US 201202O1888A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0201888 A1 BOSse et al. (43) Pub. Date: Aug. 9, 2012

(54) PHARMACEUTICAL COMPOSITIONS Publication Classification (51) Int. Cl. (75) Inventors: Paul Bosse, Charleston, SC (US); A6II 3/545 (2006.01) John Ameling, Cincinnati, OH A63L/454 (2006.01) (US); Bernard Schachtel, Jupiter, A63/495 (2006.01) FL (US); Ray Takigiku, Loveland, A6II 3/538 (2006.01) A 6LX 3/557 (2006.01) OH (US) A 6LX 3/553 (2006.01) A 6LX 3/573 (2006.01) (73) Assignee: CHARLESTON A6IR 9/24 (2006.01) LABORATORIES, INC., A6IP 25/04 (2006.01) Charleston, SC (US) A6IP 25/06 (2006.01) A6IP 7/02 (2006.01) (21) Appl. No.: 13/347,552 A6IP 25/08 (2006.01) A6IP 29/00 (2006.01) A6IP 9/00 (2006.01) (22) Filed: Jan. 10, 2012 A6IR 9/00 (2006.01) A 6LX 3/5.377 (2006.01) Related U.S. Application Data (52) U.S. Cl...... 424/472: 514/226.2: 514/230.8; (63) Continuation of application No. 12/351,704, filed on 514/323: 514/225.8: 514/255.04: 514/230.5; Jan. 9, 2009, now Pat. No. 8,124,126. 514/225.5; 514/220; 514/221; 514/171; 424/400 (57) ABSTRACT (60) Provisional application No. 61/020,139, filed on Jan. Methods and compositions are provided which comprise 9, 2008, provisional application No. 61/043,037, filed effective amounts of analgesic to treat a Subject, including on Apr. 7, 2008, provisional application No. 61/060, reducing or eliminating an adverse effect associated with the 758, filed on Jun. 11, 2008. analgesic. Patent Application Publication Aug. 9, 2012 Sheet 1 of 5 US 2012/02O1888A1

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A.

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0.3043 (7.73)

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FIG 2 Patent Application Publication Aug. 9, 2012 Sheet 3 of 5 US 2012/02O1888A1

Standard Blank

0.50 100 150 2.00 2.50 3.00 3.50 4.00 450 5.00 5.50 6.00 Minutes

FIG. 3 Patent Application Publication Aug. 9, 2012 Sheet 4 of 5 US 2012/02O1888A1

Acetaminophen Promethazine

Hydrocodone

0.50 100 1.50 2.00 2.50 3.00 3.50 4.00 450 5.00 5.50 6.00 Minutes

FIG. 4 Patent Application Publication Aug. 9, 2012 Sheet 5 of 5 US 2012/02O1888A1

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PHARMACEUTICAL COMPOSITIONS blocker, serotonin receptor agonist, vasoconstrictor, anti platelet agent, anti-convulsant, triptan, ergot, or calcitonin CROSS-REFERENCE gene-related peptide receptor antagonist; and (2) a pharma 0001. This application claims the benefit of U.S. Provi ceutically acceptable carrier or vehicle. sional Application Nos. 61/020,139, filed Jan. 9, 2008, 0013. In another embodiment this invention provides 61/043,037, filed Apr. 7, 2008, and 61/060,758, filed Jun. 11, compositions comprising (1) an effective amount of (a) an 2008, each of which is incorporated by reference herein in its opioid analgesic agent and (b) Sumatriptan or a pharmaceu entirety. tically acceptable salt thereof, and (2) a pharmaceutically acceptable carrier or vehicle. BACKGROUND OF THE INVENTION 0014. In another embodiment this invention provides compositions consisting of (1) an effective amount of (a) 0002 Available pain medications may have adverse Sumatriptan or a pharmaceutically acceptable salt thereof and effects, such as nausea, vomiting, and skin rashes and seda (b) promethazine or a pharmaceutically acceptable salt tion. As a result of Such adverse effects, many subjects are thereof, and (2) a pharmaceutically acceptable carrier or unable to tolerate recommended dosages needed for effective vehicle. pain relief because of adverse effects. Accordingly, there 0015. In another embodiment this invention provides remains a need for effective therapeutics with reduced compositions comprising (1) an effective amount of (a) an adverse effects. opioid analgesic agent, (b) a CoX-2 inhibitor agent, an anti depressant agent, an anti-convulsant agent, an anti-cholin BRIEF DESCRIPTION OF DRAWINGS ergic agent, an NMDA receptor antagonist agent, an anes 0003 FIG. 1 illustrates a chromatograph for example of a thetic agent or an O-adrenoreceptor agonist agent, (c) an standard solution. opioid antagonist agent, (d) an agent that reduces or elimi 0004 FIG. 2 illustrates one embodiment of a tablet of the nates an adverse effect of the opioid agent; and (2) a pharma invention. A. Illustrates a top view of the tablet (numerals in ceutically acceptable carrier or vehicle. square brackets refer to measurements in millimeters and 0016. In another embodiment this invention provides numerals not in square brackets are in inches); B. illustrates a compositions comprising (1) an effective amount of (a) an side view of the tablet (numerals in square brackets refer to opioid analgesic agent, (b) a non-opioid analgesic agent, (c) measurements in millimeters and numerals not in square cyclazacine or levallorphan; (d) an agent that reduces or brackets are in inches). eliminates an adverse effect of the opioid analgesic agent; and 0005 FIG.3 illustrates an example of chromatograph of a (2) a pharmaceutically acceptable carrier. diluent blank and standard solution. 0017. In another embodiment this invention provides a 0006 FIG. 4 illustrates an example of a dissolution chro composition comprising (1) an effective amount of (a) an matograph for a composition of the invention. opioid analgesic agent, (b) a non-opioid analgesic agent, (c) 0007 FIG. 5 illustrates an example of dissolution release an antiemetic; (d) an abuse deterrent agent; and (2) a phar profile for a composition of the invention. maceutically acceptable carrier. In one embodiment the abuse deterrentagent is niacin or a pharmaceutically acceptable salt SUMMARY OF THE INVENTION thereof; zinc sulfate; or sodium lauryl sulfate. 0008. In one embodiment this invention provides compo 0018. In another embodiment this invention provides sitions comprising (1) an effective amount of: (a) an opioid compositions comprising (1) an effective amount of (a) an analgesic; (b) a stimulant; (c) an antiemetic; and (2) a phar opioid analgesic agent, (b) a non-opioid analgesic agent, (c) maceutically acceptable carrier or vehicle. an opioid antagonist agent, (d) aprepitant, perphenazine, 0009. In another embodiment this invention provides acetylleucine monoethanolamine, aZasetron, benzquina compositions comprising (1) an effective amount (a) oxyc mide, bietanautine, bromopride, clebopride, diphenidol. odone or a pharmaceutically acceptable salt thereof, (b) methallatal, metopimazine, oxyperndyl, pipamazine, promethazine or a pharmaceutically acceptable salt thereof, Sulpiride, thiethylperazine, thioproperazine, or a pharmaceu (c) modafinil or a pharmaceutically acceptable salt thereof tically acceptable salt thereof, and (2) a pharmaceutically and (d) naltrexone or a pharmaceutically acceptable salt acceptable carrier or vehicle. thereof, and (2) a pharmaceutically acceptable carrier or 0019. In another embodiment this invention provides bi vehicle. layer tablets comprising: (1) a controlled-release layer com 0010. In another embodiment this invention provides prising from about 6.5 mg to about 8.5 mg of hydrocodone or compositions comprising (1) an effective amount of (a) mor a pharmaceutically acceptable salt thereof, and from about phine or a pharmaceutically acceptable salt thereof, (b) 290 to about 360 mg of acetaminophen or a pharmaceutically promethazine or a pharmaceutically acceptable salt thereof, salt; and (2) an immediate-release layer comprising from and (c) modafinil or a pharmaceutically acceptable salt about 11 mg to about 14 mg of promethazine or a pharma thereof, and (2) a pharmaceutically acceptable carrier or ceutically salt thereof. In another embodiment this invention vehicle. provides bilayer tablets comprising (1) an effective amount of 0011. In another embodiment this invention provides (a) an opioid analgesic or a pharmaceutically acceptable salt compositions comprising an effective amount ofbutalbital or thereof and (b) one or more antiemetic or a pharmaceutically a pharmaceutically acceptable salt thereof, acetaminophen acceptable salt thereof, and (2) a pharmaceutically acceptable and promethazine or a pharmaceutically acceptable salt carrier or vehicle. thereof, and a pharmaceutically acceptable carrier or vehicle. 0020. In another embodiment this invention provides 0012. In another embodiment this invention provides bilayer tablets comprising: (1) a controlled release layer com compositions comprising (1) an effective amount of (a) an prising (a) from about 6.5 mg to about 8.5 mg of hydrocodone opioid analgesic agent; (b) an anti-emetic agent and (c) a beta or a pharmaceutically acceptable salt thereof, (b) from about US 2012/020 1888 A1 Aug. 9, 2012

290 to about 360 mg of acetaminophen or a pharmaceutically of (a) an opioid analgesic agent; and (b) an antiemetic agent. acceptable salt thereof, (c) from about 135 mg to about 170 In one embodiment the photophobia is associated with mg of silicified microcrystalline cellulose, (d) from about 17 migraine headache. mg to about 23 mg of hydroxy methyl propyl cellulose, (e) 0029. In another embodiment this invention provides from about 1 mg to about 4 mg of magnesium Stearate, and (f) methods for treating or preventing headache comprising: from about 1 mg to about 4 mg of Stearic acid; and (2) an administering to a subject in need thereof (1) an effective immediate release layer comprising (a) from about 11 mg to amount of (a) triptan or a pharmaceutically acceptable salt about 14 mg of promethazine or a pharmaceutically accept thereof and (b) promethazine or a pharmaceutically accept able salt thereof, (b) from about 100 mg to about 140 mg of able salt thereof, and (2) a pharmaceutically acceptable car silicified microcrystalline cellulose, (c) from about 12 mg to rier or vehicle. In one embodiment the triptan is Sumatriptan. about 18 mg of croscarmellose sodium and (d) from about 0.8 In another embodiment the headache is migraine headache. 0030. In another embodiment this invention provides mg to about 1.5 mg of magnesium Stearate. methods for treating or preventing pain comprising: admin 0021. In another embodiment this invention provides istering to a subject in need thereof (1) an effective amount of compositions comprising (1) an effective amount of (a) (a) an opioid analgesic agent, (b) a CoX-2 inhibitor agent, an hydrocodone or a pharmaceutically acceptable Salt thereofor anti-depressant agent, an anti-convulsant agent, an anti-cho oxycodone or a pharmaceutically acceptable Salt thereof; (b) linergic agent, an NMDA receptor antagonist agent, an anes acetaminophen or a pharmaceutically acceptable salt thereof, thetic agent or an C2-adrenoreceptor agonist agent, (c) an (c) promethazine or a pharmaceutically acceptable salt opioid antagonist agent, (d) an agent that reduces or elimi thereof and (d) about 0.75 mg of naltrexone or a pharmaceu nates an adverse effect of the opioid agent; and (2) a pharma tically acceptable salt thereof, and (2) a pharmaceutically ceutically acceptable carrier or vehicle. acceptable carrier or vehicle. 0031. In another embodiment this invention provides 0022. In another embodiment this invention provides methods for treating or preventing pain comprising, admin compositions consisting of (1) an effective amount of (a) istering to a Subject in need thereof a bi-layer tablet compris oxycodone or a pharmaceutically acceptable salt thereof, (b) ing: (1) a controlled-release layer comprising from about 6.5 promethazine or a pharmaceutically acceptable salt thereof mg to about 8.5 mg of hydrocodone or a pharmaceutically and (c) naltrexone or a pharmaceutically acceptable salt acceptable salt thereof; and from about 290 to about 360 mg thereof, and (2) a pharmaceutically acceptable carrier or of acetaminophen or a pharmaceutically salt; and (2) an vehicle. immediate-release layer comprising from about 11 mg to 0023. In another embodiment this invention provides about 14 mg of promethazine or a pharmaceutically salt compositions consisting of (1) an effective amount of (a) thereof. promethazine or a pharmaceutically acceptable salt thereof, 0032. In another embodiment this invention provides (b) propoxyphene or a pharmaceutically acceptable salt methods for treating or preventing pain comprising, admin thereof (c) naproxen or a pharmaceutically acceptable salt istering to a Subject in need thereof a bi-layer tablet compris thereof, and (2) a pharmaceutically acceptable carrier or ing (1) an effective amount of (a) oxycodone or a pharmaceu vehicle. tically acceptable salt thereof and (b) promethazine or a 0024. In another embodiment this invention provides pharmaceutically acceptable salt thereof, and (2) a pharma methods for treating or preventing pain, comprising admin ceutically acceptable carrier or vehicle. istering to a Subject in need thereofan effective amount of (a) 0033. In another embodiment this invention provides an opioid analgesic agent, (b) an antiemetic agent or an anti methods for treating or preventing pain comprising, admin histamine, and (c) a stimulant agent. istering to a Subject in need thereof a bi-layer tablet compris ing: (1) a controlled release layer comprising (a) from about 0025. In another embodiment this invention provides 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically methods for treating or preventing a migraine headache com acceptable salt thereof, (b) from about 290 to about 360 mg of prising administering to a subject in need thereof an effective acetaminophen or a pharmaceutically acceptable salt thereof, amount of (a) an opioid analgesic agent; (b) an antiemetic (c) from about 135 mg to about 170 mg of silicified microc agent; and (c) a stimulant agent. rystalline cellulose, (d) from about 17 mg to about 23 mg of 0026. In another embodiment this invention provides hydroxy methyl propyl cellulose, (e) from about 1 mg to methods for treating or preventing a headache comprising about 4 mg of magnesium Stearate, and (f) from about 1 mg to administering to a subject in need thereofan effective amount about 4 mg of Stearic acid; and (2) an immediate release layer of (a) an opioid analgesic agent; and (b) an antiemetic agent. comprising (a) from about 11 mg to about 14 mg of promet In one embodiment the headache is a migraine headache, hazine or a pharmaceutically acceptable salt thereof, (b) from clusterheadache or hemicrania continua headache. In another about 100 mg to about 140 mg of silicified microcrystalline embodiment the headache is a chronic headache, tension cellulose, (c) from about 12 mg to about 18 mg of croscar headache or chronic tension headache. mellose sodium and (d) from about 0.8 mg to about 1.5 mg of 0027. In another embodiment this invention provides magnesium Stearate. methods for treating pain, comprising administering to a Sub 0034. In another embodiment this invention provides ject in need thereof an effective amount of (a) an opioid methods for treating or preventing pain comprising, admin analgesic agent, (b) an antiemetic agent; and (c) a non-opioid istering to a subject in need thereof composition consisting of analgesic agent; wherein the Subject is about 65 years of age (1) an effective amount of (a) promethazine or a pharmaceu or older. tically acceptable salt thereof, (b) propoxyphene or a phar 0028. In another embodiment this invention provides maceutically acceptable salt thereof (c) naproxen or a phar methods for treating or preventing photophobia comprising maceutically acceptable Salt thereof, and (2) a administering to a subject in need thereofan effective amount pharmaceutically acceptable carrier or vehicle. US 2012/020 1888 A1 Aug. 9, 2012

0035. In one embodiment of the invention, a composition thetic effect or calming effect when provided alone or in is in the form of a bilayer tablet, wherein the bilayer tablet combination with one or more pharmaceutically active agent comprises an immediate-release layer and a controlled-re disclosed herein. In various embodiments, the one or more lease layer, wherein each layer comprises one or more phar pharmaceutically active agent includes but is not limited to an maceutically active agents disclosed herein. opioid analgesic, a non-opioid analgesic, antiemetic or com 0036. In yet another embodiment of the invention a bilayer bination thereof. tablet comprises an effective amount of an antiemetic and the 0046. An “effective amount” when used in connection antiemetic is capable of achieving from about 70% to about with a opioid antagonist agent is an amount that is effective 80% dissolution in the stomach of a subject in about 5 to about for preventing or inhibiting abuse of a dosage form compris 10 minutes following oral administration. ing an opioid analgesic agent, wherein the antagonist agent is 0037. In another embodiment of the invention a bilayer provided in combination with one or more pharmaceutically tablet comprises an effective amount of an opioid analgesic, active agent disclosed herein. In various embodiments, the or a non-opioid analgesic, and the opioid analgesic or the one or more pharmaceutically active agent includes but is not non-opioid analgesic is capable of achieving from about 30% limited to an opioid agent, a nonopioid analgesic, a stimulant, to about 60% dissolution in the stomach of a subject in about a barbiturate, or a combination thereof. 5 to about 10 minutes following oral administration. 0047. An "effective amount” when in used in connection with one or more of the agents disclosed herein is the total DETAILED DESCRIPTION OF THE INVENTION amount of one or more of the agents that is useful for the 0038 All patents and publications and referred to herein treatment of pain. are incorporated by reference in their entirety. 0048. The term “about” means the referenced numeric 0039. The invention is generally directed to compositions indication plus or minus 10% of that referenced numeric comprising multiple pharmaceutically active agents that are indication. useful as therapeutics that alleviate, abate or eliminate one or 0049 Pharmaceutically active agents disclosed herein are more conditions in a Subject in need thereof, as further capable of use in a composition of the invention. A pharma described herein below. ceutically active agent, such as an opioid analgesic agent, 0040. An "effective amount of when used in connection nonopioid analgesic agent, antitussive agent, antiemetic with composition of the invention is an amount Sufficient to agent, antihistamine, a stimulant, or a barbituate, can be in the produce a therapeutic result in a subject in need thereof. For form of a pharmaceutically acceptable salt thereof. example atherapeutic result can include, but is not limited to, 0050. In some embodiments of the invention a composi treating or preventing pain, nausea or vomiting by a subject. tion comprises an analgesic agent (e.g., one analgesic or two, 0041 An “effective amount” when used in connection three or more analgesics) and agent (e.g., one, two or more of with an opioid analgesic agent alone or in combination is an an antihistamine or antiemetic) that reduces or eliminates an amount that is effective for treating or preventing pain, adverse effect of an analgesic agent. In various embodiments, wherein the antagonist agent is provided in combination with a composition of the invention comprises one or more phar one or more pharmaceutically active agents disclosed herein. maceutically active agents provided in Table 1 or Table 2, or In one embodiment, the one or more pharmaceutically active a pharmaceutically acceptable salt thereof. agent is an antiemetic. 0051. In one embodiment, a composition comprise, an 0.042 An “effective amount” when used in connection effective amount of an opioid analgesic agent, an effective with an antiemetic agent is an amount that is effective for amount of non-opioid analgesic agent, and an effective preventing or reducing or eliminating one or more adverse amount of an agent that reduces or eliminates an adverse effects associated with one or more pharmaceutically active effect of an analgesic agent. agent disclosed herein. In various embodiments, the one or 0052. In another embodiment of the invention a composi more pharmaceutically active agent includes but is not lim tion comprises an antiemetic and about 70 to about 80% of the ited to an opioid analgesic and/or a nonopioid analgesic. antiemetic dissolves in the stomach of a subject after about 5 0043. In further embodiments, such adverse effects which to about 10 minutes following oral administration. In one are reduced, prevented or eliminated include but are not lim embodiment, about 100% of the antiemetic dissolves in the ited to incidence of nausea or vomiting. Furthermore, an stomach of a subject about 40, about 50 or about 60 minutes “effective amount' when used in connection with an antihis following oral administration. In one embodiment, the anti tamine is an amount that is effective for preventing or reduc emetic is promethazine or a pharmaceutically acceptable salt ing the incidence of nausea or vomiting, or preventing or thereof. In another embodiment, the promethazine salt is reducing adverse effects associated with an opioid analgesic promethazine HC1. (e.g., opioid-induced nausea and Vomiting). 0053. In another embodiment of the invention a composi 0044 An “effective amount” when used in connection tion comprises an opioid analgesic and from about 30% to with a stimulant agent is an amount that is effective to about 40% of the opioid analgesic dissolves in the stomach of increase alertness, or lessen Soporific effects of an opioid a subject after about 5 to about 10 minutes following oral agent, wherein the stimulant agent is present in a dosage administration. In one embodiment, about 100% of the opioid formulation alone or in combination with one or more phar analgesic dissolves in the stomach of a subject about 40, maceutically active agent disclosed herein. In various about 50 or about 60 minutes following oral administration. embodiments, the one or more pharmaceutically active agent In one embodiment, the opioid analgesic is hydrocodone, includes but is not limited to an antiemetic agent, and a oXcycodone or a pharmaceutically acceptable salt thereof. In barbiturate. another embodiment, the hydrocodone salt is hydrocodone 0.045 An “effective amount” when used in connection bitartrate; or the oxycodone salt is oxycodone HC1. with a barbiturate agent is an amount that is effective for 0054. In one embodiment, compositions of the invention treating or preventing pain, producing a sedative effect, anes are administered to a subject at about every 4 to about 6 hours, US 2012/020 1888 A1 Aug. 9, 2012

about every 12 hours, or about every 24 hours. In one embodi release layer at about 5 to about 10 minutes following contact ment, a composition of the invention is administered once with a dissolution fluid, such as the dissolution fluid described daily. in Example 15. 0055. In one embodiment, the agent that reduces or elimi 0062. In another embodiment about 100% of a pharma nates an adverse effect is an antiemetic agent or antihista ceutically active agent is capable of achieving dissolution mine. In further embodiments, the adverse effect reduced or from the immediate-release layer at about 40 minutes follow eliminated is associated with an opioid analgesic. In an addi ing oral administration. In another embodiment about 100% tional embodiment, the adverse effect is associated with a to of a pharmaceutically active agent is capable of achieving non-opioid analgesic. dissolution from the immediate-release layer at about 40 min utes following contact with a dissolution fluid, such as the 0056. In various embodiments, an agent that reduces or dissolution fluid described in Example 15. eliminates an adverse effect of an opioid analgesic agent or a 0063. In another embodiment about 30% to about 40% of non-opioid analgesic agent includes but is not limited to a pharmaceutically active agent is capable of achieving dis promethazine, dolasetron, granisetron, ondansetron, tro solution from the controlled-release layer at about 5 to about pisetron, palonosetron, domperidone, droperidol, haloperi 10 minutes following oral administration. In another embodi dol, chlorpromazine, prochloperazine, metoclopramide, ment about 30% to about 40% of a pharmaceutically active alizapride, cyclizine, diphenhydramine, dimenhydrinate, agent is capable of achieving dissolution from the controlled meclizine, hydroxyzine, cannabis, dronabinol, nabilone, release layer at about 5 to about 10 minutes following contact midazolam, lorazepam, hyoscine, dexamethasone, tri with a dissolution fluid, such as the dissolution fluid described methobenzamide, emetrol, and propofol or a pharmaceuti in Example 15. cally acceptable salt thereof. 0064. In another embodiment about 90% of a pharmaceu 0057. In one embodiment, a composition of the invention tically active agent is capable of achieving dissolution from comprises a non-opioid analgesic agent which is acetami the controlled-release layer at about 60 minutes following nophen, ibuprofen, naproxen or flubiprofen, or a pharmaceu oral administration. In another embodiment about 90% of a pharmaceutically active agent is capable of achieving disso tically acceptable Salt thereof. In one embodiment the agent is lution from the controlled-release layer at about 60 minutes naproxen Sodium or magnesium. following contact with a dissolution fluid, Such as the disso 0058. In one embodiment, the opioid analgesic agent is lution fluid described in Example 15. hydrocodone or oxycodone, or a pharmaceutically acceptable 0065. In yet another embodiment, from about 90 to about salt thereof thiosemicarbazone, p-nitrophenylhydraZone, 100% of a pharmaceutically active agent is capable of achiev o-methyloxime, semicarbaZone, or bis (methylcarbamate) ing dissolution from the immediate-release layer at about 40, derivative, (each of the foregoing being an opioid analgesic about 50 or about 60 minutes following oral administration. agent or derivative). In a further embodiment, the opioid In yet another embodiment, from about 90 to about 100% of analgesic agent is hydrocodone bitartrate or oxycodone a pharmaceutically active agent is capable of achieving dis hydrochloride. solution from the immediate-release layer at about 40, about 0059. In another embodiment the opioid analgesic agent is 50 or about 60 minutes following contact with a dissolution a naturally occurring opiate, Such as an alkaloid occurring in fluid, such as the dissolution fluid described in Example 15. the opium poppy. In one embodiment the naturally occurring 0066. In yet another embodiment, from about 90 to about opiate is morphine, codeine, narcotine, papaverine, narceline, 100% of a pharmaceutically active agent is capable of achiev thebaine; or a pharmaceutically acceptable salt thereof. ing dissolution from the controlled-release layer at about 40, 0060. In one embodiment, a composition comprises an about 50 or about 60 minutes following oral administration. effective amount of each of an opioid analgesic, a non-opioid In yet another embodiment, from about 90 to about 100% of analgesic and an antiemtic orantihistamine, wherein the com a pharmaceutically active agent is capable of achieving dis position is capable of providing an effective plasma concen solution from the controlled-release layer at about 40, about tration of the antihistamine prior to an effective plasma con 50 or about 60 minutes following contact with a dissolution centrations of the opioid and the non-opioid analgesic, post fluid, such as the dissolution fluid described in Example 15. oral administration. For example, a composition comprising An illustrative dissolution profile for a composition of the an effective amount of each of an opioid analgesic, non invention is depicted in FIG. 5. opioid analgesic, and an antihistamine or antiemetic pro 0067. In various embodiments, the composition is in the vides an effective plasma concentration of the latter antihis form of any oral dosage form disclosed herein, including but tamine orantiemetic in about 1 to about 20 minutes, which is not limited to a pill, tablet, or capsule. In one embodiment, the Substantially earlier than effective plasma concentration of an composition is in the form of a bilayer tablet having an imme analgesic, which can be from about 20 minutes to about 12 diate-release layer and a controlled-release layer, wherein hours. In one embodiment of the invention, a composition one or more pharmaceutically active agents are present in the comprises an effective amount of each of one or more phar immediate-release layer and one or more pharmaceutically maceutically active agents disclosed herein. In one embodi active agents are present in the controlled release layer. In ment, the composition is a bilayer tablet comprising a con another embodiment, the immediate-release layer comprises trolled-release layer and an immediate-release layer. one or more antiemetic, and the controlled-release layer com 0061. In one embodiment about 70% to about 80% of a prises one or more pharmaceutically active agents disclosed pharmaceutically active agent is capable of achieving disso herein, but which are not an antiemetic or antihistamine. In a lution from the immediate-release layer at about 5 to about 10 further embodiment, an antiemetic orantihistamine is present minutes following oral administration. In another embodi in both the immediate-release and controlled-release layer. In ment about 70% to about 80% of a pharmaceutically active another embodiment, the immediate release layer comprises agent is capable of achieving dissolution from the immediate promethazine or a pharmaceutically acceptable salt thereof. US 2012/020 1888 A1 Aug. 9, 2012

In another embodiment, the promethazine salt is promethaZ injury, an inflammatory disease (e.g., pancreatitis), a non ine HC1. In another embodiment, the controlled-release layer inflammatory neuropathic or dysfunctional pain condition, or comprises an opioid analgesic. In a further embodiment, the a combination thereof. In one embodiment the subject is a opioid analgesic is hydrocodone or oxycodone, or a pharma mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, ceutically acceptable salt thereof. In one embodiment the horse, cow, pig, or non-human primate, such as a monkey, hydrocodone salt is hydrocodone bitartrate. In another chimpanzee or baboon. In one embodiment, the Subject is a embodiment, the oxycodone salt is oxycodone HC1. In a human. In one embodiment a stimulant that has anti-sedative further embodiment, the controlled-release layer further properties, which can bring pain relief to the subject with comprises one or more non-opioid analgesic. In one embodi ment, the non-opioid analgesic is acetaminophen or a phar reduced sedative effects common to Some opioid analgesic maceutically acceptable salt thereof. In one embodiment, the formulations. composition is in a form that achieves a hardness of from 0074. In some embodiments, the agent useful for reducing about 5 to about 15 kilaponds and has a thickness of about 5, or eliminating an adverse effect associated with administra about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, tion of an opioid or non-opioid analgesic agent, is promet about 8.5, about 9, about 9.5 or 10 mm. In one embodiment, hazine, dolasetron, granisetron, ondansetron, tropisetron, the tablet has a hardness of about 9.5 kilaponds. In another palonosetron, domperidone, droperidol, haloperidol, chlor embodiment, the tablet has a hardness of about 12.5 promazine, prochloperazine, metoclopramide, alizapride, kilaponds. It will be understood that as to the kilapond and cyclizine, diphenhydramine, dimenhydrinate, meclizine, thickness measurements, increments of 0.1 decimal points hydroxy Zine, cannabis, dronabinol, nabilone, midazolam, are within the scope of the invention. lorazepam, hyoscine, dexamethasone, trimethobenzamide, 0068. In one embodiment, the composition is capable of emetrol, or propofol, or pharmaceutically acceptable salt providing an effective plasma concentration of an antiemetic thereof. in about 1 minute to about 20 minutes after administration to 0075. A composition can be in any form disclosed herein, a Subject. In another embodiment, the antiemetic is promet hazine or a pharmaceutically acceptable salt thereof. In a Such as a multi-layer tablet (e.g., a bi-layer tablet). In one further embodiment the salt is promethazine HC1. embodiment, the multi-layer tablet is a bi-layer tablet that 0069. In various embodiments, a composition comprises comprises: (a) an immediate-release layer that comprises an from about 1% to about 20% by weight of an antihistamine: effective amount of an agent which reduces or eliminates an from about 10% to about 80% by weight a non-opioid anal adverse effect of an opioid analgesic; and (b) a controlled gesic; and from about 1% to about 20% by weight of an opioid release layer that comprises an effective amount of each of an analgesic. In some embodiments, the antihistamine is opioid analgesic agent and a non-opioid analgesic agent. promethazine, dolasetron, granisetron, ondansetron, tro 0076. In one embodiment, the agent that reduces or elimi pisetron, palonosetron, domperidone, droperidol, haloperi nates an adverse effect associated with administration of an dol, chlorpromazine, prochloperazine, metoclopramide, opioid or non-opioid analgesic agent is released in a Subject at alizapride, cyclizine, diphenhydramine, dimenhydrinate, a Substantially faster rate than an opioid or non-opioid anal meclizine, hydroxyzine, cannabis, dronabinol, nabilone, gesic in a composition of the invention. For example, in one midazolam, lorazepam, hyoscine, dexamethasone, tri embodiment, a plasma concentration of the agent that reduces methobenzamide, emetrol, or propofol, or pharmaceutically or eliminates an adverse effect of an opioid analgesic is acceptable salt thereof. achieved in about 1 minute to about 20 minutes following oral 0070. In one embodiment, the composition is capable pro administration, as compared with a plasma concentration of viding an effective plasma concentration of promethazine or an analgesic agent, which can be achieved in about 30 min a or a pharmaceutically acceptable salt thereof in about 1 utes to about 8 hours following oral administration. In various minute to about 20 minutes after administration to a Subject. embodiments, the compositions of the invention comprise an 0071. In one embodiment, a method is provided for reduc agent that reduces or eliminates an adverse effect associated ing or eliminating an adverse effect of an analgesic agent, with administration of an opioid analgesic or non-opioid comprising administering to a Subject in need thereof an analgesic, where the agent provides an effective plasma con composition comprising an effective amount of each of an centration in about 1 minute to about 20 minutes following opioid analgesic agent, a non-opioid analgesic agent and an oral administration. agent which reduces or eliminates a adverse effect of the 0077. In one embodiment, the agent that reduces or elimi analgesic agents. nates an adverse effect associated with an opioid or a non 0072. In one embodiment, a method is provided for treat opioid analgesic is an antihistamine orantiemetic. In various ing or preventing pain, comprising administering to a subject embodiments, AS indicated above, compositions can com in need thereof an effective amount of a composition com prise an antiemetic agent including, for example, aprepitant, prising an effective amount of each of an opioid analgesic, or dronabinol, perphenazine, palonosetron, trimethyobenza a pharmaceutically acceptable salt thereof, a non-opioid anal mide, metoclopromide, domperidone, prochlorperazine, gesic, or a pharmaceutically acceptable salt thereof, and an promethazine, chlorpromazine, trimethobenzamide, agent which reduces a adverse effect associated with the ondansetron, granisetron, hydroxy Zine, acetylleucine mono opioid or non-opiod analgesic agent. In one embodiment, the ethanolamine, alizapride, aZasetron, benzquinamide, biet agent that reduces an adverse effect is an antiemetic or an anautine, bromopride, buclizine, clebopride, cyclizine, antihistamine. dimenhydrinate, diphenidol, dolasetron, meclizine, methal 0073. In another embodiment the pain is associated with latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco cancer, chronic or acute pain, a headache, chronic headache, polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, a migraine headache, a Surgical procedure, acute or chronic thioproperazine, tropisetron, droperidol, haloperidol. physical injury, bone fracture or a crush injury, spinal cord prochloperazine, metoclopramide, diphenhydramine, can US 2012/020 1888 A1 Aug. 9, 2012

nabis, midazolam, lorazepam, hyoscine, dexamethasone, 0085. Another embodiment of this invention is directed to emetrol, propofol and a pharmaceutically acceptable salt or methods for the treatment of pain, comprising administering mixtures thereof. an effective amount of each of an opioid analgesic agent, a 0078. In one embodiment, a composition comprises an non-opioid analgesic agent and an agent that reduces or elimi effective amount of an opioid analgesic agent, a non-opioid nates an adverse effect of the opioid analgesic agent to a analgesic agent, and an agent that reduces or eliminates an subject in need thereof. adverse effect associated with administration of the opioid or I0086. The methods allow for use of analgesics in popula non-opioid analgesic. An adverse effect of opioid or non tions at risk of adverse effect such as nausea, vomiting, other opioid analgesic agents includes but is not limited to nausea, gastric upsets, skin rashes, allergic reactions such as Swelling, Vomiting, other gastric upset, skin rash, an allergic reaction difficulty breathing, closing of throat, abdominal pain, Such as Swelling, difficulty breathing, closing of throat, unusual bleeding or bruising, skin rashes, sedation, CNS abdominal pain, unusual bleeding or bruising, sedation, CNS depression, or respiratory depression. depression, or respiratory depression. In one embodiment, I0087. In one embodiment, the compositions comprise an the adverse effect that is reduced or eliminated is nausea, effective amount of each of an opioid analgesic, an anti Vomiting, constipation, or a combination thereof. emetic, and an opioid antagonist, the composition is capable 0079. In a further embodiment, the opioid analgesic agent of providing protection from a metabolic consequence of is, for example, hydrocodone, oxycodone propoxyphene, or Vomiting, particularly severe vomiting, in a subject particu fentanyl, or a pharmaceutically acceptable salt thereof; the larly prone to adverse effects associated with an opioid anal non-opioid analgesic agent is, for example, acetaminophen, gesic. An example of metabolic consequence of Vomiting is ibuprofen, ketaprofen, naproxen, or aspirin or a pharmaceu dehydration. In a further embodiment, the subject adminis tically acceptable salt thereof; and the agent useful for pre tered a composition of the invention is about 55 years of age venting and/or suppressing an adverse effect is, for example, or older, about 60 years of age or older, about 65 years of age an antihistamine such as promethazine or a pharmaceutically or older, or about 70 years of age or older. In one embodiment, acceptable salt thereof. In one embodiment of the invention, the composition administered to Such a subject comprises an the pharmaceutically acceptable salt of naproxen is naproxen opioid analgesic and one or more antiemetic agent. In one Sodium. embodiment, the composition comprises oxycodone, 0080. In one embodiment an opioid analgesic agent, a promethazine, and naltrexone, or a pharmaceutically accept non-opioid analgesic agent and an agent that reduces or elimi able salt thereof. nates an adverse effect are formulated in a bi-layer tablet. I0088. In various embodiments, a dosage form of the inven 0081. In one embodiment the bi-layer tablet comprises an tion provides an effective plasma concentration of an anti immediate-release layer and a controlled-release layer. In emetic or antihistamine at from about 1 minute to about 20 another embodiment, the immediate-release layer comprises minutes after administration, such as about 1 min, 2 min, 3 one or more pharmaceutically active agent disclosed in Table min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 1 or Table 2 and the control release layer comprise one or 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 more pharmaceutically active agents disclosed in Table 1 or min, 20 min, 21 min, 22 min, 23 min, 24 min, 25 min. In some Table 2. In a further embodiment, the immediate-release layer embodiments, the release rate occurs at Substantially faster as comprises an antiemetic or antihistamine and the controlled compared with release rates for the analgesic agents. There release layer comprises an opioid analgesic, a barbiturate, a fore, in one embodiment, after administration to a Subject, the stimulant, a triptan or a combination thereof. An illustrative antihistamine (e.g., promethazine dolasetron, granisetron, bilayer tablet is depicted in FIG. 2. In one embodiment, a ondansetron, tropisetron, palonosetron, domperidone, dro bilayer tablet of the invention has the dimensions as depicted peridol, haloperidol, chlorpromazine, prochloperazine, in FIG. 2. metoclopramide, aliZapride, cyclizine, diphenhydramine, 0082 In another embodiment the compositions comprise dimenhydrinate, meclizine, hydroxy Zine, cannabis, dronab an effective amount of each of an analgesic agent, an antitus inol, nabilone, midazolam, lorazepam, hyoscine, dexametha sive agent, and an agent that reduces or eliminates an adverse Sone, trimethobenzamide, emetrol or propofol, or a pharma effect of the analgesic agent or the antitussive agent. Under ceutically acceptable salt thereof) is released or an effective Some embodiments the antitussive is also an analgesic. plasma concentration of an antihistamine or antiemetic is 0083. In some embodiments the compositions comprise achieved before release of the opioid or non-opioid analgesic. acetaminophen, hydrocodone or oxycodone, or a pharmaceu I0089. In some embodiments, a dosage form of the inven tically acceptable salt thereof, and an antitussive agent Such tion provides an effective plasma concentration of said opioid as dolasetron, domperidone, meclizine, dronabinol, a benzo analgesic or said non-opioid analgesic at from about 20 min diazepine, an anticholinergic, hydrocodone or oxycodone, or utes to about 24 hours after administration, such as about 20 a pharmaceutically acceptable salt thereof. minutes, 30 minutes, 40 minutes, 50 minutes, 1 hr, 1.2hrs, 1.4 0084. In a further embodiment of this invention, the opioid hrs, 1.6 hrs, 1.8 hrs, 2 hrs, 2.2 hrs, 2.4 hrs, 2.6 hrs, 2.8 hrs, 3 analgesic agent is, for example, hydrocodone, or oxycodone hrs, 3.2 hrs, 3.4 hrs, 3.6 hrs, 3.8 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, or a pharmaceutically acceptable salt thereof; the non-opioid 8hrs, 9 hrs, 10hrs, 11 hrs, 12hrs, 13 hrs, 14 hrs, 15 hrs, 16 hrs, analgesic agent is, for example, acetaminophen, ibuprofen, 17 hrs., 18 hrs, 19 hrs, 20 hrs, 21 hrs, 22 hrs, 23 hrs, or 24 hrs ketoprofen, naproxen, lidocaine, or aspirin or a pharmaceu following administration. tically acceptable salt thereof; the antiemetic agent is, for 0090. In further embodiments, the opioid or non-opioid example 5-HT receptor antagonist, a dopamine antagonist, analgesic is present in an effective plasma concentration in a an antihistamine, a cannabinoid, benzodiazepines, an anti subject from about 1 hour to 24 hour or 1 day to 30 days, cholinergic, wherein all or less than all of the total amount of including but not limited to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 12, the antiemetic agent is formulated for immediate-release. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 US 2012/020 1888 A1 Aug. 9, 2012 or 30 days. In addition, administration of dosage composi and an effective amount of promethazine or a pharmaceuti tions can be effected through patch delivery systems which cally acceptable Salt thereof, combined in a single, oral pill, are known in the art. tablet or lollipop, form having dosage levels that can be safely 0091. In one embodiment compositions comprise an doubled for combating severe pain. effective amount of each of an opioid analgesics, a non-opioid 0099. In a further embodiment all or less than the entire analgesic agent, an antihistamine, anti-psychotic, anti-anxi total amount of the promethazine or a pharmaceutically ety agent, or other CNS depressant is adminstered a reduced acceptable salt thereof is formulated for immediate-release dosage of one or lessen and adverse effect (e.g. CNS depres into the subject's blood stream. sion). In another embodiment the dosage of one or more of pharmaceutically active agents is adjusted according to the 0100. In a further embodiment all or less than the entire severity of the pain and the response of the subject. amount of the hydrocodone or oxycodone, or a pharmaceu 0092. In subjects having a terminal disease or chronic tically acceptable salt thereof is formulated for controlled condition, pain management can be of a primary concern to release into the subject's body. the subject’s quality of life. 0101. In various embodiments, the agents are formulated 0093. In some of these subjects tolerance to opioid anal as a dosage form (e.g., tablet, capsule, gel, lollipop), gesics can develop with continued use. In one embodiment, parenteral, intraspinal infusion, inhalation, nasal spray, trans adjustments are made to the amounts or time-release charac dermal patch, iontophoresis transport, absorbing gel, liquid, teristics of the component of a composition, such as a com liquid tannate, Suppositorys, injection, I.V. drip, otherformu position comprising an effective amount of each of an opioid lation, or a combination thereof to treat Subjects. analgesic, a non-opioid analgesic and an antihistamine. In 0102. In another embodiment, the agents are formulated this embodiment the adjustments can provide pain relief to a as single oral dosage form such as a tablet, capsule, cachet, Subject with tolerance to opioid analgesics. In one embodi Soft gelatin capsule, hard gelatin capsule, extended release ment the amount of the opioid analgesic may be increased in capsule, tannate tablet, oral disintegrating tablet, multi-layer the composition. In another embodiment the time release tablet, effervescent tablet, bead, liquid, oral Suspension, characteristics of the opioid analgesic may be adjusted so as chewable lozenge, oral Solution, lozenge, lollipop, oral syrup, to change the ratio of immediate-release opioid analgesic to sterile packaged powder including pharmaceutically-accept controlled-release opioid analgesic. able excipients, other oral dosage forms, or a combination 0094. In one embodiment, the compositions comprise: thereof. hydrocodone, oxycodone, or a pharmaceutically acceptable (0103) In another embodiment a composition of the inven salt thereof, in a dosage range of from about 1.0 mg to about tion comprises an agent in immediate-release, quick release, 200 mg; acetaminophen or a pharmaceutically acceptable salt controlled-release, extended release, other release formula thereof in a dosage range of from about 200 mg to about 1000 tions or patterns, or a combination thereof. mg; and, promethazine or a pharmaceutically acceptable salt 0104. In one embodiment, a composition of the invention thereof in a dosage range of from about 0.5 mg to about 100 comprises three active agents, such as a decongestant, an ng. antitussive, an expectorant, a mucus-thinning drug, an anal 0095. In another embodiment, a compositions comprises: gesic or an antihistamine. For example, in one embodiment oxycodone or a pharmaceutically acceptable Salt thereof in a one of the agents is an antitussive Such as, e.g., codeine, dosage range of from about 10 mg to about 80 mg; Naltrexone dihydrocodeine, hydrocodone, dextromethorphan, dextror or a pharmaceutically acceptable salt thereof in a dosage phan, or a pharmaceutically acceptable salt thereof; the other range of from about 0.5 mg to about 0.75 mg; and, promet agent is a decongestant Such as, e.g., phenylephrine, pseu hazine or a pharmaceutically acceptable salt thereof in a doephedrine, or a pharmaceutically acceptable salt thereof. dosage range of from about 12.5 mg to about 50 mg. and the other agent is an expectorant. One will recognize that 0096. In yet another embodiment, the compositions com an active agent may fit into more than one category (e.g., prises: oxycodone or a pharmaceutically acceptable salt hydrocodone is an antitussive and opioid analgesic). thereofina dosage range of from about 10 mg to about 80 mg: 0105. In any of the embodiments disclosed herein, a com and promethazine or a pharmaceutically acceptable salt position of the invention can be administered using one or thereof in a dosage range of from about 12.5 mg to about 50 more different dosage forms which are further described mg. These compositions can be formulated using conven herein. For example, a composition comprising multiple tional technologies to provide for an extended time release active agents can be administered in Solid, semi-solid, micro over a desired dosage interval. Such as 4 hours, 6 hours, 9 emulsion, gel, patch or liquid form. Such dosage forms are hours, 12 hours, or 24 hours. In another embodiment, the further described herein. Examples of such dosage forms are compositions comprise about 7.5 mg of hydrocodone, about known, such as tablet forms disclosed in U.S. Pat. Nos. 3,048, 325 mg of acetaminophen or a pharmaceutically acceptable 526, 3,108,046, 4,786,505, 4,919,939, 4,950,484; gel forms salt thereof, and about 12.5 mg of promethazine or a pharma disclosed in U.S. Pat. Nos. 4,904,479, 6,482,435, 6,572,871, ceutically acceptable salt thereof. 5,013.726; patches for delivery of pharmaceutical composi 0097. In another embodiment, the compositions comprise tions such as those disclosed in U.S. Pat. Nos. 5,741,510, about 7.5 mg of oxycodone or a pharmaceutically acceptable 4,624,665, 4,626,539, 4,834,978, 6,469,227, 5,919,479, salt thereof, about 325 mg of acetaminophen or a pharmaceu 6,261,595, 6,303,142, 6,341,387, 6,465,006, 6,613,350, tically acceptable salt thereof, and about 12.5 mg of promet 6780426,7094228,6756053; capsule forms disclosed in U.S. hazine or a pharmaceutically acceptable salt thereof. Pat. Nos. 4,800,083, 4,532,126, 4,935.243, 6,258.380; liquid 0098. In another embodiment compositions comprise an forms disclosed in U.S. Pat. Nos. 4,625,494, 4,478,822, effective amount of hydrocodone or oxycodone, or a pharma 5,610, 184; or I.V. forms disclosed in U.S. Pat. Nos. 4,871, ceutically acceptable salt thereof; an effective amount of 353, 4,925,444, 5,484.406; each of which is incorporated acetaminophen or a pharmaceutically acceptable salt thereof; herein by reference in its entirety. US 2012/020 1888 A1 Aug. 9, 2012

0106 Immediate-release refers to the release of an active tion within about 1 hour following administration to a subject. agent Substantially immediately upon administration. In one In another embodiment, immediate-release results in com embodiment, immediate-release results in dissolution of an plete or less than complete dissolution within about 1 hour agent within 1-20 minutes after entering the stomach. Disso following rectal administration. When used in association lution can be of all or less than the entire amount of the active with the dissolution profiles discussed herein, the term agent. For example, dissolution of 100% of an agent (antihis “immediate-release' refers to wherein all or less than the tamine or antiemetic) can occur in the prescribed time. Alter entire amount of a dosage form is dissolved. natively, dissolution of less than all of the agent can occur in 0111. In some embodiments, immediate-release is about 1 minute to about 20 minutes (e.g., dissolution of about through inhalation, such that dissolution occurs in a subject's 70%, about 75%, about 80%, about 85%, about 90%, about lungs, as further described herein. Dissolution of less than all 91%, about 92%, about 93%, about 94%, about 95%, about of an active includes but is not limited to dissolution of about 96%, about 97%, about 98%, about 99%, about 99.5% or 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.9% of an agent). 99.1%, 99.2%, 99.35, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% 0107. In one embodiment, the compositions comprise an or 99.99% of the active agent. Methods for measuring disso antiemetic in an amount capable of achieving a serum level lution profiles are known (e.g., Example 15, infra). Cmax of from about 0.2 ng/mL to about 1 ng/mL at a T of 0112. In terms of a composition of the invention, “con from about 1 to about 6 hours following oraladiminstration. trolled-release' refers to the release of at least one pharma In one embodiment the antiemetic is promethazine or a phar ceutically active agent from a dosage form at a particular maceutically acceptable salt thereof. In another embodiment, desired point in time after the dosage form has is administered the pharmaceutically acceptable salt is promethazine HC1. In to a Subject. Generally, controlled-release includes Sustained a further embodiment, the composition is a bilayer tablet that but otherwise complete release. A sudden and total release in has an immediate release layer and a controlled-release layer. the stomach at a desired and appointed time or a release in the In yet a further embodiment, the controlled release layer intestines such as through the use of an enteric coating, are comprises an opioid analgesic agent or a non-opioid analge both considered controlled-release. Controlled-release can sic agent. In a further embodiment the immediate-release occur at a predetermined time or in a predetermined place layer comprises promethazine or a pharmaceutically accept within the digestive tract. It is not meant to be a passive, able salt thereof. uncontrolled process as in Swallowing a normal tablet. 0108. In another embodiment, the compositions comprise Examples include, but are not limited to, those described in promethazine or a pharmaceutically acceptable salt thereof in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; an amount capable of achieving a serum level Cmax of about 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 0.46 ng/mL at a Tmax of about 2 to about 3 hours following 5,073,543; 5,639,476; 5,354,556; 5,733,556; 5,871,776: oral administration. In one embodiment, the promethazine or 5,902,632; and 5,837.284 each of which is incorporated a pharmaceutically acceptable salt is at a dose by weight in the herein by reference in its entirety. composition of about 10 mg to about 15 mg. In another 0113. A control release dosage form begins its release and embodiment, the promethazine or pharmaceutically accept continues that release over an extended period of time. able salt is at a dose (by weight in the composition) of about Release can occur beginning almost immediately or can be 12.5 mg. In a further embodiment, the composition is in the Sustained. Release can be constant, can increase or decrease form of a bilayer tablet that has an immediate release layer over time, can be pulsed, can be continuous or intermittent, and a controlled-release layer. In yet another embodiment, the and the like. Generally, however, the release of at least one promethazine or a pharmaceutically acceptable salt is the pharmaceutically active agent from an controlled-release only pharmaceutically active agent in the immediate release dosage form will exceed the amount of time of release of the layer of a bilayer tablet of the invention. In one embodiment, drug taken as a normal, passive release tablet. Thus, for the promethazine is promethazine HC1. In yet a further example, while all of at least one pharmaceutically active embodiment, the controlled release layer comprises an opioid agent of an uncoated aspirin tablet should be released within, analgesic agent or a non-opioid analgesic agent. In a further for example, four hours, an controlled-release dosage form embodiment, the opioid analgesic is the only pharmaceuti could release a smaller amount of aspirin over a period of six cally active agent in the controlled-release layer of a bilayer hours, 12 hours, or even longer. Controlled-release in accor tablet, non-opioid analgesic is the only pharmaceutically dance with the compositions and methods described herein active agent in the controlled-release layer of a bilayer tablet generally means that the release occurs for a period of six or both the opioid analgesic and non-opioid analgesic are the hours or more, Such as 12 hours or more. only pharmaceutically active agents of the composition. 0114 Extended-release, or sustained-release, refers to the 0109. In another embodiment, immediate-release occurs release of an agent, from a composition or dosage form in when there is dissolution of an agent within 1-20 minutes which the agent is released according to a desired profile over after oral administration. In another embodiment, immediate an extended period of time. In one embodiment, controlled release results in substantially complete dissolution within release results in dissolution of an agent within 20-720 min about 1 hour following oral administration. In one embodi utes after entering the stomach. In another embodiment, con ment, an composition of the invention is capable of providing trolled-release occurs when there is dissolution of an agent an about 80% dissolution of an antiemetic in about 5 minutes within 20-720 minutes after being swallowed. In another (e.g., FIG. 5). embodiment, controlled-release occurs when there is disso 0110. In various embodiments, immediate-release occurs lution of an agent within 20-720 minutes after entering the when there is dissolution of an agent within 1-20 minutes intestine. In another embodiment, controlled-release results after administration. Dissolution can occur in a subject's in substantially complete dissolution after at least 1 hour stomach and/or intestine. In another embodiment, immedi following administration. In another embodiment, con ate-release results in complete or less than complete dissolu trolled-release results in substantially complete dissolution US 2012/020 1888 A1 Aug. 9, 2012

after at least 1 hour following oral administration. In another a subject after about 5 to about 10 minutes following oral embodiment, controlled-release results in Substantially com administration. In one embodiment, the promethazine is plete dissolution after at least 1 hour following rectal admin promethazine HC1. istration. For example, controlled-release compositions allow 0121. In one embodiment, a composition comprises delivery of an agent to a Subject over an extended period of hydrocodone or a pharmaceutically acceptable salt thereof time according to a predetermined profile. Such release rates and about 30 to about 60% of the hydrocodone or pharma can provide therapeutically effective levels of agent for an ceutically acceptable salt thereof dissolves in the stomach of extended period of time and thereby provide a longer period a subject after about 5 to about 10 minutes following oral of pharmacologic or diagnostic response as compared with administration. conventional rapid release dosage forms. Such longer periods I0122. In one embodiment, the hydrocodone salt is hydro of response provide for many inherent benefits that are not codone bitartrate. In one embodiment, a composition com achieved with immediate-release dosages. In using analge prises acetaminophen or a pharmaceutically acceptable salt sics for treatments of chronic pain, controlled-release formu thereof and 50% to about 70% of the acetaminophen or phar lations can be used instead of conventional short-acting for maceutically acceptable salt thereof dissolves in the stomach mulations. When used in connection with the dissolution of a subject after about 5 to about 10 minutes following oral profiles discussed herein, the term “controlled-release' refers administration. to wherein all or less than all of the total amount of a dosage I0123. In one embodiment, the composition comprises form, made according to methods and compositions promethazine or a pharmaceutically acceptable salt thereof, described herein, delivers an active agent over a period of hydrocodone or a pharmaceutically acceptable salt thereof time greater than 1 hour. and acetaminophen or a pharmaceutically acceptable salt 0115. In one embodiment, controlled-release refers to thereof, and at least 90% of the pharmaceutically active delayed release of an agent, from a composition or dosage agents in the composition dissolve in the stomach of a subject form in which the agent is released according to a desired after about 45 minutes following oral administration. In one profile in which the release occurs after a period of time. embodiment, the composition is a bilayer tablet comprising 0116. When present in a controlled-release oral dosage an immediate-release layer and an controlled-release layer. form, the compositions described herein can be administered 0.124. In one embodiment, the immediate release layer at a Substantially lower daily dosage level than immediate comprises promethazine or a pharmaceutically acceptable release forms. At comparable daily dosage levels, the con salt as the only pharmaceutically active agent. In another trolled-release oral solid dosage forms can provide greater in embodiment, the controlled-release layer comprises hydroc pain relief than immediate-release forms. odone or a pharmaceutically acceptable salt and acetami 0117 Bilayer Tablet nophen or a pharmaceutically acceptable salt as the only 0118. In one embodiment of the invention, the invention pharmaceutical ingredients. relates to multi-layer tablets, such as bi-layer tablets. In one 0.125. In yet another embodiment, the controlled release embodiment, the bi-layer tablet comprises: (a) an immediate layer comprises an opioid analgesic or a non-opioid analgesic release layer, and (b) a controlled-release layer. In various as the only pharmaceutically active agent. In another embodi embodiments, the immediate-release layer or the controlled ment, the controlled release layer comprises an opioid anal released layer comprises one or more pharmaceutically active gesic and a non-opioid analgesic as the only pharmaceutically agents. In one embodiment, a bilayer tablet of the invention active agents. In another embodiment the immediate release has a hardness of about 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, layer comprises an antiemetic or a stimulant as the only 12, 12.5, 13, 13.5, 14, 14.5 or 15 kilaponds (kp). In one pharmaceutically active agent. In another embodiment the embodiment, the bilayer tablet has a hardness of about 9.5 kp. immediate release layer comprises an antiemetic and a stimu In a further embodiment, a bilayer tablet of the invention has lant as the only pharmaceutically active agents. a thickness of about 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 0.126 Immediate-Release Layer mm. It will be understood that as to the kilapond and thickness I0127. In one embodiment, the immediate-release layer is measurements, increments of 0.1 decimal points are within capable of releasing about 70 to about 80% of the one or more the scope of the invention. An nonlimiting example of a pharmaceutically active agent contained therein in the stom bilayer tablet of the invention is depicted in FIG. 2. In various ach of a subject in about 5 to about 10 minutes following oral embodiments, the tablet can be rectangular, tubular, oblong administration. In one embodiment, the immediate-release (e.g., FIG. 2), circular, oval or in a capsule form. layer is capable of releasing about 90 to about 100% of one or 0119. In various embodiments, a bilayer tablet of the more pharmaceutically active agent contained therein in the invention provides an effective amount of one or more phar stomach of a Subject in about 40 minutes. maceutically active agents for about 4 to about 6 hours fol I0128. In one embodiment, the one or more pharmaceuti lowing oral administration, about 12 hours following oral cally active agent in the immediate-release layer is an anti administration, about 24 hours following oral administration, emetic. In one embodiment, the antiemetic is promethazine or or 48 hours following administration. In various embodi a pharmaceutically acceptable salt thereof. In another ments, the one or more pharmaceutically active agents pro embodiment, the antiemetic is promethazine HC1. vided in 4-6 hour, 12 hour, 24 hour or 48 hour dosing inter I0129. In one embodiment, an immediate-release layer vals. Therefore, a bilayer tablet of the invention is capable of comprises two or more agents, including an anti-emetic and a providing any of the one or more pharmaceutically active stimulant. agents disclosed herein in the foregoing dosing intervals. 0.130. In some embodiment, the immediate-release layer 0120 In one embodiment, a composition comprises comprises one or more excipients, including but not limited to promethazine or a pharmaceutically acceptable salt thereof silicified microcrystalline cellulose (e.g., HD90), croscar and about 70 to about 80% of the promethazine or pharma mellose Sodium (AC-Di-Sol), magnesium Stearate. In one ceutically acceptable salt thereof dissolves in the stomach of embodiment, the total layer weight of the immediate-release US 2012/020 1888 A1 Aug. 9, 2012

layer is from about 100 to about 300 mg, such as about 110 acceptable salt thereof. In another embodiment, the opioid mg, about 120 mg, about 130 mg, about 140 mg, about 150 analgesic is oxycodone or a pharmaceutically acceptable salt mg, about 160 mg, about 170 mg, about 180 mg, about 190 thereof. In one embodiment, the pharmaceutically acceptable mg, about 200 mg, about 210 mg, about 220 mg, about 230 salt is oxycodone HC1. In another embodiment, the pharma mg, about 240 mg, about 250 mg, about 260 mg, about 270 ceutically acceptable salt for hydrocodone is hydrocodone mg, about 280 mg, about 290 mg, or about 300 mg. bitartrate. 0131. In one embodiment, the immediate-release layer 0.139. In yet a further embodiment, the controlled-release comprises from about 75 mg to about 150 mg of silicified layer further comprises from about 290 mg to about 360 mg microcrystalline cellulose, from about 10 mg to about 20 mg acetaminophen or a pharmaceutically acceptable salt thereof. croScarmellose sodium, from about 0.5 mg to 2 mg magne In one embodiment the controlled-release layer comprises sium Stearate. In yet a further embodiment, the immediate about 325 mg acetaminophen or a pharmaceutically accept release layer comprises from about 10 to about 15 mg promet able salt thereof. hazine, or a pharmaceutically acceptable salt thereof. In 0140. In one embodiment, the immediate-release layer another embodiment, the immediate-release layer comprises comprises promethazine HCl and the controlled-release layer about 12.5 mg promethazine or a pharmaceutically accept comprises hydrocodone bitartrate. In another embodiment, able salt thereof. In another embodiment, the pharmaceuti the controlled-release layer further comprises a non-opioid cally acceptable salt is promethazine HC1. analgesic (e.g., acetaminophen). 0.132. In one embodiment, the immediate-release layer 0.141. In one embodiment, the one or more pharmaceuti comprise about 12.5 mg promethazine HCl, about 121.5 mg cally active agents of the controlled-release layer is an opioid silicified microcrystalline cellulose, about 15 mg croScarmel analgesic. In one embodiment, the opioid analgesic is hydro lose Sodium, and about 1 mg magnesium Stearate. codone or oxycodone; or a pharmaceutically acceptable salt 0133. In one embodiment, a composition comprising an thereof. In one embodiment, the immediate-release layer is effective amount of each of hydrocodone bitartrate, acetami about 150 mg in total layer weight and the controlled-release nophen and promethazine HCl is capable of dissolving in the layer is about 550 mg total weight. stomach of a Subject so that an effective plasma concentration 0.142 Furthermore, in one embodiment, the controlled of each of pharmaceutically active ingredient is present in a release layer comprises about 325 mg acetaminophen, about subject in from about 5 minutes to about 30 minutes. 7.5 mg hydrocodone bitartrate, about 152 mg silicified micro 0134 Controlled-release Layer crystalline cellulose, about 20 mg hydroxyl methyl propyl 0135. In one embodiment, the controlled-release layer is cellulose (HPMC), about 2.75 mg magnesium stearate, and capable of releasing about 30 to about 40% of the one or more about 2.75 mg Stearic acid; and the immediate-release layer pharmaceutically active agent contained therein in the stom comprises about 12.5 mg promethazine HCl, about 121 mg ach of a subject in about 5 to about 10 minutes following oral silicified microcrystalline cellulose, about 15 mg croScarmel administration. In another embodiment, the controlled-re lose Sodium, and about 1 mg magnesium Stearate. lease layer is capable of releasing about 90% of the one or 0143. In various embodiments, a bilayer tablet of the more pharmaceutically active agents are released in about 40 invention can comprise the combinations of pharmaceuti minutes after oral administration. cally active agents in Table 1 or Table 2, wherein the con 0136. In some embodiment, the controlled-release layer trolled-release layer comprises one or more opioid analgesic comprises one or more excipients, including but not limited to agents, triptan agents, non-analgesic agents, barbiturates or silicified microcrystalline cellulose (e.g., HD90), croscar stimulants, and the immediate-release layer comprises one or mellose sodium (AC-Di-Sol), Magnesium Stearate. In one more stimulants. embodiment, the total layer weight of the controlled-release 0144. In one embodiment, a stimulant is present in the layer is from about 100 to about 300 mg, such as about 110 immediate-release layer, controlled-release layer or both lay mg, about 120 mg, about 130 mg, about 140 mg, about 150 ers; the immediate-release layer comprises one or more anti mg, about 160 mg, about 170 mg, about 180 mg, about 190 emetic or antihistamines; and the controlled-release layer mg, about 200 mg, about 210 mg, about 220 mg, about 230 comprises one or more non-opioid analgesics. In addition, mg, about 240 mg, about 250 mg, about 260 mg, about 270 either layer of the bilayered tablet can comprise one or more mg, about 280 mg, about 290 mg, or about 300 mg. anti-abuse agents disclosed herein. 0.137 In one embodiment, a controlled-release layer com 0145. In one embodiment, a bilayer tablet of the invention prises from about 75 mg to about 250 mg of silicified micro comprises a controlled-release layer comprising one or more crystalline cellulose, from about 10 mg to about 40 mg analgesic agents as the only pharmaceutically active agents in hydroxylmethyl propyl cellulose, from about 0.5 mg to 5 mg the controlled-release layer. In another embodiment, a bilayer magnesium Stearate, and from about 0.5 mg to about 5 mg tablet of the invention comprises an immediate-release layer Stearic acid. comprising an antiemetic agent as the only pharmaceutically 0.138. In one embodiment, the controlled-release layer active agent in the immediate-release layer. comprises about 152 mg silicified microcrystalline cellulose, 0146 In another embodiment the controlled release layer about 20 mg hydroxylmethyl propyl cellulose, about 2.75 mg further comprises one or more of silicified microcrystalline magnesium Stearate, about 2.75 Stearic acid, about 7.5 mg cellulose, hydroxy methyl propyl cellulose, magnesium hydrocodone, or a pharmaceutically acceptable salt thereof Stearate, and Stearic acid. In another embodiment the imme and about 325 mg acetaminophen or a pharmaceutically diate-release layer further comprises one or more of: silicified acceptable salt thereof. In yet a further embodiment, the con microcrystalline cellulose, croScarmellose sodium and mag trolled-release layer comprises from about 5 mg to about 12.5 nesium stearate. In another embodiment the tablet has a hard mg hydrocodone or a pharmaceutically acceptable salt ness of about 9.5 kilopond and thickness from about 6.9 to thereof. In one embodiment, the controlled-release layer about 7.0 mm. In another embodiment the hydrocodone salt is comprises about 7.5 mg hydrocodone or a pharmaceutically hydrocodone bitartrate. In another embodiment the promet US 2012/020 1888 A1 Aug. 9, 2012

hazine salt is promethazine HCL. In another embodiment the 0153 Combination Formulations controlled release layer is an inner layer and wherein the 0154 Various embodiments of the invention are directed immediate-release layer is an outer layer. to compositions comprising an effective amount of each of an 0147 In one embodiment the opioid analgesic is oxyc analgesic and an active agent that is useful for reducing an odone or pharmaceutically acceptable salt thereof, and the adverse effect associated with Such one or more opioid anal one or more antiemetic is promethazine or a pharmaceutically gesics, or one or more non-opioid analgesic. Various embodi ments for compositions of the invention are provided in Table acceptable salt thereof. In another embodiment the effective 1 or Table 2. amount is an amount effective for treating or preventing pain 0155 Such additional active agents include antiemetics for a period of about 12 hours immediately following admin and antihistamines. In some embodiments, the analgesics are istration to a subject. In another embodiment the bi-layer opioid or non-opioid analgesics (e.g., hydrocodone or oxyc tablet comprises an immediate release layer and a controlled release layer. In another embodiment the immediate release odone, or a pharmaceutically acceptable salt thereof and layer comprises the promethazine or pharmaceutically acetaminophen or a pharmaceutically acceptable salt acceptable salt thereof, and wherein the controlled release thereof). In a further embodiment, the active agent which layer comprises the oxycodone, or a pharmaceutically reduces adverse effects of such analgesics is promethazine or acceptable salt thereof. In another embodiment about 70% of a pharmaceutically acceptable salt thereof. the promethazine or pharmaceutically acceptable salt thereof 0156. In one embodiment, a composition of the invention is capable of dissolving in a liquid solution in about 5 minutes allows for higher dosages for said analgesics in the compo after contact with the solution, and wherein about 30% of the sition, by reducing adverse effects associated with an opioid oxycodone or pharmaceutically acceptable salt is capable of or non-opioid analgesic. For example, in a subject who could not otherwise tolerate a particular dosage of an opioid anal dissolving in a liquid solution in about 10 minutes after con gesic, it is believed that a composition of the invention com tact with the solution. In another embodiment the controlled prising an effective amount of each of an opioid analgesic, a release layer further comprises an antiemetic agent. non-opioid analgesic and promethazine or a pharmaceuti 0148. In one embodiment the effective amount of the cally acceptable salt thereof, will reduce an adverse effects hydrocodone or pharmaceutically acceptable salt thereof is (e.g. nausea or vomiting) associated with an opioid analgesic, an amount effective for treating or preventing pain for a thus allowing for increased dosages to be administered. Fur period of about 12 hours immediately following administra thermore, administration can be through a single composi tion to a subject. In another embodiment the controlled tion. release layer comprises about 7.5 mg of hydrocodone or a 0157. In various embodiments, the analgesic agent of the pharmaceutically acceptable salt thereof, about 325 mg of composition is an opioid analgesic agent such as hydroc acetaminophen or a pharmaceutically acceptable salt thereof, odone, oxycodone, acetyldihydrocodeinone, diamorphine, about 152 mg of silicified microcrystalline cellulose, about 20 codeine, pethidine, alfentanil, buprenorphine, butorphanol, mg of hydroxy methyl propyl cellulose, about 2.7 mg of codeine, dezocine, fentanyl, hydromorphone, levomethadyl magnesium Stearate, and about 2.7 mg of stearic acid; and the acetate, levorphanol, meperidine, methadone, morphine Sul immediate release layer comprises about 12.5 mg of promet fate, nalbuphine, Oxymorphone, pentazocine, propoxyphene, hazine or a pharmaceutically acceptable salt thereof, about remifentanil, Sufentanil, tramadol, or a pharmaceutically 121.5 mg of silicified microcrystalline cellulose, about 15 mg acceptable salt thereof. In one embodiment, the opioid anal of croScarmellose Sodium and about 1 mg of magnesium gesic agent is hydrocodone, oxycodone, propoxyphene, or Stearate. fentanyl or a pharmaceutically acceptable salt thereof. 0149. In another embodiment the composition further 0158. In another embodiment, a dosage form comprises an comprises an effective amount of naltrexone or a pharmaceu opioid analgesic and one or more antiemetic. In another tically acceptable salt thereof. In another embodiment the embodiment, a dosage form comprises hydrocodone or oxy composition is in the form of a bi-layer tablet. In another codone or a pharmaceutically acceptable salt thereof and one embodiment the effective amount of the morphine or phar or more antiemetic, which are disclosed herein. maceutically acceptable salt thereofisanamount effective for 0159. In some embodiments, a composition of the inven treating or preventing pain for a period of about 12 hours tion comprises an opioid antagonist agent or abuse deterrent immediately following administration to a subject. agent such as nalmefene, naloxone, niacin, naltrexone or a 0150. In one embodiment the controlled release layer pharmaceutically acceptable salt thereof. The composition comprises about 7.5 mg of hydrocodone or a pharmaceuti can further comprise an antitussive such as codeine or dex cally acceptable salt thereof, and about 325 mg of acetami tromethorphan, dextrorphan, or a pharmaceutically accept nophen or a pharmaceutically acceptable salt thereof, and able salt thereof. further wherein the immediate-release layer comprises about 0160 AS stated above, a pharmaceutically active agent can 12 mg of promethazine or a pharmaceutically acceptable salt be in the form of a pharmaceutically acceptable salt. Each thereof. agent disclosed herein can be used in a composition of the 0151. In one embodiment the effective amount is an invention as its free base or its pharmaceutically acceptable amount effective for treating or preventing pain for a period of salt, prodrug, analog and complex. In various embodiments about 12 hours immediately following administration to a of the invention, with respect to a pharmaceutically active Subject. agent in a composition, a pharmaceutically acceptable salt 0152. In one embodiment the effective amount of the oxy includes, but is not limited to, metal salts, such as Sodium codone or pharmaceutically acceptable salt thereof is an salts, potassium salts, and lithium salts; alkaline earth metals, amount effective for treating or preventing pain for a period of Such as calcium salts, magnesium salts, and the like; organic about 12 hours immediately following administration to a amine salts, such as triethylamine salts, pyridine salts, Subject. picoline salts, ethanolamine salts, triethanolamine salts, dicy US 2012/020 1888 A1 Aug. 9, 2012 clohexylamine salts, N,N'-dibenzylethylenediamine salts, ment, the hydrodocone salt is hydrocodone bitartrate, the and the like; inorganic acid salts such as hydrochloride salts, oxycodone salt is oxycodone HCl, and the naproxen salt is hydrobromide salts, Sulfate salts, phosphate salts, and the naproxen Na or Mg. like; organic acid salts such as formate salts, acetate salts, 0163. In some embodiments the compositions disclosed trifluoroacetate salts, maleate salts, tartrate salts, and the like; herein may further comprise one or more of an opioidantago Sulfonate salts such as methanesulfonate salts, benzene nist agent, abuse deterrent agent, a barbiturate agent a stimu Sulfonate salts, p-toluenesulfonate salts, and the like; and lant agent or an antiemetic agent. amino acid salts, such as arginate salts, asparginate salts, 0164. Therefore, in some embodiments, a composition glutamate salts, and the like. comprises an effective amount of an opioid analgesic agent 0161 In addition, pharmaceutically acceptable salts (such as hydrocodone or oxycodone or a pharmaceutically include bitartrate, bitaritrate hydrate, hydrochloride, p-tolu acceptable salt thereof), a non-opioid analgesic agent (Such as enesulfonate, phosphate, Sulfate, trifluoroacetate, bitartrate acetaminophen or naproxen or a pharmaceutically acceptable hemipentahydrate, pentafluoropropionate, hydrobromide, salt thereof) and an active agent useful for reducing or elimi mucate, oleate, phosphate dibasic, phosphate monobasic, nating adverse effects, such as an antihistamine (e.g., promet acetate trihydrate, bis(heptafluorobutyrate), bis(pentafluoro hazine or a pharmaceutically acceptable salt thereof) or an propionate), bis(pyridine carboxylate), bis(trifluoroacetate), antiemetic, as described herein. In one embodiment the com chlorhydrate, and Sulfate pentahydrate. In one embodiment position is in the form of a bi-layer tablet that comprises an the agent is hydrocodone, a pharmaceutically acceptable salt immediate-release layer and a controlled-release layer. In a or its thiosemicarbazone, p-nitrophenylhydraZone, o-methy further embodiment the immediate-release layer comprises loXime, semicarbazone, or bis(methylcarbamate). In another one or more of an opioid agent, a non-opioid analgesic agent embodiment the agent is oxycodone, a pharmaceutically and an active agent useful for reducing or eliminating adverse acceptable salt or its thiosemicarbazone, p-nitrophenylhydra effects. In a further embodiment a controlled-release layer Zone, o-methyloxime, semicarbazone, or bis(methylcarbam comprises an effective amount of one or more of an opioid ate). In a further embodiment the agent is acetaminophen, a agent, a non-opioid analgesic agent and an active agent useful pharmaceutically acceptable salt or its thiosemicarbazone, for reducing or eliminating adverse effects associated with p-nitrophenylhydraZone, o-methyloXime, semicarbazone, or administration of an opioid analgesic agent or non-opioid bis(methylcarbamate). In another embodiment an agent is analgesic agent. In some embodiments a composition further promethazine, a pharmaceutically acceptable salt or its thi comprises an effective amount of an opioid antagonist agent osemicarbazone, p-nitrophenylhydrazone, o-methyloxime, or abuse deterrent agent. In a specific embodiment the com semicarbazone, or bis(methylcarbamate). Other representa position comprises hydrocodone or oxycodone, or a pharma tive pharmaceutically acceptable salts include, e.g., water ceutically acceptable salt thereof, acetaminophen or a phar soluble and water-insoluble salts, such as the acetate, maceutically acceptable salt thereof, or naproxen or a amsonate (4,4-diaminostilbene-2.2-disulfonate), benzene pharmaceutically acceptable Salt thereof, and promethazine sulfonate, benzonate, bicarbonate, bisulfate, bitartrate, or a pharmaceutically acceptable salt thereof. borate, butyrate, calcium edetate, camphorsulfonate, camsy 0.165 Examples of non-opioid analgesic agents useful in late, carbonate, citrate, clavulariate, dihydrochloride, edetate, the compositions of the invention include but are not limited edisylate, estolate, esylate, fiunarate, fumarate, gluceptate, to acetaminophen; a non-steroidal anti-inflammatory drug gluconate, glutamate, glycolylarsanilate, hexafluorophos (NSAID) such as a salicylate (including, for example, amox phate, hexylresorcinate, hydrabamine, hydrobromide, hydro iprin, benorilate, choline magnesium salicylate, diflunisal, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lac faislamine, methyl salicylate, magnesium salicylate), anary tobionate, laurate, malate, maleate, mandelate, mesylate, lalkanoic acid (including, for example, diclofenac, ace methylbromide, methylnitrate, methylsulfate, mucate, nap clofenac, acemetacin, bromfenac, etodolac, indometacin, Sylate, nitrate, N-methylglucamine ammonium salt, 3-hy nabumetone, Sulindac, tolmetin), a profen (including, for droxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1.1- example, ibuprofen, carprofen, fenbuprofen, flubiprofen, ket methene-bis-2-hydroxy-3-naphthoate, einbonate), aprofen, ketorolac, loxoprofen, naproxen, Suprofen), a pantothenate, phosphate/diphosphate, picrate, polygalactur fenamic acid (including, for example mefenamic acid, onate, propionate, p-toluenesulfonate, salicylate, Stearate, meclofenamic acid), an oxicam (including, for example, Subacetate. Succinate, Sulfate, Sulfosaliculate, Suramate, tan piroXicam, lomoxicam, meloxicam, tenoxicam), a pyrazoli nate, tartrate, teoclate, tosylate, triethiodide, and Valerate dine derivative (including, for example, phenylbutaZone, aza salts. A hydrate is another example of a pharmaceutically propaZone, metamizole, oxyphenbutaZone, SulfinpraZone) or acceptable salt. a pharmaceutically acceptable salt thereof: a Cox-2 inhibitor 0162. In some embodiments, a composition of the inven (such as Valdecoxib, celecoxib, rofecoxib or a pharmaceuti tion comprises an effective amount of each of an opioid cally acceptable salt thereof), a local analgesic (such as analgesic agent and a non-opioid analgesic agent, where the lidocaine, mexiletine or a pharmaceutically acceptable salt opioid analgesic agent/non-opioid analgesic agent is codeine/ thereof); an anti-depressant (such as amitriptyline, carbam acetaminophen, codeine/aspirin, codeine/naproxen, codeine/ aZepine, gabapentin, pregabalin, amoxapine, clomipramine, ibuprofen, hydrocodone/acetaminophen, hydrocodone/ibu desipramine, doSulepin, doxepin, imipramine, iprindole, profen, hydrocodone/naproxen, hydrocodone/aspirin, lofepramine, nortriptyline, opipramol, protryptyline, trimi oxycodone/acetaminophen, oxycodone/aspirin, oxycodone? pramine or a pharmaceutically acceptable salt thereof) an naproxen, oxycodone/ibuprofen, propoxyphene/aspirin, pro atypical analgesic (such as orphenadrine, cyclobenzaprine, poxyphene/ibuprofen, propoxyphenefacetaminophen, or Scopolamine, atropine, gabapentin or a pharmaceutically propoxyphene/naproxen, wherein the opioid analgesic agent acceptable salt thereof), a psychotropic agent (Such as tet or non-opioid analgesic agent is optionally in the form of a or rahydrocannabinol or a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof. In one embodi thereof), an NMDA receptor antagonist (such as ketamine, US 2012/020 1888 A1 Aug. 9, 2012 amantadine, dextromethorphan, dextrorphan, ibogaine, Zolam, lorazepam, hyoscine, dexamethasone, emetrol, phencyclidine, riluzole, tiletamine, memantine, dizocilpine, propofol and a pharmaceutically acceptable salt or mixtures patiganel, remacimide, or a pharmaceutically acceptable salt thereof. thereof), an O-adrenoreceptor agonists (such as clonidine or 0171 In another embodiment the composition can com a pharmaceutically acceptable salt thereof) and a synthetic prise an antitussive agent including, for example, dex drug having narcotic properties such as tramadol. In one tromethorphan, dextrorphan, noscapine, ethyl morphine, embodiment the non-opioid analgesic agent is acetami codeine, camphor, menthol, theobromine, guaifenesin, or the nophen, naproxen or a pharmaceutically acceptable salt like. thereof. 0172. In various embodiments of the invention, a compo 0166 The agent useful for preventing or alleviating an sition comprises at least two analgesics; and one or more adverse effect associated with administration of an opioid additional pharmaceutically active agents disclosed in Table analgesic or a non-opioid analgesic, a tripan, barbiturate or 1 or Table 2. In one embodiment, the composition further morphine narcotic, includes, for example, an antihistamine comprises one antihistamine or antiemetic. including a histamine agonist and an antagonist which is 0173. In some embodiments a composition comprises a classified according to receptor Subtype. stimulant agent. Stimulant agents useful in the methods and 0167 Such antihistamines include H1 agonists and H1 compositions of the invention include, but are not limited to, antagonists. H1 agonists or partial agonists include 2-(m- aminophylline, caffeine, dyphilline, oxitriphylline, theoph fluorophenyl)-histamine, and H1 antagonists include chlor hylline, amphetamine, benzphetamine, dextroamphetamine, pheniramine, Scopolamine, mepyramine, terfenadine, diethylpropion, mazindol, methamphetamine, methylpheni astemizole, and triprolidine. Further antagonists (which may date, dexmethylphenidate, pemoline, Sibutramine, modafinil, be further classified by their chemical structures) include the atomoxetine, phendimetrizine, phenteramine, adrafinil, phe ethanolamines carbinoxamine, dimenhydrinate, diphenhy nylpropanolamine, pSuedoephedrine, Synephrine, amphet dramine, and doxylamine; the ethylaminediamines pyril aminil, furfenorex, or a combination thereof. In some amine and tripelennamine; the piperazine derivatives dydrox embodiments, compositions comprise a stimulant agent that yZine, cyclizine, fexofenadine and meclizine; the provides an anti-sedative effect. alkylamines brompheniramine and chlorpheniramine; and 0.174. A stimulantagent can be an amphetamine, examples miscellaneous antagonists cyproheptadine, loratadine, cetriz of which include but are not limited to Methamphetamine, ine. H2 agonists include dimaprit, impromidine, and levoamphetamine, dextroamphetamine, 3.5-methyloxy amthamine; and H2 antagonists (useful in the treatment of amphetamine, 2,5-dimethoxy-4-methylthioamphetamine, gastric acid secretion) include cimetidine, ranitidine, nizati 2,5-dimethoxy-4-ethylthioamphetamine, 2,5-dimethoxy-4- dine, and famotidine; H3 agonists include R-alpha-methyl (i)-propylthioamphetamine, 2,5-dimethoxy-4-phenylthio histamine, imetit, and immepip and H3 antagonists include amphetamine, 2,5-dimethoxy-4-(n)-propylthioamphet thioperamide, iodophenpropit, and clobenpropit; and H4 amine, Brolamfetamine, 2,5-dimethoxy-4- agonists include clobenpropit, imetit, and clozapine and H4 iodoamphetamine, 2,5-Dimethoxy-4-methylamphetamine, antagonists include thioperamide. 2,5-Dimethoxy-4-butyl-amphetamine, 3,4-Dimethyl-2,5- 0168 The agent useful for preventing or suppressing a dimethoxyamphetamine, 2-Phenylethylamine, propylam adverse effect can also include an H1 blocker, such as azelas phetamine, methylphenidate, lisdexamfetamine, ethylam tine, brompheniramine, buclizine, carbinoxamine, cetrizine, phetamine, MDMA (3.4-methylenedioxy-N- chlorpheniramine, clemastine, cyclizine, cyproheptadine, methylamphetamine), MDEA (3.4-methylenedioxy-N- desloratidine, dimenhydrinate, diphenhydramine, emedas ethylamphetamine), PMA (p-methoxyamphetamine), DMA tine, feXofenadine, hydroxy Zine, ketotifen, levocabastine, (2-(2,4-Dimethoxy-phenyl)-1-methyl-ethylamine), benz loratadine, meclizine, olopatadine, phenindamine, and pro phetamine, 4-FMP (para-fluoroamphetamine), or 4-MTA moathazine. (4-Methylthioamphetamine), or a pharmaceutically accept 0169. In various embodiments compositions comprise able salt thereof. two, three, four, five, six or more active agents. In one 0.175. In one embodiment, a composition is provided that embodiment at least one of the active agents is an antiemetic comprises an effective amount of an opioid (such as hydroc or antihistamine. In other embodiment, a composition does odone, propoxyphene, fentanyl or oxycodone, or a pharma not comprise promethazine or a pharmaceutically acceptable ceutically acceptable salt thereof) and a stimulant (Such as salt. As indicated herein, a composition can comprise phar modafinil or caffeine, or a pharmaceutically acceptable salt maceutically active agents in the combinations provided in thereof). In some embodiments a composition further com Table 1 or Table 2. prises an antiemetic. In one embodiment, the antiemetic is 0170 As indicated above, compositions can comprise an promethazine or a pharmaceutically acceptable salt thereof. antiemetic agent including, for example, aprepitant, dronab In yet another embodiment, the composition further com inol, perphenazine, palonosetron, trimethyobenzamide, prises a non-analgesic agent disclosed herein. In one embodi metoclopromide, domperidone, prochlorperazine, promet ment, the non-opioid analgesic is acetaminophen or a phar hazine, chlorpromazine, trimethobenzamide, ondansetron, maceutically acceptable salt thereof, or naproxen or a granisetron, hydroxy Zine, acetylleucine monoethanolamine, pharmaceutically acceptable salt thereof. alizapride, azasetron, benzquinamide, bietanautine, bro 0176). In a further a composition is in the form of a bilayer mopride, buclizine, clebopride, cyclizine, dimenhydrinate, tablet comprising an immediate-release layer and a con diphenidol, dolasetron, meclizine, methallatal, metopi trolled-release layer, wherein the immediate-release layer mazine, nabilone, oxyperndyl, pipamazine, Scopolamine, comprises and/or the chronic-release layer comprise a stimu Sulpiride, tetrahydrocannabinol, thiethylperazine, thioprop lant agent. In one embodiment, the controlled-release layer erazine, tropisetron, droperidol, haloperidol, prochlopera comprises an opioid agent. In yet a further embodiment, the Zine, metoclopramide, diphenhydramine, cannabis, mida controlled-release layer further comprises an effective US 2012/020 1888 A1 Aug. 9, 2012

amount of a second or same stimulant agent as compared to 0181. In another embodiment an a composition comprises the immediate-release layer. In yet another embodiment, the an effective amount of each of an opioid agent (Such as immediate-release layer and/or the controlled-release layer hydrocodone, propoxyphene, fentanyl or oxycodone or a further comprises an antiemetic agent. In a further embodi pharmaceutically acceptable salt thereof); a barbiturate agent ment the immediate-release layer comprises an effective (such as butalbital or a pharmaceutically acceptable salt amount of one or more of an opioid agent, a stimulant agent thereof); a stimulantagent (such as modafinil or caffeine or a and an antiemetic agent. In another further embodiment a pharmaceutically acceptable salt thereof); and optionally a controlled-release layer comprises an effective amount of one non-opioid agent (Such as acetaminophen or naproxen or a or more of an opioid agent, a stimulant agent, and an anti pharmaceutically acceptable salt thereof). In some embodi emetic agent. In some embodiments the composition further ments the composition further comprises an antiemetic (Such comprises an effective amount of an opioid antagonist agent as promethazine or a pharmaceutically acceptable salt or abuse deterrent agent. thereof). 0177. In a specific embodiment a composition is provided 0182. In one embodiment, such a composition is in the that comprises hydrocodone or oxycodone, or a pharmaceu form of a bi-layer tablet, wherein the composition comprises tically acceptable salt thereof, modafinil or caffeine or a phar an effective amount of an opioid agent, a non-opioid analge maceutically acceptable Salt thereof and optionally promet sic agent, a barbiturate agent, a stimulantagent and optionally hazine or a pharmaceutically acceptable salt thereof. an antiemetic agent. In one embodiment the bi-layer tablet 0178. In some embodiments compositions comprise a bar comprises an immediate-release layer and a controlled-re biturate active agent. Barbiturate agents useful in the methods lease layer. In a further embodiment the immediate-release and compositions include, but are not limited to, Allobarbital, layer comprises an effective amount of one or more of an Alphenal. Amobarbital, Aprobarbital, Barbexaclone, Bar opioid agent, a non-opioid analgesic agent, a barbiturate bital, Bralobarbital, Butabarbital, Butalbital, Butobarbital, agent, a stimulant agent and an antiemetic agent. In another Butallylonal, Crotylbarbital, Cyclobarbital, Cyclopal, Ethal further embodiment a controlled-release layer comprises an lobarbital, Febarbamate, Heptabarbital, Hexethal, Hexobar effective amount of one or more of an opioid agent, a non bital, Mephobarbital, Metharbital, Methohexital, Methylphe opioid analgesic agent, a barbiturate agent, a stimulant agent nobarbital, Narcobarbital, Nealbarbital, Pentobarbital, and an antiemetic agent. In some embodiments a composition Primidone, Probarbital, Propallylonal, Proxibarbal, Proxi further comprises an effective amount of an opioidantagonist barbital, Reposal, Secbutabarbital, Secobarbital, Sigmodal, agent or abuse deterrent agent. In a specific embodiment a Talbutal. Thialbarbital. Thiamylal, Thiobarbital. Thiobut composition comprises hydrocodone, propoxyphene or oxy abarbital. Thiopental, Valofane, Vinbarbital, Vinylbital, 1,3- codone, or a pharmaceutically acceptable salt thereof; butal dimethoxymethyl 5,5-diphenyl-barbituric acid (DMMDPB). bital, naproxen, caffeine or a pharmaceutically acceptable salt 1-monomethoxymethyl 5,5-diphenylbarbituric acid thereof, and optionally promethazine or a pharmaceutically (MMMDPB), a diphenyl-barbituric acid (DPB) and their pre acceptable salt thereof. cursors, derivatives and analogs or a combination thereof and 0183 In another embodiment a composition comprises an a pharmaceutically acceptable salt thereof. effective amount of an opioid agent (hydrocodone or oxyc 0179. In another embodiment, a composition is provided odone or a pharmaceutically acceptable salt thereof); and a that comprises an effective amount of an opioid agent (Such as barbiturate agent (such as butalbital or a pharmaceutically hydrocodone, propoxyphene, fentanyl or oxycodone, or a acceptable salt thereof). In some embodiments a composition pharmaceutically acceptable salt thereof); a non-opioid agent further comprises an antiemetic (such as promethazine or a (such as acetaminophen or naproxen, or a pharmaceutically pharmaceutically acceptable salt thereof). In a further the acceptable salt thereof); a barbiturate agent (such as butalbi composition is in the form of a bi-layer tablet, wherein the tal, or a pharmaceutically acceptable salt thereof) and option composition comprises an effective amount of each of an ally an antiemetic (such as promethazine, or a pharmaceuti opioid analgesic agent, a barbiturate agent, and optionally an cally acceptable salt thereof). antiemetic agent. In one embodiment the bi-layer tablet com 0180. In a further embodiment a composition is in the prises an immediate-release layer and a controlled-release form of a bilayer tablet, wherein the composition comprises layer. In a further embodiment the immediate-release layer an effective amount of each of an opioid agent, a non-opioid comprises an effective amount of each of one or more of an analgesic agent, a barbiturate agent and an antiemetic agent. opioid analgesic agent, a barbiturate agent, or an antiemetic In one embodiment the bi-layer tablet comprises an immedi agent. In another a further embodiment a controlled-release ate-release layer and a controlled-release layer. In a further layer comprises an effective amount of each of one or more of embodiment the immediate-release layer comprises an effec an opioid analgesic agent, a barbiturate agent, or an anti tive amount of one or more of an opioid agent, a non-opioid emetic agent. In some the composition further comprises an analgesic agent, a barbiturate agent and an antiemetic agent. effective amount of an opioidantagonist agent or abuse deter In another further embodiment a controlled-release layer rent agent. In a specific embodimenta composition comprises comprises an effective amount of one or more of an opioid butalbital, hydrocodone or oxycodone, or a pharmaceutically agent, a barbiturate agent, a non-opioid analgesic agent, and acceptable salt thereofandoptionally promethazine or a phar an antiemetic agent. In some embodiments a composition maceutically acceptable salt thereof. further comprises an effective amount of an opioid antagonist 0184. In another embodiment a composition comprises an agent or abuse deterrent agent. In a specific embodiment a effective amount of a non-opioid agent (Such as acetami composition comprises hydrocodone or oxycodone, or a nophen, naproxen or ibuprofen or a pharmaceutically accept pharmaceutically acceptable salt thereofacetaminophen, or a able salt thereof); a barbiturate agent (such as butalbital or a pharmaceutically acceptable salt thereof, butalbital or a phar pharmaceutically acceptable salt thereof); and an antiemetic maceutically acceptable Salt thereof and optionally promet (such as promethazine or a pharmaceutically acceptable salt hazine or a pharmaceutically acceptable salt thereof. thereof). In one embodiment, the composition comprises US 2012/020 1888 A1 Aug. 9, 2012 about 50 mg butalbital or a pharmaceutically acceptable salt bi-layer tablet comprises an immediate-release layer and a thereof, about 325 mg N-Acetyl-p-Aminophenol or a phar controlled-release layer. In a further embodiment the imme maceutically acceptable salt thereof, and about 12.5 mg diate-release layer comprises an effective amount of each of promethazine or a pharmaceutically acceptable salt thereof. one or more of a non-opioid agent, a stimulant agent or an In one embodiment, the promethazine salt is promethazine antiemetic agent. In another further embodiment the con HC1. trolled-release layer comprises an effective amount of each of 0185. In another embodiment a composition comprises an one or more of a non-opioid agent, stimulant agent or an effective amount of each of a non-opioid agent (Such as antiemetic agent. In a specific embodiment a composition acetaminophen, naproxen or ibuprofen or a pharmaceutically comprises naproxen or a pharmaceutically acceptable salt acceptable salt thereof); a barbiturate agent (such as butalbital thereof and caffeine or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof); and a stimu thereof and optionally promethazine or a pharmaceutically lant agent (such as modafinil or caffeine or a pharmaceuti acceptable salt thereof. cally acceptable salt thereof). In some embodiments the com 0188 The present compositions can comprise one or more position further comprises an antiemetic (Such as beta blockers, serotonin receptor agonists, vasoconstrictors, promethazine or a pharmaceutically acceptable salt thereof). anti-platelet agents, anti-convulsants, triptans, ergots, or cal In a further embodiment an effective amount of a composition citonin-gene-related peptide (CGRP) receptor antagonists. is in the form of a bi-layer tablet, wherein the composition 0189 Non-limiting examples of beta blockers are acebu comprises an effective amount of each of a non-opioid anal tolol, arotinolol, atenolol, betaxolol, bisoprolol, butoxamine, gesic agent, a barbiturate agent, a stimulantagent and option carvedilol, carteolol, esmolol, carteolol, carvedilol, labetalol, ally an antiemetic agent. In one embodiment the bi-layer levobunolol, mepindolol, metoprolol, nebivolol, nadolol, tablet comprises an immediate-release layer and a controlled oXprenolol, penbutolol, propranolol, pindolol, Sotalol, and release layer. In a further embodiment the immediate-release timolol. In one embodiment, the beta blocker is propanolol. layer comprises an effective amount of one or more of a 0190. Non-limiting examples of serotonin receptor ago non-opioid analgesic agent, a barbiturate agent, a stimulant nists are buspirone, mescaline, psilocybin, cisapride, triptans, agent oran antiemetic agent. In another a further embodiment or lysergic acid diethylamide. Non-limiting examples of a controlled-release layer comprises one or more of a non vasoconstrictors are isometheptene mucate, amphetamines, opioid analgesic agent, a barbiturate agent, stimulantagent or antihistamines, cocaine, caffeine, pseudoephedrine, ergine, an antiemetic agent. In a specific embodiment a composition methylphenidate, psilocybin, or stimulants such as amphak comprises butalbital, naproxen, caffeine, or a pharmaceuti ines (e.g., drugs effective to glutagatergic AMPA receptors cally acceptable salt thereof and optionally promethazine or a and benzoylpiperidine derivatives). Non-limiting examples pharmaceutically acceptable salt thereof. of amphetamines and antihistamines are disclosed herein 0186. In another embodiment a composition comprises an above. effective amount of a barbiturate agent (such as butalbital or 0191 Non-limiting examples of anti-platelet agents are a pharmaceutically acceptable salt thereof) and a stimulant acetylsalycyclic acid, clopidogrel, ticlopidine, cilostaZol. agent (Such as modafinil or caffeine or a pharmaceutically abciximab, eptifibatide, tirofiban defibrotide and dipy acceptable salt thereof). In some embodiments the composi ridamole. tion further comprises an antiemetic (Such as promethazine or 0.192 Non-limiting examples of anti-convulsants are topi a pharmaceutically acceptable salt thereof). In another ramate, divaprex, pehnobarbital, methlyphenobarbital, meth embodiment, a composition is in the form of a bi-layer tablet, arbital, barbexaclone, Stiripentol, clobazam, clonazepam, wherein the composition comprises an effective amount of cloraZepate, diazepam, midazolam, lorazepam, nitrazepam, each of a barbiturate agent, a stimulant agent and optionally temazepam, nimetazepam, potassium bromide, felbamate, an antiemetic agent. In one embodiment the bi-layer tablet carbamazepine, oXcarbazepine, vigabatrin, progabide, tiaga comprises an immediate-release layer and a controlled-re bine, gabapentin, prgabalin, ethotoin, phenyloin, mepheny lease layer. In a further embodiment the immediate-release loin, fosphenyloin, paramethadione, trimethadione, ethadi layer comprises an effective amount of each of one or more of one, beclaminde, primidone, brivaracetam, levetiracetam, a barbiturate agent, a stimulant agent or an antiemetic agent. seletracetam, ethSuximide, phesuximide, meSuximide, aceta In another a further embodiment a controlled-release layer Zolamide, Sulthiame, methazolamide, Zonisamide, lamot comprises an effective amount of each of one or more of a rigine, pheneturide, phenacemide, Valpromide, Valnoctamide barbiturate agent, stimulantagent or an antiemetic agent. In a and pharmaceutically acceptable salt thereof. specific embodiment a composition comprises butalbital or a 0193 Non-limiting examples of calcitonin-gene-related pharmaceutically acceptable salt thereof, caffeine or a phar peptide (CGRP) receptor antagonists are MK-0974, CGRP8 maceutically acceptable Salt thereof and optionally promet 37, BIBN 4096 BS, quinine, nitrobenzamide, 4-oxobutana hazine or a pharmaceutically acceptable salt thereof. mides, cyclopropane derivatives, and benzimidazolinyl pip 0187. In another embodiment a composition comprises an eridines. effective amount of a non-opioid agent (such as ibuprofen or 0194 Non-limiting examples of triptans are naratriptan, naproxen or a pharmaceutically acceptable salt thereof) and a almotriptan, Sumatriptan, Zolmitriptan, eletriptan, froVatrip stimulant agent (Such as modafinil or caffeine or a pharma tan, or rizatriptan, or a pharmaceutically acceptable salt ceutically acceptable salt thereof). In some embodiments the thereof. In some embodiments, a oral dosage form (e.g., composition further comprises an antiemetic (Such as bilayer tablet) is provided comprising one or more triptanand promethazine or a pharmaceutically acceptable salt thereof). one or more antiemetic. In one embodiment, the triptan is In one embodiment, the composition is in the form of a Sumatriptan or a pharmaceutically acceptable salt thereof, bi-layer tablet, wherein the composition comprises an effec and the antiemetic is promethazine or a pharmaceutically tive amount of each of a non-opioid agent, a stimulant agent acceptable salt thereof. In a further embodiment, the compo and optionally an antiemetic agent. In one embodiment the sition is a bilayer tablet comprising a controlled-release layer US 2012/020 1888 A1 Aug. 9, 2012

and an immediate-release layer, wherein the controlled-re mg, 44 mg., 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, lease layer comprises an effective amount of the Sumatriptan 47.5 mg, 48 mg, 48.5 mg. 49 mg, 49.5 mg, 50 mg, 55 mg, 60 or a pharmaceutically acceptable salt thereof and the imme mg, 65mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, or 100 diate release layer comprises an effective amount of the mg. In one embodiment the opioid analgesic agent is hydro promethazine or a pharmaceutically acceptable salt thereof. codone or oxycodone or salt thereof. In another embodiment In one embodiment, the Sumatriptan salt is Sumatriptan Suc the opioid analgesic agent is present in a bi-layer tablet that cinate. comprises an immediate release and a controlled release 0.195 Non-limiting examples of ergots are ergotamine, layer. methysergide, Zonisamide and pharmaceutically acceptable 0202 In another embodiment a composition is provided salt thereof. In one embodiment, the compositions comprises: that comprises a non-opioid analgesic that is presentata dose Sumatriptan or a pharmaceutically acceptable salt thereof in a from about 200 mg to about 1000 mg, including but not dosage from about 25 mg to about 100 mg and promethazine limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg. or a pharmaceutically acceptable salt thereof in a dosage of 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg. from about 12.5 mg to about 50 mg. 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg. 0196. In various embodiments, compositions of the inven 300 mg. 305 mg. 310 mg, 315 mg. 320 mg, 325 mg, 326 mg, tion are administered in a single dosage form which com 326.5 mg, 327 mg, 327.5 mg. 328 mg, 328.5 mg, 329 mg, prises active agents as disclosed in Table 1 or Table 2 and one 329.5 mg, 330 mg. 330.5 mg, 331 mg, 331.5 mg, 332 mg, or more beta blockers, serotonin receptor agonists, vasocon 332.5 mg, 333 mg, 333.5 mg. 334 mg. 334.5 mg, 335 mg. strictors, anti-platelet agents, anti-convulsants, triptans, ergot 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, alkaloids, and calcitonin-gene-related peptide (CGRP) recep 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, tor antagonists. 341.5 mg., 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. 0197) In some embodiments, a single dosage form is a 344.5 mg., 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, multilayered tablet which comprises one or more pharmaceu 347.5 mg, 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. tically active agents which includes one or more beta block 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, ers, serotonin receptor agonists, vasoconstrictors, anti-plate 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, let agents, anti-convulsants, triptans, ergot alkaloids, or 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, calcitonin-gene-related peptide (CGRP) receptor antago 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, nists. In one embodiment, a multilayer tablet comprises at 362.5 mg, 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. least one immediate release layer and at least one controlled 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, released layer. compositions of the invention can be admin 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, istered using other dosage forms disclosed herein. 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. 0198 Inyet other embodiments, compositions comprising 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, one or more active agents disclosed herein (e.g., Table 1 or 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, Table 2) of the invention are administered prior to, concurrent 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. with, or after administration of one or more beta blockers, 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, serotonin receptor agonists, vasoconstrictors, anti-platelet 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. agents, anti-convulsants, triptans, ergot alkaloids, or calcito 390.5 mg. 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, nin-gene-related peptide (CGRP) receptor antagonists. In 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, Some embodiments the present methods for treating or pre 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, venting pain further comprise administering an effective 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg. 425 mg. amount of one or more beta blockers, serotonin receptor 430 mg, 435 mg. 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. agonists, vasoconstrictors, anti-platelet agents, anti-convul 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. sants, triptans, ergots, or CGRP receptor antagonists. 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. (0199 Dosage 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. 0200. In various embodiments compositions of the inven 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg. tion comprise multiple active agents at the same or different 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. dosages. In some embodiments, the analgesic components 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. may vary in dosages as further described herein, and the 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. antihistamine orantiemetic dosage can be adjusted according 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. to the particular analgesics used. 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. 0201 For example, in various embodiments compositions 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. are provided that comprise an opioid analgesic agent that is 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. present at from about a dose of about 1.0 mg to about 100 mg. 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. including but not limited to 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg. 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. 4.0 mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 960 mg,965 mg, 970 mg,975 mg,980 mg,985 mg, 990 mg. mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg. 995 mg. or 1000 mg. In one embodiment the non-opioid 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 analgesic agent is presentina bi-layer tablet that comprises an mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg. immediate release and a controlled release layer. 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 0203. In another embodiment the compositions comprise mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. 30.5 an antiemetic or antihistamine agent (e.g., promethazine) mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg, present at a dose from about 0.5 mg to about 200 mg of 36.5 mg, 37 mg, 37.5 mg. 38 mg, 38.5 mg. 39 mg, 39.5 mg, 40 promethazine or a pharmaeutically acceptable salt thereof, mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg. US 2012/020 1888 A1 Aug. 9, 2012

2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg. 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg. 390.5 mg. 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg. 425 mg. mg, 43 mg. 44 mg. 45 mg, 46 mg, 47 mg, 48 mg. 49 mg, 50 430 mg, 435 mg. 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg. mg, or 200 mg. In one embodiment the antiemetic or antihis 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. tamine agent is present in a bi-layer tablet that comprises an 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. immediate release and a controlled release layer. 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. 0204. In one embodiment, the compositions of the inven 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. tion comprise an opioid analgesic agent (Such as hydroc 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. odone), a pharmaceutically acceptable salt or its thiosemicar 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. baZone, p-nitrophenylhydraZone, o-methyloxime, 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. semicarbazone, or bis(methylcarbamate) (each of the forego 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. ing being a hydrocodone agent or derivative); acetami 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. nophen; and promethazine or salt thereof. Furthermore, the 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. opioid analgesic agent is present in a range of from about 1.0 960 mg,965 mg, 970 mg,975 mg,980 mg,985 mg, 990 mg. mg to about 100 mg, including but not limited to 1 mg, 1.5 mg. 995 mg. or 1000 mg. In addition, the promethazine or salt 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 thereof is present in the composition at a dose between about mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg. 0.5 mg to about 200 mg, including but not limited to 0.5 mg. 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 5.0 mg, 5.5 mg, 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg. mg, 19 mg, 19.5 mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg. 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg. 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg. mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 30 mg. 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 33.5 mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg. 38 mg, 38.5 mg. 39 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg. mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 43 mg, 43.5 mg., 44 mg. 44.5 mg, 45 mg, 45.5 mg, 46 mg, mg, 31 mg, 32 mg, 33 mg, 34 mg. 35 mg, 36 mg, 37 mg, 38 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg. 49 mg, 49.5 mg, 50 mg, 39 mg, 40 mg, 41 mg, 12 mg. 43 mg, 44 mg. 45 mg, 46 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 95 mg. or 100 mg. mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, 100 mg, 105 mg, 110 0205 Furthermore, in various embodiments, the compo mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 sitions of the invention comprise acetaminophen or a phar mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 maeutically acceptable salt thereof is present in the compo mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one embodiment sition at a range of from about 200 mg to about 1000 mg. hydrocodone or a salt thereof, acetaminophen or a salt including but not limited to 200 mg, 205 mg, 210 mg, 215 mg. thereof, and promethazine or a salt thereof are present in a 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg. bi-layer tablet that comprises an immediate release and a 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg. controlled release layer. In another embodiment the immedi 290 mg, 295 mg, 300 mg, 305 mg. 310 mg, 315 mg, 320 mg. ate release layer comprises promethazine or a salt thereof and 325 mg,326 mg,326.5 mg. 327 mg, 327.5 mg. 328 mg,328.5 the controlled release layer comprises hydrocodone or a salt mg,329 mg,329.5 mg,330 mg. 330.5 mg, 331 mg,331.5 mg. thereof and acetaminophen or a salt thereof. 332 mg,332.5 mg, 333 mg,333.5 mg,334 mg. 334.5 mg,335 0206. In various embodiments, the compositions of the mg, 335.5 mg, 336 mg,336.5 mg, 337 mg,337.5 mg,338 mg, invention comprise an opioid analgesic agent (such as hydro 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, codone or oxycodone or a pharmaeutically acceptable salt 341.5 mg, 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. thereof), acetaminophen or or a pharmaeutically acceptable 344.5 mg, 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, salt thereof and promethazine or or a pharmaeutically accept 347.5 mg. 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. able salt thereof, wherein the composition comprises the 350.5 mg. 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, respective agents, opioid analgesic agent: acetaminophenora 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, salt thereof: promethazine or or a pharmaeutically acceptable 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, salt thereof in a ratio by weight of about (1 to 2): (40 to 45):(1 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, to 2), such as about 1:40:1, 1:40:1.1, 1:40:1.2, 1:40:1.3, 1:40: 362.5 mg. 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. 1.4, 1:40:1.5, 1:40:1.6, 1:40:1.7, 1:40:1.8, 1:40:1.9, 1:40:2, 365.5 mg. 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, 1.1:40:1, 1.2:40:1, 1.3:40:1, 1.4:40:1, 1.5:40:1, 1.6:40:1, 1.7: 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, 40:1, 1.8:40:1, 1.9:40:1, 2:40:1, 1:41:1, 1:41:1. 1, 1:41:1.2, 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. 1:41:1.3, 1:41:14, 1:41:1.5, 1:41:1.6, 1:41:1.7, 1:41:1.8, US 2012/020 1888 A1 Aug. 9, 2012

1:41:19, 1:41:2, 1.1:41:1, 1.2:41:1, 1.3:41:1, 1.4:41:1, 1.5: semicarbazone, or bis(methylcarbamate) (each of the forego 41:1, 1.6:41:1, 1.7:41:1, 1.8:41:1, 1.9:41:1, 2:41:1, 1:42:1, ing being a hydrocodone agent or derivative); acetaminophen 1:42:1.1, 1:42:1.2, 1:42:1.3, 1:42:14, 1:42:1.5, 1:42:1.6, or a salt thereof; and promethazine or a salt thereof. Further 1:42:1.7, 1:42:1.8, 1:42:1.9, 1:42:2, 1.1:42:1, 1.2:42:1, 1.3: more, the oxycodone or a salt thereof is present in a range of 42:1, 1.4:42:1, 1.5:42:1, 1.6:42:1, 1.7:42:1, 1.8:42:1, 19:42: about 1 mg to about 200 mg, including but not limited to 1.0 1, 2:42:1, 1:43:1, 1:43:1. 1, 1:43:1.2, 1:43:1.3, 1:43:14, 1:43: mg, 1.5 mg, 2.5 mg, 3.0 mg. 4.0 mg. 4.5 mg, 5.0 mg, 5.5 mg. 1.5, 1:43:16, 1:43:17, 1:43:18, 1:43:19, 1:43:2, 1.1:43:1, 6.0 mg. 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 1.2:43:1, 1.3:43:1, 14:43:1, 1.5:43:1, 1.6:43:1, 1.7:43:1, 1.8: mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 43:1, 19:43:1, 2:43:1, 1:43.1:1, 1:43.1:1.1, 1:43.1:1.2, 1:43. mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 1:1.3, 1:43.1:14, 1:43.1:1.5, 1:43.1:1.6, 1:43.1:1.7, 1:43.1:1. mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg or 20 mg, 30 8, 1:43.1:1.9, 1:43.1:2, 1.1:43.1:1, 1.2:43.1:1, 1.3:43.1:1, 1.4: mg, 40 mg, 50 mg, 70 mg, 100 mg, 130 mg, 160, 190 mg, 200 43.1:1, 1.5:43.1:, 1.6:43.1:, 1.7:43.1:1, 1.8:43.1:, 1.9:43.1:1, mg. Furthermore, the acetaminophen or a salt thereof is in a 2:43.1:1, 1:43.2:1, 1:43.2:1. 1, 1:43.2:1.2, 1:43.2:1.3, 1:43.2: range of between about 200 mg to about 1000 mg, including 1.4, 1:43.2:1.5, 1:43.2:1.6, 1:43.2:1.7, 1:43.2:1.8, 1:43.2:1.9, but not limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg. 1:43.2:2, 1.1:43.2:1, 1.2:43.2:1, 1.3:43.2:, 1.4:43.2:, 1.5:43. 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg. 2:1, 1.6:43.2:1, 1.7:43.2:1, 1.8:43.2:1, 19:43.2:1, 2:43.2:1, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg. 1:43.3:1, 1:43.3:11, 1:43.3:1.2, :43.3:1.3, :43.3:14, :43.3:1. 295 mg, 300 mg. 305 mg. 310 mg, 315 mg, 320 mg. 325 mg. 5, 1:43.3:1.6, :43.3:17, 1:43.3:1.8, 1:43.3:19, 1:43.3:2, 1.1: 326 mg,326.5 mg, 327 mg, 327.5 mg. 328 mg,328.5 mg,329 43.3:1, 1.2:43.3:1, 1.3:43.3: 14:43.3:1, 1.5:43.3:1, 1.6:43. mg, 329.5 mg, 330 mg,330.5 mg, 331 mg, 331.5 mg, 332 mg, 3:1, 1.7:43.3:1, 1.8:43.3:1, 19:43.3:1, 2:43.3:1, 1:43.4:1, 332.5 mg, 333 mg, 333.5 mg. 334 mg. 334.5 mg, 335 mg. 1:43.4:1.1, :43.4:1.2, :43.4:1.3, :43.4:14, 1:43.4:1.5, :43.4:1. 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, 6, 1:43.4:1.7, 1:43.4:1.8, 1:43.4:1.9, 1:43.4:2, 1.1:43.4: , 1.2: 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, 43.4: , 1.3:43.4: , 1.4:43.4:1, 1.5:43.4: , 1.6:43.4:1, 1.7:43.4: 341.5 mg., 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. 1, 1.8:43.4:1, 19:43.4:1, 2:43.4:1, 1:43.5:1, :43.5:1.1, :43.5: 344.5 mg., 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, 1.2, 43.5:1.3, 1:43.5:14, :43.5:1.5, 1:43.5:1.6, 1:43.5:1.7, 347.5 mg, 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. 1:43.5:1.8, 1:43.5:19, 1:43.5:2, 1.1:43.5:, 1.2:43.5: , 1.3:43. 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, 5:1, 14:43.5: , 1.5:43.5:1, 1.6:43.5:1, 1.7:43.5:1, 1.8:43.5:1, 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, 1.9:43.5:1, 2:43.5:1, 1:43.6:1, :43.6:1.1, :43.6:1.2, 1:43.6:1. 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 3, :43.6:14, 1:43.6:1.5, 1:43.6:1.6, 1:43.6:1.7, 1:43.6:1.8, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 1:43.6:19, 1:43.6:2, 1.1:43.6: , 1.2:43.6:1, 1.3:43.6: , 1.4:43. 362.5 mg, 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. 6:1, 1.5:43.6:1, 1.6:43.6:1, 1.7:43.6:1, 1.8:43.6:1, 19:43.6:1, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, 2:43.6:1, 1:43.7:1:43.7:11, 1:43.7:12, 1:43.7:1.3, 1:43.7:1. 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, 4, 1:43.7:1.5, 1:43.7:16, 1:43.7:17, 1:43.7:18, 1:43.7:19, 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. 1:43.7:2, 1.1:43.7:1, 1.2:43.7:1, 1.3:43.7:1, 14:43.7:1, 1.5: 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 43.7:1, 1.6:43.7:1, 1.7:43.7:1, 1.8:43.7:1, 19:43.7:1, 2:43.7: 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, 1, 1:43.8:1, 1:43.8:1. 1, 1:43.8:1.2, 1:43.8:1.3, 1:43.8:14, 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. 1:43.8:1.5, 1:43.8:1.6, 1:43.8:1.7, 1:43.8:1.8, 1:43.8:1.9, 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, 1:43.8:2, 1.1:43.8:1, 1.2:43.8:1, 1.3:43.8:1, 14:43.8:1, 1.5: 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. 43.8:1, 1.6:43.8:1, 1.7:43.8:1, 1.8:43.8:1, 19:43.8:1, 2:43.8: 390.5 mg. 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 1, 1:43.9:1, 1:43.9:11, 1:43.9:12, 1:43.9:1.3, 1:43.9:14, 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, 1:43.9:1.5, 1:43.9:16, 1:43.9:17, 1:43.9:18, 1:43.9:19, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, 1:43.9:2, 1.1:43.9:1, 1.2:43.9:1, 1.3:43.9:1, 14:43.9:1, 1.5: 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg. 425 mg. 43.9:1, 1.6:43.9:1, 1.7:43.9:1, 1.8:43.9:1, 19:43.9:1, 2:43.9: 430 mg, 435 mg. 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. 1, 1:44:1, 1:44:1. 1, 1:44:1.2, 1:44:1.3, 1:44:14, 1:44:1.5, 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. 1:44:1.6, 1:44:1.7, 1:44:1.8, 1:44:1. 9, 1:442, 1.1:44:1, 1.2: 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. 44:1, 1.3:44:1, 1.4:44:1, 1.5:44:1, 1.6:44:1, 1.7:44:1, 1.8:44: 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. 1, 19:44:1, 2:44:1, 1:45:1, 1:45:1. 1, 1:45:1.2, 1:45:1.3, 1:45: 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg. 1.4, 1:45:1.5, 1:45:1.6, 1:45:1.7, 1:45:1.8, 1:45:19, 1:45:2, 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. 1.1:45:1, 1.2:45:1, 1.3:45:1, 1.4:45:1, 1.5:45:1, 1.6:45:1, 1.7: 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. 45:1, 1.8:45:1, 19:45:1, or 2:45:1. For example, in one 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. embodiment, the ratio of amounts for each active agent is 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. about (1): (43.33): (1.67) for hydrocodone or a salt thereof: 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. acetaminophen or a salt thereof: promethazine or a phar 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. maeutically acceptable salt thereof, respectively. In one 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. embodiment a pharmaceutically acceptable salt of hydroc 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. odone, acetaminophen orpromethazine is provided. In one 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. embodiment an opioid analgesic agent (such as hydrocodone 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. or oxycodone or a salt thereof), acetaminophen or a salt 960 mg,965 mg, 970 mg,975 mg,980 mg,985 mg, 990 mg. thereof, and promethazine or a salt thereof are present in a 995 mg. or 1000 mg. The compositions can further comprise bi-layer tablet that comprises an immediate release and a between about 0.5 mg to about 200 mg of an antihistamine controlled release layer. (e.g., promethazine or a salt thereof), including but not lim 0207. In another embodiment, the composition comprises ited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg. oxycodone, a pharmaceutically acceptable salt or its thi 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 osemicarbazone, p-nitrophenylhydraZone, o-methyloxime, mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg. US 2012/020 1888 A1 Aug. 9, 2012

11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg. 0209. In one embodiment, the compositions of the inven 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 tion comprise 6-8 mg of hydrocodone or a salt thereof (Such mg, 19 mg, 19.5 mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg. as about 6.0 mg., 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg., 6.5 mg., 6.6 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, or 8.0 mg.), mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 310-330 mg of acetaminophen (such as about 310 mg, 315 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg. 44 mg. 45 mg, 320 mg, or 325 mg), and 5-13 mg of promethazine or a mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg. 65 salt thereof (such as about 10 mg, 10.5 mg, 11.0 mg, 11.5 mg. mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, 100 mg, 105 12.0 mg, 12.5 mg, 13.0, mg, 13.5 mg, 14.0 mg, 14.5 mg, or 15 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg). In a further embodiment a pharmaceutically acceptable mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 salt of hydrocodone, acetaminophen or promethazine is pro mg, 180 mg, 185 mg, 190 mg, 195 mg. or 200 mg. In one vided. The hydrocodone and the acetaminophen can be for embodiment oxycodone or a salt thereof, acetaminophen or a mulated using conventional technologies to provide for an extended time release over a desired dosage interval. All or salt thereofand promethazine or a salt thereofare present in a some of the promethazine can be formulated for immediate bi-layer tablet that comprises an immediate release and a release to help abate common adverse effects associated with controlled release layer. the hydrocodone and acetaminophen including nausea, Vom 0208. In one embodiment, the composition comprises iting, other gastric upsets, skin rashes, allergic reactions such promethazine or a salt thereof in an amount of 12.5 mg. In one as Swelling, difficulty breathing, closing of throat, abdominal embodiment, the compositions of the invention comprise pain, unusual bleeding or bruising, sedation, CNS depression, oxycodone or a salt thereof, acetaminophen or a salt thereof or respiratory depression. In one embodiment hydrocodone, and promethazine or a salt thereof, wherein the composition acetaminophen; and promethazine are present in a bi-layer comprises the agents in a weight ratio of about (1 to 2): (40 to tablet that comprises an immediate release and a controlled 45): (1 to 2), respectively. In one embodiment a pharmaceu release layer. tically acceptable salt of oxycodone, acetaminophen orprom 0210. In one embodiment, the compositions of the inven ethazine is provided. For example, in one embodiment, the tion comprise from 1% to 20% by weight of an antihistamine weight ratio of amounts for each active agent is about (1): (such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%. 5%, (43.33): (1.67) for oxycodone or a salt thereof, acetami 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, nophen or a salt thereof and promethazine or a salt thereof, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, respectively. In one embodiment, the compositions of the 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, invention comprise an antihistamine (e.g., promethazine or a 19.5%, or 20%); from 10% to 80% by weight a non-opioid salt thereof) at a lower dosage than that which the antihista analgesic (such as 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, mine is administered alone. In one embodiment, the antihis 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, tamine is provided in the composition at a dosage to prevent 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, sedation, which may be observed with relatively higher dos 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, ages of promethazine or a salt thereof. Thus in some embodi 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, ments, promethazine is provided at 0.5 mg, 1.0 mg, 1.5 mg. 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 35.5%, 36%, 36.5%, 37%, 37.5%, 38%, 38.5%, 39%, 39.5%, mg, 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg. 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, 44%, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg. 44.5%, 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 49%, 49.5%, 50%, 50.5%, 51%, 51.5%, 52%, 52.5%, 53%, mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg. 53.5%, 54%, 54.5%, 55%, 55.5%, 56%, 56.5%, 57%, 57.5%, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 58%, 58.5%, 59%, 59.5%, 60%, 60.5%, 61%, 61.5%, 62%, mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 62.5%, 63%, 63.5%, 64%, 64.5%, 65%, 65.5%, 66%, 66.5%, mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg. 30 mg, 31 mg, 32 mg, 67%, 67.5%, 68%, 68.5%, 69%, 69.5%, 70%, 70.5%, 71%, 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 71.5%, 72%, 72.5%, 73%, 73.5%, 74%, 74.5%, 75%, 75.5%, mg, 12 mg, 43 mg, 44 mg. 45 mg, 46 mg, 47 mg, 48 mg, 49 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, 80%); mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 and from 1% to 20% by weight of an opioid analgesic (such mg, 90 mg.95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg. as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%. 5%, 5.5%, 6%, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg. 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg. 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 195 mg, or 200 mg. Therefore, an antihistamine orantiemetic 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or (e.g., promethazine or a salt thereof) can be provided at a 20%). In one embodiment an opioid analgesic agent, a non dosage that is effective for reducing adverse affects associ opioid analgesic and an antihistamine are present in a bi-layer ated with the opioid analgesic or non-opioid analgesic, but is tablet that comprises an immediate release and a controlled at a relative low enough dosage (e.g., given the Subject's release layer. weight) to prevent sedation associated with the antihistamine 0211. In one embodiment, the compositions of the inven orantiemetic. Examples of adverse effects include acute liver tion comprise 6-8 mg of oxycodone HCL (such as about 7.5 toxicity, allergic reactions such as Swelling, difficulty breath mg), 310-330 mg of acetaminophen (such as about 325 mg), ing, closing of throat, abdominal pain, nausea, unusual bleed and 6-15 mg of promethazine HCL (such as about 12.5 mg). ing or bruising. In one embodiment oxycodone or a salt The oxycodone HCL and the acetaminophen can be formu thereof, acetaminophen or a salt thereof, and promethazine or lated using conventional technologies to provide for an a salt thereofare present in a bi-layer tablet that comprises an extended time release over a desired dosage interval. All or immediate release and a controlled release layer. some of the promethazine can be formulated for immediate US 2012/020 1888 A1 Aug. 9, 2012 20 release. In one embodiment the composition is in the form of ponent of an immediate-release formulation. For example, in a bi-layer tablet comprising an immediate-release layer com a further embodiment, the immediate-release is in a capsule, prising promethazine HCL and a controlled-release layer and a tablet, a transdermal means, or achieved through injection, a controlled release layer comprising acetaminophen and intramuscular administration or other means disclosed oxycodone or a salt thereof. herein. In one embodiment an opioid analgesic agent, a 0212. In one embodiment, administration of the composi stimulant and an antihistamine are present in a bi-layer tablet tion disclosed herein that comprises an antiemetic agent (Such that comprises an immediate release and a controlled release as promethazine or a salt thereof) can produce an outcome in layer. In one embodiment the stimulant and an antihistamine a Subject, Such as reduced, abated or eliminated adverse are present in the immediate release layer and the opioid effects associated with the administration of an opioid agent analgesic agent is present in the controlled release layer. In or non-opioid agent, such as oxycodone HCL, hydrocodone another embodiment an opioid analgesic agent, a non-opioid bitartrate and acetaminophen. Reduced, abated or eliminated analgesic, a stimulant and an antihistamine are present in a adverse effects include but are not limited to including nau bi-layer tablet that comprises an immediate release and a sea, vomiting, other gastric upsets, skin rashes, allergic reac controlled release layer. In one embodiment the stimulant and tions such as Swelling, difficulty breathing, closing of throat, an antihistamine are present in the immediate release layer abdominal pain, unusual bleeding or bruising, sedation, CNS and the opioid analgesic agent and a non-opioid analgesic are depression, or respiratory depression or any combination present in the controlled release layer. thereof. 0217. In a further embodiment, a composition of the 0213 The dosages and concentrations of active agents in invention comprises: an effective amount of an opioid anal the compositions may be varied as desired, as further gesic agent; an antiemetic or antihistamine agent; and a described herein. Depending on the Subject and/or condition stimulantagent or a non-opioid agent, or both. In one embodi being treated and on the administration route, the active agent ment each agent is present at a dose of about 0.5 mg to about in a composition can generally be administered in dosages of 20 mg, 5 mg to 30 mg, 10 mg to 100 mg, including but not 0.01 mg to 500 mg per kg body weight per day, e.g. about 20 limited to about 0.5 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg/day for an average person. The dosage can be adjusted mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg. based on the mode of administration. A typical dosage may be 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg. one administration daily or multiple administrations daily. 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 0214. Of course for controlled-release dosage forms the mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 unit dose can be designed for administration over a defined mg, 20 mg, 25 mg., 30 mg., 35 mg, 40 mg. 45 mg, or 50 mg. In period of time. In some embodiments, dosage for one or a one embodiment an opioid analgesic agent, a stimulantandan combination of agents can be from about 0.01 to 5 mg, 1 to 10 antihistamine are present in a bi-layer tablet that comprises an mg, 5 to 20 mg, 10 to 50 mg, 20 to 100 mg, 50 to 150 mg, 100 immediate release and a controlled release layer. In one to 250 mg, 150 to 300 mg, 250 to 500 mg. 300 to 600 mg or embodiment the stimulant and an antihistamine are present in 500 to 1000 mg V/kg body weight. Dose levels can vary as a the immediate release layer and the opioid analgesic agent is function of the specific compound, the severity of the Symp present in the controlled release layer. toms and the susceptibility of the subject to adverse effects. 0218. In yet a further embodiment, the composition com 0215. In another embodiment a composition comprises prising: an effective amount of an opioid analgesic, a stimu multiple active agents at the same or different dosages, where lant and optionally an antiemetic or antihistamine. In one the composition comprises an effective amount of an opioid embodiment the composition comprises a stimulant at a dose analgesic; an antiemetic or antihistamine; and a stimulant. In of about 1 mg to about 350 mg, 5 mg to 25 mg, 10 mg to 50 Some embodiments the composition may further comprise a mg, 25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mg to barbiturate or a non-opioid active agent, or both. The dosage 350 mg, including but not limited to about 1.0 mg, 1.0 mg, 1.5 can be adjusted according to the particular actives selected. mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg. 6.0 mg., 6.5 mg, 7.0 mg. 0216. In one embodiment, a composition comprises an 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 effective amount of an opioid analgesic; an antiemetic or mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg. antihistamine; and a stimulant. In this embodiment the anti 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, emetic or an antihistamine (e.g., promethazine or a salt 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg. thereof), that is present at about 0.5 mg to about 60 mg. 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg. including but not limited to a dose of about 0.5 mg, 1.0 mg. 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg. 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg. mg, 5.5 mg, 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg. 260 mg, 270 mg, 280 mg, 290 mg. 300 mg. 310 mg, 320 mg. 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg. 330 mg, 340 mg. or 350 mg. In one embodiment an opioid 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 analgesic agent, a stimulant and an antihistamine are present mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 in a bi-layer tablet that comprises an immediate release and a mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg. controlled release layer. In one embodiment the stimulant and 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 an antihistamine are present in the immediate release layer mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, and the opioid analgesic agent is present in the controlled 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 release layer. mg, 41 mg, 12 mg, 43 mg, 44 mg. 45 mg, 46 mg, 47 mg, 48 0219. In various embodiments, a composition of the mg, 49 mg, 50 mg, 55 mg, 60 mg. In one embodiment, the invention comprises: an opioid analgesic, a stimulant, and an antiemetic or antihistamine is promethazine or a salt thereof. antiemetic or antihistamine, wherein the relative ratio by In various other embodiments, the antihistamine or anti weight of each of an opioid: a stimulant: an antiemetic or emetic is one described herein above. As described herein, in antihistamine is about (1 to 2): (40 to 45):(1 to 2), such as Some embodiments, the antihistamine orantiemetic is a com about 1:40:1, 1:40:1. 1, 1:40:1.2, 1:40:1.3, 1:40:1.4, 1:40:1.5, US 2012/020 1888 A1 Aug. 9, 2012 21

1:40:1.6, 1:40:1.7, 1:40:1.8, 1:40:19, 1:40:2, 1.1:40:1, 1.2: non-opioid (such as acetaminophen or naproxen salt thereof); 40:1, 1.3:40:1, 14:40:1, 1.5:40:1, 1.6:40:1, 1.7:40:1, 1.8:40: and a barbiturate (such as butalbital or a salt thereof). In some 1, 19:40:1, 2:40:1, 1:41:1, 1:41:1. 1, 1:41:1.2, 1:41:1.3, 1:41: embodiments the compositions further comprise an anti 1.4, 1:41:1.5, 1:41:1.6, 1:41:1.7, 1:41:1.8, 1:41:19, 1:41:2, emetic (such as promethazine or a salt thereof). In some 1.1:41:1, 1.2:41:1, 1.3:41:1, 1.4:41:1, 1.5:41:1, 1.6:41:1, 1.7: embodiments the composition further comprises a stimulant 41:1, 1.8:41:1, 1.9:41:1, 2:41:1, 1:42:1, 1:42:1. 1, 1:42:1.2, agent. In some embodiments the barbiturate is present at a 1:42:1.3, 1:42:14, 1:42:1.5, 1:42:1.6, 1:42:1.7, 1:42:1.8, dose of 1 mg to about 350 mg, 5 mg to 25 mg, 10 mg to 50 mg. 1:42:19, 1:42:2, 1.1:42:1, 1.2:42:1, 1.3:42:1, 1.4:42:1, 1.5: 25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mg to 350 42:1, 1.6:42:1, 1.7:42:1, 1.8:42:1, 1.9:42:1, 2:42:1, 1:43:1, mg, including but not limited to about 1.0 mg, 1.0 mg, 1.5 mg. 1:43:11, 1:43:1.2, 1:43:1.3, 1:43:14, 1:43:1.5, 1:43:1.6, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 1:43:17, 1:43:18, 1:43:19, 1:43:2, 1.1:43:1, 1.2:43:1, 1.3: mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg. 43:1, 1.4:43:1, 1.5:43:1, 1.6:43:1, 1.7:43:1, 1.8:43:1, 19:43: 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 1, 2:43:1, 1:43.1:1, 1:43.1:1. 1, 1:43.1:1.2, 1:43.1:1.3, 1:43.1: mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 1.4, 1:43.1:1.5, 1:43.1:1.6, 1:43.1:1.7, 1:43.1:1.8, 1:43.1:1.9, mg, 19 mg, 19.5 mg, 20 mg, 25 mg. 30 mg, 35 mg, 40 mg, 45 1:43.1:2, 1.1:43.1:1, 1.2:43.1:1, 1.3:43.1:1, 1.4:43.1:1, 1.5: mg, 50 mg. 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 43.1:1, 1.6:43.1:1, 1.7:43.1:1, 1.8:43.1:1, 19:43.1:1, 2:43.1: mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 1, 1:43.2:1, 1:43.2:1. 1, 1:43.2:1.2, 1:43.2:1.3, 1:43.2:14, mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 1:43.2:1.5, 1:43.2:1.6, 1:43.2:1.7, 1:43.2:1.8, 1:43.2:1.9, mg, 270 mg, 280 mg, 290 mg. 300 mg. 310 mg. 320 mg. 330 1:43.2:2, 1.1:43.2:1, 1.2:43.2:1, 1.3:43.2:1, 1.4:43.2:1, 1.5: mg, 340 mg, or 350 mg. 43.2:1, 1.6:43.2:1, 1.7:43.2:1, 1.8:43.2:1, 19:43.2:1, 2:43.2: 0221. In another embodiment the compositions comprise 1, 1:43.3:1, 1:43.3:11, 1:43.3:12, 1:43.3:1.3, 1:43.3:14, an effective amount of an opioid (such as hydrocodone, fen 1:43.3:1.5, 1:43.3:16, 1:43.3:17, 1:43.3:18, 1:43.3:19, tanyl or oxycodone or a salt thereof); a non-opioid agent (Such 1:43.3:2, 1.1:43.3:1, 1.2:43.3:1, 1.3:43.3:1, 14:43.3:1, 1.5: as acetaminophen or naproxen or a salt thereof); and a barbi 43.3:1, 1.6:43.3:1, 1.7:43.3:1, 1.8:43.3:1, 19:43.3:1, 2:43.3: turate (such as butalbital or a salt thereof). In one embodiment 1, 1:43.4:1, 1:43.4:1. 1, 1:43.4:1.2, 1:43.4:1.3, 1:43.4:14, the opioid agent (Such as hydrocodone or oxycodone or a salt 1:43.4:1.5, 1:43.4:1.6, 1:43.4:1.7, 1:43.4:1.8, 1:43.4:1.9, thereof) is present in a range of about 1 mg to about 200 mg. 1:43.4:2, 1.1:43.4:1, 1.2:43.4:1, 1.3:43.4:1, 1.4:43.4:1, 1.5: including but not limited to 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg. 43.4:1, 1.6:43.4:1, 1.7:43.4:1, 1.8:43.4:1, 19:43.4:1, 2:43.4: 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 1, 1:43.5:1, 1:43.5:1. 1, 1:43.5:1.2, 1:43.5:1.3, 1:43.5:14, mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg. 1:43.5:1.5, 1:43.5:1.6, 1:43.5:1.7, 1:43.5:1.8, 1:43.5:1.9, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 1:43.5:2, 1.1:43.5:1, 1.2:43.5:1, 1.3:43.5:1, 14:43.5:1, 1.5: mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 43.5:1, 1.6:43.5:1, 1.7:43.5:1, 1.8:43.5:1, 19:43.5:1, 2:43.5: mg, 19 mg, 19.5 mg or 20 mg, 30 mg, 40 mg, 50 mg, 70 mg. 1, 1:43.6:1, 1:43.6:1. 1, 1:43.6:1.2, 1:43.6:1.3, 1:43.6:14, 100 mg, 130 mg, 160, 190 mg, 200 mg. Furthermore, the 1:43.6:1.5, 1:43.6:1.6, 1:43.6:1.7, 1:43.6:1.8, 1:43.6:1.9, non-opioid agent (Such as acetaminophen or naproxen or a 1:43.6:2, 1.1:43.6:1, 1.2:43.6:1, 1.3:43.6:1, 1.4:43.6:1, 1.5: salt thereof) is present in a range of between about 200 mg to 43.6:1, 1.6:43.6:1, 1.7:43.6:1, 1.8:43.6:1, 19:43.6:1, 2:43.6: about 1000 mg, including but not limited to 200 mg, 205 mg. 1, 1:43.7:1, 1:43.7:11, 1:43.7:12, 1:43.7:13, 1:43.7:14, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg. 1:43.7:1.5, 1:43.7:16, 1:43.7:17, 1:43.7:18, 1:43.7:19, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg. 1:43.7:2, 1.1:43.7:1, 1.2:43.7:1, 1.3:43.7:1, 14:43.7:1, 1.5: 280 mg, 285 mg, 290 mg, 295 mg. 300 mg, 305 mg. 310 mg. 43.7:1, 1.6:43.7:1, 1.7:43.7:1, 1.8:43.7:1, 19:43.7:1, 2:43.7: 315 mg, 320 mg. 325 mg. 326 mg, 326.5 mg, 327 mg, 327.5 1, 1:43.8:1, 1:43.8:1. 1, 1:43.8:1.2, 1:43.8:1.3, 1:43.8:14, mg, 328 mg,328.5 mg,329 mg,329.5 mg, 330 mg, 330.5 mg. 1:43.8:1.5, 1:43.8:1.6, 1:43.8:1.7, 1:43.8:1.8, 1:43.8:1.9, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg,333.5 mg,334 1:43.8:2, 1.1:43.8:1, 1.2:43.8:1, 1.3:43.8:1, 14:43.8:1, 1.5: mg,334.5 mg, 335 mg,335.5 mg, 336 mg,336.5 mg, 337 mg, 43.8:1, 1.6:43.8:1, 1.7:43.8:1, 1.8:43.8:1, 19:43.8:1, 2:43.8: 337.5 mg, 338 mg, 338.5 mg. 339 mg, 339.5 mg, 340 mg. 1, 1:43.9:1, 1:43.9:11, 1:43.9:12, 1:43.9:1.3, 1:43.9:14, 340.5 mg., 341 mg, 341.5 mg., 342 mg, 342.5 mg., 343 mg, 1:43.9:1.5, 1:43.9:16, 1:43.9:17, 1:43.9:18, 1:43.9:19, 343.5 mg., 344 mg., 344.5 mg. 345 mg, 345.5 mg., 346 mg, 1:43.9:2, 1.1:43.9:1, 1.2:43.9:1, 1.3:43.9:1, 14:43.9:1, 1.5: 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, 43.9:1, 1.6:43.9:1, 1.7:43.9:1, 1.8:43.9:1, 19:43.9:1, 2:43.9: 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 1, 1:44:1, 1:44:1. 1, 1:44:1.2, 1:44:1.3, 1:44:14, 1:44:1.5, 352.5 mg, 353 mg, 353.5 mg, 354 mg. 354.5 mg, 355 mg. 1:44:1.6, 1:44:1.7, 1:44:18, 1:44:19, 1:44:2, 1.1:44:1, 1.2: 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, 44:1, 1.3:44:1, 1.4:44:1, 1.5:44:1, 1.6:44:1, 1.7:44:1, 1.8:44: 358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 1, 19:44:1, 2:44:1, 1:45:1, 1:45:1. 1, 1:45:1.2, 1:45:1.3, 1:45: 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg, 364 mg. 1.4, 1:45:1.5, 1:45:1.6, 1:45:1.7, 1:45:1.8, 1:45:19, 1:45:2, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 1.1:45:1, 1.2:45:1, 1.3:45:1, 1.4:45:1, 1.5:45:1, 1.6:45:1, 1.7: 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 45:1, 1.8:45:1, 1.9:45:1, or 2:45:1. In one embodiment an 371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg. opioid analgesic agent, a stimulant and an antihistamine are 374.5 mg, 375 mg, 375.5 mg. 376 mg, 376.5 mg, 377 mg, present in a bi-layer tablet that comprises an immediate 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg, 380 mg, release and a controlled release layer. In one embodiment the 380.5 mg. 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, stimulant and an antihistamine are present in the immediate 383.5 mg. 384 mg. 384.5 mg. 385 mg. 385.5 mg, 386 mg, release layer and the opioid analgesic agent is present in the 386.5 mg, 387 mg, 387.5 mg. 388 mg. 388.5 mg, 389 mg, controlled release layer. 389.5 mg. 390 mg. 390.5 mg. 391 mg, 391.5 mg, 392 mg, 0220. In another embodiment, compositions are provided 392.5 mg, 393 mg, 393.5 mg. 394 mg. 394.5 mg, 395 mg. that comprise an effective amount of an opioid (such as 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, hydrocodone, fentanyl or oxycodone or a salt thereof); a 398.5 mg, 399 mg,399.5 mg, 400 mg. 405 mg, 410 mg, 415 US 2012/020 1888 A1 Aug. 9, 2012 22 mg, 420 mg. 425 mg, 430 mg, 435 mg. 440 mg. 445 mg. 450 200 mg. Furthermore, the non-opioid agent (such as acetami mg, 455 mg. 460 mg. 465 mg. 470 mg. 475 mg, 480 mg. 485 nophen or naproxen or a salt thereof) is present in a range of mg, 490 mg. 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 between about 200 mg to about 1000 mg, including but not mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg. mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg. mg, 595 mg. 600 mg. 605 mg. 610 mg. 615 mg, 620 mg. 625 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg. mg, 630 mg, 635 mg, 640 mg. 645 mg, 650 mg. 655 mg. 660 300 mg. 305 mg. 310 mg, 315 mg. 320 mg, 325 mg, 326 mg, mg, 665 mg. 675 mg, 680 mg, 685 mg. 690 mg. 695 mg, 700 326.5 mg, 327 mg, 327.5 mg. 328 mg, 328.5 mg, 329 mg, mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 329.5 mg, 330 mg. 330.5 mg, 331 mg, 331.5 mg, 332 mg, mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 332.5 mg, 333 mg, 333.5 mg. 334 mg. 334.5 mg, 335 mg. mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg. 805 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, mg, 810 mg, 815 mg, 820 mg. 825 mg. 830 mg, 835 mg, 840 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, mg, 845 mg. 850 mg. 855 mg, 860 mg, 865 mg, 870 mg,875 341.5 mg., 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. mg, 880 mg. 885 mg. 890 mg. 895 mg,900 mg, 905 mg,910 344.5 mg., 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, mg, 915 mg. 920 mg,925 mg. 930 mg,935 mg,940 mg,945 347.5 mg, 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. mg,950 mg. 955 mg,960 mg. 965 mg,970 mg,975 mg,980 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, mg,985 mg, 990 mg. 995 mg. or 1000 mg. Additionally, the 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, barbiturate (e.g., butalbital or a salt thereof) is present at a 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, dose between about 0.5 mg to about 200 mg, including but not 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, limited to, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 362.5 mg, 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg. 6.0 mg., 6.5 mg, 7.0 mg. 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg. 45 390.5 mg, 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg. 65 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, 100 mg, 105 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg. 425 mg. mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 430 mg, 435 mg. 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. mg, 180 mg, 185 mg, 190 mg, 195 mg. or 200 mg. In one 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. embodiment an opioid analgesic agent, a non-opioid agent, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. and a barbiturate agent are present in a bi-layer tablet that 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. 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 embodiment the bi-layer tablet comprises 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. an antiemetic agent. Such as an antihistamine. In one embodi 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. ment the antihistamine is present in the immediate release 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. layer and the opioid analgesic agent, non-opioid agent, and 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. barbiturate agent are present in the controlled release layer. 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. 0222. In another embodiment compositions are provided 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. that comprise an effective amount of a barbiturate agent (Such 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. as butalbital or a salt thereof); a non-opioid agent (such as 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. acetaminophen or naproxen or a salt thereof); and a stimulant 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. agent (such as caffeine or a salt thereof). In one embodiment 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. the barbiturate agent (such as butalbital or a salt thereof); is 960 mg,965 mg, 970 mg,975 mg,980 mg,985 mg, 990 mg. present in a range of about 0.5 mg to about 200 mg, including 995 mg. or 1000 mg. Additionally, the stimulant agent (e.g., but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 caffeine) is present at a dose from about 0.5 mg to about 200 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 mg., 6.5 mg. mg including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg. 4.5 mg, 5.0 mg, 5.5 mg. mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 6.0 mg. 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg. mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg. 30 mg. 31 mg, 32 mg, mg, 44 mg. 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg, 95 mg, 12 mg, 43 mg, 44 mg. 45 mg. 46 mg, 47 mg, 48 mg, 49 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 90 mg.95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg. mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg. US 2012/020 1888 A1 Aug. 9, 2012

160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg. 326 mg,326.5 mg, 327 mg, 327.5 mg. 328 mg,328.5 mg,329 195 mg. or 200 mg. In one embodiment a stimulant agent, a mg, 329.5 mg, 330 mg,330.5 mg, 331 mg, 331.5 mg, 332 mg, non-opioid agent, and a barbiturate agent are present in a 332.5 mg, 333 mg, 333.5 mg. 334 mg. 334.5 mg, 335 mg. bi-layer tablet that comprises an immediate release and a 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, controlled release layer. In one embodiment the stimulant is 338.5 mg. 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, present in the immediate release layer and the non-opioid 341.5 mg., 342 mg, 342.5 mg. 343 mg, 343.5 mg., 344 mg. analgesic agent and barbiturate are present in the controlled 344.5 mg., 345 mg., 345.5 mg., 346 mg, 346.5 mg., 347 mg, release layer. In a further embodiment the bi-layer tablet 347.5 mg, 348 mg, 348.5 mg. 349 mg, 349.5 mg, 350 mg. comprises an antiemetic agent, Such as an antihistamine (e.g., 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, promethazine). In one embodiment the stimulant and an anti 353.5 mg, 354 mg., 354.5 mg, 355 mg, 355.5 mg, 356 mg, histamine are present in the immediate release layer and the 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, non-opioid analgesic agent and barbiturate are present in the 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, controlled release layer. 362.5 mg, 363 mg, 363.5 mg. 364 mg. 364.5 mg, 365 mg. 0223) In another embodiment compositions are provided 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, that comprise an effective amount of a barbiturate and a 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, stimulant. In one embodiment the composition comprises a 372.5 mg, 373 mg, 373.5 mg, 374 mg. 374.5 mg, 375 mg. stimulant at a dose of about 1 mg to about 350 mg (such as 5 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, mg to 25 mg, 10 mg to 50 mg, 25 to 100 mg, 50 to 150 mg, 100 378.5 mg. 379 mg, 379.5 mg. 380 mg. 380.5 mg, 381 mg, mg to 250 mg, 75 mg to 350 mg) including but not limited to 381.5 mg, 382 mg, 382.5 mg. 383 mg, 383.5 mg. 384 mg. about 1.0mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg. 384.5 mg. 385 mg. 385.5 mg. 386 mg, 386.5 mg, 387 mg, 6.0 mg. 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 387.5 mg. 388 mg. 388.5 mg. 389 mg, 389.5 mg. 390 mg. mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 390.5 mg. 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 393.5 mg. 394 mg. 394.5 mg. 395 mg. 395.5 mg, 396 mg, mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg. 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg. 90 399.5 mg. 400 mg, 405 mg, 410 mg. 415 mg. 420 mg. 425 mg. mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 430 mg, 435 mg. 440 mg. 445 mg. 450 mg. 455 mg. 460 mg. mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 465 mg. 470 mg. 475 mg, 480 mg. 485 mg. 490 mg. 495 mg. mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg. 300 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg. mg, 310 mg. 320 mg. 330 mg, 340 mg, or 350 mg. Addition 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg. ally, the barbiturate agent (such as butalbital or a salt thereof); 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg. is present in a range of about 0.5 mg to about 200 mg. 605 mg. 610 mg. 615 mg, 620 mg. 625 mg, 630 mg, 635 mg. including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg. 640 mg. 645 mg, 650 mg. 655 mg. 660 mg. 665 mg. 675 mg. 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg., 6.0 680 mg, 685 mg. 690 mg. 695 mg, 700 mg, 705 mg, 710 mg. mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg. 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg. 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg. 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 785 mg, 790 mg, 795 mg, 800 mg. 805 mg, 810 mg, 815 mg. mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 820 mg. 825 mg. 830 mg, 835 mg, 840 mg. 845 mg. 850 mg. mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg. 855 mg, 860 mg, 865 mg, 870 mg. 875 mg. 880 mg. 885 mg. 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 890 mg. 895 mg,900 mg,905 mg, 910 mg,915 mg,920 mg. mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 925 mg,930 mg,935 mg,940 mg,945 mg,950 mg, 955 mg. 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 960 mg,965 mg, 970 mg,975 mg,980 mg,985 mg, 990 mg. mg, 43 mg. 44 mg. 45 mg, 46 mg, 47 mg, 48 mg. 49 mg, 50 995 mg. or 1000 mg. In these embodiments the compositions mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 comprise a stimulantata dose of about 1 mg to about 350 mg. mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 (such as 5 mg to 25 mg, 10 mg to 50 mg, 25 to 100 mg, 50 to mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 150 mg, 100 mg to 250 mg. or 75 mg to 350mg), including but mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 not limited to about 1.0 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg. mg, or 200 mg. In one embodiment, a barbiturate agent, and 4.0 mg, 5.0 mg., 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 a stimulant are present in a bi-layer tablet that comprises an mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 immediate release and a controlled release layer. In a further mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg. embodiment the bi-layer tablet further comprises an anti 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 emetic agent, Such as an antihistamine (e.g. promethazine or mg, 20 mg, 25 mg, 30 mg, 35 mg. 40 mg, 45 mg, 50 mg, 60 a salt thereof). In one embodiment the stimulant and an anti mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg. histamine are present in the immediate release layer and the 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg. barbiturate agent is present in the controlled release layer. 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg. 0224. In another embodiment the compositions comprise 280 mg, 290 mg. 300 mg. 310 mg. 320 mg, 330 mg, 340 mg. an effective amount of a non-opioid agent (Such as naproxen or 350 mg. In one embodiment a non-opioid agent and a oribuprofenora salt thereof) and a stimulant (Such as caffeine stimulant are formulated as a bi-layer tablet that comprises an or a salt thereof). In some embodiments the non-opioid agent immediate release and a controlled release layer. In one (such as naproxen or ibuprofen or a salt thereof) is present in example naproxen and caffeine are formulated in a bi-layer a range of between about 200 mg to about 1000 mg, including tablet. In one embodiment the caffeine is present in the imme but not limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg. diate release layer and naproxen is present in the controlled 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg. release layer. 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg. 0225. In one embodiment, the compositions of the inven 295 mg, 300 mg. 305 mg. 310 mg, 315 mg, 320 mg. 325 mg. tion comprise an effective amount of propoxyphene or a salt US 2012/020 1888 A1 Aug. 9, 2012 24 thereof and a non-opioid agent (such as naproxen or a salt mg,905 mg, 910 mg, 915 mg,920 mg,925 mg,930 mg,935 thereof). In some embodiments the composition further com mg,940 mg,945 mg,950 mg,955 mg,960 mg. 965 mg, 970 prises an antiemetic (such as promethazine or a salt thereof). mg,975 mg,980 mg,985 mg. 990 mg. 995 mg, or 1000 mg. In some embodiments the compositions further comprise a In one embodiment propoxyphene or a salt thereof and stimulant agent. In one embodiment, the propoxyphene or naproxen (such as naproxen Sodium or naproxen magnesium) salt thereof is present in a range of about 1.0 mg to about 100 are present in a bi-layer tablet. In a further embodiment, the mg, including but not limited to 11.0 mg, 1.5 mg, 2.5 mg, 3.0 composition comprises an antiemetic or an antihistamine mg, 4.0 mg, 5.0 mg., 6.0 mg. 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg. (e.g., promethazine or a salt thereof). In one embodiment the 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 antihistamine is present in the immediate release layer and mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg. propoxyphene and naproxen are present in the controlled 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 release layer. mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg. 0226. In another embodiment, the compositions described 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 herein comprise an effective amount of an antiemetic or an mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg. 30.5 antihistamine (e.g., promethazine or a salt thereof), that is mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg, present in the range of at about 0.5 mg to about 60 mg. 36.5 mg, 37 mg, 37.5 mg. 38 mg, 38.5 mg. 39 mg, 39.5 mg, 40 including but not limited to a dose of about 0.5 mg, 1.0 mg. mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 44 mg., 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, mg, 5.5 mg, 6.0 mg., 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg. 47.5 mg, 48 mg, 48.5 mg. 49 mg, 49.5 mg, 50 mg, 55 mg, 60 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg. mg, 65mg, 70 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, or 100 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg. Furthermore, the non-opioid agent is in a range of about mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 200 mg to about 1000 mg, including but not limited to 200 mg, 20 mg. 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg. mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg. 300 mg. 305 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg,310 mg,315 mg,320 mg. 325 mg,326 mg,326.5 mg,327 mg, 41 mg, 12 mg, 43 mg, 44 mg. 45 mg, 46 mg, 47 mg, 48 mg, 327.5 mg,328 mg,328.5 mg,329 mg,329.5 mg,330 mg. mg, 49 mg, 50 mg, 55 mg, 60 mg. In one embodiment, the 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, antiemetic or antihistamine is promethazine or a salt thereof. 333.5 mg, 334 mg., 334.5 mg, 335 mg, 335.5 mg, 336 mg, In various other embodiments, the antihistamine or anti 336.5 mg, 337 mg, 337.5 mg, 338 mg, 338.5 mg, 339 mg, emetic is another described herein above. As described 339.5 mg, 340 mg, 340.5 mg, 341 mg, 341.5 mg, 342 mg, herein, in Some embodiments, the antihistamine orantiemetic 342.5 mg, 343 mg, 343.5 mg., 344 mg., 344.5 mg., 345 mg. is a component of an immediate-release formulation. For 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, example, in a further embodiment, the immediate-release is 348.5 mg. 349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, in a lollipop, capsule, a tablet, a transdermal means, through 351.5 mg, 352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg. injection, intramuscular administration or other means dis 354.5 mg. 355 mg, 355.5 mg, 356 mg, 356.5 mg, 357 mg, closed herein. 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360 mg, 0227 Dosage Forms 360.5 mg. 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, Oral Dosage Forms 363.5 mg. 364 mg. 364.5 mg, 365 mg, 365.5 mg, 366 mg, 0228 366.5 mg. 367 mg, 367.5 mg, 368 mg, 369.5 mg, 370 mg. 0229. In one embodiment the invention relates to methods 370.5 mg. 371 mg, 371.5 mg, 372 mg, 372.5 mg, 373 mg, and compositions formulated for oral delivery to a Subject in 373.5 mg, 374 mg., 374.5 mg, 375 mg, 375.5 mg, 376 mg, need. In one embodiment a composition is formulated so as to 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, deliver one or more pharmaceutically active agents to a Sub 379.5 mg. 380 mg. 380.5 mg. 381 mg, 381.5 mg, 382 mg, ject through a mucosa layer in the mouth or esophagus. In 382.5 mg. 383 mg, 383.5 mg. 384 mg. 384.5 mg, 385 mg. another embodiment the composition is formulated to deliver 385.5 mg. 386 mg, 386.5 mg. 387 mg, 387.5 mg. 388 mg, one or more pharmaceutically active agents to a subject 388.5 mg. 389 mg, 389.5 mg. 390 mg. 390.5 mg, 391 mg, through a mucosa layer in the stomach and/or intestines. 391.5 mg. 392 mg, 392.5 mg. 393 mg, 393.5 mg. 394 mg. 0230. In one embodiment compositions are provided in 394.5 mg. 395 mg. 395.5 mg, 396 mg, 396.5 mg, 397 mg, modified release dosage forms (such as immediate release, 397.5 mg,398 mg,398.5 mg,399 mg,399.5 mg, 400 mg, 405 controlled release or both), which comprise an effective mg, 410 mg. 415 mg, 420 mg. 425 mg, 430 mg, 435 mg. 440 amount of an opioid analgesic (such as oxycodone or hydro mg, 445 mg. 450 mg. 455 mg, 460 mg. 465 mg, 470 mg. 475 codone or a salt thereof), a non-opioid analgesic (Such as mg, 480 mg. 485 mg. 490 mg. 495 mg, 500 mg, 505 mg, 510 acetaminophen, naproxen or ibuprofen or a salt thereof) and mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 an antihistamine (such as promethazine or a salt thereof); and mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 one or more release controlling excipients as described mg, 585 mg, 590 mg, 595 mg. 600 mg. 605 mg. 610 mg. 615 herein. Suitable modified release dosage vehicles include, but mg, 620 mg. 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 are not limited to, hydrophilic or hydrophobic matrix devices, mg, 655 mg. 660 mg. 665 mg. 675 mg, 680 mg, 685 mg. 690 water-soluble separating layer coatings, enteric coatings, mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 osmotic devices, multi-particulate devices, and combinations mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 thereof. The compositions may also comprise non-release mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 controlling excipients. mg, 800 mg. 805 mg. 810 mg. 815 mg, 820 mg. 825 mg,830 0231. In another embodiment compositions are provided mg, 835 mg, 840 mg. 845 mg. 850 mg. 855 mg, 860 mg, 865 in enteric coated dosage forms. The compositions can also mg, 870 mg. 875 mg. 880 mg. 885 mg. 890 mg. 895 mg,900 comprise non-release controlling excipients. US 2012/020 1888 A1 Aug. 9, 2012

0232. In another embodiment compositions are provided comprise different pharmaceutically active agents. For in effervescent dosage forms. The compositions can also example a multiple dosage form can be provided which com comprise non-release controlling excipients. prises a first dosage element comprising an immediate release 0233. In another embodiment compositions can be pro form of an antihistamine (such as in a liquid form) and a vided in a dosage form that has at least one component that second dosage element comprising an opioid and/or non can facilitate the immediate release of an active agent, and at opioid analgesic, which can be in a modified release form least one component that can facilitate the controlled release (such as immediate release, controlled release, or extended of an active agent. In a further embodiment the dosage form release form). can be capable of giving a discontinuous release of the com 0240. In this example a pair of dosage elements can make pound in the form of at least two consecutive pulses separated a single unit dosage. In one embodiment a kit is provided in time from 0.1 up to 24 hours. The compositions can com comprising multiple unit dosages, wherein each unit com prise one or more release controlling and non-release control prises a first dosage element comprising an immediate release ling excipients, such as those excipients suitable for a disrupt form of an antihistamine (such as in a liquid form) and a able semi-permeable membrane and as Swellable Substances. second dosage element comprising an opioid or non opioid 0234. In another embodiment compositions are provided analgesic or both, which can be in a modified release form in a dosage form for oral administration to a subject, which (such as immediate release or controlled release, or both). In comprise one or more pharmaceutically acceptable excipi another embodiment the kit further comprises a set of instruc ents or carriers, enclosed in an intermediate reactive layer tions. In yet a further embodiment the antihistamine is comprising a gastric juice-resistant polymeric layered mate promethazine or a pharmaceutically acceptable salt thereof, rial partially neutralized with alkali and having cation the opioid analgesic is oxycodone or hydrocodone or phar exchange capacity and a gastric juice-resistant outer layer. maceutically acceptable salt thereof, the non-opioid analge 0235. In one embodiment the compositions are in the form sic is acetaminophen or a pharmaceutically acceptable salt of enteric-coated granules, as controlled-release capsules for thereof. oral administration. The compositions can further comprise 0241. In one embodiment compositions can beformulated cellulose, disodium hydrogen phosphate, hydroxypropyl cel in various dosage forms for oral, parenteral, and topical lulose, hypromellose, lactose, mannitol, and Sodium lauryl administration. The compositions may also be formulated as sulfate. a modified release dosage form, including immediate-, 0236. In another embodiment the compositions are in the delayed-, extended-, prolonged-, Sustained-, pulsatile-, con form of enteric-coated pellets, as controlled-release capsules trolled-, extended, accelerated- and fast-, targeted-, pro for oral administration. The compositions can further com grammed-release, and gastric retention dosage forms. These prise glyceryl monostearate 40-50, hydroxypropyl cellulose, dosage forms can be prepared according to known methods hypromellose, magnesium Stearate, methacrylic acid copoly and techniques (see, Remington: The Science and Practice of mer type C, polysorbate 80, Sugar spheres, talc, and triethyl Pharmacy, supra; Modified-Release Drug Delivery Technol citrate. ogy, Rathbone et al., Eds. Drugs and the Pharmaceutical 0237. In another embodiment the compositions are Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. enteric-coated controlled-release tablets for oral administra 126, which is herein incorporated by reference in its entirety). tion. The compositions can further comprise carnauba wax, 0242. In various embodiments of the invention, the com crospovidone, diacetylated monoglycerides, ethylcellulose, positions are in one or more dosage form. For example, a hydroxypropyl cellulose, hypromellose phthalate, magne composition can be administered in a solid or liquid form. sium Stearate, mannitol, Sodium hydroxide, sodium Stearyl Examples of solid dosage forms include but are not limited to fumarate, talc, titanium dioxide, and yellow ferric oxide. discrete units in capsules or tablets, as a powder or granule, or 0238. In another embodiment the compositions can fur present in a tablet conventionally formed by compression ther comprise calcium Stearate, crospovidone, hydroxypropyl molding. Such compressed tablets may be prepared by com methylcellulose, iron oxide, mannitol, methacrylic acid pressing in a Suitable machine the three or more agents and a copolymer, polysorbate 80, povidone, propylene glycol, pharmaceutically acceptable carrier. The molded tablets can Sodium carbonate, Sodium lauryl Sulfate, titanium dioxide, be optionally coated or scored, having indicia inscribed and triethyl citrate. thereon and can be so formulated as to cause immediate, 0239. The compositions provided herein can be in unit substantially immediate, slow, controlled or extended release dosage forms or multiple-dosage forms. Unit-dosage forms, of the opioid analgesics (such as oxycodone or hydrocodone) as used herein, refer to physically discrete units suitable for and/or the non opioid analgesics (such as acetaminophen) and administration to human or non-human animal Subjects and or the antihistamine (such as promethazine). Furthermore, packaged individually. Each unit-dose can contain a prede dosage forms of the invention can comprise acceptable car termined quantity of an active ingredient(s) sufficient to pro riers or salts known in the art, such as those described in the duce the desired therapeutic effect, in association with the Handbook of Pharmaceutical Excipients, American Pharma required pharmaceutical carriers or excipients. Examples of ceutical Association (1986), incorporated by reference herein unit-dosage forms include, but are not limited to, ampules, in its entirety. Syringes, and individually packaged tablets and capsules. 0243 In one embodiment, one or more pharmaceutically Unit-dosage forms may be administered in fractions or mul active agents are mixed with a pharmaceutical excipient to tiples thereof. A multiple-dosage form is a plurality of iden form a solid preformulation composition comprising a homo tical unit-dosage forms packaged in a single container, which geneous mixture of compounds described herein. When can be administered in segregated unit-dosage form. referring to these compositions as "homogeneous, it is Examples of multiple-dosage forms include, but are not lim meant that the agents are dispersed evenly throughout the ited to, vials, bottles of tablets or capsules, or bottles of pints composition so that the composition can be subdivided into or gallons. In another embodiment the multiple dosage forms unit dosage forms such as tablets or capsules. This solid US 2012/020 1888 A1 Aug. 9, 2012 26 preformulation composition can then Subdivided into unit position reactions, including oxidative reactions. Surfactants dosage forms of the type described above comprising from, can also include and can be anionic, cationic, amphoteric or for example, about 1.0 mg to about 15 mg of an opioid. Such nonionic. If desired, the tablets can also comprise nontoxic as hydrocodone or oxycodone or a pharmaceutically accept auxiliary Substances such as pH buffering agents, preserva able salt thereof. tives, e.g., antioxidants, wetting or emulsifying agents, solu 0244. The compositions can be formulated, in the case of bilizing agents, coating agents, flavoring agents, and the like. capsules or tablets, to be swallowed whole, for example with 0247 Controlled-release formulations can comprise one water. The inclusion of the side-effect-reducing agent Such as or more combination of excipients that slow the release of the an antihistamine orantiemetic to abate common symptoms of agents by coating or temporarily bonding or decreasing their nausea and vomiting are believed beneficial in that promet solubility of the active agents. Examples of these excipients hazine or a salt thereof, or the like will eliminate or minimize include cellulose ethers such as hydroxypropylmethylcellu the amount of discomfort. Adverse effects reduced or elimi lose (e.g., Methocel K4M) or silicified microcrystalline cel nated include but are not limited to nausea, vomiting, other lulose, polyvinylacetate-based excipients such as, e.g., Kol gastric upsets, skin rashes, allergic reactions such as Swelling, lidon SR, and polymers and copolymers based on difficulty breathing, closing of throat, abdominal pain, methacrylates and methacrylic acid Such as, e.g., Eudragit NE unusual bleeding or bruising, CNS Suppression and respira 30D. In one embodiment of the invention, the opioid analge tory Suppression. sic or non-opioid agents (e.g., hydrocodone or oxycodone or 0245 Frequently, subjects taking opioids have adverse a salt thereof, and acetaminophen or a salt thereof) are for effects including Vomiting that can occur shortly after taking mulated for extended or controlled-release while the promet a first or Subsequent dose. As a consequence, a portion of the hazine orasalt thereofisformulated for immediate release. In opioid dose is Subsequently lost, making it difficult to accu another embodiment, all agents are formulated for extended rately gauge replacement dosages for the Subject, and for or controlled-release. Subjects outside of a hospital or clinic environment, there 0248 Immediate-release formulations can comprise one might not be any alternative form of pain medication readily or more combination of excipients that allow for a rapid available. As a consequence, Subjects experiencing gastric release of a pharmaceutically active agent (such as from 1 discomfort such as vomiting will lack the beneficial effects of minute to 1 hour after administration). Such as an anti-emetic the opioid analgesic and experience the additional discomfort oran antihistamine. In one embodiment an immediate release and enhanced pain associated with Vomiting. This problem is excipient can be microcrystalline cellulose, sodium car solved by also administering promethazine or a salt thereof, boxymethyl cellulose, sodium starch glycolate, corn starch, which reduces side-effects. colloidal silica, Sodium Laurel Sulphate, Magnesium Stear 0246 The dosage forms described herein can be manufac ate, Prosolve SMCC(HD90), croscarmellose Sodium, tured using processes that are well known to those of skill in Crospovidone NF, Avicel PH200, and combinations of such the art. For example, for the manufacture of bi-layered tablets, excipients. the agents can be dispersed uniformly in one or more excipi 0249 Pharmaceutical carriers or vehicles suitable for ents, for example, using high shear granulation, low shear administration of the compounds provided herein include all granulation, fluid bed granulation, or by blending for direct such carriers knownto those skilled in the art to be suitable for compression. Excipients include diluents, binders, disinte the particular mode of administration. In addition, the com grants, dispersants, lubricants, glidants, stabilizers, Surfac positions can one or more components that do not impair the tants and colorants. Diluents, also termed “fillers', can be desired action, or with components that Supplement the used to increase the bulk of a tablet so that a practical size is desired action, or have another action. As noted above, the provided for compression. Non-limiting examples of diluents compositions can comprise additional (e.g., a fourth, fifth, include lactose, cellulose, microcrystalline cellulose, manni sixth, etc.) additional active agents. tol, dry starch, hydrolyzed Starches, powdered Sugar, talc, 0250 In one embodiment, the compositions comprise Sodium chloride, silicon dioxide, titanium oxide, dicalcium three or more pharmaceutically active agents wherein at least phosphate dihydrate, calcium sulfate, calcium carbonate, alu one active agent is formulated in an immediate release form. mina and kaolin. Binders can impart cohesive qualities to a In this embodiment the immediate-release form can be tablet formulation and can be used to help a tablet remain intact after compression. Non-limiting examples of Suitable included in an amount that is effective to shorten the time to binders include starch (including corn starch and pregelati its maximum concentration in the blood. By way of example, nized Starch), gelatin, Sugars (e.g., glucose, dextrose. Sucrose, certain immediate-release pharmaceutical preparations are lactose and Sorbitol), celluloses, polyethylene glycol, waxes, taught in United States Patent Publication US 2005/ natural and synthetic gums, e.g., acacia, tragacanth, Sodium 0147710A1 entitled, “Powder Compaction and Enrobing alginate, and synthetic polymers such as polymethacrylates which is incorporated herein in its entirety by reference. and polyvinylpyrrolidone. Lubricants can also facilitate tab 0251. In a further embodiment, a component of an imme let manufacture; non-limiting examples thereof include mag diate-release form or layer is a component that reduces abates nesium Stearate, calcium Stearate, Stearic acid, glyceryl or eliminates and/or Suppresses an adverse effect associated behenate, and polyethylene glycol. Disintegrants can facili with one or more opioid analgesics. tate tablet disintegration after administration, and non-limit 0252 For example, the immediate-release active can bean ing examples thereof include starches, alginic acid, antihistamine or an antiemetic, which reduces, abates or crosslinked polymers such as, e.g., crosslinked polyvinylpyr eliminates an adverse effect associated with opioid and/or rolidone, croScarmellose sodium, potassium or sodium starch non-opioid analgesics described herein. glycolate, clays, celluloses, starches, gums and the like. Non 0253. In a further embodiment, all or less than the entire limiting examples of suitable glidants include silicon dioxide, amount of the antiemetic orantihistamineagent is formulated talc and the like. Stabilizers can inhibit or retard drug decom in immediate-release form, as described herein. US 2012/020 1888 A1 Aug. 9, 2012 27

0254. A variety of known methods and materials may be levels of analgesics are maintained within atherapeutic range used to bring about the immediate release. For instance, over an extended period of time. In certain alternate embodi placement of the agent along an exterior of a tablet (e.g., ments, the matrix is encapsulated. coating the exterior or formulating the outer layer with the 0259 Tablets or capsules containing a composition agent) and/or combined with forming a tablet by compressing described herein can be coated or otherwise compounded to the powder using low compaction can produce immediate provide a dosage form affording the advantage of prolonged release of the agent from the composition. action. For example, the tablet or capsule can contain an inner 0255. In a specific embodiment, an effective amount of the dosage and an outer dosage component, the latter being in the promethazine or a salt thereof in immediate-release form may form of an envelope over the former. The two components can be coated onto a substrate. For example, where the extended be separated by an enteric layer that serves to resist disinte release of one or more analgesics from a formulation is due to gration in the stomach and permit the inner component to pass a controlled-release coating, an immediate-release layer intact into the duodenum or to be controlled in release. For comprising promethazine or a salt thereof can overcoat the controlled extended release, the capsule can also have micro controlled-release coating. In another example, an immedi drilled holes. ate-release layer can be coated onto the Surface of a substrate 0260 A coating comprising a side-effect-reducing com wherein an opioid, a non-opioid agent, a barbiturate, or a pound, in immediate release form, can be added to the outside stimulant is incorporated in a controlled release matrix. of a controlled-release tablet core to produce a final dosage Where a plurality of controlled-release substrates (e.g., mul form. Such a coating can be prepared by admixing a com tiparticulate systems including pellets, spheres, beads and the pound like promethazine with polyvinylpyrrolidone (PVP) like) are incorporated into a hard gelatin capsule, a side 29/32 or hydroxypropyl methylcellulose (HPMC) and water/ effect-reducing compound can be incorporated into the gela isopropyl alcohol and triethyl acetate. Such an immediate tin capsule via inclusion of an amount of immediate-release release coating can be spray coated onto the tablet cores. The promethazine or a salt thereof, as a powder or granulate immediate-release coating can also be applied using a press within the capsule. Alternatively, the gelatin capsule itselfcan coating process with a blend consisting of 80% by weight be coated with an immediate-release layer of promethazine. promethazine and 20% by weight of lactose and hydroxypro One skilled in the art recognizes still other alternative means pyl methylcellulose type 2910. Press-coating techniques are of incorporating an immediate release side-effect-reducing known in the art and are described in U.S. Pat. No. 6,372,254, compound into the unit dose. By including an effective which is herein incorporated by reference in its entirety. amount of immediate-release side-effect-reducing com 0261) The immediate-release or controlled-release dosage pound in the unit dose, the experience of adverse effects forms described herein can also take the form of a bi-layered including nausea, vomiting, other gastric upsets, skin rashes, tablet, which comprises a first layer and a second layer. The allergic reactions such as Swelling, difficulty breathing, clos first layer comprises a first drug that is an analgesic, antitus ing of throat, abdominal pain, unusual bleeding or bruising, sive, antihistamine, and antiemetic. The second layer com skin rashes, sedation, CNS depression, or respiratory depres prises a second drug that is an analgesic, antitussive, antihis sion in Subjects can be significantly reduced. tamine, and antiemetic. The second drug is the same as or 0256 In one embodiment, the composition comprises different from the first drug. The bi-layered tablet can provide three or more active agents wherein at least one active agent a plasma concentration within the therapeutic range of the is in controlled-release form. The controlled-release form can second drug over a period which is coextensive with at least be in an amount that is effective to protect the agent from about 70% of the period (e.g., 12 hours) within which the rapid elimination from the body. Certain preparations relating bi-layered tablet provides a plasma concentration within the to the controlled release of a pharmaceutical are taught in therapeutic range of the first drug. United States Patent Publication US 2005/0147710A1 0262. In a further embodiment of the bi-layered tablet, one entitled, “Powder Compaction and Enrobing” which is incor layer is an immediate release layer and the other layer is a porated herein in its entirety by reference. Examples of time controlled-release layer. In one example a bi-layered is for release coated beads are disclosed in U.S. Application Publi mulated using the methods disclosed in U.S. Pat. No. 4,820, cation No. 2008O131517. 522, which is herein incorporated by reference in its entirety. 0257. In a further embodiment, at least one pharmaceuti 0263. In one embodiment of the bi-layered tablet cally active agent in a controlled-release form is an opioid described herein, both layers can comprise an opioid analge analgesic agent—In one embodiment of the invention, com sic, a non-opioid analgesic and a compound to reduce or positions comprise one or more carriers that protect the Suppress adverse effects. agents against rapid elimination from the body, Such as time 0264. In a further embodiment of the bi-layered tablet release formulations or coatings. Such carriers include con described herein, the immediate-release layer comprises trolled-release formulations, including, for example, promethazine or a salt thereof and the controlled release layer microencapsulated delivery systems. The active agents can be comprises hydrocodone or oxycodone or a pharmaceutically included in the pharmaceutically acceptable carrier in acceptable salt thereof. In one embodiment the immediate or amounts sufficient to treat a subject's pain, with reduced controlled release layer can further comprise acetaminophen adverse effects. or naproxen or a salt thereof. 0258. In certain embodiments the compositions are in 0265. In one embodiment of the multi-layered tablet, the oral-dosage form and comprise a matrix that includes, for second drug can have a plasma half-life that differs from the example, a controlled-release material and an opioid or non plasma half-life of the first drug by at least about 2 hours. opioid analgesic. In certain embodiments, the matrix is com 0266. In another embodiment, an effective amount of the pressible into a tablet and can be optionally overcoated with a antiemetic agent or antihistamine in an immediate-release coating that can control the release of the opioid or non-opioid form may be coated onto a substrate. For example, where the analgesic from the composition. In this embodiment blood one or more opioid analgesics and one or more stimulant are US 2012/020 1888 A1 Aug. 9, 2012 28 components of a controlled-release formulation, an immedi be divided into or exclusively included into both immediate ate-release layer comprising the antiemetic agent or antihis release and controlled release particles. tamine can overcoat the controlled-release formulation. 0271 In a further embodiment the dosage form can be an 0267. In another embodiment, the immediate-release effervescent dosage form. Effervescent means that the dosage layer can be coated onto the Surface of a Substrate having a form, when mixed with liquid, including water and saliva, controlled release matrix. Where a plurality of controlled evolves a gas. Some effervescent agents (or effervescent release Substrates comprising an effective unit dose of an couple) evolve gas by means of a chemical reaction which pharmaceutically active agent (e.g., multiparticulate systems takes place upon exposure of the effervescent disintegration agent to water and/or to saliva in the mouth. This reaction can including pellets, spheres, beads and the like) are incorpo be the result of the reaction of a soluble acid source and an rated into a hard gelatin capsule, another agent can be incor alkali monocarbonate or carbonate Source. The reaction of porated into the gelatin capsule via inclusion of an amount of these two general compounds produces carbon dioxide gas immediate-release agent as a powder or granulate within the upon contact with water or saliva. An effervescent couple (or capsule. Alternatively, the gelatin capsule itself can be coated the individual acid and base separately) can be coated with a with an immediate-release layer. One skilled in the art recog Solvent protective or enteric coating to prevent premature nizes still other alternative means of incorporating the imme reaction. Such a couple can also be mixed with previously diate release side-effect-reducing compound into the unit lyophilized particles (such as one or more pharmaceutically dose. Therefore, in one embodiment, by including an effec active agents coated with a solvent protective or enteric coat tive amount of an antiemetic agent or antihistamine (and ing. The acid sources may be any which are safe for human optionally including a stimulant) in the unit dose, the Subject consumption and may generally include food acids, acid and is prepared for the eventual and Subsequent release of one or hydrite antacids such as, for example: citric, tartaric, amalic, more opioid analgesic in the controlled-release layer, where fumeric, adipic, and Succinics. Carbonate sources include dry the antiemetic agent orantihistamine reduces the incidence of Solid carbonate and bicarbonate salt such as, for example, or intensity of adverse effects associated with an opioid agent Sodium bicarbonate, Sodium carbonate, potassium bicarbon including but not limited to nausea, vomiting, other gastric ate and potassium carbonate, magnesium carbonate and the upsets, skin rashes, allergic reactions such as Swelling, diffi like. Reactants which evolve oxygen or other gasses and culty breathing, closing of throat, abdominal pain, unusual which are safe for human consumption are also included. In bleeding or bruising, skin rashes, sedation, CNS depression, one embodiment citric acid and sodium bicarbonate is used. or respiratory depression in Subjects can be significantly 0272. In another embodiment the dosage form can be in a reduced. candy form (e.g., matrix). Such as a lollipop or lozenge. In one 0268. The immediate-release or controlled-release dosage embodiment one or more pharmaceutically active agents is forms described herein can also take the form of a bi-layered dispersed within a candy matrix. In one embodiment the tablet, which can comprise a immediate-release layer and a candy matrix comprises one or more Sugars (such as dextrose controlled-release layer. In one embodiment the immediate or Sucrose). In another embodiment the candy matrix is a release layer comprises an antiemetic agent orantihistamine, Sugar-free matrix. The choice of a particular candy matrix is and optionally a stimulant or a non-opioid analgesic, or both. Subject to wide variation. Conventional Sweeteners such as In one embodiment, the first layer can comprise one, two, Sucrose may be utilized, or Sugar alcohols suitable for use three or more active agents. The controlled release layer can with diabetic patients, such as Sorbitol or mannitol might be comprise an opioid analgesic or non-opioid analgesic or employed. Other Sweeteners. Such as the aspartanes, can also stimulant. Such classes of active agents are described herein be easily incorporated into a composition in accordance with above. compositions described herein. The candy base may be very 0269. The immediate-release or controlled release dosage Soft and fast dissolving, or may be hard and slower dissolving. forms described herein can also take the form of pharmaceu Various forms will have advantages in different situations. tical particles manufactured by a variety of methods, includ 0273 A containing candy mass comprising at least one ing but not limited to high-pressure homogenization, wet or pharmaceutically active agent can be orally administered to a dry ball milling, or Small particle precipitation (nano spray). subject in need thereof so that the agent will be released into Other methods to make a suitable powder formulation are the the Subject's mouth as the candy mass dissolves. The drug preparation of a solution of active ingredients and excipients, rapidly enters the Subject bloodstream, and importantly, the followed by precipitation, filtration, and pulverization, or blood in the veins draining from the mouth and the pharyn followed by removal of the solvent by freeze-drying, fol geal and esophageal areas passes through a substantial por lowed by pulverization of the powder to the desired particle tion of the body (so that the drug can be absorbed) before the S17C. blood passes through the liver (where the drug may be inac 0270. In one embodiment the particles have a final size of tivated). A Subject in need thereof can include a human adult 3-1000 uM, such as at most 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or child in pain, such as a child in sickle cell crisis, a child 50, 60, 70, 80,90, 100,150, 200,250,300,350,400,450, 500, undergoing bone marrow transplant or a lumbar puncture 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 uM. In procedure, a child with cancer (e.g., metastasic cancer, leu another embodiment the pharmaceutical particles have a final kemia or lymphoma). size of 10-500 uM. In one embodiment the pharmaceutical 0274. In some embodiments of the invention the candy particles have a final size of 50-600 uM. In another embodi matrix (lollipop or lozenge) comprises a composition that ment the pharmaceutical particles have a final size of 100-800 lacks a stimulant. In one embodiment said formulation may uM. These dosage forms can include immediate-release par have a sedative effect in addition to providing pain relief to a ticles in combination with controlled-release particles in a subject in need thereof. In some other embodiments the candy ratio sufficient useful for delivering the desired dosages of matrix (lollipop or lozenge) comprises a composition that active agents. In an alternative embodiment, a dosage unit can comprises a stimulant. In these embodiments the composition US 2012/020 1888 A1 Aug. 9, 2012 29 provides an anti-sedative effect in addition to providing pain layer is a controlled release layer. For example in one embodi relief to a subject in need thereof. ment the multilayer tablet comprises at least three layers, each 0275. In one embodiment a candy mass is prepared that of which contains a different agent, such as: layer one con comprises one or more layers which may comprise different tains promethazine or a salt thereof layer two comprises pharmaceutically active agents and or rates of dissolution. In hydrocodone or oxycodone or a salt thereof; and layer three one embodiment a multilayer candy mass (such as a lollipop) comprises acetaminophen or a salt thereof. In this embodi comprises an outer layer with a concentration of one or more ment the promethazine layer may be immediate-release, pharmaceutically active agents differing from that of one or while the other two layers may be controlled-release. more inner layers. Such a drug delivery system has a variety 0279 Transdermal Dosage Forms of applications. By way of example, it may be desirable to 0280. In another embodiment, the invention relates to a quickly get a predetermined dose of a first pharmaceutically method of use and a system for the transdermal delivery of active agent into the bloodstream to obtain a desired effect one or more pharmaceutically active agents into a Subject. In and then use a different inner layer to deliver one or more one embodiment a portion of the skin of a Subject is sealed other agents. with a thin, film layer of a base material to occlude the skin 0276. The choices of matrix and the concentration of the and transport a desired dosage of at least one pharmaceuti drug in the matrix can be important factors with respect to the cally active agent across the a layer, which can be from a rate of drug uptake. A matrix that dissolves quickly can rate-controlling system in contact with the thin layer. The deliver drug into the patient's mouth for absorption more rate-controlling system can be a thin rate-controlling mem quickly than a matrix that is slow to dissolve. Similarly, a brane interposed between one or more agents and the thin candy matrix that contains one or more pharmaceutically layer. In another embodiment a reservoir delivers at least one active agents in a high concentration can release more of the pharmaceutically active agent to the layer for delivery into a one or more pharmaceutically active agents in a given period Subject. In some embodiments the pharmaceutically active of time than a candy having a low concentration. In one agents to be delivered are: an opioid analgesic, a non-opioid embodimenta candy matrix Such as one disclosed in U.S. Pat. analgesic and an antihistamine; or pharmaceutically accept No. 4,671,953 or US Application 2004/0213828 (which are able salts, Solvates, or prodrugs thereof; one or more pharma herein incorporated by reference in their entirety) is used to ceutically acceptable excipients or carriers. deliver the pharmaceutically active agents disclosed herein. 0281. In one embodiment, the rate-controlling system or 0277. The immediate-release or extended release dosage reservoir comprises at least one pharmaceutically active forms described herein can also take the form of pharmaceu agent to be delivered, is dispersed in a base material and tical particles manufactured by a variety of methods, includ contained within a container system. In one embodiment at ing but not limited to high-pressure homogenization, wet or least one pharmaceutically active agent is dissolved in the dry ball milling, or Small particle precipitation (e.g., nGimat's base material. In another embodiment at least one pharma NanoSpray). Other methods useful to make a suitable powder ceutically active agent is uniformly dispersed in the base formulation are the preparation of a solution of active ingre material. In another embodiment, the rate-controlling system dients and excipients, followed by precipitation, filtration, or reservoir comprises microparticles of at least one pharma and pulverization, or followed by removal of the solvent by ceutically active agent to be delivered Suspended in a base freeze-drying, followed by pulverization of the powder to the material and contained within a container System. In one desired particle size. In one embodiment the pharmaceutical embodiment the base material is a viscous material. The particles have a final size of 3-1000 uM, such as at most 3, 4, container system may comprise a macroporous, non-rate 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, controlling face membrane with an impervious backing to 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, form a pool or patch-like system of desired face membrane 850,900,950, 1000 uM. In another embodiment the pharma area with the face of the membrane placed over and in contact ceutical particles have a final size of 10-500 uM. In another with the thin, occluding, viscous layer on the skin. The thin embodiment the pharmaceutical particles have a final size of Viscous layer may be coated or placed on the skin repeatedly, 50-600 uM. In another embodiment the pharmaceutical par and the patch system placed on top of the thin, Viscous layer ticles have a final size of 100-800 uM. These dosage forms or the viscous layer formed in situ by exudation through the can include immediate-release particles in combination with membrane face when the patch or pool system is placed in controlled-release particles in a ratio sufficient useful for position on the skin. In one embodiment the patch or pool delivering the desired dosages of active agents. For example, container system generally is retained in a transdermal posi the immediate-release particles can comprise about 12.5 mg tion by the use of a peripheral adhesive layer about the patch of promethazine or a salt thereof, and the controlled-release or pool. In one embodiment, the face or transport area of the particles can comprise about 7.5 mg of hydrocodone or oxy membrane is covered prior to use by a removable cover such codone or a salt thereof, and about 325 mg of acetaminophen as a peelable strip of impervious sheet material. In another or a salt thereof. embodiment, microcapsules containing a drug for delivery 0278. In another embodiment, the agents are released may be suspended in a viscous base material, and the com from a multi-layered tablet that comprises at least a first layer, position then spread as a layer over the skin of the user with or a second layer and a third layer. Wherein, the layers contain without a covering material. ing a pharmaceutically active agent can be optionally sepa 0282. In other embodiments U.S. Pat. Nos. 4,906.463: rated by one or more layers of inert materials. In one embodi 4,588,580; 4,685,911, 4,626,539, 4,834,978 and 5,635,204 ment the layers containing a pharmaceutically active agent disclose useful transdermal patches which may be used for have similar rates of release, e.g., all are immediate release or the practice methods and compositions described herein, all are controlled-release. In an alternative embodiment the which are herein incorporated by reference in their entirety. layers have different rates of release. In this embodiment at 0283. In one embodiment the compositions are adminis least one layer is an immediate release layer and at least one tered to a Subject via a transdermal patch. US 2012/020 1888 A1 Aug. 9, 2012 30

0284 Suppository Dosage Form dosage, e.g., about 2-3 times the usually prescribed dose of 0285. In another embodiment, the compositions are in the the opioid. Thus, the oral dosage form would have less poten form of a Suppository. In one embodiment the Suppository is tial for parenteral as well as oral abuse. In one embodiment useful for vaginal or rectal administration. In some embodi where the opioid is hydrocodone or oxycodone or a salt ments the Suppository is effervescent. thereof and the antagonist is naltrexone or a salt thereof, the 0286. In some embodiments the suppository base material ratio of naltrexone or a salt thereof to hydrocodone or a salt contains hydrophobic or hydrophilic media, each of which thereof is from about 0.02-0.35:1 by weight, and in some can melt at body temperature. In one embodiment the Sup embodiments from about 0.05-0.2:1 by weight. In one pository base material used can be cocoa butter or similar embodiment the ratio of naltrexone or a salt thereof is in an material. In another embodiment the Suppository base mate amount from about 0.5 to about 4 mg per 15 mg of hydroc rial can be a moist polymer is then mixed with the one or more odone or a salt thereof. In another embodiment the ratio of pharmaceutically active agents and compressed into the maltrexone or a salt thereof is in an amount from about 0.75 desired form. In one embodiment at least one pharmaceuti mg to about 3 mg per 15 mg hydrocodone or a salt thereof. In cally active agent is dissolved in the Suppository base mate another example where the opioidantagonist is naltrexone or rial. In another embodiment at least one pharmaceutically a salt thereof and the opioid agent is hydromorphone or a salt active agent is uniformly dispersed in the Suppository base thereof, the ratio of naltrexone or a salt thereof to hydromor material. In another embodiment, the Suppository base mate phone or a salt thereof can be from about 0.14:1 to about rial comprises microparticles of at least one pharmaceutically 1.19:1, or from about 0.222:1 to about 0.889:1. In another active agent to be delivered Suspended in the Suppository base example where the opioid antagonist is naltrexone or a salt material. In some embodiments (such as vaginal Supposito thereof and the opioid agentis oxycodone or a salt thereof, the ries) the Suppository is effervescent. In some embodiments ratio of naltrexone or a salt thereof to oxycodone or a salt the effervescing properties are imparted for the purpose of thereof is about 0.03:1 to about 0.3:1, or from about 0.056:1 enhancing the rapid disintegration properties of the Supposi to about 0.222:1. tory. 0294. In one embodiment, the opioid is hydrocodone, 0287. In other embodiments U.S. Pat. Nos. 4,265,875 and hydromorphone, oxycodone, fentanyl, or a pharmaceutically 4.853,211 disclose useful suppositories which may be used acceptable salt thereof. for the practice of methods and compositions described 0295. In some embodiments, an opioid antagonist is herein, which are herein incorporated by reference in their administered in an amount (i) which does not cause a reduc entirety. tion in the level of analgesia elicited from the dosage form 0288 Abuse Safeguard Dosage Forms upon oral administration to a non-therapeutic level and (ii) 0289 Adverse-Effect Agents which provides at least a mildly negative, “aversive’ experi 0290. In one embodiment, the present compositions can ence in physically dependent Subjects (e.g., precipitated safeguard against abuse of the opioid analgesic agent. For abstinence syndrome) when the Subjects attempt to take at example, a composition disclosed herein can further com least twice the usually prescribed dose at a time (and often 2-3 prise an effective amount of an adverse-effect agent or times that dose or more), as compared to a comparable dose of antagonistagent that reduces or eliminates one or more of: (1) the opioid without the opioid antagonist present. In certain the capacity of the opioid analgesic agent to produce the kind embodiments, an amount of naltrexone or a salt thereof is of physical dependence in which withdrawal causes sufficient included in the oral dosage form and is less positively rein distress to bring about drug-seeking behavior; (2) the ability forcing (e.g., less “liked') to a non-physically dependent to Suppress withdrawal symptoms caused by withdrawal from opioid addict than a comparable oral dosage form without the the opioid analgesic agent; and (3) the induction of euphoria. antagonist included. In one embodiment the composition pro Useful adverse-effect agents include, but are not limited to, vides effective analgesia when orally administered. opioidantagonists. When there is a potential for an overdose, 0296. In some embodiments the oral dosage form can be then an antidote of the opioid analgesic agent can be used as administered on a twice-a-day or a once-a-day basis. the adverse-effect agent. 0297. The composition can be formulated as a controlled 0291. The phrase “adverse-effect agent' is also meant to oral formulation in any suitable tablet, coated tablet or mul encompass all pharmaceutically acceptable salts of the tiparticulate formulation known to those skilled in the art. The adverse-effect agent. controlled release dosage form can optionally include a car 0292 Opioid antagonists that can be used as an adverse rier which is incorporated into a matrix or can be applied as a effect agent include, but are not limited to, naloxone, naltr controlled release coating. exone, nalmefene, cyclazacine, levallorphan, or a salt thereof, 0298. In embodiments in which the opioid analgesic is and mixtures thereof. In certain embodiments, the opioid hydrocodone (or a pharmaceutically acceptable salt thereof), antagonist is naloxone, naltrexone or a pharmaceutically the extended release oral dosage forms may include analgesic acceptable salt thereof. doses from about 4 mg to about 60 mg of hydrocodone or a 0293. In some embodiments, the opioid agent and the salt thereof per dosage unit. In a controlled release oral dos opioidantagonist are present in a ratio of opioid antagonist to age forms where hydromorphone or a salt thereof is the thera opioid agent (analgesic) which is analgesically effective peutically active opioid, it can be included in an amount from when the combination is administered orally, but which is about 2 mg to about 64 mg hydromorphone hydrochloride. In aversive in a physically dependent Subject. In this manner, the yet another embodiment, the opioid analgesic is oxycodone combination product (antagonist/agonist) could in essence be and the controlled release oral dosage forms include from therapeutic to one population (patients in pain), while being about 2.5 mg to about 800 mg oxycodone HCL. Alternatively, unacceptable (aversive) in a different population (e.g., physi the dosage form may contain molar equivalent amounts of cally dependent subjects) when orally administered at the other salts of the opioids useful in compositions described same dose or at a higher dose than the usually prescribed herein. US 2012/020 1888 A1 Aug. 9, 2012

0299. In other embodiments U.S. Pat. Nos. 6.228,863: (e.g., water or saline), a viscous or semi-viscous gel is 6,475,494; 7.201920; and 7,172,767, 7,201.920 disclose formed. The increase in the viscosity of the solution discour useful opioid agent/opioidantagonist formulations which can ages the abuser from injecting the gel intravenously or intra be used for the methods and compositions described herein, muscularly by preventing the abuser from transferring Suffi which are herein incorporated by reference in their entirety. cient amounts of the Solution to a syringe to cause a desired 0300. In another embodiment, one or more non-opioid “high” once injected. analgesic agents, in addition to the opioid antagonist, can be 0307 Suitable polymers include one or more pharmaceu included in the dosage form. Such non-opioid drugs can tically acceptable polymers selected from any pharmaceuti provide additional analgesia, and include, for example, aspi cal polymer that will undergo an increase in Viscosity upon rin; acetaminophen; non-steroidal anti-inflammatory drugs contact with a solvent. Polymers can include polyethylene (“NSAIDS”), e.g., ibuprofen, naproxen, ketoprofen, etc.; oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a and carbomers. morphinan Such as dextromethorphan or dextrorphan, or ket 0308. In another embodiment the compositions comprise amine; cyclooxygenase-II inhibitors (“COX-II inhibitors'); an abuse deterrent agent that is a mucous membrane irritant or and/or glycine receptor antagonists. nasal passageway tissue irritant, or both. These irritants are 0301 Abuse Deterrent Agents. designed to deter abuse via the improper administration of a 0302) In another embodiment the compositions compris dosage form comprising an opioid (e.g., crushing and Snort ing an opioid analgesic safeguards against abuse by further ing). In one embodiment, Suitable mucous membrane irritants comprising one or more abuse deterrent agents. The choice of or nasal passageway tissue irritants include compounds that which abuse deterrent agent to include in a composition can are generally considered pharmaceutically inert, yet can be varied depending on the route of administration and induce irritation. Such compounds include, but are not lim intended method of treatment. For example different abuse ited to Surfactants. In one embodiment, Suitable Surfactants deterrent agents can be used in conjunction with same phar include Sodium lauryl Sulfate, poloxamer, Sorbitan maceutically active agents depending on if they are formu monoesters and glyceryl monooleates. Other Suitable com lated as an oral dosage form or a transdermal dosage form. pounds are believed to be within the knowledge of a practi Similarly, compositions intended to treat a cancer associated tioner skilled in the relevant art, and can be found in the pain in a Subject can comprise a different abuse deterrent Handbook of Pharmaceutical Excipients, 4th Ed. (2003), the agent than a composition intended to treat headache associ entire content of which is hereby incorporated by reference. ated pain in a subject. 0309. In one embodiment the irritant can be present in 0303. In one embodiment the abuse deterrent agent is for amount of from 1 to 10 percent by weight on a solid basis, mulated as a gel-forming agent, and optionally comprises one such as from about 1 to 5 percent by weight on a solid basis. or more mucous membrane irritants or nasal passageway In another embodiment, the amount of irritant can be present tissue irritants. In another embodiment, the compositions in an amount from 1 to 3 percent by weight. described herein include a composition comprising an anal 0310. In another embodiment, the irritant can deter abuse gesic, one or more gel-forming agents and one or more emet of a dosage form when a potential abuser tampers with a ics as described herein. In another embodiment, the compo dosage form described herein. Specifically, in such embodi sitions comprise an opioid analgesic, one or more mucous ments, when an abuser crushes the dosage form, the irritant is membrane irritants or nasal passageway tissue irritants and exposed. The irritant discourages inhalation of the crushed one or more emetics as described herein. In one particular dosage form by inducing pain and/or irritation of the abuser's embodiment, the compositions comprise an analgesic, one or mucous membrane and/or nasal passageway tissue. In one more gel-forming agents, one or more mucous membrane embodiment, the irritant discourages inhalation (e.g., via irritants and/or nasal passageway tissue irritants, and one or Snorting through the nose) by inducing pain and/or irritation more emetics. of the abuser's nasal passageway tissue. 0304 Suitable gel-forming agents include compounds 0311. In one embodiment, the compositions described that, upon contact with a solvent (e.g., water), absorb the herein comprise one or more mucous membrane irritants that Solvent and Swell, thereby forming a viscous or semi-Viscous cause irritation of mucous membranes located anywhere on Substance that significantly reduces and/or minimizes the or in the body, including membranes of the mouth, eyes and amount of free solvent which can contain an amount of solu intestinal tract. Such compositions can deter abuse via oral, blized drug, and which can be drawn into a Syringe. The gel intra-ocular or rectal or vaginal routes. can also reduce the overall amount of drug extractable with 0312. In another embodiment the compositions comprise the solvent by entrapping the drug in a gel matrix. In one an abuse deterrent agent that is an emetic or emesis inducing embodiment, typical gel-forming agents include pharmaceu agent. In one embodiment the emetic can be a pharmaceuti tically acceptable polymers, typically hydrophilic polymers, cally acceptable inert excipient that only induces emesis after Such as hydrogels. a certain threshold amount is ingested. In another embodi 0305. In some embodiments, the polymers exhibit a high ment, the emetic can be a pharmaceutically active emetic. degree of viscosity upon contact with a suitable solvent. The 0313. In one embodiment, the amount of emetic present in high viscosity can enhance the formation of highly viscous the compositions described herein can be tied directly to the gels when attempts are made by an abuser to crush and dis amount of drug in the composition. Thus, by controlling the Solve the contents of a dosage form in an aqueous vehicle and quantity of the emetic compound in the composition, emesis inject it intravenously. can be avoided if normal prescription directions are followed. 0306 More specifically, in certain embodiments the poly However, if an overdosage occurs by ingesting more than a meric material described herein provides viscosity to the prescribed quantity of a drug in a composition described dosage form when it is tampered. In Such embodiments, when herein, the amount of ingested emetic can exceed the thresh an abuser crushes and dissolves the dosage form in a solvent old amount necessary to induce emesis. US 2012/020 1888 A1 Aug. 9, 2012 32

0314. In some embodiments, the threshold amount of 0321. In one embodiment, compositions and methods emetic for inducing emesis can be reached when the normal described herein includes about 10 mg to about 500 mg of the prescription directions are inappropriately increased by fac flushing, itching, or pain inducing agent. In yet another tors of 2, 3, 4, 5, 6, 7, or 8 times, or more. Thus, in some embodiment, a composition comprises about 15 mg to about embodiments, the amount of emetic present in a composition 150 mg of a flushing, itching, or pain agent. In another described herein is an amount Such that the amount of emetic embodiment, a composition comprises 15, 30, 45, 60, 75, 90 ingested does not exceed the threshold amount necessary for or 105 mg of a flushing, itching, or pain inducing agent. In one inducing emesis until a Subject ingests 2, 3, 4, 5, 6, 7, or 8 or embodiment, compositions and methods described herein more times the amount of drug normally prescribed. In some includes a flushing, itching, or pain inducing agent in an amount of about 1% to 25%, typically about 3% to 15%, more embodiments, emesis can preclude death or serious illness in typically about 1%, 3%, 6%, 9%, 12%, 15% or 20% by the subject. weight, including or excluding the weight of any analgesic 0315. In one embodiment, the emetic is zinc sulfate. Zinc and/or other drug susceptible to abuse. Sulfate is an excipient, which can induce emesis when more 0322. In some embodiments of dosage forms having a than about 0.6 to 2.0 gmisingested, typically more than about controlled release layer or formulation, the amount of flush 0.6 gm, or about 5 to 25 percent by weight on a solid basis, ing inducing agent (and in other embodiments, the amount of more typically about 5 to 10 percent by weight. Accordingly, any abuse deterrent component or opioid antagonist compositions described herein can be easily designed to described herein), can exceed the threshold amount present in induce emesis if a prescribed dosage is exceeded and/or if an immediate release form. This is because in controlled prescription directions are not followed for dosage forms release formulations, the amount of drug which is Susceptible containing a composition described herein. Typically, Suit to abuse is typically higher than in an immediate release able embodiments include less than about 0.6 to 2.0 gm of formulation and the flushing inducing agent (or other abuse Zinc sulfate. deterrent component) becomes bioavailable at a slower rate 0316 For example a dosage form can induce emesis only than the immediate release form. Thus, the amount of abuse after a pre-determined number of dosage forms are ingested deterrent component which is bioavailble typically also (such as 4.5.6 or more), in this case the amount of Zinc sulfate remains below the amount Sufficient to cause an abuse deter in each dosage form should not exceed about 0.19 gm. Thus, rent effect. However, if the dosage form is tampered with if three dosage forms are ingested, the amount of emetic can (e.g., ground, chewed or crushed), a large portion of the abuse be 0.57gm, which is less than a typical threshold amount of deterrent component becomes immediately bioavailable, thus the particular emetic. However, if a fourth dosage form hav inducing one or more abuse deterrent effects. ing 0.19 gm. of Zinc sulfate is ingested, the amount of emetic 0323 Examples of abuse deterrent agents that can be used exceeds the threshold amount, and emesis is induced. in compositions described herein are disclosed in US Patent 0317. In another embodiment the compositions comprise Application Nos: US20060177380A1; US200601 10327A1; an effective amount of an abuse deterrent agent that induces and US20070231268A1, which are herein incorporated by flushing, (i.e. redness of the skin, including redness of the skin reference in its entirety. of one or more of the face, neck, chest, back and trunk and 0324 Abuse Deterrence via Chemical Modification of legs) and/or itching and/or discomfort and/or temporary pain Active Agents (a flushing/pain inducing agent or flushing inducing agent), 0325 In another embodiment the compositions comprise and/or generalized pruritis, and/or intense warmth, and/or an opioid agent that is conjugated to a chemical moiety. The chills when administered at or in excess of a threshold chemical moiety can be any chemical Substance that can be amount. attached to the opioid agent in a manner that renders it phar 0318. With respect to flushing, discomfort and pain induc macologically inactive. Analgesics and stimulants produce ing agents, a threshold amount is an amount below which one their pharmacological effects through binding to specific or more adverse effects is absent or below which a subject receptors or uptake proteins. The attachment of certain may experience a beneficial effect. chemical moieties can therefore prevent the active Substance 0319. In one embodiment, the flushing agent or itching from binding its receptor(s) or recognition site on its uptake agent or pain-inducing agent is a drug. In certain embodi protein. Further, without being bound by theory, the covalent ments, the drug is obtainable “over the counter” and in certain modification is believed to prevent the pharmacological effect embodiments, the “over the counter' drug is a vitamin. In yet by preventing the drug from crossing the blood-brain barrier. another embodiment, the vitamin is niacin. In another The attachment of the chemical moiety to the opioid agent can embodiment, the present invention includes vitamin. also prevent or substantially delay the absorption of the com 0320 Accordingly, in one embodiment the amount of pound, particularly when the compound is delivered by routes flushing, itching, or pain inducing agent present in a compo other than oral administration. sition described herein can be tied directly to the amount of 0326 In one embodiment of the invention, the chemical drug in the composition. Thus, by controlling the quantity of moiety is attached to the opioid agent in a manner in which it the flushing, itching, or pain inducing agent in the composi is not readily released by conditions found in the mouth tion, flushing, itching, or pain can be avoided if normal pre (saliva), the intranasal cavity, the Surface of the lungs, or in the scription directions are followed. However, if an overdosage serum. Extreme acid conditions encountered in the stomach occurs by ingesting more than a prescribed quantity of a drug are not present elsewhere in humans. Therefore, any acid in a composition described herein (e.g., by ingesting more dependent release mechanism will occur only after oral than the prescribed dose), the total amount of flushing, itch administration. Although, degradative enzymes are present in ing, or pain inducing agent can, in certain embodiments, the aforementioned environments, they are not generally exceed the threshold amount necessary to induce flushing, present in the high concentrations found in the intestinal tract. itching, or pain thereby inducing flushing, itching, or pain. Thus, release of the opioid agent by enzymatic cleavage will US 2012/020 1888 A1 Aug. 9, 2012

not occur rapidly when the novel compounds are adminis but are not limited to promethazine, dolasetron, granisetron, tered by routes other than oral delivery. ondansetron, tropisetron, palonosetron, domperidone, dro 0327. In another embodiment of the invention, the opioid peridol, haloperidol, chlorpromazine, prochloperazine, agent is attached to a polymer of serine (or other amino acid metoclopramide, aliZapride, cyclizine, diphenhydramine, containing a hydroxyl side chain e.g. threonine, tyrosine) via dimenhydrinate, meclizine, hydroxy Zine, cannabis, dronab side chain hydroxyl groups. Alternatively, attachment is to a inol, nabilone, midazolam, lorazepam, hyoscine, dexametha polymer of glutamic acid through the carboxyl group of the Sone, trimethobenzamide, emetrol and propofol. delta carbon of glutamic acid. The resulting ester (carbonate) 0334 Additives linkages can behydrolysed by lipases (esterases) encountered 0335 The present compositions can further comprise suit in the Small intestine. Esterases are not present at high levels able additives, including, but not limited to, diluents, binders, in Saliva or on the mucosal Surfaces of the nasal cavity, lungs, Surfactants, lubricants, glidants, coating materials, plasticiz or oral cavity. Thus, opioid agents attached to polyglutamic ers, coloring agents, flavoring agents, or pharmaceutically acid by this method would not be rapidly released by saliva or inert materials. Examples of diluents include, for example, when delivered intranasally or by inhalation. cellulose; cellulose derivatives such as microcrystalline cel 0328. In another embodiment of the invention, the opioid lulose and the like; starch; starch derivatives Such as corn agent is attached to an oligopeptide, which can consist of starch, cyclodextrin and the like; Sugar, Sugar alcohol Such as between one and five amino acids. Inafurther embodiment of lactose, D-mannitol and the like; inorganic diluents such as the invention the amino acids are a heterogenous mixture of dried aluminum hydroxide gel, precipitated calcium carbon the twenty naturally occurring amino acids. Hydrophilic ate, magnesium aluminometasilicate, dibasic calcium phos amino acids will tend to prevent passive absorption of the phate and the like. analgesic peptide conjugate through nasal membranes. In one 0336. Examples of binders include, for example, hydrox embodiment of the invention that hydrophilic amino acids be ypropylcellulose, methylcellulose, hydroxypropylmethylcel included in the oligopeptide. In another embodiment of the lulose, povidone, dextrin, pullulane, hydroxypropyl Starch, invention that lipophilic amino acids be attached closer to the polyvinyl alcohol, Scacia, agar, gelatin, tragacanth, macrogol analgesic for optimum stability. Both lipophilic and hydro and the like. philic properties (i.e., amphiphilic) can be satisfied with 0337 Examples of surfactants include, for example, between three and five amino acids. In a further embodiment Sucrose esters of fatty acids, polyoxyl Stearate, polyoxyeth of the invention that the oligopeptide that is attached to the ylene hydrogenated castor oil, polyoxyethylene polyoxypro analgesic can be an amphiphilic tripeptide. pylene glycol, Sorbitan sesquioleate, sorbitan trioleate, Sorbi 0329 Amphiphilic amino acids/oligopeptides may con tan monostearate, Sorbitan monopalmitate, Sorbitan tain (i) hydrophobic amino acids, located in positions next to monolaurate, polysorbate, glyceryl monostearate, sodium the active agent to provide increased stability; (ii) amino acid lauryl Sulfate, lauromacrogol and the like. sequences designed to be cleaved by intestinal enzymes (e.g. 0338 Examples of lubricants include, for example, stearic pepsin, trypsin, chymotrypsin, elastase, carboxypeptidases A acid, calcium Stearate, magnesium Stearate, talc and the like. and B, etc.) provide for increased bioavailability; (iii) pep 0339 Examples of glidants include, for example, dried tides longer than three amino acids for increased stability, aluminum hydroxide gel, magnesium silicate and the like. increased anti-abuse e.g. less membrane permeability, and 0340 Examples of coating materials include, for example, potentially more efficient intestinal digestion e.g. majorintes hydroxypropylmethyl cellulose 2910, aminoalkyl methacry tinal enzymes target proteins and polypeptides, (iv) or mix late copolymer E. polyvinylacetal diethylaminoacetate, mac tures thereof. In one embodiment the carrier portion of the rogol 6000, titanium oxide and the like. Examples of plasti conjugate is designed for intestinal cleavage. cizers include, for example, triethyl citrate, triacetin, 0330. In another embodiment the cleavage specificity is macrogol 6000 and the like. directed to pepsin and/or chymotrypsin. Examples of carriers 0341 Administration include XXXAA or XXAAA, where X is selected from any 0342. Described herein are methods for preventing an amino acid, except Arg, Lys, His, Pro, and Met and A is adverse effect Such as nausea, vomiting, other gastric upsets, selected from Tyr, Phe, Trp, or Leu. Examples of other carri skin rashes, itching, allergic reactions such as Swelling, dif ers are selected from XXXPheleu wherein X is Glu, XXX ficulty breathing, closing of throat, abdominal pain, unusual Pheleu wherein X is Gly; XXPheleuLeu wherein X is Glu: bleeding or bruising, skin rashes, sedation, CNS depression, and XXPheleuleu wherein X is Gly. or respiratory depression in a subject receiving, or in need of 0331. In another embodiment the cleavage specificity is opioid analgesic therapy. The prevention of an adverse effect directed to trypsin. Examples of more carriers include can be accomplished by the administration of an effective XXXAA or XXAAA wherein X is any amino acid except Pro amount of promethazine or other antihistamine with the cho and Cys and A is Arg or Lys. Examples of yet more carriers Sen analgesic agent or agents. In one embodiment, the inven are selected from XXXArgLeu wherein X is Glu; XXXAr tion provides methods for treating pain, comprising adminis gLeu wherein X is Gly: XXArgLeuLeu wherein X is Gly: tering to a subject in need thereof an effective amount of an XXXArgLeuLeu wherein X is Gly. opioid analgesic agent, a non-opioid analgesic agent, an agent 0332 Examples of chemical modifications to opioid that reduces side effects of the opioid analgesic agent and agents that can be used in compositions described herein are optionally a stimulant agent. In one embodiment, the non disclosed in US Patent Application No. 20050080012, which opioid analgesic agent is acetaminophen. In another embodi is herein incorporated by reference in its entirety. ment, the agent that reduces an adverse effect is promethaZ 0333. In another embodiment, one or more adverse-effect ine. In another embodiment, the invention provides methods reducing active agents in addition to the opioid antagonist for treating pain, comprising administering to a subject in agent or abuse deterrent component, can be included in the need thereofan effective amount of an opioid analgesic agent, dosage form. Adverse-effect-reducing active agents include a non-opioid analgesic agent, a barbiturate agent, an agent US 2012/020 1888 A1 Aug. 9, 2012 34 that reduces side effects of the opioid analgesic agent and tamine is promethazine. In one embodiment, the opioid anal optionally a stimulant agent. In another embodiment, the gesic is hydrocodone. In another embodiment the opioid invention provides methods for treating pain, comprising analgesic is oxycodone. In another embodiment, the inven administering to a subject in need thereofan effective amount tion provides methods for preventing or ameliorating an of an opioid analgesic agent, a barbiturate agent, an agent that adverse effect associated with administration of an analgesic, reduces side effects of the opioid analgesic agent and option comprising administering to a subject in need thereof an ally a stimulant agent. In another embodiment, the invention effective amount of an opioid analgesic agent, a non-opioid provides methods for treating pain, comprising administering analgesic agent, an agent that reduces side effects of the to a subject in need thereof an effective amount of an a non-opioid analgesic agent, a barbiturate agent, an agent that opioid analgesic agent and optionally a stimulant agent. In reduces side effects of the opioid analgesic agent and option one embodiment, the non-opioid analgesic agent is acetami ally a stimulant agent. In another embodiment, the invention nophen. In another embodiment, the agent that reduces an provides methods for treating pain, comprising administering adverse effect is promethazine. In another embodiment, the to a subject in need thereof an effective amount of an opioid invention provides methods for preventing or ameliorating an analgesic agent, an agent that reduces side effects of the adverse effect associated with administration of an analgesic, opioid analgesic agent and optionally a stimulant agent. comprising administering to a subject in need thereof an 0343. The administration can continue for only a relatively effective amount of an opioid analgesic agent, a non-opioid short time in the case of an acute condition requiring opioid analgesic agent, a barbiturate agent, an agent that reduces side therapy or for long periods in the case of conditions requiring effects of the opioid analgesic agent and optionally a stimu chronic use of opioid analgesics. The dosing of analgesics can lant agent. In another embodiment, the invention provides be dependent upon the condition being treated, the Subject's methods for preventing or ameliorating an adverse effect individual perception of pain and the use of the opioid on a set associated with administration of an analgesic, comprising time schedule as a prophylactic to prevent the onset of pain or administering to a subject in need thereofan effective amount on an as needed basis in response to perceived pain. The of an opioid analgesic agent, a barbiturate agent, an agent that choice of selecting a dosage of a composition that contains reduces side effects of the opioid analgesic agent and option Suitable amount of promethazine can be dependent upon the ally a stimulant agent. In another embodiment, the invention extent and severity of the adverse effects including nausea, provides methods for preventing or ameliorating an adverse Vomiting, other gastric upsets, skin rashes, allergic reactions effect associated with administration of an analgesic, com such as Swelling, difficulty breathing, closing of throat, prising administering to a subject in need thereof an effective abdominal pain, unusual bleeding or bruising, skin rashes, amount of an a non-opioid analgesic agent, a barbiturate sedation, CNS depression, or respiratory depression in a Sub agent, an agent that reduces side effects of the opioid analge ject, upon the sensitivity to side-effect-reducing compounds sic agent and optionally a stimulantagent. In another embodi Such as promethazine in a Subject, upon the likelihood of ment, the invention provides methods for preventing orame Subject losing medication by Vomiting, and/or on an as liorating an adverse effect associated with administration of needed basis in response to perceived adverse effects. The an analgesic, comprising administering to a subject in need dosage can be assessed by a prescribing professional evalu thereof an effective amount of an opioid analgesic agent, an ating the Subject, the condition treated, the analgesic to be agent that reduces side effects of the opioid analgesic agent used, diet and the expected duration of therapy. and optionally a stimulant agent. 0344. In one embodiment, compositions and methods described herein provides for a method for treating a subject 0346. In another embodiment, compositions and methods Suffering from or Susceptible to pain, comprising administer described herein provides for a method for preventing an ing to said subject an effective amount of a composition adverse effect such as nausea, vomiting, and a skin rash in a comprising an effective amount of a first component which is Subject receiving or in need of opioid therapy by the admin a non-opioid analgesic, or a pharmaceutically acceptable salt istration of an effective amount of acetaminophen or ana thereof, an effective amount of a second component which is logue thereof and promethazine with the opioid analgesic a non-opioid analgesic, or a pharmaceutically acceptable salt agent. In one embodiment, the opioid analgesic is hydroc thereofand an effective amount of a third component which is odone. In another embodiment the opioid analgesic is oxyc an antihistamine. odone. In one embodiment, administration of a composition 0345. In another embodiment, a method for treating a sub comprising a non-opioid analgesic and an antihistamine ject is provided comprising administering an effective enhances the reduction or elimination of adverse effects asso amount of a composition comprising: an effective amount of ciated with an opioid analgesic. For example, addition of a first pharmaceutically active agent which is an opioid anal promethazine and acetaminophen/ibuprofen reduces or gesic, or a pharmaceutically acceptable salt thereof, an effec eliminates an adverse effect associated with an opioid anal tive amount of a second pharmaceutically active agent which gesic in a Synergistic manner. is a non-opioid analgesic, or a pharmaceutically acceptable 0347. It is believed that administration of a composition of salt thereof; and an effective amount of a third pharmaceuti the invention would result in treatment of the subject which cally active agent which is an antihistamine oran anti-emetic. includes elimination or reduction of an adverse effect associ In one embodiment the at least one adverse effect is nausea, ated with analgesics (e.g., opioids) and enhance the beneficial Vomiting, other gastric upsets, skin rashes, allergic reactions uses of such analgesics. Such an adverse effect can otherwise Such as Swelling, difficulty breathing, closing of throat, itch render administration of certain analgesics intolerable, due to ing, abdominal pain, unusual bleeding or bruising, skin for example Vomiting, nausea, and skin rashes. Therefore, rashes, sedation, CNS depression, or respiratory depression. various embodiments of the methods of the invention are In one embodiment the non-opioid analgesic is acetami directed to target populations of subjects that are Susceptible nophen or analogue thereof. In one embodiment, the antihis to Such an adverse effect(s), thus allowing such subjects to US 2012/020 1888 A1 Aug. 9, 2012 benefit from the pain-alleviating effects of analgesic-based compositions are at least one opioid analgesic agent, an agent pain relief, administration of which would otherwise be intol that reduces side effects of the opioid analgesic agent and erable. optionally a stimulant agent. 0348 For example, by reducing the risk of vomiting, the 0352. The agents of the compositions and methods risk of Subject losing the analgesics (and losing the pain described herein can be administered by the nasal inhalation relieving beneficial effects of analgesics) by Vomiting is mini route using conventional nebulizers or by oxygen aerosoliza mized. Furthermore, administration can be adjusted to pro tion to provide convenient pain relief with reduced adverse vide the dose of side-effect-reducing compound to match the effects. The agents can be suspended or dissolved in a phar Subjects analgesic ingestion without separate intervention by macologically acceptable inhalation carrier. Examples of the health care professionals. Adding one or more additional Such carriers are distilled water, water/ethanol mixtures, and active agents, such as promethazine, to the present composi physiological saline Solution. Conventional additives includ tions is believed to result in a composition having reduced ing Sodium chloride, glucose, citric acid and the like may be potential for abuse and diversion. employed in these dosage forms to stabilize or to provide 0349 Routes of Administration isotonic media. In one embodiment of the invention, the com 0350. In various embodiments, the active agents are for positions suitable for nasal inhalation by oxygen aerosoliza mulated to be administered through oral dosage forms (e.g., tion administration comprise hydrocodone or oxycodone, tablets, capsules, gels, lollipops), inhalations, nasal sprays, acetaminophen, and promethazine. In other embodiments, an patches, absorbing gels, liquids, liquid tannates, supposito antihistamine (e.g., promethazine) can be administered sepa ries, injections, I.V. drips, other delivery methods, or a com rately, prior to, or during administration of the compositions bination thereof to treat subjects. Administration may be per described herein (e.g., those comprising hydrocodone and formed in a variety of ways, including, but not limited to acetaminophen). orally, Subcutaneously, intravenously, intranasally, intraoti 0353. The agents described herein can also be adminis cally, transdermally, topically (e.g., gels, salves, lotions, tered as a self-propelled dosage unit in aerosol form Suitable creams, etc.), intraperitoneally, intramuscularly, intrapulmo for inhalation therapy. Suitable means for employing the nary (e.g., AERX(R) inhalable technology commercially avail aerosol inhalation therapy technique are described, for able from Aradigm, or Inhance, pulmonary delivery system example, in U.S. Pat. No. 6,913,768 to Couch et al., which is commercially available from Inhale Therapeutics), vaginally, incorporated herein by reference in its entirety. The agent can parenterally, rectally, or intraocularly. be suspended in an inert propellant Such as a mixture of 0351) To prepare the present compositions, an effective dichlorodifluoromethane and dichlorotetrafluoroethane, amount of active agents can be mixed with a suitable phar together with a co-solvent such as ethanol, together with maceutically acceptable carrier. Upon mixing of the com flavoring materials and stabilizers. In one embodiment of the pounds, the resulting composition can be a solid, a half-solid, invention, the agents useful for a self-propelled dosage unit in a solution, Suspension, or an emulsion. Such compositions aerosol form administration are hydrocodone or oxycodone, can be prepared according to methods known to those skilled acetaminophen, and promethazine. In a further embodiment in the art. The forms of the resulting compositions can depend the dosage unit may further comprise an agent Such as a upon a variety of factors, including the intended mode of bronchodilator (e.g., albuterol). administration and the solubility of the compounds in the 0354. The agents of the compositions and methods selected carrier or vehicle. The effective concentration of described herein can also be administered as nasal spray/drop analgesics is sufficient for lessening oralleviating pain. In one compositions, which can conveniently and safely be applied embodiment of the invention, the components of the present to subjects to effectively treat pain with reduced adverse compositions are at least one opioid analgesic agent (e.g., effects. The compositions may further comprise a water hydrocodone/oxycodone), one non-opioid analgesic agent soluble polymer Such as polyvinylpyrrolidone, together with (e.g., acetaminophen), and one antihistamine agent (e.g., other medications such as Sumatriptan, together with bioad promethazine). In other embodiments, administration com hesive material. In one embodiment of the invention, the prises administration of an antihistamine (e.g., promethazine) components of a composition for nasal spray or drop admin separately, prior to, or during administration of the analgesic istration are hydrocodone or oxycodone agent, acetami formulations described herein (e.g., which comprises hydro nophen, and promethazine, or a pharmaceutically acceptable codone and acetaminophen). In another embodiment the salt thereof. components of the present compositions are at least one 0355 The compositions described herein can also be opioid analgesic agent, a non-opioid analgesic agent, an agent administered topically to the skin of a subject. The agents can that reduces side effects of the opioid analgesic agent and a be mixed with a pharmaceutically acceptable carrier or a base stimulant agent. In another embodiment, the components of which is suitable for topical application to skin to form a the present compositions are at least one opioid analgesic dermatological composition. Suitable examples of carrier or agent, a non-opioid analgesic agent, a barbiturate agent, an base include, but not limited to, water, glycols, alcohols, agent that reduces side effects of the opioid analgesic agent lotions, creams, gels, emulsions, and sprays. A dermatologi and optionally a stimulantagent. In another embodiment, the cal composition comprising an analgesic agent can be inte components of the present compositions are at least one grated into a topical dressing, medicated tape, dermal patch opioid analgesic agent, a barbiturate agent, an agent that absorbing geland cleansing tissues. In one embodiment of the reduces side effects of the opioid analgesic agent and option invention, the dermatological composition comprises hydro ally a stimulant agent. In another embodiment, the compo codone or oxycodone, acetaminophen, and promethazine. nents of the present compositions are at least one non-opioid 0356. The compositions described herein can also be in analgesic agent, a barbiturate agent, an agent that reduces side liquid or liquid tannate form. The liquid formulations can effects of the opioid analgesic agent and optionally a stimu comprise, for example, an agent in water-in-solution and/or lantagent. In another embodiment, components of the present Suspension form; and a vehicle comprising polyethoxylated US 2012/020 1888 A1 Aug. 9, 2012 36 castor oil, alcohol and/or a polyoxyethylated Sorbitan mono includes, but is not limited to, pain associated with cancer, oleate with or without flavoring. Each dosage form comprises chronic or acute pain, headache pain, migraine headache, an effective amount of an active agent and can optionally chronic headache, Surgical procedure, acute or chronic physi comprise pharmaceutically inert agents, such as conventional cal injury, bone fracture or crush injuries, spinal cord injury, excipients, vehicles, fillers, binders, disintegrants, pH adjust inflammatory disease (e.g., pancreatitis), noninflammatory ing Substances, buffer, solvents, Solubilizing agents, Sweet neuropathic or dysfunctional pain conditions, or a combina eners, coloring agents and any other inactive agents that can tion thereof. be included in pharmaceutical dosage forms for oral admin 0361 Various methods of drug administration known in the art or disclosed herein are utilized to deliver a composition istration. Examples of such vehicles and additives can be of present invention to a subject in need thereof. found in Remington's Pharmaceutical Sciences, 17th edition 0362. In some embodiments, methods of treatment or pre (1985). Therefore, in one embodiment a liquid composition vention comprising administering a composition of the inven of the invention comprises an opioid analgesic (e.g., hydroc tion are for treating pain or preventing pain. In some embodi odone or oxycodone), a non-opioid analgesic (e.g., acetami ments, the pain treatable or preventable via administration of nophen) and an antihistamine (e.g., promethazine). In another a composition of the invention includes but is not limited to embodiment a liquid composition of the invention comprises headache pain, and/or headache related symptoms as further at least one opioid analgesic agent, a non-opioid analgesic described herein below. agent, an agent that reduces side effects of the opioid analge 0363 Treatment or Prevention of Headache sic agent and a stimulant agent. In another embodiment, a 0364 The present compositions and methods are useful liquid composition of the invention comprises at least one for treating or preventing aheadache. Preventable or treatable opioid analgesic agent, a non-opioid analgesic agent, a bar headaches include but are not limited to migraine headaches biturate agent, an agent that reduces side effects of the opioid (with or without aura), cluster headaches, chronic headaches, analgesic agent and optionally a stimulant agent. In another tension type headaches, Hemicrania Continua, new daily per embodiment, a liquid composition of the invention comprises sistent, chronic tension type headaches or any combination at least one opioid analgesic agent, a barbiturate agent, an thereof. In one embodiment, a method for treating or prevent agent that reduces side effects of the opioid analgesic agent ing a headache comprises administering to a subject in need and optionally a stimulant agent. In another embodiment, a thereof a composition of the invention. Each of Such compo liquid composition of the invention comprises at least one sitions if fully described herein. non-opioid analgesic agent, a barbiturate agent, an agent that 0365 Migraines and clusterheadaches are both important, reduces side effects of the opioid analgesic agent and option well-known, and extensively studied medical problem. In ally a stimulant agent. In another embodiment, a liquid com many cases, they completely incapacitate a sufferer for the position of the invention comprises at least one opioid anal duration of the headache. Their physiological embodiments, gesic agent, an agent that reduces side effects of the opioid causative and aggravating factors, and current Treatments are analgesic agent and optionally a stimulant agent. discussed in detail in numerous Scientific articles, and in 0357 The compositions described herein can also be full-length medical textbooks such as Headache in Clinical administered in a Suppository form, comprising an outer layer Practice (edited by S. Silberstein et al., Oxford Univ. Press, containing the composition in a Suppository base. The Sup 1998); The Headaches, by J. Olesen; and Headache Disor pository base may, for example, be any conventional Supposi ders: A Management Guide for Practitioners, by A. Rapoport tory base material Such as glycogelatin, polyethylene glycol, and F. Sheftell (W. B. Saunders, Philadelphia, 1996), which fractionated palm kernel oil, or one or more natural, synthetic are herein incorporated by reference in their entirety. In addi or semi synthetic hard fats such as cocoa butter. Therefore, in tion, various definitions, categories, and diagnostic standards one embodiment of the invention, the base material is mixed are defined by standardized criteria that have been approved with an opioid analgesic (e.g., hydrocodone/oxycodone), a and issued by the International Headache Society (IHS), non-opioid analgesic (e.g., acetaminophen) and an antihista which were published as a supplement to the journal Ceph mine (e.g., promethazine). alalgia (Cephalalgia. 2004; 24 Suppl 1:9-160) and is herein 0358. The compositions described herein can also be incorporated by reference in its entirety. administered in injection-ready stable liquids for injection or 0366. In one embodiment a composition of the invention is I.V. drip. For example, Saline or other injection-ready liquid administered to a subject to treat, eliminate or prevent at least can be mixed with an opioid analgesic (e.g., hydrocodone or one headache symptom. An effective amount is a dosage oxycodone), a non-opioid analgesic (e.g., acetaminophen) Sufficient to reduce at least one symptom associate with a and an antihistamine (e.g., promethazine). In one embodi headache. Headache symptoms include: (1) frequency, which ment a composition disclosed herein is administered by a can be evaluated over a span of time. Such as number of Such Subject administered injection. For example a subject can headaches per week, per month, or per year; (2) duration, administer the composition via a hand-held injection device which evaluates (usually in hours) how long a headache lasts, Such as a pen type injector. In one example a Subject can use from the time it begins to develop into a migraine or cluster a device or component disclosed in U.S. Pat. Nos. 6,146.361; headache, until it has been resolved; and (3) severity (also 5,536,249; or 5.954,700 (which are herein incorporated by referred to as intensity), which is based on subjective esti reference in their entirety) to administer a pharmaceutical mates of the severity or intensity of pain or other symptoms composition disclosed herein. (such as nausea) being Suffered by patients during such head aches. In one embodiment a composition is used in a method 0359 Treatment or Prevention of Pain to reduce the frequency, duration or severity of a preventable 0360. The present compositions and methods are useful or treatable headache. for treating or preventing pain. Accordingly the present invention includes methods for treating or preventing pain, Treatment or Prevention of Photophobia comprising administering to a subject in need thereof a com 0367. In one embodiment, the invention provides methods position of the invention. Pain treatable or preventable for treating or preventing photophobia, comprising adminis US 2012/020 1888 A1 Aug. 9, 2012 37 tering to a subject in need thereof a composition of the inven of promethazine in their blood stream. The promethazine will tion. In one embodiment the composition comprises an effec reduce the adverse effects that such a target population would tive amount of each of an opioid analgesic and an antiemetic, otherwise exhibit. as disclosed herein above. In one embodiment, the antiemetic is promethazine or a pharmaceutically acceptable salt thereof Example 4 and the opioid analgesic is hydrocodone, oxycodone or a 0373 Example of an analgesic composition comprising pharmaceutically acceptable salt thereof. In a further embodi Oxycodone Hydrochloride, Acetaminophen and Promethaz ment, the composition is in the form of a bilayer tablet that ine Hydrochloride comprises an immediate-release layer and a controlled-re lease layer. In another embodiment the immediate-release layer comprises promethazine or a pharmaceutically accept able salt thereof, and the controlled-release layer comprises Analgesic Composition B hydrocodone, oxycodone or a pharmaceutically acceptable Agents mgTablet salt thereof. In a further embodiment, the photophobia is Oxycodone HCI 5 mg or 7.5 mg associated with a migraine headache. Acetaminophen 325 mg 0368. In another embodiment, the invention provides Promethazine Hydrochloride 12.5 mg methods for treating or preventing photophobia, comprising administering to a Subject in need thereof a composition comprising an effective amount of a triptan and an effective Example 5 amount of an antiemetic. In a further embodiment the triptan is a Sumatriptanora pharmaceutically acceptable salt thereof, 0374. In one example, the composition of Example 4 is in and the antiemetic is promethazine or a pharmaceutically the form of a bi-layer tablet having an immediate-release acceptable salt thereof. In one embodiment, the Sumatriptan layer comprising 12.5 mg of promethazine hydrochloride, salt is Sumatriptan Succinate. and having a controlled-release layer comprising 5 or 7.5 mg 0369. In yet a further embodiment, the composition is in of oxycodone HCl and 325 mg of acetaminophen. the form of a bilayer tablet that comprises an immediate release layer and a controlled-release layer. In another Example 6 embodiment of the invention the controlled-release layer 0375. The composition of Example 5 is orally adminis comprises Sumatriptan or a pharmaceutically acceptable salt tered with water to a subject having a tendency to exhibit thereof, and the immediate-release layer comprises promet adverse effects of opioid administration, such as gastric upset, hazine or a pharmaceutically acceptable salt thereof. nausea, vomiting, skin rash, sedation, CNS depression, or respiratory depression. Such Subjects, upon taking the com EXAMPLES position set forth in Example 5 will receive an effective Example 1 amount of promethazine which will reduce the adverse effects that such a target population would otherwise exhibit. 0370. Example of an analgesic composition comprising Hydrocodone Bitartrate, Acetaminophen and Promethazine Example 7 Hydrochloride 0376 Example of an abuse safeguard drug formulation comprising Hydrocodone Bitartrate, Acetaminophen and Promethazine Hydrochloride. Analgesic Composition A Agents mg/Tablet Hydrocodone Bitartrate 7.5 mg Analgesic Composition C Acetaminophen 325 mg Agents mgTablet Promethazine Hydrochloride 12.5 mg Hydrocodone Bitartrate 7.5 mg Acetaminophen 325 mg Promethazine HCI 12.5 mg Example 2 Naltrexone 0.75 mg 0371. In one example, the composition of Example 1 is formulated in the form of a bi-layer tablet having an imme diate-release layer comprising 12.5 mg of promethazine Example 8 hydrochloride and having a controlled-release layer compris 0377. In one example, the composition of Example 7 is in ing 7.5 mg of hydrocodone bitartrate and 325 mg of acetami the form of a bi-layered tablet having an immediate-release nophen. layer comprising 12.5 mg of promethazine hydrochloride, and having a controlled-release layer comprising 7.5 mg of Example 3 hydrocodone bitartrate and 325 mg of acetaminophen. 0372. The composition of Example 1 is orally adminis Example 9 tered with water to a subject having a tendency to exhibit adverse effects of opioid administration, Such as gastric upset, 0378. The composition of Example 7 is orally adminis nausea, vomiting, skin rash, sedation, CNS depression, or tered with water to a subject having a tendency to exhibit respiratory depression. Such Subjects, upon taking the com adverse effects of opioid administration, such as gastric upset, position set forth in Example 1 will receive a effective amount nausea, vomiting, skin rash, sedation, CNS depression, or US 2012/020 1888 A1 Aug. 9, 2012 respiratory depression. Such Subjects, upon taking the com silicified microcrystalline cellulose, about 20 mg of hydroxy position set forth in Example 7 will receive a effective amount methylpropylcellulose, about 2.7 mg of magnesium Stearate, of promethazine in their blood stream. The promethazine will and about 2.7 mg of Stearic acid; and tablet’s immediate reduce the adverse effects that such a target population would release layer comprises about 12.5 mg of promethazine or a otherwise exhibit. pharmaceutically acceptable salt thereof, about 121.5 mg of Example 10 silicified microcrystalline cellulose, about 15 mg of croscar mellose Sodium and about 1 mg of magnesium Stearate. 0379 Example of an abuse safeguard drug formulation comprising Oxycodone HCl, Acetaminophen and Promet hazine HC1. Analgesic Composition F.1 Ingredient Quantity/Tablet (mg) Analgesic Composition D Agents mg/Tablet Top Layer - Immediate Release Layer Promethazine HCI 12.5 mg Oxycodone HCI 5 mg or 7.5 mg Prosolve SMCC (HD90) 121.5 mg Acetaminophen 325 mg Croscarmellose Sodium 15 mg Promethazine HCI 12.5 mg Crospovidone NF 15 mg Naltrexone 0.5 mg or 0.75 mg Avice PH200 21.5 mg Magnesium Stearate 1 mg Total Top Layer Weight 186.5 mg Example 11 Bottom Layer - Controlled-Release Layer 0380. In one example, the composition of Example 10 is in Acetaminophen 89.5% 360.5 mg the form of a bi-layer tablet having an immediate-release Hydrocodone Bitartrate 7.5 mg layer comprising 12.5 mg of promethazine hydrochloride, Silicified Microcrystalline Cellulose 150 mg and having a controlled-release layer comprising 5 or 7.5 mg Hydroxy Methyl Propyl Cellulose 10 mg Croscarmellose Sodium 23 mg of oxycodone HCl and 325 mg of acetaminophen. Magnesium Stearate 15 mg Example 12 Total Bottom Layer Weight 566 mg 0381. The composition of Example 10 is orally adminis tered with water to a subject having a tendency to exhibit adverse effects of opioid administration, Such as gastric upset, nausea, vomiting, skin rash, sedation, CNS depression, or respiratory depression. Such Subjects, upon taking the com Analgesic Composition F.2 position set forth in Example 10 will receive a effective Ingredient Quantity/Tablet (mg) amount of promethazine in their blood stream. The promet hazine will reduce the adverse effects that such a target popu Top Layer - Immediate Release Layer lation would otherwise exhibit. Promethazine HCI 12.5 mg Silicified Microcrystalline Cellulose 121.5 mg Example 13 Croscarmellose Sodium 15 mg Magnesium Stearate 1 mg 0382 Example of a bi-layer tablet analgesic composition comprising Hydrocodone or a Pharmaceutically Acceptable Total Top Layer Weight 150.0 mg Salt Thereof, Acetaminophen and Promethazine or a Pharma Bottom Layer - Controlled-Release Layer ceutically Acceptable Salt Thereof. In one example, a bi-layer Acetaminophen 89.05% 364.96 mg tablet comprises: (1) a controlled-release layer comprising (a) Hydrocodone bitartrate 7.5 mg Silicified Microcrystalline Cellulose 152.04 mg from about 6.5 mg to about 8.5 mg of hydrocodone or a Hydroxy Methyl Propyl Cellulose 20 mg pharmaceutically acceptable salt thereof, (b) from about 290 Stearic Acid 2.75 mg to about 360 mg of acetaminophen or a pharmaceutically Magnesium Stearate 2.75 mg acceptable salt thereof, (c) from about 135 mg to about 170 Total Bottom Layer Weight 566 mg mg of silicified microcrystalline cellulose, (d) from about 17 mg to about 23 mg of hydroxy methyl propyl cellulose, (e) from about 1 mg to about 4 mg of magnesium Stearate, and (f) from about 1 mg to about 4 mg of Stearic acid; and (2) an Example 14 immediate-release layer comprising (a) from about 11 mg to about 14 mg of promethazine or a pharmaceutically accept 0383. The composition of Example 13 is orally adminis able salt thereof, (b) from about 100 mg to about 140 mg of tered with water to a subject having a tendency to exhibit silicified microcrystalline cellulose, (c) from about 12 mg to adverse effects of opioid administration, such as gastric upset, about 18 mg of croscarmellose sodium and (d) from about 0.8 nausea, vomiting, skin rash, sedation, CNS depression, or mg to about 1.5 mg of magnesium Stearate. In another respiratory depression. Such Subjects, upon taking the com example, a bi-layer tablet's controlled-release layer com position set forth in Example 13 will receive an effective prises about 7.5 mg of hydrocodone or a pharmaceutically amount of promethazine in their blood stream. The promet acceptable salt thereof, about 325 mg of acetaminophen or a hazine will reduce the adverse effects that Such a target popu pharmaceutically acceptable salt thereof, about 152 mg of lation would otherwise exhibit. US 2012/020 1888 A1 Aug. 9, 2012 39

Example 15 aliquot of the dissolution fluid was drawn using the automated sampling station equipped with a 35 um full flow filter con 0384 Dissolution Data. nected to a sampling probe. Filtrate was allowed to cool to 0385 Dissolution apparatus was a USP Rotating Paddle room temperature, to produce a final sample solution. Fluid Apparatus 2 with an automated sampling station (e.g., withdrawn was not replaced. Samples were injected in HPLC VK-8000 or equivalent). Dissolution fluid was 900 mL of for analysis after a baseline was established. Peak area de-aerated 0.01N HCl, maintained at 37.0+/-0.5° C. during responses were measured for each component: acetami dissolution procedure. The fluid was prepared by diluting 5 nophen peak eluted at about 1.5 minutes; hydrocodone bitar mL of concentrated HCl in 6000 mL of de-aerated water, and trate eluted at about 3.3 minutes and promethazine HCl eluted mixed. To measure peaks, a dual wavelength detector (e.g., at about 4.8 minutes. The resolution between each peak was Hitachi L-2420) was used, or alternatively, two separate chro calculated, as well as the tailing factor. The mean and% RSD matographic systems can be used in order to measure the values for the acetaminophen peak areas at 300 nm were peaks at two different wavelengths. measured; promethazine HCl and hydrocodone bitartrate at 0386 Standard Solution Preparation: Each ingredient was 230 nm. The five replicate injections were not more than 2.0% weighed (e.g., 21 mg of hydrocodone bitrartrate) into a 50 mL RSD. 50 ul aliquots of standard and sample solutions were Volumetric flask, and diluted to volume with dissolution Subjected to liquid chromatography. A typical chromatogram media. The resulting solution was mixed to form a stock of a standard solution is illustrated in FIG.1. solution. Different ingredients were similarly prepared to 0390 The amount of a pharmaceutically active agent in a tablet is determined by comparing the area obtained for the provide Stock Solutions (e.g., promethazine HCl, acetami peak due to the agent in a chromatogram of the dissolution nophen). 2 mL each of stock standard solutions were diluted test solution to that obtained for the corresponding peak in a with dissolution fluid and mixed to produced a final standard chromatogram of a standard solution. For example the stan Solution. For example, the concentration of hydrocodone dard peaks are provided in FIG. 3, while the test solutions are bitartrate was about 0.0084 mg/mL, promethazine HCl was provide in FIG. 4. about 0.014 mg/mL, and acetaminophen was about 0.36 mg/mL. Example 16 0387 Dissolution test solutions were prepared in 900 mL 0391 The compositions of Table 1 or Table 2 can be for of 0.01 NHCl using the USP Rotating Paddle Apparatus at 50 mulated in formulated in a variety of dosage forms (e.g., uM. An aliquot of the dissolution solution was filtered and a tablets, capsules, geld, lollipops), parenteral, intraspinal infu Sion, inhalations, nasal sprays, transdermal patches, ionto 50-pil aliquot was chromatographed on a 50-mmX4.6-mm phoresis transport, absorbing gels, liquids, liquid tannates, (i.d.) Waters sunFireTM Cs, 3.5-lum particle size column Suppositories, injections, I.V. drips, other delivery methods, using a gradient HPLC method. Mobile phase A consisted of or a combination thereof to treat subjects. In some embodi waterfacetonitrile/TFA,950/50/2 (v/v/v) and mobile phase B ments each agent disclosed in Table 1 or Table 2 can be consisted of waterfacetonitrile/TFA, 50/950/1.5 (v/v/v). The present in a composition as its pharmaceutically acceptable flow rate was 2.0 mL/minute. For example, the amount of salt. In one embodiment the hydrocodone of the compositions acetaminophen released was determined at 300 nm by com of Table 1 is in the form of hydrocodone bitartrate; in another paring the area obtained for the peak due to acetaminophen in embodiment the oxycodone of the compositions of Table 1 is the chromatogram of the dissolution test Solution to that in the form of oxycodone hydrochloride; in another embodi obtained for the corresponding peak in a chromatogram of a ment the ibuprofen of the compositions of Table 1 is in the standard solution. The amount of hydrocodone bitaritrate form of ibruprofen sodium; in another embodiment the released was determined at 230 nm by comparing the area naproxen of the compositions of Table 1 is in the form of obtained for the peak due to hydrocodone bitartrate in the naproxen Sodium; in another embodiment the promethazine chromatogram of the dissolution test solution to that obtained of the compositions of Table 1 or Table 2 is in the form of for the corresponding peak in a chromatogram of a standard promethazine hydrochloride; and in another embodiment the solution. The amount of promethazine HCl released was maltrexone of the compositions of Table 1 is in the form of determined at 230 nm by comparing the area obtained for the maltrexone hydrochloride. In some embodiments a dosage peak due to promethazine HCl in the chromatogram of the form comprising an effective amount of promethazine or a dissolution test solution to that obtained for the correspond pharmaceutically acceptable salt thereof will be orally ing peak in a chromatogram of a standard Solution. administered to a subject having a tendency to exhibit one or 0388 Paddle speed was 50 rpm; pull volume was 10 mL more adverse effect of opioid administration, such as gastric (no replacement): Pull points: 5, 10, 15, 20, 25, 30, 45 and 60 upset, nausea, vomiting, skin rash, sedation, CNS depression, minutes. The amount of each component dissolved in the or respiratory depression in response to opioid administra dissolution medium was determined by HPLC. The method tion. In one embodiment one or more of compositions of can use a high purity, bonded C18 stationary phase and a Table 1 or Table 2 are in the form of a bi-layer tablet com binary mobile phase consisting of an appropriate buffer and prising an immediate release layer and a controlled release organic modifier. layer. In one embodiment the controlled-release layer com 0389 Dissolution Procedure. 900 mL of dissolution fluid prises hydrocodone, oxycodone, propoxyphene, ibuprofen, preheated to 37° C. was placed into each vessel. Tablets of acetaminophen, naproxen or a pharmaceutically acceptable Analgesic Composition F.2 above were weighed and placed salt thereof and the immediate-release layer comprises in vessels respectively. At prescribed time intervals, 5 mL promethazine or a pharmaceutically acceptable salt thereof. US 2012/020 1888 A1 Aug. 9, 2012 40

TABLE 1. Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent

OCO Ole Acetaminophen OCO Ole Promethazine OCO Ole Butalbital OCO Ole Modafinil OCO Ole Caffeine OCO Ole OCO Ole OCO Ole Acetaminophen OCO Ole Acetaminophen Butalbital OCO Ole Acetaminophen Modafinil OCO Ole Acetaminophen Caffeine OCO Ole Acetaminophen EXOile OCO Ole Acetaminophen OCO Ole Promethazine Butalbital OCO Ole Promethazine Modafini OCO Ole Promethazine Caffeine OCO Ole Promethazine EXOile OCO Ole Promethazine OCO Ole Butalbital OCO Ole Butalbital Caffeine OCO Ole Butalbital EXOile OCO Ole Butalbital OCO Ole EXOile OCO Ole Caffeine EXOile OCO Ole OCO Ole Caffeine OCO Ole EXOile OCO Ole Acetaminophen Promethazine Butalbital OCO Ole Acetaminophen Promethazine OCO Ole Acetaminophen Promethazine Caffeine OCO Ole Acetaminophen Promethazine EXOile OCO Ole Acetaminophen Promethazine OCO Ole Acetaminophen Butalbital Modafini OCO Ole Acetaminophen Butalbital Caffeine OCO Ole Acetaminophen Butalbital EXOile OCO Ole Acetaminophen Butalbital OCO Ole Acetaminophen EXOile OCO Ole Acetaminophen OCO Ole Acetaminophen Caffeine EXOile OCO Ole Acetaminophen Caffeine OCO Ole Acetaminophen EXOile OCO Ole Promethazine Butalbital Modafini OCO Ole Promethazine Butalbital Caffeine OCO Ole Promethazine Butalbital EXOile OCO Ole Promethazine Butalbital OCO Ole Promethazine EXOile OCO Ole Promethazine Caffeine EXOile OCO Ole Promethazine OCO Ole Promethazine Caffeine OCO Ole Promethazine EXOile OCO Ole Butalbital Modafini EXOile OCO Ole Butalbital Caffeine EXOile OCO Ole Butalbital Modafini OCO Ole Butalbital Caffeine OCO Ole Butalbital EXOile OCO Ole EXOile OCO Ole Caffeine EXOile OCO Ole Acetaminophen Promethazine Butalbital OCO Ole Acetaminophen Promethazine Butalbital Caffeine OCO Ole Acetaminophen Promethazine Butalbital EXOile OCO Ole Acetaminophen Promethazine Butalbital OCO Ole Acetaminophen Promethazine Modafini EXOile OCO Ole Acetaminophen Promethazine Caffeine EXOile OCO Ole Acetaminophen Promethazine OCO Ole Acetaminophen Promethazine Caffeine OCO Ole Acetaminophen Promethazine EXOile OCO Ole Acetaminophen Butalbital EXOile OCO Ole Acetaminophen Butalbital Caffeine EXOile OCO Ole Acetaminophen Butalbital Modafini OCO Ole Acetaminophen Butalbital Caffeine US 2012/020 1888 A1 Aug. 9, 2012 41

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agen agent agent agent 71 Hydrocodone Acetaminophen — Butalbita Naltrexone Niacin 72 Hydrocodone Acetaminophen — Modafinil Naltrexone Niacin 73 Hydrocodone Acetaminophen — Caffeine Naltrexone Niacin 74 tlydrocodone — Promethazine Butalbita Modafinil Naltrexone — 75 tlydrocodone — Promethazine Butalbita Caffeine Naltrexone — 76 tlydrocodone — Promethazine Butalbita Modafinil — Niacin 77 tlydrocodone — Promethazine Butalbita Caffeine — Niacin 78 tlydrocodone — Promethazine Butalbita Naltrexone Niacin 79 tlydrocodone — Butalbita Caffeine Naltrexone Niacin 8O Hydrocodone Acetaminophen Promethazine Butalbita Modafinil Naltrexone — 81 Hydrocodone Acetaminophen Promethazine Butalbita Caffeine Naltrexone — 82 Hydrocodone Acetaminophen Promethazine Butalbita Modafinil — Niacin 83 Hydrocodone Acetaminophen Promethazine Butalbita Caffeine — Niacin 84 tlydrocodone — Promethazine Butalbita Modafinil Naltrexone Niacin 85 tlydrocodone — Promethazine Butalbita Caffeine Naltrexone Niacin 86 Hydrocodone Acetaminophen — Butalbita Modafinil Naltrexone Niacin 87 Hydrocodone Acetaminophen — Butalbita Caffeine Naltrexone Niacin 88 Hydrocodone Acetaminophen Promethazine — Modafinil Naltrexone Niacin 89 Hydrocodone Acetaminophen Promethazine — Caffeine Naltrexone Niacin 90 Hydrocodone Acetaminophen Promethazine Butalbita Naltrexone Niacin 91 Hydrocodone Acetaminophen Promethazine Butalbita Modafinil Naltrexone Niacin 92 Hydrocodone Acetaminophen Promethazine Butalbita Caffeine Naltrexone Niacin 93 Hydrocodone Naproxen 94 tlydrocodone — Promethazine — 95 tlydrocodone — Butalbita 96 tlydrocodone — Modafinil — 97 tlydrocodone — Caffeine — 98 tlydrocodone — Naltrexone — 99 tlydrocodone — Niacin OO Hydrocodone Naproxen Promethazine — O1 Hydrocodone Naproxen Butalbital O2 Hydrocodone Naproxen Modafinil — O3 Hydrocodone Naproxen Caffeine — O4 Hydrocodone Naproxen Naltrexone — 05 Hydrocodone Naproxen Niacin O6 tlydrocodone — Promethazine Butalbital O7 tlydrocodone — Promethazine — Modafinil — O8 tlydrocodone — Promethazine — Caffeine — 09 tlydrocodone — Promethazine — Naltrexone — 10 tlydrocodone — Promethazine — Niacin 11 tlydrocodone — Butalbital Modafinil — 12 tlydrocodone — Butalbital Caffeine — 13 tlydrocodone — Butalbital Naltrexone — 14 tlydrocodone — Butalbital Niacin 15 tlydrocodone — Modafinil Naltrexone — 16 tlydrocodone — Caffeine Naltrexone — 17 tlydrocodone — Modafinil — Niacin 18 tlydrocodone — Caffeine — Niacin 19 tlydrocodone — Naltrexone Niacin 2O Hydrocodone Naproxen Promethazine Butalbital 21 Hydrocodone Naproxen Promethazine — Modafinil — 22 Hydrocodone Naproxen Promethazine — Caffeine — 23 Hydrocodone Naproxen Promethazine — Naltrexone — 24 Hydrocodone Naproxen Promethazine — Niacin 25 Hydrocodone Naproxen Butalbital Modafinil — 26 Hydrocodone Naproxen Butalbital Caffeine — 27 Hydrocodone Naproxen Butalbital Naltrexone — 28 Hydrocodone Naproxen Butalbital Niacin 29 Hydrocodone Naproxen Modafinil Naltrexone — 30 Hydrocodone Naproxen Modafinil — Niacin 31 Hydrocodone Naproxen Caffeine Naltrexone — 32 Hydrocodone Naproxen Caffeine — Niacin 33 Hydrocodone Naproxen Naltrexone Niacin 34 tlydrocodone — Promethazine Butalbital Modafinil — 35 tlydrocodone — Promethazine Butalbital Caffeine — 36 tlydrocodone — Promethazine Butalbital Naltrexone — 37 tlydrocodone — Promethazine Butalbital Niacin 38 tlydrocodone — Promethazine — Modafinil Naltrexone — 39 tlydrocodone — Promethazine — Caffeine Naltrexone — 40 tlydrocodone — Promethazine — Modafinil — Niacin US 2012/020 1888 A1 Aug. 9, 2012 42

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent 41 tlydrocodone — Promethazine — Caffeine — Niacin 42 tlydrocodone — Promethazine — Naltrexone Niacin 43 tlydrocodone — Butalbita Modafinil Naltrexone — 44 tlydrocodone — Butalbita Caffeine Naltrexone — 45 tlydrocodone — Butalbita Modafinil — Niacin 46 tlydrocodone — Butalbita Caffeine — Niacin 47 tlydrocodone — Butalbita Naltrexone Niacin 48 tlydrocodone — Modafinil Naltrexone Niacin 49 tlydrocodone — Caffeine Naltrexone Niacin 50 Hydrocodone Naproxen Promethazine Butalbita Modafinil — 51 Hydrocodone Naproxen Promethazine Butalbita Caffeine — 52 Hydrocodone Naproxen Promethazine Butalbita Naltrexone — 53 Hydrocodone Naproxen Promethazine Butalbita Niacin S4 Hydrocodone Naproxen Promethazine — Modafinil Naltrexone — 55 Hydrocodone Naproxen Promethazine — Caffeine Naltrexone — 56 Hydrocodone Naproxen Promethazine — Modafinil — Niacin 57 Hydrocodone Naproxen Promethazine — Caffeine — Niacin 58 Hydrocodone Naproxen Promethazine — Naltrexone Niacin 59 Hydrocodone Naproxen Butalbita Modafinil Naltrexone — 60 Hydrocodone Naproxen Butalbita Caffeine Naltrexone — 61 Hydrocodone Naproxen Butalbita Modafinil — Niacin 62 Hydrocodone Naproxen Butalbita Caffeine — Niacin 63 Hydrocodone Naproxen Butalbita Naltrexone Niacin 64 Hydrocodone Naproxen Modafinil Naltrexone Niacin 65 Hydrocodone Naproxen Caffeine Naltrexone Niacin 66 tlydrocodone — Promethazine Butalbita Modafinil Naltrexone — 67 tlydrocodone — Promethazine Butalbita Caffeine Naltrexone — 68 tlydrocodone — Promethazine Butalbita Modafinil — Niacin 69 tlydrocodone — Promethazine Butalbita Caffeine — Niacin 70 tlydrocodone — Promethazine Butalbita Naltrexone Niacin 71 tlydrocodone — Butalbita Caffeine Naltrexone Niacin 72 Hydrocodone Naproxen Promethazine Butalbita Modafinil Naltrexone — 73 Hydrocodone Naproxen Promethazine Butalbita Caffeine Naltrexone — 74 Hydrocodone Naproxen Promethazine Butalbita Modafinil — Niacin 75 Hydrocodone Naproxen Promethazine Butalbita Caffeine — Niacin 76 tlydrocodone — Promethazine Butalbita Modafinil Naltrexone Niacin 77 tlydrocodone — Promethazine Butalbita Caffeine Naltrexone Niacin 78 Hydrocodone Naproxen Butalbita Modafinil Naltrexone Niacin 79 Hydrocodone Naproxen Butalbita Caffeine Naltrexone Niacin 8O Hydrocodone Naproxen Promethazine — Modafinil Naltrexone Niacin 81 Hydrocodone Naproxen Promethazine — Caffeine Naltrexone Niacin 82 Hydrocodone Naproxen Promethazine Butalbita Naltrexone Niacin 83 Hydrocodone Naproxen Promethazine Butalbita Modafinil Naltrexone Niacin 84 Hydrocodone Naproxen Promethazine Butalbita Caffeine Naltrexone Niacin 85 Hydrocodone Ibuprofen 86 tlydrocodone — Promethazine — 87 tlydrocodone — Butalbita 88 tlydrocodone — Modafinil — 89 tlydrocodone — Caffeine — 90 tlydrocodone — Naltrexone — 91 tlydrocodone — Niacin 92 Hydrocodone Ibuprofen Promethazine — 93 Hydrocodone Ibuprofen Butalbital 94 Hydrocodone Ibuprofen Modafinil — 95 Hydrocodone Ibuprofen Caffeine — 96 Hydrocodone Ibuprofen Naltrexone — 97 Hydrocodone Ibuprofen Niacin 98 tlydrocodone — Promethazine Butalbital 99 tlydrocodone — Promethazine — Modafinil — 2OO tlydrocodone — Promethazine — Caffeine — 2O1 tlydrocodone — Promethazine — Naltrexone — 2O2 tlydrocodone — Promethazine — Niacin 2O3 tlydrocodone — Butalbital Modafinil — 204 tlydrocodone — Butalbital Caffeine — 205 tlydrocodone — Butalbital Naltrexone — 2O6 tlydrocodone — Butalbital Niacin 2O7 tlydrocodone — Modafinil Naltrexone — 208 tlydrocodone — Caffeine Naltrexone — 209 tlydrocodone — Modafinil — Niacin 210 tlydrocodone — Caffeine — Niacin US 2012/020 1888 A1 Aug. 9, 2012 43

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent

211 OCO Ole Na EXOile Niacin 212 OCO Ole Ibuprofen Promethazine Butalbital 213 OCO Ole Ibuprofen Promethazine 214 OCO Ole Ibuprofen Promethazine Caffeine 215 OCO Ole Ibuprofen Promethazine Na EXOile 216 OCO Ole Ibuprofen Promethazine 217 OCO Ole Ibuprofen Butalbital 218 OCO Ole Ibuprofen Butalbital Caffeine 219 OCO Ole Ibuprofen Butalbital Na EXOile 220 OCO Ole Ibuprofen Butalbital 221 OCO Ole Ibuprofen Na EXOile 222 OCO Ole Ibuprofen 223 OCO Ole Ibuprofen Caffeine Na EXOile 224 OCO Ole Ibuprofen Caffeine 225 OCO Ole Ibuprofen Na EXOile 226 OCO Ole Promethazine Butalbital 227 OCO Ole Promethazine Butalbital Caffeine 228 OCO Ole Promethazine Butalbital Na EXOile 229 OCO Ole Promethazine Butalbital 230 OCO Ole Promethazine Na EXOile 231 OCO Ole Promethazine Caffeine Na EXOile 232 OCO Ole Promethazine 233 OCO Ole Promethazine Caffeine 234 OCO Ole Promethazine Na EXOile 235 OCO Ole Butalbital Na EXOile 236 OCO Ole Butalbital Caffeine Na EXOile 237 OCO Ole Butalbital 238 OCO Ole Butalbital Caffeine 239 OCO Ole Butalbital Na EXOile 240 OCO Ole Na EXOile 241 OCO Ole Caffeine Na EXOile 242 OCO Ole Oeil Promethazine Butalbital 243 OCO Ole Oeil Promethazine Butalbital Caffeine 244 OCO Ole Oeil Promethazine Butalbital Na EXOile 245 OCO Ole Oeil Promethazine Butalbital 246 OCO Ole Oeil Promethazine Na EXOile 247 OCO Ole Oeil Promethazine Caffeine Na EXOile 248 OCO Ole Oeil Promethazine 249 OCO Ole Oeil Promethazine Caffeine 250 OCO Ole Oeil Promethazine Na EXOile 251 OCO Ole Oeil bi Na EXOile 252 OCO Ole Oeil bi Caffeine Na EXOile 253 OCO Ole Oeil Bl bi 2S4 OCO Ole Oeil bi Caffeine 255 OCO Ole Oeil bi Na EXOile 2S6 OCO Ole Oeil Na EXOile 257 OCO Ole Oeil Ca eine Na EXOile 258 OCO Ole Promethazine bi Na EXOile 259 OCO Ole Promethazine bi Ca eine Na EXOile 260 OCO Ole Promethazine bi 261 OCO Ole Promethazine bi Caffeine 262 OCO Ole Promethazine bi Na EXOile 263 OCO Ole bi Ca eine Na EXOile 264 OCO Ole Ibuprofen Promethazine bi Na EXOile 26S OCO Ole Ibuprofen Promethazine bi Ca eine Na EXOile 266 OCO Ole Ibuprofen Promethazine bi 267 OCO Ole Ibuprofen Promethazine bi Ca eine 268 OCO Ole Promethazine bi Na EXOile 269 OCO Ole Promethazine bi Caffeine Na EXOile 270 OCO Ole Ibuprofen bi Na EXOile 271 OCO Ole Ibuprofen bi Ca eine Na EXOile 272 OCO Ole Ibuprofen Promethazine Na EXOile 273 OCO Ole Ibuprofen Promethazine Caffeine Na EXOile 274 OCO Ole Ibuprofen Promethazine Bl 8. bi 8. Na EXOile 275 OCO Ole Ibuprofen Promethazine Bl 8. bi 8. Na EXOile 276 OCO Ole Ibuprofen Promethazine Caffeine Na EXOile 277 Oxycodone Acetaminophen — 278 Oxycodone Promethazine 279 Oxycodone 28O Oxycodone Modafinil US 2012/020 1888 A1 Aug. 9, 2012 44

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent

281 Oxyco Ole Caffeine 282 Oxyco Ole Naltrexone 283 Oxyco Ole 284 Oxyco Ole Acetaminophen Promethazine 285 Oxyco Ole Acetaminophen Butalbital 286 Oxyco Ole Acetaminophen ini 287 Oxyco Ole Acetaminophen le 288 Oxyco Ole Acetaminophen Naltrexone 289 Oxyco Ole Acetaminophen 290 Oxyco Ole Promethazine Butalbital 291 Oxyco Ole Promethazine ini 292 Oxyco Ole Promethazine e le 293 Oxyco Ole Promethazine Na EXOile 294 Oxyco Ole Promethazine 295 Oxyco Ole Butalbital ini 296 Oxyco Ole Butalbital e le 297 Oxyco Ole Butalbital Na EXOile 298 Oxyco Ole Butalbital 299 Oxyco Ole ini Na EXOile 3OO Oxyco Ole e le Na EXOile 301 Oxyco Ole ini 3O2 Oxyco Ole e le 303 Oxyco Ole Na EXOile 3O4 Oxyco Ole Acetaminophen Promethazine Butalbital 305 Oxyco Ole Acetaminophen Promethazine ini 306 Oxyco Ole Acetaminophen Promethazine e le 307 Oxyco Ole Acetaminophen Promethazine Na EXOile 3O8 Oxyco Ole Acetaminophen Promethazine 309 Oxyco Ole Acetaminophen Butalbital ini 310 Oxyco Ole Acetaminophen Butalbital e le 311 Oxyco Ole Acetaminophen Butalbital Na EXOile 312 Oxyco Ole Acetaminophen Butalbital 313 Oxyco Ole Acetaminophen ini Na EXOile 314 Oxyco Ole Acetaminophen ini 315 Oxyco Ole Acetaminophen le Na EXOile 316 Oxyco Ole Acetaminophen ei le 317 Oxyco Ole Acetaminophen Na EXOile 318 Oxyco Ole Promethazine Butalbital ini 319 Oxyco Ole Promethazine Butalbital e le 32O Oxyco Ole Promethazine Butalbital Na EXOile 321 Oxyco Ole Promethazine Butalbital 322 Oxyco Ole Promethazine ini Na EXOile 323 Oxyco Ole Promethazine e le Na EXOile 324 Oxyco Ole Promethazine ini 325 Oxyco Ole Promethazine e le 326 Oxyco Ole Promethazine Na EXOile 327 Oxyco Ole Butalbital ini Na EXOile 328 Oxyco Ole Butalbital e le Na EXOile 329 Oxyco Ole Butalbital ini 330 Oxyco Ole Butalbital e le 331 Oxyco Ole Butalbital Na EXOile 332 Oxyco Ole ini Na EXOile 333 Oxyco Ole e le Na EXOile 334 Oxyco Ole Acetamino lel Promethazine Butalbital ini 335 Oxyco Ole Acetamino lel Promethazine Butalbital e le 336 Oxyco Ole Acetamino lel Promethazine Butalbital Na EXOile 337 Oxyco Ole Acetamino lel Promethazine Butalbital 338 Oxyco Ole Acetamino lel Promethazine ini Na EXOile 339 Oxyco Ole Acetamino lel Promethazine e le Na EXOile 340 Oxyco Ole Acetamino lel Promethazine ini 341 Oxyco Ole Acetamino lel Promethazine e le 342 Oxyco Ole Acetamino lel Promethazine Na EXOile 343 Oxyco Ole Acetamino lel Butalbital ini Na EXOile 344 Oxyco Ole Acetamino lel Butalbital e le Na EXOile 345 Oxyco Ole Acetamino lel Butalbital ini 346 Oxyco Ole Acetamino lel Butalbital e le 347 Oxyco Ole Acetamino lel Butalbital Na EXOile 348 Oxyco Ole Acetamino lel ini Na EXOile 349 Oxyco Ole Acetamino lel e le Na EXOile 350 Oxyco Ole Promethazine Butalbital ini Na EXOile US 2012/020 1888 A1 Aug. 9, 2012 45

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbitura Stimulan antagonist deterrent No. Opioid agent agent agent agen agent agent agent

351 Oxyco Ole Prome hazine Bu bi Caffeine Na EXOile 352 Oxyco Ole Prome hazine Bu bi Modafini Niacin 353 Oxyco Ole Prome hazine Bu bi Caffeine Niacin 3S4 Oxyco Ole Prome hazine Bu bi Na EXOile Niacin 355 Oxyco Ole Bu bi Caffeine Na EXOile Niacin 356 Oxyco Ole Acetaminophen Prome hazine Bu bi Na EXOile 357 Oxyco Ole Acetaminophen Prome hazine Bu bi Caffeine Na EXOile 358 Oxyco Ole Acetaminophen Prome hazine Bu bi Niacin 359 Oxyco Ole Acetaminophen Prome hazine Bu bi Caffeine Niacin 360 Oxyco Ole Prome hazine Bu bi Na EXOile Niacin 361 Oxyco Ole Prome hazine Bu bi Caffeine Na EXOile Niacin 362 Oxyco Ole Acetaminophen Bu bi Na EXOile Niacin 363 Oxyco Ole Acetaminophen Bu bi Caffeine Na EXOile Niacin 364 Oxyco Ole Acetaminophen hazine Na EXOile Niacin 365 Oxyco Ole Acetaminophen hazine Caffeine Na EXOile Niacin 366 Oxyco Ole Acetaminophen hazine Butalbi8. 8. Na EXOile Niacin 367 Oxyco Ole Acetaminophen hazine Butalbi8. 8. Na EXOile Niacin 368 Oxyco Ole Acetaminophen hazine Butalbita Caffeine Na EXOile Niacin 369 Oxyco Ole Naproxen 370 Oxyco Ole hazine 371 Oxyco Ole Butalbita 372 Oxyco Ole 373 Oxyco Ole 374 Oxyco Ole 375 Oxyco Ole 376 Oxyco Ole Naproxen 377 Oxyco Ole Naproxen Butalbital 378 Oxyco Ole Naproxen Modafinil 379 Oxyco Ole Naproxen Caffeine 380 Oxyco Ole Naproxen EXOile 381 Oxyco Ole Naproxen 382 Oxyco Ole Promethazine Butalbital 383 Oxyco Ole Promethazine Modafini 384 Oxyco Ole Promethazine Caffeine 385 Oxyco Ole Promethazine EXOile 386 Oxyco Ole Promethazine 387 Oxyco Ole Butalbital 388 Oxyco Ole Butalbital Caffeine 389 Oxyco Ole Butalbital EXOile 390 Oxyco Ole Butalbital 391 Oxyco Ole EXOile 392 Oxyco Ole Caffeine EXOile 393 Oxyco Ole 394 Oxyco Ole Caffeine 395 Oxyco Ole EXOile 396 Oxyco Ole Naproxen Promethazine Butalbital 397 Oxyco Ole Naproxen Promethazine 398 Oxyco Ole Naproxen Promethazine Caffeine 399 Oxyco Ole Naproxen Promethazine EXOile 400 Oxyco Ole Naproxen Promethazine 4O1 Oxyco Ole Naproxen Butalbital Modafini 4O2 Oxyco Ole Naproxen Butalbital Caffeine 403 Oxyco Ole Naproxen Butalbital EXOile 404 Oxyco Ole Naproxen Butalbital 40S Oxyco Ole Naproxen EXOile 4O6 Oxyco Ole Naproxen 407 Oxyco Ole Naproxen Caffeine EXOile 4.08 Oxyco Ole Naproxen Caffeine 409 Oxyco Ole Naproxen EXOile 410 Oxyco Ole Promethazine Butalbital 411 Oxyco Ole Promethazine Butalbital Caffeine 412 Oxyco Ole Promethazine Butalbital EXOile 413 Oxyco Ole Promethazine Butalbital 414 Oxyco Ole Promethazine EXOile 415 Oxyco Ole Promethazine Caffeine EXOile 416 Oxyco Ole Promethazine 417 Oxyco Ole Promethazine Caffeine 418 Oxyco Ole Promethazine EXOile 419 Oxyco Ole Butalbital EXOile 420 Oxyco Ole Butalbital Caffeine Na EXOile US 2012/020 1888 A1 Aug. 9, 2012 46

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulan antagonist deterrent No. Opioid agent agent agent agent agent agent agent

421 Oxyco Ole Butalbital Niacin 422 Oxyco Ole Butalbital Caffeine Niacin 423 Oxyco Ole Butalbital Naltrexone Niacin 424 Oxyco Ole Naltrexone Niacin 425 Oxyco Ole Caffeine Naltrexone Niacin 426 Oxyco Ole Naproxen Promethazine Butalbital 427 Oxyco Ole Naproxen Promethazine Butalbital Caffeine 428 Oxyco Ole Naproxen Promethazine Butalbital Naltrexone 429 Oxyco Ole Naproxen Promethazine Butalbital 430 Oxyco Ole Naproxen Promethazine Naltrexone 431 Oxyco Ole Naproxen Promethazine Caffeine Naltrexone 432 Oxyco Ole Naproxen Promethazine 433 Oxyco Ole Naproxen Promethazine Caffeine 434 Oxyco Ole Naproxen Promethazine Naltrexone 435 Oxyco Ole Naproxen Butalbita Naltrexone 436 Oxyco Ole Naproxen Butalbita Caffeine Naltrexone 437 Oxyco Ole Naproxen Butalbita 438 Oxyco Ole Naproxen Butalbita Caffeine 439 Oxyco Ole Naproxen Butalbita Naltrexone 440 Oxyco Ole Naproxen Naltrexone 441 Oxyco Ole Naproxen Caffeine Naltrexone 442 Oxyco Ole Promethazine Butalbita Naltrexone 443 Oxyco Ole Promethazine Butalbita Ca eine Naltrexone 444 Oxyco Ole Promethazine Butalbita 445 Oxyco Ole Promethazine Butalbita Caffeine 446 Oxyco Ole Promethazine Butalbita Naltrexone 447 Oxyco Ole Butalbita Caffeine Naltrexone 448 Oxyco Ole Naproxen Promethazine Butalbita Naltrexone 449 Oxyco Ole Naproxen Promethazine Butalbita Caffeine Naltrexone 450 Oxyco Ole Naproxen Promethazine Butalbita 451 Oxyco Ole Naproxen Promethazine Butalbita Ca eine 452 Oxyco Ole Promethazine Butalbita Naltrexone 453 Oxyco Ole Promethazine Butalbita Ca eine Naltrexone 454 Oxyco Ole Naproxen Butalbita Naltrexone 455 Oxyco Ole Naproxen Butalbita Ca eine Naltrexone 456 Oxyco Ole Naproxen Promethazine Naltrexone 457 Oxyco Ole Naproxen Promethazine Caffeine Naltrexone 458 Oxyco Ole Naproxen Promethazine Butalbita Naltrexone 459 Oxyco Ole Naproxen Promethazine Butalbita Naltrexone 460 Oxyco Ole Naproxen Promethazine Butalbita Caffeine Naltrexone 461 Oxyco Ole Ibuprofen 462 Oxyco Ole Promethazine 463 Oxyco Ole Butalbita 464 Oxyco Ole 465 Oxyco Ole 466 Oxyco Ole 467 Oxyco Ole 468 Oxyco Ole Ibuprofen 469 Oxyco Ole Ibuprofen Butalbital 470 Oxyco Ole Ibuprofen Modafinil 471 Oxyco Ole Ibuprofen Caffeine 472 Oxyco Ole Ibuprofen Naltrexone 473 Oxyco Ole Ibuprofen 474 Oxyco Ole Promethazine Butalbital 475 Oxyco Ole Promethazine 476 Oxyco Ole Promethazine 477 Oxyco Ole Promethazine Naltrexone 478 Oxyco Ole Promethazine 479 Oxyco Ole Butalbital 480 Oxyco Ole Butalbital 481 Oxyco Ole Butalbital Naltrexone 482 Oxyco Ole Butalbital 483 Oxyco Ole Naltrexone 484 Oxyco Ole Naltrexone 485 Oxyco Ole 486 Oxyco Ole 487 Oxyco Ole Naltrexone 488 Oxyco Ole Ibuprofen Promethazine Butalbital 489 Oxyco Ole Ibuprofen Promethazine 490 Oxyco Ole Ibuprofen Promethazine US 2012/020 1888 A1 Aug. 9, 2012 47

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent

491 Oxycodone Ibuprofen Promethazine Na EXOile 492 Oxycodone Ibuprofen Promethazine Niacin 493 Oxycodone Ibuprofen Butalbital 494 Oxycodone Ibuprofen Butalbital Caffeine 495 Oxycodone Ibuprofen Butalbital Na EXOile 496 Oxycodone Ibuprofen Butalbital 497 Oxycodone Ibuprofen Na EXOile 498 Oxycodone Ibuprofen 499 Oxycodone Ibuprofen Caffeine Na EXOile 500 Oxycodone Ibuprofen Caffeine 5O1 Oxycodone Ibuprofen Na EXOile 502 Oxycodone Promethazine Butalbital 503 Oxycodone Promethazine Butalbital Caffeine SO4 Oxycodone Promethazine Butalbital Na EXOile 505 Oxycodone Promethazine Butalbital SO6 Oxycodone Promethazine Na EXOile 507 Oxycodone Promethazine Caffeine Na EXOile SO8 Oxycodone Promethazine 509 Oxycodone Promethazine Caffeine 510 Oxycodone Promethazine Na EXOile 511 Oxycodone Butalbital Na EXOile 512 Oxycodone Butalbital Caffeine Na EXOile 513 Oxycodone Butalbital S1.4 Oxycodone Butalbital Caffeine 515 Oxycodone Butalbital Na EXOile S16 Oxycodone Na EXOile 517 Oxycodone Caffeine Na EXOile 518 Oxycodone Oeil Promethazine Butalbital 519 Oxycodone Oeil Promethazine Butalbital Caffeine 520 Oxycodone Oeil Promethazine Butalbital Na EXOile 521 Oxycodone Oeil Promethazine Butalbital 522 Oxycodone Oeil Promethazine Na EXOile 523 Oxycodone Oeil Promethazine Caffeine Na EXOile 524 Oxycodone Oeil Promethazine 525 Oxycodone Oeil Promethazine Caffeine 526 Oxycodone Oeil Promethazine Na EXOile 527 Oxycodone Oeil bi Na EXOile 528 Oxycodone Oeil bi Caffeine Na EXOile 529 Oxycodone Oeil Bl bi 530 Oxycodone Oeil bi Caffeine 531 Oxycodone Oeil bi Na EXOile 532 Oxycodone Oeil Na EXOile 533 Oxycodone Oeil Ca eine Na EXOile 534 Oxycodone Promethazine bi Na EXOile 535 Oxycodone Promethazine bi Ca eine Na EXOile 536 Oxycodone Promethazine bi 537 Oxycodone Promethazine bi Caffeine 538 Oxycodone Promethazine bi Na EXOile 539 Oxycodone bi Ca eine Na EXOile S4O Oxycodone Ibuprofen Promethazine bi Na EXOile S41 Oxycodone Ibuprofen Promethazine bi Ca eine Na EXOile S42 Oxycodone Ibuprofen Promethazine bi 543 Oxycodone Ibuprofen Promethazine bi Ca eine 544 Oxycodone Promethazine bi Na EXOile 545 Oxycodone Promethazine bi Ca eine Na EXOile S46 Oxycodone Ibuprofen bi Na EXOile 547 Oxycodone Ibuprofen bi Ca eine Na EXOile S48 Oxycodone Ibuprofen Promethazine Na EXOile S49 Oxycodone Ibuprofen Promethazine Caffeine Na EXOile 550 Oxycodone Ibuprofen Promethazine Bl 8. bi 8. Na EXOile 551 Oxycodone Ibuprofen Promethazine Bl 8. bi 8. Na EXOile 552 Oxycodone Ibuprofen Promethazine Caffeine Na EXOile 553 Propoxyphene Acetaminophen — 554 Propoxyphene Promethazine 555 Propoxyphene 556 Propoxyphene Modafinil 557 Propoxyphene Caffeine 558 Propoxyphene Naltrexone 559 Propoxyphene S60 Propoxyphene Acetaminophen Promethazine US 2012/020 1888 A1 Aug. 9, 2012 48

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent

561 poxy lele Acetaminophen Butalbital S62 poxy lele Acetaminophen Modafinil 563 poxy lele Acetaminophen Ca eine S64 poxy lele Acetaminophen Naltrexone 565 poxy lele Acetaminophen 566 poxy lele Promethazine Butalbital 567 poxy lele Promethazine 568 poxy lele Promethazine eine 569 poxy lele Promethazine Na EXOile 570 poxy lele Promethazine 571 poxy lele Butalbital 572 poxy lele Butalbital eine 573 poxy lele Butalbital Na EXOile 574 poxy lele Butalbital 575 poxy lele Na EXOile 576 poxy lele eine Na EXOile 577 poxy lele 578 poxy lele eine 579 poxy lele Na EXOile S8O poxy lele Acetaminophen Promethazine Butalbital 581 poxy lele Acetaminophen Promethazine 582 poxy lele Acetaminophen Promethazine eine 583 poxy lele Acetaminophen Promethazine Na EXOile S84 poxy lele Acetaminophen Promethazine 585 poxy lele Acetaminophen Butalbital S86 poxy lele Acetaminophen Butalbital eine 587 poxy lele Acetaminophen Butalbital Na EXOile 588 poxy lele Acetaminophen Butalbital 589 poxy lele Acetaminophen Na EXOile 590 poxy lele Acetaminophen 591 poxy lele Acetaminophen eine Na EXOile 592 poxy lele Acetaminophen eine 593 poxy lele Acetaminophen Na EXOile 594 poxy lele Promethazine Butalbital 595 poxy lele Promethazine Butalbital eine 596 poxy lele Promethazine Butalbital Na EXOile 597 poxy lele Promethazine Butalbital 598 poxy lele Promethazine Na EXOile 599 poxy lele Promethazine eine Na EXOile 600 poxy lele Promethazine 6O1 poxy lele Promethazine eine 602 poxy lele Promethazine Na EXOile 603 poxy lele Butalbital Na EXOile 604 poxy lele Butalbital eine Na EXOile 60S poxy lele Butalbital 606 poxy lele Butalbital eine 607 poxy lele Butalbital Na EXOile 608 poxy lele Na EXOile 609 poxy lele eine Na EXOile 610 poxy lele Acetamino lel Promethazine Butalbital 611 poxy lele Acetamino lel Promethazine Butalbital eine 612 poxy lele Acetamino lel Promethazine Butalbital Na EXOile 613 poxy lele Acetamino lel Promethazine Butalbital 614 poxy lele Acetamino lel Promethazine Na EXOile 615 poxy lele Acetamino lel Promethazine eine Na EXOile 616 poxy lele Acetamino lel Promethazine 617 poxy lele Acetamino lel Promethazine eine 618 poxy lele Acetamino lel Promethazine Na EXOile 619 poxy lele Acetamino lel Butalbital Na EXOile 62O poxy lele Acetamino lel Butalbital eine Na EXOile 621 poxy lele Acetamino lel Butalbital 622 poxy lele Acetamino lel Butalbital eine 623 poxy lele Acetamino lel Butalbital Na EXOile 624 poxy lele Acetamino lel Na EXOile 625 poxy lele Acetamino lel eine Na EXOile 626 poxy lele Promethazine Butalbital Na EXOile 627 poxy lele Promethazine Butalbital eine Na EXOile 628 poxy lele Promethazine Butalbital 629 poxy lele Promethazine Butalbital eine 630 poxy lele Promethazine Butalbital Na EXOile US 2012/020 1888 A1 Aug. 9, 2012 49

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioi Antiemetic Barbi 8. Stimulan antagonist deterrent No. Opioid agent agent agent agen agent agent agent

631 poxy lele Bu bi Caffeine Naltrexone Niacin 632 poxy lele Acetamino phen Promethazine Bu bi Modafini Naltrexone 633 poxy lele Acetamino phen Promethazine Bu bi Caffeine Naltrexone 634 poxy lele Acetamino phen Promethazine Bu bi Modafini Niacin 635 poxy lele Acetamino phen Promethazine Bu bi Caffeine Niacin 636 poxy lele Promethazine Bu bi Modafini Naltrexone Niacin 637 poxy lele Promethazine Bu bi Caffeine Naltrexone Niacin 638 poxy lele Acetamino phen Bu bi Modafini Naltrexone Niacin 639 poxy lele Acetamino phen Bu bi Caffeine Naltrexone Niacin 640 poxy lele Acetamino phen Promethazine Modafini Naltrexone Niacin 641 poxy lele Acetamino phen Promethazine Caffeine Naltrexone Niacin 642 poxy lele Acetamino phen Promethazine Bu bi Naltrexone Niacin 643 poxy lele Acetamino phen Promethazine Bu bi Modafini Naltrexone Niacin 644 poxy lele Acetamino phen Promethazine Bu bi Caffeine Naltrexone Niacin 645 poxy lele Naproxen 646 poxy lele Promethazine 647 poxy lele Bu bi 648 poxy lele Modafinil 649 poxy lele Caffeine 6SO poxy lele 651 poxy lele 652 poxy lele Naproxen 653 poxy lele Naproxen Butalbital 654 poxy lele Naproxen 655 poxy lele Naproxen Caffeine 656 poxy lele Naproxen Naltrexone 657 poxy lele Naproxen 658 poxy lele Promethazine Butalbital 659 poxy lele Promethazine Modafini 660 poxy lele Promethazine Caffeine 661 poxy lele Promethazine Na EXOile 662 poxy lele Promethazine 663 poxy lele Butalbital 664 poxy lele Butalbital Caffeine 665 poxy lele Butalbital Na EXOile 666 poxy lele Butalbital 667 poxy lele Na EXOile 668 poxy lele Caffeine Na EXOile 669 poxy lele 670 poxy lele Caffeine 671 poxy lele Na EXOile 672 poxy lele Naproxen Promethazine Butalbital 673 poxy lele Naproxen Promethazine 674 poxy lele Naproxen Promethazine Caffeine 675 poxy lele Naproxen Promethazine Na EXOile 676 poxy lele Naproxen Promethazine 677 poxy lele Naproxen Butalbital 678 poxy lele Naproxen Butalbital Caffeine 679 poxy lele Naproxen Butalbital Na EXOile 68O poxy lele Naproxen Butalbital 681 poxy lele Naproxen Na EXOile 682 poxy lele Naproxen 683 poxy lele Naproxen Caffeine Na EXOile 684 poxy lele Naproxen Caffeine 685 poxy lele Naproxen Na EXOile 686 poxy lele Promethazine Butalbital 687 poxy lele Promethazine Butalbital Caffeine 688 poxy lele Promethazine Butalbital Na EXOile 689 poxy lele Promethazine Butalbital 690 poxy lele Promethazine Modafini Na EXOile 691 poxy lele Promethazine Caffeine Na EXOile 692 poxy lele Promethazine Modafini 693 poxy lele Promethazine Caffeine 694 poxy lele Promethazine Na EXOile 695 poxy lele Butalbital Na EXOile 696 poxy lele Butalbital Caffeine Na EXOile 697 poxy lele Butalbital 698 poxy lele Butalbital Caffeine 699 poxy lele Butalbital Na EXOile 700 poxy lele Na EXOile US 2012/020 1888 A1 Aug. 9, 2012 50

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent 701 Propoxyphene — Caffeine Naltrexone Niacin 702 Propoxyphene Naproxen Promethazine Butalbital Modafinil — 703 Propoxyphene Naproxen Promethazine Butalbital Caffeine — 704 Propoxyphene Naproxen Promethazine Butalbital Naltrexone — 705 Propoxyphene Naproxen Promethazine Butalbital Niacin 706 Propoxyphene Naproxen Promethazine — Modafinil Naltrexone — 707 Propoxyphene Naproxen Promethazine — Caffeine Naltrexone — 708 Propoxyphene Naproxen Promethazine — Modafinil — Niacin 709 Propoxyphene Naproxen Promethazine — Caffeine — Niacin 710 Propoxyphene Naproxen Promethazine — Naltrexone Niacin 711 Propoxyphene Naproxen Butalbita Modafinil Naltrexone — 712 Propoxyphene Naproxen Butalbita Caffeine Naltrexone — 713 Propoxyphene Naproxen Butalbita Modafinil — Niacin 71.4 Propoxyphene Naproxen Butalbita Caffeine — Niacin 715 Propoxyphene Naproxen Butalbita Naltrexone Niacin 716 Propoxyphene Naproxen Modafinil Naltrexone Niacin 717 Propoxyphene Naproxen Caffeine Naltrexone Niacin 718 Propoxyphene — Promethazine Butalbita Modafinil Naltrexone — 719 Propoxyphene — Promethazine Butalbita Caffeine Naltrexone — 720 Propoxyphene — Promethazine Butalbita Modafinil — Niacin 721 Propoxyphene — Promethazine Butalbita Caffeine — Niacin 722 Propoxyphene — Promethazine Butalbita Naltrexone Niacin 723 Propoxyphene — Butalbita Caffeine Naltrexone Niacin 724 Propoxyphene Naproxen Promethazine Butalbita Modafinil Naltrexone — 725 Propoxyphene Naproxen Promethazine Butalbita Caffeine Naltrexone — 726 Propoxyphene Naproxen Promethazine Butalbita Modafinil — Niacin 727 Propoxyphene Naproxen Promethazine Butalbita Caffeine — Niacin 728 Propoxyphene — Promethazine Butalbita Modafinil Naltrexone Niacin 729 Propoxyphene — Promethazine Butalbita Caffeine Naltrexone Niacin 730 Propoxyphene Naproxen Butalbita Modafinil Naltrexone Niacin 731 Propoxyphene Naproxen Butalbita Caffeine Naltrexone Niacin 732 Propoxyphene Naproxen Promethazine — Modafinil Naltrexone Niacin 733 Propoxyphene Naproxen Promethazine — Caffeine Naltrexone Niacin 734 Propoxyphene Naproxen Promethazine Butalbita Naltrexone Niacin 735 Propoxyphene Naproxen Promethazine Butalbita Modafinil Naltrexone Niacin 736 Propoxyphene Naproxen Promethazine Butalbita Caffeine Naltrexone Niacin 737 Propoxyphene Ibuprofen 738 Propoxyphene — Promethazine — 739 Propoxyphene — Butalbita 740 Propoxyphene — Modafinil — 741 Propoxyphene — Caffeine — 742 Propoxyphene — Naltrexone — 743 Propoxyphene — Niacin 744 Propoxyphene Ibuprofen Promethazine — 745 Propoxyphene Ibuprofen Butalbital 746 Propoxyphene Ibuprofen Modafinil — 747 Propoxyphene Ibuprofen Caffeine — 748 Propoxyphene Ibuprofen Naltrexone — 749 Propoxyphene Ibuprofen Niacin 750 Propoxyphene — Promethazine Butalbital 751 Propoxyphene — Promethazine — Modafinil — 752 Propoxyphene — Promethazine — Caffeine — 753 Propoxyphene — Promethazine — Naltrexone — 754 Propoxyphene — Promethazine — Niacin 755 Propoxyphene — Butalbital Modafinil — 756 Propoxyphene — Butalbital Caffeine — 757 Propoxyphene — Butalbital Naltrexone — 758 Propoxyphene — Butalbital Niacin 759 Propoxyphene — Modafinil Naltrexone — 760 Propoxyphene — Caffeine Naltrexone — 761 Propoxyphene — Modafinil — Niacin 762 Propoxyphene — Caffeine — Niacin 763 Propoxyphene — Naltrexone Niacin 764 Propoxyphene Ibuprofen Promethazine Butalbital 765 Propoxyphene Ibuprofen Promethazine — Modafinil — 766 Propoxyphene Ibuprofen Promethazine — Caffeine — 767 Propoxyphene Ibuprofen Promethazine — Naltrexone — 768 Propoxyphene Ibuprofen Promethazine — Niacin 769 Propoxyphene Ibuprofen Butalbital Modafinil — 770 Propoxyphene Ibuprofen Butalbital Caffeine — US 2012/020 1888 A1 Aug. 9, 2012 51

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent 771 Propoxyphene Ibuprofen Butalbital Naltrexone — 772 Propoxyphene Ibuprofen Butalbital Niacin 773 Propoxyphene Ibuprofen Modafinil Naltrexone — 774 Propoxyphene Ibuprofen Modafinil — Niacin 775 Propoxyphene Ibuprofen Caffeine Naltrexone — 776 Propoxyphene Ibuprofen Caffeine — Niacin 777 Propoxyphene Ibuprofen Naltrexone Niacin 778 Propoxyphene — Promethazine Butalbital Modafinil — 779 Propoxyphene — Promethazine Butalbital Caffeine — 78O Propoxyphene — Promethazine Butalbital Naltrexone — 781 Propoxyphene — Promethazine Butalbital Niacin 782 Propoxyphene — Promethazine — Modafinil Naltrexone — 783 Propoxyphene — Promethazine — Caffeine Naltrexone — 784 Propoxyphene — Promethazine — Modafinil — Niacin 785 Propoxyphene — Promethazine — Caffeine — Niacin 786 Propoxyphene — Promethazine — Naltrexone Niacin 787 Propoxyphene — Butalbital Modafinil Naltrexone — 788 Propoxyphene — Butalbital Caffeine Naltrexone — 789 Propoxyphene — Butalbital Modafinil — Niacin 790 Propoxyphene — Butalbital Caffeine — Niacin 791 Propoxyphene — Butalbital Naltrexone Niacin 792 Propoxyphene — Modafinil Naltrexone Niacin 793 Propoxyphene — Caffeine Naltrexone Niacin 794 Propoxyphene Ibuprofen Promethazine Butalbital Modafinil — 795 Propoxyphene Ibuprofen Promethazine Butalbital Caffeine — 796 Propoxyphene Ibuprofen Promethazine Butalbital Naltrexone — 797 Propoxyphene Ibuprofen Promethazine Butalbital Niacin 798 Propoxyphene Ibuprofen Promethazine — Modafinil Naltrexone — 799 Propoxyphene Ibuprofen Promethazine — Caffeine Naltrexone — 800 Propoxyphene Ibuprofen Promethazine — Modafinil — Niacin 8O1 Propoxyphene Ibuprofen Promethazine — Caffeine — Niacin 802 Propoxyphene Ibuprofen Promethazine — Naltrexone Niacin 803 Propoxyphene Ibuprofen Butalbita Modafinil Naltrexone — 804 Propoxyphene Ibuprofen Butalbita Caffeine Naltrexone — 805 Propoxyphene Ibuprofen Butalbita Modafinil — Niacin 806 Propoxyphene Ibuprofen Butalbita Caffeine — Niacin 807 Propoxyphene Ibuprofen Butalbita Naltrexone Niacin 808 Propoxyphene Ibuprofen Modafinil Naltrexone Niacin 809 Propoxyphene Ibuprofen Caffeine Naltrexone Niacin 810 Propoxyphene — Promethazine Butalbita Modafinil Naltrexone — 811 Propoxyphene — Promethazine Butalbita Caffeine Naltrexone — 812 Propoxyphene — Promethazine Butalbita Modafinil — Niacin 813 Propoxyphene — Promethazine Butalbita Caffeine — Niacin 814 Propoxyphene — Promethazine Butalbita Naltrexone Niacin 815 Propoxyphene — Butalbita Caffeine Naltrexone Niacin 816 Propoxyphene Ibuprofen Promethazine Butalbita Modafinil Naltrexone — 817 Propoxyphene Ibuprofen Promethazine Butalbita Caffeine Naltrexone — 818 Propoxyphene Ibuprofen Promethazine Butalbita Modafinil — Niacin 819 Propoxyphene Ibuprofen Promethazine Butalbita Caffeine — Niacin 82O Propoxyphene — Promethazine Butalbita Modafinil Naltrexone Niacin 821 Propoxyphene — Promethazine Butalbita Caffeine Naltrexone Niacin 822 Propoxyphene Ibuprofen Butalbita Modafinil Naltrexone Niacin 823 Propoxyphene Ibuprofen Butalbita Caffeine Naltrexone Niacin 824 Propoxyphene Ibuprofen Promethazine — Modafinil Naltrexone Niacin 825 Propoxyphene Ibuprofen Promethazine — Caffeine Naltrexone Niacin 826 Propoxyphene Ibuprofen Promethazine Butalbita Naltrexone Niacin 827 Propoxyphene Ibuprofen Promethazine Butalbita Modafinil Naltrexone Niacin 828 Propoxyphene Ibuprofen Promethazine Butalbita Caffeine Naltrexone Niacin 829 Propoxyphene Ibuprofen 830 Acetaminophen — Modafinil — 831 Acetaminophen — Caffeine — 832 Oeil Modafinil — 833 Oeil Caffeine — 834 Naproxen Modafinil — 835 Naproxen Caffeine — 836 Acetaminophen — Butalbital Modafinil — 837 Acetaminophen — Butalbital Caffeine — US 2012/020 1888 A1 Aug. 9, 2012 52

TABLE 1-continued Multi-drug Compositions Opioid Abuse Composition Non-opioid Antiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agent agent agent agent agent agent agent 838 Ibuprofen Butalbital Modafinil — 839 Ibuprofen Butalbital Caffeine — 840 Naproxen Butalbital Modafinil — 841 Naproxen Butalbital Caffeine —

Note: — indicates that the respective agent is absent from a particular composition,

TABLE 2 TABLE 2-continued Multi-drug Compositions Multi-drug Compositions Composition Composition No. Trip Antiemetic agent No. Triptan Antiemetic agent

842 88 Eri promethazine 894 Eri promethazine 843 88 Eri aprepitant 895 Eri aprepitant 84.4 88 Eri dronabinol 896 Eri dronabinol 845 88 Eri periphenazine 897 Eri periphenazine 846 88 Eri palonosetron 898 Eri palonosetron 847 88 Eri trimethyobenzamide 899 Eri trimethyobenzamide 848 88 Eri metoclopromide 900 Eri metoclopromide 849 88 Eri domperidone 901 Eri domperidone 8SO 88 Eri prochlorperazine 902 Eri prochlorperazine 851 88. Eri promethazine 903 Eri promethazine 852 88 Eri chlorpromazine 904 Eri chlorpromazine 853 88 Eri trimethobenzamide 905 Eri trimethobenzamide 854 88 Eri Ondansetron 906 Eri Ondansetron 855 88 Eri granisetron 907 Eri granisetron 856 88 Eri hydroxyzine 908 Eri hydroxyzine 857 88 Eri acetylleucine 909 Eri acetylleucine 858 88 Eri monoethanolamine 910 Eri monoethanolamine 859 88 Eri alizapride 911 Eri alizapride 860 88 Eri aZaSetron 912 Eri aZaSetron 861 88 Eri benzquinamide 913 Eri benzquinamide 862 88 Eri bietanautine 914 Eri bietanautine 863 88 Eri bromopride 915 Eri bromopride 864 88 Eri buclizine 916 Eri buclizine 865 88 Eri clebopride 917 Eri clebopride 866 88 Eri cyclizine 918 Eri cyclizine 867 88 Eri dimenhydrinate 919 Eri dimenhydrinate 868 88 Eri diphenidol 920 Eri diphenidol 869 88 Eri dolasetron 921 Eri dolasetron 870 88 Eri meclizine 922 Eri meclizine 871 88 Eri methallatal 923 Eri methallatal 872 88 Eri metopimazine 924 Eri metopimazine 873 88 Eri nabilone 925 Eri nabilone 874 88 Eri oxyperndyl 926 Eri oxyperndyl 875 88 Eri pipamazine 927 Eri pipamazine 876 88 Eri Scopolamine 928 Eri Scopolamine 877 88 Eri Sulpiride 929 Eri Sulpiride 878 88 Eri tetrahydrocannabinol 930 Eri tetrahydrocannabinol 879 88 Eri thiethylperazine 931 Eri thiethylperazine 880 88 Eri thioproperazine 932 Eri thioproperazine 881 88 Eri tropisetron 933 Eri tropisetron 882 88 Eri droperidol 934 Eri droperidol 883 88 Eri haloperidol 935 Eri haloperidol 884 88 Eri prochloperazine 936 Eri prochloperazine 885 88 Eri metoclopramide 937 Eri metoclopramide 886 88 Eri diphenhydramine 938 Eri diphenhydramine 887 88 Eri cannabis 939 Eri cannabis 888 88 Eri midazolam 940 Eri midazolam 889 88 Eri lorazepam 941 Eri lorazepam 890 88 Eri hyoscine 942 Eri hyoscine 891 88 Eri dexamethasone 943 Eri dexamethasone 892 88 Eri emetrol 944 Eri emetrol 893 88 Eri propofol 945 Eri propofol US 2012/020 1888 A1 Aug. 9, 2012 53

TABLE 2-continued TABLE 2-continued Multi-drug Compositions Multi-drug Compositions Composition Composition No. Triptan Antiemetic agent No. Triptan Antiemetic agent

946 Sumatri promethazine ZO mitri benzquinamide 947 Sumatri aprepitant ZO mitri bietanautine 948 Sumatri dronabinol ZO mitri bromopride 949 Sumatri periphenazine ZO mitri buclizine 950 Sumatri palonosetron ZO mitri clebopride 951 Sumatri trimethyobenzamide ZO mitri cyclizine 952 Sumatri metoclopromide ZO mitri dimenhydrinate 953 Sumatri domperidone ZO mitri diphenidol 954 Sumatri prochlorperazine ZO mitri dolasetron 955 Sumatri promethazine ZO mitri meclizine 956 Sumatri chlorpromazine ZO mitri methallatal 957 Sumatri trimethobenzamide ZO mitri metopimazine 958 Sumatri Ondansetron ZO mitri nabilone 959 Sumatri granisetron ZO mitri oxyperndyl 960 Sumatri hydroxyzine ZO mitri pipamazine 961 Sumatri acetylleucine ZO mitri Scopolamine 962 Sumatri monoethanolamine ZO mitri Sulpiride 963 Sumatri alizapride ZO mitri etrahydrocannabinol 964 Sumatri aZaSetron ZO mitri hiethylperazine 96S Sumatri benzquinamide ZO mitri hioproperazine 966 Sumatri bietanautine ZO mitri tropisetron 967 Sumatri bromopride ZO mitri droperidol 968 Sumatri buclizine ZO mitri haloperidol 969 Sumatri clebopride ZO mitri prochloperazine 970 Sumatri cyclizine ZO mitri metoclopramide 971 Sumatri dimenhydrinate ZO mitri diphenhydramine 972 S8.ip diphenidol ZO mitri cannabis 973 Sumatri dolasetron ZO mitri midazolam 974 Sumatri meclizine ZO mitri orazepam 975 Sumatri methallatal ZO mitri hyoscine 976 Sumatri metopimazine mitri dexamethasone 977 Sumatri nabilone mitri emetrol 978 Sumatri oxyperndyl mitri propofol 979 Sumatri pipamazine Eri promethazine 98O Sumatri Scopolamine Eri aprepitant 981 Sumatri Sulpiride Eri dronabinol 982 Sumatri etrahydrocannabinol Eri periphenazine 983 Sumatri hiethylperazine Eri palomosetron 984 Sumatri hioproperazine Eri trimethyobenzamide 985 Sumatri tropisetron Eri metoclopromide 986 Sumatri droperidol Eri domperidone 987 Sumatri haloperidol Eri prochlorperazine 988 Sumatri prochloperazine Eri promethazine 989 Sumatri metoclopramide Eri chlorpromazine 990 Sumatri diphenhydramine Eri trimethobenzamide 991 Sumatri cannabis Eri Ondansetron 992 Sumatri midazolam Eri granisetron 993 Sumatri orazepam Eri hydroxyzine 994 Sumatri hyoscine Eri acetylleucine 995 Sumatri dexamethasone Eri monoethanolamine 996 Sumatri emetrol Eri alizapride 997 Sumatri propofol Eri aZaSetron 998 ZO mitrip promethazine Eri benzquinamide 999 ZO mitrip aprepitant Eri bietanautine OOO ZO mitrip dronabinol Eri bromopride OO1 ZO mitrip periphenazine Eri buclizine OO2 ZO mitrip palomosetron Eri clebopride OO3 ZO mitrip trimethyobenzamide Eri cyclizine OO)4 ZO mitrip metoclopromide Eri dimenhydrinate 005 ZO mitrip domperidone Eri diphenidol OO6 ZO mitrip prochlorperazine Eri dolasetron OO7 ZO mitrip promethazine Eri meclizine O08 ZO mitrip chlorpromazine Eri methallatal O09 ZO mitrip trimethobenzamide Eri metopimazine O10 ZO mitrip Ondansetron Eri nabilone O11 ZO mitrip granisetron Eri oxyperndyl O12 ZO mitrip hydroxyzine Eri pipamazine O13 ZO mitrip acetylleucine Eri Scopolamine O14 ZO mitrip monoethanolamine Eri Sulpiride O15 ZO mitrip alizapride Eri tetrahydrocannabinol O16 ZO mitrip aZaSetron Eri thiethylperazine US 2012/020 1888 A1 Aug. 9, 2012 54

TABLE 2-continued TABLE 2-continued Multi-drug Compositions Multi-drug Compositions Composition Composition No. Triptan Antiemetic agent No. Triptan Antiemetic agent O88 eletriptan hioproperazine 59 rizatriptan trimethyobenzamide O89 eletriptan tropisetron 60 rizatriptan metoclopromide O90 eletriptan droperidol 61 rizatriptan domperidone O91 eletriptan haloperidol 62 rizatriptan prochlorperazine O92 eletriptan prochloperazine 63 rizatriptan promethazine O93 eletriptan metoclopramide 64 rizatriptan chlorpromazine O94 eletriptan diphenhydramine 65 rizatriptan trimethobenzamide 095 eletriptan cannabis 66 rizatriptan Ondansetron O96 eletriptan midazolam 67 rizatriptan granisetron 097 eletriptan orazepam 68 rizatriptan hydroxyzine O98 eletriptan hyoscine 69 rizatriptan acetylleucine O99 eletriptan dexamethasone 70 rizatriptan monoethanolamine OO eletriptan emetrol 71 rizatriptan alizapride O1 eletriptan propofol 72 rizatriptan aZaSetron O2 rovatri promethazine 73 rizatriptan benzquinamide O3 rovatri aprepitant 74 rizatriptan bietanautine O4 rovatri dronabinol 75 rizatriptan bromopride 05 rovatri periphenazine 76 rizatriptan buclizine O6 rovatri palomosetron 77 rizatriptan clebopride O7 rovatri trimethyobenzamide 78 rizatriptan cyclizine O8 rovatri metoclopromide 79 rizatriptan dimenhydrinate 09 rovatri domperidone 8O rizatriptan diphenidol 10 rovatri prochlorperazine 81 rizatriptan dolasetron 11 rovatri promethazine 82 rizatriptan meclizine 12 rovatri chlorpromazine 83 rizatriptan methallatal 13 rovatri trimethobenzamide 84 rizatriptan metopimazine 14 rovatri Ondansetron 85 rizatriptan nabilone 15 rovatri granisetron 86 rizatriptan oxyperndyl 16 rovatri hydroxyzine 87 rizatriptan pipamazine 17 rovatri acetylleucine 88 rizatriptan Scopolamine 18 rovatri monoethanolamine 89 rizatriptan Sulpiride 19 rovatri alizapride 90 rizatriptan etrahydrocannabinol 2O rovatri aZaSetron 91 rizatriptan hiethylperazine 21 rovatri benzquinamide 92 rizatriptan hioproperazine 22 rovatri bietanautine 93 rizatriptan tropisetron 23 rovatri bromopride 94 rizatriptan droperidol 24 rovatri buclizine 95 rizatriptan haloperidol 25 rovatri clebopride 96 rizatriptan prochloperazine 26 rovatri cyclizine 97 rizatriptan metoclopramide 27 rovatri dimenhydrinate 98 rizatriptan diphenhydramine 28 rovatri diphenidol 99 rizatriptan cannabis 29 rovatri dolasetron 2OO rizatriptan midazolam 30 rovatri meclizine 2O1 rizatriptan orazepam 31 rovatri methallatal 2O2 rizatriptan hyoscine 32 rovatri metopimazine 2O3 rizatriptan dexamethasone 33 rovatri nabilone 204 rizatriptan emetrol 34 rovatri oxyperndyl 205 rizatriptan propofol 35 rovatri pipamazine 36 rovatri Scopolamine 37 rovatri Sulpiride 38 rovatri etrahydrocannabinol 0392. As to any pharmaceutically active agent disclosed in 39 rovatri hiethylperazine the foregoing Table 1 or Table 2, it should be noted that any 40 rovatri hioproperazine pharmaceutically acceptable salt of the pharmaceutically 41 rovatri tropisetron 42 rovatri droperidol active agent is within the various embodiments of the present 43 rovatri haloperidol invention. Furthermore, non-limiting examples of Such phar 44 rovatri prochloperazine maceutically acceptable salts are disclosed herein. 45 rovatri metoclopramide 46 rovatri diphenhydramine 0393 While particular embodiments described herein 47 rovatri cannabis have been shown and described herein, such embodiments are 48 rovatri midazolam 49 rovatri orazepam provided by way of example only. Numerous variations, 50 rovatri hyoscine changes, and Substitutions will now occur to those skilled in 51 rovatri dexamethasone 52 rovatri emetrol the art without departing from the invention. It should be 53 rovatri propofol understood that various alternatives to the embodiments of S4 rizatrip promethazine the invention described herein may be employed in practicing 55 rizatrip aprepitant 56 rizatrip dronabinol the invention. It is intended that the following claims define 57 rizatrip periphenazine the scope of the invention and that methods and structures 58 rizatrip palomosetron within the scope of these claims and their equivalents be covered thereby. US 2012/020 1888 A1 Aug. 9, 2012 55

1-136. (canceled) dyphline, oxitriphylline, theophhylline, amphetamine, ben 137. A composition comprising: Zphetamine, dextroamphetamine, diethylpropion, mazindol, a. an effective amount of: methamphetamine, methylphenidate, dexmethylphenidate, i.a triptan, and pemoline, Sibutramine, modafinil, atomoxetine, phendime ii. an antiemetic; and trizine, phenteramine, adrafinil, phenylpropanolamine, pSue b. a pharmaceutically acceptable carrier or vehicle. doephedrine, Synephrine, amphetaminil, and furfenorex, or a 138. A Solid composition comprising: pharmaceutically acceptable salt thereof. a. an effective amount of: 146. The composition of claim 138, further comprising a i. an opioid, and barbiturate agent, wherein the barbiturate agent is allobar ii. an antiemetic; and bital, alphenal, amobarbital, aprobarbital, barbexaclone, bar b. a pharmaceutically acceptable carrier or vehicle. bital, brallobarbital, butabarbital, butalbital, butobarbital, 139. The composition of claim 137 or 138, wherein the butallylonal, crotylbarbital, cyclobarbital, cyclopal, ethallo composition is an oral dosage form comprising: barbital, febarbamate, heptabarbital, hexethal, hexobarbital, a. an immediate-release layer comprising the antiemetic; mephobarbital, metharbital, methohexital, methylphenobar and bital, narcobarbital, nealbarbital, pentobarbital, primidone, b. a controlled-release layer comprising the opioid analge probarbital, propallylonal, proxibarbal, proxibarbital, sic or triptan. reposal, secbutabarbital, secobarbital, sigmodal, talbutal, thi 140. The composition of claim 137 or 138, wherein: albarbital, thiamylal, thiobarbital, thiobutabarbital, thiopen a. the opioid analgesic is hydrocodone, oxycodone, mor tal, valofane, vinbarbital, vinylbital, 1,3-dimethoxymethyl phine, diamorphine, codeine, pethidine, alfentanil, 5,5-diphenyl-barbituric acid, 1-monomethoxymethyl 5.5- buprenorphine, butorphanol, codeine, dezocine, fenta diphenylbarbituric acid diphenyl-barbituric acid, or a phar nyl, hydromorphone, levomethadyl acetate, levorpha maceutically acceptable salt thereof. nol, meperidine, methadone, morphine Sulfate, nalbu 147. The composition of claim 138, further comprising an phine, oxycodone, oxymorphone, pentazocine, opioid antagonist or an abuse deterrent agent, wherein the propoxyphene, remifentanil, Sufentanil, or tramadol, or opioid antagonist agent or abuse deterrent agent comprises a pharmaceutically acceptable Salt thereof, or the triptan nalmefene, naloxone, naltrexone, cyclazacine or levallor is naratriptan, almotriptan, Sumatriptan, Zolmitriptan, phan, niacin or a pharmaceutically acceptable salt thereof. eletriptan, froVatriptan, or rizatriptan, or a pharmaceuti 148. The composition of claim 138, further comprising one cally acceptable salt thereof; and or more beta blockers, serotonin receptor agonists, vasocon ... the antiemetic is aprepitant, dronabinol, perphenazine, strictors, anti-platelet agents, anti-convulsants, ergots, or cal palonosetron, trimethyobenzamide, metoclopromide, citonin-gene-related peptide (CGRP) receptor antagonists. domperidone, prochlorperazine, promethazine, chlor 149. A method of treating or preventing pain, headache, or promazine, trimethobenzamide, ondansetron, granis photophobia in a subject comprising administering to the etron, hydroxy Zine, acetylleucine monoethanolamine, subject the composition of claim 138. alizapride, aZasetron, benzquinamide, bietanautine, bro 150. The method of claim 149, wherein the headache is a mopride, buclizine, clebopride, cyclizine, dimenhydri migraine headache, a cluster headache, or a chronic tension nate, diphenidol, dolasetron, meclizine, methallatal, headache or the photophobia is associated with a migraine metopimazine, nabilone, oxyperndyl, pipamazine, Sco headache. polamine, Sulpiride, tetrahydrocannabinol, thiethylp 151. A bi-layer tablet comprising: erazine, thioproperazine, tropisetron, droperidol, halo a. a controlled-release layer comprising: peridol. prochloperazine, metoclopramide, i. from about 6.5 mg to about 8.5 mg of hydrocodone or diphenhydramine, cannabis, midazolam, lorazepam, a pharmaceutically acceptable salt thereof, hyoscine, dexamethasone, emetrol, or propofol, or a ii. from about 290 mg to about 360 mg of acetaminophen pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof, and 141. The composition of claim 137 or 138, wherein the b. an immediate-release layer comprising from about 11 antiemetic is promethazine. mg to about 14 mg of promethazine or a pharmaceuti 142. The composition of claim 138, wherein the opioid cally acceptable salt thereof, analgesic comprises from about 6.5 mg to about 8.5 mg of wherein about 90% of the promethazine or a pharma hydrocodone or a pharmaceutically acceptable salt thereof ceutically acceptable salt thereof is released in about and the antiemetic comprises from about 11 mg to about 14 1 minute to about 20 minutes following administra mg of promethazine or a pharmaceutically acceptable salt tion and about 100% of the promethazine or a phar thereof. maceutically acceptable salt thereof is released in 143. The composition of claim 137, wherein the triptan about 40 minutes following administration, wherein comprises from about 25 mg to about 100 mg Sumatriptan or about 30% to about 60% of the hydrocodone or a a pharmaceutically acceptable salt thereof and the antiemetic pharmaceutically acceptable salt thereof and the comprises from about 0.5 mg to about 60 mg of promethazine acetaminophen or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof. thereof are released within about 5 minutes to about 144. The composition of claim 138, further comprising 10 minutes following administration, wherein the bi from about 200 to about 600 mg of acetaminophen or an layer tablet provides an effective amount of promet equivalent amount of ibuprofen, carprofen, fenbuprofen, flu hazine, hydrocodone and acetaminophen or their biprofen, ketaprofen, ketorolac, loxoprofen, naproxen, or pharmaceutically acceptable salts thereof for about 4 Suprofen, or a pharmaceutically acceptable salt thereof. hours to about 6 hours following administration. 145. The composition of claim 138, further comprising a 152. The bi-layer tablet of claim 151, further comprising a stimulant, wherein the stimulant is aminophylline, caffeine, barbiturate agent wherein the barbiturate agent is allobarbital, US 2012/020 1888 A1 Aug. 9, 2012 56 alphenal, amobarbital, aprobarbital, barbexaclone, barbital, 5,5-diphenyl-barbituric acid, 1-monomethoxymethyl 5.5- brallobarbital, butabarbital, butalbital, butobarbital, butally diphenylbarbituric acid diphenyl-barbituric acid, or a phar lonal, crotylbarbital, cyclobarbital, cyclopal, ethallobarbital, maceutically acceptable salt thereof. febarbamate, heptabarbital, hexethal, hexobarbital, 153. The bi-layer tablet of claim 151, further comprising mephobarbital, metharbital, methohexital, methylphenobar one or more beta blockers, serotonin receptoragonists, vaso bital, narcobarbital, nealbarbital, pentobarbital, primidone, constrictors, anti-platelet agents, anti-convulsants, ergots, or probarbital, propallylonal, proxibarbal, proxibarbital, calcitonin-gene-related peptide (CGRP) receptor reposal, secbutabarbital, secobarbital, sigmodal, talbutal, thi antagonists. albarbital, thiamylal, thiobarbital, thiobutabarbital, thiopen tal, valofane, vinbarbital, vinylbital, 1,3-dimethoxymethyl