broken or fractured tablets that do not pass HCl blend. Half of the total specified amounts of promethaz through a 10-mesh screen are combined with the intact tablets ine HCl USP cellulose microcrystalline-silicified, and cros and are accurately weighed and recorded as the final weight. carmellose sodium for the promethazine HCl (120) are The percent loss is calculated using the following equation: screened (119). The contents of the blender are mixed (121). The pre-blend is discarded into the appropriate container (initial weight-final weight) (122) and set aside. The second half of the total specified Percent loss = --initial -weight - - - X 100 amounts of promethazine HCl USP cellulose microcrystal line-silicified, and croscarmellose Sodium for the promethaZ ine HCl blend (124) is screened (123). The contents of the 0181. In some instances, the pharmaceutical composition blender are mixed (125). The second pre-blend is discharged has a friability of 0.9% or less. In some instances, the phar into a separate appropriate container (126). The promethazine maceutical composition has a friability of 0.4% or less. In pre-blends from the separate containers (122 and 126) are Some instances, the pharmaceutical composition has a friabil added into a clean blender (127) and the contents are mixed. ity of 0.2% or less. In some instances, the pharmaceutical The magnesium Stearate (128) is passed through a screen composition has a friability of about 0.1% to about 0.9%. In US 2015/0290211 A1 Oct. 15, 2015 42

Some instances, the pharmaceutical composition has a friabil 6.35, 6.36, 6.37, 6.38, 6.39, 6.40, 6.41, 6.42, 6.43, 6.44, 6.45, ity of about 0.05% to about 0.2%. In some instances, the 6.46, 6.47, 6.48, 6.49, 6.50, 6.51, 6.52, 6.53, 6.54, 6.55, 6.56, pharmaceutical composition has a friability of about 0.05%. 6.57, 6.58, 6.59, 6.60, 6.61, 6.62, 6.63, 6.64, 6.65, 6.66, 6.67, In some instances, the pharmaceutical composition has a 6.68, 6.69, 6.70, 6.71, 6.72, 6.73, 6.74, 6.75, 6.76, 6.77, 6.78, friability of about 0.1%. In some instances, the pharmaceuti 6.79, 6.80, 6.81, 6.82, 6.83, 6.84, 6.85, 6.86, 6.87, 6.88, 6.89, cal composition has a friability of about 0.15%. In some 6.90, 6.91, 6.92, 6.93, 6.94., 6.95, 6.96, 6.97, 6.98, 6.99, 7.00, instances, the pharmaceutical composition has a friability of 7.01, 7.02, 7.03, 7.04, 7.05, 7.06, 7.07, 7.08, 7.09, 7.10, 7.11, about 0.13%. In some instances, the pharmaceutical compo 7.12, 7.13, 7.14, 7.15, 7.16, 7.17, 7.18, 7.19, or about 7.20 sition has a friability of about 0.01, 0.05, 0.10, 0.15, 0.20, . 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0185. In some instances, weight measurements and calcu 0.80, 0.85, 0.90, or about 0.95%. In some instances, the lations are conducted as follows. Approximately 100 tablets pharmaceutical composition has a friability of about 0.00, are weighed individually using an appropriate weighing 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, device. The average weight and the relative standard devia 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, tion of the weights are calculated. For example, approxi 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, mately 100 tablets are taken and weighed individually using 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or about 0.40%. a Mocon AB3 weigh balance. Pieces of tablets are not 0182. In some instances, tablet hardness measurements is included. The printed results are inspected to ensure at least calculated using a tablet hardness tester such as Key Model 90 individual weight results are recorded and that any rejected HT300 or Model HT500 or Pharma Test PTS/301. Using the results are reasonable, (i.e., double or triple weights). Any limit knob on the left side of the housing, the plunger is weight result that is outside of a range (0.5 times the theoreti adjusted according to the diameter of the tablet. The tablet is cal unit weight to 1.5 times the theoretical unit weight) is not placed broadside down on the pedestal so that it was centered included in the calculation. The software that analyzes the and was against the right side (stationary) plunger. Capsule tablet weight data assigned T1 and T2 limits to tablets based shaped tablets are placed with one end against the stationary on U.S. Pharmacopeial Convention weight variation criteria. plunger, breaking force applied end-to-end, see FIG. 4. When Individual tablet weight results are flagged and counted as round or square tablets are scored, the tablet is positioned exceeding the T1 and T2 criteria as follows: if the meantablet with the bisect parallel to the plunger contact Surface. weight is 130 mg or less, T1 limits are +10%, T2 limits are 0183 In some instances, the pharmaceutical composition +20%; if the mean tablet weight is between 130 and 325 mg. has a hardness of about 8 to about 22 kilopond (kp). In some T1 limits are +7.5%, T2 limits are +15%; if the mean table instances, the pharmaceutical composition has a hardness of weight is 325 mg or more, T1 limits are +5.0%, T2 limits are about 12-20kp. In some instances, the pharmaceutical com +10%. In some embodiments, if the items being weighed are position has a hardness of about 14-18 kp. In some instances, capsules, individual gross weight results outside of the +10% the pharmaceutical composition has a hardness of about of the calculated average range are flagged and counted as 15-17kp. In some instances, the pharmaceutical composition exceeding T1. Any individual gross weight results outside of has a hardness of about 15.5 kp to about 16.5 kp. In some the t15% of the calculated average range are flagged and instances, the pharmaceutical composition has a hardness of counted as exceeding T2. If values exist outside this range, the about 16.5 kp. In some instances, the pharmaceutical compo actual empty capsule weight is Subtracted from the mean sition has a hardness of about 8, 9, 10, 11, 12, 13, 14, 15, 16, weight to obtain a calculated net fill weight and a range of 17, 18, 19, 20, 21, or about 22 kp. In some instances, the +25% of the calculated net fill weight is determined. Tablets pharmaceutical composition has a hardness of about 8.0, 8.1, are flagged when individual results exceed the calculated 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.19.2, 9.3, 9.4, 9.5, average weight by the factor indicated. 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, In Vitro Dissolution Methods 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 0186. In vitro dissolution studies can be performed in 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, accordance with guidelines from the United Sates Pharma 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, copeial Convention, the European Pharmacopoeia, and/or the 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, Japanese Pharmacopoeia. The pharmaceutical compositions 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, described hereincan be tested for in vitro dissolution. In some 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, instances, tablets can be tested for in vitro dissolution. In 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, Some instances, more than one of the same tablets can be 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, tested for in vitro dissolution. In these cases, the more than 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, one of the same tablets can be called a test batch. The size of 21.8, 21.9, 22.0, 22.1, or about 22.2 kp. the test batch can be at least about 10% of the largest batch 0184 In some instances, the pharmaceutical composition planned. The size of the test batch can be 100,000 tablets. The has a thickness of about 5 to about 8 mm. In some instances, size of the test batch can be less than 100,000 tablets. The size the pharmaceutical composition has a thickness of about 6 to of the test batch can be more than 100,000 tablets. about 7 mm. In some instances, the pharmaceutical compo 0187. In some instances, dissolution apparatus can be a sition has a thickness of about 6.2 to about 6.8 mm. In some USP Rotating Paddle Apparatus 2 with an automated sam instances, the pharmaceutical composition has a thickness of pling station (e.g., VK-8000 or equivalent). Dissolution fluid about 6.0, 6.1, 6.2, 6.3, 6.4., 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, can be de-aerated 0.01 NHCl, maintained at 37.0+/-0.5° C. 7.3, 7.4, or about 7.5 mm. In some instances, the pharmaceu during dissolution procedure. The fluid can be prepared by tical composition has a thickness of about 6.10, 6.11, 6.12. diluting concentrated HCl in de-aerated water, and mixed. To 6.13, 6.14, 6.15, 6.16, 6.17, 6.18, 6.19, 6.20, 6.21, 6.22, 6.23, measure peaks, a dual wavelength detector (e.g., Hitachi 6.24., 6.25, 6.26, 6.27, 6.28, 6.29, 6.30, 6.31, 6.32, 6.33, 6.34, L-2420) can be used, or in Some instances, two separate US 2015/0290211 A1 Oct. 15, 2015

chromatographic systems can be used in order to measure the 0.192 Calculation of the amount released per tablet can be peaks at two different wavelengths. determined using Equation I: 0188 In some instances, standard solution preparation: each ingredient is weighed in a Volumetric flask, and diluted to volume with dissolution media. The resulting solution is mixed to form a stock solution. Different ingredients are similarly prepared to provide Stock solutions (e.g., promet hazine HCl, acetaminophen). Each aliquot of stock standard where: solutions is diluted with dissolution fluid and mixed to pro Au-The peak area response obtained in the chromatogram of duce a final standard solution. For example, the concentration the dissolution test solution. of hydrocodone bitartrate is about 0.0084 mg/mL, promet As=The peak area response obtained in the chromatogram of hazine HCl is about 0.014 mg/mL, and acetaminophen is the standard solution. about 0.36 mg/mL. Cs=The concentration of the standard solution. Vn=The volume, in mL, of the dissolution solution at sam 0189 In some instances, dissolution test solutions are pre pling time period n. It is calculated as follows: pared in 0.01 NHCl using the USP Rotating Paddle Appara tus at 50 WM. An aliquot of the dissolution solution is filtered 0193 Calculation of the amount released as a percent of and an aliquotis chromatographed on a 50-mmX4.6-mm (i.d.) the label claim was determined using the following equation: Waters SunFireTMCs, 3.5-lum particle size column using a gradient HPLC method. Mobile phase A consists of water/ Released acetonitrile/TFA, 950/50/2 (v/v/v) and mobile phase B con mg Tablet sisted of waterfacetonitrile/TFA,50/950/1.5 (v/v/v). The flow % Released = Label Claim x 100% rate can be 2.0 mL/minute. For example, the amount of acetaminophen released can be determined at 300 nm by 0194 Calculation of the amount released at second and comparing the area obtained for the peak due to acetami Subsequent time periods in mg/tablet was determined using nophen in the chromatogram of the dissolution test Solution to the following equation: that obtained for the corresponding peak in a chromatogram of a standard solution. The amount of hydrocodone bitartrate released can be determined at 230 nm by comparing the area - Ui W = Un+5X. vi obtained for the peak due to hydrocodone bitartrate in the a di I will chromatogram of the dissolution test solution to that obtained for the corresponding peak in a chromatogram of a standard where: solution. The amount of promethazine HCl released can be Wn=The mg released/tablet at time period n (corrected). determined at 230 nm by comparing the area obtained for the Un=The mg released/tablet at time n (uncorrected). peak due to promethazine HCl in the chromatogram of the n=The current time period. dissolution test solution to that obtained for the correspond i=The time period index. ing peak in a chromatogram of a standard Solution. Ui=The mg released/tablet at time period i (uncorrected). 0190. In some instances, paddle speed is 50 rpm; pull Vi=The volume, in mL, of the dissolution solution at sam volume is 10 mL (no replacement); Pull points: 5, 10, 15, 20, pling time period i. It is calculated as follows: 25, 30, 45 and 60 minutes. The amount of each component dissolved in the dissolution medium can be determined by 0.195. In some instances, in vitro dissolution testing is HPLC. The method can use a high purity, bonded C18 sta collected from at least about 24 tablets. In some instances, in tionary phase and a binary mobile phase consisting of an vitro dissolution testing can be collected from at least about: appropriate buffer and organic modifier. 10, 12, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 40, 50, or 100 0191 In some instances, dissolution fluid is preheated to tablets. In some instances, in vitro dissolution testing can be 37° C. and placed into each vessel. Tablets are weighed and collected from more than about: 10, 12, 16, 18, 20, 22, 24, 26, placed in vessels respectively. At prescribedtime intervals, an 28, 30, 32, 34, 36, 40, 50, 100 tablets or more. In some aliquot of the dissolution fluid can be drawn using the auto instances, in vitro dissolution testing can be collected from mated sampling station equipped with a 35um full flow filter less than about: 10, 12, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, connected to a sampling probe. Filtrate is allowed to cool to 36, 40, 50, 100 tablets or less. Tablets can be from the same room temperature, to produce a final sample solution. Fluid test batch. In some instances, in vitro dissolution testing can withdrawn is not replaced. Samples are injected in HPLC for be done on equal numbers of test and reference tablets (e.g. 12 analysis after a baseline is established. The resolution test tablets and 12 reference tablets). between each peak is calculated, as well as the tailing factor. 0196) Tablets can be added to a liquid, such as a dissolu The mean and % RSD values for the acetaminophen peak tion medium, to initiate dissolution of the tablet and to permit areas at 300 nm can be measured; for example promethazine sampling of the liquid to measure the amount of composition HCl and hydrocodone bitartrate at 230 nm. In some embodi released from the tablet at one or more specific time points. ments, the five replicate injections are not more than 2.0% Dissolution medium can be a solution. Dissolution medium RSD. In some embodiments, 50 uL aliquots of standard and can be a buffered solution. The buffered solution can have a sample solutions were subjected to liquid chromatography. pH of between about 4 and about 8. Dissolution medium can US 2015/0290211 A1 Oct. 15, 2015 44 be an acid. The dissolution medium can be an acid between to operate at about 25 rotations per minute (rpm). The appa about 0.001N to about 0.1N, for example 0.1N hydrochloric ratus can be set to operate at about 50 rpm. The apparatus can acid. Dissolution medium can be deaerated. Dissolution be set to operate at about 100 rpm. In some instances, the medium can contain dissolved gases. Dissolution medium apparatus can be set to operate at about: 10, 20, 25, 30, 35, 40, can be about pH 7.4. Dissolution medium can be about pH 45, 50,55, 60, 65,70, 75, 80, 85,90, 95, 100,105, 110, 115, 7.0. Dissolution medium can be about pH 6.0. Dissolution 120, 125, 130, 135, 140,145, 150, 200, or 300 rpm. Samples medium can be 0.05 M pH 7.4 phosphate buffer. Dissolution of dissolution medium can be withdrawn. medium can be deaerated water. Dissolution medium can be 0200. One or more samples of dissolution medium can be an acid. Dissolution medium can be a base. Dissolution withdrawn at one or more specified times. Samples can be medium can be 0.1 Nhydrochloric acid. Dissolution medium withdrawn following the addition of the tablet into the disso can be water. Dissolution medium can be pH 6.0 phosphate lution medium in the vessel of the apparatus. One or more buffer solution. Solutes such as surfactants can be added to samples can be collected at one or more times. In some the dissolution medium. instances, one or more samples can be collected at three 0197) In vitro dissolution testing can be performed using different times. In some instances, the final time is chosen to an apparatus as described in the General Chapters and Gen show complete release of the composition. One or more eral Methods of the Harmonization section of the United samples can be collected at about: 5, 10, 15, 20, 30, 45, 60.90, States Pharmacopeia and the National Formulary (USP-NF), or 180 minutes. A volume of dissolution medium can be such as the General Methods 711 Dissolution Standards sec withdrawn from the vessel. The volume can be defined. The tion. In some instances, a specific Volume of dissolution Volume can be unknown. The volume of dissolution medium medium can be placed into the vessel of the apparatus. A withdrawn can be the same for all times in a single in vitro Volume of about 500 mL dissolution medium can be added. A dissolution study. The volume of dissolution medium can be Volume of about 900 mL dissolution medium can be added. A withdrawn from the Zone midway between the surface of the Volume of about 1000 mL dissolution medium can be added. dissolution medium and the top of the rotating basket or blade A volume of about: 200, 300, 400, 500, 600, 700, 750, 800, and not less than 1 cm from the vessel wall. The volume of 900, 1000, 1100, 1200, 1300, 1400, 1500, 2000 mL dissolu dissolution medium withdrawn from the vessel can be tion medium can be added. The volume of dissolution replaced with an equal Volume of fresh dissolution medium. medium can not be less than 3 times that need to form a The volume of dissolution medium withdrawn from the ves saturated Solution of the composition. sel can not be replaced. In this instance, the Volume change 0198 The apparatus can be a basket, for example, as can be incorporated into the dissolution calculation. The tem described in the General Methods 711 Dissolution Standards perature of the dissolution medium in the vessels can be of the USP-NF. The basket apparatus can be used for disso Verified at one or more time points. In vitro dissolution testing lution studies of capsules. The basket apparatus can be used can be repeated with one or more additional tablets. Withdraw for dissolution studies of controlled-release formulations. of dissolution medium from the vessel can be automated. The apparatus can be a paddle, for example, as described in 0201 In some instances, the amount of composition dis the General Methods 711 Dissolution Standards of the USP solved is at least about 75% in 15 minutes. In some instances, NF. The paddle apparatus can be used for dissolution studies the amount of composition dissolved is at least about 80% in of solid formulations. The paddle apparatus can be used for 20 minutes. In some instances, the amount of composition dissolution studies of tablets. The apparatus can be a recip dissolved is at least about 85% in 30 minutes. In some rocating cylinder, for example, as described in the General instances, the amount of composition dissolved is at least Methods 711 Dissolution Standards of the USP-NF. The about 80% in 30 minutes. In some instances, the amount of reciprocating cylinder apparatus can be used for dissolution composition dissolved is at least about 75% in 60 minutes. In studies of bead-type controlled-release dosage forms. The Some instances, the amount of composition dissolved is at apparatus can be a flow cell, for example, as described in the least about 80% in 15 minutes. In some instances, the amount General Methods 711 Dissolution Standards of the USP-NF. of composition dissolved is at least about 80% in 45 minutes. The flow cell apparatus can be used for dissolution studies of 0202 Percent dissolution refers to the weight percent of a controlled-release dosage forms. The flow cell apparatus can pharmaceutical agent (for example, hydrocodone, acetami be used for dissolution studies of formulations with poor nophen, or promethazine) that is released from a tablet, see solubility. The apparatus can be a paddle over disk. The Example 6. For example, 0% dissolution of hydrocodone paddle over disk apparatus can be used for dissolution studies means no mass of hydrocodone is released from the tablet. In of transdermal dosage forms. The apparatus can be a cylinder. contrast, 100% dissolution of hydrocodone means the entire The cylinder apparatus can be used for dissolution studies of mass of hydrocodone is released from the tablet. Dissolution transdermal dosage forms. The apparatus can be a reciprocat rate refers to the weight percent of a pharmaceutical agent ing disk. The reciprocating disk apparatus can be used for released from a tablet in a given time interval (for example, 5 dissolution studies of non-disintegrating oral controlled-re minutes or less, 10 minutes or less, or 15 minutes or less). lease dosage forms. A size 40-mesh screen can be used in the 0203. In some instances, an active agent of a pharmaceu apparatus. The apparatus can be calibrated with the USP tical composition has a percent dissolution of 25, 26, 27, 28. Salicyclic Acid and Prednisone Calibrator Tablets. 29, 30, 31, 32,33,34, 35,36, 37,38, 39, 40, 41,42, 43,44, 45, 0199 The apparatus can be assembled. The dissolution 46,47, 48,49, 50, 51, 52,53,54, 55,56, 57,58, 59, 60, 61, 62, medium can be equilibrated to about 35+/-0.5 degrees Fahr 63,64, 65,66, 67,68, 69,70, 71,72, 73,74, 75,76, 77,78,79, enheit. The dissolution medium can be equilibrated to about 80, 81, 82, 83, 84,85, 86, 87, 88, 89,90,91, 92,93, 94, 95, 96, internal body temperature. One test tablet or one reference 97, 98, 99, or about 100% in about 5 minutes or less. In some tablet can be placed into the apparatus in the dissolution instances, an active agent of the pharmaceutical composition medium. The apparatus can be immediately set to operate. has a percent dissolution of about 30 to about 80% in about 5 The apparatus can be set to operate. The apparatus can be set minutes or less. In some instances, the pharmaceutical com US 2015/0290211 A1 Oct. 15, 2015

position has a percent dissolution of hydrocodone of about 33 within about 15 minutes or less is about: 79,80, 81,82, 83, 84, to about 72% in about 5 minutes or less. In some instances, the 85, 86, 87, 88, 89,90, 91, 92,93, or about 94%. In some pharmaceutical composition has a percent dissolution of instances, the pharmaceutical composition has a percent dis hydrocodone of about 35 to about 60% in about 5 minutes or solution of acetaminophen of about 75 to about 100% in about less. In some instances, the percent dissolution of hydroc 15 minutes or less. In some instances, the percent dissolution odone within about 5 minutes or less is about: 33, 34,35, 36, of acetaminophen within about 15 minutes or less is about: 37,38,39, 40, 41, 42, 43,44, 45,46, 47, 48,49, 50, 51, 52,53, 74, 75,76, 77,78, 79,80, 81, 82, 83, 84, 85,86, 87,88, 89,90, 54, 55,56, 57,58, 59, 60, 61, 62,63, 64, 65,66, 67,68, 69,70, 91, 92,93, 94, 95, 96, 97,98, 99, or about 100%. In some 71, or about 72%. In some instances, the pharmaceutical instances, the pharmaceutical composition has a percent dis composition has a percent dissolution of acetaminophen of solution of promethazine of about 86 to about 100% in about about 55 to about 80% in about 5 minutes or less. In some 15 minutes or less. In some instances, the percent dissolution instances, the percent dissolution of acetaminophen within of promethazine within about 15 minutes or less is about: 86. about 5 minutes or less is about: 57,58, 59, 60, 61, 62, 63,64, 87, 88, 89,90, 91, 92,93, 94, 95, 96, 97,98, 99, or about 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 100%. about 80%. In some instances, the pharmaceutical composi 0206. In some instances, changing a process parameter tion has a percent dissolution of promethazine of about 65 to alters a pharmaceutical composition. A non-limiting example about 100% in about 5 minutes or less. In some instances, the of the process parameter can be a compression setting. In pharmaceutical composition has a percent dissolution of Some instances, changing the compression setting alters the promethazine of about 80 to about 100% in about 5 minutes or friability of the pharmaceutical composition. In some less. In some instances, the percent dissolution of promethaZ instances, changing the compression settings alters the hard ine within about 5 minutes or less is about: 65, 66, 67,68, 69, ness of the pharmaceutical composition. In some instances, 70,71, 72,73,74, 75,76, 77,78, 79,80, 81,82, 83, 84, 85,86, changing the compression settings can alter the thickness of 87, 88, 89,90,91, 92,93, 94, 95, 96, 97, or about 98%. the pharmaceutical composition. In some instances, changing 0204. In some instances, an active agent of a pharmaceu the compression settings alters the dissolution rate of a phar tical composition has a percent dissolution of about 65 to maceutical agent within the pharmaceutical composition. In about 100% in about 10 minutes or less. In some instances, Some instances, changing a single process parameter can alter the active agent of the pharmaceutical composition has a the friability, hardness, thickness, dissolution rate, or combi percent dissolution of 25,26, 27.28, 29, 30,3132,33,34,35, nations thereof. 36, 37,38, 39, 40, 41, 42,43, 44, 45,46, 47, 48,49, 50, 51, 52, 0207. In some instances, friability of a pharmaceutical 53, 54, 55,56, 57,58, 59, 60, 61, 62,63, 64, 65,66, 67,68, 69, composition is correlated to hardness, FIG. 5 and FIG. 6. In 70,71, 72,73,74, 75,76, 77,78, 79,80, 81,82, 83, 84, 85,86, Some instances, friability of the pharmaceutical composition 87, 88, 89,90,91, 92,93,94, 95, 96, 97,98,99, or about 100% is correlated to thickness, FIG. 5 and FIG. 7. In some in about 10 minutes or less. In some instances, the pharma instances, an increase in friability correlates to a decrease in ceutical composition has a percent dissolution of hydroc hardness. In some instances, an increase in friability corre odone of about 65 to about 86% in about 10 minutes or less. lates to an increase in thickness. In some instances, a decrease In some instances, the percent dissolution of hydrocodone in friability correlates to an increase in hardness. In some within about 10 minutes or less is about: 68, 69,70, 71, 72,73, instances, a decrease in friability correlates to a decrease in 74, 75, 76, 77,78, 79,80, 81, 82, 83, 84,85, 86, or about 87%. thickness. In some instances, hardness is correlated to thick In some instances, the pharmaceutical composition has a ness, FIG. 5 and FIG. 8. In some instances, an increase in percent dissolution of acetaminophen of about 65 to about hardness correlates to a decrease in thickness. In some 100% in about 10 minutes or less. In some instances, the instances, a decrease in hardness correlates to an increase in percent dissolution of acetaminophen within about 10 min thickness. In some instances, utes or less is about: 69, 70, 71, 72,73, 74, 75, 76, 77, 78,79, 0208. In some instances, hardness is correlated to a disso 80, 81, 82, 83, 84,85, 86, 87, 88, 89,90,91, 92,93, 94, 95, 96, lution rate of a pharmaceutical agent, FIG. 5 and FIGS. 9-11. 97.98.99, or about 100%. In some instances, the pharmaceu In some instances, an increase in hardness correlates to a tical composition has a percent dissolution of promethazine decrease in dissolution rate of hydrocodone. In some of about 78 to about 100% in about 10 minutes or less. In instances, a decrease in hardness correlates to an increase in Some instances, the percent dissolution of promethazine dissolution rate of hydrocodone. In some instances, an within about 10 minutes or less is about: 79,80, 81,82, 83, 84, increase in hardness correlates to a decrease in dissolution 85, 86, 87, 88, 89,90, 91, 92,93, 94, 95, 96, 97,98, 99, or rate of acetaminophen. In some instances, a decrease in hard about 100%. ness correlates to an increase in dissolution rate of acetami 0205. In some instances, an active agent of a pharmaceu nophen. In some instances, an increase inhardness correlates tical composition has a percent dissolution of about 74 to to an increase in dissolution rate of promethazine. In some about 100% in about 15 minutes or less. In some instances, instances, a decrease in hardness correlates to a decrease in the active agent of the pharmaceutical composition has a dissolution rate of promethazine. percent dissolution of 25,26, 27.28, 29, 30,3132,33,34,35, 0209. In some instances, thickness is correlated to a dis 36, 37,38, 39, 40, 41,42, 43,44, 45,46, 47,48, 49, 50, 51, 52, solution rate of a pharmaceutical agent, FIG. 5, and FIGS. 53, 54, 55,56, 57,58, 59, 60, 61, 62,63, 64, 65,66, 67,68, 69, 12-14. In some instances, an increase in thickness correlates 70,71, 72,73,74, 75,76, 77,78, 79,80, 81,82, 83, 84, 85,86, to an increase in dissolution rate of hydrocodone. In some 87, 88, 89,90,91, 92,93,94, 95, 96, 97,98,99, or about 100% instances, a decrease in thickness correlates to a decrease in in about 15 minutes or less. In some instances, the pharma dissolution rate of hydrocodone. In some instances, an ceutical composition has a percent dissolution of hydroc increase in thickness correlates to an increase in dissolution odone of about 78 to about 95% in about 15 minutes or less. rate of acetaminophen. In some instances, a decrease in thick In some instances, the percent dissolution of hydrocodone ness correlates to a decrease in dissolution rate of acetami US 2015/0290211 A1 Oct. 15, 2015 46 nophen. In some instances, an increase in thickness correlates of acetaminophen of about 55 to about 80% within about 5 to a decrease in dissolution rate of promethazine. In some minutes or less, and a dissolution of promethazine of about 80 instances, a decrease in thickness correlates to an increase in to about 100% within about 5 minutes or less. dissolution rate of promethazine. 0219. In one instance, a pharmaceutical composition has a 0210. In one instance, a pharmaceutical composition has a hardness of about 16 kp, a friability of about 0.13%, a thick friability of about 0.1% to about 0.9%, a hardness of about 8 ness of about 6.4 mm, and a hydrocodone dissolution rate of to about 22 kp, a dissolution of hydrocodone of about 33 to about 42% within about 5 minutes or less. In one instance, the about 72% within about 5 minutes or less, a dissolution of pharmaceutical composition can have a hardness of about acetaminophen of about 55 to about 80% within about 5 16.5 kp, a friability of about 0.10%, a thickness of about 6.4 minutes or less, and a dissolution of promethazine of about 65 mm, and a hydrocodone dissolution rate of about 40% within to about 100% within about 5 minutes or less. about 5 minutes or less. In one instance, the pharmaceutical 0211. In one instance, a pharmaceutical composition has a composition has a hardness of about 15.1 kp, a friability of friability of about 0.1% to about 0.9%, a hardness of about 8 about 0.13%, a thickness of about 6.4 mm, and a hydrocodone to about 22 kp, a dissolution of hydrocodone of about 65 to dissolution rate of about 43% within about 5 minutes or less. about 86% within about 10 minutes or less, a dissolution of In one instance, the pharmaceutical composition can have a acetaminophen of about 65 to about 100% within about 10 hardness of about 15.4 kp, a thickness of about 6.5 mm, and minutes or less, and a dissolution of promethazine of about 78 a hydrocodone dissolution rate of about 42% within about 5 to about 100% within about 10 minutes or less. minutes or less. 0212. In one instance, a pharmaceutical composition has a 0220. In one instance, a pharmaceutical composition has a friability of about 0.1% to about 0.9%, a hardness of about 8 hardness of about 16.3 kp, a friability of about 0.05%, a to about 22 kp, a dissolution of hydrocodone of about 78 to thickness of about 6.4 mm, a hydrocodone dissolution rate of about 95% within about 15 minutes or less, a dissolution of about 52% within about 5 minutes or less, a hydrocodone acetaminophen of about 75 to about 100% within about 15 dissolution rate of about 70% within 10 minutes or less, and minutes or less, and a dissolution of promethazine of about 86 a hydrocodone dissolution rate of about 82% within 15 min to about 100% within about 15 minutes or less. utes or less. In one instance, the pharmaceutical composition 0213. In one instance, a pharmaceutical composition has a has a hardness of about 16.3 kp, a friability of about 0.05%, a friability of about 0.05% to about 0.2%, a hardness of about thickness of about 6.4 mm, anacetaminophen dissolution rate 12 to about 20kp, a dissolution of hydrocodone of about 35 to of about 69% within about 5 minutes or less, an acetami about 60% within about 5 minutes or less, a dissolution of nophen dissolution rate of about 81% within about 10 min acetaminophen of about 55 to about 80% within about 5 utes or less, and an acetaminophen dissolution rate of about minutes or less, and a dissolution of promethazine of about 80 87% within about 15 minutes or less. In one instance, the to about 100% within about 5 minutes or less. pharmaceutical composition has a hardness of about 16.3 kp, 0214. In one instance, a pharmaceutical composition has a a friability of about 0.05%, a thickness of about 6.4 mm, a friability of about 0.05% to about 0.2%, a hardness of about promethazine dissolution rate of about 91% within about 5 12 to about 20kp, a dissolution of hydrocodone of about 65 to minutes or less, a promethazine dissolution rate of about 94% about 86% within about 10 minutes or less, a dissolution of within about 10 minutes or less, and a promethazine dissolu acetaminophen of about 65 to about 100% within about 10 tion rate of about 95% within about 15 minutes or less. minutes or less, and a dissolution of promethazine of about 78 0221. In some instances, a tablet is formed by a manufac to about 100% within about 10 minutes or less. turing process, see Example 2. One or more pharmaceutical 0215. In one instance, the pharmaceutical composition has agents, (for example, hydrocodone) are passed through indi a friability of about 0.05% to about 0.2%, a hardness of about vidual screens and mixed in one or more blenders. Blended 12 to about 20kp, a dissolution of hydrocodone of about 78 to contents are then transferred to one or more hoppers that feed about 95% within about 15 minutes or less, a dissolution of into a tablet press. The press produces tablets with specified acetaminophen of about 75 to about 100% within about 15 parameters and at the end of the batch, the compressed tablets minutes or less, and a dissolution of promethazine of about 86 are deposited into a storage container. to about 100% within about 15 minutes or less. 0222. In some instances, active agents within a tablet 0216. In one instance, a pharmaceutical composition has a remain stable at ambient conditions for at least about one friability of about 0.05% to about 0.14%, a hardness of about month, at least about 3 months, at least about 24 months, at 14 to about 18 kp, a dissolution of hydrocodone of about 40 to least about 48 months or longer, depending on other compo about 65% within about 5 minutes or less, a dissolution of nents of the storage microenvironment, Such as temperature, acetaminophen of about 55 to about 80% within about 5 pressure, or humidity. In some cases, active agents remain minutes or less, and a dissolution of promethazine of about 80 stable at high temperature for at least about 6 months, at least to about 100% within about 5 minutes or less. about 9 months or longer. In some instances, high tempera 0217. In one instance, a pharmaceutical composition has a ture can be about: 80, 81, 82, 83, 84,85, 86, 87, 88, 89,90,91, friability of about 0.05% to about 0.14%, a hardness of about 92, 93, 94, 95, 96, 97,98, 99, 100, 101, 102, 103, or 104 15 to about 17 kp, a dissolution of hydrocodone of about 40 to degrees Fahrenheit. In some instances, high temperature can about 52% within about 5 minutes or less, a dissolution of be more than 80, 81, 82, 83, 84,85, 86, 87, 88, 89,90,91, 92, acetaminophen of about 55 to about 80% within about 5 93, 94, 95, 96, 97,98, 99, 100, 101, 102, 103, 104 degrees minutes or less, and a dissolution of promethazine of about 80 Fahrenheit or more. In some instances, high temperature can to about 100% within about 5 minutes or less. be less than 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90,91, 92, 0218. In one instance, a pharmaceutical composition has a 93, 94, 95, 96, 97,98, 99, 100, 101, 102, 103, 104 degrees friability of about 0.05% to about 0.14%, a hardness of about Fahrenheit or less. 15.5 to about 16.5 kp, a dissolution of hydrocodone of about 0223) In some instances, bioavailability (the rate and 40 to about 52% within about 5 minutes or less, a dissolution extent to which the active ingredient or active moiety in US 2015/0290211 A1 Oct. 15, 2015 47 pharmaceutical compostions disclosed hereinbecomes avail can be performed in a clinical setting. The in vivo bioavail able at the site of drug action) is documented using in vitro ability study can be performed in a laboratory setting. approaches. In some instances, such as for Soluble, perme 0228. In some instances, at least about 24 subjects are able, dissolving, or orally administered formulations, the rate enrolled in the in vivo bioavailability study. In some and extent to which the active ingredient or active moiety in instances, at least about 10, 16, 18, 20, 22, 24, 26, 28, 30, 32, pharmaceutical compostions disclosed hereinbecomes avail 34, 36, 40, 50, 100 subjects are enrolled in the study. Subjects able at the site of drug action can be documented using in vitro can be healthy. Subjects can be non-smokers. Subjects can be approaches. In some instances, an in vitro approach can be a smokers. Subjects can be between about 18 and about 50 dissolution study. Such in vivo studies can be performed in years of age. Subjects can be less than 18 years of age. accordance with guidelines from the Food and Drug Admin Subjects can be between about 11 and about 18 years of age. istration, Office of Generic Drugs, Division of Bioeduiva Subjects can be less than about 2 years of year. Subjects can lence. be between about 2 and about 11 years of age. Subjects can be 0224 Compositions described herein can be tested in vivo mammals. Subjects can be neonatal, infant, adolescent, or for the rate and extent to which the active ingredient or active adult. Subjects can be pediatric subjects. Subjects can be moiety in pharmaceutical compostions disclosed herein adult subjects. Subjects can be within 10% ideal body weight. becomes available at the site of drug action. In some Subjects can be within 15% ideal body weight. Female sub instances, tablets can be tested in vivo for bioavailability. In jects can not be pregnant. Subjects can not be selected to Some instances, more than one of the same tablets can be enroll in the study for any current or past medical condition called a test batch. The size of the test batch can be at least that might significantly affect the pharmacokinetic or phar about 10% of the largest batch planned. The size of the test macodynamics response. Written, informed consent can be batch can be 100,000 tablets. The size of the test batch can be obtained from a subject before enrollment into the study. less than 100,000 tablets. The size of the test batch can be 0229 Subjects can fast for at least about 10 hours prior to more than 100,000 tablets. administering. Subjects can fast for at least about: 8, 9, 12, 15, 16, 18, 24 hours prior to administering. Fasting can occur 0225. The composition of a reference tablet can not differ overnight. Fasting can not occur overnight. After completion from the test tablet by more than about 5% of the composi of the fasting period, Subjects can be administered one or tion. more test tablets with 240 mL of water. After completion of 0226. An in vivo bioavailability study can be a single the fasting period, Subjects can be administered one or more dose, randomized, fasting, two-period, two-treatment, two reference tablets with 240 mL of water. In some cases, a sequence crossover study. An in vivo pharmacokinetics study subject can be administered one or more tablets with about: can be in single-dose study. An in vivo bioavailability study 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, can be a multi-dose study. An in vivo bioavailability study can 340, 360, 380, 400 mL of water. In some cases, subjects can be a randomized study. An in vivo bioeduivalence study can drink an additional 240 mL of water at about: 1, 2, 4, 6, 8, or be a non-randomized study. An in vivo bioavailability study 10 hours, or combinations thereof following administering of can be a study in which all Subjects fast prior to administering. the one or more tablets and the initial 240 mL of water. An in vivo bioavailability study can compare equal doses of a Additional water can not be taken 1 hour before administer test tablet and a reference tablet. An in vivo bioavailability ing. Additional water can not be taken 1 hour after adminis study can be a crossover study. An in vivo bioavailability tering. study can be a non-crossover study. A crossover study can be 0230. Subjects can fast for at least about 4 hours following a two-period, two-treatment, two-sequence crossover study. administering. Subjects can fast for at least about 2, 3, 4, 5, 6, A crossover study can include repeated measures in all Sub 8, 10, 12 hours following administering. Meals provided to jects. An in vivo bioavailability study can be a longitudinal Subjects during the study can be standardized. Subjects can study. Subjects can receive different treatments in an in vivo not consume alcohol for about 48 hours prior to administer bioavailability study. One treatment can be experimental. ing. Subjects can not consume alcohol for about: 180, 96,72, One treatment can be standard or placebo. Subjects can 48,36, 24, 12, or 6 hours prior to administering. Subjects can receive the same number of treatments. Subjects can receive not consume alcohol until after the last blood sample is col a different number of treatments. Subjects can participate in lected for the study. Subjects can not consume additional the same number of periods. Subjects can participate in a medications at least about 2 weeks prior to administering. different number of periods. In some instances, a crossover Subjects can not consume additional medications at least study can have four periods. In some instances, a crossover about: 52, 40, 30, 20, 10, 8, 7, 6, 5, 4, 3, 2 weeks prior to study can have two periods. An in vivo bioavailability study administering. Subjects can not consume additional medica can include a washout period. An in vivo bioavailability study tions at least about 7, 6, 5, 4, 3, 2 days prior to administering. can not include a washout period. A washout period can avoid Subjects can not consume additional medications until after carry-over effects when two sequential treatments are given the last blood sample is collected for the study. close together in time to a single patient. At least a 1 week 0231. Blood samples can be collected from subjects at one washout period can be observed between treatments. At least or more time points. Venous blood can be collected. Arterial a 2 week washout period can be observed between treatments. blood can be collected. Blood can be collected from a periph 0227. A dosing sequence can include type of dose (e.g. eral intravenous line. Blood can be collected by heel or finger experimental or standard), amount of dose, frequency of puncture. Collection of a blood sample from one or more treatment, or others. Subjects can be randomly assigned to subjects can occur at about: 10, 20 30, or 45 minutes after one of one or more dosing sequences. Subjects can be ran administering. Collection of a blood sample from one or more domly assigned to one of two possible dosing sequences. The subjects can occur at about: 0, 0.17, 0.25, 0.33, 0.50, 0.67, proposed in vivo bioavailability study can be approved by an 0.75, 1, 1.25, 1.33, 1.50, 1.67, 1.75, 2, 2.25, 2.5, 2.75,3,3,33, institutional review board. The in vivo bioavailability study 3.5, 3.67, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 15, 16, 20, 24, 30, 36, US 2015/0290211 A1 Oct. 15, 2015 48

48,72, 96, 120, 144, or 168 hours after administering. Col following oral administration. In some instances, the pharma lection of a blood sample from one or more Subjects can occur ceutical composition is a bi-layer tablet comprising an imme at about: 8, 12, 15, 19, 22, 29, 33, 36,43, 50, 57, 64, 70, 80, or diate-release layer and a controlled-release layer. 90 days after administering. Blood samples can be frozen 0234. In some instances, an immediate-release layer com immediately following collection. Blood samples can remain prises promethazine or a pharmaceutically acceptable salt as frozen until assayed. Blood samples can be analyzed as soon the only pharmaceutically active agent. In another instance, as they are collected. Plasma can be separated immediately the controlled-release layer comprises hydrocodone or a following collection. Plasma can be frozen immediately fol pharmaceutically acceptable salt and acetaminophen or a lowing separation. Plasma can remain frozen until assayed. pharmaceutically acceptable salt as the only pharmaceutical ingredients. In some instances, the controlled-release layer Multi-Layer Tablets comprises hydrocodone or a pharmaceutically acceptable salt 0232 A pharmaceutical composition as described herein as the only pharmaceutical ingredients. can be multi-layer tablets, such as bi-layer tablets or two layer 0235. In some instances, a controlled-release layer com tablets. In one instance, the bi-layer tablet comprises: (a) an prises an opioid analgesic or a non-opioid analgesic as the immediate-release layer, and (b) a controlled-release layer. In only pharmaceutically active agent. In another instance, the one instance, the two layer tablet comprises: (a) an immedi controlled-release layer comprises an opioid analgesic and a ate-release layer, and (b) a controlled-release layer. In some non-opioid analgesic as the only pharmaceutically active instances, the immediate-release layer or the controlled-re agents. In some instances, the immediate-release layer com lease layer comprises one or more pharmaceutically active prises an antiemetic or a stimulant as the only pharmaceuti agents. In one instance, a bi-layer tablet herein has a hardness cally active agent. In another instance, the immediate-release of about 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, layer comprises an antiemetic and a stimulant as the only 13.5, 14, 14.5 or 15 kiloponds (kp). In one instance, the pharmaceutically active agents. bi-layer tablet has a hardness of about 9.5 kp. In a further instance, a bi-layer tablet herein has a thickness of about 5, Immediate-Release Layer 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,9.5, or 10 mm. It can be understood 0236. In some instances, an immediate-release layer is that as to the kilopond and thickness measurements, incre capable of releasing about 70 to about 80% of the one or more ments of 0.1 decimal points are within the scope herein. In pharmaceutically active agent contained therein in the stom Some instances, the tablet can be rectangular, tubular, oblong, ach of a subject in about 5 to about 10 minutes following oral circular, oval or in a capsule form. administration. In one instance, the immediate-release layer 0233. In some instances, a bi-layer tablet herein provides is capable of releasing about 90 to about 100% of one or more an effective amount of one or more pharmaceutically active pharmaceutically active agent contained therein in the stom agents for about 4 to about 8 hours following oral adminis ach of a subject in about 40 minutes. tration, about 4-6 hours following oral administration, or 0237. In some instances, a one or more pharmaceutically about 6-8 hours following oral administration. In some active agent in the immediate-release layer is an antiemetic. instances, the one or more pharmaceutically active agents can In one instance, the antiemetic is promethazine or a pharma be administered to a subject in about 4-hour, 5 hour, 6 hour, 7 ceutically acceptable salt thereof. In another instance, the hour or 8 hour dosing intervals. Therefore, a bi-layer tablet antiemetic is promethazine HC1. In some instances, an imme herein is capable of providing any of the one or more phar diate-release layer comprises two or more agents, including maceutically active agents disclosed herein in the foregoing an anti-emetic and a stimulant. dosing intervals. In some instances, a pharmaceutical com 0238. In some instances, an immediate-release layer com position comprises promethazine or a pharmaceutically prises one or more excipients, including but not limited to acceptable salt thereof and about 70 to about 80% of the silicified microcrystalline cellulose (e.g., HD90), croscar promethazine orpharmaceutically acceptable salt thereof dis mellose Sodium (AC-Di-Sol), magnesium Stearate. In one solves in the stomach of a subject after about 5 to about 10 instance, the total layer weight of the immediate-release layer minutes following oral administration. In one instance, the is from about 100 to about 300 mg, such as about 110 mg. promethazine is promethazine HC1. In some instances, a about 120 mg, about 130 mg, about 140 mg, about 150 mg. pharmaceutical composition comprises hydrocodone or a about 160 mg, about 170 mg, about 180 mg, about 190 mg. pharmaceutically acceptable salt thereof and about 30 to about 200 mg, about 210 mg, about 220 mg, about 230 mg. about 60% of the hydrocodone or pharmaceutically accept about 240 mg, about 250 mg, about 260 mg, about 270 mg. able salt thereof dissolves in the stomach of a subject after about 280 mg, about 290 mg. or about 300 mg. about 5 to about 10 minutes following oral administration. In 0239. In some instances, the immediate-release layer Some instances, the hydrocodone salt is hydrocodone bitar comprises from about 75 to about 150 mg of silicified micro trate. In one instance, a pharmaceutical composition com crystalline cellulose, from about 10 to about 20 mg croscar prises acetaminophen or a pharmaceutically acceptable salt mellose Sodium, from about 0.5 to 2 mg magnesium Stearate. thereof and 50% to about 70% of the acetaminophen or phar In yet a further instance, the immediate-release layer com maceutically acceptable salt thereof dissolves in the stomach prises from about 10 to about 15 mg promethazine, or a of a subject after about 5 to about 10 minutes following oral pharmaceutically acceptable salt thereof. In another instance, administration. In some instances, a pharmaceutical compo the immediate-release layer comprises about 12.5 mg sition comprises promethazine or a pharmaceutically accept promethazine or a pharmaceutically acceptable salt thereof. able salt thereof, hydrocodone or a pharmaceutically accept In another instance, the pharmaceutically acceptable salt is able Salt thereof and acetaminophen or a pharmaceutically promethazine HC1. In some instances, an immediate-release acceptable salt thereof, and at least 90% of the pharmaceuti layer comprise about 12.5 mg promethazine HCl, about 121.5 cally active agents in the pharmaceutical composition dis mg silicified microcrystalline cellulose, about 15 mg croscar solve in the stomach of a subject after about 45 minutes mellose Sodium, and about 1 mg magnesium Stearate. US 2015/0290211 A1 Oct. 15, 2015 49

0240. In some instances, a pharmaceutical composition pharmaceutically acceptable salt thereof. In one instance, the comprising an effective amount of each of hydrocodone bitar controlled-release layer comprises about 325 mg acetami trate, acetaminophen and promethazine HCl is capable of nophen or a pharmaceutically acceptable salt thereof. In some dissolving in the stomach of a Subject so that an effective instances, an immediate-release layer comprises promethaZ plasma concentration of each of pharmaceutically active ine HCl and the controlled-release layer comprises hydroc ingredient is present in a subject in from about 5 to about 30 odone bitartrate. In another instance, the controlled-release minutes. In one instance, a pharmaceutical composition com layer further comprises a non-opioid analgesic (e.g., acetami prising an effective amount of each of hydrocodone bitartrate nophen). and promethazine HCl is capable of dissolving in the stomach 0243 In one instance, one or more pharmaceutically of a subject so that an effective plasma concentration of each active agents of the controlled-release layer is an opioid anal of pharmaceutically active ingredient is present in a subject in gesic. In one instance, the opioid analgesic is hydrocodone or from about 5 to about 30 minutes. oxycodone; or a pharmaceutically acceptable salt thereof. In one instance, the immediate-release layer is about 150 mg in Controlled-Release Layer total layer weight and the controlled-release layer is about 0241. In some instances, a controlled-release layer is 550 mg total weight. capable of releasing about 30 to about 40% of the one or more 0244. In some instances, a controlled-release layer com pharmaceutically active agent contained therein in the stom prises about 325 mg acetaminophen, about 7.5 mg hydroc ach of a subject in about 5 to about 10 minutes following oral odone bitartrate, about 152 mg silicified microcrystalline cel administration. In another instance, the controlled-release lulose, about 20 mg hydroxyl methyl propyl cellulose layer is capable of releasing about 90% of the one or more (HPMC), about 2.75 mg magnesium stearate, and about 2.75 pharmaceutically active agents are released in about 40 min mg Stearic acid; and the immediate-release layer comprises utes after oral administration. about 12.5 mg promethazine HCl, about 121 mg silicified 0242. In some instances, a controlled-release layer com microcrystalline cellulose, about 15 mg croScarmellose prises one or more excipients, including but not limited to Sodium, and about 1 mg magnesium Stearate. In one instance, silicified microcrystalline cellulose (e.g., HD90), croscar the controlled-release layer comprises about 7.5 mg hydroc mellose sodium (AC-Di-Sol), or magnesium Stearate. In one odone bitartrate, about 152 mg silicified microcrystalline cel instance, the total layer weight of the controlled-release layer lulose, about 20 mg hydroxyl methyl propyl cellulose is from about 100 to about 300 mg, such as about 110 mg. (HPMC), about 2.75 mg magnesium stearate, and about 2.75 about 120 mg, about 130 mg, about 140 mg, about 150 mg. mg stearic acid; and the immediate-release layer comprises about 160 mg, about 170 mg, about 180 mg, about 190 mg. about 12.5 mg promethazine HCl, about 121 mg silicified about 200 mg, about 210 mg, about 220 mg, about 230 mg. microcrystalline cellulose, about 15 mg croScarmellose about 240 mg, about 250 mg, about 260 mg, about 270 mg. Sodium, and about 1 mg magnesium Stearate. about 280 mg, about 290 mg. or about 300 mg. In some instances, a controlled-release layer comprises from about 75 In some instances, a bi-layer tablet herein can comprise any mg to about 250 mg of silicified microcrystalline cellulose, combination of pharmaceutically active agents herein, from about 10 to about 40 mg hydroxyl methyl propyl cellu wherein a controlled-release layer comprises one or more lose, from about 0.5 to 5 mg magnesium Stearate, and from opioid analgesic agents, non-analgesic agents, barbiturates or about 0.5 to about 5 mg Stearic acid. In some instances, a stimulants, and an immediate-release layer comprises one or controlled-release layer comprises about 152 mg silicified more stimulants. In some instances, a stimulant is present in microcrystalline cellulose, about 20 mg hydroxyl methyl pro the immediate-release layer, controlled-release layer or both pyl cellulose, about 2.75 mg magnesium Stearate, about 2.75 layers; the immediate-release layer comprises one or more Stearic acid, about 7.5 mg hydrocodone or a pharmaceutically antiemetics; and the controlled-release layer comprises one acceptable salt thereof, about 325 mg acetaminophen or a or more non-opioid analgesics. In addition, either layer of the pharmaceutically acceptable salt thereof. In another instance, bi-layered tablet can comprise one or more anti-abuse agents the controlled-release layer comprises about 152 mg silicified disclosed herein. In some instances, a bi-layer tablet herein microcrystalline cellulose, about 20 mg hydroxyl methyl pro comprises a controlled-release layer comprising one or more pyl cellulose, about 2.75 mg magnesium Stearate, about 2.75 analgesic agents as the only pharmaceutically active agents in Stearic acid, about 7.5 mg hydrocodone or a pharmaceutically the controlled-release layer. In another instance, a bi-layer acceptable salt thereof. In yet a further instance, the con tablet herein comprises an immediate-release layer compris trolled-release layer comprises from about 5 to about 12.5 mg ing an antiemetic agent as the only pharmaceutically active hydrocodone or a pharmaceutically acceptable salt thereof. In agent in the immediate-release layer. one instance, the controlled-release layer comprises about 7.5 0245. In some instances, a controlled-release layer further mg hydrocodone or a pharmaceutically acceptable salt comprises one or more of silicified microcrystalline cellu thereof. In some instances, the controlled-release layer com lose, hydroxy methyl propyl cellulose, magnesium Stearate, prises about 5 mg hydrocodone or a pharmaceutically accept and Stearic acid. In another instance, the immediate-release able salt thereof. In some instances, the controlled-release layer further comprises one or more of silicified microcrys layer comprises about 10 mg hydrocodone or a pharmaceu talline cellulose, croscarmellose sodium and magnesium tically acceptable salt thereof. In another instance, the opioid Stearate. In another instance, the tablet has a hardness of about analgesic is oxycodone or a pharmaceutically acceptable salt 9.5 kilopond and thickness from about 6.9 to about 7.0 mm. In thereof. In one instance, the pharmaceutically acceptable salt another instance, the hydrocodone salt is hydrocodone bitar is oxycodone HC1. In some instances, the pharmaceutically trate. In another instance, the promethazine salt is promethaZ acceptable salt for hydrocodone is hydrocodone bitartrate. In ine HCL. In another instance, the controlled-release layer is Some instances, a controlled-release layer further comprises an inner layer and wherein the immediate-release layer is an from about 290 mg to about 360 mg acetaminophen or a outer layer. US 2015/0290211 A1 Oct. 15, 2015 50

0246. In some instances, an opioid analgesic is oxycodone prises about 7.5 mg of hydrocodone or a pharmaceutically or pharmaceutically acceptable salt thereof and the one or acceptable salt thereof; and further wherein the immediate more antiemetic is promethazine or a pharmaceutically release layer comprises about 12 mg of promethazine or a acceptable salt thereof. In another instance, the effective pharmaceutically acceptable salt thereof. In some instances, amount is an amount effective for treating or preventing pain an effective amount is an amount effective for treating or for a period of about 4-8 hours following administration to a preventing pain for a period of about 4-8 hours following Subject (e.g., 4-6, 4-8, 6-8 hours). In another instance, the administration to a subject (e.g., 4-6, 4-8, 6-8 hours) in need bi-layer tablet comprises an immediate-release layer and a thereof. In some instances, an effective amount of the oxyc controlled-release layer. In another instance, the two layer odone or pharmaceutically acceptable salt thereof is an tablet comprises an immediate-release layer and a controlled amount effective for treating or preventing pain for a period of release layer. In another instance, the immediate-release layer about 4-8 hours following administration to a Subject (e.g., comprises the promethazine or pharmaceutically acceptable 4-6, 4-8, 6-8 hours) in need thereof. salt thereof, and wherein the controlled-release layer com prises the oxycodone, or a pharmaceutically acceptable salt Combination Formulations thereof. In another instance, about 70% of the promethazine (0250) Some instances of the disclosure are directed to or pharmaceutically acceptable salt thereof is capable of dis pharmaceutical compositions comprising an effective Solving in a liquid Solution in about 5 minutes after contact amount of each of an analgesic and an active agent that is with the solution, and wherein about 30% of the oxycodone or useful for reducing an adverse effect associated with the pharmaceutically acceptable salt is capable of dissolving in a analgesic, such as one or more opioid analgesics, or one or liquid solution in about 10 minutes after contact with the more non-opioid analgesic. Such additional active agents Solution. In another instance, the controlled-release layer fur include an antiemetic. In some instances, an analgesic is an ther comprises an antiemetic agent. opioid or non-opioid analgesic (e.g., hydrocodone or oxyc 0247. In some instances, the effective amount of hydroc odone, or a pharmaceutically acceptable salt thereof and odone or pharmaceutically acceptable salt thereof is an acetaminophen or a pharmaceutically acceptable salt amount effective for treating or preventing pain for a period of thereof). In a further instance, the active agent which reduces about 4-8 hours following administration to a Subject (e.g., adverse effects of Such analgesics is promethazine or a phar 4-6, 4-8, 6-8 hours). In another instance, the controlled-re maceutically acceptable salt thereof. In some instances, a lease layer comprises about 7.5 mg of hydrocodone or a pharmaceutical composition disclosed herein allows for pharmaceutically acceptable salt thereof, about 360 mg of higher dosages for an analgesic in a pharmaceutical compo acetaminophen or a pharmaceutically acceptable salt thereof, sition, by reducing adverse effects associated with an opioid about 152 mg of silicified microcrystalline cellulose, about 20 or non-opioid analgesic. For example, in a subject who could mg of hydroxy methyl propyl cellulose, about 2.7 mg of not otherwise tolerate a particular dosage of an opioid anal magnesium Stearate, and about 2.7 mg of stearic acid; and the gesic, it is believed that a pharmaceutical composition dis immediate-release layer comprises about 12.5 mg of promet closed herein comprising an effective amount of each of an hazine or a pharmaceutically acceptable salt thereof, about opioid analgesic, a non-opioid analgesic and promethazine or 121.5 mg of silicified microcrystalline cellulose, about 15 mg a pharmaceutically acceptable salt thereof, can reduce an of croScarmellose Sodium and about 1 mg of magnesium adverse effects (e.g. nausea, vomiting, or constipation) asso Stearate. In another instance, the controlled-release layer ciated with an opioid analgesic, thus allowing for increased comprises about 7.5 mg of hydrocodone or a pharmaceuti dosages to be administered. Furthermore, administration can cally acceptable salt thereof, about 152 mg of silicified micro be through a single pharmaceutical composition. crystalline cellulose, about 20 mg of hydroxy methyl propyl 0251. In some instances, a pharmaceutical composition cellulose, about 2.7 mg of magnesium Stearate, and about 2.7 includes an opioid analgesic agent. In such instances, the mg of stearic acid; and the immediate-release layer comprises opioid analgesic can comprise hydrocodone, oxycodone, about 12.5 mg of promethazine or a pharmaceutically accept acetyldihydrocodeinone, diamorphine, codeine, pethidine, able salt thereof, about 121.5 mg of silicified microcrystalline alfentanil, codeine, fentanyl, hydromorphone, levorphanol, cellulose, about 15 mg of croScarmellose sodium and about 1 meperidine, methadone, morphine Sulfate, oxymorphone, mg of magnesium Stearate. propoxyphene, remifentanil, Sufentanil, tapentadol, trama 0248. In some instances, a pharmaceutical composition dol, or a pharmaceutically acceptable salt of any one of the comprises an effective amount of naltrexone or a pharmaceu foregoing, or any combination thereof. In one instance, the tically acceptable salt thereof. In another instance, the phar opioid analgesic agent is hydrocodone, oxycodone, pro maceutical composition is in the form of a bi-layer tablet. In poxyphene, or fentanyl or a pharmaceutically acceptable salt another instance, the pharmaceutical composition is in the of any one of the foregoing, or any combination thereof. form of a two layer tablet. In another instance, the effective 0252. In another instance, a dosage form comprises an amount of the morphine or pharmaceutically acceptable salt opioid analgesic and one or more antiemetics. In another thereof is an amount effective for treating or preventing pain instance, a dosage form comprises hydrocodone or oxyc for a period of about 4-8 hours following administration to a odone or a pharmaceutically acceptable salt of any one of the Subject (e.g., 4-6, 4-8, 6-8 hours). foregoing, or any combination thereof and one or more anti 0249. In some instances, a controlled-release layer com emetic, which are disclosed herein. prises about 7.5 mg of hydrocodone or a pharmaceutically 0253. In some instances, a pharmaceutical composition acceptable salt thereof, and about 360 mg of acetaminophen disclosed herein comprises an opioid antagonist agent or or a pharmaceutically acceptable salt thereof; and further abuse deterrent agent Such as nalmefene, naloxone, niacin, wherein the immediate-release layer comprises about 12 mg maltrexone or a pharmaceutically acceptable salt of any one of of promethazine or a pharmaceutically acceptable salt the foregoing, or any combination thereof. The pharmaceuti thereof. In one instance, the controlled-release layer com cal composition can further comprise an antitussive Such as US 2015/0290211 A1 Oct. 15, 2015 codeine or dextromethorphan, dextrorphan, or a pharmaceu prises an effective amount of one or more of an opioid agent, tically acceptable salt of any one of the foregoing, or any a non-opioid analgesic agent and an active agent useful for combination thereof. reducing or eliminating adverse effects associated with 0254. In some instances, a pharmaceutical composition administration of an opioid analgesic agent or non-opioid comprises an opioid analgesic and an antiemetic further com analgesic agent. In some instances, a pharmaceutical compo prises one or more of an abuse deterrent agent, a barbiturate, sition further comprises an effective amount of an opioid a non-opioid analgesic, a laxative, a stimulant, or any com antagonist agent or abuse deterrent agent. In a specific bination thereof. In one instance, the pharmaceutical compo instance, the pharmaceutical composition comprises hydro sition comprises an opioid analgesic, an antiemetic, and an codone or oxycodone, or a pharmaceutically acceptable salt abuse deterrentagent. In another instance, the pharmaceutical thereof, acetaminophen or a pharmaceutically acceptable salt composition comprises an opioid analgesic, an antiemetic, thereof, or naproxen or a pharmaceutically acceptable salt and a non-opioid analgesic. In some instances, the pharma thereof, and promethazine or a pharmaceutically acceptable ceutical composition comprises an opioid analgesic, an anti salt thereof. In a specific instance, the pharmaceutical com emetic, and a non-opioid analgesic. In another instance, the position comprises hydrocodone or oxycodone, or a pharma pharmaceutical composition comprises an opioid analgesic, ceutically acceptable salt thereof, and promethazine or a an antiemetic, and a laxative. In some instances, the pharma pharmaceutically acceptable salt thereof. In a specific ceutical composition comprises an opioid analgesic, an anti instance, the pharmaceutical composition comprises hydro emetic, and a stimulant. In some instances, the pharmaceuti codone or oxycodone, or a pharmaceutically acceptable salt cal composition comprises an opioid analgesic, an thereof, acetaminophen or a pharmaceutically acceptable salt antiemetic, a laxative, and a stimulant. In some instances, the thereof, and promethazine or a pharmaceutically acceptable pharmaceutical composition comprises an opioid analgesic, salt thereof. In a specific instance, the pharmaceutical com an antiemetic, a non-opioid analgesic, and a laxative. In position comprises hydrocodone or oxycodone, or a pharma another instance, the pharmaceutical composition comprises ceutically acceptable salt thereof, naproxen or a pharmaceu an opioid analgesic, an antiemetic, a non-opioid analgesic, a tically acceptable salt thereof, and promethazine or a laxative, and a stimulant. pharmaceutically acceptable salt thereof. 0255 In some instances, a pharmaceutical composition 0257. In some instances, an agent useful for preventing or disclosed herein comprises an effective amount of each of an alleviating an adverse effect associated with administration of opioid analgesic agent and a non-opioid analgesic agent, an opioid analgesic or a non-opioid analgesic, a tripan, a where the opioid analgesic agent/non-opioid analgesic agent barbiturate or a morphine narcotic, includes, for example, an is codeinefacetaminophen, codeinefacetylsalicylic acid, antihistamine including a histamine agonistandanantagonist codeine/naproxen, codeine/ibuprofen, hydrocodone?ac which is classified according to receptor Subtype. The agent etaminophen, hydrocodone/ibuprofen, hydrocodone? useful for preventing or Suppressing an adverse effect can also naproxen, hydrocodonefacetylsalicylic acid, oxycodone?ac include an H1, H2,H3, or H4 histamine antagonist. etaminophen, oxycodonefacetylsalicylic acid, oxycodone? 0258. In some instances, a pharmaceutical composition naproxen, Oxycodone/ibuprofen, propoxyphene/ comprises two, three, four, five, six or more active agents. In acetylsalicylic acid, propoxyphenefibuprofen, one instance, at least one of the active agents is an antiemetic propoxyphenefacetaminophen, or propoxyphene/naproxen, Such as promethazine or a pharmaceutically acceptable salt wherein the opioid analgesic agent or non-opioid analgesic thereof. As indicated herein, a pharmaceutical composition agent can be in the form of a pharmaceutically acceptable salt can comprise pharmaceutically active agents herein in any thereof. In one instance, the hydrodocone salt is hydrocodone combinations. In some instances, a pharmaceutical composi bitartrate, the oxycodone salt is oxycodone HCl, and the tion comprises at least two analgesics; and one or more addi naproxen salt is naproxen Na or Mg. tional pharmaceutically active agents disclosed herein. In one 0256 In some instances, a pharmaceutical compositions instance, the pharmaceutical composition further comprises disclosed herein can further comprise one or more of an one antiemetic. In some instances, a pharmaceutical compo opioid antagonist agent, abuse deterrent agent, a barbiturate sition comprises a stimulantagent. In some instances, a phar agent, a stimulantagent, a laxative agent, an antiemetic agent, maceutical composition comprises a stimulantagent that pro or any combination thereof. In some instances, a pharmaceu vides an anti-sedative effect. tical composition comprises an effective amount of an opioid 0259. In some instances, a pharmaceutical composition analgesic agent (Such as hydrocodone or oxycodone or a comprised an effective amount of an opioid (such as hydro pharmaceutically acceptable salt thereof), a non-opioid anal codone, propoxyphene, fentanyl or oxycodone, or a pharma gesic agent (such as acetaminophen or naproxen or a phar ceutically acceptable salt of any one of the foregoing, or any maceutically acceptable salt thereof) and an active agent use combination thereof) and a stimulant (Such as modafinil or ful for reducing or eliminating adverse effects. Such as an caffeine, or a pharmaceutically acceptable salt of any one of antiemetic (e.g., promethazine or a pharmaceutically accept the foregoing, or any combination thereof). In some able salt thereof) or an antiemetic, as described herein. In one instances, a pharmaceutical composition comprises an anti instance, the pharmaceutical composition is in the form of a emetic. In some instances, the antiemetic is promethazine or bi-layer tablet that comprises an immediate-release layer and a pharmaceutically acceptable salt thereof. In yet another a controlled-release layer. In one instance, the pharmaceutical instance, the pharmaceutical composition further comprises a composition is in the form of a two layer tablet that comprises non-analgesic agent disclosed herein. In some instances, the an immediate-release layer and a controlled-release layer. In non-opioid analgesic is acetaminophen or a pharmaceutically a further instance, the immediate-release layer comprises one acceptable salt thereof, or naproxen or a pharmaceutically or more of an opioid agent, a non-opioid analgesic agent and acceptable salt thereof. an active agent useful for reducing or eliminating adverse 0260. In some instances, a pharmaceutical composition is effects. In a further instance, a controlled-release layer com in the form of a bi-layer tablet comprising an immediate US 2015/0290211 A1 Oct. 15, 2015 52 release layer and a controlled-release layer, wherein the opioidantagonist agent or abuse deterrent agent. In a specific immediate-release layer comprises and/or the chronic-re instance, a pharmaceutical composition comprises hydroc lease layer comprise a stimulant agent. In one instance, the odone or oxycodone, or a pharmaceutically acceptable salt of controlled-release layer comprises an opioid agent. In some any one of the foregoing, or any combination thereof, instances, the controlled-release layer further comprises an acetaminophen, or a pharmaceutically acceptable salt effective amount of a second or same stimulant agent as thereof, butalbital or a pharmaceutically acceptable salt compared to the immediate-release layer. In some instances, thereof and promethazine or a pharmaceutically acceptable the immediate-release layer and/or the controlled-release salt thereof. In a specific instance, a pharmaceutical compo layer further comprises an antiemetic agent. In some sition comprises hydrocodone or oxycodone, or a pharma instances, the immediate-release layer comprises an effective ceutically acceptable salt of any one of the foregoing, or any amount of one or more of an opioid agent, a stimulant agent combination thereof, acetaminophen, or a pharmaceutically and an antiemetic agent. In some instances, a controlled acceptable salt thereof, and butalbital or a pharmaceutically release layer comprises an effective amount of one or more of acceptable salt thereof. an opioid agent, a stimulantagent, and an antiemetic agent. In 0264. In another instance, a pharmaceutical composition Some instances, the pharmaceutical composition further com comprises an effective amount of each of an opioid agent prises an effective amount of an opioid antagonist agent or (such as hydrocodone, propoxyphene, fentanyl or oxycodone abuse deterrent agent. or a pharmaceutically acceptable salt of any one of the fore 0261. In a specific instance, a pharmaceutical composition going, or any combination thereof); a barbiturate agent (Such is provided that comprises hydrocodone or oxycodone, or a as butalbital or a pharmaceutically acceptable salt thereof); a pharmaceutically acceptable salt of any one of the foregoing, stimulant agent (Such as modafinil or caffeine or a pharma or any combination thereof, modafinil or caffeine or a phar ceutically acceptable salt of any one of the foregoing, or any maceutically acceptable Salt of any one of the foregoing, or combination thereof); and a non-opioid agent (such as any combination thereof and promethazine or a pharmaceu acetaminophen or naproxen or a pharmaceutically acceptable tically acceptable salt thereof. In a specific instance, a phar salt of any one of the foregoing, or any combination thereof). maceutical composition is provided that comprises hydroc In another instance, a pharmaceutical composition comprises odone or oxycodone, or a pharmaceutically acceptable salt of an effective amount of each of an opioid agent (Such as any one of the foregoing, or any combination thereof, and hydrocodone, propoxyphene, fentanyl or oxycodone or a modafinil or caffeine or a pharmaceutically acceptable salt of pharmaceutically acceptable salt of any one of the foregoing, any one of the foregoing, or any combination thereof. or any combination thereof); a barbiturate agent (such as 0262. In another instance, a pharmaceutical composition butalbital or a pharmaceutically acceptable salt thereof); and is provided that comprises an effective amount of an opioid a stimulantagent (such as modafinil or caffeine or a pharma agent (such as hydrocodone, propoxyphene, fentanyl or oxy ceutically acceptable salt of any one of the foregoing, or any codone, or a pharmaceutically acceptable salt of any one of combination thereof). In some instances, the pharmaceutical the foregoing, or any combination thereof); a non-opioid composition further comprises an antiemetic (such as agent (such as acetaminophen or naproxen, or a pharmaceu promethazine or a pharmaceutically acceptable salt thereof). tically acceptable salt of any one of the foregoing, or any 0265. In one instance, a pharmaceutical composition is in combination thereof); a barbiturate agent (such as butalbital, the form of a bi-layer tablet, wherein the pharmaceutical or a pharmaceutically acceptable salt thereof) and an anti composition comprises an effective amount of an opioid emetic (such as promethazine, or a pharmaceutically accept agent, a non-opioid analgesic agent, a barbiturate agent, a able salt thereof). In another instance, a pharmaceutical com stimulantagent and an antiemetic agent. In one instance. Such position is provided that comprises an effective amount of an a pharmaceutical composition is in the form of a bi-layer opioid agent (such as hydrocodone, propoxyphene, fentanyl tablet, wherein the pharmaceutical composition comprises an or oxycodone, or a pharmaceutically acceptable salt of any effective amount of an opioid agent, a non-opioid analgesic one of the foregoing, or any combination thereof); a non agent, a barbiturate agent, and a stimulant agent. In one opioid agent (such as acetaminophen or naproxen, or a phar instance, such a pharmaceutical composition is in the form of maceutically acceptable Salt of any one of the foregoing, or a two layer tablet, wherein the pharmaceutical composition any combination thereof); and a barbiturate agent (Such as comprises an effective amount of an opioid agent, a non butalbital, or a pharmaceutically acceptable salt thereof). opioid analgesic agent, a barbiturate agent, a stimulant agent 0263. In a further instance, a pharmaceutical composition and an antiemetic agent. In one instance, Such a pharmaceu is in the form of a bi-layer tablet, wherein the pharmaceutical tical composition is in the form of a two layer tablet, wherein composition comprises an effective amount of each of an the pharmaceutical composition comprises an effective opioid agent, a non-opioid analgesic agent, a barbiturate amount of an opioid agent, a non-opioid analgesic agent, a agent and an antiemetic agent. In one instance, the bi-layer barbiturate agent, and a stimulant agent. In one instance, the tablet comprises an immediate-release layer and a controlled bi-layer tablet comprises an immediate-release layer and a release layer. In one instance, the two layer tablet comprises controlled-release layer. In one instance, the two layer tablet an immediate-release layer and a controlled-release layer. In comprises an immediate-release layer and a controlled-re a further instance, the immediate-release layer comprises an lease layer. In a further instance, the immediate-release layer effective amount of one or more of an opioid agent, a non comprises an effective amount of one or more of an opioid opioid analgesic agent, a barbiturate agent and an antiemetic agent, a non-opioid analgesic agent, a barbiturate agent, a agent. In another further instance, a controlled-release layer stimulant agent and an antiemetic agent. In another further comprises an effective amount of one or more of an opioid instance, a controlled-release layer comprises an effective agent, a barbiturate agent, a non-opioid analgesic agent, and amount of one or more of an opioid agent, a non-opioid an antiemetic agent. In some instances, a pharmaceutical analgesic agent, a barbiturate agent, a stimulantagent and an composition further comprises an effective amount of an antiemetic agent. In some instances, a pharmaceutical com US 2015/0290211 A1 Oct. 15, 2015 position further comprises an effective amount of an opioid thereof). In one instance, the pharmaceutical composition antagonist agent or abuse deterrent agent. In a specific comprises about 50 mg butalbital or a pharmaceutically instance, a pharmaceutical composition comprises hydroc acceptable salt thereof, about 325 mg N-Acetyl-p-Ami odone, propoxyphene or oxycodone, or a pharmaceutically nophenol or a pharmaceutically acceptable salt thereof, and acceptable salt of any one of the foregoing, or any combina about 12.5 mg promethazine or a pharmaceutically accept tion thereof, butalbital, naproxen, caffeine or a pharmaceuti able salt thereof. In one instance, the promethazine salt is cally acceptable salt of any one of the foregoing, or any promethazine HC1. combination thereof, and promethazine or a pharmaceuti 0268. In another instance, a pharmaceutical composition cally acceptable salt thereof. In a specific instance, a pharma comprises an effective amount of each of a non-opioid agent ceutical composition comprises hydrocodone, propoxyphene (such as acetaminophen, naproxen or ibuprofen or a pharma or oxycodone, or a pharmaceutically acceptable salt of any ceutically acceptable salt of any one of the foregoing, or any one of the foregoing, or any combination thereof, and butal combination thereof); a barbiturate agent (such as butalbital bital, naproxen, caffeine or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof); and a stimu of any one of the foregoing, or any combination thereof. lant agent (Such as modafinil or caffeine or a pharmaceuti 0266. In another instance, a pharmaceutical composition cally acceptable salt of any one of the foregoing, or any comprises an effective amount of an opioid agent (hydroc combination thereof). In some instances, the pharmaceutical odone or oxycodone or a pharmaceutically acceptable salt of composition further comprises an antiemetic (such as any one of the foregoing, or any combination thereof); and a promethazine or a pharmaceutically acceptable salt thereof). barbiturate agent (such as butalbital or a pharmaceutically In a further instance, an effective amount of a pharmaceutical acceptable salt thereof). In some instances, a pharmaceutical composition is in the form of a bi-layer tablet, wherein the composition further comprises an antiemetic (Such as pharmaceutical composition comprises an effective amount promethazine or a pharmaceutically acceptable salt thereof). of each of a non-opioid analgesic agent, a barbiturate agent, a In a further instance, the pharmaceutical composition is in the stimulantagent and an antiemetic agent. In a further instance, form of a bi-layer tablet, wherein the pharmaceutical compo an effective amount of a pharmaceutical composition is in the sition comprises an effective amount of each of an opioid form of a bi-layer tablet, wherein the pharmaceutical compo analgesic agent, a barbiturate agent, and an antiemetic agent. sition comprises an effective amount of each of a non-opioid In a further instance, the pharmaceutical composition is in the analgesic agent, a barbiturate agent, and a stimulantagent. In form of a bi-layer tablet, wherein the pharmaceutical compo one instance, the bi-layer tablet comprises an immediate sition comprises an effective amount of each of an opioid release layer and a controlled-release layer. In a further analgesic agent, and a barbiturate agent. In one instance, the instance, an effective amount of a pharmaceutical composi bi-layer tablet comprises an immediate-release layer and a tion is in the form of a two layer tablet, wherein the pharma controlled-release layer. In a further instance, the pharmaceu ceutical composition comprises an effective amount of each tical composition is in the form of a two layer tablet, wherein of a non-opioid analgesic agent, a barbiturate agent, a stimu the pharmaceutical composition comprises an effective lant agent and an antiemetic agent. In a further instance, an amount of each of an opioid analgesic agent, a barbiturate effective amount of a pharmaceutical composition is in the agent, and an antiemetic agent. In a further instance, the form of a two layer tablet, wherein the pharmaceutical com pharmaceutical composition is in the form of a two layer position comprises an effective amount of each of a non tablet, wherein the pharmaceutical composition comprises an opioid analgesic agent, a barbiturate agent, and a stimulant effective amount of each of an opioid analgesic agent, and a agent. In one instance, the two layer tablet comprises an barbiturate agent. In one instance, the two layer tablet com immediate-release layer and a controlled-release layer. In a prises an immediate-release layer and a controlled-release further instance, the immediate-release layer comprises an layer. In a further instance, the immediate-release layer com effective amount of one or more of a non-opioid analgesic prises an effective amount of each of one or more of an opioid agent, a barbiturate agent, a stimulantagent or an antiemetic analgesic agent, a barbiturate agent, oran antiemetic agent. In agent. In a further instance, a controlled-release layer com another instance, a controlled-release layer comprises an prises one or more of a non-opioid analgesic agent, a barbi effective amount of each of one or more of an opioid analgesic turate agent, stimulant agent or an antiemetic agent. In a agent, a barbiturate agent, or an antiemetic agent. In some specific instance, a pharmaceutical composition comprises instances, the pharmaceutical composition further comprises butalbital, naproxen, caffeine, or a pharmaceutically accept an effective amount of an opioid antagonist agent or abuse able salt of any one of the foregoing, or any combination deterrent agent. In a specific instance, a pharmaceutical com thereof and promethazine or a pharmaceutically acceptable position comprises butalbital, hydrocodone or oxycodone, or salt thereof. In a specific instance, a pharmaceutical compo a pharmaceutically acceptable salt of any one of the forego sition comprises butalbital, naproxen, caffeine, or a pharma ing, or any combination thereof and promethazine or a phar ceutically acceptable salt of any one of the foregoing, or any maceutically acceptable salt thereof. In a specific instance, a combination thereof. pharmaceutical composition comprises butalbital, hydroc 0269. In another instance, a pharmaceutical composition odone or oxycodone, or a pharmaceutically acceptable salt of comprises an effective amount of a barbiturate agent (such as any one of the foregoing, or any combination thereof. butalbital or a pharmaceutically acceptable salt thereof) and a 0267 In another instance, a pharmaceutical composition stimulant agent (Such as modafinil or caffeine or a pharma comprises an effective amount of a non-opioid agent (such as ceutically acceptable salt of any one of the foregoing, or any acetaminophen, naproxen or ibuprofen or a pharmaceutically combination thereof). In some instances, the pharmaceutical acceptable salt of any one of the foregoing, or any combina composition further comprises an antiemetic (such as tion thereof); a barbiturate agent (such as butalbital or a promethazine or a pharmaceutically acceptable salt thereof). pharmaceutically acceptable salt thereof); and an antiemetic In another instance, a pharmaceutical composition is in the (such as promethazine or a pharmaceutically acceptable salt form of a bi-layer tablet, wherein the pharmaceutical compo US 2015/0290211 A1 Oct. 15, 2015 54 sition comprises an effective amount of each of a barbiturate caffeine or a pharmaceutically acceptable salt thereof and agent, a stimulant agent and an antiemetic agent. In another promethazine or a pharmaceutically acceptable salt thereof. instance, a pharmaceutical composition is in the form of a In a specific instance, a pharmaceutical composition com bi-layer tablet, wherein the pharmaceutical composition prises naproxen or a pharmaceutically acceptable salt thereof comprises an effective amount of each of a barbiturate agent, and caffeine or a pharmaceutically acceptable salt thereof. and a stimulant agent. In one instance, the bi-layer tablet 0271 In some instances, a pharmaceutical composition comprises an immediate-release layer and a controlled-re comprises one or more beta blockers, serotonin receptorago lease layer. In another instance, a pharmaceutical composi nists, vasoconstrictors, anti-platelet agents, anti-convulsants, tion is in the form of a two layer tablet, wherein the pharma ergots, or calcitonin-gene-related peptide (CGRP) receptor ceutical composition comprises an effective amount of each antagonists. In some instances, a pharmaceutical composi of a barbiturate agent, a stimulant agent and an antiemetic tion is administered to a Subject in need thereof in a single agent. In another instance, a pharmaceutical composition is in dosage form which comprises one or more active agents and the form of a two layer tablet, wherein the pharmaceutical one or more beta blockers, serotonin receptoragonists, vaso composition comprises an effective amount of each of a bar constrictors, anti-platelet agents, anti-convulsants, ergot biturate agent, and a stimulantagent. In one instance, the two alkaloids, and calcitonin-gene-related peptide (CGRP) recep layer tablet comprises an immediate-release layer and a con tor antagonists. In some instances, a single dosage form is a trolled-release layer. In a further instance, the immediate multilayered tablet which comprises one or more pharmaceu release layer comprises an effective amount of each of one or tically active agents which includes one or more beta block more of a barbiturate agent, a stimulantagent oran antiemetic ers, serotonin receptor agonists, vasoconstrictors, anti-plate agent. In another instance, a controlled-release layer com let agents, anti-convulsants, ergot alkaloids, or calcitonin prises an effective amount of each of one or more of a barbi gene-related peptide (CGRP) receptor antagonists. In one turate agent, stimulant agent or an antiemetic agent. In a instance, a multilayer tablet comprises at least one immedi specific instance, a pharmaceutical composition comprises ate-release layer and at least one controlled-release layer. butalbital or a pharmaceutically acceptable salt thereof, caf Pharmaceutical compositions herein can be administered feine or a pharmaceutically acceptable salt thereof and using other dosage forms disclosed herein. In yet other promethazine or a pharmaceutically acceptable salt thereof. instances, a pharmaceutical composition comprises one or In a specific instance, a pharmaceutical composition com more active agents disclosed herein are administered prior to, prises butalbital or a pharmaceutically acceptable salt thereof, concurrent with, or after administration of one or more beta and caffeine or a pharmaceutically acceptable salt thereof. blockers, serotonin receptor agonists, vasoconstrictors, anti platelet agents, anti-convulsants, ergot alkaloids, or calcito 0270. In another instance, a pharmaceutical composition nin-gene-related peptide (CGRP) receptor antagonists. In comprises an effective amount of a non-opioid agent (such as Some instances, the present methods for treating or prevent ibuprofen or naproxen or a pharmaceutically acceptable salt ing pain further comprise administering an effective amount of any one of the foregoing, or any combination thereof) and of one or more beta blockers, serotonin receptor agonists, a stimulantagent (such as modafinil or caffeine or a pharma vasoconstrictors, anti-platelet agents, anti-convulsants, ceutically acceptable salt of any one of the foregoing, or any ergots, or CGRP receptor antagonists. combination thereof). In some instances, the pharmaceutical composition further comprises an antiemetic (Such as 0272. In some instances, a pharmaceutical composition promethazine or a pharmaceutically acceptable salt thereof). can comprise one or more active agents comprise an opioid In one instance, the pharmaceutical composition is in the analgesic, an antiemetic, and a laxative. In some instances, form of a bi-layer tablet, wherein the pharmaceutical compo the laxative is present in an amount effective to reduce or sition comprises an effective amount of each of a non-opioid eliminate constipation. In some instances, the laxative is agent, a stimulant agent and an antiemetic agent. In one present in an amount effective to reduce or eliminate opioid instance, the pharmaceutical composition is in the form of a induced constipation. The laxative can be a bulk-producing bi-layer tablet, wherein the pharmaceutical composition agent, a stool softener, a lubricant, a hydrating agent, a stimu comprises an effective amount of each of a non-opioid agent, lant or irritant, a serotonin agonist, a chloride channel activa and a stimulant agent. In one instance, the bi-layer tablet tor. In some instances, the pharmaceutical compositions fur comprises an immediate-release layer and a controlled-re ther comprise a non-opioid analgesic, a barbiturate, an anti lease layer. In one instance, the pharmaceutical composition abuse agent, a stimulant, or any combination thereof. is in the form of a two layer tablet, wherein the pharmaceu Dosage tical composition comprises an effective amount of each of a non-opioid agent, a stimulantagent and an antiemetic agent. 0273. In some instances, a pharmaceutical composition In one instance, the pharmaceutical composition is in the disclosed herein comprises multiple active agents at the same form of a two layer tablet, wherein the pharmaceutical com or different dosages. In some instances, the analgesic com position comprises an effective amount of each of a non ponents can vary in dosages as further described herein, and opioid agent, and a stimulant agent. In one instance, the two the antiemetic dosage can be adjusted according to the par layer tablet comprises an immediate-release layer and a con ticular analgesics used. For example, in Some instances, a trolled-release layer. In a further instance, the immediate pharmaceutical composition comprises an opioid analgesic release layer comprises an effective amount of each of one or agent that is present in a single dose from of about 0.05 mg to more of a non-opioid agent, a stimulantagent oran antiemetic about 130 mg, including but not limited to 0.05 mg, 0.1 mg, agent. In another further instance, the controlled-release layer 0.2 mg, 0.3 mg, 0.4 mg., 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 comprises an effective amount of each of one or more of a mg, 1.0 mg, 1.2 mg, 1.5 mg, 2.5 mg, 3.0 mg. 4.0 mg, 4.8355 non-opioid agent, stimulantagent oran antiemetic agent. In a mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg. specific instance, a pharmaceutical composition comprises 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg. naproxen or a pharmaceutically acceptable salt thereof and 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 US 2015/0290211 A1 Oct. 15, 2015

mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg. 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 960 mg,965 mg, 970 mg,975 mg,980 mg,985 mg, 990 mg. mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. 30.5 995 mg. or 1000 mg. In one instance, the non-opioid analge mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg, sic agent is present in a bi-layer tablet that comprises an 36.5 mg, 37 mg, 37.5 mg. 38 mg, 38.5 mg. 39 mg, 39.5 mg, 40 immediate-release and a controlled-release layer. In one mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 instance, the non-opioid analgesic agent is present in a two mg, 44 mg., 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, layer tablet that comprises an immediate-release and a con 47.5 mg, 48 mg, 48.5 mg. 49 mg, 49.5 mg, 50 mg, 55 mg, 60 trolled-release layer. mg, 65mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg, 95 mg, 100 0275. In another instance, a pharmaceutical composition mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, or 130 mg. In comprises an antiemetic agent (e.g., promethazine or a phar one instance, the opioid analgesic agent is hydrocodone, oxy maceutically acceptable salt thereof) that is present in a single codone, tapentadol, fentanyl or a pharmaceutically accept dose from about 0.5 mg to about 200 mg, including but not able salt thereof. In another instance, the opioid analgesic limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 agent is present in a bi-layer tablet that comprises an imme mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg. 6.0 mg., 6.5 mg, 7.0 mg. diate-release and a controlled-release layer. In another 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 instance, the opioid analgesic agent is present in a two layer mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 tablet that comprises an immediate-release and a controlled mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, release layer. 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 0274. In another instance, a pharmaceutical composition mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 comprises a non-opioid analgesic that is present in a single mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, dose from about 200 mg to about 1000 mg, including but not 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg. 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg., 45 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg. mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg. 65 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg. mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, 100 mg, 105 300 mg. 305 mg. 310 mg, 315 mg. 320 mg, 325 mg, 326 mg, mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 326.5 mg. 327 mg, 327.5 mg. 328 mg, 328.5 mg, 329 mg, mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 329.5 mg. 330 mg. 330.5 mg, 331 mg, 331.5 mg, 332 mg, mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one 332.5 mg, 333 mg, 333.5 mg, 334 mg. 334.5 mg, 335 mg, instance, the antiemetic agent is present in a bi-layer tablet 335.5 mg. 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, that comprises an immediate-release and a controlled-release 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, layer. In one instance, the antiemetic agent is present in a two 341.5 mg, 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. layer tablet that comprises an immediate-release and a con 344.5 mg, 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, trolled-release layer. 347.5 mg. 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. 0276. In one instance, a pharmaceutical composition dis 350.5 mg. 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, closed herein comprises an opioid analgesic agent (Such as 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, hydrocodone), a pharmaceutically acceptable salt or its thi 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, osemicarbazone, p-nitrophenylhydraZone, o-methyloxime, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, semicarbazone, or bis(methylcarbamate) (each of the forego 362.5 mg. 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. ing being a hydrocodone agent or derivative); acetami 365.5 mg. 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, nophen; and promethazine or salt thereof. In some cases, the 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, opioid analgesic agent is present in a single dose from about 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. 0.05 mg to about 130 mg, including but not limited to 0.05 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg. 0.5 mg, 0.6 mg, 0.7 mg, 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, 0.8 mg, 0.9 mg, 1 mg, 1.2 mg, 1.5 mg, 2.5 mg, 3.0 mg. 4.0 mg. 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. 4.8355 mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg. 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg. 390.5 mg. 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg. 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg, 425 mg. mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. 30.5 430 mg, 435 mg., 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg, 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. 36.5 mg. 37 mg, 37.5 mg. 38 mg, 38.5 mg. 39 mg, 39.5 mg, 40 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. mg, 44 mg., 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg. 47.5 mg, 48 mg, 48.5 mg. 49 mg, 49.5 mg, 50 mg, 55 mg, 60 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. mg, 65mg, 70 mg, 75 mg, 80 mg. 85 mg. 90 mg, 95 mg, 100 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, or 130 mg. 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. 0277. In some instances, a pharmaceutical composition 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. disclosed herein comprises acetaminophen or a pharmaceu 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. tically acceptable salt thereof that is present in a single dose 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. from about 200 mg to about 1000 mg, including but not 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg. 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg. US 2015/0290211 A1 Oct. 15, 2015 56

265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg. cally acceptable salt thereof are present in a bi-layer tablet 300 mg. 305 mg. 310 mg, 315 mg. 320 mg, 325 mg, 326 mg, that comprises an immediate-release and a controlled-release 326.5 mg. 327 mg, 327.5 mg. 328 mg, 328.5 mg, 329 mg, layer. In one instance, hydrocodone or a pharmaceutically 329.5 mg. 330 mg. 330.5 mg, 331 mg, 331.5 mg, 332 mg, acceptable salt thereof, acetaminophen or a pharmaceutically 332.5 mg, 333 mg, 333.5 mg. 334 mg. 334.5 mg, 335 mg. acceptable salt thereof, and promethazine or a pharmaceuti 335.5 mg. 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, cally acceptable salt thereof are present in a two layer tablet 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, that comprises an immediate-release and a controlled-release 341.5 mg, 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. layer. In one instance, the immediate-release layer comprises 344.5 mg, 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, promethazine or a pharmaceutically acceptable salt thereof 347.5 mg. 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. and the controlled-release layer comprises hydrocodone or a 350.5 mg. 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, pharmaceutically acceptable salt thereof and acetaminophen 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, or a pharmaceutically acceptable salt thereof. 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 0278 In some instances, a pharmaceutical composition 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, comprises an opioid analgesic, an antiemetic, without a non 362.5 mg. 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. opioid analgesic. In one instance, the opioid analgesic is 365.5 mg. 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, hydrocodone or a pharmaceutically acceptable salt thereof 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, and the antiemetic is promethazine or a pharmaceutically 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. acceptable Salt thereof. In one instance, the pharmaceutical 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, composition comprises about 5 mg of hydrocodone or a phar 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, maceutically acceptable salt thereof and about 12.5 mg of 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. promethazine or a pharmaceutically acceptable salt thereof. 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, In one instance, the pharmaceutical composition comprises 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. about 5 mg of hydrocodone bitartrate and about 12.5 mg of 390.5 mg. 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, promethazine hydrochloride. In one instance, the pharmaceu 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, tical composition comprises about 7.5 mg of hydrocodone or 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, a pharmaceutically acceptable Salt thereof and about 12.5 mg 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg, 425 mg. of promethazine or a pharmaceutically acceptable salt 430 mg, 435 mg., 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. thereof. In one instance, the pharmaceutical composition 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. comprises about 7.5 mg of hydrocodone bitartrate and about 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. 12.5 mg of promethazine hydrochloride. In one instance, the 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. pharmaceutical composition comprises about 10 mg of 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg. hydrocodone or a pharmaceutically acceptable salt thereof 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. and about 12.5 mg of promethazine or a pharmaceutically 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. acceptable Salt thereof. In one instance, the pharmaceutical 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. composition comprises about 10 mg of hydrocodone bitar 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. trate and about 12.5 mg of promethazine hydrochloride. 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. 0279. In some instances, a pharmaceutical composition 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. comprises an opioid analgesic, an antiemetic, and a non 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. opioid analgesic. In one instance the opioid analgesic is 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. hydrocodone or a pharmaceutically acceptable salt thereof, 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. the antiemetic is promethazine or a pharmaceutically accept 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. able salt thereof, and the non-opioid analgesic is acetami 960 mg. 965 mg,970 mg,975 mg,980 mg,985 mg. 990 mg. nophen or a pharmaceutically acceptable salt thereof. In one 995 mg. or 1000 mg. In some cases, the promethazine or salt instance, the pharmaceutical composition comprises about 5 thereof is present in the pharmaceutical composition at a mg of hydrocodone or a pharmaceutically acceptable salt single dose between about 0.5 mg to about 200 mg, including thereof, about 12.5 mg of promethazine or a pharmaceutically but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 acceptable salt thereof, and about 325 mg of acetaminophen mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg., 6.5 mg. ora pharmaceutically acceptable salt thereof. In one instance, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 the pharmaceutical composition comprises about 5 mg of mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 hydrocodone bitartrate, about 12.5 mg of promethazine mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 hydrochloride, and about 325 mg of acetaminophen. In one mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, instance, the pharmaceutical composition comprises about 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 7.5 mg of hydrocodone or a pharmaceutically acceptable salt mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 thereof, about 12.5 mg of promethazine or a pharmaceutically mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 acceptable salt thereof, and about 325 mg of acetaminophen mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 ora pharmaceutically acceptable salt thereof. In one instance, mg, 44 mg. 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 the pharmaceutical composition comprises about 7.5 mg of mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg, 95 hydrocodone bitartrate, about 12.5 mg of promethazine mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 hydrochloride, and about 325 mg of acetaminophen. In one mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 instance, the pharmaceutical composition comprises about 10 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or mg of hydrocodone or a pharmaceutically acceptable salt 200 mg. In one instance, hydrocodone or a pharmaceutically thereof, about 12.5 mg of promethazine or a pharmaceutically acceptable salt thereof, acetaminophen or a pharmaceutically acceptable salt thereof, and about 325 mg of acetaminophen acceptable salt thereof, and promethazine or a pharmaceuti ora pharmaceutically acceptable salt thereof. In one instance, US 2015/0290211 A1 Oct. 15, 2015 57 the pharmaceutical composition comprises about 10 mg of salt thereof. In one instance, the pharmaceutical composition hydrocodone bitartrate, about 12.5 mg of promethazine comprises about 200 mg ibuprofen and about 7.5 mg hydro hydrochloride, and about 325 mg of acetaminophen. codone bitartrate. In one instance, the pharmaceutical com 0280. In some instances, a pharmaceutical composition position comprises about 200 mg ibuprofen or a pharmaceu comprises an opioid analgesic and a non-opioid analgesic. In tically acceptable salt thereof and about 10 mg hydrocodone Some instances the opioid analgesic is hydrocodone or a ora pharmaceutically acceptable salt thereof. In one instance, pharmaceutically acceptable salt thereof and the non-opioid the pharmaceutical composition comprises about 200 mg analgesic is acetaminophen or a pharmaceutically acceptable ibuprofen and about 10 mg hydrocodone bitartrate. In one salt thereof. In one instance, the pharmaceutical composition instance, the pharmaceutical composition comprises about comprises about 300 mg acetaminophen or a pharmaceuti 200 mg ibuprofen or a pharmaceutically acceptable salt cally acceptable salt thereof and about 10 mg hydrocodone or thereof and about 2.5 mg hydrocodone or a pharmaceutically a pharmaceutically acceptable salt thereof. In one instance, acceptable Salt thereof. In one instance, the pharmaceutical the pharmaceutical composition comprises about 300 mg composition comprises about 200 mg ibuprofen and about 2.5 acetaminophen and about 10 mg hydrocodone bitartrate. In mg hydrocodone bitartrate. one instance, the pharmaceutical composition comprises 0282. In some instances, a pharmaceutical composition about 325 mg acetaminophen or a pharmaceutically accept comprises an opioid analgesic. In some instances, the opioid able salt thereof and about 7.5 mg hydrocodone or a pharma analgesic is hydrocodone or a pharmaceutically acceptable ceutically acceptable salt thereof. In one instance, the phar salt thereof. In one instance, the pharmaceutical composition maceutical composition comprises about 325 mg comprises about 10 mg hydrocodone or a pharmaceutically acetaminophen and about 7.5 mg hydrocodone bitartrate. In acceptable Salt thereof. In one instance, the pharmaceutical one instance, the pharmaceutical composition comprises composition comprises about 10 mg hydrocodone bitartrate. about 325 mg acetaminophen or a pharmaceutically accept In one instance, the pharmaceutical composition comprises able salt thereof and about 10 mg hydrocodone or a pharma about 15 mg hydrocodone or a pharmaceutically acceptable ceutically acceptable salt thereof. In one instance, the phar salt thereof. In one instance, the pharmaceutical composition maceutical composition comprises about 325 mg comprises about 15 mg hydrocodone bitartrate. In one acetaminophen and about 10 mg hydrocodone bitartrate. In instance, the pharmaceutical composition comprises about 20 one instance, the pharmaceutical composition comprises mg hydrocodone or a pharmaceutically acceptable salt about 325 mg acetaminophen or a pharmaceutically accept thereof. In one instance, the pharmaceutical composition able salt thereof and about 5 mg hydrocodone or a pharma comprises about 20 mg hydrocodone bitartrate. In one ceutically acceptable salt thereof. In one instance, the phar instance, the pharmaceutical composition comprises about 30 maceutical composition comprises about 325 mg mg hydrocodone or a pharmaceutically acceptable salt acetaminophen and about 5 mg hydrocodone bitartrate. In thereof. In one instance, the pharmaceutical composition one instance, the pharmaceutical composition comprises comprises about 30 mg hydrocodone bitartrate. In one about 300 mg acetaminophen or a pharmaceutically accept instance, the pharmaceutical composition comprises about 40 able salt thereof and about 5 mg hydrocodone or a pharma mg hydrocodone or a pharmaceutically acceptable salt ceutically acceptable salt thereof. In one instance, the phar thereof. In one instance, the pharmaceutical composition maceutical composition comprises about 300 mg comprises about 40 mg hydrocodone bitartrate. In one acetaminophen and about 5 mg hydrocodone bitartrate. In instance, the pharmaceutical composition comprises about 50 one instance, the pharmaceutical composition comprises mg hydrocodone or a pharmaceutically acceptable salt about 300 mg acetaminophen or a pharmaceutically accept thereof. In one instance, the pharmaceutical composition able salt thereof and about 7.5 mg hydrocodone or a pharma comprises about 50 mg hydrocodone bitartrate. In one ceutically acceptable salt thereof. In one instance, the phar instance, the pharmaceutical composition comprises about 60 maceutical composition comprises about 300 mg mg hydrocodone or a pharmaceutically acceptable salt acetaminophen and about 7.5 mg hydrocodone bitartrate. In thereof. In one instance, the pharmaceutical composition one instance, the pharmaceutical composition comprises comprises about 60 mg hydrocodone bitartrate. In one about 325 mg acetaminophen or a pharmaceutically accept instance, the pharmaceutical composition comprises about 80 able salt thereof and about 2.5 mg hydrocodone or a pharma mg hydrocodone or a pharmaceutically acceptable salt ceutically acceptable salt thereof. In one instance, the phar thereof. In one instance, the pharmaceutical composition maceutical composition comprises about 325 mg comprises about 80 mg hydrocodone bitartrate. In one acetaminophen and about 2.5 mg hydrocodone bitaritrate. instance, the pharmaceutical composition comprises about 0281. In some instances, a pharmaceutical composition 100 mg hydrocodone or a pharmaceutically acceptable salt comprises an opioid analgesic and a non-opioid analgesic. In thereof. In one instance, the pharmaceutical composition Some instances, the opioid analgesic is hydrocodone or a comprises about 100 mg hydrocodone bitartrate. In one pharmaceutically acceptable salt thereof and the non-opioid instance, the pharmaceutical composition comprises about analgesic is ibuprofen or a pharmaceutically acceptable salt 120 mg hydrocodone or a pharmaceutically acceptable salt thereof. In one instance, the pharmaceutical composition thereof. In one instance, the pharmaceutical composition comprises about 200 mg ibuprofen or a pharmaceutically comprises about 120 mg hydrocodone bitartrate. acceptable salt thereof and about 5 mg hydrocodone or a 0283. In some instances, a pharmaceutical composition pharmaceutically acceptable salt thereof. In one instance, the comprises an opioid analgesic and a non-opioid analgesic. In pharmaceutical composition comprises about 200 mg ibupro Some instances, the opioid analgesic is oxycodone or a phar fen and about 5 mg hydrocodone bitaritrate. In one instance, maceutically acceptable salt and the non-opioid analgesic is the pharmaceutical composition comprises about 200 mg acetaminophen or a pharmaceutically acceptable salt. In one ibuprofen or a pharmaceutically acceptable salt thereof and instance, the pharmaceutical composition comprises about about 7.5 mg hydrocodone or a pharmaceutically acceptable 325 mg acetaminophen or a pharmaceutically acceptable salt US 2015/0290211 A1 Oct. 15, 2015 thereof and about 5 mg oxycodone or a pharmaceutically composition comprises about 400 mg ibuprofen and about 5 acceptable Salt thereof. In one instance, the pharmaceutical mg oxycodone hydrochloride. composition comprises about 325 mg acetaminophen and 0285. In some instances, a pharmaceutical composition about 5 mg oxycodone hydrochloride. In one instance, the comprises an opioid analgesic. In some instances, the opioid pharmaceutical composition comprises about 325 mg analgesic is oxycodone or a pharmaceutically acceptable salt. acetaminophen or a pharmaceutically acceptable salt thereof In one instance, the pharmaceutical composition comprises and about 7.5 mg oxycodone or a pharmaceutically accept about 5 mg oxycodone or a pharmaceutically acceptable salt able salt thereof. In one instance, the pharmaceutical compo thereof. In one instance, the pharmaceutical composition sition comprises about 325 mg acetaminophen and about 7.5 comprises about 5 mg oxycodone hydrochloride. In one mg oxycodone hydrochloride. In one instance, the pharma instance, the pharmaceutical composition comprises about ceutical composition comprises about 325 mg acetami 7.5 mg oxycodone or a pharmaceutically acceptable salt nophen or a pharmaceutically acceptable salt thereof and thereof. In one instance, the pharmaceutical composition about 10 mg oxycodone or a pharmaceutically acceptable salt comprises about 7.5 mg oxycodone hydrochloride. In one instance, the pharmaceutical composition comprises about 10 thereof. In one instance, the pharmaceutical composition mg oxycodone or a pharmaceutically acceptable salt thereof. comprises about 325 mg acetaminophen and about 10 mg In one instance, the pharmaceutical composition comprises oxycodone hydrochloride. In one instance, the pharmaceuti about 10 mg oxycodone hydrochloride. In one instance, the cal composition comprises about 325 mg acetaminophen or a pharmaceutical composition comprises about 15 mg oxyc pharmaceutically acceptable salt thereof and about 2.5 mg odone or a pharmaceutically acceptable salt thereof. In one oxycodone or a pharmaceutically acceptable salt thereof. In instance, the pharmaceutical composition comprises about 15 one instance, the pharmaceutical composition comprises mg oxycodone hydrochloride. In one instance, the pharma about 325 mg acetaminophen and about 2.5 mg oxycodone ceutical composition comprises about 20 mg oxycodone or a hydrochloride. In one instance, the pharmaceutical composi pharmaceutically acceptable salt thereof. In one instance, the tion comprises about 300 mg acetaminophen or a pharmaceu pharmaceutical composition comprises about 20 mg oxyc tically acceptable salt thereof and about 10 mg oxycodone or odone hydrochloride. In one instance, the pharmaceutical a pharmaceutically acceptable salt thereof. In one instance, composition comprises about 30 mg oxycodone or a pharma the pharmaceutical composition comprises about 300 mg ceutically acceptable salt thereof. In one instance, the phar acetaminophen and about 10 mg oxycodone hydrochloride. maceutical composition comprises about 30 mg oxycodone In one instance, the pharmaceutical composition comprises hydrochloride. In one instance, the pharmaceutical composi about 300 mg acetaminophen or a pharmaceutically accept tion comprises about 40 mg oxycodone or a pharmaceutically able salt thereof and about 2.5 mg oxycodone or a pharma acceptable Salt thereof. In one instance, the pharmaceutical ceutically acceptable salt thereof. In one instance, the phar composition comprises about 40 mg oxycodone hydrochlo maceutical composition comprises about 300 mg ride. In one instance, the pharmaceutical composition com acetaminophen and about 2.5 mg oxycodone hydrochloride. prises about 60 mg oxycodone or a pharmaceutically accept In one instance, the pharmaceutical composition comprises able Salt thereof. In one instance, the pharmaceutical about 300 mg acetaminophen or a pharmaceutically accept composition comprises about 60 mg oxycodone hydrochlo able salt thereof and about 5 mg oxycodone or a pharmaceu ride. In one instance, the pharmaceutical composition com tically acceptable salt thereof. In one instance, the pharma prises about 80 mg oxycodone or a pharmaceutically accept ceutical composition comprises about 300 mg able Salt thereof. In one instance, the pharmaceutical acetaminophen and about 5 mg oxycodone hydrochloride. In composition comprises about 80 mg oxycodone hydrochlo one instance, the pharmaceutical composition comprises ride. In one instance, the pharmaceutical composition com about 300 mg acetaminophen or a pharmaceutically accept prises about 100 mg oxycodone or a pharmaceutically accept able salt thereof and about 7.5 mg oxycodone or a pharma able Salt thereof. In one instance, the pharmaceutical ceutically acceptable salt thereof. In one instance, the phar composition comprises about 100 mg oxycodone hydrochlo maceutical composition comprises about 300 mg ride. acetaminophen and about 7.5 mg oxycodone hydrochloride. 0286. In some instances, a pharmaceutical composition 0284. In some instances, a pharmaceutical composition comprises an antiemetic. In some instances, the antiemetic is comprises an opioid analgesic and a non-opioid analgesic. In promethazine or a pharmaceutically acceptable salt thereof. Some instances, the opioid analgesic is oxycodone or a phar In one instance, the pharmaceutical composition comprises maceutically acceptable salt and the non-opioid analgesic is about 25 mg promethazine or a pharmaceutically acceptable acetylsalicylic acid or a pharmaceutically acceptable salt. In salt thereof. In one instance, the pharmaceutical composition one instance, the pharmaceutical composition comprises comprises about 25 mg promethazine hydrochloride. In one about 325 mg acetylsalicylic acid or a pharmaceutically instance, the pharmaceutical composition comprises about 50 acceptable salt thereof and about 4.8355 mg oxycodone or a mg promethazine or a pharmaceutically acceptable salt pharmaceutically acceptable salt thereof. In one instance, the thereof. In one instance, the pharmaceutical composition pharmaceutical composition comprises about 325 mg acetyl comprises about 50 mg promethazine hydrochloride. In one salicylic acid and about 4.8355 mg oxycodone hydrochloride. instance, the pharmaceutical composition comprises about In some instances, the opioid analgesic is oxycodone or a 12.5 mg promethazine or a pharmaceutically acceptable salt pharmaceutically acceptable salt and the non-opioid analge thereof. In one instance, the pharmaceutical composition sic is ibuprofen or a pharmaceutically acceptable salt. In one comprises about 12.5 mg promethazine hydrochloride. In one instance, the pharmaceutical composition comprises about instance, the pharmaceutical composition comprises about 400 mg ibuprofen or a pharmaceutically acceptable salt 6.25 mg promethazine or a pharmaceutically acceptable salt thereof and about 5 mg oxycodone or a pharmaceutically thereof. In one instance, the pharmaceutical composition acceptable Salt thereof. In one instance, the pharmaceutical comprises about 6.25 mg promethazine hydrochloride. US 2015/0290211 A1 Oct. 15, 2015 59

0287. In some instances, a pharmaceutical composition a pharmaceutically acceptable salt thereof. Such as tramadol comprises an opioid analgesic. In some instances, the opioid hydrochloride, and about 12.5 mg of promethazine or a phar analgesic is tapentadol or a pharmaceutically acceptable salt maceutically acceptable salt thereof. In one instance, the thereof. Such as tapentadol hydrochloride. In one instance, the pharmaceutical composition can comprise about 100 mg tra pharmaceutical composition can comprise about 50 mg tap madol or a pharmaceutically acceptable salt thereof. Such as entadol or a pharmaceutically acceptable salt thereof. Such as tramadol hydrochloride, and about 325 mg of acetaminophen tapentadol hydrochloride. In one instance, the pharmaceuti or a pharmaceutically acceptable salt thereof. cal composition can comprise about 75 mg tapentadol or a 0291. In one instance, a pharmaceutical composition com pharmaceutically acceptable salt thereof. Such as tapentadol prises about 200 mg tramadol or a pharmaceutically accept hydrochloride. In one instance, the pharmaceutical composi able salt thereof, such as tramadol hydrochloride, about 325 tion can comprise about 100 mg tapentadol or a pharmaceu mg of acetaminophen or a pharmaceutically acceptable salt tically acceptable salt thereof. Such as tapentadol hydrochlo thereof, and about 12.5 mg of promethazine or a pharmaceu ride. In one instance, the pharmaceutical composition can tically acceptable salt thereof. In one instance, the pharma comprise about 150 mg tapentadol or a pharmaceutically ceutical composition can comprise about 200 mg tramadol or acceptable salt thereof, such as tapentadol hydrochloride. In a pharmaceutically acceptable salt thereof. Such as tramadol one instance, the pharmaceutical composition can comprise hydrochloride, and about 12.5 mg of promethazine or a phar about 200 mg tapentadol or a pharmaceutically acceptable maceutically acceptable salt thereof. In one instance, the salt thereof, such as tapentadol hydrochloride. In one pharmaceutical composition can comprise about 200 mg tra instance, the pharmaceutical composition can comprise about madol or a pharmaceutically acceptable salt thereof. Such as 250 mg tapentadol or a pharmaceutically acceptable salt tramadol hydrochloride, and about 325 mg of acetaminophen thereof, such as tapentadol hydrochloride. or a pharmaceutically acceptable salt thereof. 0288. In some instances, a pharmaceutical composition 0292. In one instance, a pharmaceutical composition com comprises an opioid analgesic, a non-opioid analgesic, and an prises about 300 mg tramadol or a pharmaceutically accept antiemetic. In some instances, the opioid analgesic is trama able salt thereof, such as tramadol hydrochloride, about 325 dol or a pharmaceutically acceptable salt thereof. Such as mg of acetaminophen or a pharmaceutically acceptable salt tramadol hydrochloride. In some instances, the non-opioid thereof, and about 12.5 mg of promethazine or a pharmaceu analgesic is acetaminophen or a pharmaceutically acceptable tically acceptable salt thereof. In one instance, the pharma salt thereof. In some instances, the antiemetic is promethaZ ceutical composition can comprise about 300 mg tramadol or ine or a pharmaceutically acceptable salt thereof. In one a pharmaceutically acceptable salt thereof, such as tramadol instance, the pharmaceutical composition can comprise about hydrochloride, and about 12.5 mg of promethazine or a phar 37.5 mg tramadol or a pharmaceutically acceptable salt maceutically acceptable salt thereof. In one instance, the thereof, such as tramadol hydrochloride, about 325 mg of pharmaceutical composition can comprise about 300 mg tra acetaminophen or a pharmaceutically acceptable salt thereof, madol or a pharmaceutically acceptable salt thereof. Such as and about 12.5 mg of promethazine or a pharmaceutically tramadol hydrochloride, and about 325 mg of acetaminophen acceptable Salt thereof. In one instance, the pharmaceutical or a pharmaceutically acceptable salt thereof. composition can comprise about 37.5 mg tramadol or a phar 0293. In some instances, a pharmaceutical composition maceutically acceptable salt thereof. Such as tramadol hydro disclosed herein comprises an opioid analgesic agent (such as chloride, and about 12.5 mg of promethazine or a pharma hydrocodone, oxycodone, tapentadol or a pharmaceutically ceutically acceptable salt thereof. In one instance, the acceptable salt of any one of the foregoing, or any combina pharmaceutical composition can comprise about 37.5 mg tion thereof), acetaminophen or a pharmaceutically accept tramadol or a pharmaceutically acceptable salt thereof. Such able salt thereof and promethazine or a pharmaceutically as tramadol hydrochloride, and about 325 mg of acetami acceptable salt thereof, wherein the pharmaceutical compo nophen or a pharmaceutically acceptable salt thereof. sition comprises the respective agents, opioid analgesic 0289. In one instance, a pharmaceutical composition com agent: acetaminophen or a salt thereof promethazine or a prises about 50 mg tramadol or a pharmaceutically acceptable pharmaceutically acceptable salt thereof in a ratio by weight salt thereof, such as tramadol hydrochloride, about 325 mg of of about (1 to 2):(40 to 45):(1 to 2), such as about 1:40:1. acetaminophen or a pharmaceutically acceptable salt thereof, 1:40:1.1, 1:40:1.2, 1:40:1.3, 1:40:14, 1:40:1.5, 1:40:1.6, and about 12.5 mg of promethazine or a pharmaceutically 1:40:1.7, 1:40:1.8, 1:40:1.9, 1:40:2, 1.1:40:1, 1.2:40:1, 1.3: acceptable Salt thereof. In one instance, the pharmaceutical 40:1, 1.4:40:1, 1.5:40:1, 1.6:40:1, 1.7:40:1, 1.8:40:1, 19:40: composition can comprise about 50 mg tramadol or a phar 1, 2:40:1, 1:41:1, 1:41:1. 1, 1:41:1.2, 1:41:1.3, 1:41:1.4, 1:41: maceutically acceptable salt thereof. Such as tramadol hydro 1.5, 1:41:1.6, 1:41:1.7, 1:41:1.8, 1:41:19, 1:41:2, 1.1:41:1, chloride, and about 12.5 mg of promethazine or a pharma 1.2:41:1, 1.3:41:1, 1.4:41:1, 1.5:41:1, 1.6:41:1, 1.7:41:1, 1.8: ceutically acceptable salt thereof. In one instance, the 41:1, 19:41:1, 2:41:1, 1:42:1, 1:42:1. 1, 1:42:1.2, 1:42:1.3, pharmaceutical composition can comprise about 50 mg tra 1:42:14, 1:42:1.5, 1:42:1.6, 1:42:1.7, 1:42:1.8, 1:42:1.9, madol or a pharmaceutically acceptable salt thereof. Such as 1:42:2, 1.1:42:1, 1.2:42:1, 1.3:42:1, 1.4:42:1, 1.5:42:1, 1.6: tramadol hydrochloride, and about 325 mg of acetaminophen 42:1, 1.7:42:1, 1.8:42:1, 19:42:1, 2:42:1, 1:43:1, 1:43:1.1, or a pharmaceutically acceptable salt thereof. 1:43:12, 1:43:1.3, 1:43:14, 1:43:1.5, 1:43:16, 1:43:1.7, 0290. In one instance, a pharmaceutical composition com 1:43:1.8, 1:43:1. 9, 1:43:2, 1.1:43:1, 1.2:43:1, 1.3:43:1, 1.4: prises about 100 mg tramadol or a pharmaceutically accept 43:1, 1.5:43:1, 1.6:43:1, 1.7:43:1, 1.8:43:1, 19:43:1, 2:43:1, able salt thereof, such as tramadol hydrochloride, about 325 1:43.1:1, 1:43.1:1. 1, 1:43.1:1.2, 1:43.1:1.3, 1:43.1:14, 1:43. mg of acetaminophen or a pharmaceutically acceptable salt 1:1.5, 1:43.1:1.6, 1:43.1:1.7, 1:43.1:1.8, 1:43.1:19, 1:43.1:2, thereof, and about 12.5 mg of promethazine or a pharmaceu 1.1:43.1:1, 1.2:43.1:1, 1.3:43.1:1, 1.4:43.1:1, 1.5:43.1:1, 1.6: tically acceptable salt thereof. In one instance, the pharma 43.1:1, 1.7:43.1:1, 1.8:43.1:1, 19:43.1:1, 2:43.1:1, 1:43.2:1, ceutical composition can comprise about 100 mg tramadol or 1:43.2:1. 1, 1:43.2:1.2, 1:43.2:1.3, 1:43.2:1.4, 1:43.2:1.5, US 2015/0290211 A1 Oct. 15, 2015 60

1:43.2:1.6, 1:43.2:1.7, 1:43.2:1.8, 1:43.2:1.9, 1:43.2:2, 1.1: 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 43.2:1, 1.2:43.2:1, 1.3:43.2:1, 1.4:43.2:1, 1.5:43.2:1, 1.6:43. mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 2:1, 1.7:43.2:1, 1.8:43.2:1, 19:43.2:1, 2:43.2:1, 1:43.3:1, mg or 20 mg. 30 mg. 40 mg, 50 mg, 70 mg, 100 mg, 130 mg. 1:43.3:11, 1:43.3:12, 1:43.3:1.3, 1:43.3:14, 1:43.3:1.5, 160, 190 mg, 200 mg. Furthermore, the acetaminophen or a 1:43.3:16, 1:43.3:17, 1:43.3:1.8, 1:43.3:19, 1:43.3:2, 1.1: salt thereof is in a range of between about 200 mg to about 43.3:1, 1.2:43.3:1, 1.3:43.3:1, 1.4:43.3:1, 1.5:43.3:1, 1.6:43. 1000 mg, including but not limited to 200 mg, 205 mg, 210 3:1, 1.7:43.3:1, 1.8:43.3:1, 19:43.3:1, 2:43.3:1, 1:43.4:1, mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 1:43.4:1. 1, 1:43.4:1.2, 1:43.4:1.3, 1:43.4:14, 1:43.4:1.5, mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 1:43.4:1.6, 1:43.4:1.7, 1:43.4:1.8, 1:43.4:1. 9, 1:43.4:2, 1.1: mg, 285 mg, 290 mg, 295 mg. 300 mg. 305 mg. 310 mg, 315 43.4:1, 1.2:43.4:1, 1.3:43.4:1, 1.4:43.4:1, 1.5:43.4:1, 1.6:43. mg, 320 mg. 325 mg. 326 mg, 326.5 mg, 327 mg, 327.5 mg. 4:1, 1.7:43.4:1, 1.8:43.4:1, 19:43.4:1, 2:43.4:1, 1:43.5:1, 328 mg,328.5 mg,329 mg, 329.5 mg. 330 mg, 330.5 mg,331 1:43.5:1.1, 1:43.5:1.2, 1:43.5:1.3, 1:43.5:14, 1:43.5:1.5, mg, 331.5 mg, 332 mg, 332.5 mg,333 mg,333.5 mg,334 mg. 1:43.5:1.6, 1:43.5:1.7, 1:43.5:1.8, 1:43.5:19, 1:43.5:2, 1.1: 334.5 mg, 335 mg, 335.5 mg. 336 mg, 336.5 mg, 337 mg, 43.5:1, 1.2:43.5:1, 1.3:43.5:1, 1.4:43.5:1, 1.5:43.5:1, 1.6:43. 337.5 mg, 338 mg, 338.5 mg. 339 mg, 339.5 mg, 340 mg. 5:1, 1.7:43.5:1, 1.8:43.5:1, 19:43.5:1, 2:43.5:1, 1:43.6:1, 340.5 mg., 341 mg, 341.5 mg., 342 mg, 342.5 mg., 343 mg, 1:43.6:1. 1, 1:43.6:1.2, 1:43.6:1.3, 1:43.6:14, 1:43.6:1.5, 343.5 mg., 344 mg., 344.5 mg. 345 mg, 345.5 mg., 346 mg, 1:43.6:1.6, 1:43.6:1.7, 1:43.6:1.8, 1:43.6:1. 9, 1:43.6:2, 1.1: 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, 43.6:1, 1.2:43.6:1, 1.3:43.6:1, 1.4:43.6:1, 1.5:43.6:1, 1.6:43. 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 6:1, 1.7:43.6:1, 1.8:43.6:1, 19:43.6:1, 2:43.6:1, 1:43.7:1, 352.5 mg, 353 mg, 353.5 mg, 354 mg. 354.5 mg, 355 mg. 1:43.7:11, 1:43.7:12, 1:43.7:1.3, 1:43.7:14, 1:43.7:1.5, 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, 1:43.7:16, 1:43.7:17, 1:43.7:1.8, 1:43.7:19, 1:43.7:2, 1.1: 358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 43.7:1, 1.2:43.7:1, 1.3:43.7:1, 1.4:43.7:1, 1.5:43.7:1, 1.6:43. 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg, 364 mg. 7:1, 1.7:43.7:1, 1.8:43.7:1, 19:43.7:1, 2:43.7:1, 1:43.8:1, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 1:43.8:1.1, 1:43.8:1.2, 1:43.8:1.3, 1:43.8:14, 1:43.8:1.5, 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 1:43.8:1.6, 1:43.8:1.7, 1:43.8:1.8, 1:43.8:19, 1:43.8:2, 1.1: 371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg. 43.8:1, 1.2:43.8:1, 1.3:43.8:1, 1.4:43.8:1, 1.5:43.8:1, 1.6:43. 374.5 mg, 375 mg, 375.5 mg. 376 mg, 376.5 mg, 377 mg, 8:1, 1.7:43.8:1, 1.8:43.8:1, 19:43.8:1, 2:43.8:1, 1:43.9:1, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg, 380 mg, 1:43.9:11, 1:43.9:12, 1:43.9:1.3, 1:43.9:14, 1:43.9:1.5, 380.5 mg. 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 1:43.9:16, 1:43.9:17, 1:43.9:1.8, 1:43.9:19, 1:43.9:2, 1.1: 383.5 mg, 384 mg., 384.5 mg, 385 mg. 385.5 mg, 386 mg, 43.9:1, 1.2:43.9:1, 1.3:43.9:1, 1.4:43.9:1, 1.5:43.9:1, 1.6:43. 386.5 mg, 387 mg, 387.5 mg. 388 mg. 388.5 mg, 389 mg, 9:1, 1.7:43.9:1, 1.8:43.9:1, 19:43.9:12:43.9:1, 1:44:1, 1:44: 389.5 mg. 390 mg. 390.5 mg. 391 mg, 391.5 mg, 392 mg, 1.1, 1:44:1.2, 1:44:1.3, 1:44:14, 1:44:1.5, 1:44:1.6, 1:44:1.7, 392.5 mg, 393 mg, 393.5 mg. 394 mg. 394.5 mg, 395 mg. 1:44:1.8, 1:44:1.9, 1:44:2, 1.1:44:1, 1.2:44:1, 1.3:44:1, 1.4: 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 44:1, 1.5:44:1, 1.6:44:1, 1.7:44:1, 1.8:44:1, 1.9:44:1, 2:44:1, 398.5 mg, 399 mg,399.5 mg, 400 mg. 405 mg, 410 mg, 415 1:45:1, 1:45:1. 1, 1:45:1.2, 1:45:1.3, 1:45:14, 1:45:1.5, 1:45: mg, 420 mg. 425 mg, 430 mg, 435 mg. 440 mg. 445 mg. 450 1.6, 1:45:1.7, 1:45:1.8, 1:45:19, 1:45:2, 1.1:45:1, 1.2:45:1, mg, 455 mg. 460 mg. 465 mg. 470 mg. 475 mg, 480 mg. 485 1.3:45:1, 14:45:1, 1.5:45:1, 1.6:45:1, 1.7:45:1, 1.8:45:1, 19: mg, 490 mg. 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 45:1, or 2:45:1. For example, in one instance, the ratio of mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 amounts for each active agent is about (1):(43.33):(1.67) for mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 hydrocodone or a salt thereof acetaminophen or a salt mg, 595 mg, 600 mg. 605 mg. 610 mg. 615 mg, 620 mg. 625 thereof: promethazine or a pharmaceutically acceptable salt mg, 630 mg, 635 mg, 640 mg. 645 mg, 650 mg. 655 mg. 660 thereof, respectively. In one instance, a pharmaceutically mg, 665 mg. 675 mg, 680 mg, 685 mg. 690 mg. 695 mg, 700 acceptable salt of hydrocodone, acetaminophen or promet mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 hazine is provided. In one instance, an opioid analgesic agent mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 (such as hydrocodone or oxycodone or a salt thereof), mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg. 805 acetaminophen or a salt thereof and promethazine or a salt mg, 810 mg, 815 mg, 820 mg. 825 mg. 830 mg, 835 mg, 840 thereof are present in a bi-layer tablet that comprises an mg, 845 mg. 850 mg. 855 mg, 860 mg, 865 mg, 870 mg. 875 immediate-release and a controlled-release layer. In one mg, 880 mg. 885 mg. 890 mg. 895 mg,900 mg, 905 mg, 910 instance, an opioid analgesic agent (Such as hydrocodone or mg, 915 mg,920 mg,925 mg,930 mg,935 mg,940 mg,945 oxycodone or a salt thereof), acetaminophen or a salt thereof. mg,950 mg, 955 mg,960 mg,965 mg, 970 mg,975 mg,980 and promethazine or a salt thereofare present in a two layer mg, 985 mg, 990 mg. 995 mg. or 1000 mg. The pharmaceu tablet that comprises an immediate-release and a controlled tical compositions can further comprise between about 0.5 release layer. mg to about 200 mg of an antiemetic (e.g., promethazine or a 0294. In some instances, a pharmaceutical composition salt thereof), including but not limited to 0.5 mg, 1.0 mg, 1.5 comprises oxycodone, a pharmaceutically acceptable salt or mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg. 4.0 mg, 4.5 mg, 5.0 mg. its thiosemicarbazone, p-nitrophenylhydrazone, o-methy 5.5 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 loXime, semicarbazone, or bis(methylcarbamate) (each of the mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 foregoing being a hydrocodone agent or derivative); acetami mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, nophen or a salt thereof, and promethazine or a salt thereof. 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 Furthermore, the oxycodone or a salt thereof is present in a mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 range of about 1 mg to about 200 mg, including but not mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg. limited to 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg. 4.5 mg, 5.0 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. 31 mg, 32 mg, 5.5 mg, 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg. mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg. mg, 41 mg, 12 mg, 43 mg, 44 mg. 45 mg, 46 mg, 47 mg, 48 US 2015/0290211 A1 Oct. 15, 2015

mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 0296. In some instances, a pharmaceutical composition mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg. disclosed herein comprises 6-8 mg of hydrocodone or a salt 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg. thereof (such as about 6.0 mg., 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg. 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 6.5 mg. 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 190 mg, 195 mg, or 200 mg. In one instance, oxycodone or a mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, salt thereof, acetaminophen or a salt thereof and promethaZ or 8.0 mg.), 310-330 mg of acetaminophen (such as about 310 ine or a salt thereof are present in a bi-layer tablet that com mg, 315 mg, 320 mg, or 325 mg), and 5-13 mg of promet prises an immediate-release and a controlled-release layer. In hazine or a salt thereof (such as about 10 mg, 10.5 mg, 11.0 one instance, oxycodone or a salt thereof, acetaminophen or a mg, 11.5 mg, 12.0 mg, 12.5 mg, 13.0, mg, 13.5 mg, 14.0 mg. salt thereofand promethazine or a salt thereofare present in a 14.5 mg, or 15 mg). In one instance, a pharmaceutically two layer tablet that comprises an immediate-release and a acceptable salt of hydrocodone, acetaminophen or promet controlled-release layer. hazine is provided. The hydrocodone and the acetaminophen can beformulated using conventional technologies to provide 0295. In some instances, a pharmaceutical composition for an extended time release over a desired dosage interval. comprises promethazine or a salt thereofinan amount of 12.5 All or some of the promethazine can beformulated for imme mg. In one instance, the pharmaceutical compositions herein diate-release to help abate common adverse effects associated comprise oxycodone or a salt thereof, acetaminophen or a salt with the hydrocodone and acetaminophen including nausea, thereof and promethazine or a salt thereof, wherein the phar Vomiting, constipation, other gastric upsets, skin rashes, aller maceutical composition comprises the agents in a weight gic reactions such as Swelling, difficulty breathing, closing of ratio of about (1 to 2):(40 to 45):(1 to 2), respectively. In one throat, abdominal pain, unusual bleeding or bruising, seda instance, a pharmaceutically acceptable Salt of oxycodone, tion, CNS depression, or respiratory depression. In one acetaminophen or promethazine is provided. For example, in instance, hydrocodone, acetaminophen; and promethazine one instance, the weight ratio of amounts for each active agent are present in a bi-layer tablet that comprises an immediate is about (1):(43.33):(1.67) for oxycodone or a salt thereof, release and a controlled-release layer. In one instance, hydro acetaminophen or a salt thereof and promethazine or a salt codone, acetaminophen; and promethazine are present in a thereof, respectively. In one instance, the pharmaceutical compositions herein comprise an antiemetic (e.g., promet two layer tablet that comprises an immediate-release and a hazine or a salt thereof) at a lower dosage than that which the controlled-release layer. antiemetic is administered alone. In one instance, the anti 0297. In some instances, a pharmaceutical composition emetic is provided in the pharmaceutical composition at a disclosed herein comprises from 1% to 20% by weight of an dosage to prevent sedation, which can be observed with rela antiemetic (such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, tively higher dosages of promethazine or a salt thereof. Thus 4.5%. 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, in Some instances, promethazine is provided at 0.5 mg, 1.0 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg. 3.5 mg. 4.0 mg. 4.5 mg. 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 5.0 mg, 5.5 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 19%. 19.5%, or 20%); from 10% to 80% by weight a non mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 opioid analgesic (such as 10%, 10.5%, 11%, 11.5%, 12%, mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 35%, 35.5%, 36%, 36.5%, 37%, 37.5%, 38%, 38.5%, 39%, mg, 40 mg. 41 mg, 12 mg, 43 mg. 44 mg., 45 mg, 46 mg, 47 39.5%, 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, mg, 48 mg. 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, mg, 80 mg. 85 mg. 90 mg, 95 mg, 100 mg, 105 mg, 110 mg. 48.5%, 49%, 49.5%, 50%, 50.5%, 51%, 51.5%, 52%, 52.5%, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg. 53%, 53.5%, 54%, 54.5%, 55%, 55.5%, 56%, 56.5%, 57%, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg. 57.5%, 58%, 58.5%, 59%, 59.5%, 60%, 60.5%, 61%, 61.5%, 185 mg, 190 mg, 195 mg. or 200 mg. For example 12.5 mg or 62%, 62.5%, 63%, 63.5%, 64%, 64.5%, 65%, 65.5%, 66%, 25 mg of promethazine or a salt thereof per dose. Therefore, 66.5%, 67%, 67.5%, 68%, 68.5%, 69%, 69.5%, 70%, 70.5%, an antiemetic (e.g., promethazine or a salt thereof) can be 71%, 71.5%, 72%, 72.5%, 73%, 73.5%, 74%, 74.5%, 75%, provided at a dosage that is effective for reducing adverse 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, affects associated with the opioid analgesic or non-opioid 80%); and from 1% to 20% by weight of an opioid analgesic analgesic, but is at a relative low enough dosage (e.g., given (such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%. 5%, the subjects weight) to prevent sedation associated with the 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, antiemetic. Examples of adverse effects include acute liver 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, toxicity, allergic reactions such as Swelling, difficulty breath 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, ing, closing of throat, abdominal pain, nausea, vomiting, con 19.5%, or 20%). In one instance, an opioid analgesic agent, a stipation, unusual bleeding or bruising. In one instance, oxy non-opioid analgesic and an antiemetic are present in a bi codone or a salt thereof, acetaminophen or a salt thereof, and layer tablet that comprises an immediate-release and a con promethazine or a salt thereofare present in a bi-layer tablet trolled-release layer. In one instance, an opioid analgesic that comprises an immediate-release and a controlled-release agent, a non-opioid analgesic and an antiemetic are present in layer. In one instance, oxycodone or a salt thereof, acetami a two layer tablet that comprises an immediate-release and a nophenora salt thereof, and promethazine or a salt thereofare controlled-release layer. present in a two layer tablet that comprises an immediate 0298. In one instance, a pharmaceutical composition dis release and a controlled-release layer. closed herein comprise 6-8 mg of oxycodone HCL (Such as US 2015/0290211 A1 Oct. 15, 2015 62 about 7.5 mg), 310-330 mg of acetaminophen (such as about mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 325 mg), and 6-15 mg of promethazine HCL (such as about mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 12.5 mg). The oxycodone HCL and the acetaminophen can be mg, 19 mg, 19.5 mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg. formulated using conventional technologies to provide for an 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 extended time release over a desired dosage interval. All or mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 some of the promethazine can be formulated for immediate mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 release. In one instance, the pharmaceutical composition is in mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg. 44 mg. 45 the form of a bi-layer tablet comprising an immediate-release mg, 46 mg, 47 mg, 48 mg, 49 mg, 50mg, 55 mg, 60 mg. In one layer comprising promethazine HCl and a controlled-release instance, the antiemetic is promethazine or a salt thereof. In layer and a controlled-release layer comprising acetami other instances, the antiemetic is one described herein above. nophen and oxycodone or a salt thereof. In one instance, the As described herein, in Some instances, the antiemetic is a pharmaceutical composition is in the form of a two layer component of an immediate-release formulation. For tablet comprising an immediate-release layer comprising example, in a further instance, the immediate-release is in a promethazine HCl and a controlled-release layer and a con capsule, a tablet, a transdermal means, or achieved through trolled-release layer comprising acetaminophen and oxyc injection, intramuscular administration or other means dis odone or a salt thereof. closed herein. In one instance, an opioid analgesic agent, a 0299. In some instances, administration of a pharmaceu stimulant and an antiemetic are presentina bi-layer tablet that tical composition disclosed herein that comprises an anti comprises an immediate-release and a controlled-release emetic agent (Such as promethazine or a salt thereof) can layer. In one instance, an opioid analgesic agent, a stimulant produce an outcome in a Subject, such as reduced, abated or and an antiemetic are present in a two layer tablet that com eliminated adverse effects associated with the administration prises an immediate-release and a controlled-release layer. In of an opioid agent or non-opioid agent, Such as oxycodone one instance, the stimulant and an antiemetic are present in HCL, hydrocodone bitartrate and acetaminophen. Reduced, the immediate-release layer and the opioid analgesic agent is abated or eliminated adverse effects include but are not lim present in the controlled-release layer. In another instance, an ited to including nausea, vomiting, constipation, other gastric opioid analgesic agent, a non-opioid analgesic, a stimulant upsets, skin rashes, allergic reactions such as Swelling, diffi and an antiemetic are present in a bi-layer tablet that com culty breathing, closing of throat, abdominal pain, unusual prises an immediate-release and a controlled-release layer. In bleeding or bruising, sedation, CNS depression, or respira another instance, an opioid analgesic agent, a non-opioid tory depression or any combination thereof. analgesic, a stimulant and an antiemetic are present in a two In some instances, dosages and concentrations of active layer tablet that comprises an immediate-release and a con agents in a pharmaceutical composition can be varied as trolled-release layer. In one instance, the stimulant and an desired, as further described herein. Depending on the subject antiemetic are present in the immediate-release layer and the and/or condition being treated and on the administration opioid analgesic agent and a non-opioid analgesic are present route, the active agent in a pharmaceutical composition can in the controlled-release layer. generally be administered in dosages of 0.01 mg to 500 mg 0301 In some instances, a pharmaceutical composition per kg body weight per day, e.g. about 20 mg/day for an disclosed herein comprises: an effective amount of an opioid average person. The dosage can be adjusted based on the analgesic agent; an antiemetic agent; and a stimulantagent or mode of administration. A typical dosage can be one admin a non-opioid agent, or both. In one instance, each agent is istration daily or multiple administrations daily. In some present at a dose of about 0.5 mg to about 20 mg, 5 mg to 30 instances, for a controlled-release dosage form the unit dose mg, 10 mg to 100 mg, including but not limited to about 0.5 can be designed for administration over a defined period of mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg. 4.0 mg, 5.0 mg., 6.0 mg. time. In some instances, dosage for one or a combination of 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, agents can be from about 0.01 to 5 mg, 1 to 10 mg, 5 to 20 mg. 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 10 to 50 mg, 20 to 100 mg, 50 to 150 mg, 100 to 250 mg, 150 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 to 300 mg, 250 to 500 mg,300 to 600 mg or 500 to 1000 mg mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg. V/kg body weight. Dose levels can vary as a function of the 35 mg, 40 mg, 45 mg. or 50 mg. In one instance, an opioid specific compound, the severity of the symptoms and the analgesic agent, a stimulant and an antiemetic are present in a susceptibility of the subject to adverse effects. In another bi-layer tablet that comprises an immediate-release and a instance, a pharmaceutical composition comprises multiple controlled-release layer. In one instance, an opioid analgesic active agents at the same or different dosages, where the agent, a stimulant and an antiemetic are present in a two layer pharmaceutical composition comprises an effective amount tablet that comprises an immediate-release and a controlled of an opioid analgesic; an antiemetic; and a stimulant. In release layer. In one instance, the stimulant and an antiemetic Some instances, the pharmaceutical composition can further are present in the immediate-release layer and the opioid comprise a barbiturate or a non-opioid active agent, or both. analgesic agent is present in the controlled-release layer. The dosage can be adjusted according to the particular actives 0302. In some instances, a pharmaceutical composition selected. can comprise: an effective amount of an opioid analgesic, a 0300. In one instance, a pharmaceutical composition com stimulant and an antiemetic. In one instance, the pharmaceu prises an effective amount of an opioid analgesic; an anti tical composition comprising: an effective amount of an emetic; and a stimulant. In this instance, the antiemetic (e.g., opioid analgesic, and a stimulant. In one instance, the phar promethazine or a salt thereof), that is present at about 0.5 mg maceutical composition comprises a stimulant at a dose of to about 60 mg, including but not limited to a dose of about 0.5 about 1 mg to about 350 mg, 5 mg to 25 mg, 10 mg to 50 mg. mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg. 3.5 mg. 4.0 mg. 25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mg to 350 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, including but not limited to about 1.0 mg, 1.0 mg, 1.5 mg. mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 US 2015/0290211 A1 Oct. 15, 2015

mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg. one instance, the stimulant and an antiemetic are present in 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 the immediate-release layer and the opioid analgesic agent is mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 present in the controlled-release layer. mg, 19 mg, 19.5 mg, 20 mg, 25 mg. 30 mg, 35 mg, 40 mg, 45 0304. In some instances, a pharmaceutical composition mg, 50 mg. 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 disclosed herein has an effective amount of an opioid (such as mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 hydrocodone, fentanyl or oxycodone or a salt thereof); a mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 non-opioid (such as acetaminophen or naproxen salt thereof); mg, 270 mg, 280 mg, 290 mg. 300 mg. 310 mg. 320 mg, 330 and a barbiturate (such as butalbital or a salt thereof). In some mg, 340 mg. or 350 mg. In one instance, an opioid analgesic instances, the pharmaceutical compositions further comprise agent, a stimulant and an antiemetic are present in a bi-layer an antiemetic (such as promethazine or a salt thereof). In tablet that comprises an immediate-release and a controlled Some instances, the pharmaceutical composition further com release layer. In one instance, an opioid analgesic agent, a prises a stimulant agent. In some instances, the barbiturate is stimulant and an antiemetic are present in a two layer tablet present at a dose of 1 mg to about 350 mg, 5 mg to 25 mg, 10 that comprises an immediate-release and a controlled-release mg to 50 mg, 25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg. layer. In one instance, the stimulant and an antiemetic are 75 mg to 350 mg, including but not limited to about 1.0 mg. present in the immediate-release layer and the opioid analge 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg. 4.0 mg, 5.0 mg., 6.0 mg., 6.5 sic agent is present in the controlled-release layer. mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 0303. In some instances, a pharmaceutical composition 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 disclosed herein comprises: an opioid analgesic, a stimulant, mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 and an antiemetic, wherein the relative ratio by weight of each mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg. of an opioid:a stimulant:an antiemetic is about (1 to 2):(40 to 35 mg, 40 mg, 45 mg, 50 mg. 60 mg, 70 mg, 80 mg, 90 mg. 45):(1 to 2), such as about 1:40:1, 1:40:1. 1, 1:40:1.2, 1:40:1. 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg. 3, 1:40:14, 1:40:1.5, 1:40:1.6, 1:40:1.7, 1:40:1.8, 1:40:1.9, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg. 1:40:2, 1.1:40:1, 1.2:40:1, 1.3:40:1, 1.4:40:1, 1.5:40:1, 1.6: 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg. 300 mg. 40:1, 1.7:40:1, 1.8:40:1, 19:40:1, 2:40:1, 1:41:1, 1:41:1.1, 310 mg. 320 mg. 330 mg, 340 mg. or 350 mg. 1:41:1.2, 1:41:1.3, 1:41:1.4, 1:41:1.5, 1:41:1.6, 1:41:1.7, 0305. In some instances, a pharmaceutical composition 1:41:1.8, 1:41:19, 1:41:2, 1.1:41:1, 1.2:41:1, 1.3:41:1, 1.4: comprises an effective amount of an opioid (such as hydroc 41:1, 1.5:41:1, 1.6:41:1, 1.7:41:1, 1.8:41:1, 1.9:41:1, 2:41:1, odone, fentanyl or oxycodone or a salt thereof); a non-opioid 1:42:1, 1:42:1. 1, 1:42:1.2, 1:42:1.3, 1:42:14, 1:42:1.5, 1:42: agent (such as acetaminophen or naproxen or a salt thereof): 1.6, 1:42:1.7, 1:42:1.8, 1:42:19, 1:42:2, 1.1:42:1, 1.2:42:1, and a barbiturate (such as butalbital or a salt thereof). In one 1.3:42:1, 1.4:42:1, 1.5:42:1, 1.6:42:1, 1.7:42:1, 1.8:42:1, 1.9: instance, the opioid agent (such as hydrocodone, oxycodone, 42:1, 2:42:1, 1:43:1, 1:43:1. 1, 1:43:12, 1:43:1.3, 1:43:14, tapentadol or a salt thereof) is present in a range of about 1 mg 1:43:1.5, 1:43:16, 1:43:17, 1:43: 1.8, 1:43:19, 1:43:2, 1.1: to about 200 mg, including but not limited to 1.0 mg, 1.5 mg. 43:1, 1.2:43:1, 1.3:43:1, 1.4:43:1, 1.5:43:1, 1.6:43:1, 1.7:43: 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg., 6.5 1, 1.8:43:1, 19:43:1, 2:43:1, 1:43.1:1, 1:43.1:1. 1, 1:43.1:1.2, mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 1:43.1:1.3, 1:43.1:14, 1:43.1:1.5, 1:43.1:1.6, 1:43.6:1, 1:43. 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 6:1. 1, 1:43.6:1.2, 1:43.6:1.3, 1:43.6:1.4, 1:43.6:1.5, 1:43.6:1. mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 6, 1:43.6:1.7, 1:43.6:1.8, 1:43.6:19, 1:43.6:2, 1.1:43.6:1, 1.2: mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg or 20 mg, 30 mg, 40 mg. 43.6:1, 1.3:43.6:1, 1.4:43.6:1, 1.5:43.6:1, 1.6:43.6:1, 1.7:43. 50 mg, 70 mg, 100 mg, 130 mg, 160, 190 mg, 200 mg. 6:1, 1.8:43.6:1, 19:43.6:1, 2:43.6:1, 1:43.7:1, 1:43.7:1.1, Furthermore, the non-opioid agent (such as acetaminophen or 1:43.7:12, 1:43.7:1.3, 1:43.7:14, 1:43.7:1.5, 1:43.7:1.6, naproxen or a salt thereof) is present in a range of between 1:43.7:17, 1:43.7:18, 1:43.7:19, 1:43.7:2, 1.1:43.7:1, 1.2: about 200 mg to about 1000 mg, including but not limited to 43.7:1, 1.3:43.7:1, 1.4:43.7:1, 1.5:43.7:1, 1.6:43.7:1, 1.7:43. 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg. 7:1, 1.8:43.7:1, 19:43.7:1, 2:43.7:1, 1:43.8:1, 1:43.8:1.1, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg. 1:43.8:1.2, 1:43.8:1.3, 1:43.8:1.4, 1:43.8:1.5, 1:43.8:1.6, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg. 1:43.8:1.7, 1:43.8:1.8, 1:43.8:1.9, 1:43.8:2, 1.1:43.8:1, 1.2: 305 mg,310 mg,315 mg,320 mg,325 mg,326 mg,326.5 mg. 43.8:1, 1.3:43.8:1, 1.4:43.8:1, 1.5:43.8:1, 1.6:43.8:1, 1.7:43. 327 mg, 327.5 mg. 328 mg,328.5 mg,329 mg,329.5 mg,330 8:1, 1.8:43.8:1, 19:43.8:1, 2:43.8:1, 1:43.9:1, 1:43.9:1.1, mg, 330.5 mg, 331 mg,331.5 mg, 332 mg, 332.5 mg,333 mg, 1:43.9:12, 1:43.9:1.3, 1:43.9:14, 1:43.9:1.5, 1:43.9:1.6, 333.5 mg. 334 mg. 334.5 mg, 335 mg, 335.5 mg, 336 mg, 1:43.9:17, 1:43.9:18, 1:43.9:19, 1:43.9:2, 1.1:43.9:1, 1.2: 336.5 mg, 337 mg, 337.5 mg, 338 mg, 338.5 mg, 339 mg, 43.9:1, 1.3:43.9:1, 1.4:43.9:1, 1.5:43.9:1, 1.6:43.9:1, 1.7:43. 339.5 mg, 340 mg, 340.5 mg, 341 mg, 341.5 mg, 342 mg, 9:1, 1.8:43.9:1, 1.9:43.9:1, 2:43.9:1, 1:44:1, 1:44:1. 1, 1:44:1. 342.5 mg., 343 mg, 343.5 mg., 344 mg., 344.5 mg., 345 mg. 2, 1:44:1.3, 1:44:14, 1:44:1.5, 1:44:1.6, 1:44:17, 1:44:18, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 1:44:1.9, 1:44:2, 1.1:44:1, 1.2:44:1, 1.3:44:1, 1.4:44:1, 1.5: 348.5 mg, 349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 44:1, 1.6:44:1, 1.7:44:1, 1.8:44:1, 1.9:44:1, 2:44:1, 1:45:1, 351.5 mg, 352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg. 1:45:1.1, 1:45:1.2, 1:45:1.3, 1:45:14, 1:45:1.5, 1:45:1.6, 354.5 mg, 355 mg, 355.5 mg, 356 mg, 356.5 mg, 357 mg, 1:45:1.7, 1:45:1.8, 1:45:1.9, 1:45:2, 1.1:45:1, 1.2:45:1, 1.3: 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360 mg, 45:1, 1.4:45:1, 1.5:45:1, 1.6:45:1, 1.7:45:1, 1.8:45:1, 19:45: 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 1, or 2:45:1. In one instance, an opioid analgesic agent, a 363.5 mg, 364 mg. 364.5 mg, 365 mg, 365.5 mg, 366 mg, stimulantandanantiemetic are present in a bi-layer tablet that 366.5 mg, 367 mg, 367.5 mg, 368 mg, 369.5 mg, 370 mg. comprises an immediate-release and a controlled-release 370.5 mg, 371 mg, 371.5 mg, 372 mg, 372.5 mg, 373 mg, layer. In one instance, an opioid analgesic agent, a stimulant 373.5 mg, 374 mg., 374.5 mg, 375 mg, 375.5 mg, 376 mg, and an antiemetic are present in a two layer tablet that com 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, prises an immediate-release and a controlled-release layer. In 379.5 mg, 380 mg. 380.5 mg. 381 mg, 381.5 mg, 382 mg, US 2015/0290211 A1 Oct. 15, 2015 64

382.5 mg. 383 mg, 383.5 mg. 384 mg. 384.5 mg, 385 mg. 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 385.5 mg. 386 mg, 386.5 mg. 387 mg, 387.5 mg. 388 mg, mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 388.5 mg. 389 mg, 389.5 mg. 390 mg. 390.5 mg, 391 mg, mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg. 391.5 mg. 392 mg, 392.5 mg. 393 mg, 393.5 mg. 394 mg. 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 394.5 mg. 395 mg. 395.5 mg, 396 mg, 396.5 mg, 397 mg, mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 397.5 mg,398 mg,398.5 mg,399 mg,399.5 mg, 400 mg, 405 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 410 mg. 415 mg, 420 mg. 425 mg, 430 mg, 435 mg. 440 mg, 43 mg. 44 mg. 45 mg, 46 mg, 47 mg, 48 mg. 49 mg, 50 mg, 445 mg. 450 mg. 455 mg, 460 mg. 465 mg, 470 mg. 475 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg, 480 mg. 485 mg. 490 mg. 495 mg, 500 mg, 505 mg, 510 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 585 mg, 590 mg, 595 mg. 600 mg. 605 mg. 610 mg. 615 mg, or 200 mg. Furthermore, the non-opioid agent (Such as mg, 620 mg. 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 acetaminophen or naproxen or a salt thereof) is present in a mg, 655 mg. 660 mg. 665 mg. 675 mg, 680 mg, 685 mg. 690 range of between about 200 mg to about 1000 mg, including mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 but not limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg. mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg. mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg. mg, 800 mg. 805 mg. 810 mg. 815 mg, 820 mg. 825 mg,830 295 mg, 300 mg. 305 mg. 310 mg, 315 mg, 320 mg. 325 mg. mg, 835 mg, 840 mg. 845 mg. 850 mg. 855 mg, 860 mg, 865 326 mg,326.5 mg, 327 mg, 327.5 mg. 328 mg,328.5 mg,329 mg, 870 mg. 875 mg. 880 mg. 885 mg. 890 mg. 895 mg,900 mg, 329.5 mg, 330 mg,330.5 mg, 331 mg, 331.5 mg, 332 mg, mg,905 mg, 910 mg, 915 mg. 920 mg,925 mg,930 mg,935 332.5 mg, 333 mg, 333.5 mg. 334 mg. 334.5 mg, 335 mg. mg,940 mg. 945 mg,950 mg. 955 mg,960 mg. 965 mg,970 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, mg,975 mg. 980 mg,985 mg. 990 mg,995 mg, or 1000 mg. 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, Additionally, the barbiturate (e.g., butalbital or a salt thereof) 341.5 mg., 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. is present at a dose between about 0.5 mg to about 200 mg. 344.5 mg., 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, including but not limited to, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg. 347.5 mg, 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg. 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 362.5 mg, 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg. 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, mg, 43 mg. 44 mg. 45 mg, 46 mg, 47 mg, 48 mg. 49 mg, 50 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 390.5 mg. 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, mg, or 200 mg. In one instance, an opioid analgesic agent, a 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, non-opioid agent, and a barbiturate agent are present in a 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, bi-layer tablet that comprises an immediate-release and a 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg. 425 mg. controlled-release layer. In a further instance, the bi-layer 430 mg, 435 mg. 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. tablet comprises an antiemetic agent, such as an antiemetic. 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. In one instance, an opioid analgesic agent, a non-opioid 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. agent, and a barbiturate agent are present in a two layer tablet 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. that comprises an immediate-release and a controlled-release 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg. layer. In a further instance, the two layer tablet comprises an 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. antiemetic agent, such as an antiemetic. In one instance, the 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. antiemetic is present in the immediate-release layer and the 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. opioid analgesic agent, non-opioid agent, and barbiturate 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. agent are present in the controlled-release layer. 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. 0306 In some instances, a pharmaceutical composition 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. disclosed herein comprises an effective amount of a barbitu 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. rate agent (such as butalbital or a salt thereof); a non-opioid 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. agent (such as acetaminophen or naproxen or a salt thereof); 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. and a stimulant agent (Such as caffeine or a salt thereof). In 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. one instance, the barbiturate agent (Such as butalbital or a salt 960 mg,965 mg, 970 mg,975 mg,980 mg,985 mg, 990 mg. thereof); is present in a range of about 0.5 mg to about 200 mg. 995 mg. or 1000 mg. Additionally, the stimulant agent (e.g., including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg. caffeine) is present at a dose from about 0.5 mg to about 200 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg. mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg. 4.5 mg, 5.0 mg, 5.5 mg. 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 6.0 mg. 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 US 2015/0290211 A1 Oct. 15, 2015

mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 tablet that comprises an immediate-release and a controlled mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 release layer. In a further instance, the bi-layer tablet further mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg. comprises an antiemetic agent, such as an antihistamine (e.g. 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 promethazine or a salt thereof). In one instance, a barbiturate mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 agent, and a stimulant are present in a two layer tablet that mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg. 30 mg, 31 mg, 32 mg, comprises an immediate-release and a controlled-release 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 layer. In a further instance, the two layer tablet further com mg, 12 mg, 43 mg, 44 mg. 45 mg, 46 mg, 47 mg, 48 mg, 49 prises an antiemetic agent. Such as an antihistamine (e.g. mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 promethazine or a salt thereof). In one instance, the stimulant mg, 90 mg.95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg. and an antihistamine are present in the immediate-release 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg. layer and the barbiturate agent is present in the controlled 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg. release layer. 195 mg, or 200 mg. In one instance, a stimulant agent, a 0308. In some instances, a pharmaceutical composition non-opioid agent, and a barbiturate agent are present in a comprises an effective amount of a non-opioid agent (such as bi-layer tablet that comprises an immediate-release and a naproxen or ibuprofen or a salt thereof) and a stimulant (Such controlled-release layer. In one instance, a stimulant agent, a as caffeine or a salt thereof). In some instances, the non non-opioid agent, and a barbiturate agent are present in a two opioid agent (such as naproxen or ibuprofen or a salt thereof) layer tablet that comprises an immediate-release and a con is present in a range of between about 200 mg to about 1000 trolled-release layer. In one instance, the stimulant is present mg, including but not limited to 200 mg, 205 mg, 210 mg, 215 in the immediate-release layer and the non-opioid analgesic mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 agent and barbiturate are present in the controlled-release mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 layer. In a further instance, the bi-layer tablet comprises an mg, 290 mg, 295 mg, 300 mg. 305 mg. 310 mg, 315 mg. 320 antiemetic agent, such as an antihistamine (e.g., promethaZ mg, 325 mg, 326 mg, 326.5 mg, 327 mg, 327.5 mg. 328 mg, ine). In a further instance, the two layer tablet comprises an 328.5 mg, 329 mg, 329.5 mg. 330 mg. 330.5 mg, 331 mg, antiemetic agent, such as an antihistamine (e.g., promethaZ 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg. 334 mg. ine). In one instance, the stimulant and an antihistamine are 334.5 mg, 335 mg, 335.5 mg. 336 mg, 336.5 mg, 337 mg, present in the immediate-release layer and the non-opioid 337.5 mg, 338 mg, 338.5 mg. 339 mg, 339.5 mg, 340 mg. analgesic agent and barbiturate are present in the controlled 340.5 mg., 341 mg, 341.5 mg., 342 mg, 342.5 mg., 343 mg, release layer. 343.5 mg, 344 mg., 344.5 mg, 345 mg, 345.5 mg, 346 mg, 0307. In some instances, a pharmaceutical composition 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, provided herein can comprise an effective amount of a barbi 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, turate and a stimulant. In one instance, the pharmaceutical 352.5 mg, 353 mg, 353.5 mg, 354 mg. 354.5 mg, 355 mg. composition comprises a stimulant at a dose of about 1 mg to 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, about 350 mg (such as 5 mg to 25 mg, 10 mg to 50 mg, 25 to 358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mg to 350 mg) 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg, 364 mg. including but not limited to about 1.0 mg, 1.0 mg, 1.5 mg, 2.5 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, mg, 3.0 mg, 4.0 mg, 5.0 mg. 6.0 mg. 6.5 mg, 7.0 mg, 7.5 mg. 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg. mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg. 374.5 mg, 375 mg, 375.5 mg. 376 mg, 376.5 mg, 377 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg, 380 mg, mg, 19.5 mg, 20 mg, 25 mg, 30 mg. 35 mg, 40 mg, 45 mg, 50 380.5 mg. 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, mg, 60 mg, 70 mg. 80 mg, 90 mg, 100 mg, 110 mg, 120 mg. 383.5 mg. 384 mg. 384.5 mg. 385 mg. 385.5 mg, 386 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg. 386.5 mg, 387 mg, 387.5 mg. 388 mg. 388.5 mg, 389 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg. 389.5 mg. 390 mg. 390.5 mg. 391 mg, 391.5 mg, 392 mg, 270 mg, 280 mg, 290 mg, 300 mg. 310 mg, 320 mg, 330 mg. 392.5 mg, 393 mg, 393.5 mg. 394 mg. 394.5 mg, 395 mg. 340 mg. or 350 mg. Additionally, the barbiturate agent (such 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, as butalbital or a salt thereof); is present in a range of about 0.5 398.5 mg, 399 mg,399.5 mg, 400 mg. 405 mg, 410 mg, 415 mg to about 200 mg, including but not limited to 0.5 mg, 1.0 mg, 420 mg. 425 mg, 430 mg, 435 mg. 440 mg. 445 mg. 450 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg. 3.5 mg. 4.0 mg. 4.5 mg. mg, 455 mg. 460 mg. 465 mg. 470 mg. 475 mg, 480 mg. 485 5.0 mg, 5.5 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 490 mg. 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, mg, 595 mg, 600 mg. 605 mg. 610 mg. 615 mg, 620 mg. 625 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 630 mg, 635 mg, 640 mg. 645 mg, 650 mg. 655 mg. 660 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 665 mg. 675 mg, 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 40 mg. 41 mg, 12 mg, 43 mg. 44 mg., 45 mg, 46 mg, 47 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 48 mg. 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 810 mg, 815 mg, 820 mg. 825 mg. 830 mg, 835 mg, 840 mg, 80 mg. 85 mg. 90 mg, 95 mg, 100 mg, 105 mg, 110 mg. mg, 845 mg. 850 mg. 855 mg, 860 mg, 865 mg, 870 mg. 875 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg. mg, 880 mg. 885 mg. 890 mg. 895 mg,900 mg, 905 mg, 910 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg. mg, 915 mg,920 mg,925 mg,930 mg,935 mg,940 mg,945 185 mg, 190 mg, 195 mg. or 200 mg. In one instance, a mg,950 mg, 955 mg,960 mg,965 mg, 970 mg,975 mg,980 barbiturate agent, and a stimulant are present in a bi-layer mg,985 mg,990 mg,995 mg. or 1000 mg. In these instances, US 2015/0290211 A1 Oct. 15, 2015 66 a pharmaceutical composition comprises a stimulantata dose 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg, 364 mg. of about 1 mg to about 350 mg. (Such as 5 mg to 25 mg, 10 mg 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, to 50 mg, 25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg. or 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 75 mg to 350 mg), including but not limited to about 1.0 mg. 371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg. 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg. 4.0 mg, 5.0 mg., 6.0 mg., 6.5 374.5 mg, 375 mg, 375.5 mg. 376 mg, 376.5 mg, 377 mg, mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg, 380 mg, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 380.5 mg. 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 383.5 mg. 384 mg. 384.5 mg. 385 mg. 385.5 mg, 386 mg, mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg. 386.5 mg, 387 mg, 387.5 mg. 388 mg. 388.5 mg, 389 mg, 35 mg, 40 mg, 45 mg, 50 mg. 60 mg, 70 mg, 80 mg, 90 mg. 389.5 mg. 390 mg. 390.5 mg. 391 mg, 391.5 mg, 392 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg. 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg. 392.5 mg, 393 mg, 393.5 mg. 394 mg. 394.5 mg, 395 mg. 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg. 300 mg. 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 310 mg. 320 mg,330 mg,340 mg. or 350 mg. In one instance, 398.5 mg, 399 mg,399.5 mg, 400 mg. 405 mg, 410 mg, 415 a non-opioid agent and a stimulant are formulated as a bi mg, 420 mg. 425 mg, 430 mg, 435 mg. 440 mg. 445 mg. 450 layer tablet that comprises an immediate-release and a con mg, 455 mg. 460 mg. 465 mg. 470 mg. 475 mg, 480 mg. 485 trolled-release layer. In one example naproxen and caffeine mg, 490 mg. 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 are formulated in a bi-layer tablet. In one instance, a non mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 opioid agent and a stimulant are formulated as a two layer mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 tablet that comprises an immediate-release and a controlled mg, 595 mg, 600 mg. 605 mg. 610 mg. 615 mg, 620 mg. 625 release layer. In one example naproxen and caffeine are for mg, 630 mg, 635 mg, 640 mg. 645 mg, 650 mg. 655 mg. 660 mulated in a two layer tablet. In one instance, the caffeine is mg, 665 mg. 675 mg, 680 mg, 685 mg. 690 mg. 695 mg, 700 present in the immediate-release layer and naproxen is mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 present in the controlled-release layer. mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 0309. In some instances, a pharmaceutical composition mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg. 805 disclosed herein comprises an effective amount of pro mg, 810 mg, 815 mg, 820 mg. 825 mg. 830 mg, 835 mg, 840 poxyphene or a salt thereof and a non-opioid agent (Such as mg, 845 mg. 850 mg. 855 mg, 860 mg, 865 mg, 870 mg. 875 naproxen or a salt thereof). In some instances, the pharma mg, 880 mg. 885 mg. 890 mg. 895 mg,900 mg, 905 mg, 910 ceutical composition further comprises an antiemetic (such as mg,915 mg,920 mg,925 mg,930 mg,935 mg,940 mg,945 promethazine or a salt thereof). In some instances, the phar mg,950 mg, 955 mg,960 mg,965 mg, 970 mg,975 mg,980 maceutical compositions further comprise a stimulant agent. mg, 985 mg, 990 mg. 995 mg, or 1000 mg. In one instance, In one instance, the propoxyphene or salt thereof is present in propoxyphene or a salt thereof and naproxen (such as a range of about 1.0 mg to about 100 mg, including but not naproxen Sodium or naproxen magnesium) are present in a limited to 11.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg. bi-layer tablet. In one instance, propoxyphene or a salt thereof 6.0 mg. 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 and naproxen (Such as naproxen Sodium or naproxen magne mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 sium) are present in a two layer tablet. In a further instance, mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 the pharmaceutical composition comprises an antiemetic mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 (e.g., promethazine or a salt thereof). In one instance, the mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg. antihistamine is present in the immediate-release layer and 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 propoxyphene and naproxen are present in the controlled mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. 30.5 mg, 31 mg, 31.5 release layer. mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg, 36.5 mg, 37 mg, 0310. In some instances, a pharmaceutical composition 37.5 mg.38 mg, 38.5 mg. 39 mg, 39.5 mg. 40 mg, 40.5 mg, 41 described herein comprises an effective amount of an anti mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg. 44 mg., 44.5 emetic (e.g., promethazine or a salt thereof), that is present in mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, the range of at about 0.5 mg to about 60 mg, including but not 48.5 mg. 49 mg, 49.5 mg, 50mg, 55 mg, 60 mg, 65mg, 70 mg. limited to a dose of about 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 75 mg, 80 mg. 85 mg, 90 mg.95 mg, or 100 mg. Furthermore, mg, 3.0 mg, 3.5 mg, 4.0 mg. 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg. the non-opioid agent is in a range of about 200 mg to about 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 1000 mg, including but not limited to 200 mg, 205 mg, 210 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 285 mg, 290 mg, 295 mg. 300 mg. 305 mg. 310 mg, 315 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg. mg, 320 mg. 325 mg. 326 mg, 326.5 mg, 327 mg, 327.5 mg. 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 328 mg,328.5 mg,329 mg, 329.5 mg,330 mg, 330.5 mg,331 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, mg, 331.5 mg, 332 mg, 332.5 mg,333 mg,333.5 mg,334 mg. 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 334.5 mg, 335 mg, 335.5 mg. 336 mg, 336.5 mg, 337 mg, mg, 43 mg. 44 mg. 45 mg, 46 mg, 47 mg, 48 mg. 49 mg, 50 337.5 mg, 338 mg, 338.5 mg. 339 mg, 339.5 mg, 340 mg. mg, 55 mg, 60 mg. In one instance, the antiemetic is promet 340.5 mg, 341 mg, 341.5 mg., 342 mg, 342.5 mg., 343 mg, hazine or a salt thereof. In other instances, the antiemetic is 343.5 mg, 344 mg., 344.5 mg. 345 mg, 345.5 mg., 346 mg, another described herein above. As described herein, in some 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, instances, the antiemetic is a component of an immediate 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, release formulation. For example, in a further instance, the 352.5 mg, 353 mg, 353.5 mg, 354 mg. 354.5 mg, 355 mg. immediate-release is in a lollipop, a capsule, a tablet, a trans 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, dermal means, through injection, intramuscular administra 358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, tion or other means disclosed herein. US 2015/0290211 A1 Oct. 15, 2015 67

0311. In some instances, any of the pharmaceutical com SulfoSuccinate, dioctyl sodium SulfoSuccinate, or dioctyl positions disclosed herein can comprise one or more laxa potassium Sulfo Succinate. For example, the pharmaceutical tives. In one instance, a pharmaceutical composition com composition can comprise about 1-1000 mg, 1-750 mg, 1-500 prises an opioid analgesic, an antiemetic, and a laxative. The mg, 1-250 mg, 1-150 mg, 1-100 mg, 1-75 mg, 1-50 mg, 1-25 laxative can in an amount effective to reduce or eliminate mg, 1-10 mg, 10-1000 mg, 10-750 mg, 10-500 mg, 10-250 constipation, Such as opioid-induced constipation. The effec mg, 10-150 mg, 10-100 mg, 1075 mg, 10-50 mg, 10-25 mg. tive amount can depend upon the laxative and/or route of 25-1000 mg, 25-750 mg, 25-500 mg, 25-250 mg, 25-150 mg, administration. In one instance, a single dose of a pharma 25-100 mg, 25-75 mg, 25-50 mg, 50-1000 mg, 50-750 mg, ceutical composition disclosed herein comprises from about 50-500 mg, 50-250 mg, 50-150 mg, 50-100 mg, 50-75 mg, 1 mg to about 1000 mg of a laxative. For example, the phar 75-1000 mg, 75-750 mg, 75-500 mg, 75-250 mg, 75-150 mg, maceutical composition can comprise about 11000 mg, 1-750 75-100 mg, 100-1000 mg, 100-750 mg, 100-500mg, 100-250 mg, 1-500 mg, 1-250 mg, 1-150 mg, 1-100 mg, 1-75 mg, 1-50 mg, 100-150 mg, 150-1000 mg, 150-750 mg, 150-500 mg, mg, 1-25 mg, 1-10 mg, 10-1000 mg, 10-750 mg, 10-500 mg. 150250 mg, 250-1000 mg, 250-750 mg, 250-500 mg, 500 10-250 mg, 10-150 mg, 10-100 mg, 10-75 mg, 10-50 mg. 1000 mg, 500-750 mg, 750-1000 mg, 1 mg, 2 mg 3 mg, 4 mg. 10-25 mg, 25-1000 mg, 25-750 mg, 25-500 mg, 25-250 mg. 5 mg, 6 mg, 7 mg, 8 mg.9 mg, 10 mg, 11 mg, 12 mg, 13 mg. 25-150 mg, 25-100 mg, 25-75 mg, 2550 mg, 50-1000 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 50-750 mg, 50-500 mg, 50-250 mg, 50-150 mg, 50-100 mg, mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg. 45 mg, 50 50-75 mg, 75-1000 mg, 75-750 mg, 75-500 mg, 75-250 mg, mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 75-150 mg, 75-100 mg, 100-1000 mg, 100-750 mg, 100500 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 100-250 mg, 100-150 mg, 150-1000 mg, 150-750 mg, mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 150-500 mg, 150-250 mg, 250-1000 mg, 250-750 mg, 250 mg, 230 mg, 240 mg, 250 mg, 275 mg. 300 mg. 325 mg, 350 500 mg, 500-1000 mg, 500-750 mg, 750-1000 mg, 1 mg, 2 mg, 375 mg, 400 mg. 425 mg. 450 mg. 475 mg, 500 mg, 550 mg, 3 mg. 4 mg, 5 mg, 6 mg, 7 mg, 8 mg.9 mg, 10 mg, 11 mg. mg, 600 mg, 650 mg, 700 mg, 750 mg. 800 mg. 850 mg,900 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 950 mg. or 1000 mg of a stool softener such as dioctyl mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg. 30 mg. 35 mg. 40 calcium SulfoSuccinate, dioctyl sodium sulfo Succinate, or mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 dioctyl potassium Sulfo Succinate. In one instance, the single mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg. dose of the pharmaceutical composition comprises from 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg. about 15 mg to about 500 mg of a stool softener such as 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg. 300 mg. dioctyl calcium sulfo Succinate, dioctyl sodium sulfosucci 325 mg, 350 mg, 375 mg, 400 mg. 425 mg. 450 mg. 475 mg. nate, or dioctyl potassium Sulfo Succinate. In another instance, 500 mg, 550 mg. 600 mg, 650 mg, 700 mg, 750 mg. 800 mg. the single dose of the pharmaceutical composition comprises 850 mg. 900 mg, 950 mg, or 1000 mg of a laxative. The from about 15 mg to about 125 mg of a stool softener such as laxative can be a bulk-producing agent (e.g., polycarbophil dioctyl calcium sulfo Succinate, dioctyl sodium sulfo Succi calcium, methylcellulose, a soluble dietary fibre, an insoluble nate, or dioctyl potassium Sulfo Succinate. In another instance, dietary fibre), a stool softener (e.g., dioctyl calcium sulfosuc the single dose of the pharmaceutical composition comprises cinate, dioctyl Sodium sulfoSuccinate, or dioctyl potassium from about 15 mg to about 500 mg of a stool softener such as SulfoSuccinate), a lubricant (e.g., mineral oil), a hydrating dioctyl calcium sulfo Succinate, dioctyl sodium sulfo Succi agent (e.g., Sodium chloride, Sodium bicarbonate, potassium nate, or dioctyl potassium Sulfo Succinate. chloride, Sodium sulfate, Sodium phosphate, potassium Sodium tartrate, magnesium citrate, magnesium hydroxide, 0314. In some instances, a single dose of a pharmaceutical magnesium sulfate, Sorbitol, lactulose, polyethylene glycol), composition disclosed herein comprises from about 1 mg to a stimulant or irritant (e.g., dantron, emodine, aloe emodin, a about 100 mg of a stimulant or irritant such as an anthracene Senna glycoside, bisacodyl, phenolphthalein), a serotonin dione, a triphenylmethane, or castor oil. Suitable anthracene agonist (e.g., tegaserod, cisapride, prucalopride), or a chlo diones include dantron (1,8-dihydroxyanthraquinone), emo dine (6-methyl-1,3,8-trihydroxyanthraquinone), aloe emodin ride channel activator (e.g., lubiprostone). (1.8-Dihydroxy-3-(hydroxymethyl)-9,10-anthracenedione), 0312. In some instances, a single dose of a pharmaceutical and Senna glycosides. Suitable triphenylmethanes include composition disclosed herein from about 0.1 g to about 20 g bisacodyl 4,4'-(pyridin-2-ylmethylene)bis(4,1-phenylene) of a bulk-producing agent such as polycarbophil calcium, diacetate and phenolphthalein. For example, the pharmaceu methyl cellulose, a soluble dietary fibre, an insoluble dietary tical composition can comprise about 1-100 mg, 1-75 mg. fibre, or any combination thereof. For example, the single 1-50 mg, 125 mg, 1-15 mg, 1-10 mg, 1-7.5 mg, 1-5 mg, 1-2.5 dose can comprise about 0.1-20 g, 0.1-15g, 0.1-10g, 0.1-7.5 mg, 2.5-100 mg, 2.5-75 mg, 2.5-50 mg, 2.5-25 mg, 2.5-15 g, 0.1-5 g, 0.1-2 g, 0.1-1 g, 0.1-0.5 g. 0.5-20 g, 0.5-15 g. mg, 2.5-10 mg, 2.5-7.5 mg, 2.5-5 mg, 5-100 mg, 5-75 mg. 0.5-10g, 0.5-7.5 g., 0.5-5 g, 0.5-2 g, 0.5-1 g, 1-20g, 1-15 g. 5-50 mg, 5-25 mg, 5-15 mg, 5-10 mg, 5-7.5 mg, 7.5-100 mg. 1-10g, 1-7.5 g. 1–5 g, 1-2g, 220g, 2-15g, 2-10g, 2-7.5g, 2-5 7.5-75 mg, 7.5-50 mg, 7.5-25 mg, 7.5-15 mg, 7.5-10 mg. g, 5-20g, 5-15 g, 5-10g, 5-7.5g, 7.5-20 g, 7.5-15g, 7.5-10g, 10-100 mg, 10-75 mg, 10-50 mg, 10-25 mg, 10-15 mg, 1020 g, 10-15 g, 15-20 g, 0.1 g, 0.2g, 0.3 g 0.4g, 0.5g, 0.6 15-100 mg, 15-75 mg, 15-50 mg, 15-25 mg, 25-100 mg. g, 0.7 g. 0.8 g. 0.9 g, 1 g, 1.1 g, 1.2g, 1.3 g, 1.4g, 1.5 g, 1.6 25-75 mg, 25-50 mg, 50-100 mg, 50-75 mg, 75-100 mg, 1 mg, g, 1.7g, 1.8g, 1.9 g, 2 g, 2.5g, 3 g, 3.5g, 4 g. 4.5g, 5g, 5.5 1.5 mg, 2 mg, 2.5 mg. 3 mg, 3.5 mg. 4 mg. 4.5 mg, 5 mg, 5.5 g, 6 g. 6.5g, 7g, 7.5g, 8 g., 8.5g, 9 g, 9.5g, 10g, 11 g, 12 g. mg, 6 mg. 6.5 mg, 7 mg, 7.5 mg. 8 mg, 8.5 mg.9 mg, 9.5 mg. 13 g, 14 g. 15 g, 16 g., 17 g. 18 g. 19 g, or 20 g of a bulk 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 producing agent. mg, 14 mg, 14.5 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 0313. In some instances, a single dose of a pharmaceutical mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 composition disclosed herein comprises from about 1 mg to mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 about 1000 mg of a stool softener such as dioctyl calcium mg, 37 mg, 38 mg, 39 mg, 40 mg. 41 mg, 42 mg, 43 mg, 44 US 2015/0290211 A1 Oct. 15, 2015

mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 10-25ug. 10-15ug, 15-100 ug, 15-75ug, 15-50 ug, 15-25ug, mg, 65mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, or 100 25-100 ug, 25-75ug, 25-50 ug, 50-100 ug, 50-75ug, 75-100 mg of the stimulant or irritant. In one instance, the single dose Lig, 1 Lig, 1.5 Lig, 2 Lig, 2.5 Lig, 3 Lig. 3.5 Lig. 4 Lig. 4.5 Lig, 5 Jug, of the pharmaceutical composition comprises from about 1 5.5ug, 6 Jug. 6.5ug, 7 Lig, 7.5ug. 8 Lig, 8.5ug, 9 Jug, 9.5ug. 10 mg to about 50 mg of the stimulant or irritant. In another Jug, 10.5 Lig, 11 Lig, 11.5ug. 12 Lig, 12.5ug. 13 Jug. 13.5ug. 14 instance, the single dose of the pharmaceutical composition Lig, 14.5 Lig, 15 Jug, 16 Jug. 17 Lig, 18 Jug. 19 Jug. 20 Lig, 21 Jug, comprises from about 5 mg to about 15 mg of the stimulant or 22 Jug, 23 Lig, 24 Jug, 25g, 26 Jug. 27 Jug. 28 Lig, 29.g., 30 Jug, irritant. 31 Lig. 32 Lig. 33 Lug. 34.g., 35ug. 36 Lig, 37 Lig. 38 Lig. 39 Lig. 0315. In some instances, a single dose of a pharmaceutical 40 Lig. 41 Lig. 42 Lig. 43 Lig. 44 Lig. 45 Lig. 46 Lig. 47 Lig. 48 yug, composition disclosed herein comprises from about 1 g to 49 g, 50 ug, 55ug, 60 Lig, 65ug, 70 ug, 75ug, 80 ug. 85 ug, about 50 g of a saline laxative Such as Sodium chloride, 90 ug, 95 ug, or 100 ug of the chloride channel activator. In Sodium bicarbonate, potassium chloride, Sodium Sulfate, one instance, the single dose of the pharmaceutical composi Sodium phosphate, potassium sodium tartrate, magnesium tion comprises from about 5ug to about 50g of the chloride citrate, magnesium hydroxide, magnesium Sulfate, or any channel activator. In another instance, the single dose of the combination thereof. For example, the single dose of the pharmaceutical composition comprises from about 20 ug to pharmaceutical composition can comprise about 1-50 g, 1-30 about 30 ug of the chloride channel activator. g, 1-25 g, 1-20 g, 1-15 g, 1-10g, 1-5 g, 5-50 g., 530 g, 5-25 g, 0318. In some instances, a single dose of a pharmaceutical 5-20 g, 5-15 g, 5-10 g, 10-50 g, 10-30 g, 10-25 g, 10-20 g, composition disclosed herein comprises from about 1 mg to 10-15 g, 15-50 g, 15-30 g, 15-25 g, 15-20g, 20-50g, 20-30 g, about 25 mg of a serotonin agonist Such as tegaserod, 20-25g, 25-50g, 25-30 g., 30-50 g, 1 g, 2 g, 3 g, 4 g., 5 g. 6 g. cisapride, or prucalopride. For example, the single dose of the 7 g. 8g.9 g, 10g, 11 g, 12 g, 13 g, 14.g. 15 g, 16 g. 17 g. 18 pharmaceutical composition can comprise about 1-25 mg. g, 19 g, 20g, 21 g, 22g, 23 g, 24g, 25g, 26 g. 27 g. 28 g, 29 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, 5-25 mg, 5-20 mg, 5-15 g, 30 g, 31 g, 32 g, 33 g, 34g, 35 g, 36 g., 37 g. 38 g. 39 g, 40 mg, 5-10 mg, 10-25 mg, 10-20 mg, 10-15 mg, 15-25 mg. g, 41 g, 42 g, 43 g., 44 g. 45 g, 46g, 47 g., 48g, 49 g, or 50 g 15-20 mg, 20-25 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 of the saline laxative. In one instance, the pharmaceutical mg, 8 mg.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg. composition comprises about 10 g of the saline laxative. In 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 another instance, the pharmaceutical composition comprises mg, or 25 mg of the serotonin agonist. In one instance, the about 20 g of the Saline laxative. In another instance, the single dose of the pharmaceutical composition comprises pharmaceutical composition comprises about 30 g of the from about 1 mg to about 10 mg of the serotonin agonist. In saline laxative. another instance, the single dose of the pharmaceutical com 0316. In some instances, a single dose of a pharmaceutical position comprises about 6 mg of the serotonin agonist. composition disclosed herein comprises from about 1 g to about 50g of a hyperosmotic agent such as Sorbitol, lactulose, Dosage Forms polyethylene glycol or glycerine. For example, the single dose of the pharmaceutical composition can comprise about Oral Dosage Forms 1-50 g, 1-30 g, 1-25 g, 1-20 g, 1-15 g, 1-10g. 1–5 g, 5-50 g, 0319. Some instances relate to methods and pharmaceuti 5-30 g, 5-25 g, 5-20 g, 5-15g, 5-10g, 10-50 g, 10-30 g, 1025 cal compositions formulated for oral delivery to a subject in g, 10-20g, 10-15g, 15-50 g, 15-30 g, 15-25 g, 15-20g, 20-50 need. In one instance, a pharmaceutical composition is for g, 20-30g, 20-25g, 25-50g, 25-30 g, 30-50 g, 1 g, 2 g, 3 g. 4 mulated so as to deliver one or more pharmaceutically active g, 5 g. 6 g. 7 g., 8 g. 9 g, 10g, 11 g, 12g, 13 g, 14.g. 15 g, 16 agents to a Subject through a mucosa layer in the mouth or g, 17g, 18g. 19 g, 20g, 21 g, 22g, 23 g, 24g, 25g, 26 g. 27 esophagus. In another instance, the pharmaceutical composi g, 28 g, 29 g, 30 g., 31 g, 32 g, 33 g., 34g, 35 g, 36 g., 37 g., 38 tion is formulated to deliver one or more pharmaceutically g, 39 g, 40 g, 41 g, 42 g, 43 g., 44.g., 45 g, 46 g. 47 g, 48g, 49 active agents to a Subject through a mucosa layer in the g, or 50 g of the hyperosmotic agent. In one instance, the stomach and/or intestines. single dose of the pharmaceutical composition comprises 0320 In some instances, a pharmaceutical composition is about 5g of the hyperosmotic agent. In another instance, the provided in controlled-release dosage forms (such as imme single dose of the pharmaceutical composition comprises diate-release, controlled-release or both), which comprise an about 10g of the hyperosmotic agent. In another instance, the effective amount of an opioid analgesic (such as oxycodone single dose of the pharmaceutical composition comprises or hydrocodone or a salt thereof), a non-opioid analgesic about 15 g of the hyperosmotic agent. In another instance, the (such as acetaminophen, naproxen or ibuprofen or a salt single dose of the pharmaceutical composition comprises thereof) and an antiemetic (Such as promethazine or a salt about 20g of the hyperosmotic agent. In another instance, the thereof); and one or more release controlling excipients as single dose of the pharmaceutical composition comprises described herein. In some instances, the opioid analgesic is about 30 g of the hyperosmotic agent. formulated for controlled release. In some instances, the non 0317. In some instances, a single dose of a pharmaceutical opioid analgesic is formulated for controlled release. In some composition disclosed herein comprises from about 1 ug to instances, the antiemetic is formulated for immediate release. about 100 ug of a chloride channel activator such as lubipro Suitable controlled-release dosage vehicles include, but are stone. For example, the single dose of the pharmaceutical not limited to, hydrophilic or hydrophobic matrix devices, composition can comprise about 1-100 ug. 1-75ug. 1-50 ug, water-soluble separating layer coatings, enteric coatings, 1-25 ug, 1-15ug, 110 ug. 1-7.5 Lig, 1-5ug, 1-2.5 Lig, 2.5-100 osmotic devices, multi-particulate devices, and combinations ug, 2.5-75 ug, 2.5-50 jug, 2.5-25 ug, 2.5-15 ug, 2.5-10 ug, thereof. The pharmaceutical compositions can also comprise 2.5-7.5ug, 2.5-5ug, 5-100 ug, 5-75ug. 5-50 ug, 5-25ug. 5-15 non-release controlling excipients. ug, 5-10 ug, 5-7.5ug, 7.5-100 ug, 7.5-75ug, 7.5-50 ug, 7.5-25 0321. In some instances, a pharmaceutical composition is ug, 7.5-15 lug, 7.5-10 ug, 10-100 lug. 10-75 ug, 10-50 ug, provided in enteric coated dosage forms. The pharmaceutical US 2015/0290211 A1 Oct. 15, 2015 69 compositions can also comprise non-release controlling bottles of pints or gallons. In another instance, the multiple excipients. In another instance, pharmaceutical compositions dosage forms comprise different pharmaceutically active are provided in effervescent dosage forms. The pharmaceu agents. For example, a multiple dosage form can be provided tical compositions can also comprise non-release controlling which comprises a first dosage element comprising an imme excipients. In some instances, a pharmaceutical composition diate-release form of an antiemetic (such as in a liquid form) is provided in a dosage form that has at least one component and a second dosage element comprising an opioid and/or that can facilitate the immediate-release of an active agent, non opioid analgesic, which can be in a controlled-release or and at least one component that can facilitate the controlled immediate-release form. In this example, a pair of dosage release of an active agent. In some instances, the dosage form elements can make a single unit dosage. is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time 0324. In one instance, a kit is provided comprising mul from 0.1 up to 8 hours. The pharmaceutical compositions can tiple unit dosages, wherein each unit comprises a first dosage comprise one or more release controlling and non-release element comprising an immediate-release form of an anti emetic (Such as in a liquid form) and a second dosage element controlling excipients. Such as those excipients Suitable for a comprising an opioid or non-opioid analgesic or both, which disruptable semi-permeable membrane and as swellable sub can be in a controlled-release form or an immediate-release Stances. form. In another instance, the kit further comprises a set of 0322. In some instances, a pharmaceutical composition is instructions. In yet a further instance, the antiemetic is provided in a dosage form for oral administration to a subject promethazine or a pharmaceutically acceptable salt thereof, in need thereof, which comprises one or more pharmaceuti the opioid analgesic is oxycodone or hydrocodone or phar cally acceptable excipients or carriers, enclosed in an inter maceutically acceptable salt thereof, the non-opioid analge mediate reactive layer comprising a gastric juice-resistant sic is acetaminophen or a pharmaceutically acceptable salt polymeric layered material partially neutralized with alkali thereof. and having cation exchange capacity and a gastric juice resistant outer layer. In some instances, a pharmaceutical 0325 In some instances, a pharmaceutical composition composition is in the form of enteric-coated granules, as disclosed herein is formulated in various dosage forms for controlled-release capsules for oral administration. The phar oral, parenteral, and topical administration. The pharmaceu maceutical compositions can further comprise cellulose diso tical compositions can also be formulated as an immediate-, dium hydrogen phosphate, hydroxypropyl cellulose, controlled-release dosage forms. The pharmaceutical compo hypromellose, lactose, mannitol, and sodium lauryl Sulfate. sitions can also be formulated as gastric retention dosage In some instances, a pharmaceutical composition is in the forms. These dosage forms can be prepared according to form of enteric-coated pellets, as controlled-release capsules known methods and techniques. In some instances, a phar for oral administration. The pharmaceutical compositions maceutical composition disclosed herein is in one or more can further comprise glyceryl monostearate 40-50, hydrox dosage form. For example, a pharmaceutical composition can ypropyl cellulose, hypromellose, magnesium Stearate, meth be administered in a solid or liquid-form. Examples of solid acrylic acid copolymer type C, polysorbate 80, Sugar spheres, dosage forms include but are not limited to discrete units in talc, and triethylcitrate. In some instances, a pharmaceutical capsules or tablets, as a powder or granule, or present in a composition is enteric-coated controlled-release tablets for tablet conventionally formed by compression molding. Such oral administration. The pharmaceutical compositions can compressed tablets can be prepared by compressing in a further comprise carnauba wax, crospovidone, diacetylated Suitable machine the three or more agents and a pharmaceu monoglycerides, ethylcellulose, hydroxypropyl cellulose, tically acceptable carrier. The molded tablets can be coated or hypromellose phthalate, magnesium Stearate, mannitol, scored, having indicia inscribed thereon and can be so formu Sodium hydroxide, Sodium Stearyl fumarate, talc, titanium lated as to cause immediate or controlled release of the opioid dioxide, and yellow ferric oxide. In some instances, a phar analgesics (such as oxycodone or hydrocodone) and/or the maceutical composition comprises calcium Stearate, non-opioid analgesics (such as acetaminophen) and or the crospovidone, hydroxypropyl methylcellulose, iron oxide, antiemetic (such as promethazine). Furthermore, dosage mannitol, methacrylic acid copolymer, polysorbate 80, povi forms herein can comprise acceptable carriers or salts known done, propylene glycol, Sodium carbonate, Sodium lauryl Sul in the art, such as those described in the Handbook of Phar fate, titanium dioxide, and triethyl citrate. maceutical Excipients, American Pharmaceutical Associa 0323 In some instances, a pharmaceutical composition tion (1986), incorporated by reference herein in its entirety. provided herein is in a unit-dosage form or multiple-dosage 0326 In some instances, one or more pharmaceutically form. Unit-dosage forms, as used herein, refer to physically active agents are mixed with a pharmaceutical excipient to discrete units Suitable for administration to human or non form a solid preformulation pharmaceutical composition human animal Subjects and packaged individually. Each unit comprising a homogeneous mixture of compounds described dose can contain a predetermined quantity of an active ingre herein. When referring to these pharmaceutical compositions dient(s) sufficient to produce the desired therapeutic effect, in as "homogeneous, it is meant that the agents are dispersed association with the required pharmaceutical carriers or evenly throughout the pharmaceutical composition so that the excipients. Examples of unit-dosage forms include, but are pharmaceutical composition can be subdivided into unit dos not limited to, ampules, syringes, and individually packaged age forms such as tablets or capsules. This solid preformula tablets and capsules. Unit-dosage forms can be administered tion pharmaceutical composition can then be subdivided into in fractions or multiples thereof. A multiple-dosage form is a unit dosage forms of the type described above comprising plurality of identical unit-dosage forms packaged in a single from, for example, about 1.0 to about 15 mg of an opioid container, which can be administered in segregated unit-dos analgesic, such as hydrocodone or oxycodone or a pharma age form. Examples of multiple-dosage forms include, but ceutically acceptable salt of any one of the foregoing, or any are not limited to, vials, bottles of tablets or capsules, or combination thereof. US 2015/0290211 A1 Oct. 15, 2015 70

0327 In some instances, a pharmaceutical composition more components that do not impair the desired action, or can be formulated, in the instance of capsules or tablets, to be with components that Supplement the desired action, or have swallowed whole, for example with water. The inclusion of another action. As noted above, the pharmaceutical compo the side-effect-reducing agent such as an antiemetic to abate sitions can comprise additional (e.g., a fourth, fifth, sixth, common symptoms of nausea or vomiting are believed ben etc.) additional active agents. eficial in that promethazine or a salt thereof, or the like can 0333. In some instances, a pharmaceutical composition eliminate or minimize the amount of discomfort. Adverse comprised three or more pharmaceutically active agents effects reduced or eliminated include but are not limited to wherein at least one active agent is formulated in an imme nausea, vomiting, other gastric upsets, constipation, skin diate-release form. In this instance, the immediate-release rashes, allergic reactions such as Swelling, difficulty breath form can be included in an amount that is effective to shorten ing, closing of throat, abdominal pain, unusual bleeding or the time to its maximum concentration in the blood. By way bruising, CNS Suppression and respiratory Suppression. of example, certain immediate-release pharmaceutical prepa 0328 Frequently, subjects taking opioids have adverse rations are taught in United States Patent Publication US effects including Vomiting that can occur shortly after taking 2005/0147710A1 entitled, “Powder Compaction and Enrob a first or Subsequent dose. As a consequence, a portion of the ing' which is incorporated herein in its entirety by reference. opioid dose is Subsequently lost, making it difficult to accu 0334. In some instances, a component of an immediate rately gauge replacement dosages for the Subject, and for release form or layer is a component that reduces abates or Subjects outside of a hospital or clinic environment, there eliminates and/or suppresses an adverse effect associated might not be any alternative form of pain medication readily with one or more opioid analgesics. For example, the imme available. As a consequence, Subjects experiencing gastric diate-release active can be an antiemetic, which reduces, discomfort such as vomiting can lack the beneficial effects of abates or eliminates an adverse effect associated with opioid the opioid analgesic and experience the additional discomfort and/or non-opioid analgesics described herein. In a further and enhanced pain associated with Vomiting. This problem is instance, all or less than the entire amount of the antiemetic Solved by also administering promethazine or a salt thereof, agent is formulated in immediate-release form, as described which reduces side-effects. herein. 0329. A dosage form described herein can be manufac 0335) A variety of methods and materials can be used to tured using processes that are well known to those of skill in bring about immediate-release. For instance, placement of the art. For example, for the manufacture of tablets (including the agent along an exterior of a tablet (e.g., coating the exte but not limited to single layer, bi-layer, two layer, coated, of rior or formulating the outer layer with the agent) and/or multi-layer tablets) or capsules, the agents can be dispersed combined with forming a tablet by compressing the powder uniformly in one or more excipients, for example, using high using low compaction can produce immediate-release of the shear granulation, low shear granulation, fluid bed granula agent from the pharmaceutical composition. tion, or by blending for direct compression. 0336. In some embodiments, an effective amount of 0330. A controlled-release formulation can comprise one promethazine or a salt thereofinan immediate-release form is or more combinations of excipients that slow the release of coated onto a substrate. For example, where the controlled the agents by coating or temporarily bonding or decreasing release of one or more analgesics from a formulation is due to their solubility of the active agents. In one instance, the opioid a controlled-release coating, an immediate-release layer analgesic or non-opioid agents (e.g., hydrocodone or oxyc comprising promethazine or a salt thereof can overcoat the odone or a salt thereof, and acetaminophen or a salt thereof) controlled-release coating. In another example, an immedi are formulated for controlled-release while the promethazine ate-release layer can be coated onto the Surface of a substrate or a salt thereof is formulated for immediate-release. In wherein an opioid agent, a non-opioid agent, a barbiturate, or another instance, the opioid analgesic or non-opioid agents a stimulant is incorporated in a controlled-release matrix. (e.g., hydrocodone or oxycodone or a salt thereof, and Where a plurality of controlled-release substrates (e.g., mul acetaminophen or a salt thereof) are formulated for con tiparticulate systems including pellets, spheres, beads and the trolled-release while the promethazine or a salt thereof is like) are incorporated into a hard gelatin capsule, a side formulated for immediate-release. In another instance, all effect-reducing compound can be incorporated into the gela agents are formulated for controlled-release. tin capsule via inclusion of an amount of immediate-release 0331. An immediate-release formulation can comprise promethazine or a salt thereof, as a powder or granulate one or more combination of excipients that allow for a rapid within the capsule. In some instances, the gelatin capsule release of a pharmaceutically active agent (such as from 1 itself can be coated with an immediate-release layer of minute to 1 hour after administration, or following contact promethazine. One skilled in the art recognizes still other with dissolution fluid, or as measured in an in vitro dissolu alternative means of incorporating an immediate-release tion study). Such as an antiemetic. In one instance, an imme side-effect-reducing compound into the unit dose. By includ diate-release excipient can be microcrystalline cellulose, ing an effective amount of immediate-release side-effect Sodium carboxymethyl cellulose, sodium starch glycolate, reducing compound in the unit dose, the experience of corn starch, colloidal silica, Sodium Laurel Sulphate, Mag adverse effects including nausea, vomiting, constipation, nesium Stearate, Prosolve SMCC (HD90), croscarmellose other gastric upsets, skin rashes, allergic reactions such as Sodium, Crospovidone NF, Avicel PH200, and combinations Swelling, difficulty breathing, closing of throat, abdominal of Such excipients. pain, unusual bleeding or bruising, skin rashes, sedation, 0332. In some instances, pharmaceutical carriers or CNS depression, or respiratory depression in subjects can be vehicles suitable for administration of the compounds pro significantly reduced. vided herein include all such carriers known to those skilled 0337. In some instances, a pharmaceutical composition in the art to be suitable for the particular mode of administra comprises three or more active agents wherein at least one tion. In addition, the pharmaceutical compositions can one or active agent is in controlled-release form. The controlled US 2015/0290211 A1 Oct. 15, 2015

release form can be in an amount that is effective to protect the lated using the methods disclosed in U.S. Pat. No. 4,820,522, agent from rapid elimination from the body. Certain prepara which is herein incorporated by reference in its entirety. In tions relating to the controlled-release of a pharmaceutical are one instance of the bi-layered tablet described herein, both taught in United States Patent Publication US 2005/ layers can comprise an opioid analgesic, a non-opioid anal 0147710A1 entitled, “Powder Compaction and Enrobing” gesic and a compound to reduce or Suppress adverse effects. which is incorporated herein in its entirety by reference. In a further instance of the bi-layered tablet described herein, Examples of time release coated beads are disclosed in U.S. the immediate-release layer comprises promethazine or a salt Application Publication No. 20080131517. thereof and the controlled-release layer comprises hydroc 0338. In a further instance, at least one pharmaceutically odone or oxycodone or a pharmaceutically acceptable salt of active agent in a controlled-release form is an opioid analge any one of the foregoing, or any combination thereof. In one sic agent. In one instance, pharmaceutical compositions com instance, the immediate or controlled-release layer can fur prise one or more carriers that protect the agents against rapid ther comprise acetaminophen or naproxen or a salt thereof. In elimination from the body, Such as time-release formulations one instance of the multi-layered tablet, the second drug can or coatings. Such carriers include controlled-release formu have a plasma half-life that differs from the plasma half-life of lations, including, for example, microencapsulated delivery the first drug by at least about 5 hours. systems. The active agents can be included in the pharmaceu 0344. In another instance, an effective amount of an anti tically acceptable carrier in amounts sufficient to treat a Sub emetic agent in an immediate-release form can be coated onto jects pain, with reduced adverse effects. a Substrate. For example, where the one or more opioid anal 0339. In some instances, a pharmaceutical composition is gesics and one or more stimulant are components of a con in an oral-dosage form and comprise a matrix that includes, trolled-release formulation, an immediate-release layer com for example, a controlled-release material and an opioid or prising the antiemetic agent can overcoat the controlled non-opioid analgesic. In certain instances, the matrix is com release formulation. pressible into a tablet and can be overcoated with a coating that can control the release of the opioid or non-opioid anal 0345. In another instance, an immediate-release layer can gesic from the pharmaceutical composition. In this instance, be coated onto the Surface of a Substrate having a controlled blood levels of analgesics are maintained withina therapeutic release matrix. Where a plurality of controlled-release sub range over an extended period of time. In certain alternate strates comprising an effective unit dose of a pharmaceuti instances, the matrix is encapsulated. cally active agent (e.g., multiparticulate systems including 0340 Tablets or capsules containing a pharmaceutical pellets, spheres, beads and the like) are incorporated into a composition described herein can be coated or otherwise hard gelatin capsule, another agent can be incorporated into compounded to provide a dosage form affording the advan the gelatin capsule via inclusion of an amount of immediate tage of prolonged action. For example, the tablet or capsule release agent as a powder or granulate within the capsule. In can contain an inner dosage and an outer dosage component, Some instances, the gelatin capsule itself can be coated with the latter being in the form of an envelope over the former. The an immediate-release layer. One skilled in the art recognizes two components can be separated by an enteric layer that still other alternative means of incorporating the immediate serves to resist disintegration in the stomach and permit the release side-effect-reducing compound into the unit dose. inner component to pass intact into the duodenum or to be Therefore, in one instance, by including an effective amount controlled in release. For controlled release, the capsule can of an antiemetic agent in the unit dose, the Subject is prepared also have micro drilled holes. for the eventual and Subsequent release of one or more opioid 0341. A coating comprising a side-effect-reducing com analgesic in the controlled-release layer, where the antiemetic pound, in immediate-release form, can be added to the out agent can reduce or prevent adverse effects associated with an side of a controlled-release tablet core to produce a final opioid agent including but not limited to nausea, vomiting, dosage form. Such a coating can be prepared by administer constipation, other gastric upsets, skin rashes, allergic reac ing a compound like promethazine with polyvinylpyrroli tions such as Swelling, difficulty breathing, closing of throat, done (PVP) 29/32 or hydroxypropyl methylcellulose abdominal pain, unusual bleeding or bruising, skin rashes, (HPMC) and waterfisopropyl alcohol and triethyl acetate. sedation, CNS depression, or respiratory depression in Sub Such an immediate-release coating can be spray coated onto jects can be significantly reduced. In some instances, a stimu the tablet cores. The immediate-release coating can also be lant is included in the unit dose. applied using a press-coating process with a blend consisting 0346. An immediate-release or controlled-release dosage of 80% by weight promethazine and 20% by weight of lactose form described herein can also take the form of a bi-layered and hydroxypropyl methylcellulose type 2910. Press-coating tablet, which can comprise an immediate-release layer and a techniques are known in the art and are described in U.S. Pat. controlled-release layer. The immediate-release or con No. 6,372,254, which is herein incorporated by reference in trolled-release dosage forms described herein can also take its entirety. the form of a two layer tablet, which can comprise an imme 0342. The immediate-release or controlled-release dosage diate-release layer and a controlled-release layer. In one forms described herein can also take the form of a bi-layered instance the immediate-release layer comprises an antiemetic or a two layer tablet, which comprises a first layer and a agent, a stimulant and a non-opioid analgesic. In one instance second layer. The first layer comprises a first drug that is an the immediate-release layer comprises an antiemetic agent analgesic, or antiemetic. The second layer comprises a sec and a stimulant. In one instance the immediate-release layer ond drug that is an analgesic, or antiemetic. The second drug comprises an antiemetic agent and a non-opioid analgesic. In is different from the first drug. one instance, the first layer can comprise one, two, three or 0343. In a further instance of a bi-layered tablet, one layer more active agents. The controlled-release layer can com is an immediate-release layer and the other layer is a con prise an opioid analgesic or non-opioid analgesic or stimu trolled-release layer. In one example a bi-layered is formu lant. Such classes of active agents are described herein above. US 2015/0290211 A1 Oct. 15, 2015 72

0347 An immediate-release or controlled-release dosage The candy base can be very Soft and fast dissolving, or can be form described herein can also take the form of pharmaceu hard and slower dissolving. Various forms can have advan tical particles manufactured by a variety of methods, includ tages in different situations. ing but not limited to high-pressure homogenization, wet or 0351 A containing candy mass comprising at least one dry ball milling, or Small particle precipitation (nano spray). pharmaceutically active agent can be orally administered to a Other methods to make a suitable powder formulation are the Subject in need thereof So that the agent can be released into preparation of a solution of active ingredients and excipients, the Subject's mouth as the candy mass dissolves. The drug followed by precipitation, filtration, and pulverization, or rapidly enters the Subject bloodstream, and importantly, the followed by removal of the solvent by freeze-drying, fol blood in the veins draining from the mouth and the pharyn lowed by pulverization of the powder to the desired particle geal and esophageal areas passes through a substantial por S17C. tion of the body (so that the drug can be absorbed) before the 0348. In some instances, particles disclosed herein have a blood passes through the liver (where the drug can be inacti final size of 3-1000 uM, such as at most 3, 4, 5, 6, 7, 8, 9, 10. vated). A subject in need thereof can include a human adult or 20, 30, 40, 50, 60, 70, 80,90, 100, 150, 200, 250, 300,3500, child in pain, such as a child in sickle cell crisis, a child 400, 4500, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, undergoing bone marrow transplant or a lumbar puncture 1000 uM. In some instances, the pharmaceutical particles procedure, a child with cancer (e.g., metastatic cancer, leu have a final size of 10-500 uM. In one instance, the pharma kemia or lymphoma). ceutical particles have a final size of 50-600 uM. In some 0352. In some instances, candy matrix (lollipop or loz instances, the pharmaceutical particles have a final size of enge) comprises a pharmaceutical composition that lacks a 100-800 uM. These dosage forms can include immediate stimulant. In some other instances, the candy matrix (lollipop release particles in combination with controlled-release par or lozenge) comprises a pharmaceutical composition that ticles in a ratio sufficient useful for delivering the desired comprises a stimulant. In these instances, the pharmaceutical dosages of active agents. In an alternative instance, a dosage composition provides an anti-sedative effect in addition to unit can be divided into or exclusively included into both providing pain relief to a Subject in need thereof. immediate-release and controlled-release particles. 0353. In some instances a candy mass is prepared that 0349. In some instances, a dosage form herein can be an comprises one or more layers which can comprise different effervescent dosage form. Effervescent means that the dosage pharmaceutically active agents and or rates of dissolution. In form, when mixed with liquid, including water and saliva, one instance, a multilayer candy mass (such as a lollipop) evolves a gas. Some effervescent agents (or effervescent comprises an outer layer with a concentration of one or more couple) evolve gas by means of a chemical reaction which pharmaceutically active agents differing from that of one or takes place upon exposure of the effervescent disintegration more inner layers. Such a drug delivery system has a variety agent to water and/or to saliva in the mouth. This reaction can of applications. By way of example, it can be desirable to be the result of the reaction of a soluble acid source and an quickly get a predetermined dose of a first pharmaceutically alkali monocarbonate or carbonate Source. The reaction of active agent into the bloodstream to obtain a desired effect these two general compounds produces carbon dioxide gas and then use a different inner layer to deliver one or more upon contact with water or saliva. An effervescent couple (or other agents. the individual acid and base separately) can be coated with a 0354. The choices of matrix and the concentration of the Solvent protective or enteric coating to prevent premature drug in the matrix can be important factors with respect to the reaction. Such a couple can also be mixed with previously rate of drug uptake. A matrix that dissolves quickly can lyophilized particles (such as one or more pharmaceutically deliver drug into the patient’s mouth for absorption more active agents coated with a solvent protective or enteric coat quickly than a matrix that is slow to dissolve. Similarly, a ing. The acid sources can be any which are safe for human candy matrix that contains one or more pharmaceutically consumption and can generally include food acids, acid and active agents in a high concentration can release more of the hydrite antacids such as, for example: citric, tartaric, amalic, one or more pharmaceutically active agents in a given period fumeric, adipic, and Succinics. Carbonate sources include dry of time than a candy having a low concentration. In one Solid carbonate and bicarbonate salt such as, for example, instance, a candy matrix Such as one disclosed in U.S. Pat. No. Sodium bicarbonate, Sodium carbonate, potassium bicarbon 4,671,953 or US Application 2004/0213828 (which is herein ate and potassium carbonate, magnesium carbonate and the incorporated by reference in their entirety) is used to deliver like. Reactants which evolve oxygen or other gasses and the pharmaceutically active agents disclosed herein. which are safe for human consumption are also included. In 0355 An immediate-release or controlled release dosage one instance, citric acid and sodium bicarbonate is used. form described herein can also take the form of pharmaceu 0350. In some instances, a dosage form disclosed herein tical particles manufactured by a variety of methods, includ can be in a candy form (e.g., matrix). Such as a lollipop or ing but not limited to high-pressure homogenization, wet or lozenge. In one instance, one or more pharmaceutically active dry ball milling, or Small particle precipitation (e.g., nGimat's agents is dispersed within a candy matrix. In one instance, the NanoSpray). Other methods useful to make a suitable powder candy matrix comprises one or more Sugars (such as dextrose formulation are the preparation of a solution of active ingre or Sucrose). In another instance, the candy matrix is a Sugar dients and excipients, followed by precipitation, filtration, free matrix. The choice of a particular candy matrix is subject and pulverization, or followed by removal of the solvent by to wide variation. Conventional Sweeteners such as Sucrose freeze-drying, followed by pulverization of the powder to the can be utilized, or sugar alcohols suitable for use with diabetic desired particle size. In some instances, the pharmaceutical patients, such as Sorbitol or mannitol might be employed. particles have a final size of 3-1000 uM, such as at most 3, 4, Other Sweeteners, such as the aspartanes, can also be easily 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80,90, 100, 150, 200, incorporated into a pharmaceutical composition in accor 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, dance with pharmaceutical compositions described herein. 850,900,950, 1000 uM. In another instance, the pharmaceu