Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer

专利摘要:
The invention relates to a pharmaceutical dosage form having a breaking strength of at least 300 N and comprising a pharmacologically active compound, an anionic polymer bearing carboxylic groups, wherein the content of the anionic polymer is ≥ 20 wt.-%, based on the total weight of the pharmaceutical dosage form, and a nonionic surfactant.
公开号:AU2013225106A1
申请号:U2013225106
申请日:2013-02-27
公开日:2014-08-28
发明作者:Lutz Barnscheid；Jessica Redmer；Sebastian Schwier
申请人:Gruenenthal GmbH；
IPC主号:A61K9-20

专利说明:
WO 2013/127831 PCT/EP2013/053894 1 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer The invention relates to a pharmaceutical dosage form having a breaking strength of at least 300 N and comprising a pharmacologically active compound, an anionic polymer bearing carboxylic groups, wherein the content of the anionic polymer is > 20 wt.-%, based on the total weight of the pharmaceutical dosage form, and a nonionic surfactant. Tamper-resistant pharmaceutical dosage forms containing pharmacologically active compounds have been known for many years. Pharmacologically active compound abuse with conventional dosage forms is typically achieved by (i) pulverization of the pharmaceutical dosage form and nasal administration of the powder; (ii) pulverization of the pharmaceutical dosage form, dissolution of the powder in a suitable liquid and intravenous administration of the solution; (iii) pulverization of the pharmaceutical dosage form and inhalation by smoking; (iv) liquid extraction of the drug from the pharmaceutical dosage form and intravenous administration of the solution; and the like. Accordingly, many of these methods of abuse require the mechanical destruction of the pharmaceutical dosage form in order to render it suitable for abuse. In the past several different methods have been developed to avoid drug abuse. Some of these concepts of rendering pharmaceutical dosage forms tamper resistant rely on the mechanical properties of the pharmaceutical dosage forms, particularly a substantially increased breaking strength (resistance to crushing). The major advantage of such pharmaceutical dosage forms is that comminuting, particularly pulverization, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially impeded. Thus, by conventional means that are available to an abuser, such pharmaceutical dosage forms cannot be converted into a form suitable for abuse, e.g. a powder for nasal administration. In this regard it can be referred to e.g., WO 2005/016313, WO 2005/016314, WO 2005/ 063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, and WO 2008/107149.
WO 2013/127831 PCT/EP2013/053894 2 These known tamper resistant pharmaceutical dosage forms, however, are not satisfactory in every respect. The tamper resistance of these known pharmaceutical dosage forms substantially relies on the presence of high molecular weight polyalkylene oxide, in particular polyethylene oxide, as matrix material, and further depends on the manufacturing process. In order to achieve a high breaking strength, the manufacturing process typically includes the application of heat and pressure to a preformed mixture comprising polyalkylene oxide and pharmacologically active substance, and requires careful selection of the process conditions. In tablet formulations, acrylic acid polymers (carbomers) are used in concentrations up to 10 wt.-% as dry or wet binders and as rate controlling agents. It is known from WO 2006/082099, that small amounts of anionic methacrylic acid and methyl methacrylate copolymers (Eudragit@) can be included into polyalkylene oxide matrices of tamper-resistant dosage forms without altering their mechanical properties. However, pharmaceutical dosage forms comprising larger amounts of anionic polymer(s) that nonetheless exhibit a sufficiently high breaking strength and impact resistance are not known so far. T. Ozeki et al., International Journal of Pharmaceutics, 165 (1998) 239-244 disclose poly(ethylene oxide)-carboxyvinylpolymer solid dispersions prepared from water/ethanol mixture as a solvent. Similarly, T. Ozeki et al., Journal of Controlled Release, 63 (2000) 287 295 relates to controlled release from solid dispersion composed of poly(ethylene oxide) Carbopol* interpolymer complex with various cross-linking degrees of Carbopol*. The polyethylene oxide employed in these studies had an average molecular weight of below 150,000 g/mol only. However, these solid dispersions are prepared by means of wet granulation using water/ethanol as the granulating fluid, and are thus not suitable for the avoidance of drug abuse. US 2008/069871 discloses oral dosage forms of therapeutic agents that are resistant to abuse and methods of their formulation. In particular, oral dosage forms that are resistant to dissolution in aqueous solutions of ethanol are described. EP 1 502 592 relates to controlled release oxycodone dosage form for oral administration to human patients, comprising an oxycodone salt; a matrix incorporating said oxycodone salt; the matrix comprising at least one acrylic resin; wherein said dosage form has an in vitro dissolution rate when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37 WO 2013/127831 PCT/EP2013/053894 3 DEG C, between 12.5 % and 42.5 % (by weight) oxycodone salt released after 1 hour, between 25 % and 56 % (by weight) oxycodone salt released after 2 hours, between 45 % and 75 % (by weight) oxycodone salt released after 4 hours and between 55 % and 85 % (by weight) oxycodone salt released after 6 hours, the in vitro dissolution rate being independent of pH between 1.6 and 7.2. US 2007/190142 discloses a dosage form and method for the delivery of drugs, particularly drugs of abuse, characterized by resistance to solvent extraction, tampering, crushing, or grinding, and providing an initial burst of release of drug followed by a prolonged period of controllable drug release. US 2011/097404 relates to an oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is not released when the dosage form is administered orally intact. WO 2010/140007 discloses a dosage form, particularly a tamper resistant dosage form, comprising: melt-extruded particulates comprising a drug; and a matrix; wherein said melt-extruded particulates are present as a discontinuous phase in said matrix. US 2011/159100 relates to controlled release formulations and methods for preparing controlled release formulations for delivery of active drug substances. The formulations may be employed to produce pharmaceutical compositions, such as controlled release dosage forms, adjusted to a specific administration scheme. WO 2012/028318 discloses a pharmaceutical dosage form exhibiting a breaking strength of at least 500 N, said dosage form containing - a pharmacologically active ingredient (A); - a physiologically acceptable polymer (B) obtainable by polymerization of a monomer composition comprising an ethylenically unsaturated monomer bearing an anionic functional group, in protonated form or a physiologically acceptable salt thereof; - a polyalkylene oxide (C) having a weight average molecular weight of at least 200,000 g/mol, wherein the content of the polyalkylene oxide (C) is at least 20 wt.-%, based on the total weight of the dosage form; wherein the pharmacologically active ingredient (A) is present in a controlled-release matrix comprising the polymer (B) and the polyalkylene oxide (C).
WO 2013/127831 PCT/EP2013/053894 4 There is a demand for tamper resistant pharmaceutical dosage forms containing pharmacologically active compounds that have advantages compared to the tamper resistant pharmaceutical dosage forms of the prior art. This object has been achieved by the subject-matter of the patent claims. A first aspect of the invention relates to a pharmaceutical dosage form having a breaking strength of at least 300 N and comprising - a pharmacologically active compound, - an anionic polymer bearing carboxylic groups, wherein the content of the anionic polymer is > 20 wt.-%, based on the total weight of the pharmaceutical dosage form, and - a nonionic surfactant. It has been surprisingly found that tamper-resistant pharmaceutical dosage forms having a high breaking strength and impact resistance can be prepared by using an anionic polymer and optionally a nonionic surfactant, and that the presence of high molecular weight polyalkylene oxide is not required. Furthermore, it has been surprisingly found that liquid extraction of the pharmacologically active compound and subsequent administration of the thus obtained liquid by the non-prescribed, parenteral route can be substantially impeded by incorporating an effective amount of anionic polymer and optionally nonionic surfactant into the pharmaceutical dosage forms. It has further been found that these ingredients can have a stabilizing effect on the pharmaceutical ingredient contained in the dosage form. The pharmaceutical dosage form according to the invention comprises a pharmaceutically active compound, preferably a pharmacologically active compound having psychotropic activity, more preferably an opioid. Preferably, the pharmacologically active compound is selected from the group consisting of opiates, opioids, stimulants, tranquilizers, and other narcotics. For the purpose of the specification, the term pharmacologically active compound also includes the free base and the physiologically acceptable salts thereof. According to the ATC index, opioids are divided into natural opium alkaloids, phenylpiperi dine derivatives, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives and others. Examples of natural opium alkaloids are morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, WO 2013/127831 PCT/EP2013/053894 5 papaveretum, and codeine. Further pharmacologically active compounds are, for example, ethylmorphine, hydrocodone, oxymorphone, and the physiologically acceptable derivatives thereof or compounds, preferably the salts and solvates thereof, preferably the hydrochlorides thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, preferably ethers, esters or amides. The following opiates, opioids, tranquillizers or other narcotics are substances with a psychotropic action, i.e. have a potential of abuse, and hence are preferably contained in the pharmaceutical dosage form according to the invention: alfentanil, allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital, anileri dine, apocodeine, axomadol, barbital, bemidone, benzylmorphine, bezitramide, bromaze pam, brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil, cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol, clonazepam, clonita zene, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydro morphone, dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipa none, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene, etorphine, faxeladol, fencamfamine, fenethylline, fenpipramide, fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol (LAAM), levo methadone, levorphanol, levophenacylmorphane, levoxemacin, lisdexamfetamine dime sylate, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine, methylmorphine, metamphetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methyl phenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine, nicomorphine, nimetazepam, nitra zepam, nordazepam, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, oxycodone, oxymorphone, Papaver somniferum, papaveretum, pernoline, pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil, tapentadol, temazepam, tetrazepam, tilidine (cis and trans), tramadol, triazolam, vinylbital, N (1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, (1 R,2R)-3-(3-dimethylamino-1 -ethyl- WO 2013/127831 PCT/EP2013/053894 6 2-methyl-propyl)phenol, (1 R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1 -(m-me thoxyphenyl)cyclohexanol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3 (3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1-dimethylamino-3(3-methoxyphe nyl)-2-methyl-pentan-3-ol, (1 RS,3RS,6RS)-6-dimethylaminomethyl-1 -(3-methoxyphenyl) cyclohexane-1,3-diol, preferably as racemate, 3-(2-dimethylaminomethyl-1 -hydroxy cyclohexyl)phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-1 -hydroxy cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, 3-(2-dimethylaminomethyl cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-cyclo hex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, (RR-SS)-2-acetoxy-4-trifluoro methyl-benzoic acid 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS) 2-hydroxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl ester, (RR-SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dimethyl aminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methoxy-benzoic acid 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-5 nitro-benzoic acid 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS) 2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1 -hydroxy cyclohexyl)-phenyl ester, and corresponding stereoisomers, in each case the corresponding derivatives thereof, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, e.g. ethers, esters or amides, and in each case the physiologically acceptable compounds thereof, in particular the acid or base addition salts thereof and solvates, e.g. hydrochlorides. In a preferred embodiment the pharmaceutical dosage form according to the invention contains an opioid selected from the group consisting of DPI-125, M6G (CE-04-410), ADL 5859, CR-665, NRP290 and sebacoyl dinalbuphine ester. Particularly preferred pharmacologically active compounds include hydromorphone, oxymor phone, oxycodone, tapentadol, and the physiologically acceptable salts thereof. In a preferred embodiment the pharmaceutical dosage form according to the invention contains one pharmacologically active compound or more pharmacologically active compounds selected from the group consisting of oxymorphone, hydromorphone and morphine. In another preferred embodiment, the pharmacologically active compound is selected from the group consisting of tapentadol, faxeladol and axomadol. In still another preferred embodiment, the pharmacologically active compound is selected from the group consisting of 1,1 -(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9- WO 2013/127831 PCT/EP2013/053894 7 tetrahydropyrano[3,4-b]indole, particularly its hemicitrate; 1,1-[3-dimethylamino-3-(2-thienyl) pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its citrate; and 1,1-[3 dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoroindole, particularly its hemicitrate. These compounds are known from, e.g., WO 2004/043967, WO 2005/066183. The pharmacologically active compound may be present in form of a physiologically acceptable salt, e.g. physiologically acceptable acid addition salt. Physiologically acceptable acid addition salts comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the active ingredient with appropriate organic and inorganic acids. Active ingredients containing an acidic proton may be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The term addition salt also comprises the hydrates and solvent addition forms which the active ingredients are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. The content of the pharmacologically active compound in the pharmaceutical dosage form is not limited. The pharmacologically active compound is present in the pharmaceutical dosage form in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the active ingredients being used, the condition being treated, the severity of said condition, the patient being treated, and whether the pharmaceutical dosage form is designed for an immediate or retarded release. Preferably, the content of the pharmacologically active compound is within the range of from 0.01 to 80 wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably 1 to 25 wt.-%, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the content of pharmacologically active compound is within the range of from 7±6 wt.-%, more preferably 7±5 wt.-%, still more preferably 5±4 wt.-%, 7±4 wt.-% or 9±4 wt.-%, most preferably 5±3 wt.-%, 7±3 wt.-% or 9±3 wt.-%, and in particular 5+2 wt.-%, 7+2 wt.-% or 9±2 wt.-%, based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the content of pharmacologically active compound is within the range of from 11 ±10 wt.-%, more preferably 11 ±9 wt.-%, still more preferably 9±6 wt.-%, 11 6 wt.-%, 13±6 wt.-% or 15±6 wt.-%, most preferably 11+4 wt.-%, 13±4 wt.-% or 15+4 wt.-%, and in particular 11±2 wt.-%, 13±2 wt.-% or 15+2 wt.-%, based on the total weight of the pharmaceutical dosage form. In a further preferred embodiment, the content of pharmacologically active compound is within the range of from 20±6 wt.-%, more preferably WO 2013/127831 PCT/EP2013/053894 8 20±5 wt.-%, still more preferably 20+4 wt.-%, most preferably 20+3 wt.-%, and in particular 20±2 wt.-%, based on the total weight of the pharmaceutical dosage form. Preferably, the total amount of the pharmacologically active compound that is contained in the pharmaceutical dosage form is within the range of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and in particular 2.5 to 80 mg. In a preferred embodiment, the pharmacologically active compound is contained in the pharmaceutical dosage form in an amount of 7.5±5 mg, 10±5 mg, 20±5 mg, 30±5 mg, 40±5 mg, 50±5 mg, 60±5 mg, 70±5 mg, 80±5 mg, 90±5 mg, 100±5 mg, 110±5 mg, 120±5 mg, 130±5, 140+5 mg, 150±5 mg, or 160±5 mg. In another preferred embodiment, the pharmacologically active compound is contained in the pharmaceutical dosage form in an amount of 5±2.5 mg, 7.5±2.5 mg, 10±2.5 mg, 15+2.5 mg, 20±2.5 mg, 25±2.5 mg, 30±2.5 mg, 35±2.5 mg, 40±2.5 mg, 45±2.5 mg, 50±2.5 mg, 55±2.5 mg, 60±2.5 mg, 65±2.5 mg, 70±2.5 mg, 75±2.5 mg, 80+2.5 mg, 85±2.5 mg, 90±2.5 mg, 95±2.5 mg, 100±2.5 mg, 105±2.5 mg, 110±2.5 mg, 115±2.5 mg, 120+2.5 mg, 125±2.5 mg, 130±2.5 mg, 135±2.5 mg, 140±2.5 mg, 145±2.5 mg, 150±2.5 mg, 1552.5 mg, or 160±2.5 mg. In a preferred embodiment, the pharmacologically active compound is oxymorphone, preferably its hydrochloride salt, and the pharmaceutical dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 5 to 40 mg. In another particularly preferred embodiment, the pharmacologically active compound is oxymorphone, preferably its hydrochloride salt, and the pharmaceutical dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 10 to 80 mg. In another preferred embodiment, the pharmacologically active compound is oxycodone, preferably its hydrochloride salt, and the pharmaceutical dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 5 to 80 mg, preferably 5 mg, 10 mg, 20 mg or 40 mg. In another particularly preferred embodiment, the pharmacologically active compound is oxycodone, preferably its hydrochloride salt, and the pharmaceutical dosage form is adapted for administration once daily. In this embodiment, the WO 2013/127831 PCT/EP2013/053894 9 pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 10 to 320 mg. In still another particularly preferred embodiment, the pharmacologically active compound is hydromorphone, preferably its hydrochloride, and the pharmaceutical dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 2 to 52 mg. In another particularly preferred embodiment, the pharmacologically active compound is hydromorphone, preferably its hydrochloride salt, and the pharmaceutical dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 4 to 104 mg. In yet another particularly preferred embodiment, the pharmacologically active compound is tapentadol, preferably its hydrochloride, and the pharmaceutical dosage form is adapted for administration twice daily. In this embodiment, the pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 25 to 250 mg. In another particularly preferred embodiment, the pharmacologically active compound is tapentadol, preferably its hydrochloride salt, and the pharmaceutical dosage form is adapted for administration once daily. In this embodiment, the pharmacologically active compound is preferably contained in the pharmaceutical dosage form in an amount of from 50 to 600 mg. The pharmaceutical dosage form according to the invention further comprises an anionic polymer bearing carboxylic groups, wherein the content of the anionic polymer is > 20 wt.-%, based on the total weight of the pharmaceutical dosage form. Preferably, the anionic polymer comprises anionic functional groups selected from carboxyl groups, sulfonyl groups, sulfate groups, and phosphoryl groups. Preferably, the anionic polymer is derived from an ethylenically unsaturated monomer selected from (alk)acrylic acids, (alk)acrylic anhydrides, alkyl (alk)acrylates, or a combination thereof; i.e. the anionic polymer is preferably obtainable by polymerization of a monomer composition comprising one or more of said ethylenically unsaturated monomers and optionally at least partial hydrolysis of the optionally present acid anhydride and/or carboxylic ester groups.
WO 2013/127831 PCT/EP2013/053894 10 Preferably, the anionic polymer is obtainable by polymerization of a monomer composition comprising an ethylenically unsaturated monomer selected from ethylenically unsaturated carboxylic acids, ethylenically unsaturated carboxylic acid anhydrides, ethylenically unsaturated sulfonic acids, and mixtures thereof. Preferred ethylenically unsaturated carboxylic acid and ethylenically unsaturated carboxylic acid anhydride monomers include the acrylic acids typified by acrylic acid itself, methacrylic acid, ethacrylic acid, alpha-chloracrylic acid, alpha-cyano acrylic acid, beta-methyl-acrylic acid (crotonic acid), alpha-phenyl acrylic acid, beta-acryloxy propionic acid, sorbic acid, alpha-chloro sorbic acid, angelic acid, cinnamic acid, p-chloro cinnamic acid, beta-styryl acrylic acid (1-carboxy-4-phenyl butadiene-1,3), itaconic acid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaric acid, tricarboxy ethylene and maleic acid anhydride. Preferred ethylenically unsaturated sulfonic acids include aliphatic or aromatic vinyl sulfonic acids such as vinylsulfonic acid, allyl sulfonic acid, vinyltoluenesulfonic acid and styrene sulfonic acid; acrylic and methacrylic sulfonic acid such as sulfoethyl acrylate, sulfoethyl methacrylate, sulfopropyl acrylate, sulfopropyl methacrylate, 2-hydroxy-3-acryloxy propyl sulfonic acid, 2-hydroxy-3-methacryloxy propyl sulfonic acid and 2-acrylamido-2-methyl propane sulfonic acid. Preferably, the monomer composition comprises acrylic acid, methacrylic acid, and/or 2-acrylamido-2-methyl propane sulfonic acid. Acrylic acid is especially preferred. For the purpose of the specification, the wording "obtainable by polymerization of a monomer composition" does not necessarily require that the anionic polymer has been obtained from such a monomer composition indeed. In other words, the anionic polymer is a polymer comprising at least one repeating unit which results from polymerization of an ethylenically unsaturated monomer bearing an anionic functional group, in protonated form or a physiologically acceptable salt thereof. The anionic polymer may be linear or branched or cross-linked. Preferably, the anionic polymer is hydrophilic, more preferably water-soluble or water swellable.
WO 2013/127831 PCT/EP2013/053894 11 The anionic polymer may be a homopolymer or a copolymer. When the anionic polymer is a homopolymer, it comprises a single type of repeating unit, i.e. it is the polymerization product of a monomer composition comprising a single type of monomer. When the anionic polymer is a copolymer, it may comprise two, three or more different repeating units, i.e. may be the polymerization product of a monomer composition comprising two, three or more different monomers. In a preferred embodiment, the anionic polymer is a copolymer, comprising from about 50 mol-% to 99.999 mol-%, and more preferably from about 75 mol-% to 99.99 mol-% repeating units bearing anionic functional groups, preferably acid groups, more preferably carboxylic groups. Preferably, the anionic polymer has an average equivalent weight of 76±50 g/mol, more preferably of 76±30 g/mol, still more preferably of 76±20 g/mol and most preferably of 76±10 g/mol per carboxyl group. In a preferred embodiment, the monomer composition from which the anionic polymer is derivable further comprises a cross-linking agent, i.e. in this embodiment the anionic polymer is cross-linked. Suitable cross-linking agents include - compounds having at least two polymerizable double bonds, e.g. ethylenically unsaturated functional groups; - compounds having at least one polymerizable double bond, e.g. an ethylenically unsaturated functional group, and at least one functional group that is capable of reacting with another functional group of one or more of the repeating units of the anionic polymer; - compounds having at least two functional groups that are capable of reacting with other functional groups of one or more of the repeating units of the anionic polymer; and - polyvalent metal compounds which can form ionic cross-linkages, e.g. through the anionic functional groups. Cross-linking agents having at least two polymerizable double bonds, preferably allyl groups, are particularly preferred.
WO 2013/127831 PCT/EP2013/053894 12 Cross-linking agents having at least two polymerizable double bonds include (i) di- or polyvinyl compounds such as divinylbenzene and divinyltoluene; (ii) di- or poly-esters of unsaturated mono- or poly-carboxylic acids with polyols including, for example, di- or triacrylic acid esters of polyols such as ethylene glycol, trimethylol propane, glycerine, or polyoxyethylene glycols; (iii) bisacrylamides such as N,N-methylenebisacrylamide; (iv) carbamyl esters that can be obtained by reacting polyisocyanates with hydroxyl group containing monomers; (v) di- or poly-allyl ethers of polyols; (vi) di- or poly-allyl esters of polycarboxylic acids such as diallyl phthalate, diallyl adipate, and the like; (vii) esters of unsaturated mono- or poly-carboxylic acids with mono-allyl esters of polyols such as acrylic acid ester of polyethylene glycol monoallyl ether; and (viii) di- or triallyl amine. In a preferred embodiment, divinyl glycol (1,5-hexadiene-3,4-diol) is contained as cross linking agent, whereas allyl or vinyl derivatives of polyols, such as allylsucrose or allyl pentaerythritol, are less preferred. This embodiment is preferably realized by polyacrylic acid polymers of polycarbophil type according to USP. In another preferred embodiment, allyl derivatives of polyols, such as allylsucrose or allyl pentaerythritol, are contained as cross-linking agent, whereas divinyl glycol (1,5-hexadiene 3,4-diol) is less preferred. This embodiment is preferably realized by polyacrylic acid polymers of carbomer type according to USP or Ph. Eur. Cross-linking agents having at least one polymerizable double bond and at least one functional group capable of reacting with other functional groups of one or more of the repeating units of the anionic polymer include N-methylol acrylamide, glycidyl acrylate, and the like. Suitable cross-linking agents having at least two functional groups capable of reacting with other functional groups of one or more of the repeating units of the anionic polymer include glyoxal; polyols such as ethylene glycol; polyamines such as alkylene diamines (e.g., ethylene diamine), polyalkylene polyamines, polyepoxides, di- or polyglycidyl ethers and the like. Suitable polyvalent metal cross-linking agents which can form ionic cross-linkages include oxides, hydroxides and weak acid salts (e.g., carbonate, acetate and the like) of alkaline earth metals (e.g., calcium magnesium) and zinc, including, for example, calcium oxide and zinc diacetate.
WO 2013/127831 PCT/EP2013/053894 13 Of all of these types of cross-linking agents, the most preferred for use herein are diol derivatives and polyol derivatives, more specifically those selected from the group consisting of allyl sucrose, allyl pentaerythritol, divinyl glycol, divinyl polyethylene glycol and (meth)acrylic acid esters of diols. In a preferred embodiment, the monomer composition from which the anionic polymer is derivable comprises the cross-linking agent in an amount of at most 1.0 mol-%, more preferably at most 0.1 mol-%, even more preferably at most about 0.01 mol-%, and most preferably at most 0.005 mol-% based on all monomers forming the anionic polymer. In a preferred embodiment, the anionic polymer is a homopolymer of acrylic acid, optionally cross-linked, preferably with allyl sucrose or allyl pentaerythritol, in particular with allyl pentaerythritol. In another preferred embodiment, the anionic polymer is a copolymer of acrylic acid and C 10
-C
30 -alkyl acrylate, optionally cross-linked, preferably with allyl pentaerythritol. In another preferred embodiment, the anionic polymer is a so-called interpolymer, namely a homopolymer of acrylic acid, optionally cross-linked, preferably with allyl sucrose or allyl pentaerythritol; or a copolymer of acrylic acid and C 10
-C
30 -alkyl acrylate, optionally cross-linked, preferably with allyl pentaerythritol; which contain a block copolymer of polyethylene glycol and a long chain alkyl acid, preferably a C 8 -Coo-alkyl acid. Polymers of this type are commercially available, e.g. under the trademark Carbopol*. When the anionic polymer is an interpolymer, it preferably exhibits a viscosity within the range of from 2,000 to 60,000 mPa-s, more preferably 2,500 to 40,000 mPa-s, still more preferably 3,000 to 15,000 mPa-s, measured by means of a Brookfield viscosimeter (RVF, 20 rpm, spindle 5) in a 0.5 wt.-% aqueous solution at pH 7.5 and 25C. Preferably, at least some of the anionic functional groups contained in the anionic polymer are present in neutralized form, i.e. they are not present in their protonated forms, but are salts with salt-forming cations instead. Suitable salt-forming cations include alkali metal, ammonium, substituted ammonium and amines. More preferably, at least some of the anionic functional groups, e.g. carboxylate and/or sulfonate anions, are salts of sodium or potassium cations. This percentage of neutralized anionic functional groups, i.e. the percentage of anionic functional groups being present in neutralized form, based on the total amount of anionic functional groups, is referred to herein as the "degree of neutralization." In a preferred WO 2013/127831 PCT/EP2013/053894 14 embodiment, the degree of neutralization is within the range of from 2.5±2.4%, more preferably 2.5±2.0%, still more preferably 2.5±1.5%, yet more preferably 2.5+1.0%, and most preferably 2.5±0.5%. In another preferred embodiment, the degree of neutralization is within the range of 35±30%, more preferably 35+25%, still more preferably 35+20%, yet more preferably 35±15%, most preferably 35±10%, and in particular 35±5%. In yet another preferred embodiment, the degree of neutralization is in the range of 65±30%, more preferably 65±25%, still more preferably 65+20%, yet more preferably 65±15%, most preferably 65±10%, and in particular 65±5%. In a preferred embodiment, the anionic polymer has a weight average molecular weight (Mw) of at least 100,000 g/mol, preferably at least 200,000 g/mol or at least 400,000 g/mol, more preferably in the range of about 500,000 g/mol to about 5,000,000 g/mol, and most preferably in the range of about 600,000 g/mol to about 2,000,000 g/mol. Suitable methods to determine Mw are known to a person skilled in the art. For instance, Mw can be determined by gel permeation chromatography (GPC). In a preferred embodiment, the pKA of the anionic polymer is 6.0±2.0, more preferably 6.0±1.5, even more preferably 6.0+1.0, and most preferably 6.0±0.5. In another preferred embodiment, the pKA of the anionic polymer is 7.0±2.0, more preferably 7.0+1.5, even more preferably 7.0±1.0, and most preferably 7.0±0.5. In still another preferred embodiment, the pKA of the anionic polymer is 8.0+2.0, more preferably 8.0+1.5, even more preferably 8.0±1.0, and most preferably 8.0±0.5. In a preferred embodiment, the pH (in 1 wt% aqueous dispersion) of the anionic polymer is 3.0±3.0, more preferably 3.0±2.0, even more preferably 3.0+1.5, and most preferably 3.0±1.0. In another preferred embodiment, the pH (in 1 wt% aqueous dispersion) of the anionic polymer is 6.0±3.0, more preferably 6.0±2.0, even more preferably 6.0+1.5, and most preferably 6.0±1.0. The anionic polymer preferably exhibits a viscosity of 2,000 to 100,000 mPa s (cp), more preferably 3,000 to 80,000 mPa s, still more preferably 4,000 to 60,000 mPa s, measured by means of a Brookfield viscometer (RVF, 20 rpm, spindle 5) in a 0.5 wt.-% aqueous solution at pH 7.5 and 25C.
WO 2013/127831 PCT/EP2013/053894 15 In a preferred embodiment, the anionic polymer exhibits a viscosity of at most 30,000 mPa s (cp), preferably at most 28,000 mPa s, more preferably at most 25,000 mPa s, still more preferably at most 20,000 mPa s or at most 15,000 mPa s, measured by means of a Brookfield viscometer (RVF, 20 rpm, spindle 5) in a 0.5 wt.-% aqueous solution at pH 7.5 and 250C. Preferably, the overall content of anionic polymer is within the range of from 20 to 95 wt.-%, more preferably 20 to 90 wt.-%, most preferably 25 to 75 wt.-%, and in particular 25 to 50 wt.-%, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the overall content of anionic polymer is at least 21 wt.-%, more preferably at least 22 wt.-%, still more preferably at least 23 wt.-% or at least 24 wt.-%, most preferably at least 26 wt.-% or 28 wt.-%, and in particular at least 30 wt.-% or at least 32 wt.-%, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the overall content of anionic polymer is within the range of 20 to 50 wt.-%, more preferably 20 to 45 wt.-%, still more preferably 20 to 40 wt.-%, most preferably 20 to 35 wt.-%, and in particular preferably 20 to 30 wt.-%. In another preferred embodiment, the overall content of anionic polymer is within the range of 20 to 50 wt.-%, more preferably 20 to 45 wt.-%, still more preferably 20 to 40 wt.-%, most preferably 20 to 35 or 25 to 40 wt.-%, and in particular preferably 25 to 35 wt.-%. In still another preferred embodiment, the overall content of anionic polymer is within the range of 35±15 wt.-%, more preferably 35±10 wt.-%, and most preferably 35±5 wt.-%. In yet another preferred embodiment, the overall content of anionic polymer is within the range of 40±20 wt.-%, more preferably 40±15 wt.-%, most preferably 40+10 wt.-%, and in particular 40±5 wt.-%. In a further preferred embodiment, the overall content of anionic polymer is within the range of 50±20 wt.-%, more preferably 50±15 wt.-%, most preferably 50+10 wt.-%, and in particular 50±5 wt.-%. Preferably, the relative weight ratio of the anionic polymer to the pharmacologically active compound is at least 0.5:1, more preferably at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1 or at least 9:1. In a preferred embodiment, the relative weight ratio of the anionic polymer to the pharmacologically active compound is within the range of from 5:1 to 1:1, more preferably 4:1 to 2:1. In a preferred embodiment, the relative weight ratio of the pharmacologically active ingredient to the anionic polymer is at most 4.5:1, more preferably at most 4.0:1, still more WO 2013/127831 PCT/EP2013/053894 16 preferably at most 3.5:1, yet more preferably at most 3.0:1, even more preferably at most 2.5:1, most preferably at most 2.0:1 and in particular at most 1.5:1. In a particularly preferred embodiment, the relative weight ratio of the pharmacologically active ingredient to the anionic polymer is at most 1.4:1, more preferably at most 1.3:1, still more preferably at most 1.2:1, yet more preferably at most 1.1:1, even more preferably at most 1.0:1, most preferably at most 0.9:1 and in particular at most 0.8:1. Preferably, the relative weight ratio of the pharmacologically active ingredient to the sum of anionic polymer and nonionic surfactant is at most 3.0:1, more preferably at most 2.8:1, still more preferably at most 2.6:1, yet more preferably at most 2.4:1, even more preferably at most 2.2:1, most preferably at most 2.0:1 and in particular at most 1.8:1. In a particularly preferred embodiment, the relative weight ratio of the pharmacologically active ingredient to the sum of anionic polymer and nonionic surfactant is at most 1.6:1, more preferably at most 1.4:1, still more preferably at most 1.2:1, yet more preferably at most 1.0:1, even more preferably at most 0.8:1, most preferably at most 0.6:1 and in particular at most 0.4:1. In a preferred embodiment, the anionic polymer is homogeneously distributed in the pharmaceutical dosage form according to the invention. Preferably, the anionic polymer forms a matrix in which the pharmacologically active compound is embedded. In a particularly preferred embodiment, the pharmacologically active compound and the anionic polymer are intimately homogeneously distributed in the pharmaceutical dosage form so that the pharmaceutical dosage form does not contain any segments where either pharmacologically active compound is present in the absence of anionic polymer, or where anionic polymer is present in the absence of pharmacologically active compound. When the pharmaceutical dosage form is film coated, the anionic polymer is preferably homogeneously distributed in the core of the pharmaceutical dosage form, i.e. the film coating preferably does not contain anionic polymer. Nonetheless, the film coating as such may of course contain one or more polymers, which however, preferably differ from the anionic polymer contained in the core. The pharmaceutical dosage form according to the invention may either contain only one, or two or more anionic polymers of various types. The anionic polymer may be combined with one or more different polymers selected from the group consisting of polyalkylene oxide, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, WO 2013/127831 PCT/EP2013/053894 17 polystyrene, polyvinylpyrrolidone, poly(hydroxy fatty acids), such as for example poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®), poly(hydroxyvaleric acid); polycapro lactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyamide, polylactide, polyacetal (for example polysaccharides optionally with modified side chains), polylactide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymers of polyethylene glycol and polybutylene terephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymers thereof, block copolymers thereof, or with mixtures of at least two of the stated polymers. In a preferred embodiment, the pharmaceutical dosage form according to the invention does not contain any polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, preferably at least 150,000 g/mol, more preferably at least 100,000 g/mol, still more preferably at least 75,000 g/mol, yet more preferably at least 50,000 g/mol, and most preferably at least 25,000 g/mol. If, however, the anionic polymer is combined with one or more polymers selected from the group consisting of polyalkylene oxides, preferably polymethylene oxide, polyethylene oxide and polypropylene oxide; the total content of polyalkylene oxide(s) having an average molecular weight of at least 200,000 g/mol is preferably 5 35 wt.-%, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the pharmaceutical dosage form according to the invention contains at least one polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, preferably at least 150,000 g/mol, more preferably at least 100,000 g/mol, still more preferably at least 75,000 g/mol, yet more preferably at least 50,000 g/mol, and most preferably at least 25,000 g/mol. In this embodiment, the total content of polyalkylene oxide(s) contained in the dosage form and having said minimum average molecular weight is preferably 35 wt.-%, more preferably 30 wt.-%, still more preferably 5 25 wt.-%, yet more preferably 5 20 wt.-%, even more preferably 5 15 wt.-%, most preferably 5 10 wt.-%, and in particular < 5 wt.-%, based on the total weight of the pharmaceutical dosage form. For the purpose of the specification, a polyalkylene oxide may comprise a single polyalkylene oxide having a particular average molecular weight, or a mixture (blend) of different polymers, such as two, three, four or five polymers, e.g., polymers of the same chemical nature but different average molecular weight, polymers of different chemical nature but same average molecular weight, or polymers of different chemical nature as well as different molecular weight.
WO 2013/127831 PCT/EP2013/053894 18 For the purpose of the specification, a polyalkylene glycol has a molecular weight of up to 20,000 g/mol whereas a polyalkylene oxide has a molecular weight of more than 20,000 g/mol. Polyalkylene glycols, if any, are preferably not taken into consideration when determining the weight average molecular weight of polyalkylene oxide. In a preferred embodiment according to the invention, the anionic polymer is combined with at least one further polymer, preferably selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, poly(hydroxy fatty acids), polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide, polylactide, poly lactide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymers of polyethylene glycol and polybutylene terephthalate, polyanhydride, polyacetal, cellulose esters, cellulose ethers and copolymers thereof. Cellulose esters and cellulose ethers are particularly preferred, e.g. methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxy ethylcellulose, hydroxypropylcellu lose hydroxypropylmethylcellu lose, carboxymethylcellulose, and the like. In a preferred embodiment, said further polymer is neither an anionic polymer nor a polyalky lene glycol or polyalkylene oxide. Nonetheless, the pharmaceutical dosage form may contain polyalkylene glycol, e.g. as plasticizer, or a polyalkylene oxide, but then, the pharmaceutical dosage form preferably is an at least ternary mixture of polymers: anionic polymer + further polymer + plasticizer or anionic polymer + further polymer + polyalkylene oxide. A ternary mixture of anionic polymer + further polymer + plasticizer is particularly preferred. In a particularly preferred embodiment, said further polymer is a hydrophilic cellulose ester or cellulose ether, preferably hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) or hydroxyethylcellulose (HEC), preferably having an average viscosity (preferably measured by capillary viscosimetry or rotational viscosimetry) of 1,000 to 150,000 mPas, more preferably 3,000 to 150,000. In a preferred embodiment, the average viscosity is within the range of 110,000±50,000 mPas, more preferably 110,000+40,000 mPas, still more preferably 110,000±30,000 mPas, most preferably 110,000+20,000 mPas, and in particular 100,000+10,000 mPas. In a preferred embodiment, the further polymer is a cellulose ester or cellulose ether, prefer ably HPMC, having a content within the range of 10±8 wt.-%, more preferably 10+6 wt.-%, still more preferably 10±5 wt.-%, yet more preferably 10+4 wt.-%, most preferably 10±3 wt.- WO 2013/127831 PCT/EP2013/053894 19 %, and in particular 10±2 wt.-%, based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the further polymer is a cellulose ester or cellulose ether, preferably HPMC, having a content within the range of 15±8 wt.-%, more preferably 15±6 wt.
%, still more preferably 15+5 wt.-%, yet more preferably 15±4 wt.-%, most preferably 15±3 wt.-%, and in particular 15+2 wt.-%, based on the total weight of the pharmaceutical dosage form. Preferably, the relative weight ratio of the sum of anionic polymer and nonionic surfactant to further polymer is within the range of from 1:1 to 10:1, more preferably from 2:1 to 8:1. In a preferred embodiment, the relative weight ratio of the sum of anionic polymer and nonionic surfactant to further polymer is at least 2.0:1, more preferably at least 2.5:1, still more preferably at least 3.0:1, yet more preferably at least 3.5:1, even more preferably at least 4.0:1, most preferably at least 4.5:1, and in particular at least 5.0:1. The pharmaceutical dosage form according to the invention further comprises a nonionic surfactant. In a preferred embodiment, the nonionic surfactant has a hydrophilic-lipophilic balance (HLB) of at least 10, preferably at least 12, more preferably at least 14, still more preferably at least 16, yet more preferably at least 18, even more preferably at least 20, most preferably at least 22, and in particular at least or more than 24. The hydrophilic-lipophilic balance (HLB value) can be estimated according to Griffin's method (Griffin, W. C.; J. Soc. Cosmet. Chem. 1 (1949) 311). Preferably, however, the HLB value is calculated by the incremental method, i.e. by adding the individual HLB increments of all hydrophobic and hydrophilic groups present in the molecule. HLB increments of many hydrophobic and hydrophilic groups can be found, e.g., in Fiedler, H.P., Encyclopedia of Excipients, Editio Cantor Verlag, Aulendorf, 6th Edition, 2007. The HLB value can further be determined experimentally, e.g. by partition chromatography or HPLC. In another preferred embodiment, the nonionic surfactant exhibits a surface tension in 0.1% aqueous solution at 250C of at least 35 dynes/cm, more preferably at least 40 dynes/cm, still WO 2013/127831 PCT/EP2013/053894 20 more preferably at least 43 dynes/cm, yet more preferably at least 45 dynes/cm, even more preferably at least 47 dynes/cm, in particular at least 50 dynes/cm. In another preferred embodiment, the nonionic surfactant exhibits a viscosity of at most 4000 mPa-s, more preferably at most 3500 mPa-s, still more preferably at most 3000 mPa-s, yet more preferably at most 2500 mPa-s, even more preferably at most 2000 mPa-s, most preferably at most 1500 mPa-s, and in particular at most 1000 mPa-s, measured at 70 0C using a model LVF or LVT Brookfield viscosimeter. Suitable non-ionic surfactants include but are not limited to - polyoxypropylene-polyoxyethylene block copolymers (e.g., poloxamers or poloxamines), preferably according to general formula (1-a)
CH
3 HO 0 H a -c - - b (1-a) wherein a and c are each independently an integer of from 5 to 250, and b is an integer of from 10 to 100; preferably, a = c # b; and/or a = c> b; or according to general formula (1-b) H. H3 k H3
CH
3
CH
3 C H O 0 - 1 . f (1-b) wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and I are each independently an integer of from 2 to 50; and preferably, the ratio (e+f+g+h)/(i+j+k+l) is an integer of from 0.015 to 30; WO 2013/127831 PCT/EP2013/053894 21 - fatty alcohols that may be linear or branched, such as cetylalcohol, stearylalcohol, cetylstearyl alcohol, 2-octyldodecane-1 -ol and 2-hexyldecane-1 -ol; - sterols, such as cholesterole; - partial fatty acid esters of sorbitan such as sorbitanmonolaurate, sorbitanmonopalmitate, sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate, sorbitansesquioleate and sorbitantrioleate; - partial fatty acid esters of polyoxyethylene sorbitan (polyoxyethylene-sorbitan-fatty acid esters), preferably a fatty acid monoester of polyoxyethylene sorbitan, a fatty acid diester of polyoxyethylene sorbitan, or a fatty acid triester of polyoxyethylene sorbitan; e.g. mono and tri- lauryl, palmityl, stearyl and oleyl esters, such as the type known under the name "polysorbat" and commercially available under the trade name "Tween" including Tween* 20 [olyoxyethylene(20)sorbitan monolaurate], Tween* 21 [olyoxyethylene(4)sorbitan monolaurate], Tween* 40 [olyoxyethylene(20)sorbitan monopalmitate], Tween* 60 [olyoxyethylene(20)sorbitan monostearate], Tween* 65 [olyoxyethylene(20)sorbitan tristearate], Tween* 80 [olyoxyethylene(20)sorbitan monooleate], Tween 81 [olyoxyethylene(5)sorbitan monooleate], and Tween* 85 [olyoxyethylene(20)sorbitan trioleate]; preferably a fatty acid monoester of polyoxyethylenesorbitan according to general formula (1-c)
HO(C
2
H
4 0)w (OC 2
H
4 )xOH 0 CH-(OC 2
H
4 )yOH
H
2
C--(OC
2
H
4 )zO-C- Alkylene--CH 3 0 (I-c) wherein (w+x+y+z) is within the range of from 15 to 100, preferably 16 to 80, more preferably 17 to 60, still more preferably 18 to 40 and most preferably 19 to 21; and alkylene is an optionally unsaturated alkylene group comprising 6 to 30 carbon atoms, more preferably 8 to 24 carbon atoms and most preferably 10 to 16 carbon atoms; - polyoxyethyleneglycerole fatty acid esters such as mixtures of mono-, di- and triesters of glycerol and di- and monoesters of macrogols having molecular weights within the range of from 200 to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate, macrogolglycerollaurate, WO 2013/127831 PCT/EP2013/053894 22 macrogolglycerolococoate, macrogolglycerollinoleate, macrogol-20-glycerolmonostearate, macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate; macrogolglycerolstearate, macrogolglycerolhydroxystearate (e.g. Cremophor* RH 40), and macrogolglycerol rizinoleate (e.g. Cremophor* EL); - polyoxyethylene fatty acid esters, the fatty acid preferably having from about 8 to about 18 carbon atoms, e.g. macrogololeate, macrogolstearate, macrogol-15-hydroxystearate, polyoxyethylene esters of 12-hydroxystearic acid, such as the type known and commercially available under the trade name "Solutol HS 15"; preferably according to general formula (1-d)
CH
3
CH
2
-(OCH
2
CH
3
)-O-CO-(CH
2 )mCH 3 (1-d) wherein n is an integer of from 6 to 500, preferably 7 to 250, more preferably 8 to 100, still more preferably 9 to 75, yet more preferably 10 to 50, even more preferably 11 to 30, most preferably 12 to 25, and in particular 13 to 20; and wherein m is an integer of from 6 to 28; more preferably 6 to 26, still more preferably 8 to 24, yet more preferably 10 to 22, even more preferably 12 to 20, most preferably 14 to 18 and in particular 16; - polyoxyethylene fatty alcohol ethers, e.g. macrogolcetylstearylether, macrogollaurylether, macrogololeylether, macrogolstearylether; - fatty acid esters of saccharose; e.g. saccharose distearate, saccharose dioleate, saccharose dipalmitate, saccharose monostearate, saccharose monooleate, saccharose monopalmitate, saccharose monomyristate and saccharose monolaurate; - fatty acid esters of polyglycerol, e.g. polyglycerololeate; - polyoxyethylene esters of alpha-tocopheryl succinate, e.g. D-alpha-tocopheryl-PEG-1000 succinate (TPGS); - polyglycolyzed glycerides, such as the types known and commercially available under the trade names "Gelucire 44/14", "Gelucire 50/13 and "Labrasol"; - reaction products of a natural or hydrogenated castor oil and ethylene oxide such as the various liquid surfactants known and commercially available under the trade name "Cremophor"; and - partial fatty acid esters of multifunctional alcohols, such as glycerol fatty acid esters, e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters, for example glycerol monostearate, glycerol monooleate, e.g. glyceryl monooleate 40, known and commercially available under the trade name "Peceol"; glycerole dibehenate, glycerole distearate, glycerole WO 2013/127831 PCT/EP2013/053894 23 monolinoleate; ethyleneglycol monostearate, ethyleneglycol monopalmitostearate, pentaerythritol monostearate. In a preferred embodiment, the nonionic surfactant is a thermosensitive polymer, in particular an inverse thermosensitive polymer, i.e. a polymer that is soluble in water at a comparatively low temperature, e.g. below or about 20 0C, but gels (forms a gel) at higher temperatures, e.g. above 35 C. For the purpose of the specification, an "inverse thermosensitive polymer" preferably is a polymer exhibiting an atypical dependency of viscosity from temperature; while aqueous dispersions of conventional polymers typically show decreased viscosities at increased temperatures, the viscosity of an aqueous dispersion of an inverse thermosensitive polymer according to the invention increases at increased temperatures, at least within a certain temperature range above ambient temperature. Preferably, the increase of viscosity that is induced by an increase of temperature leads to gel formation so that an aqueous dispersion of an inverse thermosensitive polymer according to the invention preferably forms a liquid solution at ambient temperature but a viscous gel at elevated temperature. Polymeric nonionic surfactants exhibiting these properties are known to the skilled artisan. A skilled person recognizes that viscosity and gel strength may decrease again, once a certain temperature is exceeded. Thus, an aqueous dispersion of an inverse thermosensitive polymer according to the invention preferably has a viscosity maximum, which at a concentration of 25 wt.-%, relative to the total weight of the aqueous dispersion, is preferably within the range 45±20 OC, or 55+20 OC, or 65+20 C, or 75±20 OC. Thus, the nonionic surfactant according to the invention preferably forms a liquid solution in water at ambient temperature, and when the temperature is increased, the surfactant forms an aqueous gel, at least within a certain temperature range above ambient temperature. Preferably, in pure water at a concentration of 25 wt.-% the nonionic surfactant forms an aqueous dispersion having a viscosity i, at a temperature T, of 20 0C and a viscosity 12 at a temperature T 2 of more than 20 0C (i.e. T 2 > Tj), where 12 > il. This does not necessarily mean that viscosity 12 at any temperature T 2 above 20 OC must be greater than viscosity ill at 20 0C. Instead, this means that there is at least one temperature T 2 above 20 OC at which viscosity 12 of the aqueous dispersion is greater than viscosity i, at T, (=20 0C).
WO 2013/127831 PCT/EP2013/053894 24 Preferably, an aqueous solution comprising at least 20 wt.-% or at least 25 wt.-% nonionic surfactant shows a thermoreversible behavior, i.e. the viscosity of the solution increases with increasing temperature and decreases with decreasing temperature, and repeated heating and cooling does not affect this property. Preferably, the aqueous solution exhibits a thermoreversible behavior with a maximum viscosity between 30 and 80 C. In an especially preferred embodiment, the aqueous solution is a liquid at 20 IC and forms a semi-solid gel upon heating to a temperature of at most 80 1C, more preferably 60 1C, most preferably at most 45 1C, and in particular at most 370C. Preferably, the sol-gel transition temperature, i.e. the temperature at which the phase transition occurs, is within the range of from 10 C to 80 0C, more preferably within the range of from 15 0C to 75 0C, and most preferably within the range of from 20 IC to 60 C. For example, various poloxamines and poloxamers, including poloxamer 407 and poloxamer 188, show inverse thermosensitivity. Particularly preferably, the nonionic surfactant is a polyoxypropylene-polyoxyethylene block copolymer, preferably selected from poloxamers and poloxamines, in particular polyoxypropylene-polyoxyethylene block copolymer according to general formula (I-a) and polyoxypropylene-polyoxyethylene block copolymer according to general formula (1-b). In a particular preferred embodiment, the nonionic surfactant is a polyoxypropylene polyoxyethylene block copolymer according to general formula (I-a)
CH
3 HO O H a c b (I-a) wherein a and c are each independently an integer of from 5 to 250, and b is an integer of from 10 to 100; and preferably, a = c # b; and/or a = c > b. More preferably, a and c are each independently an integer of from 10 to 120, and b is an integer of from 15 to 75; and preferably, a = c > b. Polyoxypropylene-polyoxyethylene block copolymers of this type are also known as poloxamers and are commercially available under the trade name Pluronics.
WO 2013/127831 PCT/EP2013/053894 25 In a preferred embodiment, a, b and c are each independently an integer as specified as preferred embodiments N' to N 32 in the table here below: a b c a b c N' 80±75 27±17 80±75 N 9 80±27 27±9 80±27
N
2 80±65 27±16 80±65 N 10 80±23 27±8 80±23
N
3 80±55 27±15 80±55 N 80±19 27±7 80±19
N
4 80±50 27±14 80±50 N 12 80±15 27±6 80±15
N
5 80±45 27±13 80±45 N 13 80±12 27±5 80±12
N
6 80±40 27±12 80±40 N 1 4 80±9 27±4 80±9
N
7 80±35 27±11 80±35 N 15 80±6 27±3 80±6
N
8 80±31 27±10 80±31 N 16 80±3 27±2 80±3 a b c a b c
N
17 12±11 20±15 12±11 N 25 101±80 56±35 101±80
N
18 12±8 20±12 12±8 N 26 101±55 56±21 101±55
N
19 12±5 20±8 12±5 N 27 101±31 56±12 101±31
N
2 0 12±2 20±4 12±2 N 28 101±15 56±8 101±15
N
21 64±45 37±13 64±45 N 29 141±120 44±31 141±120
N
22 64±20 37±10 64±20 N 30 141±90 44±27 141±90
N
23 64±12 37±7 64±12 N 31 141±35 44±19 141±35
N
24 64±5 37±5 64±5 N 32 141±17 44±11 141±17 In another preferred embodiment, the nonionic surfactant is a polyoxypropylene polyoxyethylene block copolymer according to general formula (I-b) eH/.H 3 . k H3
CH
3 ~
CH
3 C
.
f (I-b) WO 2013/127831 PCT/EP2013/053894 26 wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and I are each independently an integer of from 2 to 50; and preferably, the ratio (e+f+g+h)/(i+j+k+l)is from 0.015 to 30, in particular from 1 to 10. More preferably, e, f, g and h are each independently an integer of from 3 to 50, and i, j, k and I are each independently an integer of from 2 to 30. Tetrafunctional polyoxypropylene-polyoxyethylene block copolymers of this type are also known as poloxamines and are commercially available under the trade name Tetronics. Preferably, the nonionic surfactant, preferably according to general formula (I-a) or according to general formula (I-b) has an average molecular weight of at least 2,000 g/mol, more preferably at least 3,000 g/mol, still more preferably at least 4,000 g/mol, yet more preferably at least 5,000 g/mol, even more preferably at least 6,000 g/mol, most preferably at least 7,000 g/mol, and in particular at least 7,500 g/mol. In a preferred embodiment, the nonionic surfactant, preferably according to general formula (I-a) or according to general formula (I-b) has an average molecular weight of at most 30,000 g/mol, more preferably at most 25,000 g/mol, still more preferably at most 20,000 g/mol, yet more preferably at most 15,000 g/mol, even more preferably at most 12,500 g/mol, most preferably at most 10,000 g/mol, and in particular at most 9,500 g/mol. Preferably, the nonionic surfactant, preferably according to general formula (I-a) or according to general formula (I-b) has an average molecular weight as specified as preferred embodiments O' to 032 in the table here below: g/mol MW g/mol MW g/mol MW g/mol MW O' 8,600+7,500 09 8,600+1,500 O17 2,200+1,000 025 12,200+8,000 02 8,600±5,000 1O' 8,600+1,400 018 2,200+500 026 12,200+4,000 0 8,600+4,000 O11 8,600+1,300 019 2,200+250 027 12,200+3,000 04 8,600±3,000 O12 8,600+1,200 021 7,800±6,000 028 12,200+1,500 o5 8,600+2,500 O13 8,600+1,100 021 7,800+4,000 029 15,000+7,500 o6 8,600+2,250 014 8,600+1,000 O22 7,800+1,500 031 15,000+5,000 07 8,600+2,000 o15 8,600±950 023 7,800+1,000 031 15,000+3,000 08 8,600+1,750 o16 8,600+920 024 7,800±800 032 15,000+2,000 Preferably, the nonionic surfactant, preferably according to general formula (I-a) or according to general formula (I-b) has an oxyethylene content, as determined according to USP or Ph.Eur., of at least 60%, more preferably at least 70%, still more preferably at least 72%, yet WO 2013/127831 PCT/EP2013/053894 27 more preferably at least 74%, even more preferably at least 76%, most preferably at least 78%, and in particular at least 80%. Preferably, the nonionic surfactant, preferably according to general formula (1-a) or according to general formula (1-b) has an oxyethylene content, as determined according to USP or Ph.Eur., of at most 90%, more preferably at most 89%, still more preferably at most 88%, yet more preferably at most 87%, even more preferably at most 86%, most preferably at most 85%, and in particular at most 84%. Preferably, the nonionic surfactant, preferably according to general formula (1-a) or according to general formula (1-b) has an oxyethylene content, as determined according to USP or Ph.Eur., as specified as preferred embodiments P' to P 3 2 in the table here below: % OE-content % OE-content % OE-content % OE-content P' 81.8±17.0 P 9 81.8±9.0 P 17 46.5±15.0 P 25 73.0±6.0
P
2 81.8±16.0 P 0 81.8±8.0 P 18 46.5±10.0 P 26 73.0±4.0
P
3 81.8±15.0 P 1 81.8±7.0 P 19 46.5±5.0 P 2 7 75.0±5.0
P
4 81.8±14.0 P 12 81.8±6.0 P 2 0 60.0±20.0 P 28 75.0±4.0
P
5 81.8±13.0 P 13 81.8±5.0 P 2 1 60.0±15.0 P 29 75.0±3.0 p 6 81.8±12.0 P 14 81.8±4.0 P 22 70.0±10.0 P 3 0 85.0±5.0
P
7 81.8±11.0 P 15 81.8±3.0 P 23 70.0±8.0 P 3 ' 85.0±4.0 p 8 81.8±10.0 P 16 81.8±2.0 P 24 70.0±5.0 P 32 85.0±3.0 The content of the nonionic surfactant in the pharmaceutical dosage form is not limited. Preferably, the content of the nonionic surfactant in the pharmaceutical dosage form according to the invention is such that liquid extraction of the pharmacologically active compound and thus, parenteral administration of the liquid extract, is impeded. Preferably, the content of the nonionic surfactant is at least 0.1 wt.-%, more preferably at least 1.0 wt.-%, still more at least 5 wt.-%, yet more preferably at least 10 wt.-%, most preferably at least 15 wt.-%, and in particular at least 20 wt.-%, based on the total weight of the pharmaceutical dosage form. Preferably, the content of the nonionic surfactant is within the range of from 0.1 to 60 wt.-%, more preferably 5 to 50 wt.-%, still more preferably 10 to 45 wt.-%, most preferably 15 to 40 wt.-%, and in particular 20 to 35 wt.-%, based on the total weight of the pharmaceutical dosage form.
WO 2013/127831 PCT/EP2013/053894 28 In a preferred embodiment, the content of nonionic surfactant is within the range of 15±12 wt.-%, more preferably 15+10 wt.-%, most preferably 15+7 wt.-%, and in particular 15±5 wt.
%, based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the content of nonionic surfactant is within the range of 20±18 wt.-%, more preferably 20±15 wt.-%, still more preferably 20±12 wt.-%, most preferably 20±10 wt.-%, 20±7 wt.-%, and in particular 20±5 wt.-%, based on the total weight of the pharmaceutical dosage form. In a further preferred embodiment, the content of nonionic surfactant is within the range of 25+20 wt.-%, more preferably 25±17 wt.-%, still more preferably 25±15 wt.-%, even more preferably 25+10 wt.-%, most preferably 25+7 wt.-%, and in particular 25+5 wt.-%, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the content of nonionic surfactant is within the range of 30±20 wt.-%, more preferably 30+17 wt.-%, still more preferably 30±15 wt.-%, even more preferably 30±10 wt.-%, most preferably 30±7 wt.-%, and in particular 30±5 wt.-%, based on the total weight of the pharmaceutical dosage form. In another further preferred embodiment, the content of nonionic surfactant is within the range of 35+20 wt.-%, more preferably 35±17 wt.
%, still more preferably 35±15 wt.-%, even more preferably 35+10 wt.-%, most preferably 35±7 wt.-%, and in particular 35±5 wt.-%, based on the total weight of the pharmaceutical dosage form. In a further preferred embodiment, the content of nonionic surfactant is within the range of 40+25 wt.-%, more preferably 40±15 wt.-%, still more preferably 40±10 wt.-%, most preferably 40±7 wt.-%, and in particular 40±5 wt.-%, based on the total weight of the pharmaceutical dosage form. Preferably, the total amount of the nonionic surfactant that is contained in the pharmaceutical dosage form is within the range of from 0.1 to 750 mg, more preferably 10 to 500 mg, still more preferably 25 to 400 mg, yet more preferably 50 to 350 mg, most preferably 75 to 300 mg and in particular 100 to 250 mg. In a preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 100±95 mg, 100±90 mg, 100+80 mg, 100±70 mg, 100±60 mg, 100±50 mg, 100±40 mg, 100±30 mg, 100±20 mg, or 100±10 mg. In another preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 120±115 mg, 120±100 mg, 120±90 mg, 120±80 mg, 120±70 mg, 120±60 mg, 120±50 mg, 120±40 mg, 120+30 mg, 120±20 mg, or 120±10 mg. In still another preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 140±135 mg, 140±120 mg, 140±110 mg, 140±100 mg, 140±90 mg, 140±80 mg, WO 2013/127831 PCT/EP2013/053894 29 140±70 mg, 140±60 mg, 140±50 mg, 140±40 mg, 140±30 mg, 140±20 mg, or 140+10 mg. In yet another preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 160±155 mg, 160±140 mg, 160±130 mg, 160±120 mg, 160±110 mg, 160±1 00 mg, 160±90 mg, 160±80 mg, 160±70 mg, 160±60 mg, 160±50 mg, 160±40 mg, 160±30 mg, 160±20 mg, or 160±10 mg. In a preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 180±175 mg, 180±160 mg, 180±150 mg, 180±140 mg, 180±130 mg, 180±120 mg, 180±110 mg, 180±100 mg, 180+90 mg, 180±80 mg, 180±70 mg, 180±60 mg, 180±50 mg, 180+40 mg, 180±30 mg, 180±20 mg, or 180+10 mg. In another preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 200±190 mg, 200+180 mg, 200±170 mg, 200±160 mg, 200±150 mg, 200±140 mg, 200±130 mg, 200±120 mg, 200±110 mg, 200±100 mg, 200±90 mg, 200+80 mg, 200±70 mg, 200±60 mg, 200±50 mg, 200±40 mg, 200±30 mg, 200±20 mg, or 200±10 mg. In still another preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 220±210 mg, 220±200 mg, 220±180 mg, 220±160 mg, 220±150 mg, 220±140 mg, 220±130 mg, 220+120 mg, 220±110 mg, 220±100 mg, 220±90 mg, 220±80 mg, 220±70 mg, 220±60 mg, 220+50 mg, 220±40 mg, 220±30 mg, 220±20 mg, or 220±10 mg. In yet another preferred embodiment, the nonionic surfactant is contained in the pharmaceutical dosage form in an amount of 240±210 mg, 240±200 mg, 240±180 mg, 240±160 mg, 240±150 mg, 240±140 mg, 240+130 mg, 240±120 mg, 240±110 mg, 240±1 00 mg, 240±90 mg, 240±80 mg, 240±70 mg, 240+60 mg, 240±50 mg, 240±40 mg, 240±30 mg, 240±20 mg, or 240±10 mg. Preferably, the relative weight ratio of the pharmacologically active compound and the nonionic surfactant is within the range of from 20:1 to 1:20, more preferably 15:1 to 1:15, still more preferably 10:1 to 1:10, yet more preferably 5:1 to 1:10, even more preferably 2:1 to 1:5, most preferably 1:1 to 1:4, and in particular 1:1.5 to 1:3. In a preferred embodiment, the relative weight ratio of the pharmacologically active compound and the nonionic surfactant is at most 6.5:1, more preferably at most 5.0:1, still more preferably at most 4.0:1, yet more preferably at most 3.0:1, even more preferably at most 2.5:1, most preferably at most 2.0:1, and in particular at most 1.5:1. In a particularly preferred embodiment, the relative weight ratio of the pharmacologically active compound and the nonionic surfactant is at most 1.4:1, more preferably at most 1.3:1, still more preferably at most 1.2:1, yet more preferably at most 1.1:1, even more preferably at most 1.0:1, most preferably at most 0.9:1, and in particular at most 0.8:1.
WO 2013/127831 PCT/EP2013/053894 30 Preferably, the relative weight ratio of the anionic polymer and the nonionic surfactant is within the range of from 20:1 to 1:20, more preferably 15:1 to 1:15, still more preferably 10:1 to 1:10, yet more preferably 5:1 to 1:5, even more preferably 5:1 to 1:3, most preferably 3:1 to 1:2, and in particular 2:1 to 1:2. In a preferred embodiment, the nonionic surfactant is homogeneously distributed in the pharmaceutical dosage form according to the invention. Preferably, the pharmacologically active compound, the anionic polymer and the nonionic surfactant are homogeneously distributed over the pharmaceutical dosage form or, when the pharmaceutical dosage form comprises a film coating, over the coated core of the pharmaceutical dosage form. In a particularly preferred embodiment, the pharmacologically active compound, the anionic polymer and the nonionic surfactant are intimately mixed with one another, so that the pharmaceutical dosage form does not contain any segments where either pharmacologically active compound is present in the absence of anionic polymer and/or the nonionic surfactant, or where anionic polymer is present in the absence of pharmacologically active compound and/or the surfactant. Preferably, the pharmacologically active compound and the nonionic surfactant are homogeneously dispersed in the anionic polymer, preferably in molecular disperse form or solid disperse form. In other words, the pharmacologically active compound and the nonionic surfactant preferably form a solid solution or solid dispersion in the anionic polymer. Preferably, the pharmacologically active compound is embedded in a prolonged release matrix comprising the anionic polymer and the nonionic surfactant. Thus, the prolonged release matrix is preferably a hydrophilic matrix. Preferably, the release profile of the pharmacologically active compound is matrix-retarded. Preferably, the pharmacologically active compound is embedded in a matrix comprising the anionic polymer and the nonionic surfactant, said matrix controlling the release of the pharmacologically active compound from the pharmaceutical dosage form. Physiologically acceptable materials which are known to the person skilled in the art may be used as supplementary matrix materials. Polymers, particularly preferably cellulose ethers and/or cellulose esters are preferably used as supplementary hydrophilic matrix materials.
WO 2013/127831 PCT/EP2013/053894 31 Ethylcellulose, hydroxypropylmethylcellu lose, hydroxypropylcellulose, hydroxymethylcellu lose, hydroxyethylcellulose, and/or the derivatives thereof, such as the salts thereof are very particularly preferably used as matrix materials. Preferably, the pharmaceutical dosage form according to the invention is for oral administration. In a preferred embodiment, the pharmaceutical dosage form according to the invention is configured for administration once daily, preferably orally. In another preferred embodiment, the pharmaceutical dosage form according to the invention is configured for administration twice daily, preferably orally. In still another preferred embodiment, the pharmaceutical dosage form according to the invention is configured for administration thrice daily, preferably orally. For the purpose of the specification, "twice daily" means equal or nearly equal time intervals, i.e., about every 12 hours, or different time intervals, e.g., 8 and 16 hours or 10 and 14 hours, between the individual administrations. For the purpose of the specification, "thrice daily" means equal or nearly equal time intervals, i.e., about every 8 hours, or different time intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, between the individual administrations. Preferably, the pharmaceutical dosage form according to the invention causes an at least partially delayed or prolonged release of pharmacologically active compound. Controlled or prolonged release is understood according to the invention preferably to mean a release profile in which the pharmacologically active compound is released over a relatively long period with reduced intake frequency with the purpose of extended therapeutic action of the pharmacologically active compound. Preferably, the meaning of the term "prolonged release" is in accordance with the European guideline on the nomenclature of the release profile of pharmaceutical dosage forms (CHMP). This is achieved in particular with peroral administration. The expression "at least partially delayed or prolonged release" covers according to the invention any pharmaceutical dosage forms which ensure modified release of the pharmacologically active compound contained therein. The pharmaceutical dosage forms preferably comprise coated or uncoated pharmaceutical dosage forms, which are produced with specific auxiliary substances, by particular processes or by a combination of WO 2013/127831 PCT/EP2013/053894 32 the two possible options in order purposefully to change the release rate or location of release. In the case of the pharmaceutical dosage forms according to the invention, the release profile of a controlled release form may be modified e.g. as follows: extended release, repeat action release, prolonged release and sustained release. For the purpose of the specification "controlled release" preferably means a product in which the release of active compound over time is controlled by the type and composition of the formulation. For the purpose of the specification "extended release" preferably means a product in which the release of active compound is delayed for a finite lag time, after which release is unhindered. For the purpose of the specification "repeat action release" preferably means a product in which a first portion of active compound is released initially, followed by at least one further portion of active compound being released subsequently. For the purpose of the specification "prolonged release" preferably means a product in which the rate of release of active compound from the formulation after administration has been reduced over time, in order to maintain therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose. For the purpose of the specification "sustained release" preferably means a way of formulating a medicine so that it is released into the body steadily, over a long period of time, thus reducing the dosing frequency. For further details, reference may be made, for example, to K.H. Bauer, Lehrbuch der Pharmazeutischen Technologie, 6th edition, WVG Stuttgart, 1999; and Eur. Ph. The pharmaceutical dosage form according to the invention may comprise one or more pharmacologically active compounds at least in part in a further controlled release form, wherein controlled release may be achieved with the assistance of conventional materials and processes known to the person skilled in the art, for example by embedding the substances in a controlled release matrix or by applying one or more controlled release coatings. Substance release must, however, be controlled such that addition of delayed release materials does not impair the necessary breaking strength. Controlled release from the pharmaceutical dosage form according to the invention is preferably achieved by embedding the pharmacologically active compound in a matrix. Matrix materials may, for example, be hydrophilic, gel-forming materials, from which release proceeds mainly by erosion and diffusion. Preferably, the anionic polymer and the nonionic surfactant serve as matrix material, optionally in combination with auxiliary substances also acting as matrix materials.
WO 2013/127831 PCT/EP2013/053894 33 Preferably, the release profile is substantially matrix controlled, preferably by embedding the pharmacologically active compound in a matrix comprising the anionic polymer and optionally, further matrix materials, such as the nonionic surfactant and/or the optionally present further polymer. Preferably, the release profile is not osmotically driven. Preferably, release kinetics is not zero order. In preferred embodiments, in accordance with Ph. Eur., the in vitro release profile of the pharmacologically active compound complies with any same single one of the following release profiles R' to R 5: % R1 R 2 R 3 R4 R R R 8 R9 R 1 h 15±14 15±13 15±12 15±11 15±10 15±9 15±8 15±7 15±6 15±5 2 h 25±20 25±18 25±17 25±16 25±15 25±14 25±13 25±12 25±11 25±10 8 h 55±35 55±32 55±29 55±27 55±25 55±23 55±21 55±19 55±17 55±15 12 h 70±35 70±32 70±29 70±27 70±25 70±23 70±21 70±19 70±17 70±15 24 h 65 70 70 70 75 75 75 80 80 80 % R R1 R1 R 4 R 15 R 6 R 7 R 1 8 R9 R2 1 h 20±18 20±16 20±14 20±12 20±10 20±9 20±8 20±7 20±6 20±5 2 h 30±28 30±26 30±24 30±22 30±20 30±18 30±16 30±14 30±12 30±10 8 h 60±35 60±32 60±29 60±27 60±25 60±23 60±21 60±19 60±17 60±15 12 h 75±35 75±32 75±29 75±27 75±30 75±23 75±21 75±19 75±17 75±15 24 h 75 77 79 81 83 85 87 89 90 90 % R 21 R 22 R23 R24 R30 R 26 R 27 R28 R29 R 3 1 h 25±14 25±14 25±12 25±12 25±10 25±9 25±8 25±7 25±6 25±5 2 h 35±18 35±17 35±16 35±15 35±14 35±13 35±12 35±11 35±10 35±10 8 h 65±35 65±32 65±29 65±27 60±25 65±23 60±21 65±19 65±17 65±15 12 h 70 72 74 76 78 80 82 84 86 88 24 h 75 77 79 81 83 85 87 89 90 90 % R 31 R32 R33 R34 R 35
R
38 R39 R4 1 h 8±7 8±6 8±5 8±4 13±12 13±10 13±8 13±6 15±10 15±7 2 h 15±14 15±11 15±8 15±5 20±23 20±18 20±13 20±8 25±15 25±10 8 h 40±34 40±26 40±18 40±10 45±24 45±18 45±12 45±6 50±25 50±15 12 h 50 54 58 60 60±29 60±22 60±15 60±9 70±25 70±20 24 h 70 70 75 75 70 75 80 85 75 80 % R41 R42 R43 R44 R 4 5 R46 R47 R 48 R49 R WO 2013/127831 PCT/EP2013/053894 34 1 h 15±7 15±5 20±12 20±9 20±7 20±5 25±24 25±18 25±12 25±6 2 h 20±10 25±5 25±15 25±11 25±9 25±7 35±30 35±27 35±20 45±11 8 h 50±10 55±5 60±20 60±15 60±12 60±10 70±35 70±20 70±15 70±10 12 h 70±15 75±5 75±30 75±20 75±18 75±13 80±30 80±25 80±18 80±13 24 h 90 95 >95 >95 >95 98 >95 >95 98 98 Suitable in vitro conditions are known to the skilled artisan. In this regard it can be referred to, e.g., the Ph. Eur. Preferably, the in vitro release profile is measured under the following conditions: 600 ml phosphate buffer (pH 6.8) at temperature of 370C with sinker (type 1 or 2); rotation speed of the paddle: 75 min-. Preferably, the release profile of the pharmaceutical dosage form according to the invention is stable upon storage, preferably upon storage at elevated temperature, e.g. 370C, for 3 months in sealed containers. In this regard "stable" means that when comparing the initial release profile with the release profile after storage, at any given time point the release profiles deviate from one another absolutely by not more than 20%, more preferably not more than 15%, still more preferably not more than 10%, yet more preferably not more than 7.5%, most preferably not more than 5.0%. and in particular not more than 2.5%. Preferably, the pharmaceutical dosage form according to the invention is monolithic. Preferably, the pharmaceutical dosage form is a monolithic mass. In the manufacturing process of the pharmaceutical dosage form according to the invention, all polymers are preferably employed as powders. Preferably, the pharmaceutical dosage form according to the invention is thermoformed, more preferably hot-melt extruded, although also other methods of thermoforming may be used in order to manufacture the pharmaceutical dosage form according to the invention, such as press-molding at elevated temperature or heating of tablets that were manufactured by conventional compression in a first step and then heated above the softening temperature of the polymer in the tablet in a second step to form hard tablets. In this regards, thermoforming means forming or molding of a mass after the application of heat. In a preferred embodiment, the pharmaceutical dosage form is thermoformed by hot-melt extrusion. The melt extruded strands are preferably cut into monoliths, which are then preferably formed into tablets. In this regard, the term "tablets" is preferably not to be WO 2013/127831 PCT/EP2013/053894 35 understood as pharmaceutical dosage forms being made by compression of powder or granules compresss) but rather, as shaped extrudates. In a preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 100±75 mg, more preferably 100±50 mg, most preferably 100±25 mg. In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 200±75 mg, more preferably 200±50 mg, most preferably 200±25 mg. In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 250±75 mg, more preferably 250±50 mg, most preferably 250±25 mg. In still another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 300±75 mg, more preferably 300±50 mg, most preferably 300±25 mg. In yet another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 400±75 mg, more preferably 400±50 mg, most preferably 400±25 mg. In a preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 500±250 mg, more preferably 500±200 mg, most preferably 500±150 mg. In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 750±250 mg, more preferably 750±200 mg, most preferably 750±150 mg. In another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 1000±250 mg, more preferably 1000±200 mg, most preferably 1000±1 50 mg. In still another preferred embodiment, the pharmaceutical dosage form has a total weight within the range of 1250±250 mg, more preferably 1250±200 mg, most preferably 1250±150 mg. The pharmaceutical dosage form according to the invention is characterized by excellent storage stability. Preferably, after storage for 4 weeks at 400C and 75% rel. humidity, the content of pharmacologically active compound amounts to at least 90%, more preferably at least 91%, still more preferably at least 92%, yet more preferably at least 93%, most preferably at least 94% and in particular at least 95%, of its original content before storage. Suitable methods for measuring the content of the pharmacologically active compound in the pharmaceutical dosage form are known to the skilled artisan. In this regard it is referred to the Eur. Ph. or the USP, especially to reversed phase HPLC analysis. Preferably, the pharmaceutical dosage form is stored in closed, preferably sealed containers, most preferably being equipped with an oxygen scavenger, in particular with an oxygen scavenger that is effective even at low relative humidity. In a preferred embodiment, after oral administration of the pharmaceutical dosage form according to the invention, in vivo the average peak plasma level (Cmax) of the WO 2013/127831 PCT/EP2013/053894 36 pharmacologically active compound is on average reached after tmax 4.0±2.5 h, more preferably after tmax 4.0±2.0 h, still more preferably after tmax 4.0+1.5 h, most preferably after tmax 4.0±1.0 h and in particular after tmax 4.0±0.5 h. In another preferred embodiment, after oral administration of the pharmaceutical dosage form according to the invention, in vivo the average peak plasma level (Cmax) of the pharmacologically active compound is on average reached after tmax 5.0±2.5 h, more preferably after tmax 5.0±2.0 h, still more preferably after tmax 5.0+1.5 h, most preferably after tmax 5.0±1.0 h and in particular after tmax 5.0±0.5 h. In still another preferred embodiment, after oral administration of the pharmaceutical dosage form according to the invention, in vivo the average peak plasma level (Cmax) of the pharmacologically active compound is on average reached after tmax 6.0±2.5 h, more preferably after tmax 6.0±2.0 h, still more preferably after tmax 6.0+1.5 h, most preferably after tmax 6.0±1.0 h and in particular after tmax 6.0±0.5 h. In a preferred embodiment, the average value for t 1
/
2 of the pharmacologically active compound after oral administration of the pharmaceutical dosage form according to the invention in vivo is 4.0±2.5 h, more preferably 4.0±2.0 h, still more preferably 4.0±1.5 h, most preferably 4.0+1.0 h, and in particular 4.0±0.5 h. In another preferred embodiment, the average value for t 1
/
2 of the pharmacologically active compound after oral administration of the pharmaceutical dosage form according to the invention in vivo is preferably 5.0+2.5 h, more preferably 5.0±2.0 h, still more preferably 5.0±1.5 h, most preferably 5.0±1.0 h, and in particular 5.0±0.5 h. In still another preferred embodiment, the average value for t 1
/
2 of the pharmacologically active compound after oral administration of the pharmaceutical dosage form according to the invention in vivo is preferably 6.0+2.5 h, more preferably 6.0±2.0 h, still more preferably 6.0±1.5 h, most preferably 6.0+1.0 h, and in particular 6.0±0.5 h. Preferably, Cmax of the pharmacologically active compound does not exceed 0.01 ng/ml, or 0.05 ng/ml, or 0.1 ng/ml, or 0.5 ng/ml, or 1.0 ng/ml, or 2.5 ng/ml, or 5 ng/ml, or 10 ng/ml, or 20 ng/ml, or 30 ng/ml, or 40 ng/ml, or 50 ng/ml, or 75 ng/ml, or 100 ng/ml, or 150 ng/ml, or 200 ng/ml, or 250 ng/ml, or 300 ng/ml, or 350 ng/ml, or 400 ng/ml, or 450 ng/ml, or 500 ng/ml, or 750 ng/ml, or 1000 ng/ml. In a preferred embodiment, the pharmaceutical dosage form according to the invention contains no substances which irritate the nasal passages and/or pharynx, i.e. substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the patient that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active compound, for example due to increased nasal secretion or sneezing.
WO 2013/127831 PCT/EP2013/053894 37 Further examples of substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, urge to sneeze, increased formation of secretions or a combi nation of at least two of these stimuli. Corresponding substances and the quantities thereof which are conventionally to be used are known to the person skilled in the art. Some of the substances which irritate the nasal passages and/or pharynx are accordingly based on one or more constituents or one or more plant parts of a hot substance drug. Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq.. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure. The pharmaceutical dosage form according to the invention furthermore preferably contains no emetic. Emetics are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The pharmaceutical dosage form according to the invention preferably contains no emetic based on one or more constituents of ipecacuanha (ipecac) root, for example based on the constituent emetine, as are, for example, described in "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure. The pharmaceutical dosage form according to the invention preferably also contains no apomorphine as an emetic. The pharmaceutical dosage form according to the invention preferably also contains no bitter substance. Bitter substances and the quantities effective for use may be found in US 2003/0064099 Al, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference. Examples of bitter substances are aromatic oils, such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate. The pharmaceutical dosage form according to the invention accordingly preferably contains neither substances which irritate the nasal passages and/or pharynx, nor emetics, nor bitter substances.
WO 2013/127831 PCT/EP2013/053894 38 Preferably, the pharmaceutical dosage form according to the invention contains no neuroleptics, for example a compound selected from the group consisting of haloperidol, promethacine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol. In a preferred embodiment, the pharmaceutical dosage form according to the invention contains no pharmacologically active compound antagonists. In another preferred embodiment, the pharmaceutical dosage form according to the invention does contain a pharmacologically active compound antagonist. Pharmacologically active compound antagonists suitable for a given pharmacologically active compound are known to the person skilled in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof. The pharmaceutical dosage form according to the invention preferably contains an opioid as pharmacologically active compound and an opioid antagonist as pharmacologically active compound antagonist, wherein the opioid antagonist is selected from the group consisting of naloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate. Naloxone and nalmexone as well as their physiologically acceptable salts are preferred pharmacologically active compound antagonists. The content of the pharmacologically active compound antagonist in the pharmaceutical dosage form is not limited. Besides the pharmacologically active compound, the anionic polymer and the nonionic surfactant the pharmaceutical dosage form according to the invention may contain further constituents, such as conventional pharmaceutical excipients. Preferably, the pharmaceutical dosage form according to the invention contains a plasticizer. Preferred plasticizers are polyalkylene glycols, like polyethylene glycol, triacetin, fatty acids, fatty acid esters, waxes and/or microcrystalline waxes. Particularly preferred plasticizers are polyethylene glycols, such as PEG 6000. Preferably, the content of the plasticizer is within the range of from 0.1 to 30 wt.-%, more preferably 0.5 to 27.5 wt.-%, still more preferably 1.0 to 25 wt.-%, yet more preferably 5 to 25 WO 2013/127831 PCT/EP2013/053894 39 wt.-%, most preferably 10 to 20 wt.-% and in particular 12.5 to 17.5 wt.-%, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the range of 5±4 wt.-%, more preferably 5±3.5 wt.-%, still more preferably 5±3 wt.-%, yet more preferably 5±2.5 wt.-%, most preferably 5±2 wt.-%, and in particular 5±1.5 wt.-%, based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the range of 10±8 wt.-%, more preferably 10±6 wt.-%, still more preferably 10+5 wt.-%, yet more preferably 10±4 wt.-%, most preferably 10±3 wt.-%, and in particular 10+2 wt.-%, based on the total weight of the pharmaceutical dosage form. In still another preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the range of 15±8 wt.-%, more preferably 15±6 wt.-%, still more preferably 15+5 wt.-%, yet more preferably 15±4 wt.-%, most preferably 15±3 wt.-%, and in particular 15+2 wt.-%, based on the total weight of the pharmaceutical dosage form. Preferably, the relative weight ratio of the anionic polymer and the plasticizer is within the range of from 0.1:1 to 5.0:1, more preferably from 0.2:1 to 4.0:1. In a preferred embodiment, the relative weight ratio of the anionic polymer and the plasticizer is at least 0.2:1, more preferably at least 0.4:1, still more preferably at least 0.6:1, yet more preferably at least 0.8:1, even more preferably at least 1.0:1, most preferably at least 1.2:1, and in particular at least 1.4:1. Preferably, the relative weight ratio of the nonionic surfactant and the plasticizer is within the range of from 0.1:1 to 5.0:1, more preferably from 0.2:1 to 4.0:1. In a preferred embodiment, the relative weight ratio of the nonionic surfactant and the plasticizer is at least 0.2:1, more preferably at least 0.4:1, still more preferably at least 0.6:1, yet more preferably at least 0.8:1, even more preferably at least 1.0:1, most preferably at least 1.2:1, and in particular at least 1.4:1. Preferably, the relative weight ratio of the sum of anionic polymer and nonionic surfactant to the plasticizer is within the range of from 0.1:1 to 7.0:1, more preferably from 0.2:1 to 6.5:1.
WO 2013/127831 PCT/EP2013/053894 40 In a preferred embodiment, the relative weight ratio of the sum of anionic polymer and nonionic surfactant to the plasticizer is at least 0.2:1, more preferably at least 0.4:1, still more preferably at least 0.6:1, yet more preferably at least 0.8:1, even more preferably at least 1.0:1, most preferably at least 1.2:1, and in particular at least 1.4:1. In a particularly preferred embodiment, the relative weight ratio of the sum of anionic polymer and nonionic surfactant to the plasticizer is at least 1.6:1, more preferably at least 1.8:1, still more preferably at least 2.0:1, yet more preferably at least 2.2:1, even more preferably at least 2.4:1, most preferably at least 2.6:1, and in particular at least 2.8:1. The pharmaceutical dosage form according to the invention may further contain an antioxidant. Suitable antioxidants include ascorbic acid, a-tocopherol (vitamin E), butylhydroxyanisol, butylhydroxytoluene, salts of ascorbic acid (vitamin C), ascorbylic palmitate, monothioglycerine, coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters, phosphoric acid, and the derivatives thereof, such as vitamin E-succinate or vitamin E palmitate and/or sodium bisulphite, more preferably butylhydroxytoluene (BHT) or butylhydroxyanisol (BHA) and/or a-tocopherol. A particularly preferred antioxidant is a tocopherol. In a preferred embodiment, the pharmaceutical dosage form according to the invention does either not contain any antioxidant, or contains one or more antioxidants, wherein the content of all antioxidant(s) being present in the dosage form preferably amounts to at most 5.0 wt.
%, more preferably at most 2.5 wt.-%, more preferably at most 1.5 wt.-%, still more preferably at most 1.0 wt.-%, yet more preferably at most 0.5 wt.-%, most preferably at most 0.4 wt.-% and in particular at most 0.3 wt.-%, 0.2 wt.-% or 0.1 wt.-%, based on the total weight of the pharmaceutical dosage form. The pharmaceutical dosage form according to the invention may further contain a free physiologically acceptable acid. The acid may be organic or inorganic, liquid or solid. Solid acids are preferred, particularly crystalline organic or inorganic acids. Preferably, the acid is free. This means that the acidic functional groups of the acid are not all together constituents of a salt of the pharmacologically active compound. If the pharmacologically active compound is present as a salt of an acid, e.g. as hydrochloride, the pharmaceutical dosage form according to the invention preferably contains as acid another, chemically different acid which is not present as a constituent of the salt of the WO 2013/127831 PCT/EP2013/053894 41 pharmacologically active compound. In other words, monoacids that form a salt with the pharmacologically active compound are not to be considered as free acids in the meaning of the invention. When acid has more than a single acidic functional group (e.g. phosphoric acid), the acid may be present as a constituent of a salt of the pharmacologically active compound, provided that at least one of the acidic functional groups of the acid is not involved in the formation of the salt, i.e. is free. Preferably, however, each and every acidic functional group of acid is not involved in the formation of a salt with pharmacologically active compound. It is also possible, however, that free acid and the acid forming a salt with pharmacologically active compound are identical. Under these circumstances the acid is preferably present in molar excess compared to pharmacologically active compound. In a preferred embodiment, the acid contains at least one acidic functional group (e.g. C0 2 H, -SO 3 H, -P0 3
H
2 , -OH and the like) having a pKA value within the range of 2.00+1.50, more preferably 2.00±1.25, still more preferably 2.00±1.00, yet more preferably 2.00+0.75, most preferably 2.00±0.50 and in particular 2.00±0.25. In another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 2.25±1.50, more preferably 2.25±1.25, still more preferably 2.25±1.00, yet more preferably 2.25±0.75, most preferably 2.25±0.50 and in particular 2.25±0.25. In another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 2.50+1.50, more preferably 2.50+1.25, still more preferably 2.50+1.00, yet more preferably 2.50+0.75, most preferably 2.50±0.50 and in particular 2.50±0.25. In another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 2.75±1.50, more preferably 2.75+1.25, still more preferably 2.75±1.00, yet more preferably 2.75±0.75, most preferably 2.75±0.50 and in particular 2.75±0.25. In another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 3.00±1.50, more preferably 3.00+1.25, still more preferably 3.00±1.00, yet more preferably 3.00±0.75, most preferably 3.00±0.50 and in particular 3.00±0.25. In still another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 3.25±1.50, more preferably 3.25±1.25, still more preferably 3.25+1.00, yet more preferably 3.25±0.75, most preferably 3.25±0.50 and in particular 3.25±0.25. In yet another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 4.50+1.50, more preferably 4.50+1.25, still more preferably 4.50±1.00, yet more preferably 4.50±0.75, most preferably 4.50±0.50 and in particular 4.50±0.25. In yet another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 4.75±1.50, more preferably WO 2013/127831 PCT/EP2013/053894 42 4.75±1.25, still more preferably 4.75+1.00, yet more preferably 4.75±0.75, most preferably 4.75±0.50 and in particular 4.75±0.25. In yet another preferred embodiment, the acid contains at least one acidic functional group having a pKA value within the range of 5.00±1.50, more preferably 5.00±1.25, still more preferably 5.00±1.00, yet more preferably 5.00±0.75, most preferably 5.00±0.50 and in particular 5.00±0.25. Preferably, the acid is an organic carboxylic or sulfonic acid, particularly a carboxylic acid. Multicarboxylic acids and/or hydroxy-carboxylic acids are especially preferred. In case of multicarboxylic acids, the partial salts thereof are also to be regarded as multi carboxylic acids, e.g. the partial sodium, potassium or ammonium salts. For example, citric acid is a multicarboxylic acid having three carboxyl groups. As long as there remains at least one carboxyl group protonated (e.g. sodium dihydrogen citrate or disodium hydrogen citrate), the salt is to be regarded as a multicarboxylic acid. Preferably, however, all carboxyl groups of the multicarboxylic acid are protonated. Preferably, the acid is of low molecular weight, i.e., not polymerized. Typically, the molecular weight of the acid is below 500 g/mol. Examples of acids include saturated and unsaturated monocarboxylic acids, saturated and unsaturated bicarboxylic acids, tricarboxylic acids, a-hydroxyacids and p-hydroxylacids of monocarboxylic acids, a-hydroxyacids and p-hydroxyacids of bicarboxylic acids, a-hydroxy acids and p-hydroxyacids of tricarboxylic acids, ketoacids, a-ketoacids, 0-ketoacids, of the polycarboxylic acids, of the polyhydroxy monocarboxylic acids, of the polyhydroxy bicar boxylic acids, of the polyhydroxy tricarboxylic acids. Preferably, the acid is selected from the group consisting of benzenesulfonic acid, citric acid, a-glucoheptonic acid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, propanoic acid, succinic acid, tartaric acid (d, I, or dl), tosic acid (toluene sulfonic acid), valeric acid, palmitic acid, pamoic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, glutaric acid, 4-chlorobenzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, galactaric acid (mucic acid), D-glucuronic acid, 2-oxo glutaric acid, glycerophosphoric acid, hippuric acid, isethionic acid (ethanolsulfonic acid), lactobionic acid, maleic acid, maleinic acid, 1,5-naphthalene-disulfonic acid, 2-naphthalene sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfate, 3 hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, oleic acid, undecylenic acid, ascorbic acid, (+)-camphoric acid, d-camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, WO 2013/127831 PCT/EP2013/053894 43 formic acid, methanesulfonic acid, nicotinic acid, orotic acid, oxalic acid, picric acid, L-pyro glutamic acid, saccharine, salicylic acid, gentisic acid, and/or 4-acetamidobenzoic acid. Preferably, the acid is a multicarboxylic acid. More preferably, the multicarboxylic acid is selected from the group consisting of citric acid, maleic acid and fumaric acid. Citric acid is particularly preferred. The multicarboxylic acid, preferably citric acid, may be present in its anhydrous form or as a solvate and hydrate, respectively, e.g., as monohydrate. If a free physiologically acceptable acid is contained in the phramaceutical dosage form, it is preferably present in an amount of at most 5.0 wt.-%, preferably at most 2.5 wt.-%, more at most 2.0 wt.-%, at most 1.5 wt.-%, most preferably at most 1.0 wt.-% and in particular at most 0.9 wt.-%, based on the total weight of the pharmaceutical dosage form. The pharmaceutical dosage form according to the invention may also contain a natural, semi-synthetic or synthetic wax. Waxes with a softening point of at least 50 OC, more preferably 60 0C are preferred. Carnauba wax and beeswax are particularly preferred, especially carnauba wax. Preferably, the pharmaceutical dosage form according to the invention contains a coating, preferably a film-coating. Suitable coating materials are known to the skilled person. Suitable coating materials are commercially available, e.g. under the trademarks Opadry* and Eudragit*. Examples of suitable materials include cellulose esters and cellulose ethers, such as methyl cellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP); poly(meth)acrylates, such as aminoalkylmethacrylate copolymers, ethylacrylate methyl methacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinyl acetatephthalate, polyvinyl alcohol, polyvinylacetate; and natural film formers, such as shellack.
WO 2013/127831 PCT/EP2013/053894 44 In a particularly preferred embodiment, the coating is water-soluble. In a preferred embodiment, the coating is based on polyvinyl alcohol, such as polyvinyl alcohol-part. hydrolyzed, and may additionally contain polyethylene glycol, such as macrogol 3350, and/or pigments. In another preferred embodiment, the coating is based on hydroxypropylmethyl cellulose, preferably hypromellose type 2910 having a viscosity of 3 to 15 mPas. The coating of the pharmaceutical dosage form can increase its storage stability. The coating can be resistant to gastric juices and dissolve as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the pharmaceutical dosage form according to the invention passes through the stomach undissolved and the active compound is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5. Corresponding materials and methods for the delayed release of active compounds and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from "Coated Pharmaceutical dosage forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers. The pharmaceutical dosage form according to the invention is preferably tamper-resistant. Preferably, tamper-resistance is achieved based on the mechanical properties of the pharmaceutical dosage form so that comminution is avoided or at least substantially impeded. According to the invention, the term comminution means the pulverization of the pharmaceutical dosage form using conventional means usually available to an abuser, for example a pestle and mortar, a hammer, a mallet or other conventional means for pulverizing under the action of force. Thus, tamper-resistance preferably means that pulverization of the pharmaceutical dosage form using conventional means is avoided or at least substantially impeded. Preferably, the mechanical properties of the pharmaceutical dosage form according to the invention, particularly its breaking strength, substantially rely on the presence and spatial distribution of the anionic polymer and the nonionic surfactant, although its/their mere presence does typically not suffice in order to achieve said properties. The advantageous mechanical properties of the pharmaceutical dosage form according to the invention may not automatically be achieved by simply processing pharmacologically active compound, anionic polymer, and optionally further excipients, such as the nonionic surfactant, by means of WO 2013/127831 PCT/EP2013/053894 45 conventional methods for the preparation of pharmaceutical dosage forms. In fact, usually suitable apparatuses must be selected for the preparation and critical processing parameters must be adjusted, particularly pressure/force, temperature and time. Thus, even if conventional apparatuses are used, the process protocols usually must be adapted in order to meet the required criteria. Furthermore, tamper-resistance is achieved based on the poor solubility properties of the pharmaceutical dosage form in alcohol, especially ethanol, thereby effectively preventing alcohol dose dumping. The purpose of the anionic polymer that is contained in the pharmaceutical dosage form according to the invention is associated with the tamper resistance of the pharmaceutical dosage form, especially when the pharmaceutical dosage form is intended by an abuser for administration by a non-prescribed route, particularly intravenous administration of a liquid extract. In a preferred embodiment, when (i) subjecting a pharmaceutical dosage form (a) for 5 minutes in 5 mL of cold water, or (b) to boiling water and boiling the tablet for 5 minutes, respectively, (ii) closing the vessel with aluminum foil, boiling extraction only, (iii) drawing up the liquid into a syringe using a canula, preferably 0.80 x 40 mm BL/LB; 21 G x 1 1/2", through a cigarette filter, and (iv)determining the pharmacologically active compound content in the drawn liquid by HPLC analysis; the content of extracted pharmacologically active compound in the overhead liquid amounts to at most 14.5 wt.-%, 14.0 wt.-%, 13.5 wt.-%, or 13.0 wt.-%, more preferably at most 12.5 wt.-%, 12.0 wt.-%, 11.5 wt.-%, or 11.0 wt.-%, still more preferably at most 10.5 wt.-%, 10 wt.-%, 9.5 wt.-%, or 9.0 wt.-%, yet more preferably at most 8.5 wt.-%, 8.0 wt.-%, 7.5 wt.-%, or 7.0 wt.-%, even more preferably at most 6.5 wt.-%, 6.0 wt.-%, 5.5 wt.-%, or 5.0 wt.-%, most more preferably at most 4.5 wt.-%, 4.0 wt.-%, 3.5 wt.-%, or 3.0 wt.-%, and in particular at most 2.5 wt.-%, 2.0 wt.-%, 1.5 wt.-%, or 1.0 wt.-%, relative to the original total content of the pharmacologically active compound in the pharmaceutical dosage form, i.e. before it was subjected to the extraction test.
WO 2013/127831 PCT/EP2013/053894 46 In a preferred embodiment, when (i) subjecting a pharmaceutical dosage form (a) for 5 minutes in 5 mL of cold water, or (b) to boiling water and boiling the pharmaceutical dosage form for 5 minutes, respectively, (ii) closing the vessel with aluminum foil, boiling extraction only, (iii) drawing up the liquid into a 10 mL syringe using a canula, preferably 0.80 x 40 mm BL/LB; 21 G x 1 1/2", through a cigarette filter, and (iv)determining the pharmacologically active compound content in the drawn liquid by HPLC analysis. the total amount of extracted pharmacologically active compound in the overhead liquid amounts to - at most 115 mg, 110 mg, 105 mg, or 100 mg, more preferably at most 95 mg, 90 mg, 85 mg, or 80 mg, still more preferably at most 75 mg, 70 mg, 65 mg, or 60 mg, yet more preferably at most 55 mg, 50 mg, 47.5 mg, or 45 mg, even more preferably at most 42.5 mg, 40 mg, 37.5 mg, or 35 mg, most more preferably at most 32.5 mg, 30 mg, 27.5 mg, or 25 mg, and in particular at most 22.5 mg, 20 mg, 17.5 mg, or 15 mg; or - at most 14.5 mg, 14.0 mg, 13.5 mg, or 13.0 mg, more preferably at most 12.5 mg, 12.0 mg, 11.5 mg, or 11.0 mg, still more preferably at most 10.5 mg, 10 mg, 9.5 mg, or 9.0 mg, yet more preferably at most 8.5 mg, 8.0 mg, 7.5 mg, or 7.0 mg, even more preferably at most 6.5 mg, 6.0 mg, 5.5 mg, or 5.0 mg, most more preferably at most 4.5 mg, 4.0 mg, 3.5 mg, or 3.0 mg, and in particular at most 2.5 mg, 2.0 mg, 1.5 mg, or 1.0 mg. In a preferred embodiment, when (i) subjecting a pharmaceutical dosage form (a) for 30 minutes to 30 mL of solvent with continuous shaking, or (b) giving a pharmaceutical dosage form in 30 mL of purified water, heating the water until boiling and shaking for 30 minutes, during the slow cooling of the water; (ii) supplementing lost water, if any, and (iii) determining the pharmacologically active compound content in the overhead liquid by HPLC analysis; WO 2013/127831 PCT/EP2013/053894 47 the content of extracted pharmacologically active compound in the overhead liquid amounts to at most 40 wt.-%, more preferably at most 35 wt.-%, still more preferably at most 30 wt.-%, yet more preferably at most 25 wt.-% or 24 wt.-%, even more preferably at most 23 wt.-%, 22 wt.-%, 21 wt.-% or 20 wt.-%, most preferably at most 19 wt.-%, 18 wt.-%, 17 wt.-%, or 16 wt.
%, and in particular at most 15.5 wt.-%, 15.0 wt.-%, 12 wt.-%, or 10 wt.-%, relative to the original total content of the pharmacologically active compound in the pharmaceutical dosage form, i.e. before it was subjected to the extraction test. In a preferred embodiment, when (i) subjecting a pharmaceutical dosage form (a) for 30 minutes to 30 mL of solvent with continuous shaking, or (b) giving a pharmaceutical dosage form in 30 mL of purified water, heating the water until boiling and shaking for 30 minutes, during the slow cooling of the water; (ii) supplementing lost water, if any, and (iii) determining the pharmacologically active compound content in the overhead liquid by HPLC analysis; the total amount of extracted pharmacologically active compound in the overhead liquid amounts to - at most 200 mg, 190 mg, 180 mg, or 170 mg, more preferably at most 160 mg, 150 mg, 140 mg, or 135 mg, still more preferably at most 130 mg, 125 mg, 120 mg, or 110 mg, yet more preferably at most 105 mg or 100 mg, even more preferably at most 95 mg or 90 mg, most more preferably at most 85 mg or 80 mg, and in particular at most 75 mg, 70 mg, 65 mg, or 60 mg; or - at most 55 mg, 50 mg, 47.5 mg, or 45 mg, more preferably at most 42.5 mg, 40 mg, 37.5 mg, or 35 mg, still more preferably at most 32.5 mg, 30 mg, 27.5 mg, or 25 mg, yet more preferably at most 22.5 mg or 20 mg, even more preferably at most 17.5 mg or 15 mg, most more preferably at most 14 mg or 13 mg, and in particular at most 12.5 mg, 12 mg, 11.5 mg, 11 mg, 10.5 mg or 10 mg. Preferably, when a pharmaceutical dosage form according to the invention is treated with a commercial coffee mill, preferably type Bosch MKM6000, for 2 minutes, at least 40 wt.-%, more preferably at least 50 wt.-%, still more preferably at least 60 wt.-%, yet more preferably at least 65 wt.-%, even more preferably at least 70 wt.-%, most preferably at least 75 wt.-%, and in particular at least 80 wt.-%, of the total weight of the thus obtained material does not pass a sieve having a mesh size of 1.000 mm.
WO 2013/127831 PCT/EP2013/053894 48 In a preferred embodiment, when a pharmaceutical dosage form according to the invention is treated with a commercial coffee mill, preferably type Bosch MKM6000, for 2 minutes, it either remains intact and in one piece, or it is split into at most 10, preferably at most 7 or 8, more preferably at most 5 or 6, still more preferably at most 4, most preferably at most 3, and in particular at most 2 pieces. The pharmaceutical dosage form according to the invention has a breaking strength of at least 300 N, preferably at least 400 N, more preferably at least 500 N, still more preferably at least 750 N, yet more preferably at least 1000 N, most preferably at least 1250 N and in particular at least 1500 N. The "breaking strength" (resistance to crushing) of a pharmaceutical dosage form is known to the skilled person. In this regard it can be referred to, e.g., W.A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et al., Pharmaceutical dosage forms: Tablets, Vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1 edition. For the purpose of the specification, the breaking strength is preferably defined as the amount of force that is necessary in order to fracture the pharmaceutical dosage form (= breaking force). Therefore, for the purpose of the specification the pharmaceutical dosage form does preferably not exhibit the desired breaking strength when it breaks, i.e., is fractured into at least two independent parts that are separated from one another. In another preferred embodiment, however, the pharmaceutical dosage form is regarded as being broken if the force decreases by 25% (threshold value) of the highest force measured during the measurement (see below). The pharmaceutical dosage forms according to the invention are distinguished from conventional pharmaceutical dosage forms in that, due to their breaking strength, they cannot be pulverized by the application of force with conventional means, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverization, in particular devices developed for this purpose (tablet crushers). In this regard "pulverization" means crumbling into small particles that would immediately release the pharmacologically active compound in a suitable medium. Avoidance of pulverization virtually rules out oral or parenteral, in particular intravenous or nasal abuse. Conventional tablets typically have a breaking strength well below 200 N in any direction of extension. The breaking strength of conventional round tablets may be estimated according WO 2013/127831 PCT/EP2013/053894 49 to the following empirical formula: Breaking Strength [in N] = 10 x Diameter Of The Tablet [in mm]. Thus, according to said empirical formula, a round tablet having a breaking strength of at least 300 N would require a diameter of at least 30 mm). Such a tablet, however, could not be swallowed. The above empirical formula preferably does not apply to the pharmaceutical dosage forms of the invention, which are not conventional but rather special. Further, the actual mean chewing force is about 220 N (cf., e.g., P.A. Proeschel et al., J Dent Res, 2002, 81(7), 464-468). This means that conventional tablets having a breaking strength well below 200 N may be crushed upon spontaneous chewing, whereas the pharmaceutical dosage forms according to the invention may not. Still further, when applying a gravitational acceleration of about 9.81 m/s 2 , 300 N correspond to a gravitational force of more than 30 kg, i.e. the pharmaceutical dosage forms according to the invention can preferably withstand a weight of more than 30 kg without being pulverised. Methods for measuring the breaking strength of a pharmaceutical dosage form are known to the skilled artisan. Suitable devices are commercially available. For example, the breaking strength (resistance to crushing) can be measured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08 "Resistance to Crushing of Tablets". The test is intended to determine, under defined conditions, the resistance to crushing of tablets, measured by the force needed to disrupt them by crushing. The apparatus consists of 2 jaws facing each other, one of which moves towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat and larger than the zone of contact with the tablet. The apparatus is calibrated using a system with a precision of 1 Newton. The tablet is placed between the jaws, taking into account, where applicable, the shape, the break-mark and the inscription; for each measurement the tablet is oriented in the same way with respect to the direction of application of the force (and the direction of extension in which the breaking strength is to be measured). The measurement is carried out on 10 tablets, taking care that all fragments of tablets have been removed before each determination. The result is expressed as the mean, minimum and maximum values of the forces measured, all expressed in Newton. A similar description of the breaking strength (breaking force) can be found in the USP. The breaking strength can alternatively be measured in accordance with the method described therein where it is stated that the breaking strength is the force required to cause a tablet to fail (i.e., break) in a specific plane. The tablets are generally placed between two platens, WO 2013/127831 PCT/EP2013/053894 50 one of which moves to apply sufficient force to the tablet to cause fracture. For conventional, round (circular cross-section) tablets, loading occurs across their diameter (sometimes referred to as diametral loading), and fracture occurs in the plane. The breaking force of tablets is commonly called hardness in the pharmaceutical literature; however, the use of this term is misleading. In material science, the term hardness refers to the resistance of a surface to penetration or indentation by a small probe. The term crushing strength is also frequently used to describe the resistance of tablets to the application of a compressive load. Although this term describes the true nature of the test more accurately than does hardness, it implies that tablets are actually crushed during the test, which is often not the case. In a preferred embodiment of the invention, the breaking strength (resistance to crushing) is measured in accordance with WO 2005/ 016313, WO 2005/016314, and WO 2006/082099, which can be regarded as a modification of the method described in the Eur. Ph. The apparatus used for the measurement is preferably a "Zwick Z 2.5" materials tester, Fmax = 2.5 kN with a maximum draw of 1150 mm, which should be set up with one column and one spindle, a clearance behind of 100 mm and a test speed adjustable between 0.1 and 800 mm/min together with testControl software. Measurement is performed using a pressure piston with screw-in inserts and a cylinder (diameter 10 mm), a force transducer, Fmax. 1 kN, diameter = 8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M according to DIN 55350-18 (Zwick gross force Fmax= 1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC 0050N. P01 for the force transducer, Order No BO 70000 S06 for the centring device. In another preferred embodiment of the invention, the breaking strength is measured by means of a breaking strength tester e.g. Sotax*, type HT100 or type HT1 (Allschwil, Switzerland). Both, the Sotax* HT100 and the Sotax* HT1can measure the breaking strength according to two different measurement principles: constant speed (where the test jaw is moved at a constant speed adjustable from 5-200 mm/min) or constant force (where the test jaw increases force linearly adjustable from 5-100 N/sec). In principle, both measurement principles are suitable for measuring the breaking strength of the pharmaceutical dosage form according to the invention. Preferably, the breaking strength is measured at constant speed, preferably at a constant speed of 120 mm/min. In a preferred embodiment, the pharmaceutical dosage form is regarded as being broken if it is fractured into at least two separate pieces.
WO 2013/127831 PCT/EP2013/053894 51 The pharmaceutical dosage form according to the invention preferably exhibits mechanical strength over a wide temperature range, in addition to the breaking strength (resistance to crushing) optionally also sufficient hardness, impact resistance, impact elasticity, tensile strength and/or modulus of elasticity, optionally also at low temperatures (e.g. below -24 C, below -40 IC or in liquid nitrogen), for it to be virtually impossible to pulverize by spontaneous chewing, grinding in a mortar, pounding, etc. Thus, preferably, the comparatively high breaking strength of the pharmaceutical dosage form according to the invention is main tained even at low or very low temperatures, e.g., when the pharmaceutical dosage form is initially chilled to increase its brittleness, for example to temperatures below -250C, below -40 IC or even in liquid nitrogen. The pharmaceutical dosage form according to the invention is characterized by a certain degree of breaking strength. This does not mean that the pharmaceutical dosage form must also exhibit a certain degree of hardness. Hardness and breaking strength are different physical properties. Therefore, the tamper resistance of the pharmaceutical dosage form does not necessarily depend on the hardness of the pharmaceutical dosage form. For instance, due to its breaking strength, impact strength, elasticity modulus and tensile strength, respectively, the pharmaceutical dosage form can preferably be deformed, e.g. plastically, when exerting an external force, for example using a hammer, but cannot be pulverized, i.e., crumbled into a high number of fragments. In other words, the pharmaceutical dosage form according to the invention is characterized by a certain degree of breaking strength, but not necessarily also by a certain degree of form stability. Therefore, in the meaning of the specification, a pharmaceutical dosage form that is deformed when being exposed to a force in a particular direction of extension but that does not break (plastic deformation or plastic flow) is preferably to be regarded as having the desired breaking strength in said direction of extension. Preferably, the pharmaceutical dosage form according to the invention - has a breaking strength of at least 400 N, more preferably at least 500 N, still more preferably at least 750 N, and most preferably at least 1000 N; and/or - comprises a pharmacologically active compound selected from opioids, more preferably from hydromorphone, oxycodone, oxymorphone, tapentadol and the physiologically acceptable salts thereof; and/or - comprises an anionic polymer derived from a monomer composition comprising an ethylenically unsaturated monomer selected from (alk)acrylic acids, (alk)acrylic WO 2013/127831 PCT/EP2013/053894 52 anhydrides, alkyl (alk)acrylates, or a combination thereof, in particular acrylic acid, and optionally at least one cross-linking agent selected from the group consisting of allyl sucrose, allyl pentaerythritol, divinyl glycol, divinyl polyethylene glycol and (meth)acrylic acid esters of diols; and/or - comprises the anionic polymer in an amount of at least 25 wt.-%, preferably at least 30 wt.-% or at least 32 wt.-%, based on the total weight of the pharmaceutical dosage form; and/or - comprises a nonionic surfactant, (i) preferably a copolymer of ethylene oxide and propylene oxide, more preferably a block copolymer according to general formula (1-a)
CH
3 HO O H a -c b (1-a) wherein a and c are each independently an integer of from 5 to 300 and b is an integer of from 10 to 100; and/or a block copolymer according to general formula (1-b) H O1 O g e H 3 .k jH3
CH
3
CH
3 H O O -1 1 .0' L_ h - f (1-b) wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and I are each independently an integer of from 2 to 50; (ii) which is preferably contained in the pharmaceutical dosage form in an amount of at least 10 wt.-%, more preferably at least 15 wt.-%, and most preferably 15 to 40 wt.-%, based on the total weight of the pharmaceutical dosage form; and/or WO 2013/127831 PCT/EP2013/053894 53 (iii) which preferably exhibits an HLB value of at least 20, more preferably at least 24; and/or - is configured for oral administration, preferably one daily or twice daily; and/or - either does not contain any polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, preferably of at least 50,000 g/mol; or wherein the total content of polyalkylene oxide(s) having an average molecular weight of at least 200,000 g/mol or at least 50,000 g/mol, respectively, is 5 20 wt.-%, preferably 5 10 wt.-%, based on the total weight of the pharmaceutical dosage form; and/or - optionally, contains a plasticizer, preferably polyethylene glycol; and/or - optionally, contains an additional matrix polymer, preferably a cellulose ether, more preferably HPMC. The pharmaceutical dosage form according to the invention may be produced by different processes, the particularly preferred of which are explained in greater detail below. Several suitable processes have already been described in the prior art. In this regard it can be referred to, e.g., WO 2005/ 016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, and WO 2006/082099. The invention also relates to pharmaceutical dosage forms that are obtainable by any of the processes described here below. In general, the process for the production of the pharmaceutical dosage form according to the invention preferably comprises the following steps: (a) mixing all ingredients; (b) optionally pre-forming the mixture obtained from step (a), preferably by applying heat and/or force to the mixture obtained from step (a), the quantity of heat supplied preferably not being sufficient to heat the matrix material up to its softening point; (c) hardening the mixture by applying heat and force, it being possible to supply the heat during and/or before the application of force and the quantity of heat supplied being sufficient to heat the matrix material at least up to its softening point; (d) optionally singulating the hardened mixture; (e) optionally shaping the pharmaceutical dosage form; and WO 2013/127831 PCT/EP2013/053894 54 (f) optionally providing a film coating. Heat may be supplied directly, e.g. by contact or by means of hot gas such as hot air, or with the assistance of ultrasound, microwaves and/or radiation. Force may be applied and/or the pharmaceutical dosage form may be shaped for example by direct tabletting or with the assistance of a suitable extruder, particularly by means of a screw extruder equipped with two screws (twin-screw-extruder) or by means of a planetary gear extruder. The final shape of the pharmaceutical dosage form may either be provided during the hardening of the mixture by applying heat and force (step (c)) or in a subsequent step (step (e)). In both cases, the mixture of all components is preferably in the plastified state, i.e. preferably, shaping is performed at a temperature at least above the softening point of the matrix material. However, extrusion at lower temperatures, e.g. ambient temperature, is also possible and may be preferred. Shaping can be performed, e.g., by means of a tabletting press comprising die and punches of appropriate shape. A particularly preferred process for the manufacture of the pharmaceutical dosage form of the invention involves hot-melt extrusion. In this process, the pharmaceutical dosage form according to the invention is produced by thermoforming with the assistance of an extruder, preferably without there being any observable consequent discoloration of the extrudate. It has been surprisingly found that acid is capable of suppressing discoloration. In the absence of acid, the extrudate tends to develop beige to yellowish coloring whereas in the presence of acid the extrudates are substantially colorless, i.e. white. This process is characterized in that a) all components are mixed, b) the resultant mixture is heated in the extruder at least up to the softening point of the matrix material and extruded through the outlet orifice of the extruder by application of force, c) the still plastic extrudate is singulated and formed into the pharmaceutical dosage form or d) the cooled and optionally reheated singulated extrudate is formed into the pharmaceutical dosage form.
WO 2013/127831 PCT/EP2013/053894 55 Mixing of the components according to process step a) may also proceed in the extruder. The components may also be mixed in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer. The, preferably molten, mixture which has been heated in the extruder at least up to the softening point of matrix material is extruded from the extruder through a die with at least one bore. The process according to the invention requires the use of suitable extruders, preferably screw extruders. Screw extruders which are equipped with two screws (twin-screw-extruders) are particularly preferred. The extrusion is preferably performed so that the expansion of the strand due to extrusion is not more than 30%, i.e. that when using a die with a bore having a diameter of e.g. 6 mm, the extruded strand should have a diameter of not more than 8 mm. More preferably, the expansion of the strand is not more than 25%, still more preferably not more than 20%, most preferably not more than 15% and in particular not more than 10%. Preferably, extrusion is performed in the absence of water, i.e., no water is added. However, traces of water (e.g., caused by atmospheric humidity) may be present. The extruder preferably comprises at least two temperature zones, with heating of the mixture at least up to the softening point of the matrix material proceeding in the first zone, which is downstream from a feed zone and optionally mixing zone. The throughput of the mixture is preferably from 1.0 kg to 15 kg/hour. In a preferred embodiment, the throughput is from 1 to 3.5 kg/hour. In another preferred embodiment, the throughput is from 4 to 15 kg/hour. In a preferred embodiment, the die head pressure is within the range of from 2 to 100 bar. In a preferred embodiment, the die head pressure is within the range of from 25 to 100 bar. In another preferred embodiment, the die head pressure is within the range of from 2 to 25 bar. The die head pressure can be adjusted inter alia by die geometry, temperature profile and extrusion speed. The die geometry or the geometry of the bores is freely selectable. The die or the bores may accordingly exhibit a round, oblong or oval cross-section, wherein the round cross-section WO 2013/127831 PCT/EP2013/053894 56 preferably has a diameter of 0.1 mm to 15 mm and the oblong cross-section preferably has a maximum lengthwise extension of 21 mm and a crosswise extension of 10 mm. Preferably, the die or the bores have a round cross-section. The casing of the extruder used according to the invention may be heated or cooled. The corresponding temperature control, i.e. heating or cooling, is so arranged that the mixture to be extruded exhibits at least an average temperature (product temperature) corresponding to the softening temperature of the matrix material and does not rise above a temperature at which the pharmacologically active compound to be processed may be damaged. Preferably, the temperature of the mixture to be extruded is adjusted to below 180 OC, preferably below 150 OC, but at least to the softening temperature of matrix material. Typical extrusion temperatures are 120 OC and 130 OC. In a preferred embodiment, the extruder torque is within the range of from 30 to 95%. Extruder torque can be adjusted inter alia by die geometry, temperature profile and extrusion speed. After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands, the extrudates are preferably singulated. This singulation may preferably be performed by cutting up the extrudates by means of revolving or rotating knives, water jet cutters, wires, blades or with the assistance of laser cutters. Preferably, intermediate or final storage of the optionally singulated extrudate or the final shape of the pharmaceutical dosage form according to the invention is performed under oxygen-free atmosphere which may be achieved, e.g., by means of oxygen-scavengers. The singulated extrudate may be press-formed into tablets in order to impart the final shape to the pharmaceutical dosage form. The application of force in the extruder onto the at least plasticized mixture is adjusted by controlling the rotational speed of the conveying device in the extruder and the geometry thereof and by dimensioning the outlet orifice in such a manner that the pressure necessary for extruding the plasticized mixture is built up in the extruder, preferably immediately prior to extrusion. The extrusion parameters which, for each particular composition, are necessary to give rise to a pharmaceutical dosage form with desired mechanical properties, may be established by simple preliminary testing.
WO 2013/127831 PCT/EP2013/053894 57 For example but not limiting, extrusion may be performed by means of a twin-screw-extruder type ZSE 18 or ZSE27 (Leistritz, N~rnberg, Germany), screw diameters of 18 or 27 mm. Screws having eccentric ends may be used. A heatable die with a round bore having a diameter of 4, 5, 6, 7, 8, 9, or 10 mm may be used. The extrusion parameters may be adjusted e.g. to the following values: rotational speed of the screws: 120 Upm; delivery rate 2 kg/h for a ZSE 18 or 8 kg/h for a ZSE27; product temperature: in front of die 125 C; temperature of the die 135 0C; and jacket temperature: 110 0C. Preferably, extrusion is performed by means of twin-screw-extruders or planetary-gear extruders, twin-screw extruders (co-rotating or contra-rotating) being particularly preferred. The pharmaceutical dosage form according to the invention is preferably produced by thermoforming with the assistance of an extruder without any observable consequent discoloration of the extrudates. The process for the preparation of the pharmaceutical dosage form according to the invention is preferably performed continuously. Preferably, the process involves the extrusion of a homogeneous mixture of all components. It is particularly advantageous if the thus obtained intermediate, e.g. the strand obtained by extrusion, exhibits uniform properties. Particularly desirable are uniform density, uniform distribution of the active compound, uniform mechanical properties, uniform porosity, uniform appearance of the surface, etc. Only under these circumstances the uniformity of the pharmacological properties, such as the stability of the release profile, may be ensured and the amount of rejects can be kept low. A further aspect of the invention relates to the use of a pharmacologically active compound in combination with an anionic polymer for the manufacture of the pharmaceutical dosage form as described above for the treatment of pain, preferably moderate to severe pain such as moderate to severe low back pain. A further aspect of the invention relates to the use of a pharmaceutical dosage form as described above for avoiding or hindering the abuse of the pharmacologically active compound contained therein. A further aspect of the invention relates to the use of a pharmaceutical dosage form as described above for avoiding or hindering the unintentional overdose of the pharmacologically active compound contained therein.
WO 2013/127831 PCT/EP2013/053894 58 In this regard, the invention also relates to the use of a pharmacologically active compound as described above and/or an anionic polymer as described above for the manufacture of the pharmaceutical dosage form according to the invention for the prophylaxis and/or the treatment of a disorder, thereby preventing an overdose of the pharmacologically active compound, particularly due to comminution of the pharmaceutical dosage form by mechanical action. Further, the invention relates to a method for the prophylaxis and/or the treatment of a disorder comprising the administration of the pharmaceutical dosage form according to the invention, thereby preventing an overdose of the pharmacologically active compound, particularly due to comminution of the pharmaceutical dosage form by mechanical action. Preferably, the mechanical action is selected from the group consisting of chewing, grinding in a mortar, pounding, and using apparatuses for pulverizing conventional pharmaceutical dosage forms. The following examples further illustrate the invention but are not to be construed as limiting its scope. General procedure: Carbopol 71 G, tramadol hydrochloride and all other excipients were weighted and sieved to each other. The powder was mixed and dosed gravimetrically to an extruder. Hot-melt extrusion (revolution speed 100 rpm) was performed by means of a twin screw extruder of type ZSE27 micro PH 40D (Leistritz, N~rnberg, Germany) that was equipped with a heatable round die having a diameter of 10 mm (cutting length 6-7 mm or 7-8 mm). The hot extrudate was cooled by ambient air and the cooled extrusion strand was comminuted to cut pieces. The cut pieces were shaped by means of an excenter press which was equipped with a round punch. The breaking strength of the pharmaceutical dosage forms was measured by means of a Sotax* HT100. A tablet was regarded as failing the breaking strength test when during the measurement the force dropped below the threshold value of 25% of the maximum force that was observed during the measurement, regardless of whether the pharmaceutical dosage WO 2013/127831 PCT/EP2013/053894 59 form was fractured into separate pieces or not. All values are given as a mean of 10 measurements. The in vitro release profile of tramadol hydrochloride was measured in 600 ml phosphate buffer (pH 6.8) at temperature of 370C with sinker (type 1 or 2). The rotation speed of the paddle was adjusted to 75/min.
WO 2013/127831 PCT/EP2013/053894 60 Example 1: a) Composition Tablets having the following compositions were prepared: 1-1 1-2 1-3 1-4 mg wt.-% mg mg mg wt.-% mg wt.-% Tramadol HCI 80.0 13.3 80.0 13.3 80.0 13.3 80.0 13.3 Carbopol 71 G 185.0 30.85 185.0 30.85 222.0 37.0 222.0 37.0 Poloxamer 407 (LutrolR F1 27) 185.0 30.85 - - 148.0 24.7 - Poloxamer 188 (LutrolR F68) - - 185.0 30.85 - - 148.0 24.7 HPMC 100,000 mPa-s 60.0 10.0 60.0 10.0 60.0 10.0 60.0 10.0 Macrogol 6,000 90.0 15.0 90.0 15.0 90.0 15.0 90.0 15.0 600.0 100.0 600.0 100.0 600.0 100.0 600.0 100.0 C-1 mg wt.-% Tramadol HCI 80.0 13.3 Polyethylene Oxide Mw 7x1 06 370.0 61.7 HPMC 100,000 mPa-s 60.0 10.0 Macrogol 6,000 90.0 15.0 2 600.0 100.0 b) Hot-melt extrusion The following extrusion parameters were adjusted and measured, respectively: 1-1 1-2 1-3 1-4 C-1 diameter of die [mm] 10 10 10 10 10 throughput [kg/h] 3.5 3.5 3.5 3.5 3.5 melt temperature [IC] 116 115 117 115 98 performance (%) 21 22 45 49 54 melt pressure [bar] 3 5 8 12 42 strand diameter [mm] 10.3 12.2 10.5 10.5 9.9 cutting length [mm] 7.1-7.4 7.0-8.5 6.5-6.8 6-7 7.5 Crude extrudates having the following weights and dimensions were obtained: WO 2013/127831 PCT/EP2013/053894 61 n=10 1-1 1-2 1-3 1-4 C-1 min 584 578 577 575 599 weight [mg] max 629 628 624 625 627 average 612 597 602 609 613 min 6.95 6.39 6.30 6.52 6.45 length [mm] max 7.46 7.01 7.33 7.40 7.54 average 7.26 6.68 6.66 6.94 7.12 min 9.16 10.32 9.21 9.86 9.73 diameter [mm] max 10.75 11.25 11.11 10.92 10.12 average 9.75 10.79 10.33 10.44 9.97 c) Formation of tablets from extrudates Tablets were manufactured from the crude extrudates by means of a round punch having the following dimensions (no engraving): IExample Form of punch round biconcave, round, diameter 12 mm, radius of curvature 9 mm Tablets having the following weights and dimensions were obtained: n=10 1-1 1-2 1-3 1-4 C-1 min 6.61 6.31 6.08 6.17 6.27 thickness max 6.87 6.55 6.79 6.70 6.81 [mm] average 6.72 6.43 6.43 6.41 6.53 min 11.68 11.61 11.46 11.35 11.56 diameter [mm] max 12.03 12.09 12.05 11.98 11.86 average 11.90 11.90 11.67 11.66 11.71 d) In-vitro release measuring point 1-1 1-2 1-3 1-4 C-1 Dissolution % (DS) after 60 min 13 14 16 16 21 after 120 min 20 22 25 25 33 after 480 min 46 51 57 57 76 after 720 min 59 64 73 75 90 after 1440 min 82 88 94 100 101 WO 2013/127831 PCT/EP2013/053894 62 measuring point I-1 1-2 1-3 1-4 C-1 Dissolution % (0.1 N HCI) after 60 min 19 19 16 18 20 after 120 min 27 28 24 26 31 after 480 min 56 60 51 58 78 after 720 min 68 75 65 73 95 after 1440 min 90 95 90 95 102 e) Tamper resistance - breaking strength breaking strength [N] 1-1 1-2 1-3 1-4 C-1 Sotax* HT100 318 N 1877 N 1000 N 1000 N - 1000 N The corresponding force-displacement diagrams of examples 1-1, 1-2, 1-3, 1-4 and C are displayed as Figures 1-A, 1-B, 1-C, 1-D and 1-E, respectively. The deviating curve in Figure 1-C represents a measurement error (tablet displaced). f) Tamper resistance - extractability The extractable content of pharmacologically active compound was determined by (iv) subjecting a tablet (a) for 30 minutes to 30 mL of solvent with continuous shaking, or (b) giving a tablet in 30 mL of purified water, heating the water until boiling and shaking for 30 minutes, during the slow cooling of the water; (v) supplementing lost water, if any, and (vi) determining the pharmacologically active compound content in the overhead liquid by HPLC analysis. The syringeable content of pharmacologically active compound was determined by (i) subjecting a tablet (a) for 5 minutes in 5 mL of cold water, or (b) to boiling water and boiling the tablet for 5 minutes, respectively, (ii) closing the vessel with aluminum foil, boiling extraction only, (iii) drawing up the liquid into a syringe using a canula through a cigarette filter, and (iv) determining the pharmacologically active compound content in the drawn liquid by HPLC analysis. The results are shown in the table here below: WO 2013/127831 PCT/EP2013/053894 63 content [wt.-%] 1-1 1-2 1-3 1-4 C-1 faultless tablet 90.4 95.7 94.7 95.8 99.6 extraction cold water 9.7 9.9 8.6 9.3 13.9 extraction boiling water 18.6 21.5 15.1 14.9 25.7 extraction water /ethanol 60/40 v/v 8.4 8.3 8.6 9.6 9.4 drawn up into syringe 2.9 10.8 3.2 6.8 2.6 (faultless tablet) drawn up into syringe 8.1 7.2 3.4 5.5 10.8 (ground tablet)') 1): household coffee mill, type Bosch MKM6000, 180W, type KM 13; grinding time: 2 minutes g) Tamper resistance - hammer impact The test was performed by means of a free falling weight testing device Type 40-550-001, 40-550-011 ff, Coesfeld GmbH & Co. KG, Germany. The following parameters were set: Falling height: 1000 mm±1% Falling weight: 500 g±2% Form of falling weight: 25 mm x 25 mm Position of sample: loosely positioned in the center of the sample holder The measuring result was qualified according to the following scale: (A) tablet apparently undamaged (B) tablet has been compressed but is widely undamaged (C) tablet has been compressed and is lacerated at its edges (D) tablet has been disrupted into several pieces (E) tablet has been pulverized The results are shown in the table here below: 1-1 1-2 1-3 1-4 C-1 (D) (D) (D) (C) (A) h) Tamper resistance - grindability The tablets were treated by means of o commercially available household coffee mill, type Bosch MKM6000 (180 W, type KM 13). Subsequently, the thus obtained material was WO 2013/127831 PCT/EP2013/053894 64 analyzed by means of a sieving tower (Haver & Boecker, analysis sieve, diameter: 50 mm) equipped with a bottom plate, displacement ring, lid, and 14 sieves the mesh sizes ranging from 0.045 mm to 4.000 mm, namely 0.045 mm; 0.063 mm; 0.090 mm; 0.125 mm; 0.180 mm; 0.250 mm; 0.355 mm; 0.500 mm; 0.710 mm; 1.000 mm; 1.400 mm; 2.000 mm; 2.800 mm; 4.000 mm. The amplitude was set to 1.5 mm. Sieving time was 10 min. The results after 2 minutes grinding are summarized in the table here below: 2 min grinding time I-1 1-2 1-3 1-4 C-1 < 0.045 0.00 0.00 0.00 0.00 0.00 0.045-0.063 0.00 0.00 0.00 0.00 0.00 0.063-0.090 0.00 0.00 0.00 0.00 0.00 0.090-0.125 0.57 0.00 0.00 0.00 0.00 0.125-0.180 0.57 0.00 0.00 0.00 0.00 0.180-0.250 4.14 1.20 1.27 1.60 0.00 0.250-0.355 9.05 5.84 4.69 1.60 1.42 0.355-0.500 12.82 10.48 7.04 3.78 1.42 0.500-0.710 16.81 14.09 12.26 5.48 3.72 0.710-1.000 15.72 15.29 14.05 7.18 6.56 1.000-1.400 15.20 19.45 15.26 11.00 14.54 1.400-2.000 12.53 16.17 17.24 16.47 27.42 2.000-2.800 7.44 9.27 19.45 12.59 16.60 2.800-4.000 2.96 8.20 6.09 12.32 16.97 >4.000 2.19 0.00 2.65 28.00 11.35 It is clear from the above data that the dosage forms according to the invention have advantages compared to the reference with respect to extractability in cold and hot water. At the same time, breaking strength, impact resistance and indifference of the release profile to pH changes of some preferred dosage forms according to the invention are comparable to those of the reference. Example 2: Tablets having a total weight of 600 mg were manufactured in analogy to example 1. The breaking strength (measured in accordance with WO 2005/ 016313, WO 2005/016314, and WO 2006/082099) of the tablets was measured (average value, n=3). The compositions and the measured breaking strengths are summarized in the table here below: WO 2013/127831 PCT/EP2013/053894 65 ex. breaking CBPLUT (CBP+LUT): CBP: LUT: (CBP+LUT): API: API: API: strength [N] CBP:LUT PEG PEG PEG HPMC (CBP+LUT) CBP LUT 2-1 565 1.0 4.0 2.0 2.0 5.6 0.4 0.7 0.7 2-2 1500 2.0 4.0 2.7 2.7 5.6 0.4 0.5 1.1 2-3 950 1.5 2.0 1.2 1.2 4.7 0.4 0.7 1.1 2-4 1500 1.5 3.0 1.8 1.8 5.3 0.4 0.6 1.0 2-5 1500 1.5 5.0 3.0 3.0 5.8 0.3 0.6 0.9 2-6 1500 1.5 6.0 3.6 3.6 6.0 0.3 0.6 0.8 2-7 1500 1.5 4.1 2.5 2.5 6.2 0.2 0.4 0.5 2-8 1500 1.5 4.0 2.4 2.4 - 0.3 0.5 0.8 2-9 1500 1.5 4.0 2.4 2.4 5.6 0.4 0.6 0.9 2-10 1500 1.5 4.0 2.4 2.4 2.4 0.4 0.7 1.0 2-11 1500 1.5 4.0 2.4 2.4 6.8 0.1 0.1 0.2 2-12 317 1.5 4.0 2.4 2.4 4.0 1.0 1.7 2.5 2-13 337 1.5 0.4 0.2 0.2 2.4 2.5 4.2 6.3 min. 1.0 0.4 0.2 0.2 2.4 0.1 0.1 0.2 max. 2.0 6.0 3.6 3.6 6.8 2.5 4.2 6.3 CBP = Carbopol 71 G LUT = Poloxamer 188 (Lutrol* F68) PEG = Polyethylene glycol (Macrogol 6,000) HPMC = hydroxypropylmethylcellu lose (HPMC 100,000) API = active pharmaceutical ingredient (Tramadol HCI)

权利要求:
Claims (14)
[1] 1. A pharmaceutical dosage form having a breaking strength of at least 300 N and comprising - a pharmacologically active compound, - an anionic polymer bearing carboxylic groups, wherein the content of the anionic polymer is > 20 wt.-%, based on the total weight of the pharmaceutical dosage form, and - a nonionic surfactant.
[2] 2. The pharmaceutical dosage form according to claim 1, wherein the anionic polymer is obtainable by polymerization of a monomer composition comprising an ethylenically unsaturated monomer selected from ethylenically unsaturated carboxylic acids, ethylenically unsaturated carboxylic acid anhydrides, ethylenically unsaturated sulfonic acids, and mixtures thereof.
[3] 3. The pharmaceutical dosage form according to claim 1 or 2, wherein the anionic polymer is derived from an ethylenically unsaturated monomer selected from (alk)acrylic acids, (alk)acrylic anhydrides, alkyl (alk)acrylates, or a combination thereof.
[4] 4. The pharmaceutical dosage form according to claim 2 or 3, wherein the monomer composition further comprises at least one cross-linking agent selected from the group consisting of allyl sucrose, allyl pentaerythritol, divinyl glycol, divinyl polyethylene glycol and (meth)acrylic acid esters of diols.
[5] 5. The pharmaceutical dosage form according to any of the preceding claims, which either does not contain any polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, or wherein the total content of polyalkylene oxide(s) having an average molecular weight of at least 200,000 g/mol is 5 35 wt.-%, based on the total weight of the pharmaceutical dosage form.
[6] 6. The pharmaceutical dosage form according to any of the preceding claims, wherein the pharmacologically active compound is an opioid.
[7] 7. The pharmaceutical dosage form according to any of the preceding claims, wherein the nonionic surfactant WO 2013/127831 PCT/EP2013/053894 67 (i) in pure water at a concentration of 25 wt.-% forms an aqueous dispersion having a viscosity i, at a temperature of 20 0C and a viscosity 12 at a temperature of more than 20 IC, where 12 > il; and/or (ii) has an HLB value of at least 20, and/or (iii) has a surface tension in 0.1% aqueous solution at 301C of at least 35 dynes/cm; and/or (iv) has a viscosity of at most 4000 mPa-s, measured at 70 IC using a model LVF or LVT Brookfield viscosimeter.
[8] 8. The pharmaceutical dosage form according to any of the preceding claims, wherein the nonionic surfactant is a synthetic copolymer of ethylene oxide and propylene oxide.
[9] 9. The pharmaceutical dosage form according to any of the preceding claims, wherein the nonionic surfactant is selected from block copolymers according to general formula (1-a) OH 3 HO 0 H a -c - - b (1-a) wherein a and c are each independently an integer of from 5 to 300, and b is an integer of from 10to 100; and/or block copolymers according to general formula (1-b) 0C H H O g9 H ' 4 . CH 3 .k H 3 N H 3 OH 3 H 1 - . f (1-b) WO 2013/127831 PCT/EP2013/053894 68 wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and I are each independently an integer of from 2 to 50.
[10] 10. The pharmaceutical dosage form according to any of the preceding claims, wherein the content of the nonionic surfactant is at least 10 wt.-%, based on the total weight of the pharmaceutical dosage form.
[11] 11. The pharmaceutical dosage form according to any of the preceding claims, wherein the pharmacologically active compound is embedded in a prolonged release matrix comprising the anionic polymer and the optionally present nonionic surfactant.
[12] 12. The pharmaceutical dosage form according to any of the preceding claims, which is configured for administration once daily or twice daily.
[13] 13. The pharmaceutical dosage form according to any of the preceding claims, which is thermoformed.
[14] 14. The pharmaceutical dosage form according to any of the preceding claims, which is tamper-resistant.

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同族专利:

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公开号 | 公开日

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US9655853B2|2017-05-23|

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US20160271066A1|2016-09-22|

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WO2013127831A1|2013-09-06|

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US20150238422A1|2015-08-27|

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JP6117249B2|2017-04-19|

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CA2864949A1|2013-09-06|

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MX356421B|2018-05-29|

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AU2013225106B2|2017-11-02|

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EP2819656A1|2015-01-07|

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MX2014010065A|2014-09-22|

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US20130225697A1|2013-08-29|

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JP2015511950A|2015-04-23|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

CA722109A||1965-11-23|W. Mock Henry|Extrusion of ethylene oxide polymers|

---

US2524855A||1950-10-10||Process for the manufacture of |

---

US2806033A|1955-08-03|1957-09-10|Lewenstein|Morphine derivative|

---

US2987445A|1958-10-10|1961-06-06|Rohm & Haas|Drug composition|

---

US3370035A|1961-06-23|1968-02-20|Takeda Chemical Industries Ltd|Stabilization of polyalkylene oxide|

---

US3332950A|1963-03-23|1967-07-25|Endo Lab|14-hydroxydihydronormorphinone derivatives|

---

GB1147210A|1965-06-30|1969-04-02|Eastman Kodak Co|Improvements in or relating to vitamins|

---

US3652589A|1967-07-27|1972-03-28|Gruenenthal Chemie|1--2-aminomethyl cyclohexanols|

---

US3806603A|1969-10-13|1974-04-23|W Gaunt|Pharmaceutical carriers of plasticized dried milled particles of hydrated cooked rice endosperm|

---

DE2210071A1|1971-03-09|1972-09-14|PPG Industries Inc., Pittsburgh, Pa. |Process for applying and curing a wide variety of coatings|

---

US3980766A|1973-08-13|1976-09-14|West Laboratories, Inc.|Orally administered drug composition for therapy in the treatment of narcotic drug addiction|

---

US3865108A|1971-05-17|1975-02-11|Ortho Pharma Corp|Expandable drug delivery device|

---

US3966747A|1972-10-26|1976-06-29|Bristol-Myers Company|9-Hydroxy-6,7-benzomorphans|

---

US4014965A|1972-11-24|1977-03-29|The Dow Chemical Company|Process for scrapless forming of plastic articles|

---

US3941865A|1973-12-10|1976-03-02|Union Carbide Corporation|Extrusion of ethylene oxide resins|

---

US4002173A|1974-07-23|1977-01-11|International Paper Company|Diester crosslinked polyglucan hydrogels and reticulated sponges thereof|

---

DE2530563C2|1975-07-09|1986-07-24|Bayer Ag, 5090 Leverkusen|Analgesic drugs with reduced potential for abuse|

---

JPS603286B2|1977-03-03|1985-01-26|Nippon Kayaku Kk||

---

US4207893A|1977-08-29|1980-06-17|Alza Corporation|Device using hydrophilic polymer for delivering drug to biological environment|

---

US4175119A|1978-01-11|1979-11-20|Porter Garry L|Composition and method to prevent accidental and intentional overdosage with psychoactive drugs|

---

DE2822324C3|1978-05-22|1981-02-26|Basf Ag, 6700 Ludwigshafen|Manufacture of vitamin E dry powder|

---

US4211681A|1978-08-16|1980-07-08|Union Carbide Corporation|Poly compositions|

---

US4200704A|1978-09-28|1980-04-29|Union Carbide Corporation|Controlled degradation of poly|

---

NO793297L|1978-10-19|1980-04-22|Mallinckrodt Inc|PROCEDURE FOR THE MANUFACTURE OF OXYMORPHONE|

---

US4258027A|1979-03-26|1981-03-24|Mead Johnson & Company|Multi-fractionable tablet structure|

---

US4215104A|1979-03-26|1980-07-29|Mead Johnson & Company|Multi-fractionable tablet structure|

---

CA1146866A|1979-07-05|1983-05-24|Yamanouchi Pharmaceutical Co. Ltd.|Process for the production of sustained releasepharmaceutical composition of solid medicalmaterial|

---

CH648754A5|1979-08-16|1985-04-15|Ciba Geigy Ag|Pharmaceutical slow release tablet|

---

US4353887A|1979-08-16|1982-10-12|Ciba-Geigy Corporation|Divisible tablet having controlled and delayed release of the active substance|

---

US4457933A|1980-01-24|1984-07-03|Bristol-Myers Company|Prevention of analgesic abuse|

---

JPH0129764B2|1980-06-03|1989-06-14|Kissei Pharmaceutical||

---

DE3024416C2|1980-06-28|1982-04-15|Gödecke AG, 1000 Berlin|Process for the production of medicaments with sustained release of active substances|

---

US4473640A|1982-06-03|1984-09-25|Combie Joan D|Detection of morphine and its analogues using enzymatic hydrolysis|

---

US4462941A|1982-06-10|1984-07-31|The Regents Of The University Of California|Dynorphin amide analogs|

---

US4427778A|1982-06-29|1984-01-24|Biochem Technology, Inc.|Enzymatic preparation of particulate cellulose for tablet making|

---

US4485211A|1982-09-15|1984-11-27|The B. F. Goodrich Company|Polyblock copolymers and process for their preparation|

---

US4427681A|1982-09-16|1984-01-24|Richardson-Vicks, Inc.|Thixotropic compositions easily convertible to pourable liquids|

---

US4529583A|1983-03-07|1985-07-16|Clear Lake Development Group|Composition and method of immobilizing emetics and method of treating human beings with emetics|

---

US4603143A|1983-05-02|1986-07-29|Basf Corporation|Free-flowing, high density, fat soluble vitamin powders with improved stability|

---

US4612008A|1983-05-11|1986-09-16|Alza Corporation|Osmotic device with dual thermodynamic activity|

---

US4783337A|1983-05-11|1988-11-08|Alza Corporation|Osmotic system comprising plurality of members for dispensing drug|

---

US4765989A|1983-05-11|1988-08-23|Alza Corporation|Osmotic device for administering certain drugs|

---

US5082668A|1983-05-11|1992-01-21|Alza Corporation|Controlled-release system with constant pushing source|

---

US4599342A|1984-01-16|1986-07-08|The Procter & Gamble Company|Pharmaceutical products providing enhanced analgesia|

---

US4629621A|1984-07-23|1986-12-16|Zetachron, Inc.|Erodible matrix for sustained release bioactive composition|

---

AU592065B2|1984-10-09|1990-01-04|Dow Chemical Company, The|Sustained release dosage form based on highly plasticized cellulose ether gels|

---

GB8507779D0|1985-03-26|1985-05-01|Fujisawa Pharmaceutical Co|Drug carrier|

---

US4774092A|1985-06-24|1988-09-27|Ici Australia Limited|Ingestible capsules|

---

DE3665262D1|1985-06-28|1989-10-05|Carrington Lab Inc|Processes for preparation of aloe products, products produced thereby and compositions thereof|

---

US4992279A|1985-07-03|1991-02-12|Kraft General Foods, Inc.|Sweetness inhibitor|

---

US4851521A|1985-07-08|1989-07-25|Fidia, S.P.A.|Esters of hyaluronic acid|

---

EP0226061B1|1985-12-17|1994-02-16|United States Surgical Corporation|High molecular weight bioresorbable polymers and implantation devices thereof|

---

US4711894A|1986-01-16|1987-12-08|Henkel Corporation|Stabilized tocopherol in dry, particulate, free-flowing form|

---

US4940556A|1986-01-30|1990-07-10|Syntex Inc.|Method of preparing long acting formulation|

---

US5198226A|1986-01-30|1993-03-30|Syntex Inc.|Long acting nicardipine hydrochloride formulation|

---

US4764378A|1986-02-10|1988-08-16|Zetachron, Inc.|Buccal drug dosage form|

---

AU7077287A|1986-03-31|1987-10-08|Union Carbide Corporation|Alkylene oxide polymerisation catalyst|

---

DE3612211A1|1986-04-11|1987-10-15|Basf Ag|CONTINUOUS TABLET METHOD|

---

US4667013A|1986-05-02|1987-05-19|Union Carbide Corporation|Process for alkylene oxide polymerization|

---

USRE33093E|1986-06-16|1989-10-17|Johnson & Johnson Consumer Products, Inc.|Bioadhesive extruded film for intra-oral drug delivery and process|

---

US4713243A|1986-06-16|1987-12-15|Johnson & Johnson Products, Inc.|Bioadhesive extruded film for intra-oral drug delivery and process|

---

USRE34990E|1986-08-07|1995-07-04|Ciba-Geigy Corporation|Oral therapeutic system having systemic action|

---

CA1335748C|1986-09-25|1995-05-30|Jeffrey Lawrence Finnan|Crosslinked gelatins|

---

US5227157A|1986-10-14|1993-07-13|Board Of Regents, The University Of Texas System|Delivery of therapeutic agents|

---

WO1988003408A1|1986-11-10|1988-05-19|Biopure Corporation|Extra pure semi-synthetic blood substitute|

---

US4892889A|1986-11-18|1990-01-09|Basf Corporation|Process for making a spray-dried, directly-compressible vitamin powder comprising unhydrolyzed gelatin|

---

JPH0831303B2|1986-12-01|1996-03-27|オムロン株式会社|Chip type fuse|

---

AT72111T|1987-01-14|1992-02-15|Ciba Geigy Ag|THERAPEUTIC SYSTEM FOR HEAVY-SOLUBLE ACTIVE SUBSTANCES.|

---

US4892778A|1987-05-27|1990-01-09|Alza Corporation|Juxtaposed laminated arrangement|

---

US5051261A|1987-11-24|1991-09-24|Fmc Corporation|Method for preparing a solid sustained release form of a functionally active composition|

---

KR940000280Y1|1987-12-17|1994-01-19|디 엎죤 캄파니|Tri-scored drug tablet|

---

DE3812567A1|1988-04-15|1989-10-26|Basf Ag|METHOD FOR PRODUCING PHARMACEUTICAL MIXTURES|

---

US4960814A|1988-06-13|1990-10-02|Eastman Kodak Company|Water-dispersible polymeric compositions|

---

US5350741A|1988-07-30|1994-09-27|Kanji Takada|Enteric formulations of physiologically active peptides and proteins|

---

JPH0249719A|1988-08-11|1990-02-20|Dai Ichi Kogyo Seiyaku Co Ltd|Oil soluble-vitamin powder having readily water-dispersible and soluble performance|

---

GB8820327D0|1988-08-26|1988-09-28|May & Baker Ltd|New compositions of matter|

---

DE3830353A1|1988-09-07|1990-03-15|Basf Ag|METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS|

---

US5139790A|1988-10-14|1992-08-18|Zetachron, Inc.|Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith|

---

US5004601A|1988-10-14|1991-04-02|Zetachron, Inc.|Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith|

---

US4957668A|1988-12-07|1990-09-18|General Motors Corporation|Ultrasonic compacting and bonding particles|

---

US5190760A|1989-07-08|1993-03-02|Coopers Animal Health Limited|Solid pharmaceutical composition|

---

US5169645A|1989-10-31|1992-12-08|Duquesne University Of The Holy Ghost|Directly compressible granules having improved flow properties|

---

US5200197A|1989-11-16|1993-04-06|Alza Corporation|Contraceptive pill|

---

GB8926612D0|1989-11-24|1990-01-17|Erba Farmitalia|Pharmaceutical compositions|

---

EP0449775A3|1990-03-29|1992-09-02|Ciba-Geigy Ag|Polyether-polyester block copolymers and their use as dispersing agents|

---

SU1759445A1|1990-06-15|1992-09-07|Ленинградский Технологический Институт Им.Ленсовета|Method of producing encapsulated hydrophobic substances|

---

FR2664851B1|1990-07-20|1992-10-16|Oreal|METHOD OF COMPACTING A POWDER MIXTURE FOR OBTAINING A COMPACT ABSORBENT OR PARTIALLY DELITABLE PRODUCT AND PRODUCT OBTAINED BY THIS PROCESS.|

---

EP0477135A1|1990-09-07|1992-03-25|Warner-Lambert Company|Chewable spheroidal coated microcapsules and methods for preparing same|

---

US5126151A|1991-01-24|1992-06-30|Warner-Lambert Company|Encapsulation matrix|

---

US5273758A|1991-03-18|1993-12-28|Sandoz Ltd.|Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms|

---

US5149538A|1991-06-14|1992-09-22|Warner-Lambert Company|Misuse-resistive transdermal opioid dosage form|

---

JP3073054B2|1991-07-11|2000-08-07|住友精化株式会社|Method for producing alkylene oxide polymer|

---

WO1993004670A1|1991-08-30|1993-03-18|Showa Yakuhin Kako Co., Ltd.|Dry gel composition|

---

DE69229881T2|1991-10-04|1999-12-09|Yoshitomi Pharmaceutical|DELAYED RELEASE TABLET|

---

WO1993006723A1|1991-10-04|1993-04-15|Olin Corporation|Fungicide tablet|

---

DE4138513A1|1991-11-23|1993-05-27|Basf Ag|SOLID PHARMACEUTICAL RETARD FORM|

---

US5266331A|1991-11-27|1993-11-30|Euroceltique, S.A.|Controlled release oxycodone compositions|

---

ES2090714T3|1991-12-05|1996-10-16|Mallinckrodt Veterinary Inc|CARBOHYDRATE GLASS MATRIX FOR THE PROLONGED RELEASE OF A THERAPEUTIC AGENT.|

---

CA2124821C|1991-12-18|2003-10-07|Isaac Ghebre-Sellassie|Novel solid pharmaceutical dispersions|

---

US5225417A|1992-01-21|1993-07-06|G. D. Searle & Co.|Opioid agonist compounds|

---

IL105553A|1992-05-06|1998-01-04|Janssen Pharmaceutica Inc|Solid dosage form comprising a porous network of matrix forming material which disperses rapidly in water|

---

US5792474A|1992-05-22|1998-08-11|Goedecke Aktiengesellschaft|Process for the production of retarded pharmaceutical compositions|

---

GB9217295D0|1992-08-14|1992-09-30|Wellcome Found|Controlled released tablets|

---

DE4227385A1|1992-08-19|1994-02-24|Kali Chemie Pharma Gmbh|Pancreatin micropellets|

---

DE4229085C2|1992-09-01|1996-07-11|Boehringer Mannheim Gmbh|Elongated, divisible tablet|

---

JP3140465B2|1992-09-18|2001-03-05|山之内製薬株式会社|Hydrogel sustained release formulation|

---

US5472943A|1992-09-21|1995-12-05|Albert Einstein College Of Medicine Of Yeshiva University,|Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists|

---

FI101039B|1992-10-09|1998-04-15|Eeva Kristoffersson|Method for preparing medicated pellets|

---

AU679937B2|1992-11-18|1997-07-17|Johnson & Johnson Consumer Products, Inc.|Extrudable compositions for topical or transdermal drug delivery|

---

ES2138070T3|1992-12-23|2000-01-01|Saitec Srl|PROCESS FOR THE PREPARATION OF PHARMACEUTICAL FORMS OF CONTROLLED LIBERATION AND THE FORMS OBTAINED IN THIS WAY.|

---

GB2273874A|1992-12-31|1994-07-06|Pertti Olavi Toermaelae|Preparation of pharmaceuticals in a polymer matrix|

---

US6071970A|1993-02-08|2000-06-06|Nps Pharmaceuticals, Inc.|Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases|

---

DE4309528C2|1993-03-24|1998-05-20|Doxa Gmbh|Casein film or film tube, process for their production and their use|

---

IL119660A|1993-05-10|2002-09-12|Euro Celtique Sa|Controlled release formulation comprising tramadol|

---

ES2168290T3|1993-11-23|2002-06-16|Euro Celtique Sa|METHOD FOR PREPARING A SUSTAINED RELEASE COMPOSITION.|

---

KR100354702B1|1993-11-23|2002-12-28|유로-셀티크 소시에떼 아노뉨|Manufacturing method and sustained release composition of pharmaceutical composition|

---

IL109944A|1993-07-01|1998-12-06|Euro Celtique Sa|Sustained release dosage unit forms containing morphine and a method of preparing these sustained release dosage unit forms|

---

DE4329794C2|1993-09-03|1997-09-18|Gruenenthal Gmbh|Tramadol salt-containing drugs with delayed release|

---

US6461644B1|1996-03-25|2002-10-08|Richard R. Jackson|Anesthetizing plastics, drug delivery plastics, and related medical products, systems and methods|

---

EP0647448A1|1993-10-07|1995-04-12|Euroceltique S.A.|Orally administrable opioid formulations having extended duration of effect|

---

AU1266895A|1993-12-20|1995-07-10|Procter & Gamble Company, The|Process for making laxatives containing dioctyl sulfosuccinate|

---

GB9401894D0|1994-02-01|1994-03-30|Rhone Poulenc Rorer Ltd|New compositions of matter|

---

WO1995022319A1|1994-02-16|1995-08-24|Abbott Laboratories|Process for preparing fine particle pharmaceutical formulations|

---

US5458887A|1994-03-02|1995-10-17|Andrx Pharmaceuticals, Inc.|Controlled release tablet formulation|

---

DE4413350A1|1994-04-18|1995-10-19|Basf Ag|Retard matrix pellets and process for their production|

---

DK0758244T4|1994-05-06|2008-06-16|Pfizer|Controlled-release azithromycin dosage forms|

---

AT403988B|1994-05-18|1998-07-27|Lannacher Heilmittel|SOLID ORAL RETARDED PREPARATION|

---

US5460826A|1994-06-27|1995-10-24|Alza Corporation|Morphine therapy|

---

DE4426245A1|1994-07-23|1996-02-22|Gruenenthal Gmbh|1-phenyl-3-dimethylamino-propane compounds with pharmacological activity|

---

IT1274879B|1994-08-03|1997-07-25|Saitec Srl|APPARATUS AND METHOD FOR PREPARING SOLID PHARMACEUTICAL FORMS WITH CONTROLLED RELEASE OF THE ACTIVE INGREDIENT.|

---

JP3285452B2|1994-08-11|2002-05-27|サンスター株式会社|Toothpaste composition|

---

US5837790A|1994-10-24|1998-11-17|Amcol International Corporation|Precipitation polymerization process for producing an oil adsorbent polymer capable of entrapping solid particles and liquids and the product thereof|

---

AUPM897594A0|1994-10-25|1994-11-17|Daratech Pty Ltd|Controlled release container|

---

US5965161A|1994-11-04|1999-10-12|Euro-Celtique, S.A.|Extruded multi-particulates|

---

DE4446470A1|1994-12-23|1996-06-27|Basf Ag|Process for the production of dividable tablets|

---

DE19504832A1|1995-02-14|1996-08-22|Basf Ag|Solid drug preparations|

---

US5945125A|1995-02-28|1999-08-31|Temple University|Controlled release tablet|

---

DE19509807A1|1995-03-21|1996-09-26|Basf Ag|Process for the preparation of active substance preparations in the form of a solid solution of the active substance in a polymer matrix, and active substance preparations produced using this method|

---

US6117453A|1995-04-14|2000-09-12|Pharma Pass|Solid compositions containing polyethylene oxide and an active ingredient|

---

US6348469B1|1995-04-14|2002-02-19|Pharma Pass Llc|Solid compositions containing glipizide and polyethylene oxide|

---

US5900425A|1995-05-02|1999-05-04|Bayer Aktiengesellschaft|Pharmaceutical preparations having controlled release of active compound and processes for their preparation|

---

DE19522899C1|1995-06-23|1996-12-19|Hexal Pharmaforschung Gmbh|Process for the continuous sintering of a granulate|

---

SE9503924D0|1995-08-18|1995-11-07|Astra Ab|Novel opioid peptides|

---

US5759583A|1995-08-30|1998-06-02|Syntex Inc.|Sustained release poly matrices|

---

US6007843A|1995-09-29|1999-12-28|Lam Pharmaceuticals Corp.|Sustained release delivery system|

---

US5811126A|1995-10-02|1998-09-22|Euro-Celtique, S.A.|Controlled release matrix for pharmaceuticals|

---

DE19539361A1|1995-10-23|1997-04-24|Basf Ag|Process for the preparation of multilayer, solid pharmaceutical forms for oral or rectal administration|

---

US6355656B1|1995-12-04|2002-03-12|Celgene Corporation|Phenidate drug formulations having diminished abuse potential|

---

US5908850A|1995-12-04|1999-06-01|Celgene Corporation|Method of treating attention deficit disorders with d-threo methylphenidate|

---

DE19547766A1|1995-12-20|1997-06-26|Gruenenthal Gmbh|1-phenyl-2-dimethylaminomethyl-cyclohexan-1-ol compounds as active pharmaceutical ingredients|

---

DK0914097T3|1996-03-12|2002-04-29|Alza Corp|Composition and dosage form comprising opioid antagonist|

---

SK283348B6|1996-04-05|2003-06-03|Takeda Chemical Industries, Ltd.|Pharmaceutical combination containing a compound having angiotensin II and antagonistic activity|

---

US20020114838A1|1996-04-05|2002-08-22|Ayer Atul D.|Uniform drug delivery therapy|

---

US5817343A|1996-05-14|1998-10-06|Alkermes, Inc.|Method for fabricating polymer-based controlled-release devices|

---

EP1014941B2|1996-06-26|2017-05-17|The Board Of Regents, The University Of Texas System|Hot-melt extrudable pharmaceutical formulation|

---

WO1998001117A1|1996-07-08|1998-01-15|Edward Mendell Co., Inc.|Sustained release matrix for high-dose insoluble drugs|

---

DE19629753A1|1996-07-23|1998-01-29|Basf Ag|Process for the production of solid dosage forms|

---

NL1003684C2|1996-07-25|1998-01-28|Weterings B V H|Device for dispensing a liquid.|

---

DE19630236A1|1996-07-26|1998-01-29|Wolff Walsrode Ag|Biaxially stretched, biodegradable and compostable sausage casing|

---

BE1010353A5|1996-08-14|1998-06-02|Boss Pharmaceuticals Ag|Method for manufacture of pharmaceutical products, device for such a method and pharmaceutical products obtained.|

---

EP0937120B1|1996-11-05|2004-09-22|NOVAMONT S.p.A.|Biodegradable polymeric compositions comprising starch and a thermoplastic polymer|

---

US5991799A|1996-12-20|1999-11-23|Liberate Technologies|Information retrieval system using an internet multiplexer to focus user selection|

---

DE19705538C1|1997-02-14|1998-08-27|Goedecke Ag|Process for the separation of active substances in solid pharmaceutical preparations|

---

US5948787A|1997-02-28|1999-09-07|Alza Corporation|Compositions containing opiate analgesics|

---

DE19710009A1|1997-03-12|1998-09-24|Knoll Ag|Multi-phase preparation forms containing active ingredients|

---

DE19710213A1|1997-03-12|1998-09-17|Basf Ag|Process for the manufacture of solid combination dosage forms|

---

US6096339A|1997-04-04|2000-08-01|Alza Corporation|Dosage form, process of making and using same|

---

US6139770A|1997-05-16|2000-10-31|Chevron Chemical Company Llc|Photoinitiators and oxygen scavenging compositions|

---

DE19721467A1|1997-05-22|1998-11-26|Basf Ag|Process for the preparation of small-scale preparations of biologically active substances|

---

US6635280B2|1997-06-06|2003-10-21|Depomed, Inc.|Extending the duration of drug release within the stomach during the fed mode|

---

ES2248908T7|1997-06-06|2014-11-24|Depomed, Inc.|Dosage forms of drugs orally and gastric retention for continued release of highly soluble drugs|

---

US6306438B1|1997-07-02|2001-10-23|Euro-Celtique, S.A.|Stabilized sustained release tramadol formulations|

---

IE970588A1|1997-08-01|2000-08-23|Elan Corp Plc|Controlled release pharmaceutical compositions containing tiagabine|

---

AU741599B2|1997-09-10|2001-12-06|Fram Group Ip Llc|Injection molding of structural zirconia-based materials by an aqueous process|

---

US6009390A|1997-09-11|1999-12-28|Lucent Technologies Inc.|Technique for selective use of Gaussian kernels and mixture component weights of tied-mixture hidden Markov models for speech recognition|

---

US6547997B1|1997-11-28|2003-04-15|Abbot Laboratories|Method for producing solvent-free noncrystalline biologically active substances|

---

US6344535B1|1997-12-03|2002-02-05|Bayer Aktiengesellschaft|Polyether ester amides|

---

DE19753534A1|1997-12-03|1999-06-10|Bayer Ag|Biodegradable thermoplastic polyester-amides with good mechanical properties for molding, film and fiber, useful for e.g. compostable refuse bag|

---

KR100417490B1|1997-12-22|2004-02-05|유로-셀티크 소시에떼 아노뉨|A method of preventing abuse of opioid dosage forms|

---

US6375957B1|1997-12-22|2002-04-23|Euro-Celtique, S.A.|Opioid agonist/opioid antagonist/acetaminophen combinations|

---

DE19800689C1|1998-01-10|1999-07-15|Deloro Stellite Gmbh|Shaped body made of a wear-resistant material|

---

DE19800698A1|1998-01-10|1999-07-15|Bayer Ag|Biodegradable polyester amides with block-like polyester and polyamide segments|

---

WO1999045067A1|1998-03-05|1999-09-10|Mitsui Chemicals, Inc.|Polylactic acid composition and film thereof|

---

US6245357B1|1998-03-06|2001-06-12|Alza Corporation|Extended release dosage form|

---

US6090411A|1998-03-09|2000-07-18|Temple University|Monolithic tablet for controlled drug release|

---

US6110500A|1998-03-25|2000-08-29|Temple University|Coated tablet with long term parabolic and zero-order release kinetics|

---

EP1070346A1|1998-04-02|2001-01-24|Applied Materials, Inc.|Method for etching low k dielectrics|

---

CA2327685C|1998-04-03|2008-11-18|Bm Research A/S|Controlled release composition|

---

US5962488A|1998-04-08|1999-10-05|Roberts Laboratories, Inc.|Stable pharmaceutical formulations for treating internal bowel syndrome containing isoxazole derivatives|

---

DE19822979A1|1998-05-25|1999-12-02|Kalle Nalo Gmbh & Co Kg|Film with starch or starch derivatives and polyester urethanes and process for their production|

---

US6333087B1|1998-08-27|2001-12-25|Chevron Chemical Company Llc|Oxygen scavenging packaging|

---

DE19841244A1|1998-09-09|2000-03-16|Knoll Ag|Method and device for making tablets|

---

US6268177B1|1998-09-22|2001-07-31|Smithkline Beecham Corporation|Isolated nucleic acid encoding nucleotide pyrophosphorylase|

---

CN1327384A|1998-10-20|2001-12-19|韩国科学技术研究院|Bioflavonoids as plasma high density lipoprotein level increasing agent|

---

US20060240105A1|1998-11-02|2006-10-26|Elan Corporation, Plc|Multiparticulate modified release composition|

---

ES2141688B1|1998-11-06|2001-02-01|Vita Invest Sa|NEW ESTERS DERIVED FROM SUBSTITUTED FENIL-CICLOHEXIL COMPOUNDS.|

---

DE19855440A1|1998-12-01|2000-06-08|Basf Ag|Process for the production of solid dosage forms by melt extrusion|

---

EP1005863A1|1998-12-04|2000-06-07|Synthelabo|Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof|

---

DE19856147A1|1998-12-04|2000-06-08|Knoll Ag|Divisible solid dosage forms and methods for their preparation|

---

US6238697B1|1998-12-21|2001-05-29|Pharmalogix, Inc.|Methods and formulations for making bupropion hydrochloride tablets using direct compression|

---

WO2000040205A2|1999-01-05|2000-07-13|Copley Pharmaceutical Inc.|Sustained release formulation with reduced moisture sensitivity|

---

CA2321107A1|1999-02-04|2000-08-10|Nichimo Co., Ltd.|Materials for preventing arteriosclerosis, immunopotentiating materials, vertebrates fed with these materials and eggs thereof|

---

US7374779B2|1999-02-26|2008-05-20|Lipocine, Inc.|Pharmaceutical formulations and systems for improved absorption and multistage release of active agents|

---

US6375963B1|1999-06-16|2002-04-23|Michael A. Repka|Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof|

---

US20030118641A1|2000-07-27|2003-06-26|Roxane Laboratories, Inc.|Abuse-resistant sustained-release opioid formulation|

---

MXPA02000725A|1999-07-29|2003-07-14|Roxane Lab Inc|Opioid sustained released formulation.|

---

US6562375B1|1999-08-04|2003-05-13|Yamanouchi Pharmaceuticals, Co., Ltd.|Stable pharmaceutical composition for oral use|

---

KR100345214B1|1999-08-17|2002-07-25|이강춘|The nasal transmucosal delivery of peptides conjugated with biocompatible polymers|

---

DE19940740A1|1999-08-31|2001-03-01|Gruenenthal Gmbh|Pharmaceutical salts|

---

DE19940944B4|1999-08-31|2006-10-12|Grünenthal GmbH|Retarded, oral, pharmaceutical dosage forms|

---

CA2388560A1|1999-08-31|2001-03-08|Grunenthal Gmbh|Sustained-release form of administration containing tramadol saccharinate|

---

DE19960494A1|1999-12-15|2001-06-21|Knoll Ag|Device and method for producing solid active substance-containing forms|

---

ES2160534B1|1999-12-30|2002-04-16|Vita Invest Sa|NEW ESTERS DERIVED FROM -2-HYDROXIBENZOATE 3- PHENYL.|

---

US6680070B1|2000-01-18|2004-01-20|Albemarle Corporation|Particulate blends and compacted products formed therefrom, and the preparation thereof|

---

EE05171B1|2000-02-08|2009-06-15|Euro-Celtique, S.A.|Oral dosage form containing opioid agonist in liberated form and isolated opioid antagonist, process for its preparation and its use in medicine|

---

US20020015730A1|2000-03-09|2002-02-07|Torsten Hoffmann|Pharmaceutical formulations and method for making|

---

DE10015479A1|2000-03-29|2001-10-11|Basf Ag|Solid oral dosage forms with delayed release of active ingredient and high mechanical stability|

---

US8012504B2|2000-04-28|2011-09-06|Reckitt Benckiser Inc.|Sustained release of guaifenesin combination drugs|

---

US6572887B2|2000-05-01|2003-06-03|National Starch And Chemical Investment Holding Corporation|Polysaccharide material for direct compression|

---

US6419954B1|2000-05-19|2002-07-16|Yamanouchi Pharmaceutical Co., Ltd.|Tablets and methods for modified release of hydrophilic and other active agents|

---

BR0111125A|2000-05-23|2004-12-28|Cenes Pharmaceuticals Inc|Nrg-2 Nucleic Acid Molecules, Polypeptides, and Diagnostic and Therapeutic Methods|

---

DE10029201A1|2000-06-19|2001-12-20|Basf Ag|Retarded release oral dosage form, obtained by granulating mixture containing active agent and polyvinyl acetate-polyvinyl pyrrolidone mixture below the melting temperature|

---

US6488962B1|2000-06-20|2002-12-03|Depomed, Inc.|Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms|

---

US6607748B1|2000-06-29|2003-08-19|Vincent Lenaerts|Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture|

---

DE10036400A1|2000-07-26|2002-06-06|Mitsubishi Polyester Film Gmbh|White, biaxially oriented polyester film|

---

US6883976B2|2001-07-30|2005-04-26|Seikoh Giken Co., Ltd.|Optical fiber ferrule assembly and optical module and optical connector using the same|

---

US6642205B2|2000-09-25|2003-11-04|Pro-Pharmaceuticals, Inc.|Methods and compositions for reducing side effects in chemotherapeutic treatments|

---

JP2004509634A|2000-09-27|2004-04-02|ダニスコ　エイ／エス|Antibacterial agent|

---

AU9490201A|2000-09-28|2002-04-08|Dow Chemical Co|Polymer composite structures useful for controlled release systems|

---

GB0026137D0|2000-10-25|2000-12-13|Euro Celtique Sa|Transdermal dosage form|

---

US6344215B1|2000-10-27|2002-02-05|Eurand America, Inc.|Methylphenidate modified release formulations|

---

WO2002035991A2|2000-10-30|2002-05-10|The Board Of Regents, The University Of Texas System|Spherical particles produced by a hot-melt extrusion/spheronization process|

---

KR20030051760A|2000-10-30|2003-06-25|유로-셀티크 소시에떼 아노뉨|Controlled release hydrocodone formulations|

---

DE10109763A1|2001-02-28|2002-09-05|Gruenenthal Gmbh|Pharmaceutical salts|

---

JP2002265592A|2001-03-07|2002-09-18|Sumitomo Seika Chem Co Ltd|Process for producing alkylene oxide polymer|

---

WO2002071860A1|2001-03-13|2002-09-19|L.A. Dreyfus Co.|Gum base and gum manufacturing using particulated gum base ingredients|

---

JP3967554B2|2001-03-15|2007-08-29|株式会社ポッカコーポレーション|Flavonoid compound and method for producing the same|

---

US20020132395A1|2001-03-16|2002-09-19|International Business Machines Corporation|Body contact in SOI devices by electrically weakening the oxide under the body|

---

EP1241110A1|2001-03-16|2002-09-18|Pfizer Products Inc.|Dispensing unit for oxygen-sensitive drugs|

---

US20020187192A1|2001-04-30|2002-12-12|Yatindra Joshi|Pharmaceutical composition which reduces or eliminates drug abuse potential|

---

JP4481569B2|2001-05-01|2010-06-16|ユニオンカーバイドケミカルズアンドプラスティックステクノロジーエルエルシー|Poly with reduced amount of formic acid compound|

---

CA2446550C|2001-05-11|2012-03-06|Endo Pharmaceuticals, Inc.|Abuse-resistant controlled-release opioid dosage form|

---

US6623754B2|2001-05-21|2003-09-23|Noveon Ip Holdings Corp.|Dosage form of N-acetyl cysteine|

---

WO2002094172A2|2001-05-22|2002-11-28|Euro-Celtique|Compartmentalized dosage form|

---

US20030064122A1|2001-05-23|2003-04-03|Endo Pharmaceuticals, Inc.|Abuse resistant pharmaceutical composition containing capsaicin|

---

WO2003002100A1|2001-06-26|2003-01-09|Farrell John J|Tamper-proof narcotic delivery system|

---

US20030008409A1|2001-07-03|2003-01-09|Spearman Steven R.|Method and apparatus for determining sunlight exposure|

---

US8329216B2|2001-07-06|2012-12-11|Endo Pharmaceuticals Inc.|Oxymorphone controlled release formulations|

---

BR0210855A|2001-07-06|2006-10-24|Penwest Pharmaceuticals Compan|Method of Manufacturing Extended Release Formulations|

---

EP1404333A1|2001-07-06|2004-04-07|Endo Pharmaceuticals Inc.|Oxymorphone controlled release formulations|

---

JP2003020517A|2001-07-10|2003-01-24|Calp Corp|Resin composition for compound fiber|

---

WO2003007802A2|2001-07-18|2003-01-30|Euro-Celtique, S.A.|Pharmaceutical combinations of oxycodone and naloxone|

---

US7141250B2|2001-08-06|2006-11-28|Euro-Celtique S.A.|Pharmaceutical formulation containing bittering agent|

---

US7332182B2|2001-08-06|2008-02-19|Purdue Pharma L.P.|Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant|

---

US7157103B2|2001-08-06|2007-01-02|Euro-Celtique S.A.|Pharmaceutical formulation containing irritant|

---

US7842307B2|2001-08-06|2010-11-30|Purdue Pharma L.P.|Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent|

---

HU0401344A2|2001-08-06|2004-11-29|Euro-Celtique S.A.|Pharmaceutical compositions to prevent abuse of opioids and process for producing them|

---

US7144587B2|2001-08-06|2006-12-05|Euro-Celtique S.A.|Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent|

---

MXPA04001208A|2001-08-06|2004-07-08|Euro Celtique Sa|Compositions and methods to prevent abuse of opioids.|

---

AU2002321879A1|2001-08-06|2003-03-03|Thomas Gruber|Pharmaceutical formulation containing dye|

---

US20030068375A1|2001-08-06|2003-04-10|Curtis Wright|Pharmaceutical formulation containing gelling agent|

---

WO2003013433A2|2001-08-06|2003-02-20|Euro-Celtique S.A.|Sequestered antagonist formulations|

---

US20030044458A1|2001-08-06|2003-03-06|Curtis Wright|Oral dosage form comprising a therapeutic agent and an adverse-effect agent|

---

US20030049272A1|2001-08-30|2003-03-13|Yatindra Joshi|Pharmaceutical composition which produces irritation|

---

US6691698B2|2001-09-14|2004-02-17|Fmc Technologies Inc.|Cooking oven having curved heat exchanger|

---

US20030059467A1|2001-09-14|2003-03-27|Pawan Seth|Pharmaceutical composition comprising doxasozin|

---

US20040126428A1|2001-11-02|2004-07-01|Lyn Hughes|Pharmaceutical formulation including a resinate and an aversive agent|

---

US20030068276A1|2001-09-17|2003-04-10|Lyn Hughes|Dosage forms|

---

US20030092724A1|2001-09-18|2003-05-15|Huaihung Kao|Combination sustained release-immediate release oral dosage forms with an opioid analgesic and a non-opioid analgesic|

---

DK1429734T3|2001-09-21|2008-05-13|Egalet As|Solid dispersions of carvedilol for controlled release|

---

WO2003024430A1|2001-09-21|2003-03-27|Egalet A/S|Morphine polymer release system|

---

AU2002342755A1|2001-09-26|2003-04-14|Klaus-Jurgen Steffens|Method and device for producing granulates that comprise at least one pharmaceutical active substance|

---

WO2003026743A2|2001-09-26|2003-04-03|Penwest Pharmaceuticals Company|Opioid formulations having reduced potential for abuse|

---

US6837696B2|2001-09-28|2005-01-04|Mcneil-Ppc, Inc.|Apparatus for manufacturing dosage forms|

---

EP1438028A1|2001-09-28|2004-07-21|McNEIL-PPC, INC.|Modified release dosage forms|

---

DE60210317T2|2001-10-09|2006-12-21|The Procter & Gamble Company, Cincinnati|AQUEOUS COMPOSITIONS FOR SURFACE TREATMENT|

---

US6592901B2|2001-10-15|2003-07-15|Hercules Incorporated|Highly compressible ethylcellulose for tableting|

---

JP2003125706A|2001-10-23|2003-05-07|Lion Corp|Mouth freshening preparation|

---

PE20030527A1|2001-10-24|2003-07-26|Gruenenthal Chemie|DELAYED-RELEASE PHARMACEUTICAL FORMULATION CONTAINING 3- PHENOL OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND ORAL TABLETS CONTAINING IT|

---

US6723340B2|2001-10-25|2004-04-20|Depomed, Inc.|Optimal polymer mixtures for gastric retentive tablets|

---

TWI312285B|2001-10-25|2009-07-21|Depomed Inc|Methods of treatment using a gastric retained gabapentin dosage|

---

CA2409552A1|2001-10-25|2003-04-25|Depomed, Inc.|Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract|

---

US20030091630A1|2001-10-25|2003-05-15|Jenny Louie-Helm|Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data|

---

US20030152622A1|2001-10-25|2003-08-14|Jenny Louie-Helm|Formulation of an erodible, gastric retentive oral diuretic|

---

US20030104052A1|2001-10-25|2003-06-05|Bret Berner|Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract|

---

CA2464653C|2001-10-29|2011-10-18|Therics, Inc.|System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing|

---

CA2464528A1|2001-11-02|2003-05-15|Elan Corporation, Plc|Pharmaceutical composition|

---

CA2484528A1|2001-12-06|2003-06-19|Michael P. Hite|Isoflavone composition for oral delivery|

---

FR2833838B1|2001-12-21|2005-09-16|Ellipse Pharmaceuticals|METHOD FOR MANUFACTURING A TABLET INCLUDING A MORPHINIC ANALGESIC AND TABLET OBTAINED|

---

AUPS044502A0|2002-02-11|2002-03-07|Commonwealth Scientific And Industrial Research Organisation|Novel catalysts and processes for their preparation|

---

US20040033253A1|2002-02-19|2004-02-19|Ihor Shevchuk|Acyl opioid antagonists|

---

US20030190343A1|2002-03-05|2003-10-09|Pfizer Inc.|Palatable pharmaceutical compositions for companion animals|

---

US6572889B1|2002-03-07|2003-06-03|Noveon Ip Holdings Corp.|Controlled release solid dosage carbamazepine formulations|

---

US6753009B2|2002-03-13|2004-06-22|Mcneil-Ppc, Inc.|Soft tablet containing high molecular weight polyethylene oxide|

---

WO2003084520A2|2002-04-05|2003-10-16|Euro-Celtique S.A.|Pharmaceutical preparation containing oxycodone and naloxone|

---

DE10217232B4|2002-04-18|2004-08-19|Ticona Gmbh|Process for the production of filled granules from polyethylene of high or ultra-high molecular weight|

---

AU2003234159A1|2002-04-22|2003-11-03|Purdue Research Foundation|Hydrogels having enhanced elasticity and mechanical strength properties|

---

MXPA04010769A|2002-04-29|2005-07-05|Alza Corp|Methods and dosage forms for controlled delivery of oxycodone.|

---

US20050106249A1|2002-04-29|2005-05-19|Stephen Hwang|Once-a-day, oral, controlled-release, oxycodone dosage forms|

---

CA2486075A1|2002-05-13|2003-11-20|Endo Pharmaceuticals Inc.|Abuse-resistant opioid solid dosage form|

---

DE10250083A1|2002-06-17|2003-12-24|Gruenenthal Gmbh|Dosage form protected against abuse|

---

US7776314B2|2002-06-17|2010-08-17|Grunenthal Gmbh|Abuse-proofed dosage system|

---

US7399488B2|2002-07-05|2008-07-15|Collegium Pharmaceutical, Inc.|Abuse-deterrent pharmaceutical compositions of opiods and other drugs|

---

US20040011806A1|2002-07-17|2004-01-22|Luciano Packaging Technologies, Inc.|Tablet filler device with star wheel|

---

US20070196481A1|2002-07-25|2007-08-23|Amidon Gregory E|Sustained-release tablet composition|

---

AU2003259336A1|2002-08-21|2004-03-11|Phoqus Pharmaceuticals Limited|Use of an aqueous solution of citric acid and a water-soluble sugar like lactitol as granulation liquid in the manufacture of tablets|

---

US7388068B2|2002-08-21|2008-06-17|Clariant Produkte Gmbh|Copolymers made of alkylene oxides and glycidyl ethers and use thereof as polymerizable emulsifiers|

---

US20040052844A1|2002-09-16|2004-03-18|Fang-Hsiung Hsiao|Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins|

---

AT413163T|2002-09-17|2008-11-15|Wyeth Corp|GRANULATED FORMULATION OF THE RAPAMYCINESTER CCL-779|

---

US7815924B2|2002-09-20|2010-10-19|Fmc Corporation|Cosmetic composition containing microcrystalline cellulose|

---

DE60319252T2|2002-09-21|2009-03-05|Zhang, Shuyi|FORMULATION OF ACETAMINOPHES AND TRAMADOL WITH DELAYED RELEASE|

---

JP5189242B2|2002-09-23|2013-04-24|アルケルメスファーマアイルランドリミテッド|Abuse-resistant pharmaceutical composition|

---

DE10250087A1|2002-10-25|2004-05-06|Grünenthal GmbH|Dosage form protected against abuse|

---

CA2503155A1|2002-10-25|2004-05-06|Labopharm Inc.|Sustained-release tramadol formulations with 24-hour efficacy|

---

DE10250084A1|2002-10-25|2004-05-06|Grünenthal GmbH|Dosage form protected against abuse|

---

US20050186139A1|2002-10-25|2005-08-25|Gruenenthal Gmbh|Abuse-proofed dosage form|

---

US20050191244A1|2002-10-25|2005-09-01|Gruenenthal Gmbh|Abuse-resistant pharmaceutical dosage form|

---

DE10250088A1|2002-10-25|2004-05-06|Grünenthal GmbH|Dosage form protected against abuse|

---

AT399538T|2003-03-26|2008-07-15|Egalet As|MATRIX PREPARATIONS FOR THE CONTROLLED PHARMACEUTICALS|

---

DE10252667A1|2002-11-11|2004-05-27|Grünenthal GmbH|New spiro--tetrahydropyrano--indole) derivatives, are ORL1 receptor ligands useful e.g. for treating anxiety, depression, epilepsy, senile dementia, withdrawal symptoms or especially pain|

---

US20040091528A1|2002-11-12|2004-05-13|Yamanouchi Pharma Technologies, Inc.|Soluble drug extended release system|

---

US20040185097A1|2003-01-31|2004-09-23|Glenmark Pharmaceuticals Ltd.|Controlled release modifying complex and pharmaceutical compositions thereof|

---

US7442387B2|2003-03-06|2008-10-28|Astellas Pharma Inc.|Pharmaceutical composition for controlled release of active substances and manufacturing method thereof|

---

WO2004082620A2|2003-03-13|2004-09-30|Controlled Chemicals, Inc.|Oxycodone conjugates with lower the abuse potential and extended duration of action|

---

EP1610767B1|2003-03-26|2011-01-19|Egalet A/S|Morphine controlled release system|

---

MY135852A|2003-04-21|2008-07-31|Euro Celtique Sa|Pharmaceutical products|

---

JP5501553B2|2003-04-21|2014-05-21|ユーロ−セルティークエス．エイ．|Anti-modified dosage form containing coextrusion adverse agent particles and process|

---

US8778382B2|2003-04-30|2014-07-15|Purdue Pharma L.P.|Tamper resistant transdermal dosage form|

---

US8906413B2|2003-05-12|2014-12-09|Supernus Pharmaceuticals, Inc.|Drug formulations having reduced abuse potential|

---

CN1473562A|2003-06-27|2004-02-11|辉 刘|Mouth cavity quick dissolving quick disintegrating freeze-dried tablet and its preparing method|

---

US20050015730A1|2003-07-14|2005-01-20|Srimanth Gunturi|Systems, methods and computer program products for identifying tab order sequence of graphically represented elements|

---

RU2339365C2|2003-08-06|2008-11-27|Грюненталь Гмбх|Drug dosage form, protected from unintended application|

---

US8075872B2|2003-08-06|2011-12-13|Gruenenthal Gmbh|Abuse-proofed dosage form|

---

DE10336400A1|2003-08-06|2005-03-24|Grünenthal GmbH|Anti-abuse dosage form|

---

US20070048228A1|2003-08-06|2007-03-01|Elisabeth Arkenau-Maric|Abuse-proofed dosage form|

---

EP1842533B1|2003-08-06|2013-05-01|Grünenthal GmbH|Dosage form that is secured against misuse|

---

US20050063214A1|2003-09-22|2005-03-24|Daisaburo Takashima|Semiconductor integrated circuit device|

---

AT464049T|2003-09-25|2010-04-15|Euro Celtique Sa|PHARMACEUTICAL COMBINATIONS OF HYDROCODON AND NALTREXONE|

---

AU2004277980A1|2003-09-30|2005-04-14|Alza Corporation|Osmotically driven active agent delivery device providing an ascending release profile|

---

US20060172006A1|2003-10-10|2006-08-03|Vincent Lenaerts|Sustained-release tramadol formulations with 24-hour clinical efficacy|

---

US20060009478A1|2003-10-15|2006-01-12|Nadav Friedmann|Methods for the treatment of back pain|

---

WO2005041968A2|2003-10-29|2005-05-12|Alza Corporation|Once-a-day, oral, controlled-release, oxycodone dosage forms|

---

US7201920B2|2003-11-26|2007-04-10|Acura Pharmaceuticals, Inc.|Methods and compositions for deterring abuse of opioid containing dosage forms|

---

WO2005053656A1|2003-12-04|2005-06-16|Pfizer Products Inc.|Spray-congeal process using an extruder for preparing multiparticulate crystalline drug compositions containing preferably a poloxamer and a glyceride|

---

JP4917893B2|2003-12-09|2012-04-18|ユーロ−セルティークエス．エイ．|Unauthorized use prevention coextrusion agent type containing agonist and adverse agent, and method for producing the same|

---

WO2005060942A1|2003-12-19|2005-07-07|Aurobindo Pharma Ltd|Extended release pharmaceutical composition of metformin|

---

DE10360792A1|2003-12-23|2005-07-28|Grünenthal GmbH|Spirocyclic cyclohexane derivatives|

---

DE10361596A1|2003-12-24|2005-09-29|Grünenthal GmbH|Process for producing an anti-abuse dosage form|

---

WO2005065646A2|2003-12-29|2005-07-21|Alza Corporation, Inc.,|Novel drug compositions and dosage forms|

---

WO2005079752A2|2004-02-11|2005-09-01|Rubicon Research Private Limited|Controlled release pharmaceutical compositions with improved bioavailability|

---

TWI350762B|2004-02-12|2011-10-21|Euro Celtique Sa|Particulates|

---

GB0403100D0|2004-02-12|2004-03-17|Euro Celtique Sa|Particulates|

---

BRPI0606339A2|2005-01-28|2009-06-16|Euro Celtique Sa|alcohol resistant dosage forms|

---

KR100789227B1|2004-02-23|2008-01-02|유로-셀띠끄 소시에떼 아노님|Abuse resistance opioid transdermal delivery device|

---

TWI483944B|2004-03-30|2015-05-11|Euro Celtique Sa|Oxycodone hydrochloride composition,pharmaceutical dosage form,sustained release oral dosage form,and pharmaceutically acceptable package having less than 25 ppm 14-hydroxycodeinone|

---

US20050220877A1|2004-03-31|2005-10-06|Patel Ashish A|Bilayer tablet comprising an antihistamine and a decongestant|

---

DE102004019916A1|2004-04-21|2005-11-17|Grünenthal GmbH|Anti-abuse drug-containing patch|

---

DE102004020220A1|2004-04-22|2005-11-10|Grünenthal GmbH|Process for the preparation of a secured against misuse, solid dosage form|

---

PL1740156T3|2004-04-22|2011-12-30|Gruenenthal Gmbh|Method for the production of an abuse-proof, solid form of administration|

---

WO2005105036A1|2004-04-28|2005-11-10|Natco Pharma Limited|Controlled release mucoadhesive matrix formulation containing tolterodine and a process for its preparation|

---

TWI428271B|2004-06-09|2014-03-01|Smithkline Beecham Corp|Apparatus and method for pharmaceutical production|

---

EP1612203B1|2004-06-28|2007-08-01|Grünenthal GmbH|Crystalline forms of --3--phenol hydrochloride|

---

ITMI20041317A1|2004-06-30|2004-09-30|Ibsa Inst Biochimique Sa|PHARMACEUTICAL FORMULATIONS FOR THE SAFE ADMINISTRATION OF DRUGS USED IN THE TREATMENT OF DRUG ADDICTION AND PROCEDURE FOR THEIR OBTAINING|

---

DE102004032103A1|2004-07-01|2006-01-19|Grünenthal GmbH|Anti-abuse, oral dosage form|

---

DE102004032049A1|2004-07-01|2006-01-19|Grünenthal GmbH|Anti-abuse, oral dosage form|

---

KR101204657B1|2004-07-01|2012-11-27|그뤼넨탈 게엠베하|Oral dosage form safeguarded against abuse containing 1r,2r-3-3-dimethylamino-1-ethyl-2-methyl-propyl-phenol|

---

AU2005259476B2|2004-07-01|2010-07-29|Gruenenthal Gmbh|Oral dosage form safeguarded against abuse|

---

DE102004032051A1|2004-07-01|2006-01-19|Grünenthal GmbH|Process for the preparation of a secured against misuse, solid dosage form|

---

AR049839A1|2004-07-01|2006-09-06|Gruenenthal Gmbh|PROCEDURE FOR THE PRODUCTION OF A SOLID PHARMACEUTICAL FORM, PROTECTED AGAINST ABUSE|

---

WO2006010440A1|2004-07-27|2006-02-02|Unilever Plc|Hair care compositions|

---

US20070077297A1|2004-09-30|2007-04-05|Scolr Pharma, Inc.|Modified release ibuprofen dosage form|

---

US20060068009A1|2004-09-30|2006-03-30|Scolr Pharma, Inc.|Modified release ibuprofen dosage form|

---

US20060177380A1|2004-11-24|2006-08-10|Acura Pharmaceuticals, Inc.|Methods and compositions for deterring abuse of orally administered pharmaceutical products|

---

US20080152595A1|2004-11-24|2008-06-26|Acura Pharmaceuticals, Inc.|Methods and compositions for deterring abuse of orally administered pharmaceutical products|

---

US20070231268A1|2004-11-24|2007-10-04|Acura Pharmaceuticals, Inc.|Methods and compositions for deterring abuse of orally administered pharmaceutical products|

---

HUE033306T2|2005-01-26|2017-11-28|Taiho Pharmaceutical Co Ltd|Anticancer drug containing alpha, alpha, alpha-trifluorothymidine and thymidine phosphorylase inhibitor|

---

DE102005005446A1|2005-02-04|2006-08-10|Grünenthal GmbH|Break-resistant dosage forms with sustained release|

---

DE102005005449A1|2005-02-04|2006-08-10|Grünenthal GmbH|Process for producing an anti-abuse dosage form|

---

US20060194759A1|2005-02-25|2006-08-31|Eidelson Stewart G|Topical compositions and methods for treating pain and inflammation|

---

EP1695700A1|2005-02-28|2006-08-30|Euro-Celtique S.A.|Dosage form containing oxycodone and naloxone|

---

KR100941761B1|2005-03-04|2010-02-11|유로-셀띠끄 소시에떼 아노님|Method of reducing alpha, beta unsaturated ketones in opioid compositions|

---

US7732427B2|2005-03-31|2010-06-08|University Of Delaware|Multifunctional and biologically active matrices from multicomponent polymeric solutions|

---

RU2406480C2|2005-04-08|2010-12-20|Озфарма Пти Лтд|Transbuccal delivery system|

---

WO2006122021A1|2005-05-10|2006-11-16|Novartis Ag|Extrusion process for making compositions with poorly compressible therapeutic compounds|

---

CA2611081C|2005-06-03|2016-05-31|Egalet A/S|A drug delivery system for delivering active substances dispersed in a dispersion medium|

---

WO2007005716A2|2005-06-30|2007-01-11|Cinergen, Llc|Methods of treatment and compositions for use thereof|

---

RU2008104638A|2005-07-07|2009-08-20|Фарнэм Компаниз, Инк. |PHARMACEUTICAL COMPOSITIONS OF WELL-SOLUBLE MEDICINAL PRODUCTS IN WATER, PROVIDING THEIR Slow-Motion Release|

---

US8858993B2|2005-07-25|2014-10-14|Metrics, Inc.|Coated tablet with zero-order or near zero-order release kinetics|

---

EP1909760A1|2005-08-03|2008-04-16|Eastman Chemical Company|Tocopheryl polyethylene glycol succinate powder and process for preparing same|

---

WO2007043710A1|2005-10-14|2007-04-19|The Kitasato Institute|Novel dihydropseudoerythromycin derivatives|

---

US20070092573A1|2005-10-24|2007-04-26|Laxminarayan Joshi|Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist|

---

PL116330U1|2005-10-31|2007-04-02|Alza Corp|Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation|

---

US8329744B2|2005-11-02|2012-12-11|Relmada Therapeutics, Inc.|Methods of preventing the serotonin syndrome and compositions for use thereof|

---

US9125833B2|2005-11-02|2015-09-08|Relmada Therapeutics, Inc.|Multimodal abuse resistant and extended release opioid formulations|

---

US8652529B2|2005-11-10|2014-02-18|Flamel Technologies|Anti-misuse microparticulate oral pharmaceutical form|

---

FR2892937B1|2005-11-10|2013-04-05|Flamel Tech Sa|MICROPARTICULAR ORAL PHARMACEUTICAL FORM ANTI-MEASURING|

---

US20100172989A1|2006-01-21|2010-07-08|Abbott Laboratories|Abuse resistant melt extruded formulation having reduced alcohol interaction|

---

US20090317355A1|2006-01-21|2009-12-24|Abbott Gmbh & Co. Kg,|Abuse resistant melt extruded formulation having reduced alcohol interaction|

---

WO2007085024A2|2006-01-21|2007-07-26|Abbott Gmbh & Co. Kg|Dosage form and method for the delivery of drugs of abuse|

---

EP1813276A1|2006-01-27|2007-08-01|Euro-Celtique S.A.|Tamper resistant dosage forms|

---

WO2007093450A2|2006-02-17|2007-08-23|Birds Pharma Gmbh Berolina Innovative Research & Development Services|Deuterated catecholamine derivatives and medicaments comprising said compounds|

---

ZA200807571B|2006-03-01|2009-08-26|Ethypharm Sa|Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion|

---

WO2007103105A2|2006-03-02|2007-09-13|Mallinckrodt Inc.|Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds|

---

WO2007103286A2|2006-03-02|2007-09-13|Spherics, Inc.|Rate-controlled bioadhesive oral dosage formulations|

---

US8465759B2|2006-03-24|2013-06-18|Auxilium Us Holdings, Llc|Process for the preparation of a hot-melt extruded laminate|

---

CA2647809C|2006-03-24|2016-08-16|Auxilium Pharmaceuticals, Inc.|Stabilized compositions containing alkaline labile drugs|

---

US20070224637A1|2006-03-24|2007-09-27|Mcauliffe Joseph C|Oxidative protection of lipid layer biosensors|

---

US10960077B2|2006-05-12|2021-03-30|Intellipharmaceutics Corp.|Abuse and alcohol resistant drug composition|

---

US9023400B2|2006-05-24|2015-05-05|Flamel Technologies|Prolonged-release multimicroparticulate oral pharmaceutical form|

---

US20070292508A1|2006-06-05|2007-12-20|Balchem Corporation|Orally disintegrating dosage forms|

---

CN101091721A|2006-06-22|2007-12-26|孙明|Method for preparing new type asshide|

---

JP4029109B1|2006-07-18|2008-01-09|タマ生化学株式会社|Complex powder of vitamin E and proline and method for producing the same|

---

US20080075771A1|2006-07-21|2008-03-27|Vaughn Jason M|Hydrophilic opioid abuse deterrent delivery system using opioid antagonists|

---

SA2709B1|2006-08-25|2011-07-20|بيورديو فارما إل. بي.|Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic|

---

US8445018B2|2006-09-15|2013-05-21|Cima Labs Inc.|Abuse resistant drug formulation|

---

CA2699142C|2007-09-13|2016-05-17|Cima Labs Inc.|Abuse resistant drug formulation|

---

US20080069891A1|2006-09-15|2008-03-20|Cima Labs, Inc.|Abuse resistant drug formulation|

---

US8187636B2|2006-09-25|2012-05-29|Atlantic Pharmaceuticals, Inc.|Dosage forms for tamper prone therapeutic agents|

---

KR101400824B1|2006-09-25|2014-05-29|후지필름 가부시키가이샤|Resist composition, resin for use in the resist composition, compound for use in the synthesis of the resin, and pattern-forming method usign the resist composition|

---

US20080085304A1|2006-10-10|2008-04-10|Penwest Pharmaceuticals Co.|Robust sustained release formulations|

---

GB0624880D0|2006-12-14|2007-01-24|Johnson Matthey Plc|Improved method for making analgesics|

---

NZ577560A|2007-01-16|2012-01-12|Egalet Ltd|Use of i) a polyglycol and ii) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse|

---

WO2008094877A2|2007-01-30|2008-08-07|Drugtech Corporation|Compositions for oral delivery of pharmaceuticals|

---

CN100579525C|2007-02-02|2010-01-13|东南大学|Sustained release preparation of licardipine hydrochloride and its preparing process|

---

CN101057849A|2007-02-27|2007-10-24|齐齐哈尔医学院|Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method|

---

AU2008223091B2|2007-03-02|2014-04-24|Farnam Companies, Inc.|Sustained release pellets comprising wax-like material|

---

DE102007011485A1|2007-03-07|2008-09-11|Grünenthal GmbH|Dosage form with more difficult abuse|

---

EP1980245A1|2007-04-11|2008-10-15|Cephalon France|Bilayer lyophilized pharmaceutical compositions and methods of making and using same|

---

WO2008132707A1|2007-04-26|2008-11-06|Sigmoid Pharma Limited|Manufacture of multiple minicapsules|

---

US20110020408A1|2007-05-17|2011-01-27|Ranbaxy Laboratories Limited| multilayered modified release formulation comprising amoxicillin and clavulanate|

---

US8202542B1|2007-05-31|2012-06-19|Tris Pharma|Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings|

---

US8821928B2|2007-06-04|2014-09-02|Egalet Ltd.|Controlled release pharmaceutical compositions for prolonged effect|

---

US20100035886A1|2007-06-21|2010-02-11|Veroscience, Llc|Parenteral formulations of dopamine agonists|

---

JP2010532358A|2007-07-01|2010-10-07|ピーター ハバウシ，ジョセフ|Formulation with chewable outer layer|

---

KR20100055431A|2007-07-20|2010-05-26|애보트 게엠베하 운트 콤파니 카게|Formulations of nonopioid and confined opioid analgesics|

---

US20090022798A1|2007-07-20|2009-01-22|Abbott Gmbh & Co. Kg|Formulations of nonopioid and confined opioid analgesics|

---

WO2009034541A2|2007-09-11|2009-03-19|Ranbaxy Laboratories Limited|Controlled release pharmaceutical dosage forms of trimetazidine|

---

US20100303883A1|2007-10-17|2010-12-02|Axxia Pharmaceuticals, Llc|Polymeric drug delivery systems and thermoplastic extrusion processes for producing such systems|

---

ES2619329T3|2007-11-23|2017-06-26|Grünenthal GmbH|Tapentadol compositions|

---

WO2009075782A1|2007-12-06|2009-06-18|Durect Corporation|Methods useful for the treatment of pain, arthritic conditions, or inflammation associated with a chronic condition|

---

WO2009074609A1|2007-12-12|2009-06-18|Basf Se|Salts of active ingredients with polymeric counter-ions|

---

BRPI0821732A2|2007-12-17|2015-06-16|Labopharm Inc|Controlled release formulations, solid dosage form, and use of controlled release formulation|

---

MX2010008138A|2008-01-25|2010-08-10|Gruenenthal Gmbh|Pharmaceutical dosage form.|

---

KR100970665B1|2008-02-04|2010-07-15|삼일제약주식회사|Sustained release tablet containing alfuzosin or its salt|

---

EP2262483A2|2008-03-05|2010-12-22|Panacea Biotec Limited|Modified release pharmaceutical compositions comprising mycophenolate and processes thereof|

---

EP2100598A1|2008-03-13|2009-09-16|Laboratorios Almirall, S.A.|Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease|

---

EP2273983B1|2008-05-09|2016-07-20|Grünenthal GmbH|Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step|

---

ES2393949T3|2008-07-03|2013-01-02|Novartis Ag|Granulation process in molten state|

---

CA2734646C|2008-08-20|2016-06-28|James W. Mcginity|Hot-melt extrusion of modified release multi-particulates|

---

US20100099696A1|2008-10-16|2010-04-22|Anthony Edward Soscia|Tamper resistant oral dosage forms containing an embolizing agent|

---

JP5713911B2|2008-10-27|2015-05-07|アルザ・コーポレーシヨン|Extended-release oral acetaminophen / tramadol dosage form|

---

WO2010057036A2|2008-11-14|2010-05-20|Portola Pharmaceuticals, Inc.|Solid composition for controlled release of ionizable active agents with poor aqueous solubility at low ph and methods of use thereof|

---

MX2011006173A|2008-12-12|2011-09-01|Paladin Labs Inc|Narcotic drug formulations with decreased abuse potential.|

---

CA2746888C|2008-12-16|2015-05-12|Labopharm Limited|Misuse preventative, controlled release formulation|

---

EP2700400A1|2009-01-26|2014-02-26|Egalet Ltd.|Controlled release formulation with continuous efficacy|

---

DK2393487T3|2009-02-06|2017-01-23|Egalet Ltd|Pharmaceutical compositions resistant to abuse|

---

BRPI0924543B8|2009-03-18|2021-05-25|Evonik Roehm Gmbh|controlled release pharmaceutical composition, and its preparation process|

---

EP2246063A1|2009-04-29|2010-11-03|Ipsen Pharma S.A.S.|Sustained release formulations comprising GnRH analogues|

---

GB0909680D0|2009-06-05|2009-07-22|Euro Celtique Sa|Dosage form|

---

NZ597283A|2009-06-24|2013-07-26|Egalet Ltd|Controlled release formulations|

---

WO2011008298A2|2009-07-16|2011-01-20|Nectid, Inc.|Novel axomadol dosage forms|

---

EP2456427B1|2009-07-22|2015-03-04|Grünenthal GmbH|Hot-melt extruded controlled release dosage form|

---

PE20120572A1|2009-07-22|2012-06-06|Gruenenthal Chemie|HANDLING RESISTANT STABILIZED OXIDATION DOSAGE FORM|

---

KR101588896B1|2009-08-10|2016-02-15|엘지디스플레이 주식회사|Back light unit and liquid crystal display using the same|

---

US20120231083A1|2010-11-18|2012-09-13|The Board Of Trustees Of The University Of Illinois|Sustained release cannabinoid medicaments|

---

CN102821757B|2010-02-03|2016-01-20|格吕伦塔尔有限公司|By extrusion mechanism for powdery medicine compositions|

---

ES2592277T3|2010-04-02|2016-11-29|Buzzz Pharmaceuticals Limited|Transdermal deterrent formulations of abuse of opioid agonists and agonists|

---

GB201006200D0|2010-04-14|2010-06-02|Ayanda As|Composition|

---

ES2689520T3|2010-04-23|2018-11-14|Kempharm, Inc.|Therapeutic formulation to reduce drug side effects|

---

FR2960775A1|2010-06-07|2011-12-09|Ethypharm Sa|MICROGRANULES RESISTANT TO MISMATCH|

---

US20120059065A1|2010-09-02|2012-03-08|Grünenthal GmbH|Tamper Resistant Dosage Form Comprising An Anionic Polymer|

---

RU2607499C2|2010-09-02|2017-01-10|Грюненталь Гмбх|Destruction-resistant dosage form containing anionic polymer|

---

BR112013005194A2|2010-09-02|2016-05-03|Grünenthal GmbH|tamper-resistant dosage form comprising inorganic salt|

---

EP2635258A1|2010-11-04|2013-09-11|AbbVie Inc.|Drug formulations|

---

GB201020895D0|2010-12-09|2011-01-26|Euro Celtique Sa|Dosage form|

---

AU2011346758C1|2010-12-23|2015-09-03|Purdue Pharma L.P.|Tamper resistant solid oral dosage forms|

---

WO2012112952A1|2011-02-17|2012-08-23|QRxPharma Ltd.|Technology for preventing abuse of solid dosage forms|

---

LT2680832T|2011-03-04|2019-10-25|Gruenenthal Gmbh|Aqueous pharmaceutical formulation of tapentadol for oral administration|

---

US8858963B1|2011-05-17|2014-10-14|Mallinckrodt Llc|Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia|

---

CA2837077A1|2011-06-01|2012-12-06|Fmc Corporation|Controlled release solid dose forms|

---

EP2726065A4|2011-06-30|2014-11-26|Neos Therapeutics Lp|Abuse resistant drug forms|

---

BR112014001091A2|2011-07-29|2017-02-14|Grünenthal GmbH|tamper resistant tablet that provides immediate release of the drug|

---

AR087360A1|2011-07-29|2014-03-19|Grünenthal GmbH|PROOF OF HANDLING TABLET PROVIDING IMMEDIATE RELEASE OF PHARMACY|

---

FR2979242A1|2011-08-29|2013-03-01|Sanofi Sa|COMPRESSES AGAINST ABUSIVE USE, BASED ON PARACETAMOL AND OXYCODONE|

---

PE20141171A1|2011-10-06|2014-09-21|Gruenenthal Chemie|ORAL PHARMACEUTICAL DOSAGE FORM RESISTANT TO ALTERATION INCLUDING OPIOID AGONIST AND OPIOID ANTAGONIST|

---

AU2012338872B2|2011-11-17|2017-06-22|Grünenthal GmbH|Tamper-resistant oral pharmaceutical dosage form comprising a pharmacologically active ingredient, an opioid antagonist and/or aversive agent, polyalkylene oxide and anionic polymer|

---

CN104010630A|2011-12-09|2014-08-27|普渡制药公司|Pharmaceutical Dosage Forms Comprising Poly And Polyethylene Oxide|

---

WO2013127830A1|2012-02-28|2013-09-06|Grünenthal GmbH|Tamper-resistant pharmaceutical dosage form comprising nonionic surfactant|

---

EP2819656A1|2012-02-28|2015-01-07|Grünenthal GmbH|Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer|

---

AU2013203493B2|2012-03-02|2016-02-04|Rhodes Pharmaceuticals L.P.|Tamper resistant immediate release formulations|

---

PL2838512T3|2012-04-18|2018-12-31|Grünenthal GmbH|Tamper resistant and dose-dumping resistant pharmaceutical dosage form|

---

US10064945B2|2012-05-11|2018-09-04|Gruenenthal Gmbh|Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc|

---

RS56685B1|2012-05-11|2018-03-30|Gruenenthal Gmbh|Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc|

---

WO2014059512A1|2012-10-15|2014-04-24|Isa Odidi|Oral drug delivery formulations|

---

EP3003279A1|2013-05-29|2016-04-13|Grünenthal GmbH|Tamper-resistant dosage form containing one or more particles|

---

AU2014273226B2|2013-05-29|2019-06-27|Grunenthal Gmbh|Tamper resistant dosage form with bimodal release profile|

---

CA2817728A1|2013-05-31|2014-11-30|Pharmascience Inc.|Abuse deterrent immediate release formulation|

---

KR20160031526A|2013-07-12|2016-03-22|그뤼넨탈 게엠베하|Tamper-resistant dosage form containing ethylene-vinyl acetate polymer|

---

US9770514B2|2013-09-03|2017-09-26|ExxPharma Therapeutics LLC|Tamper-resistant pharmaceutical dosage forms|

---

WO2015065547A1|2013-10-31|2015-05-07|Cima Labs Inc.|Immediate release abuse-deterrent granulated dosage forms|

---

WO2015103379A1|2013-12-31|2015-07-09|Kashiv Pharma, Llc|Abuse-resistant drug formulations|

---

PT3105253T|2014-02-12|2018-10-04|Hoffmann La Roche|Anti-jagged1 antibodies and methods of use|

---

EP3254163A4|2015-02-05|2018-08-15|Grey Orange Pte. Ltd.|Apparatus and method for navigation control|US7776314B2|2002-06-17|2010-08-17|Grunenthal Gmbh|Abuse-proofed dosage system|

---

EP1610767B1|2003-03-26|2011-01-19|Egalet A/S|Morphine controlled release system|

---

DE10336400A1|2003-08-06|2005-03-24|Grünenthal GmbH|Anti-abuse dosage form|

---

US20070048228A1|2003-08-06|2007-03-01|Elisabeth Arkenau-Maric|Abuse-proofed dosage form|

---

DE102005005446A1|2005-02-04|2006-08-10|Grünenthal GmbH|Break-resistant dosage forms with sustained release|

---

DE102005005449A1|2005-02-04|2006-08-10|Grünenthal GmbH|Process for producing an anti-abuse dosage form|

---

US8821928B2|2007-06-04|2014-09-02|Egalet Ltd.|Controlled release pharmaceutical compositions for prolonged effect|

---

MX2010008138A|2008-01-25|2010-08-10|Gruenenthal Gmbh|Pharmaceutical dosage form.|

---

CA2751667C|2009-02-06|2016-12-13|Egalet Ltd.|Immediate release composition resistant to abuse by intake of alcohol|

---

NZ597283A|2009-06-24|2013-07-26|Egalet Ltd|Controlled release formulations|

---

PE20120572A1|2009-07-22|2012-06-06|Gruenenthal Chemie|HANDLING RESISTANT STABILIZED OXIDATION DOSAGE FORM|

---

EP2456427B1|2009-07-22|2015-03-04|Grünenthal GmbH|Hot-melt extruded controlled release dosage form|

---

RU2607499C2|2010-09-02|2017-01-10|Грюненталь Гмбх|Destruction-resistant dosage form containing anionic polymer|

---

BR112013005194A2|2010-09-02|2016-05-03|Grünenthal GmbH|tamper-resistant dosage form comprising inorganic salt|

---

BR112014001091A2|2011-07-29|2017-02-14|Grünenthal GmbH|tamper resistant tablet that provides immediate release of the drug|

---

AR087360A1|2011-07-29|2014-03-19|Grünenthal GmbH|PROOF OF HANDLING TABLET PROVIDING IMMEDIATE RELEASE OF PHARMACY|

---

EP2819656A1|2012-02-28|2015-01-07|Grünenthal GmbH|Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer|

---

PL2838512T3|2012-04-18|2018-12-31|Grünenthal GmbH|Tamper resistant and dose-dumping resistant pharmaceutical dosage form|

---

US10064945B2|2012-05-11|2018-09-04|Gruenenthal Gmbh|Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc|

---

CA2877774C|2012-07-12|2017-07-18|Mallinckrodt Llc|Extended release, abuse deterrent pharmaceutical compositions|

---

AU2014273226B2|2013-05-29|2019-06-27|Grunenthal Gmbh|Tamper resistant dosage form with bimodal release profile|

---

EP3003279A1|2013-05-29|2016-04-13|Grünenthal GmbH|Tamper-resistant dosage form containing one or more particles|

---

KR20160031526A|2013-07-12|2016-03-22|그뤼넨탈 게엠베하|Tamper-resistant dosage form containing ethylene-vinyl acetate polymer|

---

CA2919892C|2013-08-12|2019-06-18|Pharmaceutical Manufacturing Research Services, Inc.|Extruded immediate release abuse deterrent pill|

---

US9492444B2|2013-12-17|2016-11-15|Pharmaceutical Manufacturing Research Services, Inc.|Extruded extended release abuse deterrent pill|

---

WO2015078891A1|2013-11-26|2015-06-04|Farmaceutici Formenti S.P.A.|Preparation of a powdery pharmaceutical composition by means of cryo-milling|

---

WO2015095391A1|2013-12-17|2015-06-25|Pharmaceutical Manufacturing Research Services, Inc.|Extruded extended release abuse deterrent pill|

---

WO2015120201A1|2014-02-05|2015-08-13|Kashiv Pharma, Llc|Abuse-resistant drug formulations with built-in overdose protection|

---

WO2015173195A1|2014-05-12|2015-11-19|Grünenthal GmbH|Tamper resistant immediate release capsule formulation comprising tapentadol|

---

CA2949422A1|2014-05-26|2015-12-03|Grunenthal Gmbh|Multiparticles safeguarded against ethanolic dose-dumping|

---

ES2809458T3|2014-07-17|2021-03-04|Pharmaceutical Manufacturing Res Services Inc|Liquid filled, abuse deterrent and immediate release dosage form|

---

US20160106737A1|2014-10-20|2016-04-21|Pharmaceutical Manufacturing Research Services, Inc.|Extended Release Abuse Deterrent Liquid Fill Dosage Form|

---

WO2016170094A1|2015-04-24|2016-10-27|Grünenthal GmbH|Tamper-resistant fixed dose combination providing fast release of two drugs from particles|

---

WO2016170096A1|2015-04-24|2016-10-27|Grünenthal GmbH|Tamper-resistant fixed dose combination providing fast release of two drugs from different particles|

---

EP3285745A1|2015-04-24|2018-02-28|Grünenthal GmbH|Tamper-resistant dosage form with immediate release and resistance against solvent extraction|

---

EP3285744A1|2015-04-24|2018-02-28|Grünenthal GmbH|Tamper-resistant fixed dose combination providing fast release of two drugs from particles and a matrix|

---

US10183018B2|2015-05-28|2019-01-22|Lumosa Therapeutics Co., Ltd.|Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester|

---

US11234974B2|2015-05-28|2022-02-01|Lumosa Therapeutics Co., Ltd.|Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester|

---

AU2016319203A1|2015-09-10|2018-02-22|Grünenthal GmbH|Protecting oral overdose with abuse deterrent immediate release formulations|

法律状态:
2018-03-01| FGA| Letters patent sealed or granted (standard patent)|

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2020-09-24| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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EP12001301||2012-02-28||

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EP12001301.6||2012-02-28||

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PCT/EP2013/053894|WO2013127831A1|2012-02-28|2013-02-27|Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer|

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