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US 20140275038A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0275038A1 Shah et al. (43) Pub. Date: Sep. 18, 2014

(54) ABUSE DETERRENT COMPOSITIONS AND Publication Classification METHODS OF USE (51) Int. Cl. (71) Applicant: uprig. Detry Ishologies, LLC, A613 L/485 (2006.01) y 2C, A6II 45/06 (2006.01) (72) Inventors: Manish S. Shah, West Caldwell, NJ (52) U.S. Cl. (US); Ray J. DiFalco, Ridgewood, NJ CPC ...... A61K 31/485 (2013.01); A61K 45/06 (US); Stefan Aigner, Valley Cottage, NY (2013.01) (US) USPC ...... 514/217.11: 514/282 (73) Assignee: Inspirion Delivery Technologies, LLC, Valley Cottage, NY (US) 57 ABSTRACT (21) Appl. No.: 14/218,791 (57) (22) Filed: Mar 18, 2014 O O Orallyy administrable ppharmaceutical compositions,p methods Related U.S. Application Data of administration, and methods of making the same are pro (60) Provisional application No. 61/799,096, filed on Mar. vided. The pharmaceutical compositions provide abuse deter 15, 2013. rent properties. Patent Application Publication Sep. 18, 2014 US 2014/0275038A1

Morphine ARER 100 mg Extraction in Ethanol (N =5)

100 90 Zintact 30 Minutes

80 EX Intact 240 Minutes O E Ground 30 Minutes O NGround 240 Minutes O

O

O

20

10

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ZZZZZZZ Water 5%. Ethanol 10%. Ethanol 20% Ethanol 40%. Ethanol

F.G. 1 US 2014/0275038A1 Sep. 18, 2014

ABUSE DETERRENT COMPOSITIONS AND 0007. , also known as 14-hydroxydihydro METHODS OF USE morphinone and 4.5C.-epoxy-3, 14-dihydroxy-17-methyl morphinan-6-one, is an opioid analgesic used for the treat CROSS REFERENCE TO RELATED ment of pain. Major metabolites of oxymorphone include APPLICATION oxymorphone-3-glucuronide and 6-hydroxy-oxymorphone. 0008 , which is also known as 4.5C.-epoxy 0001. This application claims the benefit of U.S. Patent 3-methoxy-17-methylmorphinan-6-one, is an opioid analge Provisional Application No. 61/799,096, filed on Mar. 15, sic used for the treatment of pain. Major metabolites of hydro 2013, which is incorporated herein by reference. codone include norhydrocodone and . 0009 Hydromorphone, which is also known as 4.5-C.- FIELD OF THE INVENTION epoxy-3-hydroxy-17-methyl morphinan-6-one, is an opioid 0002 The present invention provides orally administrable analgesic. Major metabolites of hydromorphone include pharmaceutical compositions, methods of administration, hydromorphone-3-glucuronide, hydromorphone-3-gluco and methods of making the same. side and dihydroisomorphine-6-glucuronide. 0010 , which is also known as a (5C,6C.)-7,8- BACKGROUND OF THE INVENTION didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6- ol, is an opioid used for its analgesic, antitussive, antidiar 0003. The present invention relates to orally administrable rheal, antihypertensive, anxiolytic, antidepressant, sedative pharmaceutical compositions, and specifically relates to and hypnotic properties. Major metabolites of codeine compositions that are designed to reduce the potential for include codeine-6-glucuronide (C6G), norcodeine, hydroc improper administration of medications and their use in a odone, , morphine-3-glucuronide, morphine-6-glu non-indicated or non-prescribed manner. The present inven curonide, and normorphine. tion can comprise any drug, and it is especially useful with 0011 Central nervous stimulants are often used to medications that are Subject to abuse. Such as drugs affecting increase mental alertness, and they can results in feelings of the central nervous system. For example, the present inven exhilaration and energy. Examples of Such drugs include tion is particularly useful for pain medications, medications amphetamines such as methylphenidate, dextroamphet to reduce or eliminate anxiety attacks, stimulants and sleep ing pills. With these general types of drugs, there is the poten amine, and lisdexamfetamine. 0012 Methylphenidate, which is also known as methyl tial of abuse and improper administration that may result in phenyl(piperidin-2-yl)acetate, is a drug often used for treat drug overdose, addiction, Suboptimal efficacy, and/or death. ment of narcolepsy, attention-deficit/hyperactivity disorder, 0004 Opioid agonists are substances that act by attaching and depression. Major metabolites of methylphenidate to specific proteins called opioid receptors, which are found include but are not limited to ethylphenidate, ritalinic acid in the brain, spinal cord, and gastrointestinal tract. When (CL-phenyl-2-piperidine acetic acid), hydroxymethylpheni these drugs attach to certain opioid receptors in the brain and spinal cord, they can effectively block the transmission of date, and hydroxyritalinic acid. pain messages to the brain. Opioid analgesics Such as oxyc 0013 Dextroamphetamine, which is also known as (2S)- odone, morphine, oxymorphone, hydrocodone and hydro 1-phenylpropan-2-amine, is a drug used for treatment of nar morphone are Successful and therapeutically useful pain colepsy, attention-deficit/hyperactivity disorder, and depres medications. Opioids undergo phase 1 metabolism by the sion. Major metabolites of dextroamphetamine include but cytochrome P450(CYP) pathway, phase 2 metabolism by are not limited to 4-hydroxyamphetamine, benzoic acid, phe conjugation, or both, as described in Smith H. "Opioid nylacetone, hippuric acid, 4-hydroxynorephedrine, and Metabolism.” Mayo Clin. Proc., 2009; 84(7):613-624. norephedrine. 0005 Morphine, also known as (5C,6O)-7,8-didehydro-4, 0014 Lisdexamfetamine, also known as lisdexamfe 5-epoxy-17-methylmorphinan-3,6-diol, is an example of a tamine, is another stimulant. It is a prodrug of phenethy potent opioid analgesic used in the treatment of acute, lamine and amphetamines such as dextroamphetamine. chronic, and severe pain. Major metabolites of morphine 00.15 Benzodiazepines are commonly used to treat anxi include morphine-3-glucuronide (M3G), morphine-6-glucu ety. Examples of benzodiazepines include, but are not limited ronide (M6G), hydromorphone, normorphine (NM) and to alprazolam, lorazepam, and diazepam. minor metabolites Such as morphine-3,6-diglucuronide, mor 0016 Alprazolam, which is also known as 8-chloro-1- phine-3-ethereal Sulfate, normorphine-6-glucuronide, and methyl-6-phenyl-4H-1,2,4-triazolo 4.3-a 1,4)benzodiaz normorphine-3-glucuronide. Morphine-6-glucuronide epine, is a short acting anxiolytic. Major metabolites of alpra (M6G), a major metabolite of morphine, is formed by glucu Zolam include, but are not limited to 4-hydroxyalprazolam ronidation. M6G and morphine both demonstrate analgesic and O-hydroxyalprazolam. activity. 0017 Lorazepam, which is also known as (RS)-7-Chloro 0006. , also known as (5R,9R,13S, 14S)-4,5C.- 5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzo epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, diazepin-2-one, is an anxiolytic agent having intermediate is an opioid analgesic used for the treatment of pain. Major duration of action. Major metabolites of lorazepam include, metabolites of oxycodone include norOxycodone, C. oxy but are not limited to, 3-O-phenolic glucuronide and codol, B oxycodol, oxymorphone, C. Oxymorphol. 3 oxymor lorazepam glucuronide. phol, , C. noroxycodol, B noroxycodol. 0018 Diazepam, which is also known as 7-chloro-1,3- noroxymorphone, 14-hydroxydihydrocodeine, and 14-hy dihydro-1-methyl-5-phenyl-1,4-benzodiazepin-2(3H)-one, droxydihydromorphine. Oxymorphone and noroxycodone is a commonly used anxiolytic. Major metabolites of diaz are the most commonly known major metabolites of oxyc epam include, but are not limited to desmethyldiazepam, odone. eSmethyldiazepam, oxazepam, and temazepam. US 2014/0275038A1 Sep. 18, 2014

0019 While pain medications, medications to reduce or composition is released after 60 minutes under the following eliminate anxiety attacks (psychotherapeutic drugs), stimu dissolution conditions: DI water, 500 mL, USP Apparatus 2 lants and sleeping pills can be safe, effective, and therapeu (Paddle), 50 rpm, 37° C. tically useful when administered properly, such drugs are 0024. The present invention also provides an orally Susceptible to abuse. Examples of Such compositions include administrable pharmaceutical composition comprising a but are not limited to ROXICODONER) (oxycodone tablets), drug, wherein the composition is configured Such that when OXYCONTINR) (oxycodone tablets), DILAUDIDR (hydro the pharmaceutical composition is administered intranasally morphone tablets), OPANAR and OPANA ER(R) (oxymor in physically compromised form to a subject, the area under phone tablets), MS CONTINR) (morphine tablets), CON the curve (AUC) of drug after a period of time is less than CERTAR, METHYLINR, RITALINR, RITALIN LAR), and 200% of the AUC of the drug achieved after oral administra EQUASYM KL(R) (methylphenidate tablets and capsules), tion of an intact form of the pharmaceutical composition after FOCALINR) (dexmethylphenidate capsules), ADDER the same period of time. ALL(R), DEXEDRINE(R), and DEXTROSTATR) (dextroam 0025. The present invention provides an orally adminis phetamine tablets and capsules), VYVANSER (lisdexamfe trable pharmaceutical composition comprising a drug, tamine capsules), ATIVANR) (lorazepam), XANAX(R) wherein the composition is configured such that when the (alprazolam), and VALIUM(R) (diazepam). pharmaceutical composition is administered intranasally in 0020. A sense of euphoria or “high can be experienced physically compromised form to a Subject, the area under the with high serum concentrations of these drugs. Individuals curve (AUC) of a major metabolite of the drug after a period seeking to abuse these drugs will often tamper with oral of time is at least 15% of the AUC of the major metabolite dosage forms containing the drugs to achieve this "high. For achieved after oral administration of an intact form of the example, a large amount of tablets can be placed in a liquid to pharmaceutical composition after the same period of time. form a solution, and abusers either consume the liquid or 0026. The present invention also provides an orally more often filter and inject the solution. These tablets can also administrable pharmaceutical composition comprising a be crushed into a powder or Small particle sizes and Snorted drug, wherein the composition is configured Such that when intranasally. Nasal insufflation, which is another term for the the pharmaceutical composition is administered intranasally inhalation of Substances through the nose, is a common and in physically compromised form to a Subject, the ratio of the harmful practice among abusers. Long-term practice of nasal area under the curve (AUC) of the drug to the AUC of a major insufflation can result in permanent damage to nasal tissue metabolite of the drug (drug:major metabolite) achieved after and increased incidence of toxicity and overdose. There is a a period of time is less than 25 times the ratio of the AUC of need in the art for pharmaceutical compositions which mini the drug to the AUC of the major metabolite (drug: major mize the ability for abuse, and when administered properly, metabolite) achieved after the same period of time after oral provide an adequate and effective amount of drug. administration of the pharmaceutical composition in an intact 0021. It is an object of the present invention to provide a form. pharmaceutical composition that reduces the potential for 0027. The present invention also provides an orally improper administration drugs but which, when administered administrable pharmaceutical composition comprising a as directed through oral administration, is capable of deliver drug, wherein the composition is configured Such that when ing a therapeutically effective dose to a Subject. In particular, the pharmaceutical composition is administered intranasally the present invention addresses the need for an orally admin in physically compromised form to a Subject, the sum of the istrable drug product which, compared to conventional for area under the curve (AUC) of the drug and the AUC of a mulations, decreases the ability of an individual to achieve a major metabolite of the drug after a period of time is less than “high” or euphoria effect through injection or insufflation. the sum of the AUC of the drug and the AUC of the major metabolite achieved after the same period of time after oral SUMMARY OF THE INVENTION administration of the pharmaceutical composition in an intact form. 0022. The present invention provides an oral pharmaceu 0028. The present invention also provides an orally tical composition in unit dosage form comprising a drug, a administrable pharmaceutical composition comprising a pH-dependent agent, and a pH-independent agent, wherein drug, wherein the composition is configured Such that when about 60% or more of the total amount of drug in the phar the pharmaceutical composition is administered intranasally maceutical composition is released after 60 minutes under the in physically compromised form to a Subject, the ratio of the following dissolution conditions: 0.1 NHCl, 500 mL, USP area under the curve (AUC) of the drug to the AUC of a major Apparatus 2 (paddle), 50 rpm, 37°C.; and wherein about 25% metabolite of the drug (drug:major metabolite) achieved after or less of the total amount of drug in the pharmaceutical a period of time is about 10 or less. composition is released after 60 minutes under the following 0029. The present invention also provides a plurality of dissolution conditions: DI water, 500 mL, USP Apparatus 2 particles having a particle size distribution (D50) of about 100 (Paddle), 50 rpm, 37° C. um to about 1000 um, wherein the particles each comprise a 0023 The present invention also provides an oral pharma drug and one or more pharmaceutically acceptable excipients ceutical composition in unit dosage form comprising a drug, and wherein the particles are configured Such that the amount a pH-dependent agent, and a pH-independent agent, wherein of drug released from the plurality of particles is no greater about 50% or more of the total amount of drug in the phar than 500% of the amount of drug released from an intact unit maceutical composition is released after 8 hours under the dosage form comprising the same amount (w/w) as the plu following dissolution conditions: 0.1 NHCl, 500 mL, USP rality of particles, under the following identical conditions: Apparatus 2 (paddle), 50 rpm, 37°C.; and wherein about 25% 30 mL of ethanol, 25°C., agitated at 100 rpm for a period of or less of the total amount of drug in the pharmaceutical time. US 2014/0275038A1 Sep. 18, 2014

0030 The present invention also provides a plurality of which when administered orally as directed, will provide a particles having a particle size distribution (D50) of about 100 therapeutically effective amount of a drug to a subject within um to about 1000 um, wherein the particles each comprise a the intended time when the pharmaceutical composition is in drug and one or more pharmaceutically acceptable excipients an acidic pH. However, when the Surrounding environment of and wherein the particles are configured such that the rate of the oral pharmaceutical composition is at a neutral or alkaline drug released from the plurality of particles is no greater than pH, such as if the composition is placed in a water or basic 500% of the rate of drug released from an intact unit dosage liquid medium, then the release of the drug from the dosage form comprising the same amount (W/w) as the plurality of form may be retarded or reduced. particles, under the following identical conditions: 30 mL of 0038. The present invention provides immediate-release ethanol, 25°C., agitated at 100 rpm for a period of time. and extended-release formulations. The pharmaceutical com 0031. The present invention also provides a plurality of position of the invention can comprise either or both extended particles comprising: an active layer comprising a drug and a release formulations, with a typical in vivo or in vitro slow first polymer, and a barrier layer comprising a second poly release of drug over a period of about 6 to about 24 hours, mer, wherein the active layer and barrier layer are bonded, preferably at least 80% of the drug released at about 6 to about and wherein the particles are configured Such that the amount 24 hours, as well as conventional immediate release formu of drug released from the plurality of particles is no greater lations, preferably with a release of at least 80%, more pref than 500% of the amount of drug released an intact unit erably at least 90% and most preferably at least 95%, of the dosage form comprising the same amount (w/w) as the plu drug in one hour, designed for oral administration. rality of particles, under the following identical conditions: 0039. The present invention provides an oral pharmaceu 30 mL of ethanol, 25°C., agitated at 100 rpm for a period of tical composition in unit dosage form comprising a drug, a time. pH-dependent agent, and a pH-independent agent, wherein 0032. The present invention also provides a plurality of about 60% or more of the total amount of drug in the phar particles comprising: an active layer comprising a drug and a maceutical composition is released after 60 minutes under the first polymer, and a barrier layer comprising a second poly following dissolution conditions: 0.1 NHCl, 500 mL, USP mer, wherein the active layer and barrier layer are bonded, Apparatus 2 (paddle), 50 rpm, 37°C.; and wherein about 25% and wherein the particles are configured such that the rate of or less of the total amount of drug in the pharmaceutical drug released from the plurality of particles is no greater than composition is released after 60 minutes under the following 500% of the rate of drug released from an intact unit dosage dissolution conditions: DI water, 500 mL, USP Apparatus 2 form comprising the same amount (w/w) as the plurality of (Paddle), 50 rpm, 37°C. In particular, in some embodiments, particles, under the following identical conditions: 30 mL of when the pharmaceutical composition is placed in the hydro ethanol, 25°C., agitated at 100 rpm for a period of time. chloric acid medium, about 60% or more, preferably about 0033. In some embodiments, the orally administrable 70% or more, preferably about 80% or more, more preferably compositions comprise two or more of the above features. about 90% or more of the total amount of drug in the phar 0034. The present invention also provides a method of maceutical composition is released after 60 minutes. In some treating a condition, comprising administering to a patient in embodiments, when the pharmaceutical composition is need thereof a pharmaceutical composition of the invention. placed in the deionized water medium, about 25% or less, The present invention also provides a method of reducing the preferably about 15% or less, and more preferably about 10% intensity, frequency and/or quality of euphoria, and a method or less of the total amount of drug in the pharmaceutical of decreasing the rate at which euphoria occurs associated composition is released after 60 minutes. with administration of the drug, wherein the method com 0040. The present invention also provides an oral pharma prises administration of a pharmaceutical composition of the ceutical composition in unit dosage form comprising a drug, present invention. The present invention also provides a a pH-dependent agent, and a pH-independent agent, wherein method of reducing the potential of abuse in a Subject taking no more than 50% of the total amount of drug in the pharma an opioid or stimulant-containing composition. ceutical composition is released within 1 hour and about 50% 0035. The present invention also provides a method of or more of the total amount of drug in the pharmaceutical making such oral pharmaceutical compositions and a method composition is released after 8 hours under the following of treating a medical condition comprising administering to a dissolution conditions: 0.1 NHCl, 500 mL, USP Apparatus 2 Subject in need thereof the oral pharmaceutical composition (paddle), 50 rpm, 37°C.; and wherein about 25% or less of the of the present invention. total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution BRIEF DESCRIPTION OF THE FIGURE conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C. In particular, in some embodiments, when the 0036 FIG. 1 describes the results of the experiment pharmaceutical composition is placed in the hydrochloric described in Example 4. acid medium, about 60% or more, preferably about 70% or more, more preferably about 80% or more of the total amount DETAILED DESCRIPTION OF THE INVENTION of drug in the pharmaceutical composition is released after 8 0037. The present invention provides an abuse deterrent hours. In some embodiments, when the pharmaceutical com oral pharmaceutical composition in unit dosage form which, position is placed in the deionized water medium, about 25% when administered orally, can provide a therapeutic amount or less, preferably about 15% or less, and more preferably of a drug to a subject to accomplish a pharmaceutical effect, about 10% or less of the total amount of drug in the pharma Such as pain relief, while minimizing the ability of a potential ceutical composition is released after 60 minutes. abuser to experience a “high’ through improper administra 0041. The combination of the pH-dependent agent and tion of the composition, such as injection or insufflation. The pH-independent agent may contribute to the abuse deterrent present invention provides for pharmaceutical compositions, aspect of the pharmaceutical composition. When the pharma US 2014/0275038A1 Sep. 18, 2014 ceutical composition is in a Surrounding environment which 0046. The pharmaceutical composition may be formu is at or exceeds a particular pH, then the pH-dependent agent lated for immediate release or extended release characteris and pH-independent agent may contribute to inhibiting the tics. The term “extended release' is used to refer to a compo release of the drug from the pharmaceutical composition. In sition which is formulated to provide for the gradual release Some embodiments, when the pharmaceutical composition is ofan drug over an extended period of time, preferably over 2 placed in an acidic medium in vivo or in vitro. Such as below to 48 hours, more preferably over 4 to 36 hours, and most a pH of about 6, more preferably about 5 or below, even more preferably over 6 to 24 hours. The term “extended release' preferably about 4 or below, and most preferably about 3.5 or includes controlled release and delayed release and may below, the pharmaceutical composition releases about 60% or optionally contain an immediate release component. In some more of the total amount of drug in the composition after a embodiments of the present invention containing an extended time period of about 60 minutes for immediate release for release portion, preferably <25%, more preferably <20%, of mulations and about 8 hours for extended release formula the drug is released in the first hour from the composition; tions. In some embodiments, about 75% or more, more pref preferably 15-50%, more preferably 20-45%, of the drug is erably about 90% or more of the total amount of drug in the released in the first two (2) hours from the composition; pharmaceutical composition is released from the pharmaceu preferably 40-80%, more preferably 45-75%, of the drug is tical composition after a time period of about 60 minutes for released in the first four (4) hours from the composition; and immediate release formulations and about 8 hours for preferably >75%, more preferably >80%, of the drug is extended release formulations. In some embodiments, these released after eight (8) hours from the composition. In some amounts are released after 30 minutes for immediate release other embodiments of the present invention containing an formulations. However, when the Surrounding environment extended release portion, preferably about 5% to about 25% of the pharmaceutical composition is at or above a particular of the drug is released after 1 hour, from about 40% to about pH, such as for example, at or above about 6.5, the release of 75% of the drug is released after 8 hours, and not less than the drug from the pharmaceutical composition may be 80% is released after 18 hours. In some alternative embodi affected. The release of the drug is considered to be affected, ments of the present invention containing an extended release for example, if the amount and/or rate of release of drug is portion, preferably about 10% to about 30% of the drug is reduced. In some embodiments, when the pharmaceutical released after 2 hours, from about 40% to about 70% of the composition is placed in a medium having a pH of about 6 or drug is released after 8 hours, and at least about 80% of the higher, more preferably about 6.5 or higher, and most prefer drug is released after 22 hours. In some embodiments, the ably about 7 or higher, the pharmaceutical composition pharmaceutical composition is formulated for immediate releases about 25% or less, more preferably about 15% or release. The term "immediate release' is used to refer to a less, and most preferably about 10% or less of the total pharmaceutical composition which is formulated to release amount of drug in the composition after 60 minutes of place about 80% or more of an drug after 4 hours, more preferably ment in the medium. In some embodiments, the medium is after 2 hours, and most preferably after 1 hour after oral deionized water. In some embodiments, the medium is an administration. In preferred embodiments, the pharmaceuti alkaline medium. cal composition is formulated to release about 80% or more, 0042. In some embodiments, when the pharmaceutical more preferably about 90% or more, even more preferably composition is placed in a medium having a pH of about 6 or about 95% of the drug in the pharmaceutical composition higher, preferably between 6.5 and 7.5, the amount and/or after about 1 hour after oral administration of the unit dosage rate of release of the drug from the pharmaceutical composi form (for example, after swallowing the tablet or capsule or tion in 60 minutes may be reduced by about 10% or more, other dosage form). preferably about 25% or more, more preferably about 50% or 0047. The term “pH-dependent agent” refers to a compo more, and most preferably about 75% or more, compared to nent which is affected by the pH of the surrounding environ the amount and/or rate of release after placement in a medium ment. In particular, the pH-dependent agent may be a com having a pH below about 5, preferably below about 4. In some pound, Such as a polymer, whose characteristics, such as embodiments, placement of the pharmaceutical composition chemical and/or physical properties, vary according to the pH in a medium of pH of about 6 or higher, preferably between of the Surrounding environment. The Surrounding environ 6.5 and 7.5, may result in at least 90% reduction in the amount ment could comprise any type of liquid medium, Such as and/or rate of release of drug from the pharmaceutical com gastric fluid. In some embodiments wherein the pharmaceu position in 60 minutes, compared to the amount and/or rate of tical composition is orally administered to a subject, the Sur release after placement in a medium having a pH below about rounding liquid may comprise gastric fluid. In some other 5, preferably below about 4. embodiments, the Surrounding liquid may be an in vitro bath, 0043. The “medium' can refer to any surrounding envi Such as water, an acidic or an alkaline solution. In some ronment, whether in vivo or in vitro, e.g. gastric fluid or any embodiments, the pH-dependent agent is affected by (i.e., liquid, such as a solvent oran aqueous solution or Suspension. dissolves when exposed to) a decrease in pH. In some 0044) The present invention provides an oral pharmaceu embodiments, the pH-dependent agent is affected when the tical composition in unit dosage form comprising a drug, a pH is below about 6, preferably below 5, more preferably pH-dependent agent, and a pH-independent agent. below 4, even more preferably below 3. In some embodi 0045. The term “unit dosage form” refers to intact (i.e., not ments, the characteristics of the pH-dependent agent may be physically compromised) physically discrete units suitable as affected to a greater degree at different pHs. For example, the unitary dosages for administration to a Subject. Examples of pH-dependent agent's physical or chemical characteristics unit dosage forms include, but are no limited to tablets, cap may be affected to a greater degree at a pH of 4 or lower, Sules, microtablets, granules, pellets, lollipops, and lozenges. compared to at a pH of 5. In preferred embodiments, the unit dosage form comprises a 0048. The pH-dependent agent may comprise a com tablet. pound such as a pharmaceutical excipient. In some embodi US 2014/0275038A1 Sep. 18, 2014 ments, the pH-dependent agent comprises a pH-dependent more outer portions. For example, in some embodiments, the polymer. Examples of pH-dependent polymers include, but pH-dependent agent and pH-independent agent may be com are not limited to certain methacrylate-based polymers. Such prised in one or more layers or coatings which cover the as cationic polymers with a dimethylaminoethyl ammonium portion, part, or section of the pharmaceutical composition group. These polymers are marketed under trade names Such which comprises the drug (for example, a core or layer con as EUDRAGITR E 100, and EUDRAGITR E PO. In pre taining the drug). In these embodiments, the layer or coating ferred embodiments, the pH-dependent polymer comprises may partially or Substantially cover the drug-containing por EUDRAGITRE 100, or poly(butyl methacrylate-co-(2-dem tion, part, or section of the pharmaceutical composition. The ethylaminoeethyl) methacrylate-co-methyl methacrylate), term “substantially cover” means that preferably about 70% 1:2:1. EUDRAGITR E100 is a cationic polymer with dim or more, more preferably about 80% or more, even more ethylaminoethyl methacrylate as a functional group (CAS preferably about 90% or more, and most preferably about Registry No. 24938-16-7). 95% or more of the part of the composition comprising the 0049. The “pH-independent agent” refers to a component drug is covered. In some embodiments, 100% coverage is whose characteristics do not generally vary according to the suitable. pH of the Surrounding environment. In particular, the pH 0052. In embodiments wherein the pH-dependent agent independent agent may be a compound. Such as a polymer, and pH-independent agent are comprised in one or more whose characteristics, such as chemical and/or physical prop layers or coatings which cover the portion, part or section of erties, do not vary significantly with changes in the pH of the the composition which comprises the drug, the drug-contain Surrounding environment. The pH-independent agent may ing portion, part, or section may be in any form. For example, comprise a compound such as a pharmaceutical excipient. In the drug-containing portion, part, or section may be a tablet Some embodiments, the pH-independent agent comprises a core or a capsule, and the pH-dependent agent and pH-inde pH-independent polymer. Examples of pH-independent pendent agent may be comprised in a coating which partially agents include cellulose-type agents, including but not lim or Substantially covers the tablet core or capsule. In some ited to hydroxyethyl cellulose polymers, ethylcellulose poly embodiments, the active-ingredient portion, part, or section mers, methylcellulose polymers, and hydroxypropyl methyl may comprise the pharmaceutical composition disclosed in cellulose polymers; and certain methacrylate-based U.S. Pat. No. 7,955,619, which is incorporated by reference polymers, including but not limited to methacrylate/acrylate in its entirety, and the pH-dependent agent and pH-indepen copolymers with trimethyl-ammonioethyl-amethacylate as a dent agent may be comprised in one or more coatings. In functional group, and neutral polymers of methacrylate/acry some embodiments, the pharmaceutical may comprise a lates. Cellulose-type agents are marketed under trade names matrix comprising the pH-dependent agent and the pH-inde such as ETHOCEL(R) and METHOCEL(R), which include a pendent agent, and the drug is distributed within the matrix. number of Subtypes based on physical/chemical properties. 0053. In some embodiments wherein the pharmaceutical Examples of pH-independent methacrylate-based polymers composition comprises a coating or layer comprising the include those marketed under trade names Such as pH-dependent agent and the pH-independent agent and the EUDRAGITR) RL 30D, EUDRAGITR) RL PO, coating or layer which covers or Surrounds the part of the EUDRAGITR) RL 100, EUDRAGITR) RL 12.5, pharmaceutical composition comprising the active compo EUDRAGITR) RS 30D, EUDRAGITR) RS PO, nent, the release of the drug may be affected by a reduction of EUDRAGITR) RS 100, EUDRAGITR) RS 12.5, the dissolution of the coating or layer. For example, at a EUDRAGITR NE 30D, EUDRAGITR NE 40D, and certain pH. Such as at normal gastric pH, the coating or layer EUDRAGITRNM30D. In some preferred embodiments, the may dissolve substantially and then a Substantial amount of pH-independent agent comprises an ethylcellulose polymer, the drug is released from the pharmaceutical composition. such as those marketed under the trade name ETHOCEL(R). In However, at another pH, for example, above pH 6, the disso preferred embodiments, the pH-independentagent comprises lution of the coating or layer may be reduced, preferably ETHOCEL(R) 45, which is an ethylcellulose having a viscos significantly, and/or the coating or layer may remain partially ity of about 41-49. or Substantially intact, and the total amount of the drug is not 0050. In some embodiments, the pharmaceutical compo released from the pharmaceutical composition. In some sition may comprise a portion, part, or section which com embodiments wherein the pH-dependent agent and pH-inde prises both the pH-dependent agent and pH-independent pendent agents are comprised in a matrix in which the drug is agent. For example, the composition may comprise a layer or distributed, a similar effect may be achieved. For example, at coating which comprises both the pH-dependent agent and a certain pH, for example, at normal gastric pH, the matrix the pH-independent agent. In some other embodiments, the may release the total amount of drug from pharmaceutical pH-dependent agent and pH-independent agent may each be composition. However, at another pH, for example, at about present in separate parts or sections (such as, separate layers) pH 6 or above, the matrix may remain Substantially intact or of the pharmaceutical composition. In some other embodi otherwise not release the total amount of the drug from the ments, the multiple sections containing pH-dependent agent pharmaceutical composition. In some embodiments, the may be distributed within a section comprising the pH-inde reduced amount and rate of release makes it difficult for pendent agent, or vice versa. Subjects to abuse the drug by injection to attain a “high, as in 0051. In some embodiments, the composition may com Some cases, the pharmaceutical composition may be partially prise the drug in a portion, part, or section of the pharmaceu or substantially undissolved, and it is difficult to draw up a tical composition which is separate from the part(s) or section large amount of drug in a Syringe. (s) of the pharmaceutical composition which comprises the 0054. In some embodiments, the weight ratio of pH-de pH-dependentagent and the pH-independentagent. The com pendent agent.pH-independent agent present in the composi position may comprise the drug in an inner portion, and the tion is about 50:1 to 1:50, preferably 25:1 to 1:25, and more pH-dependent agent and pH-independent agent in one or preferably 10:1 to 1:1. In some preferred embodiments, the US 2014/0275038A1 Sep. 18, 2014 pH-dependent agent and pH-independent agent are com , etonitaZene, hydrocodone, hydromorphone, prised in the same portion, part, or section of the composition, hydroxypethidine, , , levorpha Such as in a layer or coating, and the weight ratio of pH nol, levophenacylmorphan, , meperidine, meptazi dependent agent: pH-independent agent is about 10:1 to 10:6. nol, , , , morphine, myro more preferably about 10:2 to 10:4, and most preferably phine, narceline, , norlevorphanol, about 10:3. In preferred embodiments, the composition com normethadone, , nalbuphene, normorphine, norpi prises a cationic polymer with dimethyl-aminoethyl meth panone, , oxycodone, oxymorphone, papavereturn, acrylate as a functional group, preferably EUDRAGITR) , phenadoxone, phenomorphan, , E100 (a pH-dependent agent), and an ethylcellulose polymer, phenoperidine, , , propheptazine, preferably ETHOCELR 45 (a pH-independent agent), in a promedol, properidine, propoxyphene, , , ratio of EUDRAGITOR E100:ETHOCELOR) 45 of about 10:3. and . Any opioid orpharmaceutically acceptable salt 0055. The term “drug includes any compound which has or ester thereof may be used in the abuse deterrent composi pharmacological or biological activity. A drug may comprise tion. Preferred opioids include , sufentanil, carfenta an active pharmaceutical ingredient or a salt, ester, or deriva nil, lofentanil, , hydromorphone, oxycodone, mor tive thereof. In some embodiments, the drug include, but are phine, hydroxycodone, propoxyphene, pentazocine, not limited to analgesics, anti-inflammatory agents, anti-hel methadone, tilidine, , , levorpha minthics, anti-arrhythmic agents, anti-asthma agents, anti nol, codeine, Oxymorphone, meperidine, and dihydroco bacterial agents, anti-viral agents, anti-coagulants, anti-de deinone. More preferred opioids include oxycodone, hydro mentia agents, anti-depressants, anti-diabetics, anti codone, codeine, morphine, oxymorphone and epileptics, anti-fungal agents, anti-gout agents, anti hydromorphone, and pharmaceutically acceptable salts and hypertensive agents, anti-malarials, anti-migraine agents, esters thereof. anti-muscarinic agents, anti-neoplastic agents, immunosup 0.058 Examples of barbiturates include, but are not limited pressants, anti-protozoal agents, anti-thyroid agents, anti-tus to mephobarbital (which is sometimes marketed under the sives, anxiolytics, sedatives, hypnotics, neuroleptics, neuro tradename MEBARAL(R) and pentobarbital sodium (which protective agents, 13-blockers, cardic inotropic agents, cell is sometimes marketed under the tradename NEMB adhesion inhibitors, corticosteroids, cytokine receptor activ UTAL(R). Barbiturates are often prescribed to treat anxiety, ity modulators, diuretics, anti-Parkinson's agents, gastro-in tension, and sleep disorders. testinal agents, histamine H-receptor antagonists, keratolyt 0059 Examples of benzodiazepines and benzodiazepine ics, lipid regulating agents, muscle relaxants, nitrates and derivatives include, but are not limited to diazepam (some other anti-anginal agents, non-steroid anti-asthma agents, times marketed under the tradename VALIUM(R), alpra nutritional agents, opioid analgesics, sex hormones, stimu Zolam (sometimes marketed under the tradename lants and anti-erectile dysfunction agents; and salts, esters, XANAX(R), triazolam (HALCIONR), and estazolam and mixtures thereof. In preferred embodiments, the drug is (PROSOM(R). Benzodiazepines are often prescribed to treat one that is often abused. Such as a central nervous system stimulant or depressant. Examples of central nervous system anxiety, acute stress reactions, and panic attacks. stimulants include, but are not limited to, amphetamines and 0060 An example of another CNS depressant is Zaleplon, agents such as cocaine. Examples of central nervous depres which is sometimes marked under the tradename SONATAR). sants include, but are not limited to but are not limited to 0061 The present invention provides for compositions opioids, barbiturates, benzodiazepines, and other anxiety and comprising one or more drugs. In some embodiments, the sleep medications. compositions comprise one or more opioids. The present 0056 Stimulants increase heart rate, blood pressure and invention also provides for compositions comprising one or metabolism, sometimes providing feelings of exhilaration more opioids, wherein the compositions do not comprise an and energy and increased mental alertness. Amphetamines opioid antagonist or any other non-opioid agonist. The Such as methylphenidate (sometimes marketed under the present invention provides for compositions comprising one tradename RITALINR) and dextroamphetamine (sometimes or more drugs but not comprising any adverse agent. Adverse marketed under the tradenames ADDERALL(R) and agents refer for agents which reduce or eliminate one or more DEXEDRINE(R) are often prescribed for the treatment of pharmacological effects of the drug or agents which cause an narcolepsy, attention-deficit/hyperactivity disorder, and undesired physiological reaction, such as emesis. Adverse depression that has not responded to other treatments. They agents include, but are not limited to antagonists such as also may be used for short-term treatment of obesity. Indi opioidantagonists, mucous membrane irritants, and emetics. viduals may become addicted to the sense of well-being and The present invention provides compositions which do not enhanced energy that stimulants can generate. Taking high comprise or natrexone. doses of stimulants repeatedly overa short time, however, can 0062 Preferred embodiments of the invention include an lead to feelings of hostility or paranoia. Additionally, taking drug in the amounts as follows: oxycodone or a pharmaceu high doses of stimulants may result in dangerously high body tically acceptable salt thereof, which is present in an amount temperatures and an irregular heartbeat. of about 5 mg to about 400 mg; morphine or a pharmaceuti 0057 Examples of opioids include, but are not limited to cally acceptable salt thereof, which is present in an amount of the following: alfentanil, allylprodine, alphaprodine, anilleri about 15 mg to about 800 mg: hydromorphone or a pharma dine, , , buprenorphine, butor ceutically acceptable salt thereof, which is present in an phanol, clonitaZene, codeine, , dextromora amount of about 1 mg to about 64 mg: hydrocodone or a mide, , diampromide, diamorphone, pharmaceutically acceptable salt thereof, which is present in , , , dimephep an amount of about 5 mg to about 400 mg; and oxymorphone tanol, dimethylthiambutene, dioxaphetyl butyrate, dipi or a pharmaceutically acceptable salt thereof, which is panone, , ethoheptazine, ethylmethylthiambutene, present in an amount of about 4 mg to about 80 mg. US 2014/0275038A1 Sep. 18, 2014

0063. In some embodiments, the compositions of the ethyl alcohol) and/or water. In preferred embodiments, the present invention comprise morphine or a pharmaceutically physically compromised composition is in a chopped, acceptable salt thereof. Salts of morphine include, but are not ground, or crushed form. A pharmaceutical composition may limited to sulfate, sulfate pentahydrate, hydrochloride, hydro be physically compromised in a number of ways, including chloride trihydrate, meconate, Valerate, acetate, citrate, bitar but not limited to use of a pill crusher, a pill splitter, a mortar trate, Stearate, phthalate, hydrobromide, hydroiodide, and pestle, a Solid object Such as a hammer or a spoon, a sharp mucate, nitrate, salicylate, phenylpropionate, phosphate, object Such as a razor, a grinder Such as a coffee bean grinder, methyliodide, isobutyrate, hypophosphite, tannate, tartrate, or a blender. In some embodiments, the average particle size methylbromide, methylsulfonate, and those disclosed in EP of the physically compromised pharmaceutical composition 0.137600, which is incorporated herein by reference. In pre is less than 6 mm, alternatively less than 5 mm, alternatively ferred embodiments, the composition comprises morphine less than 4 mm, alternatively less than 3 mm, alternatively less Sulfate or morphine Sulfate pentahydrate. than 2 mm, alternatively less than 1 mm, alternatively less 0064. In some embodiments, the compositions of the than 0.5 mm, alternatively less than 0.25 mm. present invention comprise oxycodone or a pharmaceutically 0069. The present invention provides orally administrable acceptable salt thereof. Salts of oxycodone include, but are pharmaceutical compositions comprising a drug and option not limited to hydrochloride, hydrobromide, hydroiodide, ally comprising a pH-dependent agent and pH-independent Sulfate, bisulfate, nitrate, citrate, tartrate, bitartrate, phos agent. The orally administrable pharmaceutical compositions phate, malate, maleate, fumarate, Succinate, acetate, tereph may optionally comprise a coating. thalate, and pamoate. In preferred embodiments, the compo 0070. The area under the curve, or “AUC” refers to the area sition comprises oxycodone hydrochloride. under the serum concentration curve, or the integral of the 0065. In some embodiments, the compositions of the blood serum concentration of the drug Substance over a present invention comprise oxymorphone or a pharmaceuti period of time. The AUC achieved after a period of time refers cally acceptable salt thereof. Examples of oxymorphone to the AUC calculated after an amount of time after adminis include, but are not limited to hydrochloride, sulfate, nitrate, tration. In some embodiments, the period of time is about 30 phosphate, hydrobromide, malate, maleate, ascorbate, cit minutes to about 24 hours after administration. In some rate, tartarate, pamoate, laurate, Stearate, palmitate, oleate, embodiments, the period of time is selected from the group myristate, lauryl Sulfate, linoleate, and linolenate. In some consisting of about 30 minutes, about 1 hour, about 2 hours, preferred embodiments, the composition comprises oxymor about 4 hours, about 8 hours, about 12 hours, and about 24 phone hydrochloride. hours and the AUC is calculated at any of these time points 0066. In some embodiments, the compositions of the after administration. In some preferred embodiments, the present invention comprise hydrocodone or a pharmaceuti period of time is selected from the group consisting of about cally acceptable salt thereof. Salts of hydrocodone include, 0.5 hours, 1 hour, and 2 hours. In some embodiments, the but are not limited to, bitartrate, bitartrate hydrate, hydrochlo AUC may refer to the “AUC”. The term “AUC” refers to ride, p-toluenesulfonate, phosphate, thiosemicarbazone, Sul the AUC from time zero (“0”) to “t” wherein “t” is the last fate, trifluoroacetate, hemipentahydrate, pentafluoropropi time point with measurable concentration for individual for Onate, p-nitrophenylhydraZone, o-methyloxime, mulation. The sum of the AUC of the drug and the AUC of the semicarbazone, hydrobromide, mucate, oleate, phosphate major metabolite refers to the total amount of AUC of both the dibasic, phosphate monobasic, acetate trihydrate, bis(hep drug and the major metabolite, calculated at the same time tafluorobutyrate), bis(methylcarbamate), bis(pentafluoropro point. pionate), bis(pyridine carboxylate), bis(trifluoroacetate), 0071. The present invention also provides an orally chlorhydrate, and sulfate pentahydrate. In some preferred administrable pharmaceutical composition comprising a embodiments, the compositions of the present invention com drug, wherein the composition is configured Such that when prise hydrocodone bitartrate. the pharmaceutical composition is administered intranasally 0067. In some embodiments, the compositions of the in physically compromised form to a subject, the area under present invention comprise hydromorphone or a pharmaceu the curve (AUC) of drug after a period of time is less than tically acceptable salt thereof. Salts of hydromorphone 200% of the AUC of the drug achieved after oral administra include, but are not limited to, sulfate, hydrochloride, sodium tion of an intact form of the pharmaceutical composition after chloride, trifluoracetate, thiosemicarbazone hydrochloride, the same period of time. In some embodiments, the AUC of pentafluoropropionate, p-nitrophenyl-hydroZone, hydrazine, the drug after a period of time is less than 175%, alternatively hydrobromide, mucate, methylbromide, oleate, n-oxide, less than 150%, or alternatively less than 125% of the AUC of acetate, phosphate dibasic, phosphate monobasic, acetate tri the drug achieved after oral administration of an intact form hydrate, bis(heptafluorobutyrate), bis(methylcarbamate), of the pharmaceutical composition after the same period of (bis-pentafluoropropionate), bis(pyridine-3-carboxylate), bis time. (trifluoroacetate), bitartrate, chlorohydrate, and sulfate pen 0072 The present invention provides an orally adminis tahydrate. In some preferred embodiments, the compositions trable pharmaceutical composition comprising a drug, of the present invention comprise hydromorphone hydrochlo wherein the composition is configured such that when the ride. pharmaceutical composition is administered intranasally in 0068. The pharmaceutical composition is “physically physically compromised form to a Subject, the area under the compromised when it is in a form other than an intact form. curve (AUC) of a major metabolite of the drug after a period A pharmaceutical composition is physically compromised of time is at least 15% of the AUC of the major metabolite when the physical integrity of the pharmaceutical composi achieved after oral administration of an intact form of the tion or dosage form is compromised. This can be achieved by pharmaceutical composition after the same period of time. In Various means such as by chopping, grinding, crushing, or some embodiments, the AUC of a major metabolite of the placing into solvents, such as those containing alcohol (e.g., drug after a period of time is at least 20%, alternatively at least US 2014/0275038A1 Sep. 18, 2014

25%, alternatively at least 30%, alternatively at least 35%, form. The “ratio of the AUC of the drug to the AUC of a major alternatively at least 40%, alternatively at least 45% of the metabolite” refers to the AUC of the drug, divided by the AUC AUC of the major metabolite achieved after oral administra of a major metabolite. In some embodiments, the ratio of the tion of an intact form of the pharmaceutical composition after area under the curve (AUC) of the drug to the AUC of a major the same period of time. metabolite of the drug (drug:major metabolite) achieved after 0073. A metabolite is a compound derived from the parent a period of time is less than 20 times, alternatively less than 10 drug through Phase I and/or Phase II metabolic pathways. A times the ratio of the AUC of the drug to the AUC of the major major metabolite of a drug may refer to a metabolite which in metabolite (drug: major metabolite) achieved after the same the human plasma accounts for 10% of the parent drug sys period of time after oral administration of the pharmaceutical temic exposure or administered dose. The major metabolite composition in an intact form. In some embodiments, when may refer to active or inactive metabolites. the AUC is the AUC, the ratio of the area under the curve 0074 Preferably, when the drug is morphine, the major (AUC) of the drug to the AUC of a major metabolite of the metabolite is selected from the group consisting of mor drug (drug: major metabolite) achieved after a period of time phine-3-glucuronide (M3G), morphine-6-glucuronide is less than 20 times, alternatively less than 10 times, alterna (M6G), hydromorphone, normorphine (NM) and minor tively less than 8 times, alternatively less than 5 times, alter metabolites such as morphine-3,6-diglucuronide, morphine natively less than 3 times, the ratio of the AUC of the drug to 3-ethereal Sulfate, normorphine-6-glucuronide, and normor the AUC of the major metabolite (drug:major metabolite) phine-3-glucuronide. Preferably, when the drug is oxyc achieved after the same period of time after oral administra odone, the major metabolite is selected from the group tion of the pharmaceutical composition in an intact form. In consisting of noroxycodone, C. oxycodol, B oxycodol, oxy some embodiments, when the period of time is about 0.5 hour, morphone, C. oxymorphol, B oxymorphol, noroxymorphone, the ratio of the area under the curve (AUC) of the drug to the C. noroxycodol, B noroxycodol, noroxymorphone, 14-hy AUC of a major metabolite of the drug (drug:major metabo droxydihydrocodeine, and 14-hydroxydihydromorphine. lite) achieved after a period of time is about 1 to 10, alterna Preferably, when the drug is oxymorphone, the major tively about 2 to 8, alternatively about 4 to 7 times the ratio of metabolite is selected from the group consisting of oxymor the AUC of the drug to the AUC of the major metabolite phone-3-glucuronide and 6-hydroxy-oxymorphone. Prefer (drug:major metabolite) achieved after the same period of ably, when the drug is hydromorphone, the major metabolite time after oral administration of the pharmaceutical compo is selected from the group consisting of hydromorphone-3- sition in an intact form. In some embodiments, when the glucuronide, hydromorphone-3-glucoside and dihydroiso period of time is about 1 hour, the ratio of the area under the morphine-6-glucuronide. Preferably, when the drug is curve (AUC) of the drug to the AUC of a major metabolite of codeine, the major metabolite is selected from the group the drug (drug: major metabolite) achieved after a period of consisting of codeine-6-glucuronide (C6G), norcodeine, time is about 1 to 15, alternatively about 2 to 10, alternatively hydrocodone, morphine, morphine-3-glucuronide, mor about 5 to 8 times the ratio of the AUC of the drug to the AUC phine-6-glucuronide, and normorphine. Preferably, when the of the major metabolite (drug:major metabolite) achieved drug is methylphenidate, the major metabolite is selected after the same period of time after oral administration of the from the group consisting of ethylphenidate, ritalinic acid pharmaceutical composition in an intact form. In some (C-phenyl-2-piperidine acetic acid), hydroxymethylpheni embodiments, when the period of time is about 2 hours, the date, and hydroxyritalinic acid. Preferably, when the drug is ratio of the area under the curve (AUC) of the drug to the AUC amphetamine or dextroamphetamine, the major metabolite is of a major metabolite of the drug (drug: major metabolite) selected from the group consisting of 4-hydroxyamphet achieved after a period of time is about 1 to 10, alternatively amine, benzoic acid, phenylacetone, hippuric acid, 4-hydrox about 2 to 8, alternatively about 3 to 6 times the ratio of the ynorephedrine, and norephedrine. Preferably, when the drug AUC of the drug to the AUC of the major metabolite (drug: Is lisdexamfetamine, the major metabolite is selected from major metabolite) achieved after the same period of time after the group consisting of phenethylamine and dextroamphet oral administration of the pharmaceutical composition in an amine. Preferably, when the drug is alprazolam, the major intact form. metabolite is selected from the group consisting of 4-hy 0076. The present invention also provides an orally droxyalprazolam and C-hydroxyalprazolam. Preferably, administrable pharmaceutical composition comprising a when the drug is lorazepam, the major metabolite is selected drug, wherein the composition is configured Such that when from the group consisting of 3-O-phenolic glucuronide and the pharmaceutical composition is administered intranasally lorazepam glucuronide. Preferably, when the drug is diaz in physically compromised form to a Subject, the ratio of the epam, the major metabolite is seleted from the group consist area under the curve (AUC) of the drug to the AUC of a major ing of desmethyldiazepam, esmethyldiazepam, oxazepam, metabolite of the drug (drug:major metabolite) achieved after and temazepam. a period of time is about 10 or less. In some embodiments, the 0075. The present invention also provides an orally ratio of the area under the curve (AUC) of the drug to the AUC administrable pharmaceutical composition comprising a of the major metabolite (drug:major metabolite) achieved drug, wherein the composition is configured such that when after a period of time is about 8 or less, or alternatively about the pharmaceutical composition is administered intranasally 6 or less. In some embodiments wherein the AUC is the in physically compromised form to a subject, the ratio of the AUC, the ratio of the area under the curve (AUC) of the area under the curve (AUC) of the drug to the AUC of a major drug to the AUC of the major metabolite (drug:major metabo metabolite of the drug (drug:major metabolite) achieved after lite) achieved after a period of time is about 0.1 to about 4. a period of time is less than 25 times the ratio of the AUC of alternatively about 0.2 to about 3, alternatively about 0.3 to the drug to the AUC of the major metabolite (drug:major about 1, or alternatively about 0.4 to about 0.5. In some metabolite) achieved after the same period of time after oral embodiments wherein the period of time is about 0.5 hour, the administration of the pharmaceutical composition in an intact ratio of the area under the curve (AUC) of the drug to the AUC US 2014/0275038A1 Sep. 18, 2014 of the major metabolite (drug:major metabolite) achieved ngth/mL, alternatively about 25 ngh/mL to about 100 ngh/ after a period of time is about 1 to about 10, alternatively mL, or alternatively about 40 ngh/mL to about 80 ngh/mL. about 2 to about 8, or alternatively about 3 to about 6. In some 007.9 The present invention also provides an orally embodiments wherein the period of time is about 1 hour, the administrable pharmaceutical composition comprising mor ratio of the area under the curve (AUC) of the drug to the AUC phine or a salt thereof, wherein the composition is configured of the major metabolite (drug:major metabolite) achieved Such that when the pharmaceutical composition is adminis after a period of time is about 1 to about 5, alternatively about tered intranasally in physically compromised form to a Sub 2 to about 4, or alternatively about 2 to about 3. In some ject, the sum of the area under the curve (AUC) of morphine embodiments wherein the period of time is about 2 hours, the and the AUC of a major metabolite, such as morphine-6- ratio of the area under the curve (AUC) of the drug to the AUC glucuronide (M6G), after a period of time is less than 20 of the major metabolite (drug:major metabolite) achieved ngth/mL/mg (ngth/mL per mg of morphine). In some embodi after a period of time is about 0.5 to about 5, alternatively ments wherein the composition comprises morphine and the about 0.75 to about 3, or alternatively about 1 to about 2. AUC is the AUC, the sum of the AUC of morphine and the AUC of M6G is about 1 ngh/mL/mg to about 18 ngh/mL/ 0077. The present invention also provides an orally mg, alternatively about 5 ngh/mL/mg to about 15 ngh/mL/ administrable pharmaceutical composition comprising a mg, or alternatively about 8 ngh/mL/mg to about 12 ngh/ drug, wherein the composition is configured such that when mL/mg. In some embodiments wherein the composition the pharmaceutical composition is administered intranasally comprises morphine and the time period is about 0.5 hour, the in physically compromised form to a Subject, the sum of the sum of the AUC of morphine and the AUC of M6G is less than area under the curve (AUC) of the drug and the AUC of a 0.5 ngh/mL/mg, alternatively about 0.01 ngh/mL/mg to major metabolite of the drug after a period of time is less than about 0.3 ngh/mL/mg, alternatively about 0.02 ngh/mL/mg the sum of the AUC of the drug and the AUC of the major to about 0.1 ngh/mL/mg, or alternatively about 0.03 ngh/ metabolite achieved after the same period of time after oral mL/mg to about 0.07 ngh/mL/mg. In some embodiments administration of the pharmaceutical composition in an intact wherein the composition comprises morphine and the time form. In some embodiments, the sum of the area under the period is about 1 hour, the sum of the AUC of morphine and curve (AUC) of the drug and the AUC of a major metabolite the AUC of M6G is less than 1 ngh/mL/mg, alternatively of the drug after a period of time at least 10% lower, alterna about 0.05 ngh/mL/mg to about 0.75ngh/mL/mg, alterna tively at least 20% lower, alternatively at least 25% lower, tively about 0.1 ngh/mL/mg to about 0.5 ngh/mL/mg, or alternatively at least 30% lower, alternatively at least 35% alternatively about 0.15 ngh/mL/mg to about 0.35 ngh/mL/ lower, alternatively at least 40% lower, or alternatively at least mg. In some embodiments wherein the composition com 45% lower than the sum of the AUC of the drug and the AUC prises morphine and the time period is about 2 hours, the Sum of the major metabolite achieved after the same period of time of the AUC of morphine and the AUC of M6G is less than 5 after oral administration of the pharmaceutical composition ngth/mL/mg, alternatively about 0.1 ngh/mL/mg to about 2.5 in an intact form. ngth/mL/mg, alternatively about 0.5 ngh/mL/mg to about 2 0078. The present invention also provides an orally ngth/mL/mg, or alternatively about 0.75 ngh/mL/mg to administrable pharmaceutical composition comprising 60 about 1.5 ngh/mL/mg. mg of morphine or a salt thereof, wherein the composition is 0080. The present invention also provides an orally configured such that when the pharmaceutical composition is administrable pharmaceutical composition comprising 60 administered intranasally in physically compromised form to mg of morphine or a salt thereof, wherein the composition is a subject, the sum of the area under the curve (AUC) of configured Such that when the pharmaceutical composition is morphine and the AUC of a major metabolite, such as mor administered intranasally in physically compromised form to phine-6-glucuronide (M6G), after a period of time is less than a subject, the area under the curve (AUC) of the morphine 900 ngh/mL. In some embodiments wherein the composition after a period of time is less than 400 ngh/mL. In some comprises 60 mg morphine and the AUC is the AUC, the embodiments wherein the composition comprises 60 mg sum of the AUC of morphine and the AUC of M6G is about morphine and the AUC is the AUC, the AUC of morphine is 100 ngh/mL to about 800 ngh/mL, alternatively about 200 about 50 ngh/mL to about 300 ngh/mL, alternatively about ngh/mL to about 700 ngh/mL, alternatively about 300 ngh/ 100 ngh/mL to about 200 ngh/mL, or alternatively about 125 mL to about 600 ngh/mL, or alternatively about 500 ngh/mL ngth/mL to about 175 ng-h/mL. In some embodiments to about 600 ngh/mL. In some embodiments wherein the wherein the composition comprises 60 mg morphine and the composition comprises 60 mg morphine and the time period time period is about 0.5 hour, the AUC of morphine is less is about 0.5 hour, the sum of the AUC of morphine and the than 10 ngh/mL, alternatively about 0.5 ngh/mL to about 8 AUC of M6G is less than 50 ngh/mL, alternatively about 0.5 ngth/mL, alternatively about 1 ngh/mL to about 5 ngh/mL, ngth/mL to about 25 ngh/mL, alternatively about 1 ngh/mL or alternatively about 2ngth/mL to about 3 ngh/mL. In some to about 10 ngh/mL, or alternatively about 1 ngh/mL to embodiments wherein the composition comprises 60 mg about 5 ngh/mL. In some embodiments wherein the compo morphine and the time period is about 1 hour, the AUC of sition comprises 60 mg morphine and the time period is about morphine is less than 50 ngh/mL, alternatively about 2.5 1 hour, the sum of the AUC of morphine and the AUC of M6G ngth/mL to about 25 ngh/mL, alternatively about 5 ngh/mL is less than 75 ngh/mL, alternatively about 1 ngh/mL to to about 15 ngh/mL, or alternatively about 8 ngh/mL to about 50 ngh/mL, alternatively about 5 ngh/mL to about 25 about 12 ngh/mL. In some embodiments wherein the com ngh/mL, or alternatively about 10 ngh/mL to about 20 ngh/ position comprises 60 mg morphine and the time period is mL. In some embodiments wherein the composition com about 2 hours, the AUC of morphine is less than 100 ngh/mL, prises 60 mg morphine and the time period is about 2 hours, alternatively about 5 ngh/mL to about 75 ngh/mL, alterna the sum of the AUC of morphine and the AUC of M6G is less tively about 10 ngh/mL to about 50 ngh/mL, or alternatively than 250 ngh/mL, alternatively about 5 ngh/mL to about 150 about 25 ngh/mL to about 35 ngh/mL. US 2014/0275038A1 Sep. 18, 2014

0081. The present invention also provides an orally ject, the area under the curve (AUC) of a major metabolite administrable pharmaceutical composition comprising mor such as morphine-6-glucuronide (M6G) after a period of time phine or a salt thereof, wherein the composition is configured is at least about 0.5 ngh/mL/mg (ngth/mL per mg of mor Such that when the pharmaceutical composition is adminis phine). In some embodiments wherein the composition com tered intranasally in physically compromised form to a Sub prises morphine and the AUC is the AUC, the AUC of M6G ject, the area under the curve (AUC) of morphine after a is about 1 ngh/mL/mg to about 20 ngh/mL/mg, alternatively period of time is less than 10 ngh/mL/mg (ngh/mL per mg of about 2.5 ngh/mL/mg to about 15 ngh/mL/mg, or alterna morphine). In some embodiments wherein the composition tively about 5 ngh/mL/mg to about 10 ngh/mL/mg. In some comprises morphine and the AUC is the AUC, the AUC of embodiments wherein the composition comprises morphine morphine is about 1 ngh/mL/mg to about 8 ngh/mL/mg, and the time period is about 0.5 hour, the AUC of M6G is at alternatively about 2 ngh/mL/mg to about 6 ngh/mL/mg, or least about 0.005 ngh/mL/mg, alternatively about 0.006 alternatively about 3 ngh/mL/mg to about 4 ngh/mL/mg. In ngth/mL/mg to about 1 ngh/mL/mg, alternatively about Some embodiments wherein the composition comprises mor 0.008 ngh/mL/mg to about 0.5 ngh/mL/mg, or alternatively phine and the time period is about 0.5 hour, the AUC of about 0.01 ngh/mL/mg to about 0.25 ngh/mL/mg. In some morphine is less than 0.5 ngh/mL/mg, alternatively about embodiments wherein the composition comprises morphine 0.01 ngh/mL/mg to about 0.2 ngh/mL/mg, alternatively and the time period is about 1 hour, the AUC of M6G is at least about 0.02 ngh/mL/mg to about 0.1 ngh/mL/mg, or alterna about 0.01 ngh/mL/mg, alternatively about 0.02 ngh/mL/mg tively about 0.03 ngh/mL/mg to about 0.05 ngh/mL/mg. In to about 1 ngh/mL/mg, alternatively about 0.03 ngh/mL/mg Some embodiments wherein the composition comprises mor to about 0.5 ngh/mL/mg, or alternatively about 0.05 ngh/ phine and the time period is about 1 hour, the AUC of mor mL/mg to about 0.1 ngh/mL/mg. In some embodiments phine is less than 1 ngh/mL/mg, alternatively about 0.05 wherein the composition comprises morphine and the time ngth/mL/mg to about 0.75 ngh/mL/mg, alternatively about period is about 2 hours, the AUC of morphine is at least about 0.1 ngh/mL/mg to about 0.5 ngh/mL/mg, or alternatively 0.1 ngh/mL/mg, alternatively about 0.2ngh/mL/mg to about about 0.15 ngh/mL/mg to about 0.25 ngh/mL/mg. In some 5 ngh/mL/mg, alternatively about 0:25 ngh/mL/mg to about embodiments wherein the composition comprises morphine 1 ngh/mL/mg, or alternatively about 0.4 ngh/mL/mg to and the time period is about 2 hours, the AUC of morphine is about 0.75ngh/mL/mg. less than 2.5 ngh/mL/mg, alternatively about 0.1 ngh/mL/ I0084. The present invention further provides for a plural mg to about 2 ngh/mL/mg, alternatively about 0.2 ngh/mL/ ity of particles which may optionally comprise a pH-depen mg to about 1 ngh/mL/mg, or alternatively about 0.3 ngh/ dent agent and pH-independent agent and/or may optionally mL/mg to about 0.75 ngh/mL/mg. provide the above-described pharmacokinetic effects. 0082. The present invention also provides an orally I0085. The present invention also provides a plurality of administrable pharmaceutical composition comprising 60 particles having a particle size distribution (D50) of about 100 mg of morphine or a salt thereof, wherein the composition is um to about 1000 um, wherein the particles each comprise a configured such that when the pharmaceutical composition is drug and one or more pharmaceutically acceptable excipients administered intranasally in physically compromised form to and wherein the particles are configured Such that the amount a subject, the area under the curve (AUC) of a major metabo of drug released from the plurality of particles is no greater lite such as morphine-6-glucuronide (M6G) after a period of than 500% of the amount of drug released from an intact unit time is at least 100 ngh/mL. In some embodiments wherein dosage form comprising the same amount (w/w) as the plu the composition comprises 60 mg morphine and the AUC is rality of particles, under the following identical conditions: the AUC, the AUC of M6G is about 150 ngh/mL to about 30 mL of ethanol, 25°C., agitated at 100 rpm for a period of 750 ngh/mL, alternatively about 200 ngh/mL to about 500 time. ngh/mL, or alternatively about 300 ngh/mL to about 400 I0086. The present invention also provides a plurality of ngth/mL. In some embodiments wherein the composition particles having a particle size distribution (D50) of about 100 comprises 60 mg morphine and the time period is about 0.5 um to about 1000 um, wherein the particles each comprise a hour, the AUC of M6G is at least about 0.1 ngh/mL, alterna drug and one or more pharmaceutically acceptable excipients tively about 0.2 ngh/mL to about 5 ngh/mL, alternatively and wherein the particles are configured such that the rate of about 0.3 ngh/mL to about 1 ngh/mL, or alternatively about drug released from the plurality of particles is no greater than 0.4 ngh/mL to about 0.75 ngh/mL. In some embodiments 500% of the rate of drug released from an intact unit dosage wherein the composition comprises 60 mg morphine and the form comprising the same amount (W/w) as the plurality of time period is about 1 hour, the AUC of M6G is at least about particles, under the following identical conditions: 30 mL of 0.5 ngh/mL, alternatively about 1 ngh/mL to about 15 ngh/ ethanol, 25°C., agitated at 100 rpm for a period of time. mL, alternatively about 1.5 ngh/mL to about 5 ngh/mL, or I0087. The present invention also provides a plurality of alternatively about 0.4 ngh/mL to about 0.75 ngh/mL. In particles comprising: an active layer comprising a drug and a Some embodiments wherein the composition comprises 60 first polymer, and a barrier layer comprising a second poly mg morphine and the time period is about 2 hours, the AUC of mer, wherein the active layer and barrier layer are bonded, M6G is at least about 5 ngh/mL, alternatively about 10 ngh/ and wherein the particles are configured Such that the amount mL to about 75 ngh/mL, alternatively about 15 ngh/mL to of drug released from the plurality of particles is no greater about 50 ngh/mL, or alternatively about 20 ngh/mL to about than 500% of the amount of drug released an intact unit 40 ngh/mL. dosage form comprising the same amount (w/w) as the plu 0083. The present invention also provides an orally rality of particles, under the following identical conditions: administrable pharmaceutical composition comprising mor 30 mL of ethanol, 25°C., agitated at 100 rpm for a period of phine or a salt thereof, wherein the composition is configured time. Such that when the pharmaceutical composition is adminis I0088. The present invention also provides a plurality of tered intranasally in physically compromised form to a Sub particles comprising: an active layer comprising a drug and a US 2014/0275038A1 Sep. 18, 2014 first polymer, and a barrier layer comprising a second poly released from an intact unit dosage form comprising the same mer, wherein the active layer and barrier layer are bonded, amount (w/w) of the plurality of particles. In some embodi and wherein the particles are configured such that the rate of ments, when the plurality of particles is subjected to 30 mL of drug released from the plurality of particles is no greater than 20% ethanol, agitated at 100 rpm for 240 minutes, the amount 500% of the rate of drug released from an intact unit dosage of drug released and/or the rate of drug released from the form comprising the same amount (W/w) as the plurality of plurality of particles is about 100% to about 400%, alterna particles, under the following identical conditions: 30 mL of tively about 150% to about 350%, alternatively about 200% ethanol, 25°C., agitated at 100 rpm for a period of time. to about 300% of the amount of drug released and/or the rate 0089. The agitation may be performed with any agitator, of drug released from an intact unit dosage form comprising preferably a USPType I basket or a Type II paddle. the same amount (w/w) of the plurality of particles. In some 0090. In some embodiments, the period of time of agita embodiments, when the plurality of particles is subjected to tion is about 15 minutes to about 300 minutes. In some 30 mL of 40% ethanol, agitated at 100 rpm for 30 minutes, the embodiments, the period of time is about 30 minutes or about amount of drug released and/or the rate of drug released from 240 minutes. In some embodiments, the ethanol may be 5% the plurality of particles is about 75% to about 300%, alter ethanol, 10% ethanol, 20% ethanol, or 40% ethanol. In some natively about 100% to about 200%, alternatively about embodiments, the amount of drug released and/or the rate of 125% to about 175% of the amount of drug released and/or drug released from the plurality of particles is about 500% or the rate of drug released from an intact unit dosage form less of the amount of drug released and/or the rate of drug comprising the same amount (w/w) of the plurality of par released from an intact unit dosage form comprising the same ticles. In some embodiments, when the plurality of particles is amount (w/w) of the plurality of particles. The same amount subjected to 30 mL of 40% ethanol, agitated at 100 rpm for may refer to total weight of the plurality of particles or the 240 minutes, the amount of drug released and/or the rate of total amount of drug. In some embodiments, the amount or drug released from the plurality of particles is about 100% to rate is about 50% to about 500%, alternatively about 100% to about 500%, alternatively about 250% to about 450%, alter about 400%, alternatively about 125% to about 300%, or natively about 350% to about 450% of the amount of drug alternatively about 125% to about 200%. released and/or the rate of drug released from an intact unit 0091. In some embodiments, when the plurality of par dosage form comprising the same amount (w/w) of the plu ticles is subjected to 30 mL of 5% ethanol, agitated at 100 rpm rality of particles. for 30 minutes, the amount of drug released and/or the rate of drug released from the plurality of particles is about 75% to 0092. In some embodiments, the plurality of particles has about 300%, alternatively about 100% to about 200%, alter a particle size distribution (D50) of about 100 um to about natively about 125% to about 175% of the amount of drug 1000 um. Particle size distribution (D50) is also known as the released and/or the rate of drug released from an intact unit median diameter or medium value of the particle size distri dosage form comprising the same amount (w/w) of the plu bution, and it refers to the value of the particle diameter at rality of particles. In some embodiments, when the plurality 50% in the cumulative distribution. In some embodiments, of particles is subjected to 30 mL of 5% ethanol, agitated at the plurality of particles comprises a D50 of about 100 um to 100 rpm for 240 minutes, the amount of drug released and/or about 1000 um, alternatively about 250 um to about 750 um, the rate of drug released from the plurality of particles is about alternatively about 400 um to about 600 um. 75% to about 300%, alternatively about 100% to about 200%, 0093. In some embodiments, the present invention com alternatively about 125% to about 175% of the amount of prises a plurality of particles comprising: an active layer drug released and/or the rate of drug released from an intact comprising a drug and a first polymer, and a barrier layer unit dosage form comprising the same amount (w/w) of the comprising a second polymer. The active layer may comprise plurality of particles. In some embodiments, when the plural one drug or a combination of two or more drugs. In some ity of particles is subjected to 30 mL of 10% ethanol, agitated embodiments, the active layer comprises a drug which is at 100 rpm for 30 minutes, the amount of drug released and/or substantially homogeneously distributed in the first polymer. the rate of drug released from the plurality of particles is about “Substantially homogenously distributed” means that more 75% to about 500%, alternatively about 100% to about 400%, than 80%, more preferably more than 90%, and most prefer alternatively about 200% to about 350% of the amount of ably more than 95% of the drug(s) is homogeneously distrib drug released and/or the rate of drug released from an intact uted. In some embodiments, the first polymer comprises a unit dosage form comprising the same amount (w/w) of the diffusion polymer. Examples of diffusion polymers include, plurality of particles. In some embodiments, when the plural but are not limited to: a quaternary ammonium acrylic or ity of particles is subjected to 30 mL of 10% ethanol, agitated methacrylic polymers, an acrylic or a methacrylic ester at 100 rpm for 240 minutes, the amount of drug released copolymers or a mixture thereof, which can also be used as and/or the rate of drug released from the plurality of particles Sustained release agents. Common tradenames include vari is about 75% to about 400%, alternatively about 100% to ous grades of EUDRAGITRs (all from Röhm), and SURE about 300%, alternatively about 125% to about 250% of the LEASER (from COLORCONR). The preferred polymers of amount of drug released and/or the rate of drug released from the diffusion layer are acrylic or methacrylic polymers and an intact unit dosage form comprising the same amount (w/w) particularly ethyl acrylate or methyl methylacrylate disper of the plurality of particles. In some embodiments, when the sions. Additional examples of first polymer include, but are plurality of particles is subjected to 30 mL of 20% ethanol, not limited to: cellulose, chitin, collagen, nylon, poly(alkyl agitated at 100 rpm for 30 minutes, the amount of drug cyanoacrylate), polyethylene, poly(ethylene-co-vinyl released and/or the rate of drug released from the plurality of acetate), poly(hydroxyethyl methacrylate), poly(hydrox particles is about 100% to about 500%, alternatively about ypropylethyl methacrylate), poly(methyl methacrylate), poly 200% to about 450%, alternatively about 300% to about (vinyl alcohol-co-methacrylate), poly(vinyl chloride), poly 450% of the amount of drug released and/or the rate of drug isobutene, polyurethane, and silicone rubber. In some US 2014/0275038A1 Sep. 18, 2014

embodiments, the active layer may comprise the first polymer LEASE(R) from COLORCONR), AQUACOATR) from and one or more additional polymers. FMCR, and mixtures of EUDRAGITR NE 30 D and AQUA 0094. The barrier layer comprises a second polymer. In COATR), polyethylene glycol, polyethylene oxides, polyeth some preferred embodiments, the barrier layer does not com ylenes, polypropylenes, polyvinyl chlorides, polycarbonates, prise a drug. However, in some embodiments, the barrier polystyrenes, and the like. In some embodiments, the com layer may comprise one or more drugs. In some preferred position comprises polyacrylate and polyethylene glycol and embodiments, the second polymer and the first polymer are in particular, a polyacrylate dispersion. In some embodi the same polymers. In some alternative embodiments, the ments, the pharmaceutical composition further comprises a second polymer differs from the first polymer. In some layer comprising a hydrophilic polymer or a polymer which, embodiments, the second polymer comprises polyacrylates when contacted with a liquid, absorbs at least a portion of the and the copolymers thereof (such as those marked under the liquid and forms a gel. tradename EUDRAGITR NE 30 D), EUDRAGITR FS 30 D, 0099. The pharmaceutical composition may optionally EUDRAGITR) RS 30 D, SURELEASER from COLOR contain Sustained or extended release and/or enteric coating. CONR), AQUACOATR) from FMCR, and mixtures of Examples of Such materials are cellulose acetate phthalate, EUDRAGITR NE 30 D and AQUACOATR, polyethylene hydroxypropyl methylcellulose phthalate, polyvinyl acetate glycol, polyethylene oxides, polyethylenes, polypropylenes, phthalate, methacrylic acid:acrylic ester copolymer, hydrox polyvinyl chlorides, polycarbonates, polystyrenes, and the ypropyl methylcellulose acetate Succinate, shellac, cellulose like. The preferred polymers of the barrier layer are polyacry acetate trimellitate, and mixtures thereof. The pharmaceutical late and polyethylene glycol and in particular, a polyacrylate composition may also contain water-soluble polymers such dispersion. In some embodiments, the second polymer of the as polyvinylpyrrolidone, hydroxypropyl cellulose, hydrox barrier layer does not substantially dissolve in the gastrointes ypropyl methylcellulose, polyethylene glycol having a tinal tract, mucous membranes, blood vessels or lungs and molecular weight of from 1,700 to 20,000 and polyvinyl may pass through the body in a Substantially undissolved alcohol and monomers therefor and mixtures thereof. The use form. “Substantially undissolved” means that less than 30%, of Sustained, extended and enteric coating materials is gen more preferably less than 20%, and most preferably less than erally known in the pharmaceutical arts, and as would be 10% of the polymer is dissolved. understood to one skilled in the art, any suitable Sustained, 0095. In some preferred embodiments, the active layer and extended and enteric coating materials or similar agents may barrier layer are bonded. The bonding of the active layer and be used in conjunction with the present invention and barrier layer may contribute to the abuse deterrent effect. The embodiments thereof. active layer and barrier layer may be bonded by any method 0100 Other components may be added to any or all of the known in the art, including but not limited to physical or various layers provided that they do not interfere with the chemical bonding. In some embodiments, the active layer and drug and provide a desired benefit to the pharmaceutical. barrier layer may be physically bonded and the bond may be Exemplary of Such other components are: plasticizers, anti facilitated by the use of a tablet press or heat curing and choice adhesive, inert fillers, lipophilic agents and pigments used in of polymers. In some embodiments, the active layer and bar a known manner. Tackiness of the water-dispersible film rier layer comprise the same polymer, and the layers are heat forming Substance may be overcome by simply incorporating cured or pressed together with a tablet press. In preferred an anti-adhesive in the coating. Examples of anti-adhesive are embodiments, the active layer and barrier layer are bonded in metallic Stearates, microcrystalline cellulose, calcium phos a manner such that the relative surface area of the active layer increases only marginally, for example, no more than about phate, and talc. Those of ordinary skill in the art would under 50%, preferably no more than about 25%, most preferably no stand the need for and applicability of such other components more than about 10%, when particles comprising the active to overcome manufacturing, shelf-life or release profile layer and barrier layer are subjected to physical compromise, issues. for example, grinding in a mortar and pestle, pill crusher, or 0101 The pharmaceutical composition of the present spoon for 300 seconds. invention may also further comprise one or more pharmaceu 0096. In some embodiments, the plurality of particles tically acceptable excipients including, but are not limited to, comprises the above-described active layer and barrier layer, the following: plasticizers, anti-adhesives, fillers/diluents/ and additionally or alternatively has the above-described par binders, disintegrants, glidants and lubricants, Surfactants, ticle size distribution (D50) of 100 um to about 1000 um. colorants, flavoring agents, pH adjusting agents, solubilizing 0097. The present invention also provides for pharmaceu agents, wetting agents, solvent resistant agents and buffering tical compositions in unit dosage form comprising the plural agents. Other Suitable pharmaceutically acceptable excipi ity of particles. In some embodiments, the pharmaceutical ents are described in Remington. The Science and Practice of composition comprises a monolithic unit dosage form Such as Pharmacy, Lippincott Williams and Wilkins, Baltimore, Md. a tablet comprising the plurality of particles. The monolithic (1995), incorporated herein by reference. unit dosage form may be produced by any known method in 0102) Examples of plasticizers include, but are not limited the art, for example, by compressing the plurality of particles to, triacetin, acetylated monoglyceride, olive oil, acetyl tribu in a tablet press. tyl citrate, acetyl triethyl citrate, glycerin, Sorbitol, polyeth 0098. In some embodiments, the pharmaceutical compo ylene glycol, and polypropyleneglycol. sition comprises a tablet comprising one or more layers. In 0103 Examples of anti-adhesives include, but are not lim Some embodiments, the composition comprises a layer com ited to, metallic Stearates, microcrystalline cellulose, calcium prising a drug and one or more hydrophobic polymers. In phosphate, AEROSILR) 200, and talc. Those of ordinary skill Some embodiments, the hydrophobic polymers comprise in the art would understand the need for and applicability of polyacrylates and the copolymers thereof (such as those Such other components to overcome manufacturing, shelf-life marked under the tradename EUDRAGITR NE 30 D, SURE or release profile issues. US 2014/0275038A1 Sep. 18, 2014

0104 Examples of fillers/diluents/binders include, but are -continued not limited to. Sucrose, Sorbitol, mannitol, Various grades of lactose, various grades of microcrystalline cellulose, dex mg tab trins, maltodextrins, starches or modified starches, sodium approximate amounts phosphate, calcium phosphate, calcium carbonate, gelatin, polyvinylpyrrolidone, and sodium carboxymethylcellulose. Ingredient Test A Test B Present in 0105 Examples of disintegrants include, but are not lim Eudragit NM3OD 12.5 12.5 2. Coating ited to, cellulose derivatives, including microcrystalline cel Oxycodone hydrochloride 30 30 2” Coating lulose, low-substituted hydroxypropyl cellulose, croScarmel Surfactant 1 1 2. Coating lose sodium, alginic acid, insoluble polyvinlypyrrolidone, Glidant 2 2 2. Coating EUDRAGIT (RE100 10 3rd Coating and sodium carboxymethyl starch. ETHOCEL (R) 45 (ethylcellulose) 3 3 Coating 0106 Examples of glidants and lubricants may be incor Plasticizer 2 3 Coating porated Such as Stearic acid, metallic Stearates, talc, waxes, Lubricant 5 3 Coating and glycerides with high melting temperatures, colloidal Opadry II film-coating 10 10 4" Coating silica, Sodium Stearyl fumarate, polyethyleneglycols, and alkyl Sulphates. TOTALTABLETWEIGHT about about 0107 Examples of surfactants include, but are not limited 550 mg 530 mg to, non-ionic Surfactants (such as various grades of polysor bate); anionic Surfactants (such as docusate sodium and Sodium lauryl Sulfate), and cationic Surfactants (such as ben 0112 The following tables show the dissolution profile of Zalkonium chloride). An example of an amphoteric Surfactant TEST A tablets, which are tablets of the present invention; is 1,2-diacyl-L-phosphatidylcholine. TEST B tablets and ROXICODONE(R) tablets, which are 0108. Other appropriate pharmaceutically acceptable comparative tablets. excipients may include colorants, flavoring agents, pHadjust ing agents, solubilizing agents, wetting agents, solvent resis 0113 TABLE 1 shows the dissolution profile in acidic tant agents and buffering agents. conditions (0.1 NHydrochloric acid). 0109 The present invention also provides methods of making the pharmaceutical composition of the present inven TABLE 1 tion. In some embodiments, the method may comprise form Comparative Dissolution Profile in 0.1N Hydrochloride acid; ing a core or layer comprising a drug, and applying a coating 500 mL. Paddles, 50 rpm. TEST A tablets, TEST B tablets, vs. comprising pH-dependent agent and a pH-independent agent ROXICODONE (R) (immediate release oxycodone) 30 mg to the core or layer. The coating may be applied by any tablets conventional technique, including, but not limited to, pan Time coating, fluid bed coating or spray coating. The coating may (minutes) TESTA TESTB ROXICODONE (R) be applied, for example, as a solution, Suspension, spray, dust 5 21 55 32 or powder. In preferred embodiments, the one or more coat 10 64 88 62 ings are applied by spray coating. 15 92 103 92 0110. The present invention also provides methods of 30 99 106 100 treating or reducing the symptoms associated with a medical 45 1OO 106 102 condition, comprising administering to a Subject in need 60 101 107 103 thereof the pharmaceutical composition of the present inven tion. In some embodiments, the medical condition is a dis ease, disorder, illness, medical state, syndrome, or morbidity 0114 TABLE 2 shows the dissolution profile in neutral pH which would be improved, alleviated, treated, cured, or ame conditions (deionized water). liorated by the administration of drug. TABLE 2 EXAMPLES Comparative Dissolution Profile in DIWater; 500 mL. Paddles, 50 rpm. TEST A tablets, TEST B tablets, vs. ROXICODONE (R) Example 1 immediate release Oxycodone) 30 mg tablets 0111. The following formulations were tested: Time (minutes) TESTA TESTB ROXICODONE (R)

5 O.1 62 59 mg tab 10 O.3 92 81 approximate amounts 15 O6 98 88 30 1.4 99 92 Ingredient Test A Test B Present in 45 2.9 1OO 98 60 4.6 1OO 100 Binder(s) 300 3OO Tablet Core Filler(s) 50 50 Tablet Core Glidant 5 5 Tablet Core Lubricant 10 10 Tablet Core Eudragit NE 30D 67 67 1 Coating Example 2 Filler 25 25 1 Coating Surfactant O.25 0.25 1 Coating Glidant 5 5 1 Coating 0115 The following coating formulations were tested, Eudragit NE30D 12.5 12.5 2. Coating both in acidic medium (HCl) and neutral pH medium (deion ized water): US 2014/0275038A1 Sep. 18, 2014 14

Amount in Ing Ingredients Coating 1 Coating 2 Coating 3 Coating 4 Coating 5 Coating 6

EUDRAGIT (RE100 1O.O 2O.O 1O.O 1O.O OO 1O.O DBS 1.5 3.0 1.5 1.5 1S 1.5 Magnesium Stearate 3.5 7.0 3.5 3.5 3.5 3.5 ETHOCEL (R) 45 O.O O.O 2.0 3.0 3.0 S.O *Ethanol 135 270 153 162 72 18O Total weight gain 1S.O 3O.O 17.0 18.0 8.0 2O.O Release in HCI Acceptable Acceptable Acceptable Acceptable Acceptable Not acceptable; NLT 75% required after 45 minutes Release in D Very fast: Very fast: Release Acceptable Very fast: Acceptable Water not not more than not acceptable acceptable 10% after acceptable 60 minutes: not acceptable *Evaporated during the process Dissolution data for the above examples in 0.1 NHCl and Dl Water

% Released for the above examples in 0.1 NHCl and D. Water Time Coating 1 Coating 2 Coating 3 Coating 4 Coating 5 Coating 6 (min) HCl Water HCl Water HCl Water HCl Water HCl Water HCl Water 5 49 40 57 58 53 2 21 O 50 51 2 O 10 7S 69 79 7S 83 4 64 1. 76 75 13 O 1S 91 84 92 92 99 8 92 2 91 89 26 O 3O 98 95 97 9S 101 18 99 2 95 95 38 1 45 99 98 99 98 102 26 100 3 96 98 S1 1 60 101 102 100 101 102 3S 101 4 98 1OO 68 2

Example 3 Example 4 0116. The following study was conducted to determine the relative bioavailability and abuse potential of equivalent 0119 The following study was conducted to determine the doses of a crushed and intact formulation. The study was a effect of ethanol on the amount of drug released and rate of randomized, double-blind study, wherein 26 subjects were drug release. The study compared the effect of ethanol on tested. The following formulation was tested: particles having a particle size distribution (D50) of about 425 0117. An extended release tablet formulation of the um, compared to the effect of ethanol on an intact tablet present invention containing 60 mg of morphine Sulfate pen dosage form containing the equivalent amount of particles. tahydrate was tested. Both the particles and the intact dosage forms were placed 0118. The following mean exposures (AUC) were under identical conditions: 30 mL of ethanol (5%, 10%, 20%, observed after oral administration of a 60 mg intact tablet and and 40%), agitated at 100 rpm at 25°C. for either 30 minutes intranasal administration of a ground 60 mg tablet. or 240 minutes. The results can be found in FIG. 1.

MORPHINE M6G AUC (ng h/mL AUC (ng h/mL intranasal oral intranasal oral administration of administration administration of administration of ground tablet of intact tablet ground tablet intact tablet Cmax 24.03 17.72 49.41 106.98 AUC O-t 158.3 13286 385.58 830.12 AUCO-O.S 2.53 1.76 O.48 1.84 AUCO-1 10.17 6.96 3.84 17.33 AUC O-2 31.4 21.5 30.89 95.04 AUCO-8 109.96 85.64 233.64 537.79 AUCO-12 130.18 101.14 2.94.23 649.01 AUC O-24 162.78 132.92 398.2 830.29 US 2014/0275038A1 Sep. 18, 2014

What is claimed: cine, diampromide, diamorphone, dihydrocodeine, dihydro 1. An orally administrable pharmaceutical composition morphine, dimenoxadol, dimepheptanol, dimethylthiam comprising a drug, wherein the composition is configured butene, dioxaphetyl butyrate, , eptazocine, Such that when the pharmaceutical composition is adminis ethoheptazine, ethylmethylthiambutene, ethylmorphine, eto tered intranasally in physically compromised form to a Sub nitaZene, hydrocodone, hydromorphone, hydroxypethidine, ject, the area under the curve (AUC) of a major metabolite of isomethadone, ketobemidone, , levophenacyl the drug after a period of time is at least 15% of the AUC of the morphan, lofentanil, meperidine, , metazocine, major metabolite achieved after oral administration of an methadone, metopon, morphine, myrophine, narceline, nico intact form of the pharmaceutical composition after the same morphine, norlevorphanol, normethadone, nalorphine, nal period of time. buphene, normorphine, norpipanone, opium, oxycodone, 2. The orally administrable pharmaceutical composition of oxymorphone, papavereturn, pentazocine, phenadoxone, claim 1, wherein the area under the curve (AUC) of a major phenomorphan, phenazocine, phenoperidine, piminodine, metabolite of the drug after a period of time is at least 20% of piritramide, propheptazine, promedol, properidine, pro the AUC of the major metabolite achieved after oral admin poxyphene, Sufentanil, tilidine, and tramadol. istration of an intact form of the pharmaceutical composition 10. The orally administrable pharmaceutical composition after the same period of time. of claim 1, wherein the drug is morphine. 3. The orally administrable pharmaceutical composition of claim 1, wherein the area under the curve (AUC) of a major 11. An orally administrable pharmaceutical composition metabolite of the drug after a period of time is at least 25% of comprising 60 mg of morphine or a salt thereof, wherein the the AUC of the major metabolite achieved after oral admin composition is configured Such that when the pharmaceutical istration of an intact form of the pharmaceutical composition composition is administered intranasally in physically com after the same period of time. promised form to a subject, the area under the curve (AUC) of 4. The orally administrable pharmaceutical composition of morphine-6-glucuronide (M6G) after a period of time is at claim 1, wherein the period of time is selected from the group least 100 ngh/mL. consisting of 0.5 hour, 1 hour, and 2 hours. 12. The orally administrable pharmaceutical composition 5. The orally administrable pharmaceutical composition of of claim 11, wherein the composition is configured Such that claim 1, wherein the AUC of a major metabolite of the drug when the pharmaceutical composition is administered intra after a period of time is at least 40% of the AUC of the major nasally in physically compromised form to a subject, the metabolite achieved after oral administration of an intact AUC of morphine-6-glucuronide (M6G) is at least 100 form of the pharmaceutical composition after the same period ngth/mL. of time. 13. The orally administrable pharmaceutical composition 6. The orally administrable pharmaceutical composition of of claim 11, wherein the composition is configured Such that claim 1, wherein the composition comprises a drug, a pH when the pharmaceutical composition is administered intra dependent agent, and a pH-independent agent, wherein about nasally in physically compromised form to a subject, the 60% or more of the total amount of drug in the pharmaceutical AUC of morphine-6-glucuronide (M6G) is about 150 to composition is released after 60 minutes under the following about 750 ngh/mL. dissolution conditions: 0.1 NHCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37°C.; and wherein about 25% or less of the 14. The orally administrable pharmaceutical composition total amount of drug in the pharmaceutical composition is of claim 11, wherein the composition is configured Such that released after 60 minutes under the following dissolution when the pharmaceutical composition is administered intra conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 nasally in physically compromised form to a subject, the rpm, 37° C. AUC of morphine-6-glucuronide (M6G) is about 200 to 7. The orally administrable pharmaceutical composition of about 500 ngh/mL. claim 1, wherein the composition comprises a drug, a pH 15. The orally administrable pharmaceutical composition dependent agent, and a pH-independent agent, wherein no of claim 11, wherein the composition comprises morphine or more than 50% of the total amount of drug in the pharmaceu a salt thereof, a pH-dependent agent, and a pH-independent tical composition is released within 1 hour and about 50% or agent, wherein about 60% or more of the total amount of drug more of the total amount of drug in the pharmaceutical com in the pharmaceutical composition is released after 60 min position is released after 8 hours under the following disso utes under the following dissolution conditions: 0.1 NHCl, lution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and (paddle), 50 rpm, 37°C.; and wherein about 25% or less of the wherein about 25% or less of the total amount of drug in the total amount of drug in the pharmaceutical composition is pharmaceutical composition is released after 60 minutes released after 60 minutes under the following dissolution under the following dissolution conditions: DI water, 500 conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C. rpm, 37° C. 16. The orally administrable composition of claim 11, 8. The orally administrable pharmaceutical composition of wherein the composition comprises morphine or a salt claim 1, wherein the drug is selected from the group consist thereof, a pH-dependent agent, and a pH-independent agent, ing of central nervous stimulants, opioids, barbiturates, ben wherein no more than 50% of the total amount of drug in the Zodiazepines, and sedatives. pharmaceutical composition is released within 1 hour and 9. The orally administrable pharmaceutical composition of about 50% or more of the total amount of drug in the phar claim 1, wherein the drug is selected from the group consist maceutical composition is released after 8 hours under the ing of alfentanil, allylprodine, alphaprodine, anilleridine, ben following dissolution conditions: 0.1 NHCl, 500 mL, USP Zylmorphine, bezitramide, buprenorphine, butorphanol, Apparatus 2 (paddle), 50 rpm, 37°C.; and wherein about 25% clonitaZene, codeine, desomorphine, , dezo or less of the total amount of drug in the pharmaceutical US 2014/0275038A1 Sep. 18, 2014

composition is released after 60 minutes under the following 37° C.; and wherein about 25% or less of the total amount of dissolution conditions: DI water, 500 mL, USP Apparatus 2 drug in the pharmaceutical composition is released after 60 (Paddle), 50 rpm, 37° C. minutes under the following dissolution conditions: DI water, 17. An orally administrable pharmaceutical composition 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C. comprising 60 mg of morphine or a salt thereof, wherein the 23. An orally administrable pharmaceutical composition composition is configured Such that when the pharmaceutical comprising morphine or a salt thereof, wherein the composi composition is administered intranasally in physically com tion is configured Such that when the pharmaceutical compo promised form to a subject, the area under the curve (AUC) of sition is administered intranasally in physically compromised morphine-6-glucuronide (M6G) after a period of time is at form to a subject, the area under the curve (AUC) of mor least 0.1 ngh/mL, wherein the period of time is selected from phine-6-glucuronide (M6G) after a period of time is at least the group consisting of 0.5 hour, 1 hour, and 2 hours. about 0.5 ngh/mL/mg (ngh/mL per mg of morphine). 18. The orally administrable pharmaceutical composition 24. The orally administrable pharmaceutical composition of claim 17, wherein the composition is configured such that of claim 23, wherein the composition is configured Such that when the pharmaceutical composition is administered intra when the pharmaceutical composition is administered intra nasally in physically compromised form to a subject, the AUC nasally in physically compromised form to a subject, the of morphine-6-glucuronide (M6G) at 0.5 hour is about 0.2 to AUC of morphine-6-glucuronide (M6G) is about 1 to about about 750 ngh/mL. 20 ngh/mL/mg (ngth/mL per mg of morphine). 19. The orally administrable pharmaceutical composition 25. The orally administrable pharmaceutical composition of claim 17, wherein the composition is configured such that of claim 23, wherein the composition is configured Such that when the pharmaceutical composition is administered intra when the pharmaceutical composition is administered intra nasally in physically compromised form to a subject, the AUC nasally in physically compromised form to a subject, the of morphine-6-glucuronide (M6G) at 1 hour is about 1 to AUC of morphine-6-glucuronide (M6G) is about 2.5 to about 15 ngh/mL. about 15 ngh/mL/mg (ngth/mL per mg of morphine). 20. The orally administrable pharmaceutical composition 26. The orally administrable composition of claim 23, of claim 17, wherein the composition is configured such that wherein the composition comprises morphine, a pH-depen when the pharmaceutical composition is administered intra dent agent, and a pH-independent agent, wherein about 60% nasally in physically compromised form to a subject, the AUC or more of the total amount of morphine in the pharmaceutical of morphine-6-glucuronide (M6G) at 2 hour is about 10 to composition is released after 60 minutes under the following about 75 ngh/mL. dissolution conditions: 0.1 NHCl, 500 mL, USP Apparatus 2 21. The orally administrable pharmaceutical composition (paddle),50 rpm, 37°C.; and wherein about 25% or less of the of claim 17, wherein the composition comprises a drug, a total amount of morphine in the pharmaceutical composition pH-dependent agent, and a pH-independent agent, wherein is released after 60 minutes under the following dissolution about 60% or more of the total amount of drug in the phar conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 maceutical composition is released after 60 minutes under the rpm, 37° C. following dissolution conditions: 0.1 NHCl, 500 mL, USP 27. The orally administrable composition of claim 23, Apparatus 2 (paddle), 50 rpm, 37°C.; and wherein about 25% wherein the composition comprises morphine, a pH-depen or less of the total amount of drug in the pharmaceutical dent agent, and a pH-independent agent, wherein no more composition is released after 60 minutes under the following than 50% of the total amount of morphine in the pharmaceu dissolution conditions: DI water, 500 mL, USP Apparatus 2 tical composition is released within 1 hour and about 50% or (Paddle), 50 rpm, 37° C. more of the total amount of morphine in the pharmaceutical 22. The orally administrable composition of claim 17, composition is released after 8 hours under the following wherein the composition comprises a drug, a pH-dependent dissolution conditions: 0.1 NHCl, 500 mL, USP Apparatus 2 agent, and a pH-independent agent, wherein no more than (paddle), 50 rpm, 37°C.; and wherein about 25% or less of the 50% of the total amount of drug in the pharmaceutical com total amount of morphine in the pharmaceutical composition position is released within 1 hour and about 50% or more of is released after 60 minutes under the following dissolution the total amount of drug in the pharmaceutical composition is conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 released after 8 hours under the following dissolution condi rpm, 37° C. tions: 0.1 NHCl,500 mL, USP Apparatus 2 (paddle), 50 rpm,