US 2014022O126A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/022012.6 A1 Tygesen et al. (43) Pub. Date: Aug. 7, 2014

(54) ABUSE-DETERRENT PHARMACEUTICAL (60) Provisional application No. 61/668,741, filed on Jul. 6, COMPOSITIONS FOR CONTROLLED 2012. RELEASE (30) Foreign Application Priority Data (71) Applicant: EGALET LTD., LONDON (GB) Jul. 6, 2012 (DK) ...... PA 2012 70405 (72) Inventors: Peter Holm Tygesen, Vaerlose (DK); Karsten Lindhardt, Haslev (DK); Publication Classification Martin Rex Olsen, Holbaek (DK); Gina Engslev Fischer, Vaerlose (DK); Jan (51) Int. Cl. Martin Overgard, Frederikssund (DK); A619/20 (2006.01) Georg Boye, Hedehusene (DK); Nikolaj A613 L/485 (2006.01) Skak, Virum (DK); Torben Elhauge, (52) U.S. Cl. Copenhagen K (DK) CPC ...... A61K9/2031 (2013.01); A61 K3I/485 (2013.01) (73) Assignee: EGALET LTD., LONDON (GB) USPC ...... 424/465; 514/282 (21) Appl. No.: 14/249,965 (57) ABSTRACT (22) Filed: Apr. 10, 2014 The present disclosure relates to pharmaceutical composi Related U.S. Application Data tions that are abuse resistant and may also provide controlled (63) Continuation of application No. 13/933,053, filed on release. The present disclosure also relates to the use of phar Jul. 1, 2013. maceutical compositions in the treatment of pain. Patent Application Publication Aug. 7, 2014 Sheet 1 of 20 US 2014/022O126 A1

3. f s ls- iss-se a Ry,------. -&--- res ---Y --- -a- r \Y. . t N ^F

Fig. 1 Patent Application Publication Aug. 7, 2014 Sheet 2 of 20 US 2014/022O126 A1

Fig. 2 Patent Application Publication Aug. 7, 2014 Sheet 3 of 20 US 2014/022O126 A1

Patent Application Publication Aug. 7, 2014 Sheet 4 of 20 US 2014/022O126 A1

OO . 80 8 . i 8 40

Y --57F-51A 2 O -- 1577-051A coffee grinded 15 sec

Time (min)

Fig. 4 Patent Application Publication Aug. 7, 2014 Sheet 5 of 20 US 2014/022O126 A1

28: ------% 80%

{u:iative %

24.5% fe.9% Size interva as

Fractiles 10% fractile 25% fractile 50% fractile f5% fractile 90% fractile

Fig. 5 Patent Application Publication Aug. 7, 2014 Sheet 6 of 20 US 2014/022O126 A1

s - 1577-051B Untampered Buffer pH 6.8 i 4 40% why etiao - 1577-051B ampered Buffer pH 6.8 f 40% ww ethano 2 -o-1577-051B Untampered Buffer ph 6.8

O 2 3 4 O SO SOO f 8O 900 Tine (min)

Fig. 6 Patent Application Publication Aug. 7, 2014 Sheet 7 of 20 US 2014/022O126 A1

- 9% 80% 63%

i:riate %

37.9% f3.3% 88% Size interfa as

Fractiles 10% fractile 25% fractile 50% fractile f5% fractile 90% fractile

Fig. 7 Patent Application Publication Aug. 7, 2014 Sheet 8 of 20 US 2014/022O126 A1

--581065 --581-065 Coffee grinder 5 Sec if cus O 2 3. 40 SO SO Time (min)

Fig. 8 Patent Application Publication Aug. 7, 2014 Sheet 9 of 20 US 2014/022O126 A1

--- 3:

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Size interwat aris)

Fractiles 10% fractile 25% fractile 50% fractile A5% fractile 90% fractile

Fig. 9 Patent Application Publication Aug. 7, 2014 Sheet 10 of 20 US 2014/022O126 A1

100 90 80 70 60 50 40 30 2 -0-158.066 Untampered 1C -H1583-066 Tampered

Time (min)

Fig. 10 Patent Application Publication Aug. 7, 2014 Sheet 11 of 20 US 2014/022O126 A1

8%

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Fractiles 10% fractile 25% fractile 50% fractile 75% fractile 90% fractile

Fig. 11 Patent Application Publication Aug. 7, 2014 Sheet 12 of 20 US 2014/022O126 A1

100 90 80 70 60 50 40 30 2O --OxyContin OP 40 mg. Jntampered 10 -HOxyContin OP 4.3 mg Tampered 2 sec

O 2O: 4. 66 3CO OO 1200 Time (min)

Fig. 12 Patent Application Publication Aug. 7, 2014 Sheet 13 of 20 US 2014/022O126 A1

& Faciency

Fractiles 10% fractile 25% fractile 50% fractile f5% fractile 90% fractile

Fig. 13 Patent Application Publication Aug. 7, 2014 Sheet 14 of 20 US 2014/022O126 A1

110 100 ------90 -- 80 70 60 50 ----2-QQ60-Q67, buffer pH 6.8 40 30 - 2-0.066-067, buffer phi 6.8, 20 40%, wif wethano 10 O 2 3) & S SO SO 9 11 Time (min)

Fig. 14 Patent Application Publication Aug. 7, 2014 Sheet 15 of 20 US 2014/022O126 A1

100.0 A ------?' - a 8O,O : ,' ar - & OxyContin CP 40 mg, ampered r -- St Continus 60 mg, ampered s ? f * - Morphine 230 mg, ampered 60,0 f are OxyContin OP40 mg, Jrtarr pered ,' ? --MS: Continus 60 mg, Untampered

40, -: f --Morphine 230 mg, Untampered

20,

O. 10,0 200 30,0: 400 50,0 6O, O. Time (min)

Fig. 15 Patent Application Publication Aug. 7, 2014 Sheet 16 of 20 US 2014/022O126 A1

100 80

d O

--Opana ER 40 mg, Tampered 20 --OxyContin OP 80 mg, Tampered -e-Morphine 200 mg, Tampered -HMST continus 60 mg, Tampered

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Fig. 16 Patent Application Publication Aug. 7, 2014 Sheet 17 of 20 US 2014/022O126 A1

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Fig. 17 Patent Application Publication Aug. 7, 2014 Sheet 18 of 20 US 2014/022O126 A1

MST Continus

&Fury uulsati's

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Fractiles 10% fractile 25% fractile 50% fractile 75% fractile 90% fractile

Fig. 18 Patent Application Publication Aug. 7, 2014 Sheet 19 of 20 US 2014/022O126 A1

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Frequency

Cumulativ Naša. aiaasa Sieterial

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Fig. 19 Patent Application Publication Aug. 7, 2014 Sheet 20 of 20 US 2014/022O126 A1

SFreunity & Cumultifs

Seiteral)

Fractiles 10% fractile 25% fractile 50% fractile f5% fractile 90% fractile

Fig. 20 US 2014/0220 126 A1 Aug. 7, 2014

ABUSE-DETERRENT PHARMACEUTICAL 0010 FIG. 5 shows particle size reduction results of one COMPOSITIONS FOR CONTROLLED embodiment of a ground (tampered) pharmaceutical compo RELEASE sition, as disclosed herein, comprising PEO 400,000 daltons. 0011 FIG. 6 shows in vitro dissolution results of the RELATED APPLICATIONS release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40% V/v ethanol. The 0001. This application claims the benefit of U.S. Provi release of oxycodone is shown for intact tablets (untampered) sional Application No. 61/668,741, filed on Jul. 6, 2012, the and ground tablets (tampered) of one embodiment of a phar contents of which are incorporated herein by reference. maceutical composition, as disclosed herein, comprising 0002 All patent and non-patent references cited in the PEO 600,000 daltons. application are hereby incorporated by reference in their 0012 FIG. 7 shows particle size reduction results of one entirety. embodiment of a ground (tampered) pharmaceutical compo sition as disclosed herein comprising PEO 600,000 daltons. FIELD OF INVENTION 0013 FIG. 8 shows in vitro dissolution results of the 0003. The present disclosure relates to pharmaceutical release of hydromorphone (%) versus time (minutes) in phos compositions. In certain embodiments, the pharmaceutical phate buffer solution pH 6.8. The release of hydromorphone compositions according to the present description are abuse is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical compo deterrent and may provide controlled release. sition, as disclosed herein, comprising PEO 2,000,000 dal BACKGROUND OF INVENTION tOnS. 0014 FIG. 9 shows particle size reduction results of one 0004 Increased attention has been drawn to the abuse of embodiment of a ground (tampered) pharmaceutical compo prescription pharmaceutical compositions. The abuse, or sition, as disclosed herein, comprising PEO 2,000,000 dal non-medicinal use, of prescription pharmaceutical composi tOnS. tions has been reported to be an increasing problem. In North 0015 FIG. 10 shows in vitro dissolution results of the America, abuse of prescription pharmaceutical compositions release of oxymorphone (%) versus time (minutes) in phos has become an important issue for the U.S. Food and Drug phate buffer solution pH 6.8. The release of oxymorphone is Administration (FDA), and the pharmaceutical industry is shown for intact tablets (untampered) and ground tablets striving to develop abuse-deterrent pharmaceutical composi (tampered) of one embodiment of a pharmaceutical compo tions in order to reduce the potential for misuse of prescrip sition as disclosed herein comprising PEO 10,000,000 dal tion pharmaceutical compositions. Prescription pharmaceu tOnS. tical compositions that are typically misused fall, primarily, 0016 FIG. 11 shows particle size reduction results of one into three groups: 1) Opioids prescribed for pain; 2) Central embodiment of a ground (tampered) pharmaceutical compo Nervous System (CNS) depressants prescribed for anxiety or sition as disclosed herein comprising PEO 10,000,000 dal sleep problems; and 3) Stimulants, prescribed, for example, tOnS. for attention deficit hyperactivity, narcolepsy, or obesity. 0017 FIG. 12 shows in vitro dissolution results of the 0005 Methods for abusing prescription pharmaceutical release of oxycodone (%) versus time (minutes) in phosphate compositions are varied and can include, for example, extrac buffer solution pH 6.8. The release of oxycodone is shown for tion, melting, Volatilization, physical tampering (e.g., grind intact tablets (untampered) and ground tablets (tampered) of ing, grating, crushing, etc.), or direct administration. For pur OxycontinR OP40 mg. poses of abuse, methods of administering active drug 0018 FIG. 13 shows particle size reduction results of a Substances obtained from prescription pharmaceutical com ground OxycontinR OP40 mg tablet. positions or of the pharmaceutical compositions themselves 0019 FIG. 14 shows in vitro dissolution results of the are similarly diverse and include, for example, injection, release of morphine (%) versus time (minutes) in phosphate Smoking, Snorting, Swallowing, Sublingual or buccal admin buffer solution pH 6.8 with and without 40% V/v ethanol. The istration, chewing, and administration as Suppository. Alco release of morphine is shown for intact tablets of one embodi hol-induced dose dumping of active drug Substance from ment of a pharmaceutical composition, as disclosed herein. prescription pharmaceutical compositions also presents 0020 FIG. 15 shows in vitro dissolution results of release potential abuse and safety problems. of active Substance (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of active substance is DESCRIPTION OF DRAWINGS shown for intact tablets and groundtablets (groundina Krups F203 coffee grinder) of Oxycontin R OP40 mg. MST Conti 0006 FIG. 1 shows a drawing of a MoulineX-1411R cof nus(R 60 mg, and an embodiment of a pharmaceutical com fee grinder chamber with stainless steel blades. position, as disclosed herein, containing 200 mg of morphine. 0007 FIG. 2 shows a drawing of a Krups. F203 coffee 0021 FIG.16 shows in vitro dissolution results of release grinder chamber with stainless steel blades. ofactive substance (%) versus time (minutes) in dilute hydro 0008 FIG. 3 shows a drawing of a nutmeg grater surface chloric acid. The release of active substance is shown for with a stainless steel star blade. grated tablets (Nutmeg grater) of Opana(R) ER 40 mg. Oxy 0009 FIG. 4 shows in vitro dissolution results of the continR OP80 mg. MST Continus(R 60 mg, and an embodi release of morphine (%) versus time (minutes) in phosphate ment of a pharmaceutical composition, as disclosed herein, buffer solution pH 6.8. The release of morphine is shown for containing 200 mg of morphine. intact tablets (untampered) and ground tablets (tampered) of 0022 FIG. 17 shows particle size reduction results of a one embodiment of a pharmaceutical composition, as dis grated tablet of an embodiment of a pharmaceutical compo closed herein, comprising PEO 400,000 daltons. sition, as disclosed herein, containing 200 mg of morphine. US 2014/0220 126 A1 Aug. 7, 2014

0023 FIG. 18 shows particle size reduction results of a side the context of abuse. For example, a patient taking a grated MST Continus(R 60 mg tablet. prescription pharmaceutical composition for medicinal pur 0024 FIG. 19 shows particle size reduction results of a poses may inadvertently cause delivery of a dose of active grated Opana R. ER 40 mg tablet. drug Substance that is too high or absorbed too quickly by 0025 FIG. 20 shows particle size reduction results of a self-administering a pharmaceutical composition shortly grated OxycontinR OP80 mg tablet. before, simultaneously with, or shortly after, consumption or intake of an alcoholic beverage or another pharmaceutical DETAILED DESCRIPTION OF THE INVENTION composition containing alcohol (e.g., an over-the-counter 0026. The present disclosure provides novel abuse-deter cold or flu medicine). rent pharmaceutical compositions, which are resistant to 0032. The term “physical tampering, as used herein, abuse and tampering. In certain embodiments, the pharma refers to any kind of physical interference or manipulation ceutical compositions according to the present description, that may result in particle size reduction of a pharmaceutical even without containing an outer shell, exhibit hardness that composition. Hence, compositions that are resistant to physi is resistant to physical tampering. In particular embodiments, cal tampering are formulated in Such a way that the compo the pharmaceutical compositions disclosed herein may be sition cannot readily be size reduced to a form that is suitable formulated in Such a way that the composition maintains a for abuse. Such as, for example, injection or Snorting, because desired release profile of the active drug substance, even if the the tablet cannot easily be ground, grated, dissolved, and the pharmaceutical composition is subjected to physical tamper like. Examples of physical tampering include, but are not ing. limited to, crushing, grinding, grating, cutting, crisping, and 0027. One embodiment of the present disclosure provides other methods of particle size reduction. an abuse-deterrent pharmaceutical composition, comprising: 0033. The term “controlled release.” as used herein, (a) an active drug Substance; (b) a polyethylene oxide; and (c) denotes pharmaceutical composition that provide extended optionally, a plasticizer, wherein the pharmaceutical compo release of an active drug Substance from the composition for sition does not provide immediate release of the active drug an extended period of time. In certain circumstances, the term Substance after physical tampering, and wherein when at least “controlled release' is used to designate a release at a desired one polyethylene oxide has a molecular weight of at least rate during a predetermined release period. Additional or 1,000,000 daltons, then the pharmaceutical composition alternative terms, such as, for example, “modified’. comprises at least 5% w/w plasticizer. “delayed, “sustained, “prolonged”, “extended release 0028. In particular embodiments, the pharmaceutical may be used, in certain embodiments, as synonyms to the compositions disclosed herein may comprise a controlled term “controlled release.” released abuse-deterrent pharmaceutical composition with a 0034. The term “immediate release.” as used herein, route of administration that may prevent or limit the feeling of denotes a pharmaceutical composition that releases the active euphoria combined with preventing or making it more diffi drug substance (80% release) within at the most 30 minutes, cult to abuse the active drug Substance from the composition when subjected to dissolution test according to USP35, NF by, for example, injection, Smoking, Snorting, Swallowing, 30, (711), Apparatus 2. Sublingual or buccal administration, chewing, and adminis tration as Suppository. Polyethylene Oxide 0029. The abuse-deterrent pharmaceutical compositions 0035. The pharmaceutical compositions of the present dis according to the present description can be further understood closure comprise a polyethylene oxide. Polyethylene oxides when studied relative to a comparator. Comparison of the (PEOs) are linear polydisperse nonionic polymers composed abuse-deterrent pharmaceutical compositions disclosed of repeating units of ethylene oxide. Their chemical formula herein to a comparator assesses the incremental and mean is HOCH2CH2O.H., where n represents the average number ingful improvement in the ability of said pharmaceutical of oxyethylene groups. See the structural presentation of compositions to deter abuse or misuse. polyethylene oxide below, whereinn is the average number of 0030. In addition, certain embodiments of the present dis oxyethylene groups. Depending on preparation method, high closure relate to the use of the disclosed pharmaceutical com molecular weight PEO may have one terminal methyl group. positions in the treatmentofa clinical condition (such as pain) in an individual in need thereof.

DEFINITIONS u-N-1N H 0031. For purposes of the present disclosure, “dose dump ing refers to an unintended, rapid release of the entire 0036 Polyethylene oxides that are suitable for use in the amount or a significant fraction of the active drug Substance pharmaceutical compositions according to the present contained within a prescription pharmaceutical composition description are those having an average molecular weight of over a short or accelerated period of time. For purposes of at least about 200,000 daltons, such as an average molecular abuse, alcohol-induced dose dumping may facilitate isolation weight of in the range of about 200,000 to about 10,000,000 or concentration of active drug Substances from a prescription daltons, for example in the range of about 250,000 to about pharmaceutical composition. Alternatively, dose dumping in 10,000,000 daltons, such as in the range of about 300,000 to the presence of alcohol may increase the ease with which a about 10,000,000 daltons, for example in the range of about prescription pharmaceutical composition can be abused sim 350,000 to about 10,000,000 daltons, such as in the range of ply through the intake of analcoholic beverage concomitantly about 400,000 to about 10,000,000 daltons. In certain with the prescription pharmaceutical composition. Moreover, embodiments, the polyethylene oxides that are suitable for alcohol-induced dose dumping may present safety issues out use in the compositions disclosed herein are those having an US 2014/0220 126 A1 Aug. 7, 2014

average molecular weight of at the most 1,000,000 daltons, important to note that, in Such cases, it is necessary to use Such as an average molecular weight of in the range of about polyethylene oxides, which have an average molecular 200,000 to about 1,000,000 daltons, for example in the range weight closest to the desired molecular weight to ensure a of about 300,000 to about 1,000,000 daltons, such as in the narrow chain length distribution. In certain Such embodi range of about 400,000 to about 1,000,000 daltons. In another ments, for example, equal amounts of polyethylene oxide embodiment, the polyethylene oxides that are suitable for use 200,000 daltons and polyethylene oxide 600,000 daltons may in the compositions disclosed herein are those having an be mixed to obtain polyethylene oxide 400,000 daltons. average molecular weight of at the most 500,000 daltons, 0043. A composition as described herein may comprise Such as an average molecular weight of in the range of about more than one different kind of polyethylene oxide, such as 2. 200,000 to about 500,000 daltons, for example in the range of for example 3. Such as 4, for example 5. Such as more than 5 about 250,000 to about 500,000 daltons, such as in the range different polyethylene oxides. In certain such embodiments, of about 300,000 to about 500,000 daltons, for example in the the composition comprises 1 to 4 different polyethylene range of about 350,000 to about 500,000 daltons, such as in oxides. In one such embodiment, the composition comprises the range of about 400,000 to about 500,000 daltons. In yet 1 to 3 different polyethylene oxides. In another such embodi another embodiment, the polyethylene oxides suitable for use ment, the composition comprises 2 different polyethylene in the compositions described herein are those having an oxides. average molecular weight of at the most 400,000 daltons, 0044) The polyethylene oxide used in compositions such as in the range of about 100,000 to about 400,000 dal according to the present description may have a melting point tons, for example in the range of about 200,000 to about higher than the body temperature of the individual (e.g., a 400,000 daltons, such as in the range of about 300,000 to human) in which the pharmaceutical composition is to be 400,000 daltons. In one embodiment, the pharmaceutical used. Thus, in particular embodiments, the polyethylene composition comprises polyethylene oxides having an aver oxides employed in the pharmaceutical compositions age molecular weight of 400,000 daltons. described herein may have a melting point of in the range of 0037. In certain embodiments, the polyethylene oxides 38°C. to 200° C., such as in the range of 38°C. to 150° C., for suitable for use in the compositions described herein are those example in the range of 38°C. to 120°C., such as in the range having an average molecular weight selected from 200,000 of 38°C. to 100° C., for example in the range of 65° C. to 100° daltons, 250,000 daltons, 300,000 daltons, 350,000 daltons, C. 400,000 daltons, 450,000 daltons, 500,000 daltons, 550,000 daltons, 600,000 daltons, 650,000 daltons, 700,000 daltons, Plasticizer 750,000 daltons, 800,000 daltons, 850,000 daltons, 900,000 0045. A composition as described herein may also com daltons, 950,000 daltons, 1,000,000 daltons, 2,000,000 dal prise at least one plasticizer. tons, 3,000,000 daltons, 4,000,000 daltons, 5,000,000 dal 0046. In particular embodiments, the composition com tons, 7,000,000 daltons, 10,000,000 daltons. prises a poloxamer. 0038. In certain embodiments, the total concentration of 0047. A composition as described herein may comprise polyethylene oxide for use in the composition is in the range more than one different kind of plasticizer, such as 2, for of 5 to 99.9% w/w, such as from 10 to 99.9% w/w, such as example 3, such as more than 3 different plasticizers. In from 10 to 98% w/w, such as from 20 to 98% w/w, such as certain Such embodiments, the composition comprises 1 to 3 from 30 to 98% w/w, such as from 40 to 98% w/w, such as different plasticizers. In one Such embodiment, the composi from 50 to 98% w/w, such as from 60 to 98% w/w, such as tion comprises 2 different plasticizers. In another Such from 70 to 98% w/w, calculated as w/w % of the composition. embodiment, the different kind of plasticizer is a different 0039. In particular embodiments, the level of polyethylene kind of poloxamer. oxide 200,000 daltons to achieve the desired viscosity as 0048. In one embodiment, the composition comprises one described herein may be at least 1,020 mg, for polyethylene or more plasticizers, preferably one or more plasticizers oxide 300,000 daltons it is at least 544 mg. for polyethylene selected from the group consisting of poloxamers, such as oxide 400,000 daltons it is at least 435 mg, for polyethylene poloxamer 188 and/or poloxamer 407. oxide 600,000 daltons it is at least 324 mg. for polyethylene 0049. In some embodiments, the composition comprises oxide 900,000 daltons it is at least 243 mg, for polyethylene at least one poloxamer. Poloxamers may be copolymers or oxide 1,000,000 daltons it is at least 203 mg for polyethylene block copolymers and are a range of non-ionic Surfactants of oxide 2,000,000 daltons and 4,000,000 daltons it is at least polyethylene glycol (PEG) and polypropylene glycol (PPG). 162 mg and for polyethylene oxide 5,000,000 daltons, 7,000, 0050. The poloxamer may be Diol EO/PO block copoly 000 daltons and 10,000,000 daltons it is at least 122 mg. mers, which, for example, in chemical abstracts are described 0040. In some embodiments, the upper level of polyethyl under the Scientific name hydroxy-hydroxypoly(oxyethyl ene oxide 200,000 to 10,000,000 daltons to achieve the ene) poly(oxypropylene)-poly(oxyethylene)-block copoly desired viscosity in pharmaceutical compositions described mer in combination with the CAS register number. In specific herein is approximately 1,100 mg. embodiments, a suitable poloxamer for use in a composition 0041. The compositions as described herein may com of the disclosure has a HLB value of at least about 18 such as, prise mixtures of polyethylene oxides with different average for example, at least approximately 20, preferably at least 24. molecular weights, for example, in order to obtain polyeth In certain embodiments, the average molecular weight of a ylene oxides with a desirable average molecular weight. suitable poloxamer is typically at least about 2,000 daltons. Thus, in some embodiments, the pharmaceutical comprises 0051 Block copolymers of ethylene oxide and propylene different polyethylene oxide materials with different average oxide that may be included in the composition described molecular weights. herein have a molecular weight of at least 2,000 daltons, 0042. In certain embodiments, in order to obtain polyeth typically in the range of 3,000 to 30,000 daltons, such as in the ylene oxide with a desirable average molecular weight, it is range of 4,000 to 15,000 daltons. US 2014/0220 126 A1 Aug. 7, 2014

0052 Exemplary poloxamers that may be used in the com and/or acetyl triethylcitrate as plasticizer. However, in other positions disclosed herein have the formula HO(CHO)a embodiments, other plasticizers may also be used to provide (CHO) (CHO)H, where 'a' is an integer from 10 to 150, desired material properties. such as from 30 to 140, for example from 50 to 100, such as 0055. In certain embodiments, the amount of plasticizer in from 65 to 90, for example from 70 to 90, and “b' is an integer the composition is in the range of from 0 to 60% w/w, for from 10 to 80, such as from 15 to 80, for example from 20 to example in the range of 0 to 50% w/w, such as in the range of 60, such as from 25 to 55. 0 to 40% w/w, for example in the range of 0 to 30% w/w, such as in the range of 0 to 20% w/w. In some embodiments, the 0053 Other plasticizers may be incorporated in the com amount of plasticizer in the composition is at least 1% w/w, position of the pharmaceutical compositions as described for example at least 5% w/w, such as for example at least 10% herein. A Suitable plasticizer may be selected from mono- and W/w. In some embodiments, the amount of plasticizer in the di-acetylated monoglycerides, diacetylated monoglycerides, matrix composition is at the most 20% w/w, such as in the acetylated hydrogenated cottonseed glyceride, glyceryl range of 0 to 20% w/w, for example 5 to 20% w/w, such as in cocoate, polyethylene glycols (for example with a molecular the range of 10 to 20% w/w, for example 15 to 20% w/w. In weight below 35,000 daltons) or polyethylene oxides (for other embodiments the amount of plasticizer in the matrix example with a molecular weight of about 35,000 to 600,000 composition is at least 5% w/w, such as in the range of 5 to daltons), dipropylene glycol salicylate glycerin, fatty acids 25% w/w, for example 5 to 15% w/w, such as in the range of and esters, phthalate esters, phosphate esters, amides, diocyl 5 to 10% W/w. phthalate, phthalylglycolate, mineral oils, hydrogenated veg 0056. In some embodiments, the plasticizer is a polox etable oils, vegetable oils, acetylated hydrogenated soybean amer. In certain such embodiments, the amount of poloxamer oil glycerides, castor oil, acetyl tributyl citrate, acetyltriethyl in the composition is at the most 20% w/w, such as in the range of 0 to 20% w/w, for example 5 to 20% w/w, such as in citrate, methyl abietate, nitrobenzene, carbon disulfide, beta the range of 10 to 20% w/w, for example 15 to 20% w/w. In naphtyl salicylate, sorbitol, sorbitol glyceryl tricitrate, fatty other embodiments, the amount of poloxamer in the compo alcohols, cetostearyl alcohol, cetyl alcohol, Stearyl alcohol, sition is at least 5% w/w, such as in the range of 5 to 25% w/w, oleyl alcohol, myristyl alcohol. Sucrose octaacetate, alfa-to for example 5 to 15% w/w, such as in the range of 5 to 10% copheryl polyethylene glycol succinate (TPGS), tocopheryl wfw. derivative, diacetylated monoglycerides, diethylene glycol 0057. In particular such embodiments, the composition monostearate, ethylene glycol monostearate, glyceryl comprises one or more plasticizer(s) and one or more poly monooleate, glyceryl monostearate, propylene glycol mer(s). monostearate, macrogol esters, macrogol Stearate 400, mac rogol stearate 2,000, polyoxyethylene 50 stearate, macrogol Active Drug Substance ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, 0.058 An active drug substance suitable for use in the octocinols, tyloxapol, poloxamers, polyvinyl alcohols, pharmaceutical compositions described herein is a therapeu polysorbate 20, polysorbate 40, polysorbate 60, polysorbate tically, prophylactically and/or diagnostically active drug 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, substance (herein also abbreviated as “active substance' or Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan “active drug substance'). monostearate, Sorbitan sesquioleate, Sorbitan trioleate, Sorbi 0059 Examples of specific active drug substances suitable tan tristearate and Sucrose esters, amyl oleate, butyl oleate, for use in the pharmaceutical compositions provided herein butyl Stearate, diethylene glycol monolaurate, glycerol tribu include: tyrate, Cumar W-1, Cumar MH-1, Cumar V-1, Flexol B-400, 0060 Anti-inflammatory and antirheumatic active drug monomeric polyethylene ester, Piccolastic A-5, Piccalastic Substances, such as, for example: butylpyrazolidines, phe A-25, Beckolin, Clorafin 40, acetyl tributyl citrate, acetyl nylbutaZone, mofebutaZone, oxyphenbutaZone, clofeZone, triethyl citrate, benzyl benzoate, butoxyethyl stearate, butyl kebuZone, acetic acid derivatives and related Substances, and glycol esters of fatty acids, butyl diglycol carbonate, indometacin, Sulindac, tolmetin, Zomepirac, diclofenac, butyl ricinoleate, butyl phthalyl butyl glycolate, camphor, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, dibutyl sebacate, dibutyl tartrate, diphenyl oxide, glycerine, acemetacin, difenpiramide, Oxametacin, proglumetacin, HB-40, hydrogenated methyl ester of rosin, methoxyethyl ketorolac, aceclofenac, bufeXamac, oxicams, piroxicam, oleate, monoamylphthalate, Nevillac 10, Paracril 26, techni tenoxicam, droxicam, lornoxicam, meloxicam, methotrexate, cal hydroabietyl alcohol, Methylene glycol dipelargonate, propionic acid derivatives, ibuprofen, naproxen, ketoprofen, Solid aliphatic alcohols, and mixtures thereof. fenoprofen, fenbufen, benoxaprofen, Suprofen, pirprofen, 0054. In particular embodiments, the composition com flurbiprofen, indoprofen, tiaprofenic acid, Oxaprozin, ibu prises cetostearyl alcohol, castor oil, dibutyl sebacate, poly proxam, dexibuprofen, flunoxaprofen, alminoprofen, dexke ethylene oxides and/or poloxamer as plasticizer. In another toprofen, fenamates, mefenamic acid, tolfenamic acid, flufe embodiment, the composition comprises polyethylene gly namic acid, meclofenamic acid, coxibs, celecoxib, rofecoxib, cols, cetostearyl alcohol, cetyl alcohol, Stearyl alcohol, alfa Valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone, tocopheryl polyethylene glycol succinate (TPGS), toco niflumic acid, azapropaZone, glucosamine, benzydamine, pheryl derivative, diacetylated monoglycerides, diethylene glucosaminoglycan polysulfate, produaZone, orgotein, nime glycol monostearate, ethylene glycol monostearate, glyceryl Sulide, feprazone, diacerein, morniflumate, tenidap, monooleate, glyceryl monostearate, propylene glycol oxaceprol, chondroitin Sulfate, feprazone, dipyrocetyl, ace monostearate, macrogol esters, macrogol Stearate 400, mac tylsalicylic acid, quinolines, oxycinchophen, gold prepara rogol stearate 2000, polyoxyethylene 50 stearate, macrogol tions, Sodium aurothiomalate, Sodium aurotiosulfate, aurano ethers, poloxamers, polysorbate 40, polysorbate 60, polysor fin, aurothioglucose, aurotioprol, penicillamine and bate 65, polysorbate 80, polysorbate 85, acetyl tributyl citrate bucillamine; US 2014/0220 126 A1 Aug. 7, 2014

0061 Analgesics, such as, for example: opioids, natural close to antihistamines, etanautine, orphenadrine (chloride), opium alkaloids, morphine, opium, hydromorphone, nico ethers of tropine or tropine derivatives, benzatropine, etyben morphine, oxycodone, dihydrocodeine, diamorphine, tapen Zatropine; tadol, papavereturn, codeine, phenylpiperidine derivatives, 0066 Dopaminergic active drug Substances, such as, for ketobemidone, pethidine, fentanyl, diphenylpropylamine example: dopa and dopa derivatives, levodopa, melevodopa, derivatives, dextromoramide, piritramide, dextropro etilevodopa, adamantane derivatives, amantadine, dopamine poxyphene, bezitramide, methadone, benzomorphan deriva agonists, bromocriptine, pergolide, dihydroergocryptine tives, pentazocine, phenazocine, oripavine derivatives, mesylate, ropinirole, pramipexole, cabergoline, apomor buprenorphine, morphinan derivatives, butorphanol, nalbu phine, piribedil, rotigotine, monoamine, oxidase B inhibitors, phine, tilidine, tramadol, dezocine, Salicylic acid and deriva Selegiline, rasagiline, other dopaminergic agents, such as, for tives, acetylsalicylic acid, aloxiprin, choline Salicylate, example: tolcapone, entacapone, budipine; Sodium salicylate, Salicylamide, Salsalate, ethenZamide, mor 0067. Antipsychotic active drug substances, such as, for pholine Salicylate, dipyrocetyl, benorilate, diflunisal, potas example: phenothiazines with aliphatic side-chain, chlorpro sium salicylate, guacetisal, carbasalate calcium, imidazole mazine, levomepromazine, promazine, acepromazine, triflu salicylate, pyrazolones, phenaZone, metamizole Sodium, promazine, cyamemazine, chlorproethazine, phenothiazines aminophenaZone, propyphenaZone, nifenaZone, anilides, with piperazine structure, dixyrazine, fluiphenazine, per paracetamol, phenacetin, bucetin, propacetamol, other anal phenazine, prochlorperazine, thiopropazate, trifluoperazine, gesics and antipyretics, such as, for example: rimazolium, acetophenazine, thioproperazine, butaperazine, perazine, glafenine, floctafenine, Viminol, nefopam, flupirtine, phenothiazines with piperidine structure, periciazine, thior Ziconotide; idazine, mesoridazine, pipotiazine, butyrophenone deriva 0062 Anaesthetics, such as, for example: ethers, diethyl tives, haloperidol, trifluperidol, melperone, moperone, ether, vinyl ether, halogenated hydrocarbons, halothane, pipamperone, bromperidol, benperidol, droperidol, flu chloroform, methoxyflurane, enflurane, trichloroethylene, anisone, indole derivatives, oxypertine, molindone, sertin isoflurane, desflurane, sevoflurane, barbiturates, methohexi dole, Ziprasidone, thioxanthene derivatives, flupentiXol, clo tal, hexobarbital, thiopental, narcobarbital, opioid anaesthet penthixol, chlorprothixene, tiotixene, Zuclopenthixol. ics, fentanyl, alfentanil, Sufentanil, phenoperidine, anilleri diphenylbutylpiperidine derivatives, fluspirilene, pimozide, dine, remifentanil, other general anaesthetics, such as, for penfluridol, diazepines, oxazepines, thiazepines, loxapine, example: droperidol, ketamine, propanidid, alfaxalone, eto clozapine, olanzapine, quetiapine, neuroleptics, tetrabena midate, propofol, hydroxybutyric acid, nitrous oxide, esket zine, benzamides, Sulpiride, Sultopride, tiapride, remoX amine, Xenon, esters of aminobenzoic acid, ipride, amisulpride, veralipride, levosulpiride, lithium, other metabutethamine, procaine, tetracaine, chloroprocaine, ben antipsychotics, such as, for example prothipendyl, risperi Zocaine, amides, bupivacaine, lidocaine, mepivacaine, prilo done, clotiapine, mosapramine, Zotepine, aripiprazole, pali calne, butanilicaine, cinchocaine, etidocaine, articaine, ropi peridone; vacaine, levobupivacaine, esters of benzoic acid, cocaine, 0068 Anxiolytic active drug substances, such as, for other local anaesthetics, such as, for example: ethyl chloride, example: benzodiazepine derivatives, diazepam, chlordiaz dyclonine, phenol, capsaicin; epoxide, medazepam, oxazepam, potassium cloraZepate, 0063 Antimigraine active drug Substances, such as, for lorazepam, adinazolam, bromazepam, clobazam, ketazolam, example: ergot alkaloids, dihydroergotamine, ergotamine, prazepam, alprazolam, halazepam, pinazepam, camazepam, methysergide, lisuride, corticosteroid derivatives, nordazepam, fludiazepam, ethyl loflazepate, etizolam, clo flumedroxone, selective serotonin (5HT1) agonists, tiazepam, cloxazolam, tofisopam, diphenylmethane deriva Sumatriptan, naratriptan, Zolmitriptan, rizatriptan, almotrip tives, hydroxy Zine, captodiame, carbamates, meprobamate, tan, eletriptan, froVatriptan, other antimigraine preparations, emylcamate, mebutamate, dibenzo-bicyclo-octadiene derivatives, benzoctamine, azaspirodecanedione derivatives, pizotifen, clonidine, iprazochrome, dimetotiazine, Oxetor buspirone, other anxiolytics, such as, for example: mephe One, noxalone, gedocarnil, etifoxine; 0064 Antiepileptic active drug substances, such as, for 0069. Hypnotic and sedative active drug substances, such example: barbiturates and derivatives, methylphenobarbital, as, for example: barbiturates, pentobarbital, amobarbital, phenobarbital, primidone, barbexaclone, metharbital, hydan butobarbital, barbital, aprobarbital, secobarbital, talbutal, toin derivatives, ethotoin, phenyloin, amino(diphenylhydan vinylbital, vinbarbital, cyclobarbital, heptabarbital, reposal, toin) Valeric acid, mephenyloin, fosphenyloin, oxazolidine methohexital, hexobarbital, thiopental, etallobarbital, allo derivatives, paramethadione, trimethadione, ethadione, suc barbital, proxibarbal, aldehydes and derivatives, chloral cinimide derivatives, ethoSuximide, phensuximide, mesuX hydrate, chloralodol, acetylglycinamide chloral hydrate, imide, benzodiazepine derivatives, clonazepam, carboxam dichloralphenaZone, paraldehyde, benzodiazepineemepro ide derivatives, carbamazepine, oXcarbazepine, rufinamide, nium derivatives, flurazepam, nitrazepam, flunitrazepam, fatty acid derivatives, valproic acid, valpromide, aminobu estazolam, triazolam, lormetazepam, temazepam, mida tyric acid, vigabatrin, progabide, tiagabine, other antiepilep Zolam, brotizolam, quazepam, loprazolam, doxefazepam, tics, such as, for example: Sultiame, phenacemide, lamot cinolazepam, piperidinedione derivatives, glutethimide, met rigine, felbamate, topiramate, gabapentin, pheneturide, hyprylon, pyrithyldione, benzodiazepine related drugs, Zopi levetiracetam, Zonisamide, pregabalin, Stiripentol, lacosa clone, Zolpidem, Zaleplon, ramelteon, other hypnotics and mide, beclamide; sedatives, such as, for example: methaqualone, clomethiaz 0065 Anticholinergic active drug substances, such as, for ole, bromisoval, carbromal, Scopolamine, propiomazine, tri example: tertiary amines, trihexyphenidyl, biperiden, metix clofos, ethchlorVynol, Valerian, hexapropymate, bromides, ene, procyclidine, profenamine, dexetimide, phenglutarim apronal, Valnoctamide, methylpentynol, niaprazine, melato ide, maZaticol, bornaprine, tropatepine, ethers chemically nin, dexmedetomidine, dipiperonylaminoethanol: US 2014/0220 126 A1 Aug. 7, 2014

0070 Antidepressant active drug substances, such as, for 2C-D (2,5-dimethoxy-4-methylphenethylamine), 2C-I example: non-selective monoamine reuptake inhibitors, (4-iodo-2,5-dimethoxy-phenethylamine), 2C-T-2 (2.5- desipramine, imipramine, imipramine oxide, clomipramine, dimethoxy-4-ethylthiophenethylamine), 2C-T-4 (2.5- opipramol, trimipramine, lofepramine, dibenzepin, amitrip dimethoxy-4-isopropyl thiophenethylamine), 2C-T-7 (2.5- tyline, nortriptyline, protriptyline, doxepin, iprindole, meli dimethoxy-4-(n)-propylthiopenethylamine), 3.4-methylene tracen, butriptyline, doSulepin, amoxapine, dimetacrine, dioxymethamphetamine, 3,4,5-trimethoxyamphetamine, amineptine, maprotiline, quinupramine, selective serotonin 3.4-methylenedioxyamphetamine, 3.4-methylenedioxy-N- reuptake inhibitors, Zimeldine, fluoxetine, citalopram, paroX ethylamphetamine, 3-methylfentanyl, 3-methylthiofentanyl, etine, Sertraline, alaproclate, fluvoxamine, etoperidone, esci 4-bromo-2,5-dimethoxyamphetamine, 4-bromo-2,5- talopram, monoamine oxidase inhibitors, isocarboxazid, dimethoxyphenethylamine, 4-methoxyamphetamine, 4-me nialamide, phenelzine, tranylcypromine, iproniazide, ipro thyl-2,5-dimethoxyamphetamine, 4-methylaminorex (cis clozide, monoamine oxidase A inhibitors, moclobemide, toloxatone, other antidepressants. Such as, for example: isomer), 5-MeO-DIPT (5-methoxy-N,N-diisopropyl oxitriptan, tryptophan, mianserin, nomifensine, traZodone, tryptamine). 5-MeO-DMT (5-methoxy-N,N-dimethyl nefazodone, minaprine, bifemelane, Viloxazine, oxafloZane, tryptamine), 5-methoxy-3,4-methylenedioxyamphetamine, mirtazapine, medifoxamine, tianeptine, pivagabine, ven acetorphin, acetorphine, acetyl-alpha-methylfentanyl. lafaxine, milnacipran, reboxetine, gepirone, dulloxetine, ago acetyl-alpha-methylfentanyl, acetyldihydrocodeine, acetyl melatine, desvenlafaxine, centrally acting sympathomimet methadol, acetylmethadol, alfentanil, allobarbital, allylpro ics, such as, for example: amfetamine, dexamfetamine, din, allylprodine, alphacetylmethadol except levo-al lisdexamfetamine, metamfetamine, methylphenidate, dexm phacetylmethadol, alpha-ethyltryptamine, aphameprodine, ethylphenidate, pemoline, fencamfamin, modafinil, fenoZo alphamethadol, alphamethadol, alpha-methylfentanyl. lone, atomoxetine, fenetylline, Xanthine derivatives, caffeine, alpha-methylthiofentanyl, alphaprodine, alprazolam, propentofylline, other psychoStimulants and nootropics, such amfepramon, amfetaminil, amineptin, a minorex, amobar as, for example meclofenoxate, pyritinol, piracetam, deanol, bital, amphetamine, dextroamphetamine, amynitrit (all iso fipexide, citicoline, oxiracetam, pirisudanol, linopirdine, mers of the amyl group), anabolic steroids, anilleridine, aprobarbital, barbital, barbituric acid derivative, BDB (3,4- nizofenone, aniracetam, acetylcarnitine, idebenone, prolin methylenedioxyphenyl)-2-butanamine), benzethidin, ben tane, pipradrol, pramiracetam, adrafinil, Vinpocetine; Zethidine, benzoylecgonine, benzphetamine, benzphetamine, 0071 Anti-dementia active drug subtances, such as, for benzylmethylketon, benzylmorphine, betacetylmethadol, example: anticholinesterases, tacrine, donepezil, rivastig beta-hydroxy-3-methylfentanyl, beta-hydroxyfentanyl, mine, galantamine, other anti-dementia drugs, memantine, betameprodine, betameprodine, betamethadol, betaprodine, and ginkgo biloba, bezitramide, bezitramide, boldenone, brolamfetamin, bro 0072 Other nervous system active drug substances, such mazepam, brotizolam, bufotenine, buprenorphine, butabar as, for example: parasympathomimetics, anticholinesterases, bital, butalbital, butobarbital, butorphanol, BZP (A2) (1-ben neostigmine, pyridostigmine, distigmine, ambenonium, cho Zylpiperazin), camazepam, cannabis, carfentanil, catha line esters, carbachol, bethanechol, other parasympathomi edulis, cathine, cathinone, chloral betaine, chloral hydrate, metics, such as, for example: pilocarpine, choline alfoscerate; chlordiazepoxide, chlorhexadol, chlorotestosterone (same as 0073 Active drug substances used in addictive disorders, clostebol), chlorphentermine, clobazam, clonazepam, cloni Such as, for example: nicotine, bupropion, Varenicline, disul taZene, clonitaZene, cloraZepate, clortermine, clostebol, clo furam, calcium carbimide, acamprosate, naltrexone, tiazepam, cloxazolam, coca leaves, cocaine, codeine, codeine buprenorphine, methadone, levacetylmethadol, lofexidine, & isoquinoline alkaloid, codeine methylbromide, codeine-N- betahistine, cinnarizine, flunarizine, acetylleucine, ganglio oxide, codoxim, cyclobarbital (hexemal NFN), cyprenor sides and ganglioside derivatives, tirilazad, riluzole, Xalip phine, dehydrochlormethyltestosterone, delorazepam, deso roden, hydroxybutyric acid, amifampiridine; morphine, deXamfetamine, dexfenfluramine, 0074. Opium alkaloids and derivatives, such as, for dexmethylphenidate, dextromoramide, dextropropoxyphene, example: ethylmorphine, hydrocodone, codeine, opium alka diacetylmorphine, diampromide, diazepam, dichloral loids with morphine, normethadone, noscapine, pholcodine, phenaZone, diethylpropion, diethylthiambutene, diethyl dextromethorphan, thebacon, dimemorfan, acetyldihydroco tryptamine, difenoxin, dihydrocodeine, dihydroetorphine, deine, benzonatate, benproperine, clobutinol, isoaminile, dihydromorphine, dihydrotestosterone, dimenoxadol, dime pentoxyverine, oxolamine, oxeladin, clo?edanol, pipaZetate, pheptanol, dimethylthiambutene, dimethyltryptamine, diox bibenzonium bromide, butamirate, fedrilate, Zipeprol, dibu aphetylbutyrate, diphenoxylate, dipipanone, diprenorphine, nate, droxypropine, prenoxdiazine, dropropizine, cloperas dronabinol, drostanolone, drotebanol, ecgonine, estaZolam, tine, meprotiXol, piperidione, tipepidine, morclofone, nepi ethchlorvynol, ethinamate, ethyl loflazepate, ethylestrenol, malone, levodropropizine, dimethoxanate. ethylmethylthiambutene, ethylmorphine, ethylmorphine, eti 0075. In certain embodiments, the active drug substance cyclidin, etilamfetamine, etonitaZene, etorphine, etoxeridine, may, for example, be an active drug Substance with abuse etryptamine, fencamfamin, fenethylline, fenetylline, fenflu potential that presents a safety risk. Such active drug Sub ramine, femproporex, fentanyl, fludiazepam, flunitrazepam, stance may, for example, be selected from: fluoxymesterone, flurazepam, formebolone, fungi and spores 0076) 1-(1-phenylcyclohexyl)pyrrolidine, 1-(2-phenyl of the sepcies psilocype semilanceata, furethidine, gammahy ethyl)-4-phenyl-4-acetoxypiperidine, 1-1-(2-thienyl)-cy droxybutanic acid, glutethimide, halazepam, haloxazolam, clohexylpiperidine, 1-1-(2-thienyl)cyclohexylpyrrolidine, heroine, hydrocodone, hydrocodone & isoquinoline alkaloid, 1-methyl-4-phenyl-4-propionoxy-piperidine, 1-phenylcy hydromorphinol, hydromorphone, hydroxypethidine, clohexylamine, 1-piperidinocyclohexanecarbonitrile, 2.5- ibogaine, isobutylnitrit, isomethadone, ketamine, ketazolam, dimethoxy-4-ethylamphetamine, 2,5-dimethoxyamphet ketobemidone, levamfetamine, levo-alphacetylmethadol, amine, 2C-B-(4-bromo-2,5-dimethoxypenethylamine), levo-methamphetamine, levomethorphan, levomoramide, US 2014/0220 126 A1 Aug. 7, 2014 levophenacylmorphan, levorphanol, lisdeXamfetamin, lopra pentazocine, phenadoxone, phenomorphan, phenazocine, Zolam, lorazepam, lormetazepam, lysergic acid, lysergic acid phenoperidine, piminodine, piritramide, propheptazine, amide, lysergic acid diethylamide, marijuana, mazindol, promedol, properidine, propiram, propoxyphene, Sufentanil, MBDN (N-methyl-1-(3.4-methylenedioxyphenyl)-2-butan tilidine, tramadol, thebaine, levo-alphacetylmethadol amine), mCPP (1-(3-chlorphenyl)piperazine), mebutamate, (LAAM), remifentanil, carfentanyl, ohmefentanyl, MPPP mecloqualone, medazepam, mefenorex, MeOPP (1-(4-meth prodine, PEPAP levomethorphan, etorphine, lefetamine, lop oxyphenyl)piperazine), meperidine, meperidine intermedi eramide, diphenoxylate or pethidine. ate, meprobamate, mescaline, mesocarb, mesterolone, 0078 Even further examples of active drug substances metamfetamine, metazocine, methadone, methadone inter Suitable for use in the pharmaceutical compositions described mediate, methamphetamine, methandienone, methandra herein include anabolic steroids, cannabis, cocaine and diaz none, methandriol, methandrostenolone, methaqualone, epam. methcathinone, methenolone, methohexital, methyldesor 0079. In one embodiment, the active drug substance is phine, methyldihydromorphine, methylphenidate, meth selected from the group consisting of the therapeutic classes ylphenobarbital (mephobarbital), methyltestosterone, meth including non-steroidal anti-inflammatory Substances and yprylone, metopone, mibolerone, midazolam, modafinil, antirheumatic active drug Substances. moramide-intermediate, morpheridine, morphine, morphine 0080. In other embodiments, the active drug substance is methylbromide, morphine methylsulfonate, morphine-N-ox selected from therapeutic classes including analgesics, opio ide, myrophine, N,N-dimethylamphetamine, nabilone, nalor ids, antipyretics, anaesthetics, antimigraine agents, antiepi phine, nandrolone, N-ethyl-1-phenylcyclohexylamine, leptics, anti-parkinson agents, dopaminergic agents, antipsy N-ethyl-3-piperidyl benzilate, N-ethylamphetamine, N-hy chotics, anxiolytics, sedatives, antidepressants, droxy-3,4-methylenedioxyamphetamine, nicocodeine, nic psychostimulants agents, dopamine, noradrenaline, nico ocodine, nicodicodine, nicomorphine, nimetazepam, tinic, alfa-andrenergic, serotonin, H3 antagonists used for nitrazepam, N-methyl-3-piperidyl benzilate, noracymeth ADHD and nootropics agents used in addictive disorders. adol, norcodeine, nordiazepam, norethandrolone, norlevor I0081. In still further embodiments, the active drug sub phanol, normethadone, normorphine, norpipanone, norpi stance is selected from therapeutic classes including anaes panone, opium, Oxandrolone, oxazepam, oxazolam, thetics, centrally-acting analgesics, sedative-hypnotics, anxi oxycodone, oxymesterone, oxymetholone, oxymorphone, olytics, appetite Suppressants, decongestants, antitussives, para-fluorofentanyl, parahexyl, paraldehyde, pemoline, pen antihistamines, antiemetics, antidiarrheals, and drugs used to tazocine, pentobarbital, petrichloral, peyote, phenadoxone, treat narcolepsy and attention deficit hyperactivity disorder. phenampromide, phenazocine, phencyclidine, phendimetra I0082 In certain embodiments, the active drug substance is Zine, phenmetrazine, phenobarbital, phenomorphan, pheno associated with abuse syndromes and the active drug Sub peridine, phentermine, phenylacetone, pholcodine, piminod stance may, for example, be selected from opioids, CNS ine, pinazepam, pipradrole, piritramide, PMMA depressants, CNS stimulants, cannabinoids, nicotine-like (paramethyxymethyl amphetamine), prazepam, prohep compounds, glutamate antagonists and N-methyl-D-aspar tazine, properidine, propiram, psilocybine, psilocyn, pyrov tate (NMDA) antagonists. alerone, quazepam, pacemethorphane, racemoramide, I0083. In specific embodiments, the active drug substance racemorphane, remifentanil, Salvia divinorum, Salvinorin A, is an analgesic. Examples of analgesics Suitable for use in the secobarbital, secobarbital, sibutramine, SPA, stanolone, pharmaceutical compositions described herein include, for stanozolol, Sufentanil, Sulfondiethylmethane, Sulfonethyl example, opioids, natural opium alkaloids, morphine, opium, methane, Sulfonmethane, talbutal, temazepam, tenamfe hydromorphone, nicomorphine, oxycodone, dihydrocodeine, tamin, testolactone, testosterone, tetrahydrocannabinols, tet diamorphine, tapentadol, papavereturn, codeine, phenylpip razepam, TFMPP (1-(3-triflourmethylphenyl)piperazine), eridine derivatives, ketobemidone, pethidine, fentanyl, thebacon, thebaine, thiamylal, thiofentanyl, thiopental, tile diphenylpropylamine derivatives, dextromoramide, piritra tamine & Zolazepam in combination, tilidine, trenbolone, mide, dextropropoxyphene, bezitramide, methadone, benzo triazolam, trimeperidine, vinbarbital, Zaleplon, Zipeprol, morphan derivatives, pentazocine, phenazocine, oripavine Zolpidem and Zopiclon. derivatives, buprenorphine, morphinan derivatives, butorpha 0077. Other suitable examples of active drug substances nol, nalbuphine, tilidine, tramadol, dezocine, Salicylic acid Suitable for use in the pharmaceutical compositions described and derivatives, acetylsalicylic acid, aloxiprin, choline Sali herein include, for example, alfentanil, allylprodine, cylate, Sodium salicylate, Salicylamide, Salsalate, ethenza alphaprodine, aniloridine, benzylmorphine, bezitramide, mide, morpholine salicylate, dipyrocetyl, benorilate, buprenorphine, butophanol, clonitaZene, codeine, cyclazo diflunisal, potassium salicylate, guacetisal, carbasalate cal cine, desomorphine, dextromoramide, dezocine, diapromide, cium, imidazole Salicylate, pyrazolones, phenaZone, metami dihydrocodeine, dihydromorphine, dimenoxadol, dimephet Zole sodium, aminophenaZone, propyphenaZone, nifenaZone, anol, dimethylthiambutene, dioxaphetyl butyrate, dipi anilides, paracetamol, phenacetin, bucetin, propacetamol. panone, eptazocine, ethoheptazine, ethylmethylthiambutene, other analgesics and antipyretics such as, for example, rima ethylmorphine, etonitaZene, fentanyl, heroin, hydrocodone, Zolium, glafenine, floctafenine, Viminol, nefopam, flupirtine, hydromorphone, hydroxypethidine, isomethadone, dextro Ziconotide. propoxyphene, ketobemidone, levallorphan, levorphanol, I0084. In certain such embodiments, the active drug sub levophenacylmorphan, lofentanil, meperidine, meptazinol, stance is an opioid. Where an opioid is included as an active metazocine, methadone, metopon, morphine, morphine drug Substance, the opioid may be selected from naturally 6-glucuronide, morphine 3-glucuronide, myrophine, nalbu occurring opioids, synthetic opioids and semisynthetic opio phine, narccine, nicomorphine, norlevorphanol, normetha ids. done, nalorphine, normorphine, norpipanone, opium, oxyc I0085. In another embodiment, the active drug substance is odone, oxycodeine, Oxymorphone, papavereturn, selected from amfetamine, dexamfetamine, lisdexamfe US 2014/0220 126 A1 Aug. 7, 2014

tamine, metamfetamine, methylphenidate, dexmethylpheni 0095. Furthermore, in some embodiments, the active drug date and combinations thereof. Substance may be in any of its crystalline, polymorphous, I0086. In some embodiments, the pharmaceutical compo semi-crystalline, amorphous or polyamorphous forms and sitions disclosed herein includes an opioid, the opioid is mixtures thereof. selected from buprenorphine, codeine, dextromoramide, 0096. The concentration of the active drug substance in the dihydrocodeine, fentanyl, hydrocodone, hydromorphone, pharmaceutical composition for use according to the disclo morphine, pentazocine, oxycodeine, oxycodone, oxymor Sure depends on the specific active drug Substance, the disease phone, norhydrocodone, noroxycodone, morphine-6-glucu to be treated, the condition of the patient, the age and gender ronode, tramadol, tapentadol and dihydromorphine. of the patient etc. The above-mentioned active drug sub 0087. Where an opioid is used as an active drug substance, stances may be known active drug Substances and a person the opioid may be present in any of its crystalline, polymor skilled in the art will be able to find information as to the phous, semi-crystalline, and amorphous or polyamorphous dosage of each active drug Substance and, accordingly, will forms. Furthermore, in some embodiments, an opioid used as know how to determine the amount of each active drug Sub an active drug Substance may be present in one or more forms stance in the pharmaceutical composition. selected from its crystalline, polymorphous, semi-crystalline, 0097. The active drug substance may be a new chemical and amorphous or polyamorphous forms. entity for which the amount of information is limited. In such 0088 Specific embodiments of the pharmaceutical com cases, the dosage has to be evaluated based on available positions disclosed herein include an opioid as an active drug preclinical and/or clinical data. Substance, the active drug Substance is selected from mor 0098. In some embodiments, the active drug substance is phine, oxycodone, hydrocodone, hydromorphone, norhydro typically present in the composition in an amount of from 5 to codone, oxymorphone, noroxycodone, morphine-6-glucu about 90% w/w such as, for example, from about 5 to about ronode and pharmaceutically acceptable salts of any of the 80% w/w, from about 5 to about 70% w/w, from about 5 to aforementioned, such as from the group consisting of oxyc about 60% w/w, from about 5 to about 50% w/w, from about odone hydrochloride, hydrocodone bitartrate, hydromor 5 to about 40% w/w, from about 5 to about 30% w/w, from phone hydrochloride and morphine Sulphate pentahydrate. about 5 to about 20% w/w, from about 5 to about 10% w/w. 0089. In certain embodiments, the pharmaceutical com 0099. In certain embodiments, when the active drug sub positions as described herein are suitable for use for water stance is an opioid. Such as, for example, morphine, oxyc soluble as well as slightly soluble or insoluble active drug odone, hydromorphone or oxymorphone orpharmaceutically substances. acceptable salts thereof, then said opioid is typically present in the compositions in a concentration of in the range of 5 to 0090. In some embodiments, all of the above mentioned 70% w/w, for example in the range of 5 to 60% w/w, such as active drug Substances may also be in the form of pharma in the range of 5 to 50% w/w, for example in the range of 5 to ceutically acceptable salts, uncharged or charged molecules, 45% w/w, such as in the range of 5 to 40% w/w, for example molecular complexes, Solvates, or anhydrates thereof, and, if in the range of 5 to 35% w/w, such as in the range of 5 to 30% relevant, isomers, enantiomers, racemic mixtures, and mix w/w, for example in the range of 5 to 25% w/w, such as in the tures thereof. range of 5 to 20% w/w, for example in the range of 5 to 15% 0091. In particular embodiments, the pharmaceutical w/w, such as in the range of 5 to 10% w/w. compositions described herein may comprise pharmaceuti 0100. In certain embodiments, the active drug substance is cally acceptable salts of any of the above mentioned active typically present in the composition in an amount of from 1 to drug Substances. about 90% w/w such as, for example, from about 1 to about 0092. The term “pharmaceutically acceptable salts' of an 80% w/w, from about 1 to about 70% w/w, from about 1 to active drug Substance includes alkali metal salts such as, for about 60% w/w, from about 1 to about 50% w/w, from about example, Sodium or potassium salts, alkaline earth metal salts 1 to about 40% w/w, from about 1 to about 30% w/w, from Such as, for example, calcium and magnesium salts, and salts about 1 to about 20% w/w, from about 1 to about 10% w/w. with organic or inorganic acid Such as, for example, hydro 0101. In certain embodiments, when the active drug sub chloric acid, hydrobromic acid, nitric acid, Sulfuric acid, stance is an opioid. Such as, for example, morphine, oxyc phosphoric acid, citric acid, formic acid, maleic acid, Succinic odone, hydromorphone or oxymorphone orpharmaceutically acid, tartaric acid, methansulphonic acid, toluenesulphonic acceptable salts thereof, then said opioid is typically present acid etc. in the compositions in a concentration of in the range of 1 to 0093. The term “pharmaceutically acceptable salts' of an 70% w/w, for example in the range of 1 to 60% w/w, such as opioid includes alkali metal salts such as, for example, in the range of 1 to 50% w/w, for example in the range of 1 to Sodium or potassium salts, alkaline earth metal salts such as, 45% w/w, such as in the range of 1 to 40% w/w, for example for example, calcium and magnesium salts, and salts with in the range of 1 to 35% w/w, such as in the range of 1 to 30% organic or inorganic acids such as, for example hydrochloric w/w, for example in the range of 1 to 25% w/w, such as in the acid, hydrobromic acid, nitric acid, Sulfuric acid, phosphoric range of 1 to 20% w/w, for example in the range of 1 to 15% acid, citric acid, formic acid, maleic acid, Succinic acid, tar w/w, such as in the range of 1 to 10% w/w. taric acid, methanSulphonic acid, toluenesulphonic acid etc or 0102. In certain embodiments, the compositions comprise tartrate acid. In particular embodiments, pharmaceutically a load of the active drug Substance, such as an opioid. A load acceptable opioid salts may be selected from the group con is generally less than 50% w/w of the active drug substance. sisting of Sulphate salts, hydrochloride salts and bitartrate For example, in certain Such embodiments, the compositions salts. may include an active drug Substance in an amount selected 0094. The term “solvates' includes hydrates or solvates from less than 40% w/w and less than 30% w/w. wherein other solvates than water are involved such as, for 0103) In some embodiments, a pharmaceutical composi example, organic Solvents like chloroform and the like. tion as described herein may comprise one active drug Sub US 2014/0220 126 A1 Aug. 7, 2014

stance or more than one different active drug Substances. ticular, in certain embodiments, the polyglycol is at least Typically, the amount of the active drug Substance corre thermoplastic. Suitable polyglycols for use in the composi sponds to a daily or part of a daily therapeutic dose. tion include, for example, polyethylene glycols (for example 0104. In certain embodiments, the pharmaceutical com with a molecular weight below 35,000 daltons), as well as position provides for administration 1-6 times a day, normally derivatives of polyethylene glycol, Such as mono or 1-4 times daily, Such as 1-3 times daily, such as 1-2 times daily dimethoxypolyethylene glycols (mPEGs), polyethylene or 1 time daily. oxides and/or block copolymers of ethylene oxide and pro 0105. In one embodiment, the pharmaceutical composi pylene oxide. tion provides for twice-daily administration. In another 0110. In some embodiments, in addition to a polymer of a embodiment, the pharmaceutical composition provides for polyethylene oxide, the composition may comprise an addi once-daily administration. tional polymer. Such as, for example, at least one polymer selected from: modified or unmodified water soluble natural Pharmaceutically Acceptable Excipients polymers such as glucomannan, galactan, glucan, polygalac 0106 The pharmaceutical compositions described herein turonic acid, polyxylane, polygalactomannans, rhanogalac may also contain other excipients in order to achieve one or turonan, polyxyloglycan, arabinogalactan, and starch, cellu more desired properties. Such as, for example, better stability lose, chitosan, alginate, fibrin, collagen, gelatin, hyaluronic of the active drug Substance or the pharmaceutical composi acid, amylopectin, pectin including low methylated or meth tion itself, enhance the abuse-deterrent properties, loading of oxylated pectins, dextran and fatty acids and alcohols; Syn the active drug Substance or delivery characteristics, such as thetic polymers such as Carbopol, carbomer, carbomer release rate or release profile of an active drug Substance. homopolymer, carboxyvinyl polymer, polyvinylpyrrolidone Further, in some embodiments, the compositions described (PVP), PVA, PVB, Eudragit L methyl ester, Eudragit L. herein may include excipients that facilitate manufacture and Eudragit RL, Eudragit RS, Eudragit E. Eudragit S, PHPV, production of dosage forms such as, for example, tablets PHA, PCL, PLGA and PLA; and hydrogels made from the suitable for administration to individuals in need thereof. polymers or combined polymers mentioned above and or 0107. In certain embodiments, a suitable pharmaceuti from polymers originated from HEMA, HEEMA, MEMA, cally acceptable excipient for use in compositions according MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, to the present description may be selected from fillers, dilu HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and ents, disintegrants, glidants, pH-adjusting agents, viscosity PEGDMA. adjusting agents, Solubility increasing or decreasing agents, 0111. In certain embodiments, the composition as osmotically active agents and solvents. described herein may comprise one or more gelling agents. 0108. In some embodiments, suitable excipients include Examples are polymers selected from the group consisting of conventional tablet or capsule excipients. These excipients modified or unmodified water soluble natural polymers such may be, for example, diluents such as dicalcium phosphate, as glucomannan, galactan, glucan, polygalacturonic acid, calcium Sulfate, lactose or Sucrose or other disaccharides, polyxylane, polygalactomannans, polyxyloglycan, ara cellulose, cellulose derivatives, kaolin, mannitol, dry starch, binogalactan, starch, cellulose, chitosan, alginate, fibrin, col glucose or other monosaccharides, dextrin or other polysac lagen, gelatin, amylopectin, pectin including low methylated charides, sorbitol, inositol or mixtures thereof binders such or methoxylated pectins, dextran; synthetic polymers such as as alginic acid, calcium alginate, sodium alginate, starch, PVA and PVB; and hydrogels made from the polymers or gelatin, Saccharides (including glucose. Sucrose, dextrose and combined polymers mentioned above and or from polymers lactose), carboxymethylcellulose, methylcellulose, Veegum, originated from: HEMA, HEEMA, MEMA, MEEMA, larch arabolactan, polyethylene glycols, ethylcellulose, EDGMA, NVPVAc, AA, acrylamide, MAA, HPMA, PEGA, water, alcohols, waxes, polyvinylpyrrolidone such as PVP PEGMA, PEGDMA, PEGDA, and/or PEGDMA, hydrox K90 or mixtures thereof lubricants such as talc, silicium ypropyl cellulose, methylcellulose, hydroxyethyl cellulose, dioxide, magnesium Stearate, calcium Stearate, Stearic acid, ethylcellulose, hydroxypropyl methylcellulose phthalate, hydrogenated vegetable oils, sodium benzoate, sodium chlo hydroxypropyl methylcellulose acetate Succinate or other ride, leucine, carbowax 4000, magnesium lauryl Sulfate, cellulose derivates, carboxymethylcellulose sodium, car Sodium laurilsulfate, Stearyl alcohol, Polysorbate 20, boxymethylcellulose calcium, carrageenans, guar gum, gel Polysorbate 60, Polysorbate 80, Macrogol stearate, Macrogol langum, Xanthan gum, tragacanth, and arabic gum. lauryl ether, Stearoyl macrogolglycerides, Sorbitan Stearate, 0112. In some embodiments, exemplary stabilizers Sorbitan laurate, Macrogol glycerol hydroxyStearat, colloidal (chemical) include TPG, for example, in the form of TPGS silicon dioxide and mixtures thereof, disintegrants such as (Vitamin E Polyethylene glycol succinate) and BHT, BHA, starches, clays, cellulose derivatives including crosscarmel t-butyl hydroquinone, butylhydroxy toluene, calcium ascor lose, gums, aligns, various combinations of hydrogencarbon bate, gallic acid, hydroquinone, maltol, octyl gallate, sodium ates with weak acids (e.g., Sodium hydrogencarbonate?tar bisulfite, sodium metabisulfite, tocopherol and derivates taric acid or citric acid) crosprovidone, sodium starch thereof, citric acid, tartaric acid, and ascorbic acid. Other glycolate, agar, cation exchange resins, citrus pulp, Veegum, stabilisers include trivalent phosphorous, such as, for glycollate, natural sponge, bentonite, Sucralfate, calcium example, phosphite, phenolic antioxidants, hydroxylamines, hydroxyl-apatite or mixtures thereof. lactones such as Substituted benzofuranones, hindered phe 0109. In certain embodiments, in addition to a polymer of nols, thiosynergists and/or hindered amines, acids (ascorbic a polyethylene oxide, the composition may comprise an addi acid, erythorbic acid, etidronic acid, hypophosphorous acid, tional polymer Such as polyglycols selected from Substan nordihydroguaiaretic acid, propionic acid etc.), phenols, tially water Soluble, thermoplastic, crystalline, semi-crystal dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene, line or amorphous or a mixture of substantially water soluble, organic and inorganic salts (calcium ascorbate, sodium ascor crystalline, semi-crystalline or amorphous polymers. In par bate, sodium bisulphite, sodium metabisulfite, sodium sulfite, US 2014/0220 126 A1 Aug. 7, 2014

potassium bisulphite, potassium metabisulphite), esters (cal acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, cium ascorbate, dilauryl thiodipropionate, dimyristyl thio malonic acid, mandelic acid, oxalic acid, oxamic acid, dipropionate, distearyl thiodipropionate), pyranon (maltol), pimelic acid, or pyruvic acid. and vitamin E (tocopherol, D-alpha-tocopherol, DL-al 0118. In certain embodiments, suitable inorganic acids pha-tocopherol, tocopheryl acetate, d-alpha-tocopheryl that may be included in the compositions described herein acetate, d1-alpha-tocopheryl acetate. However, other anti include, for example, pyrophosphoric, glycerophosphoric, oxidative agents known in the art may also be used. Other phosphoric Such as ortho and meta phosphoric, boric acid, suitable stabilizers may be selected from, for example, sorbi hydrochloric acid, or sulfuric acid. tol glyceryl tricitrate, and Sucrose octaacetate. 0119. In particular embodiments, examples of suitable 0113. In one embodiment, a composition as described inorganic compounds that may be included in the composi herein comprises one or more stabilizers selected from above tions described herein include, for example, aluminium, cal mentioned group of stabilizers. In one such embodiment, the cium or kalium. composition comprises butylhydroxytoluene and/or TPGS as I0120 In particular embodiments, examples of organic bases that may be included in the compositions described a stabilizer. In another Such embodiment, the composition herein include, for example, p-nitrophenol. Succinimide, ben comprises gallic acid and/or ascorbic acid as a stabilizer. Zenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, 0114. In certain embodiments, a release modifier may be pyrrole, diethanolamine, ethyleneamine tris(hydroxymethyl) incorporated in a composition as described herein. A suitable aminomethane, hydroxylamine and derivates of amines, release modifier may be selected from fatty acids and esters, Sodium citrate, aniline or hydrazine. Examples of inorganic fatty alcohols, cetyl alcohol, Stearyl alcohol, mineral oils, bases that may be included in the compositions described hydrogenated vegetable oils, vegetable oils, acetylated herein include, for example, aluminium oxide Such as, for hydrogenated soybean oil glycerides, Castor oil, phosphate example, aluminium oxide trihydrate, alumina, Sodium esters, amides, phthalate esters, glyceryl cocoate oleyl alco hydroxide, potassium hydroxide, calcium carbonate, ammo hol, myristyl alcohol. Sucrose octaacetate, diacetylated nium carbonate, ammonium hydroxide or KOH. monoglycerides, diethylene glycol monostearate, ethylene I0121. In some embodiments, pharmaceutically acceptable glycol monostearate, glyceryl monooleate, glyceryl salts of an organic acid that may be included in the composi monostearate, propylene glycol monostearate, macrogol tions described herein include, for example, an alkali metal esters, macrogol Stearate 400, macrogol Stearate 2000, poly salt or an alkaline earth metal salt such as, for example, oxyethylene 50 stearate, macrogol ethers, cetomacrogol sodium phosphate, sodium dihydrogenphosphate, disodium 1000, lauromacrogols, poloxamers, polyvinyl alcohols, Sor hydrogenphosphate etc., potassium phosphate, potassium bitan monolaurate, Sorbitan monooleate, Sorbitan mono dihydrogenphosphate, potassium hydrogenphosphate etc., palmitate, Sorbitan monostearate, Sorbitan sesquioleate, Sor calcium phosphate, dicalcium phosphate etc., Sodium sulfate, bitan trioleate, sorbitan tristearate, ethylcellulose, cellulose potassium Sulfate, calcium Sulfate, sodium carbonate, sodium acetate, cellulose propionate, cellulose nitrate, cellulose hydrogencarbonate, potassium carbonate, potassium hydro derivative selected from the group consisting of methylcellu gencarbonate, calcium carbonate, magnesium carbonate etc., lose, carboxymethylcellulose and salts thereof, cellulose Sodium acetate, potassium acetate, calcium acetate, sodium acetate phthalate, microcrystalline cellulose, ethylhydroxy Succinate, potassium Succinate, calcium Succinate, sodium ethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, citrate, potassium citrate, calcium citrate, sodium tartrate, hydroxyethylmethylcellulose, hydroxypropylcellulose, potassium tartrate or calcium tartrate. hydroxymethylcellulose and hydroxymethylpropylcellulose, I0122. In certain embodiments, suitable inorganic salts for cellulose acetate, polylactic acid or polyglycolic acid and that may be used in a composition as described herein copolymers thereof, methacrylates, a co-polymer of meth include, for example, sodium chloride, potassium chloride, acrylate-galactomannan etc., polyvinyl alcohols, glycerin calcium chloride or magnesium chloride. ated gelatine and cocoa butter. 0123. In some embodiments, the composition may com 0115. In some embodiments, other suitable release modi prise at least one saccharide. Where a saccharide is included fiers may be selected from inorganic acids, inorganic bases, in a composition as described herein, the saccharide may be inorganic salts, organic acids or bases and pharmaceutically selected from, for example, glucose, ribose, arabinose, acceptable salts thereof, saccharides, oligosaccharides, Xylose, lyxose, Xylol, allose, altrose, inosito, glucose, Sorbi polysaccharides, polyethylene glycol derivatives and cellu tol, mannose, gulose, glycerol, idose, galactose, talose, man lose and cellulose derivatives. nitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, Sucrose, fructose, lactose, dextrin, dextran, amylase or Xylan. 0116. Alternatively or additionally, in particular embodi 0.124. In certain embodiments, the composition may also ments, a composition according to the present description comprise cellulose and/or cellulose derivatives selected from may include a pharmaceutically acceptable excipient selected the group consisting of methylcellulose, carboxymethylcel from a mono-, di-, oligo, polycarboxylic acid or amino acids lulose and salts thereof, microcrystalline cellulose, ethylhy Such as, for example, acetic acid, Succinic acid, citric acid, droxyethylcellulose, ethylcellulose, cellulose acetate, cellu tartaric acid, acrylic acid, benzoic acid, malic acid, maleic lose proprionate, cellulose nitrate, cellulose acetate phthalate, acid, Sorbic acid etc., aspartic acid or glutamic acid etc. ethylmethylcellulose, hydroxyethylcellulose, hydroxyethyl 0117. In some embodiments, suitable organic acids that methylcellulose, hydroxypropylcellulose, hydroxymethyl may be included in the compositions described herein cellulose and hydroxymethylpropylcellulose. include, for example, acetic acid/ethanoic acid, adipic acid, 0.125 Furthermore, in particular embodiments, the com angelic acid, ascorbic acid/vitamin C, carbamic acid, cin positions described herein may comprise one or more agents namic acid, citramalic acid, formic acid, fumaric acid, gallic selected from Sweetening agents, flavouring agents and acid, gentisic acid, glutaconic acid, glutaric acid, glyceric colouring agents in order to provide an elegant and palatable US 2014/0220 126 A1 Aug. 7, 2014 preparation. Examples include maltol, citric acid, water may be any geometrical shape having the same cross section soluble FD&C dyes and mixtures thereof with corresponding area throughout the length of the geometrical shape. Within lakes and direct compression Sugars such as Di-Pac from the present context, cross sections are perpendicular to the Amstar. In addition, coloured dye migration inhibitors such axis of the cylinder. By way of example, if the cylindrical as; tragacanth, acacia or attapulgite talc may be added. Spe shape is elongated then the cross sections are perpendicular to cific examples include calcium carbonate, 1,3,5-trihydroxy the longitudinal axis. Preferably, the cylindrical shape is elon benzene, chromium-cobalt-aluminium oxide, ferric ferrocya gated. The cross section of a cylinder within the meaning of nide, ferric oxide, Iron ammonium citrate, iron (III) oxide the present disclosure may have any two-dimensional shape, hydrated, iron oxides, carmine red, magnesium carbonate and for example the cross section may be circular, oval, parabola, titanium dioxide. hyperbola, rectangular, triangular, otherwise angular, star shaped or an irregular shape. Accordingly, the cylindrical Preparation shape may for example be an elliptic cylinder, a parabolic 0126 The pharmaceutical compositions of the disclosure cylinder, a hyperbolic cylinder or a prism. A prism within the may be produced by various methods which are either known present context is a cylinder whose cross-section is a polygon. perse in the pharmaceutical industry or which, for example, I0134. In some embodiments, the pharmaceutical compo are used in the production of polymer-based materials, sition according to the present description may have any depending upon the desired embodiment and the materials common tablet shapes. Exemplary tablet shapes may include, employed in the pharmaceutical composition in question. The for example, standard convex, standard convex bisect not pharmaceutical compositions according to the present flush, Standard convex quadrisect flush, standard convex description may be produced by methods that are relatively straight-through bisect, compound cup, convex with bevel. simple and inexpensive. flat-faced plain, flat-faced bevel-edged, flat-faced bevel 0127 Suitable preparation methods for pharmaceutical edged bisect, flat-faced bevel-edged quadrisect, flat-faced compositions according to the present description include radius-edged, lozenge, modified ball, core rod type (hole in conventional tablet compression, hot melt-processing and center), capsule, modified capsule, oval, bullet, arrowhead, other methods of preparing pharmaceutical compositions. In triangle, arc triangle, square, pillow (arc Square), rectangle, certain embodiments, hot melt-processing technology and modified rectangle, diamond, pentagon, hexagon, octagon the use of thermoplastic and thermosetting plastic polymers natural edge, heart, half moon and almond. A skilled person are able to give pharmaceutical compositions with low poros would know the various kinds of shape that a tablet may be ity, high viscosity and breaking strengths, like properties such formed in. as for example plastic which is difficult to tear down. In I0135) In a particular embodiment, the pharmaceutical particular embodiments, a combination of one or more of the composition is prepared for oral intake, preferably for oral aforementioned methods may be employed for use in the intake by Swallowing. Accordingly, the size of the pharma preparation of pharmaceutical compositions disclosed ceutical composition may be in a range that allows for oral herein. intake by Swallowing. 0128. In some embodiments, the pharmaceutical compo sitions described herein are prepared by hot melt-processing. Cosmetic Coat In one such embodiment, the pharmaceutical compositions 0.136. In some embodiments, the pharmaceutical compo are prepared by, for example, 1, 2 or multiple component sition according to the present description may also contain a extrusion, molding, 1, 2 or multiple component injection cosmetic coat that fully covers the composition. In certain molding. In another such embodiment, the pharmaceutical Such embodiments, the cosmetic coat may be selected from compositions are prepared by 1, 2 or multiple component the group consisting of taste-masking coats, coats with aque injection molding. ous moisture barriers and/or oxidative barriers to improve the 0129. In embodiments where a preparation is needed in stability of the composition, and coat containing colouring order to make the pharmaceutical composition either before agents, Sweetening agents and/or flavouring agents in order to or after the above-mentioned preparation steps, the prepara provide an elegant and palatable pharmaceutical composition tion may also comprise separate steps, such as, for example, and/or to easy distinguishable dose strengths. wet granulation, dry granulation, melt granulation, pelletiz 0.137 It can be particularly useful to coat compositions ing, curing, spray coating, electrostatic coating, dip coating or having different dose strengths or active drug Substances with other forms of preparation methods. cosmetic coats of different colours so that the differentactives 0130. In one embodiment, the pharmaceutical composi and dose strengths are easily distinguished. tion is prepared by conventional tablet compression. 0.138. In certain embodiments, the cosmetic coat contains 0131. In another embodiment, the pharmaceutical compo an active drug Substance. sitions are prepared by conventional tablet compression and 0.139. Where provided, the cosmetic coat may, in particu hot melt processing. lar embodiments, be easily soluble in aqueous media in order to facilitate contact of the composition with the Surrounding Geometry aqueous media rapidly after administration. In one Such 0132) The pharmaceutical compositions according to the embodiment, the cosmetic coat is dissolved within 30 min present description may be formed as cylindrical composi utes after immersed in aquesous medie Such as, for example, tions. In certain embodiments, the pharmaceutical composi phosphate buffer solution pH 6.8. tions are formed as a cylindrical shape optionally with one or two tapered end(s). Administration 0.133 For purposes of the pharmaceutical compositions 0140. The pharmaceutical composition according to the according to the present description, the cylindrical shape present description can be designed for oral administration. US 2014/0220 126 A1 Aug. 7, 2014

For example, in certain embodiments, the pharmaceutical 20, 30, 40, 60 or 80 mg. In another such embodiments, the compositions may be produced as tablets, for oral intake by pharmaceutical composition includes oxycodone as an active Swallowing one or more intact tablets of the pharmaceutical drug substance and the dosage is selected from 10, 15, 20, 30. composition. 40, 60 or 80 mg. 0141 A pharmaceutical composition as described herein 0.147. In still another embodiment, when the active drug may comprise one active drug Substance or more than one Substance included in the pharmaceutical compositions is an different active drug Substance. opioid, the dosage may be selected from a range of 1 to 1,000 0142. In certain embodiments, a pharmaceutical compo mg, a range of 8 to 1,000 mg, a range of 1 to 500 mg, a range sition containing an active drug Substance according to the of 1 to 250 mg, a range of 8 to 500 mg, a range of 8 to 250 mg present description is typically formulated for oral adminis a range of 1 to 100 mg, a range of 8 to 100 mg, a range of 1 to tration. Due to the possibility of controlling the release rate of 75 mg, a range of 8 to 75 mg, a range of 1 to 64 mg and a range the active drug Substance, in particular embodiments, the of 8 to 64 mg of the opioid. In certain such embodiments, the pharmaceutical composition may be adapted for oral admin pharmaceutical composition includes opioids or a pharma istration 1-6 times a day, such as 1-4 times daily, including 1-3 ceutically acceptable salt thereof as an active drug Substance times, 1-2 times or twice or once daily. and the dosage is selected from 8, 12, 16, 32 or 64 mg. In 0143. In some embodiments, the pharmaceutical compo certain such embodiments, the pharmaceutical composition sitions according to the present description can be prepared includes hydromorphone as an active drug Substance and the for delivery of the desired dosage of active drug substance. In dosage is selected from 8, 12, 16, 32 or 64 mg. particular embodiments, the dosage may be dependent on the 0.148. In still another embodiment, when the active drug individual to whom the pharmaceutical composition as Substance included in the pharmaceutical compositions is an described herein is being administered and the active drug opioid, the dosage may be selected from a range of 1 to 1,000 Substance. mg, a range of 5 to 1,000 mg, a range of 1 to 500 mg, a range 0144. In particular embodiments, the dosage for each of 1 to 250 mg, a range of 5 to 500 mg, a range of 5 to 250 mg administration, wherein dosages are in the range of 1 to 1,000 a range of 1 to 100 mg, a range of 5 to 100 mg, a range of 1 to mg, Such as in the range of 5 to 1,000 mg, for example in the 50mg, a range of 5 to 50mg, a range of 1 to 40 mg, and a range range of 8 to 1,000 mg, such as in the range of 10 to 1,000 mg. of 5 to 40 mg of the opioid. In certain such embodiments, the for example in the range of 30 to 1,000 mg, such as in the pharmaceutical composition includes opioids or a pharma range of 1 to 750 mg, for example in the range of 1 to 500 mg. ceutically acceptable salt thereof as an active drug Substance such as in the range of 1 to 250mg of an active drug substance. and the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40 mg. In certain Such embodiments, the dosage for each adminis In certain such embodiments, the pharmaceutical composi tration is in a range selected from 5 to 500 mg and 5 to 250 mg tion includes oxymorphone as an active drug Substance and of an active drug Substance. the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40 mg. 0145. In some embodiments, when the active drug sub 0149. In particular embodiments, the above-mentioned stance included in the pharmaceutical compositions is an dosages are relevant when the individual in need of treatment opioid, the dosage may be selected from a range of 1 to 1000 is a human being, such as an adult human being. mg, a range of 10 to 1000 mg, a range of 15 to 1000 mg, a range of 20 to 1000 mg, a range of 30 to 1000 mg, a range of Individuals in Need of Treatment 1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg. 0150. In some embodiments, the pharmaceutical compo a range of 15 to 500 mg, a range of 15 to 250 mg, a range of sition of the disclosure is prepared for administration to an 20 to 500 mg, a range of 20 to 250 mg, a range of 30 to 500 mg. individual in need thereof. In certain such embodiments, the a range of 30 to 250 mg, a range of 10 to 200 mg, a range of individual may be a mammal, and in specific embodiments 15 to 200 mg, a range of 20 to 200 mg, and a range of 30 to 200 the individual is a human being. mg of the opioid. In certain Such embodiments, the pharma 0151. In certain embodiments, the pharmaceutical com ceutical composition includes opioid or a pharmaceutically position is for treatment of pain and accordingly, the indi acceptable salt thereof as an active drug Substance and the vidual in need of treatment is an individual suffering from dosage is selected from 10, 15, 20, 30, 50, 60, 80, 100 or 200 pain. mg. In certain such embodiments, the pharmaceutical com 0152. In certain embodiments, wherein the active drug position includes morphine as an active drug Substance and Substance is an opioid, then the pharmaceutical compositions the dosage is selected from 10, 15, 20,30, 50, 60, 80,90, 100, are suitable for treatment of moderate to severe pain such as 120, 180 or 200 mg. severe pain. 0146 In another embodiment, when the active drug sub 0153. In some embodiments, examples of individuals, stance included in the pharmaceutical compositions is an who may benefit from treatment with the pharmaceutical opioid, the dosage may be selected from a range of 1 to 1,000 compositions according to the disclosure, include, for mg, a range of 10 to 1,000 mg, a range of 1 to 500 mg, a range example, the following: of 1 to 250 mg, a range of 10 to 500 mg, a range of 10 to 250 0154 The individual may be an individual suffering from mg, a range of 1 to 150 mg, a range of 10 to 150 mg, a range chronic pain, Such as moderate to severe chronic pain; of 1 to 100 mga range of 10 to 100 mg, a range of 1 to 80 mg 0155 The individual may be an individual suffering from and a range of 10 to 80 mg of the opoid. In certain such cancer and the pharmaceutical composition may be useful for embodiments, the pharmaceutical composition includes continuous treatment of pain or even moderate to severe pain, opioids or a pharmaceutically acceptable salt thereof as an Such as severe pain in an individual Suffering from cancer, active drug Substance and the dosage is selected from 10, 15. 0156 The individual may also be an individual who has 20, 30, 40, 60 or 80 mg. In certain such embodiments, the suffered a moderate to severe injury; pharmaceutical composition includes hydrocodone as an 0157. The individual may be an individual suffering from active drug Substance and the dosage is selected from 10, 15. pain associated with Surgical conditions, such as a pre-Surgi US 2014/0220 126 A1 Aug. 7, 2014

cal individual (an individual in need of Surgery) or a post 2, paddle employing water optionally buffered to a specific Surgical individual (an individual who has undergone Sur pH as dissolution medium (medium 1), and tsoo, W/w (40% gery); V/v ethanol in medium 1) denotes the time it takes to release 0158. The individual may also be an individual suffering 50% w/w of the active drug substance from the pharmaceu from or having Suffered from a myocardial infarction, sickle tical composition in an in vitro dissolution test according to cell crises, kidney Stone or severe back pain; USP35, NF 30, (711), Apparatus 2, paddle employing 40% 0159. The individual may also be an individual suffering V/v ethanol in medium 1 as dissolution medium. from degenerative pain, herniated disc pain, fibromyalgia, 0.165. In certain embodiments, the ratio Rs is at the most neuropathic pain and/or nociceptive pain; and 3 or at the most 2. Notably, in certain such embodiments, the 0160 The individual may also be an individual suffering ratio Rso provided by the pharmaceutical compositions from arthritis, Such as arthritis osteo, arthritis rheumatoid, described herein is from 1 to 1.5 such as, for example, from 1 arthritis psoriatica and/or arthritis urica. to 1.4, from 1 to 1.3, from 1 to 1.2, from 1 to 1.1, from 1 to No Alcohol-Induced Dose Dumping 1.05, about 1, from 1 to 0.95 or from 1 to 0.9. 0166 In particular embodiments, the same may also apply 0161 The pharmaceutical compositions according to the for ratios determined, for example, when 25%, 30%, 40%, present description may be formulated or configured to pro 60%, 70%, 80%, 90% and/or 95% w/w has been released, the vide a reduced risk for alcohol-induced dose dumping. conditions being as described above. 0162. In specific embodiments, the pharmaceutical com positions according to the present description may be formu Abuse-Deterrent lated or configured Such that the pharmaceutical composition does not exhibit alcohol induced dose-dumping. In Such 0167. The pharmaceutical compositions according to the embodiments, the composition exhibits a solubility and/or present description are abuse-deterrent Such that abuse active drug Substance release rate in alcohol containing media administration is reduced, prevented or avoided. Abuse (for example, ethanol containing media) that is lower than or administration typically includes injection and/or Snorting. equal to the solubility and/or release rate in aqueous media 0168 Injection may be avoided by providing a non-inject that does not include alcohol (for example, water, phosphate able composition having such high viscosity that injection is buffer medium pH 6.8 or dilute hydrochloric acid). In some Such embodiments, the polyethylene oxide and excipients difficult or impossible, because a liquid solution cannot be selected for use in the pharmaceutical composition are pro obtained. vided in relative amounts that result in an unchanged or lower 0169. The term “non-injectable composition, as used dissolution rate and/or release rate of the active drug Sub herein, refers to pharmaceutical compositions having a vis stance in alcohol containing media (for example, ethanol cosity of at least 95 mPas, for example at least about 100 containing media) as compared to the solubility and/or mPas, such as at least about 105 mPas, for example at least release rate exhibited in aqueous media that does not include about 110 mPa's, such as at least about 120 mPa's, for alcohol (for example, water, phosphate buffer medium pH 6.8 example at least about 130 mPas, such as at least about 140 or dilute hydrochloric acid). In certain such embodiments, the mPas, for example at least about 150 mPas, such as at least dissolution and/or release rate of the active drug Substance about 160 mPas, for example, at least about 170 mPas, such from the pharmaceutical composition in alcohol containing as at least about 180mPas, for example at least about 190 media (for example, ethanol containing media) is at least 1.25 mPas, such as at least about 200 mPas. for example at least times lower, such as at least 1.5 times lower, Such as at least 2 about 220 mPas, such as at least about 240 mPa's, where the times lower, Such as at least 5 times, such as at least 10 times viscosity is measured according to “Viscosity Test #2. lower than the dissolution and/or release rate of the active described in the “Viscosity test disclosure. In particular drug Substance in aqueous media that does not include alco embodiments, the term “non-injectable composition, as used hol (for example, water, phosphate buffer medium pH 6.8. herein, refers to pharmaceutical compositions having a vis dilute hydrochloric acid, and the like). cosity of at least 170 mPas, where the viscosity is measured 0163 More specifically, in some embodiments, the phar according to “Viscosity Test #2,” described in the “Viscosity maceutical composition may be formulated or configured to test disclosure. mitigate or prevent alcohol-induced dose dumping. In certain 0170 Furthermore, the term “non-injectable composi embodiments, the solubility or release rate of the composition tion, as used herein, may also refer to pharmaceutical com is lower or substantially the same in alcohol than that in water. positions having a viscosity in a range selected from between In certain such embodiments, the solubility or release rate of about 0.5 Pars to about 3,000 Pas, between about 0.5 Pars to the composition is equal or at least 1.25 times lower Such as at about 2,500 Pas, between about 0.5 Pa's to about 2,000 Pas, least 1.5 times lower; at least 2 times lower in alcohol than in between about 0.5 Pars to about 1,700 Pas, between about 5 water, notably 5 times or 10 times lower. Pa's to about 3,000 Pas, between about 10 Pa's to about 3,000 0164. In particular embodiments, the pharmaceutical Pa's, between about 20 Pars to about 3,000 Pas, between compositions according to the present description may be about 30 Pa's to about 3,000 Pas, between about 40 Pa's to configured or formulated to mitigate or prevent alcohol-in about 3,000 Pas, between about 45 Pars to about 3,000 Pas, duced dose dumping. In certain Such embodiments, the phar between about 45 Pa's to about 2,500 Pas, between about 45 maceutical compositions are formulated Such that the ratio Pa's to about 2,000 Pas, between about 45 Pa's to about 1,700 (Rs) between to w/w (40% V/v ethanol in medium 1) and Pa's, between about between about 46 Pa's to about 1,700 too, W/w (medium 1) is 1 or more. tsoo, W/w (medium 1) Pas, where the viscosity is measured according to “Viscosity denotes the time it takes to release 50% w/w of the active drug Test #1.” described in the “Viscosity test disclosure. In par Substance from the pharmaceutical composition in an in vitro ticular embodiments, the term “non-injectable composition.” dissolution test according to USP35, NF 30, (711), Apparatus as used herein, refers to pharmaceutical compositions having US 2014/0220 126 A1 Aug. 7, 2014

a viscosity of at least about 46 Pas, where the viscosity is the compromised pharmaceutical composition, the ease with measured according to Viscosity Test #1, described in the which Such extracted active drug Substance can be injected is “Viscosity test disclosure. evaluated. 0171 Snorting may be avoided by providing a non-snort able composition, which cannot be tampered into Small par Crisping ticles or powder form such that Snorting is made impossible. 0179 The crisping test methods as described herein 0172. In certain embodiments of the pharmaceutical com include methods intended to circumvent the controlled positions described herein, the term “non-Smortable compo release mechanism in or interfere with the controlled release sition” refers to compositions wherein at least 90 wt % of the profile of a pharmaceutical composition. Crisping is a heating particles obtained after physical tampering of the composi process designed to remove, reduce, or degrade at least some tion is larger than about 1,050 um, Such as larger than about of the unwanted or undesired excipients contained within a 1,100 um, Such as larger than about 1,150 um. In particular dosage form and make the dosage form easier to abuse the embodiments, the term “non-Smortable composition, as used active drug Substance. Crisping may be employed to make it herein, refers to a composition where at least 90 wt % of the easier to crush the composition into Small particles or a pow particles obtained after physical tampering of the pharmaceu der form so that Snorting is made possible, or to make it easier tical composition is larger than 1,100 um. to dissolve the composition into an injectable liquid solution, 0173. In certain circumstances, an abuser may tamper with dispersion, or Suspension. pharmaceutical compositions in a manner or by using a 0180 Crisping or heating methods, such as, for example, method that achieves maximal size reduction of the pharma heating in an oven, a microwave oven, a spoon over an open ceutical composition in a minimal amount of time, while flame, and the like, may be employed by a potential abuser to obtaining Small particles, a powder, or other similar products, it make it easier to reduce the particle size and/or the Viscosity which can be dissolved or administered as easily as possible. of the pharmaceutical compositions. The heating is normally 0.174. A series of abuse or tampering methods have been stopped when the pharmaceutical composition starts to turn a developed to illustrate the extent of the pharmaceutical com brown colour. Further processes designed to facilitate or positions described herein of being abuse-deterrent. enable abuse Such as, for example, particle size reduction, 0.175. If a pharmaceutical composition disintegrates into extraction and/or injection are typically initiated after the particles, then it may be possible to dissolve or Suspend the crisping process is completed. particles and use them for abuse purposes. Moreover, if it is 0181. In certain embodiments, the pharmaceutical com possible to disintegrate (e.g., crush) a pharmaceutical com positions according to the present description are not made position, then it is possible to use the powder for Snorting or easier to crush into snortable particles or powder form or to Sniffing and, in this way, abuse the composition. However, if dissolve into an injectable liquid solution by crisping. In it is not possible to crush a pharmaceutical composition, then certain embodiments, Stearate may be added to the pharma there will be no particles to use for such abuse purposes. In ceutical composition as described herein to facilitate the particular embodiments, the pharmaceutical compositions colour change of the composition to a brown and/or dark described herein cannot be crushed into particles by the appa colour or even to facilitate the composition burning when ratus (e.g., tablet hardness tester) specified in Ph. Eur. exposed to a crisping process. In a particular embodiment, the 0176 A particle size reduction test method has been devel Stearate added is magnesium Stearate, calcium Stearate and/or oped to evaluate abuse potential when the pharmaceutical Stearic acid. composition is Subjected to physical tampering. 0177. In some embodiments, a pharmaceutical composi Particle Size Reduction tion is abuse-deterrent, provided that the pharmaceutical 0182. The particle size reduction test methods described composition does not change its release profile from a con herein include methods for reducing the particle size of the trolled release to an immediate release of the active drug pharmaceutical compositions via physical tampering, Such Substance Subsequent to physical tampering (e.g., particle as, for example, crushing, hammering, chopping, grinding. size reduction test, where the test program is successfully grating, cutting, and other means of particle size reduction. completed), which indicates that the pharmaceutical compo 0183 The particle size reduction test can be carried out sition is abuse-deterrent. In some such embodiments, tests on using a number of mechanical and electrical tools that are a pharmaceutical composition Subjected to physical tamper common household items or are readily commercially avail ing may also result in equipment failure, and in Such an able. Tools that may be used in carrying out particle size instance, the test program is considered successfully com reduction testing include, for example, a mortar and pestle, a pleted, indicating a pharmaceutical composition as abuse hammer, a grater, a food chopper, a coffee grinder, and the deterrent. like. 0.178 If a pharmaceutical composition is crushed or bro 0.184 Pharmaceutical compositions and dosage forms (in ken into Small pieces or Small particles, an increased exposed cluding, for example, tablets), that have been Subjected to Surface area is created, which may increase the release rate of physical tampering may be further analyzed by use of image the active drug Substance. Such an increase in release rate processing and/or particle size analysis. Pharmaceutical com may lead to an increased potential for abuse. If a change in the positions Subjected to physical tampering may be analyzed by release profile of the active drug substance from a controlled collecting the different fractions and analyzing, such as, for release to an immediate release is noticed, the pharmaceutical example, by weighing and/or dissolving to assess the contents composition is considered to have failed. At Such a point, the of active drug substance in the different fractions and/or to pharmaceutical composition is considered to have potential assess the dissolution rate. For comparison, a control disso for abuse, such as by Snorting or chemical extraction and it is lution test as described in the "Dissolution test disclosure evaluated. If the active drug substance can be extracted from may be performed using intact tablets (e.g., tablets that have US 2014/0220 126 A1 Aug. 7, 2014

not been subjected to physical tampering), and the results Solvent. In an embodiment, the amount of active drug Sub from the control dissolution test may be used as control data. stance in the solvent may be measured at at least three time points within the first 60 minutes, so as to evaluate the rate at Extraction which the active drug substance is released into the solvent. 0190. Extraction of active drug substance from pharma 0185. The extraction test methods described herein ceutical compositions can be performed by dissolving, for include methods for evaluating the extractability of active example, tablets in different types of solvents. In particular drug Substance(s) from pharmaceutical compositions in dif embodiments, the tablets in different solvents may be shaken ferent types of solvents. The extraction test can be carried out and/or continuous shaken. In other embodiments, the tablets using approximately 3 ml of water to prepare a solution of for in different solvents may be unshaken or undisturbed. The example, MS Contin R) for injection. Solvents can be chosen to cover a broad range of liquids with Shaking low and high pH, with some being some polar and some non-polar. In certain embodiments, the solvents may be cat 0186. Different amount of solvents and ways of handling egorized into five groups: Such as for example, aqueous solu the solutions have been tested. In certain embodiments, in tions, such as, for example, solution pH 1.2: buffer pH 6.8; order to ensure that as much as possible of the active drug buffer pH 10.0; water; and water--ethanol (40% V/v); bever Substance has been extracted, shaking is selected as an extrac ages, such as, for example; Coca-Cola(R); quinine containing tion method. In certain such embodiments, extraction of an Soft drinks, such as, for example; tonic water and bitter active drug Substance from a pharmaceutical composition lemon; Coca-Cola R+ethanol (40% V/v); and vodka; common may be facilitated by placing a pharmaceutical composition household liquids, such as, for example, 1% acetic acid; etha in at least one solvent and shaking the pharmaceutical com nol; methylethylketone; and acetone. position and the at least one solvent. (0191 In some embodiments, it has been shown to be dif 0187. In particular embodiments, in order to ensure that as ficult to extract active substances from the pharmaceutical much as possible of the active drug Substance has been composition described herein in Solvents such as beverages. extracted, continuous shaking is selected as an extraction In certain such embodiments, it has been shown to be difficult method. In one embodiment, extraction of an active drug to extract active Substances from the pharmaceutical compo Substance from a pharmaceutical composition may be facili sition described herein in Solvents such as carbonated and/or tated by placing a pharmaceutical composition in at least one soft drinks, including Coca-Cola(R), and the like. solvent and continuously shaking the pharmaceutical compo sition and the at least one solvent. In some embodiments, Injection “continuous shaking as used herein, refers to shaking for at 0.192 The injection test methods described herein include least 1 second, for at least 5 seconds, for at least 30 seconds, methods for evaluating the abuse potential of active drug for at least 1 min, for at least 5 minutes, for at least 10 minutes, Substance from pharmaceutical compositions both quantita for at least 15 minutes, for at least 30 minutes, for at least 45 tively (i.e., such as, for example, time, yield, and unit opera minutes, for at least 60 minutes, for at least 2 hours, for at least tions required) and qualitatively (i.e., such as, for example, 4 hours, for at least 8 hours, for at least 12 hours, for at least appearance). 24 hours, for at least 2 days, for at least 3 days, for at least 4 0193 In some embodiments, the general strategy behind days, for at least 5 days, for at least 6 days, for at least 1 week, the injection test methods, as described herein, is to mimic the for at least 2 weeks, for at least a month. actual procedures applied by drug abusers when preparing a pharmaceutical composition for injection and injecting it. In Unshaken/Undisturbed Some such embodiments, the study design is therefore 0188 In another embodiment, as an extraction method, divided into three parts, such as, for example, preparation, the pharmaceutical composition may be placed in at least one filtration, and injection. solvent and left unshaken and/or undisturbed for a period of 0194 In certain embodiments, the objective is to record time. In certain embodiments, the pharmaceutical composi the time and effort required to prepare a solution or dispersion tion may be placed in at least one solvent and left unshaken that can be used for injection and the obtained yield of the and/or undisturbed for at least 4 hours, at least 8 hours, at least active drug Substance. As described herein, drug abusers are, 12 hours, at least 24 hours, at least 48 hours, and at least 72 typically, only prepared to spend a limited amount of time for hours. In certain Such embodiments, the pharmaceutical com preparing a pharmaceutical composition for abuse. In certain position may be placed in at least one solvent and left such embodiments, all of the tests disclosed herein can be unshaken and/or undisturbed, and the active drug Substance performed in an aqueous media, which is a commonly-used in the solvent may be first measured after at least 24 hours. Solvent for injection. Finally, the appearance of the resulting 0189 The amount of active drug substance in the solvent Solution/dispersion is assessed in order to evaluate the likeli may be measured at select time points within the first 60 hood that a drug abuser would inject the resulting injectable minutes. In some embodiments, the amount of active drug a SS. Substance in the solvent may be measured at least one time, at 0.195. In certain embodiments, the pharmaceutical com least two times, at least three times, at least four times, at least positions described herein have predominantly high Viscous five times, and at least six times, within the first 60 minutes of properties analogous to plastic. In an aqueous medium or in placing the pharmaceutical composition in the at least one the gastrointestinal tract, the pharmaceutical compositions Solvent. In particular embodiments, the amount of active Sub described herein transforms from having high viscous prop stance in the solvent may be measured at least one time, at erties to having predominately elastic properties that control least two times, at least three times, at least four times, at least the release rate of active drug Substance, and which resist five times, and at least six times, within the first 24 hours of rapid extraction and/or injection. In particular embodiments, placing the pharmaceutical composition in the at least one the predominately elastic properties of the pharmaceutical US 2014/0220 126 A1 Aug. 7, 2014

compositions in an aqueous medium or in the gastrointestinal may form a strong adhesion to the nose and nasal tissue walls tract provides a controlled-release profile of the active drug and, thereby, result in discomfort in the nasal cavity of the Substance in an individual. abuser. 0200. In some embodiments, it has been shown to be dif 0196. The high viscosity of the composition turns not only ficult to inject the abuse-deterrent pharmaceutical composi the composition into a non-injectable dispersion/gel, but also tion when the viscosity of the composition is at least 46 Pais, significantly delays the Solubility of the composition to com where the Viscosity is measured according to Viscosity Test pletely form into a gelatinous mass. In some embodiments, #1, described in the “Viscosity test disclosure. the high viscosity of the composition turns not only the com 0201 In certain embodiments, it has been shown to be position into a non-injectable dispersion/gel, but also signifi difficult to inject the abuse-deterrent pharmaceutical compo cantly deters the abuse of the pharmaceutical composition by sition when the viscosity of the composition is at least 100 eluting at least one polymer from the composition into the mPas, where the Viscosity is measured according to “Viscos Solvent, which turns the solvent into a gelatinous mass. In ity Test #2, described in the “Viscosity test disclosure. Some such embodiments, the at least one polymer is a poly 0202 In some embodiments, the abuse-deterrent pharma ethylene oxide. In certain embodiments, the average molecu ceutical compositions, as described herein, may form a gel lar weight of the at least one polyethylene oxide eluting from that resists passage or is difficult to inject through a needle. the composition into the solvent is less than 5,000,000 dal 0203. In further embodiments, the abuse-deterrent phar tons, for example less than 4,000,000 daltons, such as less maceutical compositions, as described herein, may further than 3,000,000 daltons, for example less than 2,000,000 dal include a viscosity increasing agent, Such as, for example, a tons, such as less than 1,000,000 daltons, for example less gelling agent, and the like. than 800,000 daltons, such as less than 600,000 daltons, for example less than 500,000 daltons. EXAMPLES 0197) In particular embodiments, the high viscosity of the 0204 Certain embodiments of the disclosure are further composition is in a range selected from between about 0.5 illustrated in the following non-limiting examples. Pa's to about 3,000 Pas, between about 0.5 Pars to about 2,500 Pas, between about 0.5 Pa's to about 2,000 Pas, Dissolution Test between about 0.5 Pars to about 1,700 Pas, between about 5 0205 Dissolution tests were performed in accordance Pa's to about 3,000 Pas, between about 10 Pasto about 3,000 with USP35, NF30, (711), Apparatus 2 (paddle method). The Pa's, between about 20 Pars to about 3,000 Pas, between dissolution medium consisted either of phosphate buffer about 30 Pa's to about 3,000 Pas, between about 40 Pa's to solution pH 6.8 with/without ethanol or of dilute hydrochloric about 3,000 Pas, between about 45 Pa's to about 3,000 Pas, acid with/without ethanol. The volume of the dissolution between about 45 Pars to about 2,500 Pas, between about 45 medium was 900 ml and the rotation speed of the paddles was Pa's to about 2,000 Pas, between about 45 Pasto about 1,700 50 rpm or 75 rpm throughout the dissolution run. Samples Pa's, between about between about 46 Pa's to about 1,700 were withdrawn at suitable time intervals and analysed for Pas, where the viscosity is measured according to “Viscosity content of active drug substance by means of UV-detector or Test #1.” described in the “Viscosity test disclosure. In a HPLC with UV-detector. specific embodiment, the viscosity of the composition at least about 46 Pas, where the viscosity is measured according to Dissolution Test (Immediate Release) Viscosity Test #1, described in the “Viscosity test disclosure. 0206 For the immediate-release test, the dissolution 0198 In certain embodiments, the high viscosity of the medium consisted of dilute hydrochloric acid. The volume of composition is at least 95 mPas, for example at least about the dissolution medium was 900 ml and the rotation speed of 100 mPas, such as at least about 105 mPas, for example at the paddles was 75 rpm throughout the dissolution run. least about 110 mPa's, such as at least about 120 mPa's, for example at least about 130 mPas, such as at least about 140 Dissolution Test (Controlled Release) mPas, for example at least about 150 mPas, such as at least about 160 mPas, for example, at least about 170 mPas, such 0207 For the controlled-release test, the dissolution as at least about 180mPas, for example at least about 190 medium consisted of phosphate buffer solution pH 6.8. The mPas, such as at least about 200 mPas. for example at least Volume of the dissolution medium was 900 ml and the rota about 220 mPas, such as at least about 240 mPa's, where the tion speed of the paddles was 50 rpm throughout the dissolu viscosity is measured according to “Viscosity Test #2. tion run. described in the “Viscosity test disclosure. In particular embodiments, the high Viscosity of the composition is at least No Alcohol-Induced Dose Dumping Test 170 mPas, where the viscosity is measured according to 0208 For the no alcohol-induced dose dumping test, the “Viscosity Test #2,” described in the “Viscosity test disclo dissolution medium consisted of phosphate buffer solution SUC. pH 6.8 with/without 40% w/v ethanol. The volume of the 0199 The high viscosity of the composition deters direct dissolution medium was 900 ml and the rotation speed of the injection and also serves as a significant barrier to prevent paddles was 50 rpm throughout the dissolution run. Volatilization (e.g., inhalation) of the incorporated active drug Substance at elevated temperature or Snorting if the compo Crisping Test sition is crushed or broken into Small pieces or Small particles. 0209 Three (3) whole tablets were placed in a 50 ml glass In certain embodiments, the composition results in a highly bottle. The bottle was placed in the center of a microwave Viscous and/or unclear, opaque or cloudy dispersion/gel upon oven and heated for a predetermined amount of time (e.g., 8 contact with and/or immersion in an aqueous medium, which and 16 minutes) at maximum effect (900 W). Afterwards, 9 US 2014/0220 126 A1 Aug. 7, 2014

ml of purified water was added to the bottle. The bottle was for the particles (e.g., a black paper square) and light (to avoid placed on a flatbed laboratory shaker (IKA-Werke HS-501 reflections) plus a calibrated light microscopy scale bar from digital) and was shook continuously (speed 150/min) for 3 Leitz. days at ambient temperature to dissolve the tablets and to 0218. A sample was spread onto the black background, reduce clumping. and the particles were separated. The position of the camera setup was adjusted and focused such that entire sample was Viscosity Test inside the approximate view-area for the camera before pic 0210 Four (4) tablets were weighed and placed in a bottle tures were taken. with 12 ml purified water. The bottle was placed on a flatbed 0219. Data were processed by using the software: Raw laboratory shaker (IKA-Werke HS-501 digital) and was Therapee 3.0.1.0 (Conversion of RAW-files to uncompressed shook continuously (speed 150/min) for 3 days at ambient TIFF.), Image.J 1.45b (Thresholding of TIFF images (bina temperature to dissolve the tablets and to reduce clumping. rization) and particle size measuring (data rendering)) and 0211 Viscosity can be measured using a Brookfield Microsoft Excel 2010 (data analysis). RVDV-E viscometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 15 (0.5-1700 Pas), a 7R Preparation of Pharmaceutical Compositions tube, a small sample adapter SC4-45Y and tested in the range of 1, 5, 10 and 20 rpm, respectively, or with spindle number 21 0220. A general method for the preparation of a pharma (0.05-170 Pas), a 13R tube, and a small sample adapter ceutical composition, as disclosed herein, is described below. SC4-45Y at 20 rpm. The temperature was controlled and in 0221) An accurate amount of the polymer (i.e., in the the range of 21-22°C. examples below: polyethylene oxide) is loaded into a MTI Viscosity Test #1 mixer followed by an accurate amount of the active drug Substance and/or plasticizer and/or other pharmaceutically 0212. In one viscosity test (Viscosity Test #1), the viscos acceptable excipient(s), if any. The mixing is performed at ity can be measured using a Brookfield RVDV-E Viscometer 900-2000 rpm and at a time period up to 20 min. At the start (Brookfield Engineering, Middleboro, Mass. USA) with of the mixing the temperature is about 19-21°C. and the final spindle number 15 (0.5-1700 Pas), a 7R tube, and a small temperature of the mixture is about 30-50° C. The mixture is sample adapter SC4-45Y at 5 rpm. The temperature was then allowed to cool to room temperature and is ready to be controlled and in the range of 21-22°C. fed into an injection moulding machine. The injection moul ding machine used is an Arburg Allrounder 420 C1000-60/ Viscosity Test #2 60. 0213. In another viscosity test (Viscosity Test #2), the viscosity can be measured using a Brookfield RVDV-E vis Example 1 cometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 21 (0.05-170 Pas), a 13R tube, and a Preparation of a Pharmaceutical Composition small sample adapter SC4-45Y at 20 rpm. The temperature Containing PEO 400,000 for Use According to the was controlled and in the range of 21-22°C. Disclosure Particle Size Reduction Test 0222. A composition (batch No. 1577-051A) according to 0214 Particle size reduction of pharmaceutical composi the disclosure was prepared from the following ingredients: tions was tested using a coffee grinder and/or a nutmeg grater. The methods described herein are used to evaluate the efforts required to reduce the particle size of the pharmaceutical Composition ng compositions via physical grinding or grating of the tablets. PEO 400,000 436.2 Poloxamer 188 116.3 0215 Tablets were ground in either a Moulinex-1411R Morphine Sulphate 29.1 coffee grinder with stainless steel blades (model: the original Pentahydrate grinder; 50 g 180 W AR100G31/6WO) at 10 000-20 000 rpm or a Krups. F203 coffee grinder with stainless steel blades (Model: 75 g 200 W F2034210/6WO-1512 R) at 30000-50 0223 The composition was prepared as described above. 000 rpm for 15 seconds or to no more particle size reduction 0224. The composition was subjected to the dissolution or equipment failure and, afterwards, analyzed by use of test (controlled release) described above. The results are Image Processing. A drawing of the coffee grinder chamber is shown in FIG. 4 as the release of morphine (%) versus time shown in FIGS. 1 and 2. (minutes) in phosphate buffer solution pH 6.8. The release of 0216 Tablets were grated by using a nutmeg grater with a morphine is shown for intact tablets and ground tablets stainless steel star blade or a Microplane(R) grater with stain (ground in a Moulinex-1411R coffee grinder). less steel Zester grater or a fine or spice blade for 1/2 minutes. A drawing of the nutmeg grater with stainless steel starblade 0225. The viscosity of the composition was measured as is shown in FIG. 3. described above. The viscosity was found to be 93 Pa's at 5 0217. The samples were analyzed using an image process rpm (using Viscosity Test #1). ing setup comprising a digital SLR with RAW or TIFF capa 0226 Particle size reduction of the composition was mea bilities (Canon EOS 350D, resolution 3466x2306 (8 MP) or Sured as described above. The average particle size was Nikon D3100, resolution 4608x3272 (14.2MP)), a fixed lens 0.706+ 1.63 mm and the five largest particles were: 12.1 mm: (Canon EF 100 mm 1:2:8 USM Macro or Tamron 90 mm 3.0 mm; 2.7 mm; 2.2 mm; and 1.9 mm. The results are shown 1:2:8 Macro), a stable camera stand, a Suitable background in FIG. 5. US 2014/0220 126 A1 Aug. 7, 2014 18

Example 2 Example 4 Preparation of a Pharmaceutical Composition Preparation of a Pharmaceutical Composition Containing PEO 600,000 for Use According to the Containing PEO 10,000,000 According to the Disclosure Disclosure 0227. A composition (batch No. 1577-051B) according to 0237. A composition (batch no. 1581-066) according to the disclosure was prepared from the following ingredients: the disclosure was prepared from the following ingredients:

Composition ng Composition ng PEO 600,000 348 PEO 10,000,000 110 Poloxamer 188 93 Poloxamer 188 8O Oxycodone HCI 23.25 Oxymorphone HCI 10 0238. The composition was prepared as described above. 0228 The composition was prepared as described above. 0239. The composition was subjected to the dissolution 0229. The composition was subjected to the dissolution test (controlled release) described above. The results are test (controlled release) described above. The results are shown in FIG. 10 as the release of oxymorphone (%) versus shown in FIG. 6 as the release of oxycodone (%) versus time time (minutes) in phosphate buffer solution pH 6.8 for intact (minutes) in phosphate buffer solution pH 6.8 with and with tablets and ground tablets (ground in a Moulinex-1411R cof out 40% V/v ethanol. The release of oxycodone is shown for fee grinder). intact tablets and ground tablets (ground in a Moulinex 0240. The viscosity of the composition was measured as 1411R coffee grinder). described above. The viscosity was found to be 79.6 Pa's at 5 0230. The viscosity of the composition was measured as rpm (using Viscosity Test #1). described above. The viscosity was found to be 74 Pa's at 5 0241 Particle size reduction of the composition was mea rpm (using Viscosity Test #1). Sured as described above. The average particle size was 0231 Particle size reduction of the composition was mea 0.547+0.640 mm and the five largest particles were 5.8 mm; sured as described above. The average particle size was 4.8 mm; 4.7 mm; 4.7 mm; and 4.4 mm. The results are shown 0.455+0.639 mm and the five largest particles were; 12.1 mm: in FIG. 11. 4.0 mm; 3.9 mm; 3.8 mm; and 3.7 mm. The results are shown in FIG. 7. Example 5 0242 OxycontinR OP40 mg Example 3 0243. OxycontinR OP40 mg was subjected to the disso lution test (controlled release) described above. The results Preparation of a Pharmaceutical Compositions are shown in FIG. 12 as the release of oxycodone (%) versus Containing PEO 2,000,000 for Use According to the time (minutes) in phosphate buffer solution pH 6.8 for intact Disclosure tablets and ground tablets (ground in a Moulinex-1411R cof 0232 A composition (batch No. 1581-065) according to fee grinder). the disclosure was prepared from the following ingredients: 0244. The viscosity of OxycontinR OP 40 mg was mea sured as described above. The viscosity was found to be 46 Pa's at 5 rpm (using Viscosity Test #1). Composition ng 0245 Particle size reduction of Oxycontin R OP 40 mg was measured as described above. The average particle size PEO 2,000,000 188 Poloxamer 188 SO.2 was 0.341+0.301 mm and the five largest particles were 3.0 Hydromorphone HCI 12.55 mm, 2.7 mm; 2.7 mm; 2.6 mm; and 2.4 mm. The results are shown in FIG. 13. 0233 The composition was prepared as described above. Example 6 0234. The composition was subjected to the dissolution test (controlled release) described above. The results are Preparation of Morphine Prolonged Release shown in FIG. 8 as the release of hydromorphone (%) versus Pharmaceutical Composition for Use According to time (minutes) in phosphate buffer solution pH 6.8 for intact the Disclosure tablets and ground tablets (ground in a Moulinex-1411R cof 0246 A 200 mg morphine composition (batch No. fee grinder). 12-0060-067) according to the disclosure was prepared from 0235. The viscosity of the compositions was measured as the following ingredients: described above. The viscosity was found to be 46 Pa's at 5 rpm (using Viscosity Test #1). 0236 Particle size reduction of the composition was mea Composition Mg Sured as described above. The average particle size was PEO 200 OOO 291.6 0.495+0.643 mm and the five largest particles were 10.5 mm: PEO 600 OOO 291.6 3.6 mm; 3.6 mm; 3.5 mm; and 3.5 mm. The results are shown Morphine Sulphate in FIG. 9. US 2014/0220 126 A1 Aug. 7, 2014 19

-continued Composition Mg Composition Mg PEO 200 OOO 291.6 Pentahydrate 1972 PEO 600 OOO 291.6 BHT O.8 Morphine Sulphate Pentahydrate 1972 BHT O.8 0247 The composition was subjected to the no alcohol induced dose dumping test described above. The results are shown in FIG. 14 as release of morphine (%) versus time 0253) The composition was subjected to the dissolution (minutes) in phosphate buffer solution pH 6.8 with/without test (controlled release) described above. The results are 40% V/v ethanol. The release of morphine is shown for intact shown in FIG.15 as the release of active substance (%) versus tablets. time (minutes) in phosphate buffer solution pH 6.8. The release of active substance is shown for intact tablets and Example 7 ground tablets (ground in a Krups F203 coffee grinder). For comparison, MST Continus(R 60 mg and OxycontinR OP40 Crisping Test mg were subjected to the same test. The results are shown in FIG. 15. 0248. A 60 mg morphine composition (batch No. 12-066 067) according to the disclosure was prepared from the fol lowing ingredients: Example 9 Test of Particle Size Reduction of Pharmaceutical Composition Mg Compositions by Use of a Nutmeg Grater PEO 200 OOO 3S4.3 0254. A 200 mg morphine composition (batch No. 2654 PEO 600 OOO 3S4.3 Morphine Sulphate 056) according to the disclosure was prepared from the fol Pentahydrate 60 lowing ingredients: BHT O.8 Composition Mg 0249. The composition was subjected to the crisping test PEO 200 OOO 291.6 described above. For comparison, MST Continus(R 60 mg. PEO 600 OOO 291.6 OxycontinR OP80 mg and Opana(R) ER 40 mg (containing Morphine Sulphate hydroxypropyl methylcellulose (HPMC)) were subjected to Pentahydrate 1972 the same crisping test. BHT O.8 0250. The composition of MST Continus(R) and the com position of MS ContinR are identical. MST Continus(R) is the 0255. The composition was subjected to the dissolution European trademark and MS ContinR) is the American trade test (immediate release) described above. The results are mark. shown in FIG.16 as the release of active substance (%) versus 0251. The results are shown in Table 1 below. time (minutes) in dilute hydrochloric acid. The release of active Substance is shown for grated tablets (Nutmeg grater). TABLE 1. For comparison, MST Continus(R 60 mg. OxycontinR OP80 Morphine MST Oxycontin (R) Opana (R) mg and Opana R. ER 40 mg were subjected to the same test. Crisping composition Continus (R) OP ER The results are shown in FIG. 16. (minutes) 60 mg 60 mg 80 mg 40 mg 0256 Particle size reduction of the composition was mea O Viscosity >2400 75 >2400 >2400 Sured as described above. The average particle size was (mPas) 1.94+2.57 mm and the five largest particles were 21.4 mm: Injectable No Yes No No Assay (%) 1OO 98 99 98 15.1 mm; 12.8 mm; 8.7 mm; and 7.8 mm. The results are 8 Viscosity >2400 93 60 >2400 shown in FIG. 17. (mPas) 0257 For comparison, MST Continus(R 60 mg. Oxycon Injectable No Yes Yes No Assay (%) 99 99 99 98 tin R OP80 mg and Opana R. ER 40 mg were subjected to the 16 Viscosity >2400 O O 30 same test. For MST Continus(R 60 mg. the average particle (mPas) size was 0.410+0.250 mm and the five largest particles were Injectable No Yes Yes Yes 4.9 mm; 4.7 mm; 4.1 mm; 3.7 mm; and 3.5 mm. For Oxycon Assay (%) 97 96 73 99 tin R OP 80 mg, the average particle size was 0.596+0.337 mm and the five largest particles were 5.9 mm; 5.0 mm; 4.3 mm, 3.4 mm; and 3.1 mm. For Opana(R) ER 40 mg. the Example 8 average particle size was 0.513+0.489 mm and the five largest particles were 9.4 mm; 8.7 mm; 7.8 mm; 6.8 mm; and 6.4 mm. Test of Particle Size Reduction of Pharmaceutical The results are shown in FIGS. 18-20. Compositions by Use of a Coffee Grinder 0258. The five largest particles were lumps; some were big 0252. A 200 mg morphine composition (batch No. 2654 lumps and also big and flakey. 056) according to the disclosure was prepared from the fol 0259 The dimensions of the tablets are shown in Table 2 lowing ingredients: below. US 2014/0220 126 A1 Aug. 7, 2014 20

TABLE 2 TABLE 3-continued

Depth, mm Free Length, Height, Width, (convex solvent Assay Viscosity Tablet ill l l tablet) Formulation (ml) (%) (mPas) Injectable Note Morphine composition 19.5 6.2 7.4 NA Opana (R) ER 40 mg 200 mg MST Continus (R) 60 mg 7.25 4.5 7.25 NA Water S.O SO.1 73 Yes Swollen transparent Oxycontin (R) OP80 mg 9.5 4.25 9.5 NA tablets Opona (R) ER 40 mg 8.6 3.5 8.6 O.S Coca-Cola (R) 4.6 45.8 105 Yes Swollen transparent tablets

Example 10 1-21. (canceled) 22. An abuse-deterrent tablet formulated for oral adminis Extraction Test tration of an opioid, the tablet comprising: a tablet composition free of an outer shell, the tablet com 0260 A 60 mg morphine composition (batch No. 12-066 position comprising: 067) according to the disclosure was prepared from the fol about 1-50% w/w of the opioid; and lowing ingredients: about 10-98% w/w of a polyethylene oxide (PEO) hav ing an average molecular weight of less than about 1,000,000 daltons; and Composition Mg optionally, a cosmetic coat covering at least a portion of the PEO 200 OOO 3S4.3 tablet composition, the cosmetic coat being formulated PEO 600 OOO 3S4.3 to dissolve within 30 minutes after contact with an aque Morphine Sulphate Pentahydrate 60 ous media, BHT O.8 wherein the tablet composition does not provide immedi ate release of the opioid even after the abuse-deterrent tablet is subjected to physical tampering selected from 0261 The composition was subjected to the extraction test crushing, grinding, grating, cutting, or crisping. described above. Two (2) tablets were placed in a 50 ml 23. The abuse deterrent tablet of claim 22, wherein the beaker, 10 ml solvent (purified water or Coca-Cola(R) was opioid is selected from the group consisting of buprenor added, and the beaker was sealed with ParafilmR). The beaker phine, codeine, dextromoramide, dihydrocodeine, fentanyl. with tablets was left undisturbed at 25° C./60% RH for 24 hydrocodone, hydromorphone, morphine, pentazocine, oxy hours. The free solvent was poured into a tared empty beaker, codeine, oxycodone, oxymorphone, norhydrocodone, the viscosity of the free solvent was measured by the viscosity noroxycodone, morphine-6-glucuronode, tramadol, tapenta test as described above (Viscosity Test #2), and the active dol, dihydromorphine, and pharmaceutically acceptable salts drug Substance content in the free solvent (assay) was deter or solvates thereof. mined using HPLC with UV-detector. 24. The abuse deterrent tablet of claim 22, wherein the 0262 By comparison, MST Continus(R 60 mg. Oxycon opioid comprises morphine and pharmaceutically acceptable tin ROP80 mg, and Opana RER 40 mg were subjected to the salts or solvates thereof. same extraction test. 25. The abuse deterrent tablet of claim 23, wherein the 0263. The results of are shown in table 3 below. concentration of PEO within the tablet composition is above 40% w/w. TABLE 3 26. The abuse deterrent tablet of claim 25, wherein the concentration of PEO within the tablet composition is within Free a range selected from 50% w/w to 98% w/w, 60% w/w to 98% solvent Assay Viscosity Formulation (ml) (%) (mPas) Injectable Note w/w, and 70% w/w to 98% w/w. 27. The abuse deterrent tablet of claim 26, wherein the Morphine composition 60 mg average molecular weight of the PEO included in the tablet Water 5.8 30.8 >2400 No Tablet shape composition ranges from about 400,000 daltons to about disappeared 900,000 daltons. Coca-Cola (R) 3.2 24.4 >2400 No Partly dissolved 28. The abuse deterrent tablet of claim 27, wherein the the rest having a tablet composition is formulated to exhibit a release rate of white core opioid in ethanol that is equal to or lower than the release rate MST Continus (R) 60 mg of opioid in water. Water 9.3 87.9 O Yes Intact Spongy 29. The abuse deterrent tablet of claim 27, wherein the looking Coca-Cola (R) 8.8 92.9 O Yes Intact Spongy tablet composition is formulated to exhibit a viscosity looking selected from a viscosity of at least 170 mPas, as measured Oxycontin (R) OP80 mg by Viscosity Test #2, and a viscosity of at least 46 Pas, as measured by Viscosity Test #1. Water 5.5 36.5 160 Yes Swollen transparent tablets 30. The abuse deterrent tablet of claim 27 formulated to Coca-Cola (R) 5.5 48.4 68 Yes Swollen transparent provide a tablet that yields a non-Smortable composition when tablets Subjected to physical tampering selected from crushing, ham mering, grinding, grating, and cutting. US 2014/022012.6 A1 Aug. 7, 2014

31. An abuse-deterrent tablet formulated for oral adminis about 1-40% w/w of the opioid; tration of an opioid, the tablet comprising: about 60-98% w/w of a polyethylene oxide (PEO) a tablet composition free of an outer shell, the tablet com selected from a single PEO having an average position comprising: molecular weight of less than about 1,000,000 daltons about 1-50% w/w of the opioid; and and a PEO blend comprising two or more PEOs, about 10-98% w/w of a polyethylene oxide (PEO) blend wherein each of the two or more PEOs exhibit a comprising two or more PEOs, wherein each of the different average molecular weight and the average two or more PEOs exhibit a different average molecu molecular weight of the blend of the two or more lar weight and the average molecular weight of the PEOs included in the tablet composition is less than blend of the two or more PEOs included in the tablet about 1,000,000 daltons; and composition is less than about 1,000,000 daltons; and at least 1% w/w of a plasticizer; and optionally, a cosmetic coat covering at least a portion of the optionally, a cosmetic coat covering at least a portion of the tablet composition, the cosmetic coat being formulated tablet composition, the cosmetic coat being formulated to dissolve within 30 minutes after contact with an aque to dissolve within 30 minutes after contact with an aque ous media, ous media, wherein the tablet composition does not provide immedi wherein the tablet composition does not provide immedi ate release of the opioid even after the abuse-deterrent ate release of the opioid even after the abuse-deterrent tablet is subjected to physical tampering selected from tablet is subjected to physical tampering selected from crushing, grinding, grating, cutting, or crisping. crushing, grinding, grating, cutting, or crisping. 32. The abuse deterrent tablet of claim 31, wherein the 42. The abuse deterrent tablet of claim 41, wherein the opioid is selected from the group consisting of buprenor opioid is selected from the group consisting of buprenor phine, codeine, dextromoramide, dihydrocodeine, fentanyl. phine, codeine, dextromoramide, dihydrocodeine, fentanyl. hydrocodone, hydromorphone, morphine, pentazocine, oxy hydrocodone, hydromorphone, morphine, pentazocine, oxy codeine, oxycodone, oxymorphone, norhydrocodone, codeine, oxycodone, oxymorphone, norhydrocodone. noroxycodone, morphine-6-glucuronode, tramadol, tapenta noroxycodone, morphine-6-glucuronode, tramadol, tapenta dol, dihydromorphine, and pharmaceutically acceptable salts dol, dihydromorphine, and pharmaceutically acceptable salts or solvates thereof. or solvates thereof. 33. The abuse deterrent tablet of claim 31, wherein the 43. The abuse deterrent tablet of claim 41, wherein the opioid comprises morphine and pharmaceutically acceptable opioid comprises morphine and pharmaceutically acceptable salts or solvates thereof. salts or solvates thereof. 34. The abuse deterrent tablet of claim 32, wherein the 44. The abuse deterrent tablet of claim 42, wherein the concentration of the PEO blend within the tablet composition concentration of the PEO or PEO blend included in the tablet is above 40% w/w. composition is within a range selected from 70% w/w to 98% 35. The abuse deterrent tablet of claim 34, wherein the wfw. concentration of the PEO blend within the tablet composition 45. The abuse deterrent tablet of claim 44, wherein the is within a range selected from 50% w/w to 98% w/w, 60% average molecular weight of the PEO or PEO blend included w/w to 98% w/w, and 70% w/w to 98% w/w. in the tablet composition ranges from about 400,000 daltons 36. The abuse deterrent tablet of claim 35, wherein the to about 900,000 daltons. average molecular weight of the PEO blend included in the 46. The abuse deterrent tablet of claim 45, wherein the tablet composition ranges from about 400,000 daltons to tablet composition is formulated to exhibit a release rate of about 900,000 daltons. opioid in ethanol that is equal to or lower than the release rate 37. The abuse deterrent tablet of claim 36, wherein the PEO of opioid in water. blend includes a first PEO having an average molecular 47. The abuse deterrent tablet of claim 45, wherein the weight of about 200,000 daltons combined with a second tablet composition is formulated to exhibit a viscosity PEO having an average molecular weight of about 600,000 selected from a viscosity of at least 170 mPa's, as measured daltons and the average molecular weight of the PEO blend by Viscosity Test #2, and a viscosity of at least 46 Pas, as included in the tablet composition is about 400,000 daltons. measured by Viscosity Test #1. 38. The abuse deterrent tablet of claim 36, wherein the 48. The abuse deterrent tablet of claim 45, wherein the tablet composition is formulated to exhibit a release rate of plasticizer is selected from the group consisting of poloxamer opioid in ethanol that is equal to or lower than the release rate having an average molecular weight in the range of about of opioid in water. 3,000 to about 30,000 daltons. 39. The abuse deterrent tablet of claim 36, wherein the 49. The abuse deterrent tablet of claim 45 formulated to tablet composition is formulated to exhibit a viscosity provide a tablet that yields a non-smortable composition when selected from a viscosity of at least 170 mPa's, as measured Subjected to physical tampering selected from crushing, ham by Viscosity Test #2, and a viscosity of at least 46 Pas, as mering, grinding, grating, and cutting. measured by Viscosity Test #1. 50. A method for treating an individual suffering from 40. The abuse deterrent tablet of claim 36 formulated to moderate to severe pain, the method comprising administer provide a tablet that yields a non-snortable composition when ing to the individual an abuse-deterrant tablet comprising: Subjected to physical tampering selected from crushing, ham a tablet composition free of an outer shell, the tablet com mering, grinding, grating, and cutting. position comprising: 41. An abuse-deterrent tablet formulated for oral adminis about 1-40% w/w of the opioid; tration of an opioid, the tablet comprising: about 60-98% w/w of a polyethylene oxide (PEO) a tablet composition free of an outer shell, the tablet com selected from a single PEO having an average position comprising: molecular weight of less than about 1,000,000 daltons US 2014/0220 126 A1 Aug. 7, 2014 22

and a PEO blend comprising two or more PEOs, wherein each of the two or more PEOs exhibit a different average molecular weight and the average molecular weight of the blend of the two or more PEOs included in the tablet composition is less than about 1,000,000 daltons; and optionally, a cosmetic coat covering at least a portion of the tablet composition, the cosmetic coat being for mulated to dissolve within 30 minutes after contact with an aqueous media, wherein the tablet composition does not provide immedi ate release of the opioid even after the abuse-deterrent tablet is Subjected to physical tampering selected from crushing, grinding, grating, cutting, or crisping. 51. The method of claim 50, wherein administering the abuse-resistant tablet comprises administering an abuse-re sistant tablet that further comprises a plasticizer, wherein the plasticizer is included at a concentration of at least 1% w/w. k k k k k