CA2877183A1 - Abuse deterrent pharmaceutical compositions for controlled release - Google Patents

Abstract

The present invention relates to pharmaceutical compositions that are abuse resistant and may also provide controlled release. The present invention also relates to the use of said pharmaceutical compositions in the treatment of pain.

Description

Abuse Deterrent Pharmaceutical Compositions for Controlled Release All patent and non-patent references cited in the application are hereby incorporated by reference in their entirety.
Field of invention The present invention relates to pharmaceutical compositions. In particular embodiments, pharmaceutical compositions are abuse deterrent and provide controlled release.
Background of invention Increased attention has been drawn to the abuse of prescription pharmaceutical compositions. The abuse, or non-medicinal use, of prescription pharmaceutical compositions has been reported to be an increasing problem. In North America abuse of prescription pharmaceutical compositions has become an important issue for the U.S. Food and Drug Administration (FDA) and the pharmaceutical industry is striving to develop abuse deterrent pharmaceutical compositions in order to reduce the potential for misuse of prescription pharmaceutical compositions. Prescription pharmaceutical compositions that are typically misused fall, primarily into three groups: 1) Opioids prescribed for pain; 2) Central nervous System (CNS) depressants prescribed for anxiety or sleep problems; and 3) Stimulants, prescribed, for example, for attention deficit hyperactivity, narcolepsy or obesity.
Methods for abusing prescription pharmaceutical compositions are varied and include, for example, extraction, melting, volatilization, physical tampering (e.g.
grinding, grating, crushing, ect.) or direct administration. For purposes of abuse, methods of administering active drug substances obtained from prescription pharmaceutical compositions or of the pharmaceutical compositions themselves are similarly diverse and include, for example, injection, smoking, snorting, swallowing, sublingual or buccal administration, chewing, and administration as suppository. Alcohol-induced dose dumping of active drug substance from prescription pharmaceutical compositions also presents potential abuse and safety problems.
One way to decrease abuse is to develop controlled released abuse deterrent pharmaceutical composition with a route of administration preventing the feeling of

2 PCT/EP2013/063851 euphoria combined with difficulties of abusing the active drug substance from the composition by for example injection, smoking, snorting, swallowing, sublingual or buccal administration, chewing, and administration as suppository.
Such pharmaceutical composition can be difficult to develop. However, hot melt-processing technology and use of thermoplastic and thermosetting plastic polymers are able to give pharmaceutical compositions with low porosity, high viscosity and breaking strengths, like properties such as for example plastic which is difficult to tear down.
Although, the pharmaceutical composition cannot totally eliminate abuse, but the present invention shows evidence of its resistance to common tampering practices that translate to an incremental improvement towards reducing nonmedical use of prescription pharmaceutical compositions.
Extend of abuse deterrent can best be understood when studied relative to a comparator. Comparison to a comparator assesses the incremental and meaningful improvement in the ability to deter abuse or misuse.
The present invention provides a novel abuse deterrent pharmaceutical composition, which shows excellent resistant towards physical tampering.
WO 2010/088911 describes a pharmaceutical composition that is resistant to abuse including a shell that covers a matrix composition, said shell having an opening from which the active drug substance is released after administration to a subject.
The shell is formulated to exhibit hardness that is resistant to physical tampering.
WO 2008/086804 describes an abuse resistant poiyglycol-based pharmaceutical composition. The composition contains one or more polyglycols and one or more active drug substances and it is resistant to crushing, melting and/or extraction.
Moreover, such compositions have the same or lower solubility in ethanolic-aqueous medium, i.e. they are not subject to ethanol-induced dose dumping effect. The abuse resistant effect is obtained by a combination of the shell that covers a matrix composition and the matrix composition, said shell having an opening from which the active drug substance is released after administration to a subject. The shell and matrix composition are formulated to exhibit resistant to physical / chemical tampering.

3 PCT/EP2013/063851 WO 2008/023261 describes a tamper resistant oral pharmaceutical dosage form obtained by preparing the dosage form by direct tablet compression and then cured the shaped dosage form to the softening temperature of polyethylene oxide. The composition contains polyethylene oxide of at least 1 000 000 daltons.
WO 2005/016313 describes a dosage form that is thermoshaped without being extruded and that is safeguarded from abuse. The dosage form comprises at least one synthetic or natural polymer having a breaking strength of at least 500 N in addition to one or more active substances that could be subject to abuse and optionally physiologically acceptable adjuvants such as for example hydroxypropyl methylcellulose. The document only discloses one specific composition, which comprises Tramadol hydrochloride, polyethylene oxide, hydroxypropyl methylcellulose, polyethyleneglycol and butylhydroxytoluol.
WO 2010/032128 describes a solid oral extended release pharmaceutical dosage form comprising poly (c-caprolactone) and an active agent. In certain embodiments the pharmaceutical dosage form further comprises polyethylene oxide. In certain embodiments the dosage form is a solid tamper resistant oral extended release dosage form, which is resistant to milling, grinding and alcohol extraction.
US 2009/202634 describes a pharmaceutical dosage form comprising at least one pharmaceutically active ingredient. In some embodiments the dosage form comprises one or more hydrophilic polymers such as hydroxypropyl methylcellulose and polyalkylene oxide, which in some embodiments could be polyethylene oxide. In some embodiments, the dosage form is preferably tamper-resistant.
Summary of invention There is thus a need for developing novel pharmaceutical compositions, which show resistant towards physical tampering.
The abuse deterrent pharmaceutical compositions disclosed in WO 201 0/08891 1 and

4 include an outer shell and a matrix composition. The shell included in the pharmaceutical composition is formulated to exhibit a hardness that resists physical tampering. The shell might provide a FDA (US Food and Drug Administration) demand for long-term safety studies. To avoid long-term safety studies and faster time to market of an abuse deterrent pharmaceutical composition without an outer shell is developed.
The present invention provides a novel abuse deterrent pharmaceutical composition, which shows excellent resistant towards physical tampering. It was surprisingly found that the pharmaceutical composition without containing an outer shell exhibits hardness that is resistant to physical tampering.
The pharmaceutical composition is formulated in such a way that the matrix composition maintains a desired release profile of the active drug substance even if the pharmaceutical composition is subjected to physical tampering.
Thus, one aspect of the present invention is to provide an abuse deterrent pharmaceutical composition consisting of a matrix composition comprising a homogenous mixture of:
(a) an active drug substance, (b) a polyethylene oxide, and (c) optionally a plasticizer, wherein the pharmaceutical composition does not provide immediate release after physical tampering; and with the proviso that when at least one polyethylene oxide has a molecular weight of at least 1 000 000 daltons then the matrix composition comprises at least 5 c/ow/w plasticizer, and with the proviso that the composition does not comprise hydroxypropyl methylcellulose and with the proviso that the composition does not comprise poly(E-caprolactone).
Description of drawings Figure 1 shows a drawing of a Moulinex-1411R coffee grinder chamber with stainless steel blades Figure 2 shows a drawing of a Krups F203 coffee grinder chamber with stainless steel blades Figure 3 shows a drawing of nutmeg grater surface with stainless steel star blade Figure 4 shows in vitro dissolution results of the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of morphine is shown for

5 intact tablets and ground tablets of PEO 400 000 daltons containing pharmaceutical composition Figure 5 shows particle size reduction results of ground PEO 400 000 daltons containing pharmaceutical composition Figure 6 shows in vitro dissolution results of the release of oxycodone CVO
versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40 %v/v ethanol. The release of oxycodone is shown for intact tablets and ground tablets of PEO 600 daltons containing pharmaceutical composition Figure 7 shows particle size reduction results of ground PEO 600 000 daltons containing pharmaceutical composition Figure 8 shows in vitro dissolution results of the release of hydromorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of hydromorphone is shown for intact tablets and ground tablets of PEO 2 000 000 daltons containing pharmaceutical composition Figure 9 shows particle size reduction results of ground PEO 2 000 000 daltons containing pharmaceutical composition Figure 10 shows in vitro dissolution results of the release of oxymorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of oxymorphone is shown for intact tablets and ground tablets of PEO 10 000 000 daltons containing pharmaceutical composition Figure 11 shows particle size reduction results of ground PEO 10 000 000 daltons containing pharmaceutical composition

6 PCT/EP2013/063851 Figure 12 shows in vitro dissolution results of the release of oxycodone (1)/0) versus time (minutes) in phosphate buffer solution pH 6.8. The release of oxycodone is shown for intact tablets and ground tablets of Oxycontin OP 40 mg Figure 13 shows particle size reduction results of ground Oxycontin OP 40 mg tablet Figure 14 shows in vitro dissolution results of the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40 %v/v ethanol. The release of morphine is shown for intact tablets Figure 15 shows in vitro dissolution results of release of active substance (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of active substance is shown for intact tablets and ground tablets (ground in a Krups F203 coffee grinder) of morphine composition 200 mg, MST Continus 60 mg and Oxycontin OP 40 mg tablets Figure 16 shows in vitro dissolution results of release of active substance ( /0) versus time (minutes) in dilute hydrochloric acid. The release of active substance is shown for grated tablets (Nutmeg grater) of morphine composition 200 mg, MST Continus mg, Opana ER 40 mg and Oxycontin OP 80 mg tablets Figure 17 shows particle size reduction results of grated morphine composition 200 mg tablet Figure 18 shows particle size reduction results of grated MST Continus 60 mg tablet Figure 19 shows particle size reduction results of grated Opana ER 40 mg tablet Figure 20 shows particle size reduction results of grated Oxycontin OP 80 mg tablet Detailed description of the invention The present disclosure provides novel abuse deterrent pharmaceutical compositions, which are resistant to abuse and tampering. In certain embodiments, the pharmaceutical compositions disclosed herein, even without containing an outer shell, exhibit hardness that is resistant to physical tampering.

PCT/EP2013/(163851

7 One embodiment of the present disclosure provides an abuse deterrent pharmaceutical composition consisting of a matrix composition comprising a mixture of: (a) an active drug substance, (b) a polyethylene oxide, and (c) optionally a plasticizer, wherein the pharmaceutical composition does not provide immediate release of the active drug substance after physical tampering; and with the proviso that when at least one polyethylene oxide has a molecular weight of at least 1 000 000 daltons then the composition comprises at least 5 % w/w plasticizer, and with the proviso that the composition does not comprise hydroxypropyl methylcellulose and with the proviso that the composition does not comprise poly(;-caprolactone).
In addition, certain embodiments of the present disclosure relate to the use of the disclosed pharmaceutical compositions in the treatment of a clinical condition (such as pain) in an individual in need thereof.
Definitions For purposes of the present disclosure, "dose dumping" refers to an unintended, rapid release of the entire amount or a significant fraction of the active drug substance contained within a prescription pharmaceutical composition over a short or accelerated period of time. For purposes of abuse, alcohol-induced dose dumping may facilitate isolation or concentration of active drug substances from a prescription pharmaceutical composition. Alternatively, dose dumping in the presence of alcohol may increase the ease with which a prescription pharmaceutical composition can be abused simply through the intake of an alcoholic beverage concomitantly with the prescription pharmaceutical composition. Moreover, alcohol-induced dose dumping may present safety issues outside the context of abuse. For example, a patient taking a prescription pharmaceutical composition for medicinal purposes may inadvertently cause delivery of a dose of active drug substance that is too high or absorbed too quickly by self-administering a pharmaceutical composition shortly before, simultaneously with or shortly after, consumption or intake of an alcoholic beverage or another pharmaceutical composition containing alcohol (e.g. an over-the-counter cold or flu medicine).
By the term "physical tampering" as used herein refers to any kind of physical interference or manipulation that may result in particle size reduction of the

8 PCT/EP2013/063851 pharmaceutical composition. Hence, compositions that are resistant to physical tampering are formulated in such a way that the composition cannot readily be size reduced to a form that is suitable for abuse, such as for example injection or snorting, because the tablet cannot easily be ground, grated, dissolved or the like.
Examples of physical tampering includes, but are not limited to, crushing, grinding, grating, cutting, crisping and other methods of particle size reduction.
In the present context, the term "controlled release" denotes pharmaceutical composition that releases the active drug substance. Controlled release refers to extending the release of an active drug substance from the composition for an extended period of time. In the present context the term "controlled release"
is used to designate a release a desired rate during a predetermined release period.
Terms like for example "modified", "delayed", "sustained", "prolonged", "extended"
release are in the present context synonyms to the term "controlled release".
In the present context, the term "immediate release" denotes a pharmaceutical composition that releases the active drug substance (80% release) within at the most 30 minutes, when subjected to dissolution test according to USP 35, NF 30, (711), Apparatus 2.
Polyethylene oxide The matrix composition of the pharmaceutical compositions of the present invention comprises a polyethylene oxide. Polyethylene oxides (PE05) are linear polydisperse nonionic polymers composed of repeating units of ethylene oxide. Their chemical formula is HO[CH2CH2O]nH, where n represents the average number of oxyethylene groups. See the structural presentation of polyethylene oxide below, wherein n is the average number of oxyethylene groups. Depending on preparation method high molecular weight PEO may have one terminal methyl group.
.n H
Polyethylene oxides, that are suitable for use in the matrix composition are those having an average molecular weight of at least 200 000 daltons, such as an average molecular weight of in the range of 200 000 to 10 000 000 daltons, for example in the

9 range of 300 000 to 10 000 000 daltons, such as in the range of 400 000 to 10 daltons. In one embodiment the polyethylene oxides are thoses having an average molecular weight of at the most 1 000 000 daltons, such as an average molecular weight of in the range of 200 000 to 1 000 000 daltons, for example in the range of 300 000 to 1 000 000 daltons, such as in the range of 400 000 to 1 000 000 daltons, In another embodiment the polyethylene oxides are thoses having an average molecular weight of at the most 500 000 daltons, such as an average molecular weight of in the range of 200 000 to 500 000 daltons, for example in the range of 300 000 to daltons, such as in the range of 400 000 to 500 000 daltons. In yet another embodiment the polyethylene oxides are thoses having an average molecular weight of at the most 400 000 daltons, such as in the range of 200 000 to 400 000 daltons, for example in the range of 300 000 to 400 000 daltons. In one embodiment, the matrix composition comprises polyethylene oxides having an average molecular weight of 400 000 daltons.
In certain embodiments, polyethylene oxides suitable for use in the matrix compositions described herein are those having an average molecular weight selected from daltons, 300 000 daltons, 400 000 daltons, 600 000 daltons, 900 000 daltons, 1 000 daltons, 2 000 000 daltons, 4 000 000 daltons, 5 000 000 daltons, 7 000 daltons, 10 000 000 daltons.
In certain embodiments, the total concentration of polyethylene oxide for use in the composition is in the range of 5 to 99.9% w/w, such as from 10 to 99.9% w/w, such as from 10 to 98% w/w, such as from 20 to 98% w/w, such as from 30 to 98% w/w, such as from 40 to 98% w/w, such as from 50 to 98% w/w, such as from 60 to 98% w/w, such as from 70 to 98% w/w calculated as w/w A) of the composition.
In particular embodiments, the level of polyethylene oxide 200 000 daltons to achieve the desired viscosity as described herein may be at least 1020 mg, for polyethylene oxide 300 000 daltons it is at least 544 mg, for polyethylene oxide 400 000 daltons it is at least 435 mg, for polyethylene oxide 600 000 daltons it is at least 324 mg, for polyethylene oxide 900 000 daltons it is at least 243 mg, for polyethylene oxide 1 000 000 daltons it is at least 203 mg for polyethylene oxide 2 000 000 daltons and 000 daltons it is at least 162 mg and for polyethylene oxide 5 000 000 daltons, 7 000 000 daltons and 10 000 000 daltons it is at least 122 mg.

10 PCT/EP2013/063851 The upper level of polyethylene oxide 200 000 to 10 000 000 daltons to achieve the desired viscosity in pharmaceutical composition described herein is approximately 1100 mg.
The matrix compositions as described herein may comprise mixtures of polyethylene oxides with different average molecular weights, for example, in order to obtain polyethylene oxides with a desirable average molecular weight. Thus, in some embodiments, the pharmaceutical comprises different polyethylene oxide materials with different average molecular weights.
In order to obtain polyethylene oxide with a desirable average molecular weight, it is important to note that in such cases it is necessary to use polyethylene oxides, which have an average molecular weight closest to the desired molecular weight to ensure a narrow chain length distribution. For example mixing equal amounts of polyethylene oxide 200 000 and polyethylene oxide 600 000 to obtain polyethylene oxide 400 000.
A matrix composition as described herein may comprise more than one different kind of polyethylene oxide, such as 2, for example 3, such as 4, for example 5, such as more than 5 different polyethylene oxides. In certain such embodiments, the composition comprises 1 to 4 different polyethylene oxides. In one such embodiment, the composition comprises 1 to 3 different polyethylene oxides. In another such embodiment, the composition comprises 2 different polyethylene oxides.
The polyethylene oxide used in the matrix compositions described herein may have a melting point higher than the body temperature of the individual (for example, a human) in which the pharmaceutical composition is to be used. Thus, in particular embodiments, the polyethylene oxides employed in the pharmaceutical compositions described herein may have a melting point of in the range of 38 C to 200 C, such as in the range of 38 C to 150 C, for example in the range of 38 C to 120 C, such as in the range of 38 C to 100 C, for example in the range of 65 C to 100 C.
Plasticizer A matrix composition of the pharmaceutical composition as described herein may also comprise at least one plasticizer.

11 In one such embodiment, the matrix composition comprises poloxamer.
A matrix composition as described herein may comprise more than one different kind of plasticizer, such as 2, for example 3, such as more than 3 different plasticizers. In certain such embodiments, the composition comprises 1 to 3 different plasticizers. In one such embodiment, the composition comprises 2 different plasticizers. In another such embodiment the different kind of plasticizer is different kind of poloxamer.
In one embodiment, the matrix composition comprises one or more plasticizers, preferably one or more plasticizers selected from the group consisting of poloxamers, such as poloxamer 188 and/or poloxamer 407.
In some embodiments, the matrix composition comprises at least one poloxamer.
Poloxamers are copolymers or block copolymers and are a range of non-ionic surfactants of polyethylene glycol (PEG) and polypropylene glycol (PPG).
The poloxamer may be Diol EO/P0 block copolymers, which for example in chemical abstracts are described under the scientific name hydroxy-hydroxypoly (oxyethylene) poly(oxypropylene)-poly(oxyethylene)-block copolymer in combination with the CAS
register number. In specific embodiments, a suitable poloxamer for use in a matrix composition of the invention has a HLB value of at least about 18 such as, for example, at least approximately 20, preferably at least 24. The average molecular weight of a suitable poloxamer is typically at least about 2 000 daltons.
Block copolymers of ethylene oxide and propylene oxide that may be included in the matrix composition described herein have a molecular weight of at least 2 000 daltons, typically in the range of 3 000 to 30 000 daltons, such as in the range of 4 000 to 15 000 daltons.
Exemplary poloxamers that may be used have the formula HO(C2H40)a(C3H60)b(C2H40)al-1, where "a" is an integer from 10 to 150, such as from 30 to 140, for example from 50 to 100, such as from 65 to 90, for example from 70 to 90, and "b" is an integer from 10 to 80, such as from 15 to 80, for example from 20 to 60, such as from 25 to 55.

12 PCT/EP2013/063851 Other plasticizers may be incorporated in the matrix composition of the pharmaceutical compositions as described herein. A suitable plasticizer may be selected from mono-and di-acetylated monoglycerides, diacetylated monoglycerides, acetylated hydrogenated cottonseed glyceride, glyceryl cocoate, polyethylene glycols (for example with a molecular weight below 35 000 daltons) or polyethylene oxides (for example with a molecular weight of about 35 000 to 600 000 daltons), dipropylene glycol salicylate glycerin, fatty acids and esters, phthalate esters, phosphate esters, amides, diocyl phthalate, phthalyl glycolate, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, castor oil, acetyl tributyl citrate, acetyl triethyl citrate, methyl abietate, nitrobenzene, carbon disulfide, beta-naphtyl salicylate, sorbitol, sorbitol glyceryl tricitrate, fatty alcohols, cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol, sucrose octaacetate, alfa-tocopheryl polyethylene glycol succinate (TPGS), tocopheryl derivative, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters, amyl oleate, butyl oleate, butyl stearate, diethylene glycol monolaurate, glycerol tributyrate, Cumar W-1 , Cumar MH-1 , Cumar V-1 , Flexol 8-400, monomeric polyethylene ester, Piccolastic A-5, Piccalastic A-25, Beckolin, Clorafin 40, acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, butoxyethyl stearate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl ricinoleate, butyl phthalyl butyl glycolate, camphor, dibutyl sebacate, dibutyl tartrate, diphenyl oxide, glycerine, HB-40, hydrogenated methyl ester of rosin, methoxyethyl oleate, monoamylphthalate, Nevillac 10, Paracril 26, technical hydroabietyl alcohol, Methylene glycol dipelargonate, solid aliphatic alcohols and mixtures thereof.
In one embodiment, the matrix composition comprises cetostearyl alcohol, castor oil, dibutyl sebacate, polyethylene oxides and/or poloxamer as plasticizer. In another embodiment, the matrix composition comprises polyethylene glycols,cetostearyl

13 PCT/EP2013/063851 alcohol, cetyl alcohol, stearyl alcohol, alfa-tocopheryl polyethylene glycol succinate (TPGS), tocopheryl derivative, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, poloxamers, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, acetyl tributyl citrate and/or acetyl triethyl citrate as plasticizer.
However other plasticizers may also be used to provide desired material properties.
In certain embodiments, the amount of plasticizer in the matrix composition is in the range of from 0 to 60% w/w, for example in the range of 0 to 50% w/w, such as in the range of 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 amount of plasticizer in the matrix composition is at least 1`)/0 w/w, for example at least 5% w/w, such as for example at least 10 % w/w. In some embodiments the amount of plasticizer in the matrix 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 the range of 10 to 20% w/w, for example 15 to 20%
w/w. In other embodiments the amount of plasticizer in the matrix composition is at least 5 A w/w, such as in the range of 5 to 25% w/w, for example 5 to 15%
w/w, such as in the range of 5 to 10% w/w.
In some embodiments the plasticizer is a poloxamer. In certain such embodiments the amount of poloxamer in the matrix 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 the range of 10 to 20%
w/w, for example 15 to 20% w/w. In other embodiments the amount of poloxamer in the matrix composition is at least 5 % w/w, such as in the range of 5 to 25% w/w, for example 5 to 15% w/w, such as in the range of 5 to 10% w/w.
In particular such embodiments, the matrix composition comprises one or more plasticizer(s) and one or more polymer(s).
Active drug substance An active drug substance suitable for use in the pharmaceutical compositions described herein is a therapeutically, prophylactically and/or diagnostically active drug substance (herein also abbreviated "active drug substance").

14 PCMP2013/063851 Examples of specific active drug substances suitable for use in the pharmaceutical compositions provided herein include:
Anti-inflammatory and antirheumatic active drug substances, such as, for example:
butylpyrazolidines, phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone, acetic acid derivatives and related substances, indometacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, oxicams, piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, methotrexate, propionic acid derivatives, ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen, dexketoprofen, fenamates, mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid, coxibs, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitin sulfate, feprazone, dipyrocetyl, acetylsalicylic acid, quinolines, oxycinchophen, gold preparations, sodium aurothiomalate, sodium aurotiosulfate, auranofin, aurothioglucose, aurotioprol, penicillamine and bucillamine;
Analgesics, such as, for example: opioids, natural opium alkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, tapentadol, papaveretum, codeine, phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide, dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives, pentazocine, phenazocine, oripavine derivatives, buprenorphine, morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic acid and derivatives, acetylsalicylic acid, aloxiprin, choline salicylate, sodium salicylate, salicylamide, salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate, diflunisal, potassium salicylate, guacetisal, carbasalate calcium, imidazole salicylate, pyrazolones, phenazone, metamizole sodium, aminophenazone, propyphenazone, nifenazone, anilides, paracetamol, phenacetin, bucetin, propacetamol, other analgesics and antipyretics, such as, for example: rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide;

15 PCT/EP2013/063851 Anaesthetics, such as, for example: ethers, diethyl ether, vinyl ether, halogenated hydrocarbons, halothane, chloroform, methoxyflurane, enflurane, trichloroethylene, isoflurane, desflurane, sevoflurane, barbiturates, methohexital, hexobarbital, thiopental, narcobarbital, opioid anaesthetics, fentanyl, alfentanil, sufentanil, phenoperidine, anileridine, remifentanil, other general anaesthetics, such as, for example:
droperidol, ketamine, propanidid, alfaxalone, etomidate, propofol, hydroxybutyric acid, nitrous oxide, esketamine, xenon, esters of aminobenzoic acid, metabutethamine, procaine, tetracaine, chloroprocaine, benzocaine, amides, bupivacaine, lidocaine, mepivacaine, prilocaine, butanilicaine, cinchocaine, etidocaine, articaine, ropivacaine, levobupivacaine, esters of benzoic acid, cocaine, other local anaesthetics, such as, for example: ethyl chloride, dyclonine, phenol, capsaicin;
Antimigraine active drug substances, such as, for example: ergot alkaloids, dihydroergotamine, ergotamine, methysergide, lisuride, corticosteroid derivatives, flumedroxone, selective serotonin (5HT1) agonists, sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, other antimigraine preparations, pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone;
Antiepileptic active drug substances, such as, for example:barbiturates and derivatives, methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, hydantoin derivatives, ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin, oxazolidine derivatives, paramethadione, trimethadione, ethadione, succinimide derivatives, ethosuximide, phensuximide, mesuximide, benzodiazepine derivatives, clonazepam, carboxamide derivatives, carbamazepine, oxcarbazepine, rufinamide, fatty acid derivatives, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine, other antiepileptics, such as, for example:
sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide;
Anticholinergic active drug substances, such as, for example: tertiary amines, trihexyphenidyl, biperiden, metixene, procyclidine, profenamine, dexetimide, phenglutarimide, mazaticol, bornaprine, tropatepine, ethers chemically close to antihistamines, etanautine, orphenadrine (chloride), ethers of tropine or tropine derivatives, benzatropine, etybenzatropine;

16 Dopaminergic active drug substances, such as, for example: dopa and dopa derivatives, levodopa, melevodopa, etilevodopa, adamantane derivatives, amantadine, dopamine agonists, bromocriptine, pergolide, dihydroergocryptine mesylate, ropinirole, pramipexole, cabergoline, apomorphine, piribedil, rotigotine, monoamine, oxidase B
inhibitors, selegiline, rasagiline, other dopaminergic agents, such as, for example:
tolcapone, entacapone, budipine;
Antipsychotic active drug substances, such as, for example: phenothiazines with aliphatic side-chain, chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine, chlorproethazine, phenothiazines with piperazine structure, dixyrazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, phenothiazines with piperidine structure, periciazine, thioridazine, mesoridazine, pipotiazine, butyrophenone derivatives, haloperidol, trifluperidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, fluanisone, indole derivatives, oxypertine, molindone, sertindole, ziprasidone, thioxanthene derivatives, flupentixol, clopenthixol, chlorprothixene, tiotixene, zuclopenthixol, diphenylbutylpiperidine derivatives, fluspirilene, pimozide, penfluridol, diazepines, oxazepines, thiazepines, loxapine, clozapine, olanzapine, quetiapine, neuroleptics, tetrabenazine, benzamides, sulpiride, sultopride, tiapride, remoxipride, amisulpride, veralipride, levosulpiride, lithium, other antipsychotics, such as, for example prothipendyl, risperidone, clotiapine, mosapramine, zotepine, aripiprazole, paliperidone;
Anxiolytic active drug substances, such as, for example: benzodiazepine derivatives, diazepam, chlordiazepoxide, medazepam, oxazepam, potassium clorazepate, lorazepam, adinazolam, bromazepam, clobazam, ketazolam, prazepam, alprazolam, halazepam, pinazepam, camazepam, nordazepam, fludiazepam, ethyl loflazepate, etizolam, clotiazepam, cloxazolam, tofisopam, diphenylmethane derivatives, hydroxyzine, captodiame, carbamates, meprobamate, emylcamate, mebutamate, dibenzo-bicyclo-octadiene derivatives, benzoctamine, azaspirodecanedione derivatives, buspirone, other anxiolytics, such as, for example:
mephenoxalone, gedocarnil, etifoxine;

17 PCT/EP2013/063851 Hypnotic and sedative active drug substances, such as, for example:
barbiturates, pentobarbital, amobarbital, butobarbital, barbital, aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbital, reposal, methohexital, hexobarbital, thiopental, etallobarbital, allobarbital, proxibarbal, aldehydes and derivatives, chloral hydrate, chloralodol, acetylglycinamide chloral hydrate, dichloralphenazone, paraldehyde, benzodiazepineemepronium derivatives, flurazepam, nitrazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam, loprazolam, doxefazepam, cinolazepam, piperidinedione derivatives, glutethimide, methyprylon, pyrithyldione, benzodiazepine related drugs, zopiclone, zolpidem, zaleplon, ramelteon, other hypnotics and sedatives, such as, for example: methaqualone, clomethiazole, bromisoval, carbromal, scopolamine, propiomazine, triclofos, ethchlorvynol, valerian, hexapropymate, bromides, apronal, valnoctamide, methylpentynol, niaprazine, melatonin, dexmedetomidine, dipiperonylaminoethanol;
Antidepressant active drug substances, such as, for example: non-selective monoamine reuptake inhibitors, desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepin, amitriptyline, nortriptyline, protriptyline, doxepin, iprindole, melitracen, butriptyline, dosulepin, amoxapine, dimetacrine, amineptine, maprotiline, quinupramine, selective serotonin reuptake inhibitors, zimeldine, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, escitalopram, monoamine oxidase inhibitors, isocarboxazid, nialamide, phenelzine, tranylcypromine, iproniazide, iproclozide, monoamine oxidase A
inhibitors, rnoclobemide, toloxatone, other antidepressants, such as, for example:
oxitriptan, tryptophan, mianserin, nomifensine, trazodone, nefazodone, minaprine, bifemelane, viloxazine, oxaflozane, mirtazapine, medifoxamine, tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone, duloxetine, agomelatine, desvenlafaxine, centrally acting sympathomimetics, such as, for example:
amfetamine, dexamfetamine, lisdexamfetamine, metamfetamine, methylphenidate, dexmethylphenidate, pemoline, fencamfamin, modafinil, fenozolone, atomoxetine, fenetylline, xanthine derivatives, caffeine, propentofylline, other psychostimulants and nootropics, such as, for example meclofenoxate, pyritinol, piracetam, deanol, fipexide, citicoline, oxiracetam, pirisudanol, linopirdine, nizofenone, aniracetam, acetylcarnitine, idebenone, prolintane, pipradrol, pramiracetam, adrafinil, vinpocetine;

18 PCT/EP2013/063851 Anti-dementia active drug subtances, such as, for example:
anticholinesterases, tacrine, donepezil, rivastigmine, galantamine, other anti-dementia drugs, memantine, ginkgo biloba;
Other nervous system active drug substances, such as, for example:
parasympathomimetics, anticholinesterases, neostigmine, pyridostigmine, distigmine, ambenonium, choline esters, carbachol, bethanechol, other parasympathomimetics, such as, for example: pilocarpine, choline alfoscerate;
Active drug substances used in addictive disorders, such as, for example:
nicotine, bupropion, varenicline, disulfiram, calcium carbimide, acamprosate, naltrexoneõ
buprenorphine, methadone, levacetylmethadol, lofexidine, betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides and ganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyric acid, amifampridine;
Opium alkaloids and derivatives, such as, for example: ethylmorphine, hydrocodone, codeine, opium alkaloids with morphine, normethadone, noscapine, pholcodine, dextromethorphan, thebacon, dimemorfan, acetyldihydrocodeine, benzonatate, benproperine, clobutinol, isoaminile, pentoxyverine, oxolamine, oxeladin, clofedanol, pipazetate, bibenzonium bromide, butamirate, fedrilate, zipeprol, dibunate, droxypropine, prenoxdiazine, dropropizine, cloperastine, meprotixol, piperidione, tipepidine, morclofone, nepinalone, levodropropizine, dimethoxanate.
In certain embodiments, the active drug substance may, for example, be an active drug substance with abuse potential that presents a safety risk. Such active drug substance may, for example, be selected from:
1-(1-phenylcyclohexyl)pyrrolidine, 1-(2-phenylethyl)-4-pheny1-4-acetoxypiperidine, 1-[1-(2-thieny1)- cyclohexylpiperidine, 1-[1-(2-thienyl)cyclohexyl]pyrrolidine, 1-methy1-4-phenyl-4-propionoxy-piperidine, 1-phenylcyclohexylamine, 1-piperidinocyclohexanecarbonitrile, 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxyamphetamine, 2C-B-(4-bromo-2,5-dimethoxypenethylamine), 2C-D (2,5-dimethoxy-4-methylphenethylamine), 2C-I (4-iodo-2,5-dimethoxy-phenethylamine), T-2 (2,5-dimethoxy-4-ethylthiophenethylamine), 2C-T-4 (2,5-dimethoxy-4-isopropyl thiophenethylamine), 2C-T-7 (2,5-dimethoxy-4-(n)-propylthiopenethylamine), 3,4-

19 PCT/EP2013/063851 methylene-dioxymethamphetamine, 3,4,5-trimethoxyamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-N-ethylamphetamine, 3-methylfentanyl, 3-methylthiofentanyl, 4-brorno-2,5-dimethoxyamphetamine, 4-bromo-2,5-dimethoxyphenethylamine, 4-methoxyamphetamine, 4-methyl-2,5-dimethoxyamphetamine, 4-methylaminorex (cis isomer), 5-Me0-DIPT (5-methoxy-N,N-diisopropyltryptamine), 5-Me0-DMT (5-methoxy-N,N-dimethyltryptamine), 5-methoxy-3,4-methylenedioxyamphetamine, acetorphin, acetorphine, acetyl-alpha-methylfentanyl, acetyl-alpha-methylfentanyl, acetyldihydrocodeine, acetylmethadol, acetylmethadol, alfentanil, allobarbital, allylprodin, allylprodine, alphacetylmethadol except levo-alphacetylmethadol, alpha-ethyltryptamine, aphameprodine, alphamethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprodine, alprazolam, amfepramon, amfetaminil, amineptin, aminorex, amobarbital, amphetamine, dextroamphetamine, amylnitrit (all isomers of the amyl group), anabolic steroids, anileridine, aprobarbital, barbital, barbituric acid derivative, BDB (3,4- methylenedioxyphenyI)-2-butanamine), benzethidin, benzethidine, benzoylecgonine, benzphetamine, benzphetamine, benzylmethylketon, benzylmorphine, betacetylmethadol, beta-hydroxy-3-methylfentanyl, beta-hydroxyfentanyl, betameprodine, betameprodine, betamethadol, betaprodine, bezitramide, bezitramide, boldenone, brolamfetamin, bromazepam, brotizolam, bufotenine, buprenorphine, butabarbital, butalbital, butobarbital, butorphanol, BZP (A
2)(1- benzylpiperazin), camazepam, cannabis, carfentanil, catha edulis, cathine, cathinone, chloral betaine, chloral hydrate, chlordiazepoxide, chlorhexadol, chlorotestosterone (same as clostebol), chlorphentermine, clobazam, clonazepam, clonitazene, clonitazene, clorazepate, clortermine, clostebol, clotiazepam, cloxazolam, coca leaves, cocaine, codeine, codeine & isoquinoline alkaloid, codeine methylbromide, codeine-N-oxide, codoxim, cyclobarbital (hexemal NFN), cyprenorphine, dehydrochlormethyltestosterone, delorazepam, desomorphine, dexamfetamine, dexfenfluramine, dexmethylphenidate, dextromoramide, dextropropoxyphene, diacetylmorphine, diampromide, diazepam, dichloralphenazone, diethylpropion, diethylthiambutene, diethyltryptamine, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, dihydrotestosterone, dimenoxadol, dimepheptanol, dimethylthiambutene, dimethyltryptamine, dioxaphetyl butyrate, diphenoxylate, dipipanone, diprenorphine, dronabinol, drostanolone, drotebanol, ecgonine, estazolam, ethchlorvynol, ethinamate, ethyl loflazepate, ethylestrenol, ethylmethylthiambutene, ethylmorphine, ethylmorphine, eticyclidin, etilamfetamine, etonitazene, etorphine,

20 PCT/EP2013/063851 etoxeridine, etryptamine, fencamfamin, fenethylline, fenetylline, fenfluramine, fenproporex, fentanyl, fludiazepam, flunitrazepam, fluoxymesterone, flurazepam, formebolone, fungi and spores of the sepcies psilocype semilanceata, furethidine, gammahydroxybutanic acid, glutethimide, halazepam, haloxazolam, heroine, hydrocodone, hydrocodone & isoquinoline alkaloid, hydromorphinol, hydromorphone, hydroxypethidine, ibogaine, isobutylnitrit, isomethadone, ketamine, ketazolam, ketobemidone, levamfetamine, levo- alphacetylmethadol, levo-methamphetamine, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, lisdexamfetamin, loprazolam, lorazepam, lormetazepam, lysergic acid, lysergic acid amide, lysergic acid diethylamide, marijuana, mazindol, MBDN (N-methy1-1-(3,4-methylenedioxypheny1)-butanamine), mCPP (1-(3- chlorphenyl)piperazine), mebutamate, mecloqualone, medazepam, mefenorex, MeOPP (1-(4-methoxyphenyl)piperazine), meperidine, meperidine intermediate, meprobamate, mescaline, mesocarb, mesterolone, metamfetamine, metazocine, methadone, methadone intermediate, methamphetamine, methandienone, methandranone, methandriol, methandrostenolone, methaqualone, methcathinone, methenolone, methohexital, methyldesorphine, methyldihydromorphine, methylphenidate, methylphenobarbital (mephobarbital), methyltestosterone, methyprylone, metopone, mibolerone, midazolam, modafinil, moramide-intermediate, morpheridine, morphine, morphine methylbromide, morphine methylsulfonate, morphine-N-oxide, myrophine, N,N-dimethylamphetamine, nabilone, nalorphine, nandrolone, N-ethyl-1-phenylcyclohexylamine, N-ethyl-3-piperidyl benzilate, N- ethylamphetamine, N-hydroxy-3,4-methylenedioxyamphetamine, nicocodeine, nicocodine, nicodicodine, nicomorphine, nimetazepam, nitrazepam, N-methy1-3- piperidyl benzilate, noracymethadol, norcodeine, nordiazepam, norethandrolone, norlevorphanol, normethadone, normorphine, norpipanone, norpipanone, opium, oxandrolone, oxazepam, oxazolam, oxycodone, oxymesterone, oxymetholone, oxymorphone, para-fluorofentanyl, parahexyl, paraldehyde, pemoline, pentazocine, pentobarbital, petrichloral, peyote, phenadoxone, phenampromide, phenazocine, phencyclidine, phendimetrazine, phenmetrazine, phenobarbital, phenomorphan, phenoperidine, phentermine, phenylacetone, pholcodine, piminodine, pinazepam, pipradrole, piritramide, PMMA (paramethyxymethyl amphetamine), prazepam, proheptazine, properidine, propiram, psilocybine, psilocyn, pyrovalerone, quazepam, pacemethorphane, racemoramide, racemorphane, remifentanil, salvia divinorum, salvinorin A, secobarbital, secobarbital, sibutramine, SPA, stanolone, stanozolol, sufentanil, sulfondiethylmethane, sulfonethylmethane, sulfonmethane,

21 PCT/EP2013/063851 talbutal, temazepam, tenamfetamin, testolactone, testosterone, tetrahydrocannabinols, tetrazepam, TFMPP (1-(3-triflourmethylphenyl)piperazine), thebacon, thebaine, thiamylal, thiofentanyl, thiopental, tiletamine & zolazepam in combination, tilidine, trenbolone, triazolam, trimeperidine, vinbarbital, zaleplon, zipeprol, zolpidem and zopiclon.
Other suitable examples of active drug substances suitable for use in the pharmaceutical compositions described herein include, for example, alfentanil, allylprodine, alphaprodine, aniloridine, benzylmorphine, bezitramide, buprenorphine, butophanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diapromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobennidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, morphine 6- glucuronide, morphine 3-glucuronide, myrophine, nalbuphine, narccine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxycodeine, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, thebaine, levo- alphacetylmethadol (LAAM), remifentanil, carfentanyl, ohmefentanyl, MPPP, prodine, PEPAP, levomethorphan, etorphine, lefetamine, loperamide, diphenoxylate or pethidine.
Even further examples of active drug substances suitable for use in the pharmaceutical compositions described herein include anabolic steroids, cannabis, cocaine and diazepam.
In one embodiment, the active drug substance is selected from the group consisting of the therapeutic classes including non-steroidal anti-inflammatory substances and antirheumatic active drug substances.
In other embodiments, the active drug substance is selected from therapeutic classes including analgesics, opioids, antipyretics, anaesthetics, antimigraine agents,

22 PCT/EP2013/063851 antiepileptics, anti-parkinson agents, dopaminergic agents, antipsychotics, anxiolytics, sedatives, antidepressants, psychostimulants agents, dopamine, noradrenaline, nicotinic, alfa-andrenergic, serotonin, H3 antagonists used for ADHD and nootropics agents used in addictive disorders.
In still further embodiments, the active drug substance is selected from therapeutic classes including anaesthetics, centrally-acting analgesics, sedative-hypnotics, anxiolytics, appetite suppressants, decongestants, antitussives, antihistamines, antiemetics, antidiarrheals, and drugs used to treat narcolepsy and attention deficit hyperactivity disorder.
In certain embodiments, the active drug substance is associated with abuse syndromes and the active drug substance may, for example, be selected from opioids, CNS
depressants, CNS stimulants, cannabinoids, nicotine-like compounds, glutamate antagonists and N-methyl-D-aspartate (NMDA) antagonists.
In specific embodiments, the active drug substance is an analgesic. Examples of analgesics suitable for use in the pharmaceutical compositions described herein include, for example, opioids, natural opium alkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, tapentadol, papaveretum, codeine, phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide, dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives, pentazocine, phenazocine, oripavine derivatives, buprenorphine, morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic acid and derivatives, acetylsalicylic acid, aloxiprin, choline salicylate, sodium salicylate, salicylamide, salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate, diflunisal, potassium salicyiate, guacetisai, carbasalate calcium, imidazole salicylate, pyrazolones, phenazone, metamizole sodium, aminophenazone, propyphenazone, nifenazone, anilides, paracetamol, phenacetin, bucetin, propacetamol, other analgesics and antipyretics such as, for example, rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide.
In certain such embodiments, the active drug substance is an opioid. Where an opioid is included as an active drug substance, the opioid may be selected from naturally occurring opioids, synthetic opioids and semisynthetic opioids.

23 PCT/EP2013/063851 In another embodiment, the active drug substance is selected from amfetamine, dexannfetamine, lisdexamfetamine, nnetamfetamine, methylphenidate, dexmethylphenidate and combinations thereof.
In some embodiments the matrix composition of pharmaceutical compositions including an opioid, the opioid is selected from buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol and dihydromorphine.
Where an opioid is used as an active drug substance, the opioid may be present in any of its crystalline, polymorphous, semi-crystalline, amorphous or polyamorphous forms.
Furthermore, an opioid used as an active drug substance may be present in one or more forms selected from its crystalline, polymorphous, semi-crystalline, amorphous or polyamorphous forms.
In specific embodiments the matrix composition of the pharmaceutical compositions including an opioid as an active drug substance, the active drug substance is selected from morphine, oxycodone, hydrocodone, hydromorphone, norhydrocodone, oxymorphone, noroxycodone, morphine-6-glucuronode and pharmaceutically acceptable salts of any of the aforementioned, such as from the group consisting of oxycodone hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride and morphine sulphate pentahydrate.
Pharmaceutical compositions as described herein are suitable for use for both water soluble as well as slightly soluble or insoluble active drug substances.
All of the above mentioned active drug substances may also be in the form of pharmaceutically acceptable salts, uncharged or charged molecules, molecular complexes, solvates or anhydrates thereof, and, if relevant, isomers, enantiomers, racemic mixtures, and mixtures thereof.

24 PCT/EP2013/063851 In particular, the pharmaceutical compositions described herein may comprise pharmaceutically acceptable salts of any of the above mentioned active drug substances.
The term "pharmaceutically acceptable salts" of an active drug substance includes alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and salts with organic or inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc.
The term "pharmaceutically acceptable salts" of an opioid includes alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and salts with organic or inorganic acids such as, for example hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc or tartrate acid. In particular embodiments, pharmaceutically acceptable opioid salts may be selected from the group consisting of sulphate salts, hydrochloride salts and bitartrate salts.
The term "solvates" includes hydrates or solvates wherein other solvates than water are involved such as, for example, organic solvents like chloroform and the like.
Furthermore, the active drug substance may be in any of its crystalline, polymorphous, semi-crystalline, amorphous or polyamorphous forms and mixtures thereof.
The concentration of the active drug substance in the matrix composition of a pharmaceutical composition for use according to the invention depends on the specific active drug substance, the disease to be treated, the condition of the patient, the age and gender of the patient etc. The above-mentioned active drug substances may be known active drug substances and a person skilled in the art will be able to find information as to the dosage of each active drug substance and, accordingly, will know how to determine the amount of each active drug substance in the matrix composition of a pharmaceutical composition.

25 PCT/EP2013/063851 The active drug substance may be a new chemical entity for which the amount of information is limited. In such cases, the dosage has to be evaluated based on available preclinical and/or clinical data.
The active drug substance is typically present in the matrix composition in an amount of from 5- 90 %w/w such as, for example, from about 5 to about 80% w/w, from about 5 to about 70% w/w, from about 5 to about 60% w/w, from about 5 to about 50%
w/w, from about 5 to about 40% w/w, from about 5 to about 30% w/w, from about 5 to about 20% w/w, from about 5 to about 10% w/w.
When the active drug substance is an opioid, such as, for example, morphine, oxycodone, hydrocodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof, then said opioid is typically present in the matrix compositions in a concentration of in the range of 5 to 70% w/w, for example in the range of 5 to 60%
w/w, such as in the range of 5 to 50% w/w, for example in the range of 5 to 45% w/w, such as in the range of 5 to 40% w/w, for example in the range of 5 to 35%
w/w, such as in the range of 5 to 30% w/w, for example in the range of 5 to 25% w/w, such as in the range of 5 to 20% w/w, for example in the range of 5 to 15% w/w, such as in the range of 5 to 10% w/w.
In certain embodiments, the active drug substance is typically present in the matrix composition in an amount of from 1-90 %w/w such as, for example, from about 1 to about 80% w/w, from about 1 to about 70% w/w, from about 1 to about 60% w/w, from about 1 to about 50% w/w, from about 1 to about 40% w/w, from about 1 to about 30%
w/w, from about 1 to about 20% w/w, from about 1 to about 10% w/w.
In certain embodiments, when the active drug substance is an opioid, such as, for example, morphine, oxycodone, hydrocodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof, then said opioid is typically present in the matrix compositions in a concentration of in the range of 1 to 70% w/w, for example in the range of 1 to 60% w/w, such as in the range of 1 to 50% w/w, for example in the range of 1 to 45% w/w, such as in the range of 1 to 40% w/w, for example in the range of 1 to 35% w/w, such as in the range of 1 to 30% w/w, for example in the range of 1 to 25% w/w, such as in the range of 1 to 20% w/w, for example in the range of 1 to 15%
w/w, such as in the range of 1 to 10% w/w.

26 In certain embodiments, the matrix compositions comprise a load of the active drug substance, such as an opioid. A load is generally less than 50% w/w of the active drug substance. For example, in certain such embodiments, the matrix compositions may include an active drug substance in an amount selected from less than 40% w/w and less than 30% w/w.
A pharmaceutical composition as described herein may comprise one active drug substance or more than one different active drug substances. Typically, the amount of the active drug substance corresponds to a daily or part of a daily therapeutic dose.
In certain embodiments, the pharmaceutical composition provides for administration 1-6 times a day, normally 1-4 times daily, such as 1-3 times daily, such as 1-2 times daily or 1 time daily.
In one embodiment, the pharmaceutical composition provides for twice-daily administration. In another embodiment, the pharmaceutical composition provides for once-daily administration.
Pharmaceutically acceptable excipients The matrix composition of the pharmaceutical compositions described herein may also contain other excipients in order to achieve one or more desired properties, such as for example a better stability of the active drug substance or the pharmaceutical composition itself, enhance the abuse deterrent properties, loading of the active drug substance or delivery characteristics, such as release rate or release profile of an active drug substance. Further, the matrix composition of a pharmaceutical composition may include excipients that facilitate manufacture and production of dosage forms such as for example tablets suitable for administration to individuals in need thereof.
A suitable pharmaceutically acceptable excipient for use in the invention may be selected from fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.

27 PCT/EP2013/063851 Suitable excipients include conventional tablet or capsule excipients. These excipients may be, for example, diluents such as dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrin or other polysaccharides, sorbitol, inositol or mixtures thereof; binders such as alginic acid, calcium alginate, sodium alginate, starch, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), carboxymethylcellulose, methylcellulose, veegum, larch arabolactan, polyethylene glycols, ethylcellulose, water, alcohols, waxes, polyvinylpyrrolidone such as PVP K90 or mixtures thereof; lubricants such as talc, silicium dioxide, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, sodium benzoate, sodium chloride, leucine, carbowax 4000, magnesium lauryl sulfate, Sodium laurilsulfate, Stearyl alcohol, Polysorbate 20, Polysorbate 60, Polysorbate 80, Macrogol stearate, Macrogol lauryl ether, Stearoyl macrogolglycerides, Sorbitan stearate, Sorbitan laurate, Macrogol glycerol hydroxystearat, colloidal silicon dioxide and mixtures thereof, disintegrants such as starches, clays, cellulose derivatives including crosscarmellose, gums, aligns, various combinations of hydrogencarbonates with weak acids (e.g., sodium hydrogencarbonate/tartaric acid or citric acid) crosprovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum, glycollate, natural sponge, bentonite, sucralfate, calcium hydroxyl-apatite or mixtures thereof.
In addition to a polymer of a polyethylene oxide, the matrix composition may comprise an additional polymer such as polyglycols selected from substantially water soluble, thermoplastic, crystalline, semi-crystalline or amorphous or a mixture of substantially water soluble, crystalline, semi-crystalline or amorphous polymers. In particular, in certain embodiments, the polyglycol is at least thermoplastic. Suitable polyglycols for use in the matrix composition include, for example, polyethylene glycols (for example with a molecular weight below 35 000 daltons), as well as derivatives of polyethylene glycol, such as mono or dimethoxypolyethylene glycols (mPEGs), polyethylene oxides and/or block copolymers of ethylene oxide and propylene oxide.
In addition to a polymer of a polyethylene oxide, the matrix composition may comprise an additional polymer, such as, for example, at least one polymer selected from:
modified or unmodified water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, rhanogalacturonan, polyxyloglycan, arabinogalactan, and starch, cellulose, chitosan, alginate, fibrin,

28 PCT/EP2013/063851 collagen, gelatin, hyaluronic acid, amylopectin, pectin including low methylated or methoxylated pectins, dextran and fatty acids and alcohols; synthetic polymers such as Carbopol, carbomer, carbomer homopolymer, carboxyvinyl polymer, polyvinylpyrrolidone (PVP), PVA, PVB, Eudragit L methyl ester, Eudragit L, Eudragit RL, Eudragit RS, Eudragit E, Eudragit S, PHPV, PHA, PCL, PLGA and PLA; and hydrogels made from the polymers or combined polymers mentioned above and or from polymers originated from HEMA, HEEMA, MEMA, MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and PEGDMA.
The matrix composition as described herein may comprise one or more gelling agents.
Examples are polymers selected from the group consisting of modified or unmodified water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, polyxyloglycan, arabinogalactan, starch, cellulose, chitosan, alginate, fibrin, collagen, gelatin, amylopectin, pectin including low methylated or methoxylated pectins, dextran;
synthetic polymers such as PVA and PVB; and hydrogels made from the polymers or combined polymers mentioned above and or from polymers originated from: HEMA, HEEMA, MEMA, MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and/or PEGDMA, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate or other cellulose derivates, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carrageenans, guar gum, gellan gum, xanthan gum, tragacanth and arabic gum.
Exemplary stabilizers (chemical) include TPG, for example, in the form of TPGS
(Vitamin E Polyehtylene glycol succinate) and BHT, BHA, t-butyl hydroquinone, butylhydroxy toluene, calcium ascorbate, gallic acid, hydroquinone, maitol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol and derivates thereof, citric acid, tartaric acid, and ascorbic acid. Other stabilisers include trivalent phosphorous, such as, for example, phosphite, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones, hindered phenols, thiosynergists and/or hindered amines, acids (ascorbic acid, erythorbic acid, etidronic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid etc.), phenols, dodecyl gallate, octyl gallate, 1 ,3,5-trihydroxybenzene, organic and inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium

29 PCT/EP2013/063851 bisulphite, potassium metabisulphite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate), pyranon (maltol), and vitamin E (tocopherol, D-[alpha]ocopherol, DL-[alpha]-tocopherol, tocopheryl acetate, d-[alpha]-tocopheryl acetate, dl-[alpha]ocopheryl acetate.
However, other anti- oxidative agents known in the art may also be used. Other suitable stabilizers may be selected from, for example, sorbitol glyceryl tricitrate, sucrose octaacetate.
In one embodiment, a matrix composition as described herein comprises one or more stabilizers selected from above mentioned group of stabilizers. In one such embodiment, the composition comprises butylhydoxytoluene and/or TPGS as a stabilizer. In another such embodiment, the composition comprises gallic acid and/or ascorbic acid as a stabilizer.
A release modifier may be incorporated in a matrix composition as described herein. A
suitable release modifier may be selected from fatty acids and esters, fatty alcohols, cetyl alcohol, stearyl alcohol, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, Castor oil, phosphate esters, amides, phthalate esters, glyceryl cocoate oleyl alcohol, myristyl alcohol, sucrose octaacetate, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, poloxamers, polyvinyl alcohols, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, ethylcellulose, cellulose acetate, cellulose propionate, cellulose nitrate, cellulose derivative selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose, cellulose acetate, polylactic acid or polyglycolic acid and copolymers thereof, methacrylates, a co-polymer of methacrylate-galactomannan etc., polyvinyl alcohols, glycerinated gelatine and cocoa butter.

30 PCT/EP2013/063851 Other suitable release modifiers may be selected from inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, polyethylene glycol derivatives and cellulose and cellulose derivatives.
Alternatively or additionally, a matrix composition according to the present description may include a pharmaceutically acceptable excipient selected from a mono-, di-, oligo, polycarboxylic acid or amino acids such as, for example, acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, sorbic acid etc., aspartic acid or glutamic acid etc.
Suitable organic acids that may be included in the matrix compositions described herein include, for example, acetic acid/ ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid, or pyruvic acid.
Suitable inorganic acids that may be included in the matrix compositions described herein include, for example, pyrophosphoric, glycerophosphoric, phosphoric such as ortho and meta phosphoric, boric acid, hydrochloric acid, or sulfuric acid.
Examples of suitable inorganic compounds that may be included in the matrix compositions described herein include, for example, aluminium, calcium or kalium.
Examples of organic bases that may be included in the matrix compositions described herein include, for example, p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline or hydrazine. Examples of inorganic bases that may be included in the matrix compositions described herein include, for example, aluminium oxide such as, for example, aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide or KOH.

31 Pharmaceutically acceptable salts of an organic acid that may be included in the matrix compositions described herein include, for example, an alkali metal salt or an alkaline earth metal salt such as, for example, sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate etc., potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate etc., calcium phosphate, dicalcium phosphate etc., sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate etc., sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate or calcium tartrate.
Suitable inorganic salts for that may be used in a matrix composition as described herein include, for example, sodium chloride, potassium chloride, calcium chloride or magnesium chloride.
The matrix composition may comprise at least one saccharide. Where a saccharide is included in a composition as described herein, the saccharide may be selected from, for example, glucose, ribose, arabinose, xylose, lyxose, xylol, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, glycerol, idose, galactose, talose, mannitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, sucrose, fructose, lactose, dextrin, dextran, amylase or xylan.
The matrix composition may also comprise cellulose and/or cellulose derivatives selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylcellulose, cellulose acetate, cellulose proprionate, cellulose nitrate, cellulose acetate phthalate, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.
Furthermore, the matrix compositions described herein may comprise one or more agents selected from sweetening agents, flavouring agents and colouring agents in order to provide an elegant and palatable preparation. Examples include maltol, citric acid, water soluble FD&C dyes and mixtures thereof with corresponding lakes and direct compression sugars such as Di-Pac from Amstar. In addition, coloured dye

32 PCT/EP2013/063851 migration inhibitors such as; tragacanth, acacia or attapulgite talc may be added.
Specific examples include calcium carbonate, 1,3,5-trihydroxybenzene, chromium-cobalt- aluminium oxide, ferric ferrocyanide, ferric oxide, Iron ammonium citrate, iron (111) oxide hydrated, iron oxides, carmine red, magnesium carbonate and titanium dioxide.
Preparation The pharmaceutical composition of the invention may be produced by various methods which are either known per se in the pharmaceutical industry or which, for example, are used in the production of polymer-based materials, depending upon the desired embodiment and the materials employed in the pharmaceutical composition in question. The pharmaceutical compositions according to the present description may be produced by methods that are relatively simple and inexpensive.
Suitable preparation methods for pharmaceutical compositions according to the invention include conventional tablet compression, hot melt-processing and other methods of preparing pharmaceutical compositions. Also a combination of one or more of the aforementioned may be employed.
The pharmaceutical compositions described herein are prepared by hot melt-processing. In one such embodiment, the pharmaceutical compositions are prepared by, for example; 1, 2 or multiple component extrusion, molding, 1, 2 or multiple component injection molding. In another such embodiment, the pharmaceutical compositions are prepared by 1, 2 or multiple component injection molding.
In cases where a preparation is needed in order to make the pharmaceutical composition either before/or after the above mentioned preparation steps, the preparation may also comprise separate steps such as for example wet granulation, dry granulation, melt granulation, pelletizing, curing, spray coating, electrostatic coating, dip coating or other forms of preparation methods.
In one embodiment, the pharmaceutical composition is prepared by conventional tablet compression.

33 PCT/EP2013/063851 In another embodiment, the pharmaceutical compositions are prepared by conventional tablet compression and hot melt processing.
Geometry In specific embodiments, the pharmaceutical compositions described herein are formed as cylindrical compositions. In certain such embodiments, the pharmaceutical compositions are formed as a cylindrical shape optionally with one or two tapered end(s).
For purposes of the pharmaceutical compositions described herein, the cylindrical shape may be any geometrical shape having the same cross section area throughout the length of the geometrical shape. Within the present context, cross sections are perpendicular to the axis of the cylinder. By way of example, if the cylindrical shape is elongated then the cross sections are perpendicular to the longitudinal axis.
Preferably, the cylindrical shape is elongated. The cross section of a cylinder within the meaning of the present invention may have any two-dimensional shape, for example the cross section may be circular, oval, parabola, hyperbola, rectangular, triangular, otherwise angular, star shaped or an irregular shape. Accordingly, the cylindrical shape may for example be an elliptic cylinder, a parabolic cylinder, a hyperbolic cylinder or a prism. A prism within the present context is a cylinder whose cross-section is a polygon.
In some embodiments of the present invention, the pharmaceutical composition may have any common tablet shapes. As examples of tablet shapes can for example be mentioned standard convex, standard convex bisect not flush, standard convex quadrisect flush, standard convex straight-through bisect, compound cup, convex with bevel, flat-faced plain, flat-faced bevel-edged, flat-faced bevel-edged bisect, flat-faced bevel-edged quadrisect, flat-faced radius-edged, lozenge, modified ball, core rod type (hole in center), capsule, modified capsule, oval, bullet, arrowhead, triangle, arc triangle, square, pillow (arc square), rectangle, modified rectangle, diamond, pentagon, hexagon, octagon natural edge, heart, half moon and almond. A skilled person would know the various kinds of shape that a tablet may be formed in.

34 PCT/EP2013/063851 In a particular embodiment, the pharmaceutical composition is prepared for oral intake, preferably for oral intake by swallowing. Accordingly, the size of the pharmaceutical composition may be in a range that allows for oral intake by swallowing.
Cosmetic coat In some cases the pharmaceutical composition of the present invention may also contain a cosmetic coat that fully covers the matrix composition. Said cosmetic coat may be selected from the group consisting of taste-masking coats, coats with aqueous moisture barriers and/or oxidative barriers to improve the stability of the composition, and coat containing colouring agents, sweetening agents and/or flavouring agents in order to provide an elegant and palatable pharmaceutical composition and/or to easy distinguishable dose strengths.
It can be particularly useful to coat matrix compositions having different dose strengths or active drug substances with cosmetic coats of different colours so that the different actives and dose strengths are easily distinguished.
In certain embodiments, the cosmetic coat contains an active drug substance.
Where provided, the cosmetic coat may be easily soluble in aqueous media in order to facilitate contact of the matrix composition with the surrounding aqueous media rapidly after administration. In one such embodiment, the cosmetic coat is dissolved within 30 minutes after immersed in aquesous medie such as, for example, phosphate buffer solution pH 6.8.
Administration The pharmaceutical composition according to the invention can be designed for oral administration. For example, the pharmaceutical compositions described herein may be produced as tablets, for oral intake by swallowing one or more intact tablets of the pharmaceutical composition.
A pharmaceutical composition as described herein may comprise one active drug substance or more than one different active drug substance.

A pharmaceutical composition according to the invention containing an active drug substance as described herein is typically formulated for oral administration.
Due to the possibility of controlling the release rate of the active drug substance, the pharmaceutical composition may be adapted for oral administration 1-6 times a day, 5 such as 1-4 times daily, including 1-3 times, 1-2 times or twice or once daily.
The pharmaceutical compositions described herein can be prepared for delivery of the desired dosage of active drug substance. The dosage may be dependent on the individual to whom the pharmaceutical composition of the invention is being 10 administered and the active drug substance.
In particular embodiments, the dosage for each administration, wherein dosages are in the range of 1 to 1000 mg, such as in the range of 5 to 1000 mg, for example in the range of 8 to 1000 mg, such as in the range of 10 to 1000 mg, for example in the range 15 of 30 to 1000 mg, such as in the range of 1 to 750 mg, for example in the range of 1 to 500 mg, such as in the range of 1 to 250 mg of an active drug substance. In certain such embodiments, the dosage for each administration is in a range selected from 5 to 500 mg and 5 to 250 mg of an active drug substance.
20 In one embodiment, when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1000 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 1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of 15 to 500 mg, a range of 15 to 250 mg, a range of 20 to 500 mg, a 25 range of 20 to 250 mg, a range of 30 to 500 mg, a range of 30 to 250 mg, a range of 10 to 200 mg, a range of 15 to 200 mg, a range of 20 to 200 mg, and a range of 30 to 200 mg of the opioid. In certain such embodiments, the pharmaceutical composition includes opioid or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 10, 15, 20, 30, 50, 60, 80, 100 or 200 mg.
30 In certain such embodiments, the pharmaceutical composition includes morphine as an active drug substance and the dosage is selected from 10, 15, 20, 30, 50, 60, 80, 90, 100, 120, 180 or 200 mg.
In another embodiment, when the active drug substance included in the

35 pharmaceutical compositions is an opioid, the dosage may be selected from a range of CA 02877183 2014-12-1.8

36 PCT/EP2013/063851 1 to 1000 mg, a range of 10 to 1000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of 10 to 250 mg, a range of 1 to 150 mg, a range of 10 to 150 mg, a range of 1 to 100 mg a range of 10 to 100 mg, a range of 1 to 80 mg and a range of 10 to 80 mg of the opoid. In certain such embodiments, the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg. In certain such embodiments, the pharmaceutical composition includes hydrocodone as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg. In another such embodiments, the pharmaceutical composition includes oxycodone as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg.
In still another embodiment, when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1000 mg, a range of 8 to 1000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 8 to 500 mg, a range of 8 to 250 mg a range of 1 to 100 mg, a range of 8 to 100 mg, a range of 1 to 75 mg, a range of 8 to 75 mg, a range of 1 to 64 mg and a range of 8 to 64 mg of the opioid. In certain such embodiments, the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 8, 12, 16, 32 or 64 mg. In certain such embodiments, the pharmaceutical composition includes hydromorphone as an active drug substance and the dosage is selected from 8, 12, 16, 32 or 64 mg.
In still another embodiment, when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1000 mg, a range of 5 to 1000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 5 to 500 mg, a range of 5 to 250 mg a range of 1 to 100 mg, a range of 5 to 100 mg, a range of 1 to 50 mg, a range of 5 to 50 mg, a range of 1 to 40 mg, and a range of 5 to 40 mg of the opioid. In certain such embodiments, the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as 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 pharmaceutical composition includes oxymorphone as an active drug substance and the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40 mg.

37 Above-mentioned dosages are in particular relevant when the individual in need of treatment is a human being, such as an adult human being.
Individuals in need of treatment The pharmaceutical composition of the invention is prepared for administration to an individual in need thereof. Said individual may be a mammal, and in specific embodiments the individual is a human being.
In certain embodiments, the pharmaceutical composition is for treatment of pain and accordingly, the individual in need of treatment is an individual suffering from pain.
In embodiments of the invention, wherein the active drug substance is an opioid, then the pharmaceutical compositions are suitable for treatment of moderate to severe pain such as severe pain.
Examples of individuals, who may benefit from treatment with the pharmaceutical compositions according to the invention, include, for example, the following:
The individual may be an individual suffering from chronic pain, such as moderate to severe chronic pain;
The individual may be an individual suffering from cancer and the pharmaceutical composition may be useful for continuous treatment of pain or even moderate to severe pain, such as severe pain in an individual suffering from cancer;
The individual may also be an individual who has suffered a moderate to severe injury;
The individual may be an individual suffering from pain associated with surgical conditions, such as a pre-surgical individual (an individual in need of surgery) or a post surgical individual (an individual who has undergone surgery);
The individual may also be an individual suffering from or having suffered from a myocardial infarction, sickle cell crises, kidney stone or severe back pain;

38 The individual may also be an individual suffering from degenerative pain, herniated disc pain, fibromyalgia, neuropathic pain and/or nociceptive pain; and The individual may also be an individual suffering from arthritis, such as arthritis osteo, arthritis rheumatoid, arthritis psoriatica and/or arthritis urica.
No alcohol dose dumping Pharmaceutical compositions as described herein may be formulated or configured to provide a reduced risk for alcohol induced dose dumping.
In specific embodiments, the pharmaceutical compositions described herein may be formulated or configured such that the pharmaceutical composition does not exhibit alcohol induced dose dumping. In such embodiments, the composition exhibits a solubility and/or active drug substance release rate in alcohol containing media (for example, ethanol containing media) that is lower than or equal to the solubility and/or release rate in aqueous media that does not include alcohol (for example., water, phosphate buffer medium pH 6.8 or dilute hydrochloric acid). In some such embodiments, the polyethylene oxide and excipients selected for use in the pharmaceutical composition are provided in relative amounts that result in an unchanged or lower dissolution rate and/or release rate of the active drug substance in alcohol containing media (for example, ethanol containing media) as compared to the solubility and/or release rate exhibited in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8 or dilute hydrochloric acid). In certain such embodiments, the dissolution and/or release rate of the active drug substance from the pharmaceutical composition in alcohol containing media (for example, ethanol containing media) is at least 1.25 times lower, such as at least 1.5 times lower, such as at least 2 times lower, such as at least 5 times, such as at least 10 times lower than the dissolution and/or release rate of the active drug substance in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8, dilute hydrochloric acid, and the like).
More specifically, the invention may provide a pharmaceutical composition may be formulated or configured to mitigate or prevent alcohol-induced dose dumping.
Typically, the solubility or release rate of the composition is lower or substantially the same in alcohol than that in water. More specifically, the solubility or release rate of the

39 PCT/EP2013/063851 composition is equal or at least 1.25 times lower such as at least 1.5 times lower; at least 2 times lower in alcohol than in water, notably 5 times or 10 times lower.
In particular embodiments, the pharmaceutical compositions described herein may be formulated to mitigate or prevent alcohol induced dose dumping. In certain such embodiments, the pharmaceutical compositions are formulated such that the ratio (R50) between t50% w/w (40% v/v ethanol in medium 1) and t50% W/W (medium 1) is 1 or more.
tam w/w (medium 1) denotes the time it takes to release 50% w/w of the active drug substance from the pharmaceutical composition in an in vitro dissolution test according to USP 35, NF 30, (711), Apparatus 2, paddle employing water optionally buffered to a specific pH as dissolution medium (medium 1), and t50% W/W (40% v/v ethanol in medium 1) denotes the time it takes to release 50% w/w of the active drug substance from the pharmaceutical composition in an in vitro dissolution test according to USP 35, NF 30, (711), Apparatus 2, paddle employing 40% v/v ethanol in medium 1 as dissolution medium.
In a specific embodiment, the ratio R50 is at the most 3 or at the most 2.
Notably, in certain such embodiments, the ratio R50 provided by the pharmaceutical compositions described herein is from 1 to 1.5 such as, for example, from 1 to 1.4, from 1 to 1.3, from 1 to 1.2, from 1 to 1.1, from 1 to 1.05, about 1, from 1 to 0.95 or from 1 to 0.9.
The same may also apply for ratios determined, for example, when 25%, 30%,

40%, 60%, 70%, 80%, 90% and/or 95% w/w has been released, the conditions being as described above.
Abuse deterrent In some embodiments, the pharmaceutical compositions as described herein are abuse-deterrent such that abuse administration is reduced, prevented or avoided.
Abuse administration typically includes injection and/or snorting.
Injection may be avoided by providing a non-injectable composition having such high viscosity that injection is difficult or impossible, because a liquid solution cannot be obtained.

In certain embodiments of the pharmaceutical compositions disclosed herein, the term "non-injectable composition," as used herein, refers to pharmaceutical compositions having a viscosity of at least about 90 mPa.s, such as at least about 95 mPa's, for example at least about 100 mPa.s, such as at least about 105 mPa.s, for example at least about 110 mPa.s, such as at least about 120 mPa.s, for example at least about 130 mPa.s, such as at least about 140 mPa.s, for example at least about 150 mPa.s, such as at least about 160 mPa.s, for example, at least about 170 mPa.s, such as at least about 180 mPa.s, for example at least about 190 mPa's, such as at least about 200 noPa.s= for example at least about 220 mPa.s, such as at least about 240 mPa.s.
In certain such embodiments, the viscosity is measured using the methods disclosed in the paragraph "Viscosity test." In particular embodiments, the term "non-injectable composition," as used herein, refers to viscosity of the pharmaceutical compositions is at least 100 mPa-s, where the viscosity is measured by using the method disclosed in the paragraph "Viscosity test."
Snorting may be avoided by providing a non-snortable composition, which cannot be tampered into small particles or powder form such that snorting is made impossible.
In certain embodiments of the pharmaceutical compositions described heren, the term "non-snortable composition" refers to compositions wherein at least 90 wt % of the particles obtained after physical tampering of the composition is larger than about 1050 pm, such as larger than about 1100 pm, such as larger than about 1150 pm. In particular embodiments, the term "non-snortable composition," as used herein, refers to a composition where at least 90 wt% of the particles obtained after physical tampering of the pharmaceutical composition is larger than 1100 pm.
In certain circumstances, an abuser may tamper with pharmaceutical compositions in a manner or by using a method that achieves maximal size reduction of the pharmaceutical composition in a minimal amount of time, while obtaining small particles, a powder, or other similar products, which can be dissolved or administered as easily as possible.
A series of abuse or tampering methods have been developed to illustrate the extent of the pharmaceutical composition described herein of being abuse deterrent.

41 PCT/EP2013/063851 If the pharmaceutical composition disintegrates into particles, then it may be possible to dissolve or suspend the particles and use them for abuse purposes. Moreover, if it is possible to disintegrate (e.g. crush) the composition, then it is possible to use the powder for snorting or sniffing and in this way abuse the composition.
However, if it is not possible to crush the composition, then there will be no particles to use for such abuse purposes. In particular embodiments, the pharmaceutical compositions described herein cannot be crushed into particles by the apparatus (e.g.
tablet hardness tester) specified in Ph. Eur.
Particle size reduction test method has been developed to evaluate abuse potential when the pharmaceutical composition is subjected to physical tampering.
In some embodiments, a pharmaceutical composition is abuse deterrent, provided that the pharmaceutical composition does not change its release profile from a controlled release to an immediate release of the active drug substance subsequent to physical tampering such as, for example, particle size reduction test, where the test program is successfully completed, which indicates that the pharmaceutical composition is abuse deterrent. Tests on pharmaceutical compositions subjected to physical tampering may also result in equipment failure, and in such an instance, the test program is considered successfully completed, indicating a pharmaceutical composition as abuse deterrent.
If a pharmaceutical composition is crushed or broken into small pieces or small particles, an increased exposed surface area is created, which may increase the release rate of the active drug substance. Such an increase in release rate may lead to an increased potential for abuse. If a change in the release profile of the active drug substance from a controlled release to an immediate release is noticed, the pharmaceutical composition is considered to have failed. At such a point, pharmaceutical composition has potential for abuse, such as by snorting or chemical extraction and it is evaluated. If the active drug substance can be extracted from the compromised pharmaceutical composition, the ease with which such extracted active drug substance can be injected is evaluated.
Crisping The crisping test methods as described herein include methods intended to circumvent the controlled release mechanism in or interfere with the controlled release profile of a

42 PCT/EP2013/063851 pharmaceutical composition. Crisping is a heating process designed to remove, reduce or degrade at least some of the unwanted or undersired excipients and make it easier to abuse the active drug substance. Crisping may be employed to make it easier to crush the composition into small particles/or a powder form so that snorting is made possible or to make it easier to dissolve the composition into an injectable liquid solution or suspension.
Crisping or heating methods such as, for example, heating in an oven, a microwave oven, or a spoon over an open flame, and the like, may be used to make it easier to reduce the particle size and/or the viscosity of the pharmaceutical compositions. The heating is normally stopped when the pharmaceutical composition start to turn a brown colour and further abuse methods such as, for example particle size reduction, extraction and/or injection are started.
In certain embodiments, the pharmaceutical compositions of the present invention are not made easier to crush into snortable particles or powder form or to dissolve into an injectable liquid solution by crisping.
In some embodiments, stearate is added to the pharmaceutical composition to facilitate the colour change of the composition to a brown and/or dark colour or even to facilitate the composition to burn. In some such embodiments, the stearate added is magnesium stearate, calcium stearate and/or stearic acid.
Particle size reduction The particle size reduction test methods described herein include methods for reducing the particle size of the pharmaceutical compositions via physical tampering, such as, for example, crushing, hammering, chopping, grinding, grating, cutting and other means of particle size reduction.
The particle size reduction test can be carried out using a number of mechanical and electrical tools found in common households or commonly available in retail.
The types of tools are, such as, for example; mortar & pestle; hammer; grater; food chopper coffee grinder, and the like.

43 PCT/EP2013/063851 Pharmaceutical compositions such as for example tablets, subjected to physical tampering may be further analyzed by use of image processing and/or run through a particle size analyzer. By collecting the different fractions and analyzing, such as, for example, by weighing and/or dissolving to assess the contents of active drug substance in the different fractions and/or to assess the dissolution rate. As control dissolution test on intact tablets is performed as described in the section describing dissolution testing and the results are applied as control data.
Extraction The extraction test methods described herein include methods for evaluating the extractability of active drug substance from pharmaceutical compositions in different types of solvents. In some embodiemtns, approximately 3 ml of water often may be used to prepare a solution of, for example, MS Contin0 for injection.
Different amount of solvents and ways of handling the solutions have been tested. In certain such embodiments, in order to ensure that as much as possible of the active drug substance has been extracted, shaking has been selected as an extraction method. In certain such embodiments, extraction of an active drug substance from a pharmaceutical composition may be facilitated by placing a pharmaceutical composition in at least one solvent and shaking the pharmaceutical composition and the at least one solvent.
In particular embodiments, in order to ensure that as much as possible of the active drug substance has been extracted, continuous shaking has been selected as an extraction method. In one embodiment, extraction of an active drug substance from a pharmaceutical composition may be facilitated by placing a pharmaceutical composition in at least one solvent and continuously shaking the pharmaceutical composition and the at least one solvent. In some embodiments, "continuous shaking,"
as used herein, refers to shaking for at least 1 second, for at least 5 seconds, for at least 30 seconds, for at least 1 min, for at least 5 minutes, for at least 10 minutes, for at least 15 minutes, for at least 30 minutes, for at least 45 minutes, for at least 60 minutes, for at least 2 hours, for at least 4 hours, for at least 8 hours, for at least 12 hours, for at least 24 hours, for at least 2 days, for at least 3 days, for at least 4 days, for at least 5 days, for at least 6 days, for at least 1 week, for at least 2 weeks, for at least a month.

44 In another embodiment, the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed for a period of time. In certain embodiments, the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed for at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, and at least 72 hours. In certain such embodiments, the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed, and the active drug substance in the solvent may be first measured after at least 24 hours.
In some embodiments, the amount of active drug substance in the solvent may be measured at select time points within the first 60 minutes. In some such embodiments, the amount of active drug substance in the solvent may be measured at least one time, at least two times, at least three times, at least four times, at least five times, and at least six times, within the first 60 minutes of placing the pharmaceutical composition in the at least one solvent. In particular embodiments, the amount of active substance in the solvent may be measured at least one time, at least two times, at least three times, at least four times, at least five times, and at least six times, within the first 24 hours of placing the pharmaceutical composition in the at least one solvent.
Extraction of active drug substance from pharmaceutical compositions can be performed by dissolving, for example, tablets in different types of solvents.
In particular embodiments, the tablets in different solvents may be shaken and/or continuous shaken. In other embodiments, the tablets in different solvents may be unshaken or undisturbed. The solvents can be chosen to cover a broad range of liquids with low and high pH, with some being some polar and some non-polar. The solvents may be categorized into five groups: such as for example, aqueous solutions, such as, for example, solution pH 1.2; buffer pH 6.8; buffer pH 10.0; water; and water +
ethanol (40 %v/v); beverages, such as, for example; Coca-Cola ; quinine containing soft drinks, such as, for example; tonic water and bitter lemon; Coca-Cola + ethanol (40 %v/v);
and vodka; common household liquids, such as, for example, 1% acetic acid;
ethanol;
methylethylketone; and acetone.
In some embodiments, it has been shown to be difficult to extract active substances from the pharmaceutical composition described herein in solvents such as beverages.
In certain such embodiments it has been shown to be difficult to extract active substances from the pharmaceutical composition described herein in solvent such as carbonated and/or soft drinks, including Coca-Cola , and the like.
Injection 5 The injection test methods described herein include methods for evaluating the abuse potential of active substance from pharmaceutical compositions both quantitatively (i.e., such as, for example, time, yield, and unit operations required) and qualitatively (i.e., such as, for example, appearance).
10 The general strategy behind the injection test method, as decribed herein, is to mimic the actual procedures applied by drug abusers when preparing a pharmaceutical composition for injection and injecting it. The study design is therefore divided into three parts; such as for example, preparation, filtration and injection.
15 The objective is to record the time and effort required to prepare a solution or dispersion that can be used for injection and the obtained yield of the active drug substance. As described herein, drug abusers, typically, are only prepared to spend a limited amount of time for preparing a pharmaceutical composition for abuse.
All tests can be performed in an aqueous media, which is a commonly used solvent for 20 injection. Finally, the appearance of the resulting solution/dispersion is assessed in order to evaluate the likelihood that a drug abuser would inject the resulting injectable mass.
In certain embodiments the pharmaceutical compositions described herein have 25 predominantly high viscous properties analogous to plastic. In an aqueous medium or in the gastrointestinal tract, the pharmaceutical composition transforms from having high viscous properties to having predominately elastic properties that control the release rate of active drug substance and which resist rapid extraction and/or injection.
In particular embodiments, the predominately elastic properties of the pharmaceutical 30 compositions in an aqueous medium or in the gastrointestinal tract provide a controlled-release profile of the active drug substance in an individual.
The high viscosity (0.5-1700 Pa=s) turns not only the matrix composition into a non-injectable dispersion/gel but also significantly delays the solubility to completely forms 35 into a gelatinous mass. In some embodiments, the high viscosity of the composition turns not only the composition into a non-injectable dispersion/gel, but also significantly deters the abuse of the pharmaceutical composition by eluting at least one polymer from the composition into the solvent, which turns the solvent into a gelatinous mass.
In some such embodiments, the at least one polymer is a polyethylene oxide. In certain embodiments, the average molecular weight of the at least one polyethylene oxide eluting from the composition into the solvent is less than 5 000 000 daltons, such as less than 4 000 000 daltons, such as less than 3 000 000 daltons, for example less than 2 000 000 daltons, such as less than 1 000 000 daltons, for example less than 800 000 daltons, such as less than 600 000 daltons, for example less than 500 daltons.
In particular embodiments, the viscosity of the composition is in a range selected from between about 0.5 Pa-s to about 3000 Pa=s, between about 0.5 Pa-s to about Pa=s, between about 0.5 Pa-s to about 2000 Pa-s, between about 0.5 Pa-s to about 1700 Pa=s, between about 5 Pas to about 3000 Pa=s, between about 10 Pa-s to about 3000 Pas, between about 20 Pa-s to about 3000 Pa=s, between about 30 Pa-s to about 3000 Pa=s, between about 40 Pa=s to about 3000 Pa-s, between about 45 Pa=s to about 3000 Pa-s, between about 45 Pa-s to about 2500 Pas, between about 45 Pa-s to about 2000 Pa-s, between about 45 Pa-s to about 1700 Pa-s, between about between about 46 Pa-s to about 1700 Pas. In a specific embodiment, the viscosity of the composition is at least about 46 Pa=s.
Furthermore, the high viscosity of the matrix composition deters direct injection and also serves as a significant barrier to prevent volatilization (e.g.
inhalation) of the incorporated active drug substance at elevated temperature or snorting if the matrix composition is crushed or broken into small pieces or small particles. In certain embodiments, composition results in a highly viscous and/or unclear, opaque or cloudy dispersion/gel upon contact with an aqueous medium, which may form a strong adhesion to the nose and nasal tissue walls and thereby results in discomfort in the nasal cavity of the abuser.
In some embodiments, it has been shown to be difficult to inject the abuse deterrent pharmaceutical composition when the viscosity of the composition is at least 46 Pa s.
Viscosity may be determined using a Brookfield DV-E viscometer, measured at ambient temperature and 5 rpm.

In embodiments of the invention, the abuse deterrent pharmaceutical compositions as described herein may form a gel that resists passage or is difficult to inject through a needle.
In further embodiments, the abuse deterrent pharmaceutical compositions as described herein may further include a viscosity increasing agent, such as, for example, a gelling agent, and the like.
Examples The invention is further illustrated in the following non-limiting examples.
Dissolution test Dissolution tests were performed in accordance with USP 35, NF 30, (711), Apparatus 2 (paddle method). The dissolution medium consisted either of phosphate buffer solution pH 6.8 with/without ethanol or of dilute hydrochloric acid with/without ethanol.
The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm or 75 rpm throughout the dissolution run. Samples were withdrawn at suitable time intervals and analysed for content of active drug substance by means of UV-detector or HPLC with UV-detector.
In the immediate release test, the dissolution medium consisted of dilute hydrochloric acid. The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 75 rpm throughout the dissolution run.
In the controlled release test, the dissolution medium consisted of phosphate buffer solution pH 6.8. The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm throughout the dissolution run.
In the no alcohol dose dumping test, the dissolution medium consisted of phosphate buffer solution pH 6.8 with/without 40% v/v ethanol. The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm throughout the dissolution run.
Crisping test Three whole tablets were placed in a 50 ml glass bottle. The bottle was placed in the center of a microwave oven and heated for a predetermined amount of time (e.g.
8 and 16 minutes) at maximum effect (900 W). Afterwards 9 ml of purified water was added to the bottle and the bottle was placed on a flatbed laboratory shaker (IKA-Werke HS-501 digital) and was shook continuously (speed 150/min) for 3 days at ambient temperature to dissolve the tablets and to reduce clumping.
Viscosity test Four tablets were weighed and placed in a bottle with 12 ml purified water.
The bottle was placed on a flatbed laboratory shaker (IKA-VVerke HS-501 digital) and was shook continuously (speed 150/min) for 3 days at ambient temperature to dissolve the tablets and to reduce clumping.
Viscosity was measured using a Brookfield RVDV-E viscometer (Brookfield Engineering, Middleboro, MA USA) with spindle number 15 (0.5-1700 Pas), a 7R
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 (0.05-170 Pa.$), a 13R tube, a small sample adapter SC4-45Y at 20 rpm. The temperature was controlled and in the range of 22 C.
Particle size reduction test Particle size reduction of pharmaceutical compositions was tested using of a coffee grinder and/or a nutmeg grater. The method aims to evaluate the efforts required to reduce the particle size of the pharmaceutical compositions via physical grinding or grating of the tablets.
Tablets were ground in either; a Moulinex-1411 R coffee grinder with stainless steel blades (model: the original grinder; 50 g -180W AR100G31/6W0) at 10 000-20 000 rpm or a Krups F203 coffee grinder with stainless steel blades (Model: 75 g ¨

F2034210/6W0-1512 R) at 30 000-50 000 rpm for 15 seconds or to no more particle size reduction or equipment failure and afterwards analyzed by use of Image Processing. A drawing of the coffee grinder chamber is shown in figure 1 and figure 2.
Tablets were grated by using a nutmeg grater with stainless steel star blade or a Microplane grater with stainless steel zester grater or fine or spice blade for 11/2 minutes. A drawing of the nutmeg grater with stainless steel star blade is shown in figure 3.
The samples were analyzed using an image processing setup comprising; a digital SLR with RAW or TIFF capabilities (Canon EOS 350D, resolution 3466x2306 (8MP) or Nikon D3100, resolution 4608x3272 (14,2MP)), a fixed lens (Canon EF 100mm 1:2:8 USM Macro or Tamron 90mm 1:2:8 Macro), a stable camera stand, a suitable background for the particles (e.g. a black paper square) and light (to avoid reflections) plus a calibrated light microscopy scale bar from Leitz.
A sample was spread onto the black background, and the particles were separated.
The position of the camera setup was adjusted and focused such that entire sample was inside the approximate view-area for the camera before pictures were taken.
Data were processed by using the software: RawTherapee 3Ø1.0 (Conversion of RAW-files to uncompressed TIFF.), ImageJ 1.45b (Thresholding of TIFF images (binarization) and particle size measuring (data rendering)) and Microsoft Excel 2010 (data analysis).
Preparation of a pharmaceutical composition A general method for the preparation of a pharmaceutical composition is described below.
An accurate amount of the polymer (i.e. in the examples below: polyethylene oxide) is loaded into a MTI mixer followed by an accurate amount of the active drug substance and/or plasticizer and/or other pharmaceutically acceptable excipients(s), if any. The mixing is performed at 900-2000 rpm and at a time period up to 20 min. At the start of the mixing the temperature is about 19-21 C and the final temperature of the mixture is about 30-50 C. The mixture is then allowed to cool to room temperature and is ready to be fed into an injection moulding machine. The injection moulding machine used is an Arburg Allrounder 420 C 1000-60/60.
Example 1 Preparation of PEO 400 000 containing pharmaceutical composition for use according to the invention A composition (batch No. 1577-051A) according to the invention was prepared from the following ingredients:
Composition Mg PEO 400 000 436.2 Poloxamer 188 116.3 Morphine Sulphate 29.1 Pentahydrate The composition was prepared as described above.
The composition was subjected to the dissolution test (controlled release) described above. The results are shown in figure 4 as the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of morphine is shown for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
The viscosity of the composition was measured as described above. The viscosity was found to be 93 Pas at 5 rpm.
Particle size reduction of the composition was measured as described above.
The average particle size was 0.706 1.63 mm and the five largest particles were;
12.1;
3.0; 2.7; 2.2; 1.9 mm. The results are shown in figure 5.
Example 2 Preparation of PEO 600 000 containing pharmaceutical composition for use according to the invention A composition (batch No. 1577-051B) according to the invention was prepared from the following ingredients:
Composition Mg Poloxamer 188 93 Oxycodone HCI 23.25 The composition was prepared as described above.

The composition was subjected to the dissolution test (controlled release) described above. The results are shown in figure 6 as the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40 % v/v ethanol. The release of oxycodone is shown for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
The viscosity of the composition was measured as described above. The viscosity was found to be 74 Pas at 5 rpm.
Particle size reduction of the composition was measured as described above.
The average particle size was 0.455 0.639 mm and the five largest particles were; 12.1;
4.0; 3.9; 3.8; 3.7 mm. The results are shown in figure 7.
Example 3 Preparation of PEO 2 000 000 containing pharmaceutical composition for use according to the invention A composition (batch No. 1581-065) according to the invention was prepared form the following ingredients:
Composition Mg Poloxamer 188 50.2 Hydromorphone HCI 12.55 The composition was prepared as described above.
The composition was subjected to the dissolution test (controlled release) described above. The results are shown in figure 8 as the release of hydromorphone ( /0) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
The viscosity of the compositions was measured as described above. The viscosity was found to be 46 Pas at 5 rpm.

Particle size reduction of the composition was measured as described above.
The average particle size was 0.495 0.643 mm and the five largest particles were; 10.5;
3.6; 3.6; 3.5; 3.5 mm. The results are shown in figure 9.
Example 4 Preparation of PEO 10 000 000 containing pharmaceutical composition according to the invention A composition (batch no. 1581-066) according to the invention was prepared from the following ingredients:
Composition Mg Poloxamer 188 80 Oxymorphone HCI 10 The composition was prepared as described above.
The composition was subjected to the dissolution test (controlled release) described above. The results are shown in figure 10 as the release of oxymorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
The viscosity of the composition was measured as described above. The viscosity was found to be 79.6 Pas at 5 rpm.
Particle size reduction of the composition was measured as described above.
The average particle size was 0.547 0.640 mm and the five largest particles were; 5.8;
4.8; 4.7; 4.7; 4.4 mm. The results are shown in figure 11.
Example 5 Oxycontire OP 40 mg Oxycontin OP 40 mg was subjected to the dissolution test Controlled release) described above. The results are shown in figure 12 as the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
The viscosity of Oxycontin OP 40 mg was measured as described above. The viscosity was found to be 46 Pa.s at 5 rpm.
Particle size reduction of Oxycontin OP 40 mg was measured as described above.
The average particle size was 0.341 0.301 mm and the five largest particles were;
3.0; 2.7; 2.7; 2.6; 2.4 mm. The results are shown in figure 13.
Example 6 Preparation of morphine prolonged release pharmaceutical composition for use according to the invention A 200 mg morphine composition (batch No. 12-0060-067) according to the invention was prepared from the following ingredients:
Composition Mg PEO 200 000 291.6 PEO 600 000 291.6 Morphine Sulphate Pentahydrate 197.2 BHT 0.8 The composition was subjected to the no alcohol dose dumping test described above.
The results are shown in figure 14 as release of morphine (`)/0) versus time (minutes) in phosphate buffer solution pH 6.8 with/without 40% v/v ethanol. The release of morphine is shown for intact tablets.
Example 7 Crisping test A 60 mg morphine composition (batch No. 12-066-067) according to the invention was prepared from the following ingredients:
Composition Mg PEO 200 000 354.3 PEO 600 000 354.3 Morphine Sulphate Pentahydrate 60 BHT 0.8 The composition was subjected to the crisping test described above. By comparition MST Continus 60 mg, Oxycontin OP 80 mg and Opana ER 40 mg (contains among others hydroxypropyl methylcellulose HPMC) were subjected to the same crisping test.
Acccording to the authority is the composition of MST Continus0 and MS Contin0 identical. MST Continus0 is the European trademark and MS Contin0 is the American trademark.
The results are shown in table 1 below.
Crisping (minutes) Morphine MST Continus5¨Oxycontin() OP Opana ER
composition 60 mg 60 mg 80 mg 40 mg 0 Viscosity >2400 75 >2400 >2400 (mPas) Injectable No Yes No No Assay (%) 100 98 99 98 8 Viscosity >2400 93 60 >2400 (mPas) Injectable No Yes Yes No Assay (%) 99 99 99 98 16 Viscosity >2400 0 0 30 (mPas) Injectable No Yes Yes Yes Assay (%) 97 96 73 99 Example 8 Test of particle size reduction of pharmaceutical compositions by use of a Krups coffee grinder A 200 mg morphine composition (batch No. 2654-056) according to the invention was prepared from the following ingredients:

Composition Mg PEO 200 000 291.6 PEO 600 000 291.6 Morphine Sulphate Pentahydrate 197.2 BHT 0.8 The composition was subjected to the dissolution test (controlled release) described above. The results are shown in figure 15 as the release of active substance (%) 5 versus time (minutes) in phosphate buffer solution pH 6.8. The release of active substance is shown for intact tablets and ground tablets (ground in a Krups coffee grinder). By comparision MST Continus 60 mg and Oxycontin OP 40 mg were subjected to the same test. The results are shown in figure 15.
10 Example 9 Test of particle size reduction of pharmaceutical compositions by use of a nutmeg grater A 200 mg morphine composition (batch No. 2654-056) according to the invention was prepared from the following ingredients:
Composition Mg PEO 200 000 291.6 PEO 600 000 291.6 Morphine Sulphate Pentahydrate 197.2 BHT 0.8 The composition was subjected to the dissolution test (immediate release) described above. The results are shown in figure 16 as the release of active substance (%) versus time (minutes) in dilute hydrochloric acid. The release of active substance is shown for grated tablets (Nutmeg grater). By comparision MST Continus 60 mg, Oxycontin OP 80 mg and Opana ER 40 mg were subjected to the same test. The results are shown in figure 16.

CA 02877183 2014-12-1.8 Particle size reduction of the composition was measured as described above.
The average particle size was 1.94 2.57 mm and the five largest particles were;
21.4;
15.1; 12.8; 8.7; 7.8 mm. The results are shown in figure 17.
By comparision MST Continus 60 mg, Oxycontirì OP 80 mg and Opana ER 40 mg were subjected to the same test. For MST COntinUs 60 mg the average particle size was 0.410 0.250 mm and the five largest particles were; 4.9; 4.7; 4.1; 3.7;
3.5 mm.
For Oxycontin OP 80 mg the average particle size was 0.596 0.337 mm and the five largest particles were; 5.9; 5.0; 4.3; 3.4; 3.1 mm. For Opana ER 40 mg the average particle size was 0.513 0.489 mm and the five largest particles were; 9.4;
8.7; 7.8;
6.8; 6.4 mm. The results are shown in figure 18-20.
The five largest particles were lumps; some were big lumps and also big and flakey lumps.
The dimensions of the tablets are shown in table 2 below.
Tablet Length, mm Height, mm Width, mm Depth, mm (convex tablet) Morphine composition 19.5 6.2 7.4 N/A
200 mg MST Continus 60 mg 7.25 4.5 7.25 N/A
Oxycontin OP 80 mg 9.5 4.25 9.5 N/A
Opona ER 40 mg 8.6 3.5 8.6 0.5 Example 10 Extraction test A 60 mg morphine composition (batch No. 12-066-067) according to the invention was prepared from the following ingredients:
Composition Mg PEO 200 000 354.3 PEO 600 000 354.3 Morphine Sulphate Pentahydrate 60 BHT 0.8 The composition was subjected to the extraction test. Two tablets were placed in a 50 ml beaker, 10 ml solvent (purified water or Coca-Cola 0) was added and the beaker was sealed with Parafilm0. The beaker with tablets was left undisturbed at 25 C /60%
RH for 24 hours. The free solvent was poured into a tared empty beaker, the viscosity of the free solvent was measured by the viscosity test as described above and the active drug substance content in the free solvent (assay) was determined by using HPLC with UV-detector.
By comparision MST Continus 60 mg, Oxycontin OP 80 mg and Opana ER 40 mg were subjected to the same extraction test.
The results are shown in table 3 below.
' Formulation Free solvent Assay Viscosity Injectable Note (m1) (%) (mPa s) Morphine composition 60 mg Water 5.8 30.8 >2400 No Tablet shape disappeared Coca-Cola 3.2 24.4 >2400 No Partly dissolved the rest having a white core ________________________________________________________ [ MST Continus 60 mg I Water 9.3 87.9 0 l Yes Intact Spongy __________________________________________________________ looking ___ Coca-Cola 8.8 92.9 0 Yes Intact Spongy looking Oxycontin OP 80 mg Water 5.5 36.5 160 Yes Swollen __________________________________________________________ tran_parent tablets Coca-Cola 5.5 48.4 68 Yes Swollen __________________________________________________________ transparent tablets Opana ER 40 mg Water 5.0 50.1 73 Yes Swollen transparent tablets Coca-Cola 4.6 45.8 '105 Yes Swollen transparent tablets

Claims (16)

Claims

1. An abuse deterrent pharmaceutical composition consisting of a matrix composition and optionally a cosmetic coat, said matrix composition comprising a homogenous mixture of:
(a) 1-50% w/w of an active drug substance, wherein the active drug substance in the matrix composition is an opioid or a pharmaceutically acceptable salt or solvate thereof, (b) 20-98% w/w of a polyethylene oxide (PEO) having an average molecular weight of in the range of 200,000 to 1,000,000 daltons, and (c) optionally a plasticizer, wherein the pharmaceutical composition in addition to the matrix composition optionally further contains a cosmetic coat that fully covers the matrix composition, wherein the pharmaceutical composition exhibits a hardness that is resistant to physical tampering.

2. The pharmaceutical composition according to claim 1, wherein the active drug substance is selected from the group consisting of buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol and dihydromorphine or a pharmaceutically acceptable salt or solvate thereof.

. The pharmaceutical composition according to any one of claims 1 and 2, wherein the polyethylene oxide is selected from the group consisting of polyethylene oxide daltons, 300 000 daltons, 400 000 daltons, 600 000 daltons, 900 000 daltons and mixtures thereof.

4. The pharmaceutical composition according to any of the preceding claims, wherein the plasticizer in the matrix composition is selected from the group consisting of poloxameror polyethylene oxides having a molecular weight of 35 000 to 600 000 daltons and mixtures thereof.

5. The pharmaceutical composition according to any of the preceding claims, wherein the matrix composition comprises a further active drug substance.

6. The pharmaceutical composition according to any of the preceding claims, wherein the matrix composition further comprises one or more excipients selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents, solvents, gelling agents, stabilizers, release modifier, carboxylic acids, amino acids, inorganic compounds, saccharides, cellulose, cellulose derivatives, sweetening agents, flavouring agents and colouring agents.

7. The pharmaceutical composition according to any of the preceding claims, wherein the cosmetic coat is selected from the group consisting of taste-masking coat, coat with aqueous moisture barrier agents, coat with oxidative barrier agents, coat with colouring agents and coat with sweetening/flavouring agents, wherein said cosmetic coat dissolve within 30 minutes such as 15 minutes after immersed in aquesous medie such as, for example, phosphate buffer solution pH 6.8.

8. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition is formulated for oral administration.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is formulated as a tablet.

10. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition has a solubility and/or release rate in ethanol that is equal to or lower than that in water

11. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition is resistant to isolation of the active drug substance as determined by the dissolution test, the viscosity test and the particle size reduction test as described in the specification.

12. The pharmaceutical composition according to any of the preceding claims, wherein at least 90 wt% of the particles obtained after physical tampering of the pharmaceutical composition is larger than 1100 µm.

13. The pharmaceutical composition according to any of the preceding claims, wherein the viscosity of the pharmaceutical composition is higher than 100 mPa s.

14. The pharmaceutical composition according to any of the preceding claims for use in the treatment of pain.

15. A method of treating a clinical condition in an individual in need thereof, said method comprising administering a pharmaceutical composition according to any of claims 1-14 to an individual in need thereof.

16. The method according to claim 15, wherein the individual is a human being.