US20130225697A1 - Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer - Google Patents

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

Info

Publication number
US20130225697A1
US20130225697A1 US13778186 US201313778186A US2013225697A1 US 20130225697 A1 US20130225697 A1 US 20130225697A1 US 13778186 US13778186 US 13778186 US 201313778186 A US201313778186 A US 201313778186A US 2013225697 A1 US2013225697 A1 US 2013225697A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
preferably
dosage form
pharmaceutical dosage
mg
wt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13778186
Inventor
Lutz BARNSCHEID
Jessica Redmer
Sebastian Schwier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Grunenthal GmbH
Original Assignee
Grunenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Abstract

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.

Description

  • This application claims priority of U.S. Provisional Patent Application No. 61/603,986, filed on Feb. 28, 2012, and European Patent Application No. 12 001 301.6, filed on Feb. 28, 2012, the entire contents of which patent applications are incorporated herein by reference.
  • 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.
  • 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 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).
  • 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 described hereinbelow.
  • 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.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • The invention will now be described in greater detail with reference to the drawings, wherein:
  • FIGS. 1-A, 1-B, 1-C, 1-D and 1-E, respectively, show the corresponding force-displacement diagrams of examples I-1, I-2, I-3, I-4 and C.
  • 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, phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives, morphinan derivatives and others. Examples of natural opium alkaloids are morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, 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, anileridine, apocodeine, axomadol, barbital, bemidone, benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil, cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, 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), levomethadone, levorphanol, levophenacylmorphane, levoxemacin, lisdexamfetamine dimesylate, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine, methylmorphine, metamphetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine, nicomorphine, nimetazepam, nitrazepam, 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, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)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-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS,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-cyclohex-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, oxymorphone, 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-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 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, 155±2.5 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 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.
  • 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.
  • 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.
  • 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.
  • 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 C10-C30-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 C10-C30-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 C8-C30-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 25° C.
  • 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 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 25° C.
  • 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 25° C.
  • 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 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, polystyrene, polyvinylpyrrolidone, poly(hydroxy fatty acids), such as for example poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®), poly(hydroxyvaleric acid); polycaprolactone, 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 ≦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 ≦25 wt.-%, yet more preferably ≦20 wt.-%, even more preferably ≦15 wt.-%, most preferably ≦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.
  • 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, polylactide/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, hydroxyethylcellulose, hydroxypropylcellulose hydroxypropylmethylcellulose, carboxymethylcellulose, and the like.
  • In a preferred embodiment, said further polymer is neither an anionic polymer nor a polyalkylene 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, preferably 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.-%, 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 25° C. of at least 35 dynes/cm, more preferably at least 40 dynes/cm, still 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° C. 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 (I-a)
  • Figure US20130225697A1-20130829-C00001
        • 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 (I-b)
  • Figure US20130225697A1-20130829-C00002
        • wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and l 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;
      • 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 [polyoxyethylene(20)sorbitan monolaurate], Tween® 21 [polyoxyethylene(4)sorbitan monolaurate], Tween® 40 [polyoxyethylene(20)sorbitan monopalmitate], Tween® 60 [polyoxyethylene(20)sorbitan monostearate], Tween® 65 [polyoxyethylene(20)sorbitan tristearate], Tween® 80 [polyoxyethylene(20)sorbitan monooleate], Tween 81 [polyoxyethylene(5)sorbitan monooleate], and Tween® 85 [polyoxyethylene(20)sorbitan trioleate]; preferably a fatty acid monoester of polyoxyethylenesorbitan according to general formula (I-c)
  • Figure US20130225697A1-20130829-C00003
        • 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, macrogolglycerolococoate, macrogolglycerollinoleate, macrogol-20-glycerolmonostearate, macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate; macrogolglycerolstearate, macrogolglycerolhydroxystearate (e.g. Cremophor® RH 40), and macrogolglycerolrizinoleate (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 (I-d)

  • CH3CH2—(OCH2CH3)n—O-CO-(CH2)mCH3  (I-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 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° C., 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° C., or 55±20° C., or 65±20° C., or 75±20° C.
  • 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 η1 at a temperature T1 of 20° C. and a viscosity η2 at a temperature T2 of more than 20° C. (i.e. T2>T1), where η21. This does not necessarily mean that viscosity η2 at any temperature T2 above 20° C. must be greater than viscosity η1 at 20° C. Instead, this means that there is at least one temperature T2 above 20° C. at which viscosity η2 of the aqueous dispersion is greater than viscosity η1 at T1 (=20° C.).
  • 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° C. and forms a semi-solid gel upon heating to a temperature of at most 80° C., more preferably 60° C., most preferably at most 45° C., and in particular at most 37° C.
  • 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° C., more preferably within the range of from 15° C. to 75° C., and most preferably within the range of from 20° C. 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 (I-b).
  • In a particular preferred embodiment, the nonionic surfactant is a polyoxypropylene-polyoxyethylene block copolymer according to general formula (I-a)
  • Figure US20130225697A1-20130829-C00004
  • 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.
  • In a preferred embodiment, a, b and c are each independently an integer as specified as preferred embodiments N1 to N32 in the table here below:
  • a b c
    N1 80 ± 75 27 ± 17 80 ± 75
    N2 80 ± 65 27 ± 16 80 ± 65
    N3 80 ± 55 27 ± 15 80 ± 55
    N4 80 ± 50 27 ± 14 80 ± 50
    N5 80 ± 45 27 ± 13 80 ± 45
    N6 80 ± 40 27 ± 12 80 ± 40
    N7 80 ± 35 27 ± 11 80 ± 35
    N8 80 ± 31 27 ± 10 80 ± 31
    N9 80 ± 27 27 ± 9  80 ± 27
    N10 80 ± 23 27 ± 8  80 ± 23
    N11 80 ± 19 27 ± 7  80 ± 19
    N12 80 ± 15 27 ± 6  80 ± 15
    N13 80 ± 12 27 ± 5  80 ± 12
    N14 80 ± 9  27 ± 4  80 ± 9 
    N15 80 ± 6  27 ± 3  80 ± 6 
    N16 80 ± 3  27 ± 2  80 ± 3 
    N17 12 ± 11 20 ± 15 12 ± 11
    N18 12 ± 8  20 ± 12 12 ± 8 
    N19 12 ± 5  20 ± 8  12 ± 5 
    N20 12 ± 2  20 ± 4  12 ± 2 
    N21 64 ± 45 37 ± 13 64 ± 45
    N22 64 ± 20 37 ± 10 64 ± 20
    N23 64 ± 12 37 ± 7  64 ± 12
    N24 64 ± 5  37 ± 5  64 ± 5 
    N25 101 ± 80  56 ± 35 101 ± 80 
    N26 101 ± 55  56 ± 21 101 ± 55 
    N27 101 ± 31  56 ± 12 101 ± 31 
    N28 101 ± 15  56 ± 8  101 ± 15 
    N29 141 ± 120 44 ± 31 141 ± 120
    N30 141 ± 90  44 ± 27 141 ± 90 
    N31 141 ± 35  44 ± 19 141 ± 35 
    N32 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)
  • Figure US20130225697A1-20130829-C00005
  • wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and l 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 l 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 O1 to O32 in the table here below:
  • g/mol Mw
    O1 8,600 ± 7,500
    O2 8,600 ± 5,000
    O3 8,600 ± 4,000
    O4 8,600 ± 3,000
    O5 8,600 ± 2,500
    O6 8,600 ± 2,250
    O7 8,600 ± 2,000
    O8 8,600 ± 1,750
    O9 8,600 ± 1,500
    O10 8,600 ± 1,400
    O11 8,600 ± 1,300
    O12 8,600 ± 1,200
    O13 8,600 ± 1,100
    O14 8,600 ± 1,000
    O15 8,600 ± 950
    O16 8,600 ± 920
    O17 2,200 ± 1,000
    O18 2,200 ± 500
    O19 2,200 ± 250
    O20 7,800 ± 6,000
    O21 7,800 ± 4,000
    O22 7,800 ± 1,500
    O23 7,800 ± 1,000
    O24 7,800 ± 800
    O25 12,200 ± 8,000 
    O26 12,200 ± 4,000 
    O27 12,200 ± 3,000 
    O28 12,200 ± 1,500 
    O29 15,000 ± 7,500 
    O30 15,000 ± 5,000 
    O31 15,000 ± 3,000 
    O32 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 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 (I-a) or according to general formula (I-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 (I-a) or according to general formula (I-b) has an oxyethylene content, as determined according to USP or Ph.Eur., as specified as preferred embodiments P1 to P32 in the table here below:
  • % OE-content
    P1  81.8 ± 17.0
    P2  81.8 ± 16.0
    P3  81.8 ± 15.0
    P4  81.8 ± 14.0
    P5  81.8 ± 13.0
    P6  81.8 ± 12.0
    P7  81.8 ± 11.0
    P8  81.8 ± 10.0
    P9 81.8 ± 9.0
    P10 81.8 ± 8.0
    P11 81.8 ± 7.0
    P12 81.8 ± 6.0
    P13 81.8 ± 5.0
    P14 81.8 ± 4.0
    P15 81.8 ± 3.0
    P16 81.8 ± 2.0
    P17  46.5 ± 15.0
    P18  46.5 ± 10.0
    P19 46.5 ± 5.0
    P20  60.0 ± 20.0
    P21  60.0 ± 15.0
    P22  70.0 ± 10.0
    P23 70.0 ± 8.0
    P24 70.0 ± 5.0
    P25 73.0 ± 6.0
    P26 73.0 ± 4.0
    P27 75.0 ± 5.0
    P28 75.0 ± 4.0
    P29 75.0 ± 3.0
    P30 85.0 ± 5.0
    P31 85.0 ± 4.0
    P32 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.
  • 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, 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±100 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±100 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.
  • 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. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, 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 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.
  • 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 R1 to R50:
  • % R1 R2 R3 R4 R5 R6 R7 R8 R9 R10
    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
    % R11 R12 R13 R14 R15 R16 R17 R18 R19 R20
    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
    % R21 R22 R23 R24 R30 R26 R27 R28 R29 R30
    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
    % R31 R32 R33 R34 R35 R36 R37 R38 R39 R40
    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 R45 R46 R47 R48 R49 R50
    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 37° C. with sinker (type 1 or 2); rotation speed of the paddle: 75 min−1.
  • 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. 37° C., 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 understood as pharmaceutical dosage forms being made by compression of powder or granules (compressi) 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±150 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 40° C. 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 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 t1/2 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 t1/2 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 t1/2 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 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. 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 combination 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 and 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 and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, N.Y., 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 A1, 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.
  • 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 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.
  • 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, α-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 α-tocopherol. A particularly preferred antioxidant is α-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 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. —CO2H, —SO3H, —PO3H2, —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 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, α-hydroxyacids and β-hydroxylacids of monocarboxylic acids, α-hydroxyacids and β-hydroxyacids of bicarboxylic acids, α-hydroxy-acids and β-hydroxyacids of tricarboxylic acids, ketoacids, α-ketoacids, β-ketoacids, of the polycarboxylic acids, of the polyhydroxy monocarboxylic acids, of the polyhydroxy bicarboxylic acids, of the polyhydroxy tricarboxylic acids.
  • Preferably, the acid is selected from the group consisting of benzenesulfonic acid, citric acid, α-glucoheptonic acid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, propanoic acid, succinic acid, tartaric acid (d, l, 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, 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° C., more preferably 60° C. 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.
  • 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 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
  • 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,
    closing the vessel with aluminum foil, boiling extraction only,
    drawing up the liquid into a syringe using a canula, preferably 0.80×40 mm BL/LB; 21G×1½″, through a cigarette filter, and
    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.
  • In a preferred embodiment, when
  • 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,
    closing the vessel with aluminum foil, boiling extraction only,
    drawing up the liquid into a 10 mL syringe using a canula, preferably 0.80×40 mm BL/LB; 21 G×1½″, through a cigarette filter, and
    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
  • 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;
    supplementing lost water, if any, and
    determining the pharmacologically active compound content in the overhead liquid by HPLC analysis;
    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
  • 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;
    supplementing lost water, if any, and
    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.
  • 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 to the following empirical formula: Breaking Strength [in N]=10×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/s2, 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, 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 manufacturers 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® HT1 can 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.
  • 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° C. 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 maintained 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 −25° C., below −40° C. 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 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 (I-a)
  • Figure US20130225697A1-20130829-C00006
          • 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 (I-b)
  • Figure US20130225697A1-20130829-C00007
          • wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and l 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
        • (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 ≦20 wt.-%, preferably ≦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
    • (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.
  • 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 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° C., preferably below 150° C., but at least to the softening temperature of matrix material. Typical extrusion temperatures are 120° C. and 130° C.
  • 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.
  • For example but not limiting, extrusion may be performed by means of a twin-screw-extruder type ZSE 18 or ZSE27 (Leistritz, Nurnberg, 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° C.; and jacket temperature: 110° C.
  • 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.
  • 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, Nurnberg, 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 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 37° C. with sinker (type 1 or 2). The rotation speed of the paddle was adjusted to 75/min.
  • EXAMPLE 1
  • a) Composition
  • Tablets having the following compositions were prepared:
  • I-1 I-2 I-3 I-4
    mg wt.-% mg mg mg wt.-% mg wt.-%
    Tramadol HCl 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 (Lutrol ® F127) 185.0 30.85 148.0 24.7
    Poloxamer 188 (Lutrol ® 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
    Σ 600.0 100.0 600.0 100.0 600.0 100.0 600.0 100.0
  • C-1
    mg wt.-%
    Tramadol HCl 80.0 13.3
    Polyethylene Oxide Mw 7 × 106 370.0 61.7
    HPMC 100,000 mPa · s 60.0 10.0
    Macrogol 6,000 90.0 15.0
    Σ 600.0 100.0
  • b) Hot-Melt Extrusion
  • The following extrusion parameters were adjusted and measured, respectively:
  • I-1 I-2 I-3 I-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 [° C.] 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:
  • n = 10 I-1 I-2 I-3 I-4 C-1
    weight [mg] min 584 578 577 575 599
    max 629 628 624 625 627
    average 612 597 602 609 613
    length [mm] min 6.95 6.39 6.30 6.52 6.45
    max 7.46 7.01 7.33 7.40 7.54
    average 7.26 6.68 6.66 6.94 7.12
    diameter [mm] min 9.16 10.32 9.21 9.86 9.73
    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):
  • Example 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 I-1 I-2 I-3 I-4 C-1
    thickness [mm] min 6.61 6.31 6.08 6.17 6.27
    max 6.87 6.55 6.79 6.70 6.81
    average 6.72 6.43 6.43 6.41 6.53
    diameter [mm] min 11.68 11.61 11.46 11.35 11.56
    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
  • I-1 I-2 I-3 I-4 C-1
    measuring point
    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
    measuring point
    Dissolution %
    (0.1N HCl)
    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] I-1 I-2 I-3 I-4 C-1
    Sotax ® HT100 318 N 877 N ≧1000 N ≧1000 N ≧1000 N
  • The corresponding force-displacement diagrams of examples I-1, I-2, I-3, I-4 and C are displayed as FIGS. 1-A, 1-B, 1-C, 1-D and 1-E, respectively.
  • The deviating curve in FIG. 1-C represents a measurement error (tablet displaced).
  • f) Tamper Resistance—Extractability
  • The extractable content of pharmacologically active compound was determined by
      • (i) 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;
      • (ii) supplementing lost water, if any, and
      • (iii) 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:
  • content [wt.-%] I-1 I-2 I-3 I-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)
    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×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:
  • I-1 I-2 I-3 I-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 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 I-2 I-3 I-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:
  • breaking CBP: (CBP + LUT): CBP: LUT: (CBP + LUT): API: API: API:
    ex. strength [N] 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 = hydroxypropylmethylcellulose (HPMC 100,000)
    API = active pharmaceutical ingredient (Tramadol HCl)

Claims (15)

  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, 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, 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 claim 1, 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 ≦35 wt.-%, based on the total weight of the pharmaceutical dosage form.
  6. 6. The pharmaceutical dosage form according to claim 1, wherein the pharmacologically active compound is an opioid.
  7. 7. The pharmaceutical dosage form according to claim 1, wherein the nonionic surfactant
    (i) in pure water at a concentration of 25 wt.-% forms an aqueous dispersion having a viscosity η1 at a temperature of 20° C. and a viscosity η2 at a temperature of more than 20° C., where η21; and/or
    (ii) has an HLB value of at least 20, and/or
    (iii) has a surface tension in 0.1% aqueous solution at 30° C. of at least 35 dynes/cm; and/or
    (iv) has a viscosity of at most 4000 mPa·s, measured at 70° C. using a model LVF or LVT Brookfield viscosimeter.
  8. 8. The pharmaceutical dosage form according to claim 1, wherein the nonionic surfactant is a synthetic copolymer of ethylene oxide and propylene oxide.
  9. 9. The pharmaceutical dosage form according to claim 1, wherein the nonionic surfactant is selected from block copolymers according to general formula (I-a)
    Figure US20130225697A1-20130829-C00008
    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 block copolymers according to general formula (I-b)
    Figure US20130225697A1-20130829-C00009
    wherein e, f, g and h are each independently an integer of from 1 to 150, and i, j, k and l are each independently an integer of from 2 to 50.
  10. 10. The pharmaceutical dosage form according to claim 1, 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 claim 1, 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 claim 1, which is configured for administration once daily or twice daily.
  13. 13. The pharmaceutical dosage form according to claim 1, which is thermoformed.
  14. 14. The pharmaceutical dosage form according to claim 1, which is tamper-resistant.
  15. 15. A method of treating pain in a patient in need thereof, said method comprising administering to said patient a dosage form according to claim 6.
US13778186 2012-02-28 2013-02-27 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer Abandoned US20130225697A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US201261603986 true 2012-02-28 2012-02-28
EP12001301 2012-02-28
EP12001301.6 2012-02-28
US13778186 US20130225697A1 (en) 2012-02-28 2013-02-27 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13778186 US20130225697A1 (en) 2012-02-28 2013-02-27 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US14636801 US20150238422A1 (en) 2012-02-28 2015-03-03 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US15166573 US9655853B2 (en) 2012-02-28 2016-05-27 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14636801 Continuation US20150238422A1 (en) 2012-02-28 2015-03-03 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer

Publications (1)

Publication Number Publication Date
US20130225697A1 true true US20130225697A1 (en) 2013-08-29

Family

ID=47754522

Family Applications (3)

Application Number Title Priority Date Filing Date
US13778186 Abandoned US20130225697A1 (en) 2012-02-28 2013-02-27 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US14636801 Pending US20150238422A1 (en) 2012-02-28 2015-03-03 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US15166573 Active US9655853B2 (en) 2012-02-28 2016-05-27 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer

Family Applications After (2)

Application Number Title Priority Date Filing Date
US14636801 Pending US20150238422A1 (en) 2012-02-28 2015-03-03 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US15166573 Active US9655853B2 (en) 2012-02-28 2016-05-27 Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer

Country Status (5)

Country Link
US (3) US20130225697A1 (en)
EP (1) EP2819656A1 (en)
JP (1) JP6117249B2 (en)
CA (1) CA2864949A1 (en)
WO (1) WO2013127831A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US9730885B2 (en) 2012-07-12 2017-08-15 Mallinckrodt Llc Extended release, abuse deterrent pharmaceutical compositions

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Unbreakable dosage forms with delayed release
WO2009092601A1 (en) 2008-01-25 2009-07-30 Grünenthal GmbH Pharmaceutical dosage form
ES2560210T3 (en) 2009-07-22 2016-02-17 Grünenthal GmbH Dosage form resistant to manipulation for opiádes sensitive to oxidation
RU2607499C2 (en) 2010-09-02 2017-01-10 Грюненталь Гмбх Destruction-resistant dosage form containing anionic polymer
US20130225697A1 (en) 2012-02-28 2013-08-29 Grunenthal Gmbh Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
CA2913209A1 (en) 2013-05-29 2014-12-04 Grunenthal Gmbh Tamper resistant dosage form with bimodal release profile
JP2017518980A (en) 2014-05-12 2017-07-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Containing tapentadol, modified prevent immediate release capsule formulation
CA2949422A1 (en) 2014-05-26 2015-12-03 Grunenthal Gmbh Multiparticles safeguarded against ethanolic dose-dumping
EP3285748A1 (en) 2015-04-24 2018-02-28 Grünenthal GmbH Tamper-resistant fixed dose combination providing fast release of two drugs from different particles
CA2983648A1 (en) 2015-04-24 2016-10-27 Grunenthal Gmbh Tamper-resistant fixed dose combination providing fast release of two drugs from particles and a matrix
JP2018515455A (en) 2015-04-24 2018-06-14 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper resistant fixed dose combination resulting in rapid release of the two drugs from the particles
JP2018517676A (en) 2015-04-24 2018-07-05 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Modified anti formulations resistant to immediate and solvent extraction

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020187192A1 (en) * 2001-04-30 2002-12-12 Yatindra Joshi Pharmaceutical composition which reduces or eliminates drug abuse potential
US20030077297A1 (en) * 1999-02-26 2003-04-24 Feng-Jing Chen Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US20070190142A1 (en) * 2006-01-21 2007-08-16 Abbott Gmbh & Co. Kg Dosage forms for the delivery of drugs of abuse and related methods
US20070231268A1 (en) * 2004-11-24 2007-10-04 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products

Family Cites Families (493)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2524855A (en) 1950-10-10 Process for the manufacture of
CA722109A (en) 1965-11-23 W. Mock Henry Extrusion of ethylene oxide polymers
US2806033A (en) 1955-08-03 1957-09-10 Lewenstein Morphine derivative
US2987445A (en) 1958-10-10 1961-06-06 Rohm & Haas Drug composition
US3370035A (en) 1961-06-23 1968-02-20 Takeda Chemical Industries Ltd Stabilization of polyalkylene oxide
US3332950A (en) 1963-03-23 1967-07-25 Endo Lab 14-hydroxydihydronormorphinone derivatives
GB1147210A (en) 1965-06-30 1969-04-02 Eastman Kodak Co Improvements in or relating to vitamins
US3652589A (en) 1967-07-27 1972-03-28 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US3806603A (en) 1969-10-13 1974-04-23 W Gaunt Pharmaceutical carriers of plasticized dried milled particles of hydrated cooked rice endosperm
DE2210071A1 (en) 1971-03-09 1972-09-14
US3980766A (en) 1973-08-13 1976-09-14 West Laboratories, Inc. Orally administered drug composition for therapy in the treatment of narcotic drug addiction
US3865108A (en) 1971-05-17 1975-02-11 Ortho Pharma Corp Expandable drug delivery device
US3966747A (en) 1972-10-26 1976-06-29 Bristol-Myers Company 9-Hydroxy-6,7-benzomorphans
US4014965A (en) 1972-11-24 1977-03-29 The Dow Chemical Company Process for scrapless forming of plastic articles
US3941865A (en) 1973-12-10 1976-03-02 Union Carbide Corporation Extrusion of ethylene oxide resins
US4002173A (en) 1974-07-23 1977-01-11 International Paper Company Diester crosslinked polyglucan hydrogels and reticulated sponges thereof
DE2530563C2 (en) 1975-07-09 1986-07-24 Bayer Ag, 5090 Leverkusen, De
JPS603286B2 (en) 1977-03-03 1985-01-26 Nippon Kayaku Kk
US4207893A (en) 1977-08-29 1980-06-17 Alza Corporation Device using hydrophilic polymer for delivering drug to biological environment
US4175119A (en) 1978-01-11 1979-11-20 Porter Garry L Composition and method to prevent accidental and intentional overdosage with psychoactive drugs
DE2822324C3 (en) 1978-05-22 1981-02-26 Basf Ag, 6700 Ludwigshafen
US4211681A (en) 1978-08-16 1980-07-08 Union Carbide Corporation Poly(ethylene oxide) compositions
US4200704A (en) 1978-09-28 1980-04-29 Union Carbide Corporation Controlled degradation of poly(ethylene oxide)
FI793235A (en) 1978-10-19 1980-04-20 Mallinckrodt Inc Foerfarande Foer framstaellning of oxomorfon
US4215104A (en) 1979-03-26 1980-07-29 Mead Johnson & Company Multi-fractionable tablet structure
US4258027A (en) 1979-03-26 1981-03-24 Mead Johnson & Company Multi-fractionable tablet structure
CA1146866A (en) 1979-07-05 1983-05-24 Yamanouchi Pharmaceutical Co. Ltd. Process for the production of sustained release pharmaceutical composition of solid medical material
US4353887A (en) 1979-08-16 1982-10-12 Ciba-Geigy Corporation Divisible tablet having controlled and delayed release of the active substance
BE884760A (en) 1979-08-16 1981-02-13 Ciba Geigy scored tablet allowing a controlled release and delayed active substance
US4457933A (en) 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
JPH0129764B2 (en) 1980-06-03 1989-06-14 Kissei Pharmaceutical
DE3024416C2 (en) 1980-06-28 1982-04-15 Goedecke Ag, 1000 Berlin, De
US4473640A (en) 1982-06-03 1984-09-25 Combie Joan D Detection of morphine and its analogues using enzymatic hydrolysis
US4462941A (en) 1982-06-10 1984-07-31 The Regents Of The University Of California Dynorphin amide analogs
US4427778A (en) 1982-06-29 1984-01-24 Biochem Technology, Inc. Enzymatic preparation of particulate cellulose for tablet making
US4485211A (en) 1982-09-15 1984-11-27 The B. F. Goodrich Company Poly(glycidyl ether)block copolymers and process for their preparation
US4427681A (en) 1982-09-16 1984-01-24 Richardson-Vicks, Inc. Thixotropic compositions easily convertible to pourable liquids
US4529583A (en) 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 (en) 1983-05-02 1986-07-29 Basf Corporation Free-flowing, high density, fat soluble vitamin powders with improved stability
US4765989A (en) 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
US4783337A (en) 1983-05-11 1988-11-08 Alza Corporation Osmotic system comprising plurality of members for dispensing drug
US5082668A (en) 1983-05-11 1992-01-21 Alza Corporation Controlled-release system with constant pushing source
US4612008A (en) 1983-05-11 1986-09-16 Alza Corporation Osmotic device with dual thermodynamic activity
US4599342A (en) 1984-01-16 1986-07-08 The Procter & Gamble Company Pharmaceutical products providing enhanced analgesia
US4629621A (en) 1984-07-23 1986-12-16 Zetachron, Inc. Erodible matrix for sustained release bioactive composition
DK450985D0 (en) 1984-10-09 1985-10-03 Dow Chemical Co Dosage form maintained release preparations, based on highly plasticized celluloseethergeler
GB8507779D0 (en) 1985-03-26 1985-05-01 Fujisawa Pharmaceutical Co Drug carrier
WO1987000045A1 (en) 1985-06-24 1987-01-15 Ici Australia Limited Ingestible capsules
EP0328775B1 (en) 1985-06-28 1993-10-20 Carrington Laboratories, Inc. Processes for preparation of aloe products, products produced thereby and compositions thereof
US4992279A (en) 1985-07-03 1991-02-12 Kraft General Foods, Inc. Sweetness inhibitor
US4851521A (en) 1985-07-08 1989-07-25 Fidia, S.P.A. Esters of hyaluronic acid
EP0226061B1 (en) 1985-12-17 1994-02-16 United States Surgical Corporation High molecular weight bioresorbable polymers and implantation devices thereof
US4711894A (en) 1986-01-16 1987-12-08 Henkel Corporation Stabilized tocopherol in dry, particulate, free-flowing form
US5198226A (en) 1986-01-30 1993-03-30 Syntex (U.S.A.) Inc. Long acting nicardipine hydrochloride formulation
US4940556A (en) 1986-01-30 1990-07-10 Syntex (U.S.A.) Inc. Method of preparing long acting formulation
US4764378A (en) 1986-02-10 1988-08-16 Zetachron, Inc. Buccal drug dosage form
EP0239973A3 (en) 1986-03-31 1989-11-08 Union Carbide Corporation Catalyst and process for alkylene oxide polymerization
DE3612211A1 (en) 1986-04-11 1987-10-15 Basf Ag Continuous method for tableting
US4667013A (en) 1986-05-02 1987-05-19 Union Carbide Corporation Process for alkylene oxide polymerization
US4713243A (en) 1986-06-16 1987-12-15 Johnson & Johnson Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
USRE33093E (en) 1986-06-16 1989-10-17 Johnson & Johnson Consumer Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
USRE34990E (en) 1986-08-07 1995-07-04 Ciba-Geigy Corporation Oral therapeutic system having systemic action
CA1335748C (en) 1986-09-25 1995-05-30 Jeffrey Lawrence Finnan Crosslinked gelatins
US5227157A (en) 1986-10-14 1993-07-13 Board Of Regents, The University Of Texas System Delivery of therapeutic agents
EP0277289B8 (en) 1986-11-10 2003-05-21 Biopure Corporation Extra pure semi-synthetic blood substitute
US4892889A (en) 1986-11-18 1990-01-09 Basf Corporation Process for making a spray-dried, directly-compressible vitamin powder comprising unhydrolyzed gelatin
JPH0831303B2 (en) 1986-12-01 1996-03-27 オムロン株式会社 Chip type pigweed -'s
EP0277092B1 (en) 1987-01-14 1992-01-29 Ciba-Geigy Ag Therapeutic system for slightly soluble active ingredients
US4892778A (en) 1987-05-27 1990-01-09 Alza Corporation Juxtaposed laminated arrangement
US5051261A (en) 1987-11-24 1991-09-24 Fmc Corporation Method for preparing a solid sustained release form of a functionally active composition
DE3877971D1 (en) 1987-12-17 1993-03-11 Upjohn Co Triple notched drug tablet.
DE3812567A1 (en) 1988-04-15 1989-10-26 Basf Ag A process for preparing pharmaceutical mixtures
US4960814A (en) 1988-06-13 1990-10-02 Eastman Kodak Company Water-dispersible polymeric compositions
US5350741A (en) 1988-07-30 1994-09-27 Kanji Takada Enteric formulations of physiologically active peptides and proteins
JPH0249719A (en) 1988-08-11 1990-02-20 Dai Ichi Kogyo Seiyaku Co Ltd Oil soluble-vitamin powder having readily water-dispersible and soluble performance
GB8820327D0 (en) 1988-08-26 1988-09-28 May & Baker Ltd New compositions of matter
DE3830353A1 (en) 1988-09-07 1990-03-15 Basf Ag shaping process for the continuous preparation of solid pharmaceutical
US5139790A (en) 1988-10-14 1992-08-18 Zetachron, Inc. Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith
US5004601A (en) 1988-10-14 1991-04-02 Zetachron, Inc. Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith
US4957668A (en) 1988-12-07 1990-09-18 General Motors Corporation Ultrasonic compacting and bonding particles
US5190760A (en) 1989-07-08 1993-03-02 Coopers Animal Health Limited Solid pharmaceutical composition
US5169645A (en) 1989-10-31 1992-12-08 Duquesne University Of The Holy Ghost Directly compressible granules having improved flow properties
US5200197A (en) 1989-11-16 1993-04-06 Alza Corporation Contraceptive pill
GB8926612D0 (en) 1989-11-24 1990-01-17 Erba Farmitalia Pharmaceutical compositions
EP0449775A3 (en) 1990-03-29 1992-09-02 Ciba-Geigy Ag Polyether-polyester block copolymers and their use as dispersing agents
FR2664851B1 (en) 1990-07-20 1992-10-16 Oreal Method for compacting a powder mixture to obtain an absorbent or partially friable compact product and product obtained by this process.
EP0477135A1 (en) 1990-09-07 1992-03-25 Warner-Lambert Company Chewable spheroidal coated microcapsules and methods for preparing same
US5126151A (en) 1991-01-24 1992-06-30 Warner-Lambert Company Encapsulation matrix
US5273758A (en) 1991-03-18 1993-12-28 Sandoz Ltd. Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms
US5149538A (en) 1991-06-14 1992-09-22 Warner-Lambert Company Misuse-resistive transdermal opioid dosage form
JP3073054B2 (en) 1991-07-11 2000-08-07 住友精化株式会社 Manufacturing method of the alkylene oxide polymer
DE69231856D1 (en) 1991-08-30 2001-07-05 Showa Pharm Chem Ind dry gel composition
WO1993006723A1 (en) 1991-10-04 1993-04-15 Olin Corporation Fungicide tablet
DE69229881T2 (en) 1991-10-04 1999-12-09 Yoshitomi Pharmaceutical A sustained release tablet
DE4138513A1 (en) 1991-11-23 1993-05-27 Basf Ag A solid pharmaceutical sustained-release form
US5266331A (en) 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
CA2125148C (en) 1991-12-05 1999-05-11 Siva N. Raman A carbohydrate glass matrix for the sustained release of a therapeutic agent
DK0617612T3 (en) 1991-12-18 1998-04-14 Warner Lambert Co A process for the preparation of a solid dispersion
US5225417A (en) 1992-01-21 1993-07-06 G. D. Searle & Co. Opioid agonist compounds
WO1993023017A1 (en) 1992-05-06 1993-11-25 Janssen Pharmaceutica, Inc. Pharmaceutical and other dosage forms
DE59302200D1 (en) 1992-05-22 1996-05-15 Goedecke Ag A process for producing sustained-release drug preparations
GB9217295D0 (en) 1992-08-14 1992-09-30 Wellcome Found Controlled released tablets
DE4227385A1 (en) 1992-08-19 1994-02-24 Kali Chemie Pharma Gmbh pancreatin
DE4229085C2 (en) 1992-09-01 1996-07-11 Boehringer Mannheim Gmbh Elongated dividable tablet
JP3140465B2 (en) 1992-09-18 2001-03-05 山之内製薬株式会社 Hydrogel sustained-release preparation
US5472943A (en) 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 (en) 1992-10-09 1998-04-15 Eeva Kristoffersson Process for the preparation of drug pellets
DK0598606T3 (en) 1992-11-18 1999-11-22 Johnson & Johnson Consumer Extrudable compositions for topical transdermal delivery of drugs
DE69326163T2 (en) 1992-12-23 2000-05-04 Saitec Srl A process for the manufacturing of dosage forms and controlled release dosage forms and the thus obtained
GB9227166D0 (en) 1992-12-31 1993-02-24 Toermaelae Pertti O A method for preparing pharmaceutical compositions
US6071970A (en) 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 (en) 1993-03-24 1998-05-20 Doxa Gmbh Film or film tubing from casein, process for their preparation and their use
US5849240A (en) 1993-11-23 1998-12-15 Euro-Celtique, S.A. Method of preparing sustained release pharmaceutical compositions
DK0699436T4 (en) 1993-05-10 2013-04-08 Euro Celtique Sa Controlled release preparation
EP0654263B1 (en) 1993-11-23 2002-01-23 Euro-Celtique S.A. Method for preparing a sustained release composition
ES2124372T5 (en) 1993-07-01 2004-07-16 Euro-Celtique S.A. Sustained release compositions containing morphine.
DE4329794C2 (en) 1993-09-03 1997-09-18 Gruenenthal Gmbh Medicines containing tramadol sustained release
US6461644B1 (en) 1996-03-25 2002-10-08 Richard R. Jackson Anesthetizing plastics, drug delivery plastics, and related medical products, systems and methods
EP2036558A3 (en) 1993-10-07 2010-04-28 Euro-Celtique S.A. Orally administrable opioid formulations having extended duration of effect
WO1995017174A1 (en) 1993-12-20 1995-06-29 The Procter & Gamble Company Process for making laxatives containing dioctyl sulfosuccinate
GB9401894D0 (en) 1994-02-01 1994-03-30 Rhone Poulenc Rorer Ltd New compositions of matter
DE69530973T2 (en) 1994-02-16 2004-05-19 Abbott Laboratories, Abbott Park A process for preparing finely divided pharmaceutical formulations
US5458887A (en) 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
DE4413350A1 (en) 1994-04-18 1995-10-19 Basf Ag Slow-release matrix pellets, and methods for their preparation
RU2130311C1 (en) 1994-05-06 1999-05-20 Пфайзер Инк. Medicinal controlled-releasing forms of azithromycin
ES2132589T3 (en) 1994-05-18 1999-08-16 Lannacher Heilmittel Preparation oral delayed effect.
US5460826A (en) 1994-06-27 1995-10-24 Alza Corporation Morphine therapy
DE4426245A1 (en) 1994-07-23 1996-02-22 Gruenenthal Gmbh 1-phenyl-3-dimethylaminopropane compounds having pharmacological activity
DE69521406T2 (en) 1994-08-03 2002-05-02 Saitec Srl Apparatus and method for preparing solid forms with controlled release of active ingredient
JP3285452B2 (en) 1994-08-11 2002-05-27 サンスター株式会社 Dentifrice composition
US5837790A (en) 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
WO1996012466A1 (en) 1994-10-25 1996-05-02 Daratech Pty. Ltd. Controlled release container with core and outer shell
US5965161A (en) 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
DE4446470A1 (en) 1994-12-23 1996-06-27 Basf Ag A process for the production of divisible tablets
DE19504832A1 (en) 1995-02-14 1996-08-22 Basf Ag Solid drug preparations
US5945125A (en) 1995-02-28 1999-08-31 Temple University Controlled release tablet
DE19509807A1 (en) 1995-03-21 1996-09-26 Basf Ag A process for the preparation of drug formulations in the form of a solid solution of the active ingredient in a polymer matrix, with this method produced active substance preparations
US6348469B1 (en) 1995-04-14 2002-02-19 Pharma Pass Llc Solid compositions containing glipizide and polyethylene oxide
US6117453A (en) 1995-04-14 2000-09-12 Pharma Pass Solid compositions containing polyethylene oxide and an active ingredient
US5900425A (en) 1995-05-02 1999-05-04 Bayer Aktiengesellschaft Pharmaceutical preparations having controlled release of active compound and processes for their preparation
DE19522899C1 (en) 1995-06-23 1996-12-19 Hexal Pharmaforschung Gmbh Process for the continuous sintering of granules
CA2229797A1 (en) 1995-08-18 1997-02-27 Astra Aktiebolag Novel opioid peptides
US5759583A (en) 1995-08-30 1998-06-02 Syntex (U.S.A.) Inc. Sustained release poly (lactic/glycolic) matrices
US6063405A (en) 1995-09-29 2000-05-16 L.A.M. Pharmaceuticals, Llc Sustained release delivery system
US5811126A (en) 1995-10-02 1998-09-22 Euro-Celtique, S.A. Controlled release matrix for pharmaceuticals
DE19539361A1 (en) 1995-10-23 1997-04-24 Basf Ag A process for producing multilayer, solid drug forms for oral or rectal administration
US6355656B1 (en) 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US5908850A (en) 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
DE19547766A1 (en) 1995-12-20 1997-06-26 Gruenenthal Gmbh 1-phenyl-2-dimethylaminomethyl-cyclohexan-1-ol compounds as pharmaceutical active ingredients
EP0914097B1 (en) 1996-03-12 2002-01-16 Alza Corporation Composition and dosage form comprising opioid antagonist
CA2577233C (en) 1996-04-05 2009-08-18 Takeda Pharmaceutical Company Limited Pharmaceutical composition containing angiotensin ii antagonist
US20020114838A1 (en) 1996-04-05 2002-08-22 Ayer Atul D. Uniform drug delivery therapy
US5817343A (en) 1996-05-14 1998-10-06 Alkermes, Inc. Method for fabricating polymer-based controlled-release devices
EP2065055A1 (en) 1996-06-26 2009-06-03 Board of Regents, The University of Texas System Holt-melt extrudable pharmaceutical formulation
ES2322405T3 (en) 1996-07-08 2009-06-19 Penwest Pharmaceuticals Co. Matrix controlled to high doses insoluble drugs release.
DE19629753A1 (en) 1996-07-23 1998-01-29 Basf Ag A process for the preparation of solid dosage forms
NL1003684C2 (en) 1996-07-25 1998-01-28 Weterings B V H A device for dispensing a liquid.
DE19630236A1 (en) 1996-07-26 1998-01-29 Wolff Walsrode Ag Biaxially stretched, biodegradable and compostable sausage casing
DE69731114D1 (en) 1996-11-05 2004-11-11 Novamont Spa contain Biologiscgh abbaure polymer compositions, starch and a thermoplastic polymer
US5991799A (en) 1996-12-20 1999-11-23 Liberate Technologies Information retrieval system using an internet multiplexer to focus user selection
DE19705538C1 (en) 1997-02-14 1998-08-27 Goedecke Ag Process for the separation of active ingredients in solid pharmaceutical preparations
US5948787A (en) 1997-02-28 1999-09-07 Alza Corporation Compositions containing opiate analgesics
DE19710009A1 (en) 1997-03-12 1998-09-24 Knoll Ag Multi-phase active ingredient-containing formulations
DE19710213A1 (en) 1997-03-12 1998-09-17 Basf Ag A process for producing solid combination drug forms
US6096339A (en) 1997-04-04 2000-08-01 Alza Corporation Dosage form, process of making and using same
US6139770A (en) 1997-05-16 2000-10-31 Chevron Chemical Company Llc Photoinitiators and oxygen scavenging compositions
DE19721467A1 (en) 1997-05-22 1998-11-26 Basf Ag A process for preparing small-scale preparations of biologically active substances
US6635280B2 (en) 1997-06-06 2003-10-21 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
ES2248908T7 (en) 1997-06-06 2014-11-24 Depomed, Inc. Dosage forms of drugs orally and gastric retention for sustained release of drugs highly soluble
WO1999001111A1 (en) 1997-07-02 1999-01-14 Euro-Celtique, S.A. Stabilized sustained release tramadol formulations
US6399100B1 (en) 1997-08-01 2002-06-04 Elan Corporation, Plc Controlled release pharmaceutical compositions containing tiagabine
JP2003525828A (en) 1997-09-10 2003-09-02 アライドシグナル インコーポレイテッド Injection molding by a wet method structural materials based on zirconia
US6009390A (en) 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
ES2174538T3 (en) 1997-11-28 2002-11-01 Knoll Ag Procedure for obtaining substances exempt solvent, noncrystalline, biologically active.
US6344535B1 (en) 1997-12-03 2002-02-05 Bayer Aktiengesellschaft Polyether ester amides
DE19753534A1 (en) 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
US6228863B1 (en) 1997-12-22 2001-05-08 Euro-Celtique S.A. Method of preventing abuse of opioid dosage forms
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
DE19800689C1 (en) 1998-01-10 1999-07-15 Deloro Stellite Gmbh Molding of a wear-resistant material
DE19800698A1 (en) 1998-01-10 1999-07-15 Bayer Ag Biodegradable polyester with block-type structure polyester and polyamide segments
DE69918233D1 (en) 1998-03-05 2004-07-29 Mitsui Chemicals Inc composition polylactic acid and derived film
US6245357B1 (en) 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US6090411A (en) 1998-03-09 2000-07-18 Temple University Monolithic tablet for controlled drug release
US6110500A (en) 1998-03-25 2000-08-29 Temple University Coated tablet with long term parabolic and zero-order release kinetics
EP1070346A1 (en) 1998-04-02 2001-01-24 Applied Materials, Inc. Method for etching low k dielectrics
WO1999051208A1 (en) 1998-04-03 1999-10-14 Bm Research A/S Controlled release composition
US5962488A (en) 1998-04-08 1999-10-05 Roberts Laboratories, Inc. Stable pharmaceutical formulations for treating internal bowel syndrome containing isoxazole derivatives
DE19822979A1 (en) 1998-05-25 1999-12-02 Kalle Nalo Gmbh & Co Kg Film with starch or starch derivatives and polyester urethanes, as well as processes for their preparation
US6333087B1 (en) 1998-08-27 2001-12-25 Chevron Chemical Company Llc Oxygen scavenging packaging
DE19841244A1 (en) 1998-09-09 2000-03-16 Knoll Ag Method and apparatus for the manufacture of tablets
US6268177B1 (en) 1998-09-22 2001-07-31 Smithkline Beecham Corporation Isolated nucleic acid encoding nucleotide pyrophosphorylase
CN1327384A (en) 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 (en) 1998-11-02 2006-10-26 Elan Corporation, Plc Multiparticulate modified release composition
ES2141688B1 (en) 1998-11-06 2001-02-01 Vita Invest Sa New esters derived from substituted phenyl-cyclohexyl compounds.
DE19855440A1 (en) 1998-12-01 2000-06-08 Basf Ag A method for producing solid dosage forms by melt extrusion
EP1005863A1 (en) 1998-12-04 2000-06-07 Synthelabo Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof
DE19856147A1 (en) 1998-12-04 2000-06-08 Knoll Ag Divisible solid dosage forms and methods for their preparation
US6238697B1 (en) 1998-12-21 2001-05-29 Pharmalogix, Inc. Methods and formulations for making bupropion hydrochloride tablets using direct compression
WO2000040205A3 (en) 1999-01-05 2000-09-28 Shubha Chungi Sustained release formulation with reduced moisture sensitivity
KR20010034730A (en) 1999-02-04 2001-04-25 아키라 이가키 Arteriosclerosis-preventing material, immune-activating material, and vertebrate that has eaten such materials, and eggs thereof
US6375963B1 (en) 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
CA2379987A1 (en) 1999-07-29 2001-02-08 Roxane Laboratories, Inc. Opioid sustained-released formulation
US20030118641A1 (en) 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US6562375B1 (en) 1999-08-04 2003-05-13 Yamanouchi Pharmaceuticals, Co., Ltd. Stable pharmaceutical composition for oral use
KR100345214B1 (en) 1999-08-17 2002-07-25 이강춘 The nasal transmucosal delivery of peptides conjugated with biocompatible polymers
EP1207866B1 (en) 1999-08-31 2004-10-13 Grünenthal GmbH Delayed-action form of administration containing tramadol saccharinate
DE19940944B4 (en) 1999-08-31 2006-10-12 Grünenthal GmbH Sustained release, oral pharmaceutical forms of administration
DE19940740A1 (en) 1999-08-31 2001-03-01 Gruenenthal Gmbh pharmaceutical salts
DE19960494A1 (en) 1999-12-15 2001-06-21 Knoll Ag Apparatus and method for producing solid forms containing active substance
ES2160534B1 (en) 1999-12-30 2002-04-16 Vita Invest Sa New esters derived from (RR, SS) -2-hydroxybenzoate of 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl.
US6680070B1 (en) 2000-01-18 2004-01-20 Albemarle Corporation Particulate blends and compacted products formed therefrom, and the preparation thereof
ES2415407T3 (en) 2000-02-08 2013-07-25 Euro-Celtique S.A. oral formulations of opioid agonists resistant tamper
US20020015730A1 (en) 2000-03-09 2002-02-07 Torsten Hoffmann Pharmaceutical formulations and method for making
DE10015479A1 (en) 2000-03-29 2001-10-11 Basf Ag Solid oral dosage forms with delayed release of active ingredient and high mechanical stability
US8012504B2 (en) 2000-04-28 2011-09-06 Reckitt Benckiser Inc. Sustained release of guaifenesin combination drugs
US6572887B2 (en) 2000-05-01 2003-06-03 National Starch And Chemical Investment Holding Corporation Polysaccharide material for direct compression
US6419954B1 (en) 2000-05-19 2002-07-16 Yamanouchi Pharmaceutical Co., Ltd. Tablets and methods for modified release of hydrophilic and other active agents
JP5324732B2 (en) 2000-05-23 2013-10-23 スネス ファーマシューティカルズ インコーポレイテッド Nrg-2 nucleic acid molecules, polypeptides, and diagnostic and therapeutic methods
DE10029201A1 (en) 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 (en) 2000-06-20 2002-12-03 Depomed, Inc. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms
US6607748B1 (en) 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 (en) 2000-07-26 2002-06-06 Mitsubishi Polyester Film Gmbh White, biaxially oriented polyester film
US6883976B2 (en) 2001-07-30 2005-04-26 Seikoh Giken Co., Ltd. Optical fiber ferrule assembly and optical module and optical connector using the same
US6642205B2 (en) 2000-09-25 2003-11-04 Pro-Pharmaceuticals, Inc. Methods and compositions for reducing side effects in chemotherapeutic treatments
JP2004509908A (en) 2000-09-27 2004-04-02 ダニスコ エイ/エス Antibacterial agents
WO2002026928A1 (en) 2000-09-28 2002-04-04 The Dow Chemical Company Polymer composite structures useful for controlled release systems
GB0026137D0 (en) 2000-10-25 2000-12-13 Euro Celtique Sa Transdermal dosage form
US6344215B1 (en) 2000-10-27 2002-02-05 Eurand America, Inc. Methylphenidate modified release formulations
WO2002035991A3 (en) 2000-10-30 2002-08-01 Univ Texas Spherical particles produced by a hot-melt extrusion/spheronization process
JP2004512354A (en) 2000-10-30 2004-04-22 ユーロ−セルティーク,エス.エイ. Hydrocodone controlled-release formulation
JP2002265592A (en) 2001-03-07 2002-09-18 Sumitomo Seika Chem Co Ltd Process for producing alkylene oxide polymer
WO2002071860A1 (en) 2001-03-13 2002-09-19 L.A. Dreyfus Co. Gum base and gum manufacturing using particulated gum base ingredients
JP3967554B2 (en) 2001-03-15 2007-08-29 国立大学法人名古屋大学 Flavonoid compounds and a method of manufacturing the same
US20020132395A1 (en) 2001-03-16 2002-09-19 International Business Machines Corporation Body contact in SOI devices by electrically weakening the oxide under the body
EP1241110A1 (en) 2001-03-16 2002-09-18 Pfizer Products Inc. Dispensing unit for oxygen-sensitive drugs
JP2004530748A (en) 2001-05-01 2004-10-07 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・コーポレイション Poly reducing the amount of formic acid compound (alkylene oxide)
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
US6623754B2 (en) 2001-05-21 2003-09-23 Noveon Ip Holdings Corp. Dosage form of N-acetyl cysteine
US7125561B2 (en) 2001-05-22 2006-10-24 Euro-Celtique S.A. Compartmentalized dosage form
US20030064122A1 (en) 2001-05-23 2003-04-03 Endo Pharmaceuticals, Inc. Abuse resistant pharmaceutical composition containing capsaicin
US7968119B2 (en) 2001-06-26 2011-06-28 Farrell John J Tamper-proof narcotic delivery system
US20030008409A1 (en) 2001-07-03 2003-01-09 Spearman Steven R. Method and apparatus for determining sunlight exposure
EP1406630A1 (en) 2001-07-06 2004-04-14 Endo Pharmaceuticals Inc. Parenteral administration of 6-hydroxy-oxymorphone for use as an analgesic
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
DE60223254D1 (en) 2001-07-06 2007-12-13 Penwest Pharmaceuticals Co The sustained release formulations of oxymorphone
JP2003020517A (en) 2001-07-10 2003-01-24 Calp Corp Resin composition for compound fiber
WO2003007802A3 (en) 2001-07-18 2003-11-27 Christopher D Breder Pharmaceutical combinations of oxycodone and naloxone
US7157103B2 (en) 2001-08-06 2007-01-02 Euro-Celtique S.A. Pharmaceutical formulation containing irritant
US7842307B2 (en) 2001-08-06 2010-11-30 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent
US7332182B2 (en) 2001-08-06 2008-02-19 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
US7144587B2 (en) 2001-08-06 2006-12-05 Euro-Celtique S.A. Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
EP1414413A1 (en) 2001-08-06 2004-05-06 Euro-Celtique S.A. Compositions and methods to prevent abuse of opioids
US7141250B2 (en) 2001-08-06 2006-11-28 Euro-Celtique S.A. Pharmaceutical formulation containing bittering agent
US20030044458A1 (en) 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US20030157168A1 (en) * 2001-08-06 2003-08-21 Christopher Breder Sequestered antagonist formulations
WO2003015531A3 (en) 2001-08-06 2003-11-06 Thomas Gruber Pharmaceutical formulation containing dye
CA2456322A1 (en) 2001-08-06 2003-02-20 Euro-Celtique, S.A. Compositions and methods to prevent abuse of opioids
US20030049272A1 (en) 2001-08-30 2003-03-13 Yatindra Joshi Pharmaceutical composition which produces irritation
US20030059467A1 (en) 2001-09-14 2003-03-27 Pawan Seth Pharmaceutical composition comprising doxasozin
US6691698B2 (en) 2001-09-14 2004-02-17 Fmc Technologies Inc. Cooking oven having curved heat exchanger
US20030068276A1 (en) 2001-09-17 2003-04-10 Lyn Hughes Dosage forms
US20040126428A1 (en) 2001-11-02 2004-07-01 Lyn Hughes Pharmaceutical formulation including a resinate and an aversive agent
US20030092724A1 (en) 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 (en) 2001-09-21 2008-05-13 Egalet As Solid dispersions of carvedilol for the Controlled Release
EP1429744A1 (en) 2001-09-21 2004-06-23 Egalet A/S Morphine polymer release system
JP2005523876A (en) 2001-09-26 2005-08-11 ペンウェスト ファーマシューティカルズ カンパニー Opioid formulations potential for abuse is reduced
WO2003028698A3 (en) 2001-09-26 2003-10-23 Klaus-Juergen Steffens Method and device for producing granulates that comprise at least one pharmaceutical active substance
EP1429724B1 (en) 2001-09-28 2013-11-06 McNeil-PPC, Inc. Dosage form containing a confectionery composition
US6837696B2 (en) 2001-09-28 2005-01-04 Mcneil-Ppc, Inc. Apparatus for manufacturing dosage forms
DE60210317T2 (en) 2001-10-09 2006-12-21 The Procter & Gamble Company, Cincinnati Aqueous compositions for surface treatment
US6592901B2 (en) 2001-10-15 2003-07-15 Hercules Incorporated Highly compressible ethylcellulose for tableting
JP2003125706A (en) 2001-10-23 2003-05-07 Lion Corp Mouth freshening preparation
DK1439829T3 (en) 2001-10-24 2005-10-10 Gruenenthal Gmbh Medicament containing 3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol with delayed release of the active substance
US20030091630A1 (en) 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 (en) 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
CA2409552A1 (en) 2001-10-25 2003-04-25 Depomed, Inc. Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
US20030104052A1 (en) 2001-10-25 2003-06-05 Bret Berner Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
DK1439825T3 (en) 2001-10-25 2013-06-17 Depomed Inc Methods of Treatment using the gastric impacted gabapentin dosage form
US6723340B2 (en) 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
WO2003037244A3 (en) 2001-10-29 2004-01-22 Therics Inc System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing
CA2464528A1 (en) 2001-11-02 2003-05-15 Elan Corporation, Plc Pharmaceutical composition
EP1463515A4 (en) 2001-12-06 2005-01-12 Scolr Pharma Inc Isoflavone composition for oral delivery
FR2833838B1 (en) 2001-12-21 2005-09-16 Ellipse Pharmaceuticals Method of manufacturing a tablet including a morphine-like analgesic and compresses obtained
US7572750B2 (en) 2002-02-11 2009-08-11 University Of Wollongong Catalysts and processes for their preparation
US20040033253A1 (en) 2002-02-19 2004-02-19 Ihor Shevchuk Acyl opioid antagonists
US20030190343A1 (en) 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals
US6572889B1 (en) 2002-03-07 2003-06-03 Noveon Ip Holdings Corp. Controlled release solid dosage carbamazepine formulations
US6753009B2 (en) 2002-03-13 2004-06-22 Mcneil-Ppc, Inc. Soft tablet containing high molecular weight polyethylene oxide
EP1639997A1 (en) 2002-04-05 2006-03-29 Euro-Celtique S.A. Matrix for sustained, invariant and independant release of active compounds
DE10217232B4 (en) 2002-04-18 2004-08-19 Ticona Gmbh A method for preparing filled granules of polyethylenes high or ultra-high molecular weight
US6960617B2 (en) 2002-04-22 2005-11-01 Purdue Research Foundation Hydrogels having enhanced elasticity and mechanical strength properties
US20050106249A1 (en) 2002-04-29 2005-05-19 Stephen Hwang Once-a-day, oral, controlled-release, oxycodone dosage forms
ES2320435T3 (en) 2002-04-29 2009-05-22 Alza Corporation Method and dosage forms for the controlled administration of oxycodone.
WO2003094812A1 (en) 2002-05-13 2003-11-20 Endo Pharmaceuticals Inc. Abuse-resistant opioid solid dosage form
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
DE10250083A1 (en) 2002-06-17 2003-12-24 Gruenenthal Gmbh Abuse-proofed dosage form
US7399488B2 (en) 2002-07-05 2008-07-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US20040011806A1 (en) 2002-07-17 2004-01-22 Luciano Packaging Technologies, Inc. Tablet filler device with star wheel
US20070196481A1 (en) 2002-07-25 2007-08-23 Amidon Gregory E Sustained-release tablet composition
US7388068B2 (en) 2002-08-21 2008-06-17 Clariant Produkte (Deutschland) Gmbh Copolymers made of alkylene oxides and glycidyl ethers and use thereof as polymerizable emulsifiers
WO2004017947A1 (en) 2002-08-21 2004-03-04 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
US20040052844A1 (en) 2002-09-16 2004-03-18 Fang-Hsiung Hsiao Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins
CN100415233C (en) 2002-09-17 2008-09-03 惠氏公司 Oral formulations
WO2004026263A3 (en) 2002-09-20 2004-07-01 Fmc Corp Cosmetic composition containing microcrystalline cellulose
WO2004026308A1 (en) 2002-09-21 2004-04-01 Shuyi Zhang Sustained release compound of acetamidophenol and tramadol
WO2004026262A3 (en) 2002-09-23 2004-06-10 Verion Inc Abuse-resistant pharmaceutical compositions
DE10250087A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Abuse-proofed dosage form
DE10250088A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Abuse-proofed dosage form
DE10250084A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Abuse-proofed dosage form
US20050191244A1 (en) 2002-10-25 2005-09-01 Gruenenthal Gmbh Abuse-resistant pharmaceutical dosage form
US20050186139A1 (en) 2002-10-25 2005-08-25 Gruenenthal Gmbh Abuse-proofed dosage form
JP2006507277A (en) 2002-10-25 2006-03-02 ラボファーマ インコーポレイテッド 24 hours effective sustained-release tramadol formulation
DE602004025159D1 (en) 2003-03-26 2010-03-04 Egalet As Matrix preparations for the controlled administration of drugs
DE10252667A1 (en) 2002-11-11 2004-05-27 Grünenthal GmbH New spiro-((cyclohexane)-tetrahydropyrano-(3,4-b)-indole) derivatives, are ORL1 receptor ligands useful e.g. for treating anxiety, depression, epilepsy, senile dementia, withdrawal symptoms or especially pain
US20040091528A1 (en) 2002-11-12 2004-05-13 Yamanouchi Pharma Technologies, Inc. Soluble drug extended release system
US20040185097A1 (en) 2003-01-31 2004-09-23 Glenmark Pharmaceuticals Ltd. Controlled release modifying complex and pharmaceutical compositions thereof
US7442387B2 (en) 2003-03-06 2008-10-28 Astellas Pharma Inc. Pharmaceutical composition for controlled release of active substances and manufacturing method thereof
CA2518834A1 (en) 2003-03-13 2004-09-30 Controlled Chemicals, Inc. Oxycodone conjugates with lower the abuse potential and extended duration of action
EP2301526B1 (en) 2003-03-26 2016-03-23 Egalet Ltd. Morphine controlled release system
CA2519556C (en) 2003-04-21 2011-01-18 Benjamin Oshlack Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same
ES2341546T3 (en) 2003-04-21 2010-06-22 Euro-Celtique S.A. tamper resistant opioid for delivery products.
CA2522529C (en) 2003-04-30 2015-10-20 Purdue Pharma L.P. Tamper resistant transdermal dosage form
US8906413B2 (en) 2003-05-12 2014-12-09 Supernus Pharmaceuticals, Inc. Drug formulations having reduced abuse potential
CN1473562A (en) 2003-06-27 2004-02-11 辉 刘 Mouth cavity quick dissolving quick disintegrating freeze-dried tablet and its preparing method
US20050015730A1 (en) 2003-07-14 2005-01-20 Srimanth Gunturi Systems, methods and computer program products for identifying tab order sequence of graphically represented elements
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Abuse-proofed dosage form
US20070183980A1 (en) 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Dosage form that is safeguarded from abuse
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
RU2339365C2 (en) 2003-08-06 2008-11-27 Грюненталь Гмбх Drug dosage form, protected from unintended application
US20050063214A1 (en) 2003-09-22 2005-03-24 Daisaburo Takashima Semiconductor integrated circuit device
CA2539027C (en) 2003-09-25 2010-02-23 Euro-Celtique S.A. Pharmaceutical combinations of hydrocodone and naltrexone
KR20060097008A (en) 2003-09-30 2006-09-13 알자 코포레이션 Osmotically driven active agent delivery device providing an ascending release profile
US20060172006A1 (en) 2003-10-10 2006-08-03 Vincent Lenaerts Sustained-release tramadol formulations with 24-hour clinical efficacy
US20060009478A1 (en) 2003-10-15 2006-01-12 Nadav Friedmann Methods for the treatment of back pain
RU2006118323A (en) 2003-10-29 2007-12-10 Алза Корпорейшн (Us) Dosage forms with controlled release of oxycodone for a single oral administration
US7201920B2 (en) 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
ES2600577T3 (en) 2003-12-04 2017-02-09 Bend Research, Inc. Spray-solidification method using an extruder to prepare compositions in multiparticulate crystalline drugs
DE602004005076T2 (en) 2003-12-09 2007-11-15 Euro-Celtique S.A. Co-extruded safety dosage form manufacturing processes with an active ingredient and an adverse agent and for
WO2005060942A1 (en) 2003-12-19 2005-07-07 Aurobindo Pharma Ltd Extended release pharmaceutical composition of metformin
DE10360792A1 (en) 2003-12-23 2005-07-28 Grünenthal GmbH Spirocyclic cyclohexane derivatives
DE10361596A1 (en) 2003-12-24 2005-09-29 Grünenthal GmbH A process for preparing a secured against misuse dosage form
WO2005065646A3 (en) 2003-12-29 2005-12-08 Alza Corp Inc Novel drug compositions and dosage forms
WO2005079752A3 (en) 2004-02-11 2006-12-14 Rubicon Res Private Ltd Controlled release pharmaceutical compositions with improved bioavailability
EP3228308A1 (en) 2005-01-28 2017-10-11 Euro-Celtique S.A. Alcohol resistant dosage forms
CA2555423C (en) 2004-02-12 2018-07-24 Euro-Celtique S.A. Melt-extruded multiparticulates for the controlled release of an active agent
GB0403100D0 (en) 2004-02-12 2004-03-17 Euro Celtique Sa Particulates
KR100789227B1 (en) 2004-02-23 2008-01-02 유로-셀띠끄 소시에떼 아노님 Abuse resistance opioid transdermal delivery device
DE602005026786D1 (en) 2004-03-30 2011-04-21 Euro Celtique Sa A process for producing oxycodone hydrochloride with less than 25 ppm 14-hydroxycodeinone
US20050220877A1 (en) 2004-03-31 2005-10-06 Patel Ashish A Bilayer tablet comprising an antihistamine and a decongestant
DE102004019916A1 (en) 2004-04-21 2005-11-17 Grünenthal GmbH secured against misuse medicated plaster
DE102004020220A1 (en) 2004-04-22 2005-11-10 Grünenthal GmbH A process for preparing a secured against misuse, solid dosage form
WO2005102286A1 (en) 2004-04-22 2005-11-03 Grünenthal GmbH Method for the production of an abuse-proof, solid form of administration
WO2005105036A1 (en) 2004-04-28 2005-11-10 Natco Pharma Limited Controlled release mucoadhesive matrix formulation containing tolterodine and a process for its preparation
ES2427169T3 (en) 2004-06-09 2013-10-29 Glaxosmithkline Llc Apparatus for pharmaceutical production
DE602004007905T2 (en) 2004-06-28 2008-05-08 Grünenthal GmbH Crystalline forms of (-) - (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) -phenol hydrochloride
US20060003010A1 (en) 2004-06-30 2006-01-05 Ibsa Institut Biochimique S.A. Pharmaceutical formulations for the safe administration of drugs used in the treatment of drug addiction and processes for obtaining the same
DE102004032103A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Abuse-proofed, oral dosage form
DE102004032049A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Abuse-proofed, oral dosage form
JP5700904B2 (en) 2004-07-01 2015-04-15 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング (1r, 2r) -3- (3- Dimethylamino-1-ethyl-2-methyl-propyl) - abuse prevention oral dosage forms containing phenol
EP1765298B1 (en) 2004-07-01 2012-10-24 Gruenenthal Gmbh Method for producing a solid dosage form, which is safeguarded against abuse, while using a planetary gear extruder
DE102004032051A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH A process for preparing a secured against misuse, solid dosage form
JP5259183B2 (en) 2004-07-01 2013-08-07 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Protected oral dosage form against abuse
JP2008508201A (en) 2004-07-27 2008-03-21 ユニリーバー・ナームローゼ・ベンノートシヤープ Hair care composition
US20060068009A1 (en) 2004-09-30 2006-03-30 Scolr Pharma, Inc. Modified release ibuprofen dosage form
US20070077297A1 (en) 2004-09-30 2007-04-05 Scolr Pharma, Inc. Modified release ibuprofen dosage form
US20060177380A1 (en) 2004-11-24 2006-08-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20080152595A1 (en) 2004-11-24 2008-06-26 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
ES2630002T3 (en) 2005-01-26 2017-08-17 Taiho Pharmaceutical Co., Ltd. anticancer drug containing alpha, alpha, alpha-trifluorothymidine and thymidine phosphorylase inhibitor
DE102005005449A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH A process for preparing a secured against misuse dosage form
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Unbreakable dosage forms with delayed release
US20060194759A1 (en) 2005-02-25 2006-08-31 Eidelson Stewart G Topical compositions and methods for treating pain and inflammation
EP1695700A1 (en) 2005-02-28 2006-08-30 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
WO2006094672A1 (en) 2005-03-04 2006-09-14 Euro-Celtique S.A. Method of reducing alpha, beta unsaturated ketones in opioid compositions
US7732427B2 (en) 2005-03-31 2010-06-08 University Of Delaware Multifunctional and biologically active matrices from multicomponent polymeric solutions
WO2006105615A1 (en) 2005-04-08 2006-10-12 Ozpharma Pty Ltd Buccal delivery system
CN102552162A (en) 2005-05-10 2012-07-11 诺瓦提斯公司 Extrusion process for making compositions with poorly compressible therapeutic compounds
CA2611081C (en) 2005-06-03 2016-05-31 Egalet A/S A drug delivery system for delivering active substances dispersed in a dispersion medium
WO2007005716A3 (en) 2005-06-30 2007-11-22 Najib Babul Methods of treatment and compositions for use thereof
RU2008104638A (en) 2005-07-07 2009-08-20 Фарнэм Компаниз, Инк. (Us) The pharmaceutical compositions are well soluble in water medicaments that ensure their slow release
US8858993B2 (en) 2005-07-25 2014-10-14 Metrics, Inc. Coated tablet with zero-order or near zero-order release kinetics
EP1909760A1 (en) 2005-08-03 2008-04-16 Eastman Chemical Company Tocopheryl polyethylene glycol succinate powder and process for preparing same
WO2007043710A9 (en) 2005-10-14 2007-06-07 Kitasato Inst Novel dihydropseudoerythromycin derivatives
US20070092573A1 (en) 2005-10-24 2007-04-26 Laxminarayan Joshi Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist
DE202006014131U1 (en) 2005-10-31 2007-01-04 Alza Corp., Mountain View Oral dosage form useful for treating pain comprises an opioid and a dosing structure that provides extended release of the opioid in the presence of alcohol
US8329744B2 (en) 2005-11-02 2012-12-11 Relmada Therapeutics, Inc. Methods of preventing the serotonin syndrome and compositions for use thereof
FR2892937B1 (en) 2005-11-10 2013-04-05 Flamel Tech Sa microparticulate oral pharmaceutical form anti-misuse
US8652529B2 (en) 2005-11-10 2014-02-18 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
US20090317355A1 (en) 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20100172989A1 (en) 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
EP1813276A1 (en) 2006-01-27 2007-08-01 Euro-Celtique S.A. Tamper resistant dosage forms
FR2898056B1 (en) 2006-03-01 2012-01-20 Ethypharm Sa Tablets resistant to crushing intended to prevent the illicit diversion
EP1994034B1 (en) 2006-03-02 2009-11-11 Mallinckrodt, Inc. Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds
US20100226855A1 (en) 2006-03-02 2010-09-09 Spherics, Inc. Rate-Controlled Oral Dosage Formulations
US20070224637A1 (en) 2006-03-24 2007-09-27 Mcauliffe Joseph C Oxidative protection of lipid layer biosensors
US8465759B2 (en) 2006-03-24 2013-06-18 Auxilium Us Holdings, Llc Process for the preparation of a hot-melt extruded laminate
CA2647809C (en) 2006-03-24 2016-08-16 Auxilium Pharmaceuticals, Inc. Stabilized compositions containing alkaline labile drugs
US20140010860A1 (en) 2006-05-12 2014-01-09 Isa Odidi Abuse and alcohol resistant drug composition
US9023400B2 (en) 2006-05-24 2015-05-05 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
US20070292508A1 (en) 2006-06-05 2007-12-20 Balchem Corporation Orally disintegrating dosage forms
CN101091721A (en) 2006-06-22 2007-12-26 孙明 Method for preparing new type asshide
JP4029109B1 (en) 2006-07-18 2008-01-09 タマ生化学株式会社 The composite powder and a method of manufacturing vitamin e and proline
US20080020032A1 (en) 2006-07-21 2008-01-24 Michael Crowley Hydrophobic abuse deterrent delivery system for hydromorphone
CN102688241B (en) 2006-08-25 2017-04-12 普渡制药公司 Anti containing an opioid analgesic oral dosage form is tampered
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
JP5730572B2 (en) 2007-09-13 2015-06-10 シマ ラブス インク. Abuse-resistant formulation
US20080069891A1 (en) 2006-09-15 2008-03-20 Cima Labs, Inc. Abuse resistant drug formulation
KR101400824B1 (en) 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
US8187636B2 (en) 2006-09-25 2012-05-29 Atlantic Pharmaceuticals, Inc. Dosage forms for tamper prone therapeutic agents
US20080085304A1 (en) 2006-10-10 2008-04-10 Penwest Pharmaceuticals Co. Robust sustained release formulations
GB0624880D0 (en) 2006-12-14 2007-01-24 Johnson Matthey Plc Improved method for making analgesics
CA2674536C (en) 2007-01-16 2016-07-26 Egalet A/S 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
WO2008094877A3 (en) 2007-01-30 2008-10-30 Drugtech Corp Compositions for oral delivery of pharmaceuticals
CN100579525C (en) 2007-02-02 2010-01-13 东南大学 Sustained release preparation of licardipine hydrochloride and its preparing process
CN101057849A (en) 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
CA2678367C (en) 2007-03-02 2014-07-08 Farnam Companies, Inc. Sustained release compositions using wax-like materials
DE102007011485A1 (en) 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with impeded abuse
EP1980245A1 (en) 2007-04-11 2008-10-15 Cephalon France Bilayer lyophilized pharmaceutical compositions and methods of making and using same
WO2008134071A1 (en) 2007-04-26 2008-11-06 Theraquest Biosciences, Inc. Multimodal abuse resistant extended release formulations
CA2685118C (en) 2007-04-26 2016-11-01 Sigmoid Pharma Limited Manufacture of multiple minicapsules
US20110020408A1 (en) 2007-05-17 2011-01-27 Ranbaxy Laboratories Limited multilayered modified release formulation comprising amoxicillin and clavulanate
US8202542B1 (en) 2007-05-31 2012-06-19 Tris Pharma Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings
CA2687192C (en) 2007-06-04 2015-11-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
US20100035886A1 (en) 2007-06-21 2010-02-11 Veroscience, Llc Parenteral formulations of dopamine agonists
CA2690956C (en) 2007-07-01 2017-01-03 Joseph Peter Habboushe Combination tablet with chewable outer layer
US20090022798A1 (en) 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
KR20100055431A (en) 2007-07-20 2010-05-26 애보트 게엠베하 운트 콤파니 카게 Formulations of nonopioid and confined opioid analgesics
EP2200591A2 (en) 2007-09-11 2010-06-30 Ranbaxy Laboratories Limited Controlled release pharmaceutical dosage forms of trimetazidine
WO2009051819A1 (en) 2007-10-17 2009-04-23 Axxia Pharmaceuticals, Llc Polymeric drug delivery systems and thermoplastic extrusion processes for producing such systems
CN104958282B (en) 2007-11-23 2018-05-29 格吕伦塔尔有限公司 Tapentadol composition
JP2011506319A (en) 2007-12-06 2011-03-03 デュレクト コーポレーション Pain, methods useful in the treatment of inflammation associated with an arthritic condition or chronic disease,
EP2229151B1 (en) 2007-12-12 2012-08-08 Basf Se Salts of active ingredients with polymeric counter-ions
US8486448B2 (en) 2007-12-17 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
WO2009092601A1 (en) 2008-01-25 2009-07-30 Grünenthal GmbH Pharmaceutical dosage form
KR100970665B1 (en) 2008-02-04 2010-07-15 삼일제약주식회사 Sustained release tablet containing alfuzosin or its salt
JP2011513391A (en) 2008-03-05 2011-04-28 パナセア バイオテック リミテッド Sustained release pharmaceutical compositions containing mycophenolate AND METHOD
EP2100598A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease
EP2273983B1 (en) 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
KR20110031485A (en) 2008-07-03 2011-03-28 노파르티스 아게 Melt granulation process
CA2734646C (en) 2008-08-20 2016-06-28 James W. Mcginity Hot-melt extrusion of modified release multi-particulates
WO2010044842A1 (en) 2008-10-16 2010-04-22 University Of Tennessee Research Foundation Tamper resistant oral dosage forms containing an embolizing agent
KR101631140B1 (en) 2008-10-27 2016-06-20 알자 코퍼레이션 Extended release oral acetaminophen/tramadol dosage form
WO2010057036A3 (en) 2008-11-14 2011-06-09 Portola Pharmaceuticals, Inc. Solid composition for controlled release of ionizable active agents with poor aqueous solubility at low ph and methods of use thereof
WO2010066034A8 (en) 2008-12-12 2010-08-19 Paladin Labs Inc. Narcotic drug formulations with decreased abuse potential
ES2509497T3 (en) 2008-12-16 2014-10-17 Paladin Labs Inc. Controlled release formulation to avoid misuse
CA2750400A1 (en) 2009-01-26 2010-07-29 Egalet A/S Controlled release formulations with continuous efficacy
WO2010088911A1 (en) 2009-02-06 2010-08-12 Egalet A/S Pharmaceutical compositions resistant to abuse
EP2408436B1 (en) 2009-03-18 2017-02-22 Evonik Röhm GmbH Controlled release pharmaceutical composition with resistance against the influence of ethanol employing a coating comprising neutral vinyl polymers and excipients
EP2246063A1 (en) 2009-04-29 2010-11-03 Ipsen Pharma S.A.S. Sustained release formulations comprising GnRH analogues
GB0909680D0 (en) 2009-06-05 2009-07-22 Euro Celtique Sa Dosage form
WO2010149169A3 (en) * 2009-06-24 2011-06-16 Egalet A/S Controlled release formulations
WO2011008298A3 (en) 2009-07-16 2011-06-16 Nectid, Inc. Novel axomadol dosage forms
WO2011009602A1 (en) 2009-07-22 2011-01-27 Grünenthal GmbH Hot-melt extruded controlled release dosage form
ES2560210T3 (en) 2009-07-22 2016-02-17 Grünenthal GmbH Dosage form resistant to manipulation for opiádes sensitive to oxidation
KR101588896B1 (en) 2009-08-10 2016-02-15 엘지디스플레이 주식회사 A liquid crystal display device using a backlight unit and this
US20120231083A1 (en) 2010-11-18 2012-09-13 The Board Of Trustees Of The University Of Illinois Sustained release cannabinoid medicaments
CN102821757B (en) 2010-02-03 2016-01-20 格吕伦塔尔有限公司 Preparation of a powdered pharmaceutical composition by an extruder
JP2013523780A (en) 2010-04-02 2013-06-17 オールトランツ インコーポレイティド Opiate agonists and agonists - abuse deterrent transdermal formulation of the antagonist
GB201006200D0 (en) 2010-04-14 2010-06-02 Ayanda As Composition
EP2560624B1 (en) 2010-04-23 2018-07-04 KemPharm, Inc. Therapeutic formulation for reduced drug side effects
FR2960775A1 (en) 2010-06-07 2011-12-09 Ethypharm Sa Microgranules resistant to diversion
RU2607499C2 (en) 2010-09-02 2017-01-10 Грюненталь Гмбх Destruction-resistant dosage form containing anionic polymer
WO2012028319A1 (en) 2010-09-02 2012-03-08 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
CN103179956A (en) 2010-09-02 2013-06-26 格吕伦塔尔有限公司 Tamper resistant dosage form comprising an anionic polymer
US20120202838A1 (en) 2010-11-04 2012-08-09 Abbott Laboratories Drug formulations
GB201020895D0 (en) 2010-12-09 2011-01-26 Euro Celtique Sa Dosage form
CA2822769C (en) 2010-12-23 2016-10-04 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US20120321716A1 (en) 2011-02-17 2012-12-20 Michael Vachon Technology for preventing abuse of solid dosage forms
EP3287123A1 (en) 2011-03-04 2018-02-28 Grünenthal GmbH Aqueous pharmaceutical formulation of tapentadol for oral administration
US8858963B1 (en) 2011-05-17 2014-10-14 Mallinckrodt Llc Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia
US20120328697A1 (en) 2011-06-01 2012-12-27 Fmc Corporation Controlled Release Solid Dose Forms
US20140127300A1 (en) 2011-06-30 2014-05-08 Neos Therapeutics, Lp Abuse resistant drug forms
CA2839123A1 (en) 2011-07-29 2013-02-07 Grunenthal Gmbh Tamper-resistant tablet providing immediate drug release
KR20140053158A (en) 2011-07-29 2014-05-07 그뤼넨탈 게엠베하 Tamper-resistant tablet providing immediate drug release
FR2979242A1 (en) 2011-08-29 2013-03-01 Sanofi Sa Compresses against misuse, has basic paracetamol and oxycodone
US20130090349A1 (en) 2011-10-06 2013-04-11 Grünenthal GmbH Tamper-resistant oral pharmaceutical dosage form comprising opioid agonist and opioid antagonist
KR20140096062A (en) 2011-11-17 2014-08-04 그뤼넨탈 게엠베하 Tamper-resistant oral pharmaceutical dosage form comprising a pharmacologically active ingredient, an opioid antagonist and/or aversive agent, polyalkylene oxide and anionic polymer
JP6144274B2 (en) 2011-12-09 2017-06-07 パーデュー、ファーマ、リミテッド、パートナーシップ Poly (epsilon - caprolactone) and pharmaceutical dosage forms containing polyethylene oxide
US20130225697A1 (en) 2012-02-28 2013-08-29 Grunenthal Gmbh Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US20130225625A1 (en) 2012-02-28 2013-08-29 Grunenthal Gmbh Tamper-resistant pharmaceutical dosage form comprising nonionic surfactant
EP3170492A1 (en) 2012-03-02 2017-05-24 Rhodes Pharmaceuticals L.P. Tamper resistant immediate release formulations
CN104394851B (en) 2012-04-18 2017-12-01 格吕伦塔尔有限公司 Dose anti-tampering and anti - dumping pharmaceutical dosage forms
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
CN104428002B (en) 2012-05-11 2017-08-11 格吕伦塔尔有限公司 Thermoformed tamper resistant pharmaceutical dosage form containing zinc
WO2014059512A1 (en) 2012-10-15 2014-04-24 Isa Odidi Oral drug delivery formulations
EP3003279A1 (en) 2013-05-29 2016-04-13 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
CA2913209A1 (en) 2013-05-29 2014-12-04 Grunenthal Gmbh Tamper resistant dosage form with bimodal release profile
CA2817728A1 (en) 2013-05-31 2014-11-30 Pharmascience Inc. Abuse deterrent immediate release formulation
CA2917136A1 (en) 2013-07-12 2015-01-15 Grunenthal Gmbh Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US9770514B2 (en) 2013-09-03 2017-09-26 ExxPharma Therapeutics LLC Tamper-resistant pharmaceutical dosage forms
WO2015065547A1 (en) 2013-10-31 2015-05-07 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
WO2015103379A1 (en) 2013-12-31 2015-07-09 Kashiv Pharma, Llc Abuse-resistant drug formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030077297A1 (en) * 1999-02-26 2003-04-24 Feng-Jing Chen Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US20020187192A1 (en) * 2001-04-30 2002-12-12 Yatindra Joshi Pharmaceutical composition which reduces or eliminates drug abuse potential
US20070231268A1 (en) * 2004-11-24 2007-10-04 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20070190142A1 (en) * 2006-01-21 2007-08-16 Abbott Gmbh & Co. Kg Dosage forms for the delivery of drugs of abuse and related methods

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884029B2 (en) 2003-03-26 2018-02-06 Egalet Ltd. Morphine controlled release system
US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9358295B2 (en) 2009-02-06 2016-06-07 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US9730885B2 (en) 2012-07-12 2017-08-15 Mallinckrodt Llc Extended release, abuse deterrent pharmaceutical compositions
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form

Also Published As

Publication number Publication date Type
WO2013127831A1 (en) 2013-09-06 application
JP6117249B2 (en) 2017-04-19 grant
CA2864949A1 (en) 2013-09-06 application
US9655853B2 (en) 2017-05-23 grant
US20150238422A1 (en) 2015-08-27 application
US20160271066A1 (en) 2016-09-22 application
JP2015511950A (en) 2015-04-23 application
EP2819656A1 (en) 2015-01-07 application

Similar Documents

Publication Publication Date Title
US7201920B2 (en) Methods and compositions for deterring abuse of opioid containing dosage forms
US8383152B2 (en) Pharmaceutical dosage form
US7776314B2 (en) Abuse-proofed dosage system
EP1897545A1 (en) Tamper resistant oral pharmaceutical dosage forms comprising an opioid analgesic
US20060110327A1 (en) Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20080075771A1 (en) Hydrophilic opioid abuse deterrent delivery system using opioid antagonists
US20060177380A1 (en) Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20050191244A1 (en) Abuse-resistant pharmaceutical dosage form
US20110077238A1 (en) Methods and compositions for deterring abuse
US20050214223A1 (en) Abuse-safeguarded dosage form
US20090203709A1 (en) Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor
US20080248113A1 (en) Abuse-proofed oral dosage form
US8192722B2 (en) Abuse-proof dosage form
US20090005408A1 (en) Process for the production of an abuse-proofed dosage form
US8114383B2 (en) Abuse-proofed dosage form
US20050236741A1 (en) Process for the production of an abuse-proofed solid dosage form
US8075872B2 (en) Abuse-proofed dosage form
US20090004267A1 (en) Dosage Form with Impeded Abuse
US20060188447A1 (en) Process for the production of an abuse-proofed dosage form
US8114384B2 (en) Process for the production of an abuse-proofed solid dosage form
US20070183980A1 (en) Dosage form that is safeguarded from abuse
WO2006002884A1 (en) Oral dosage form safeguarded against abuse
WO2006002883A1 (en) Method for producing a solid dosage form, which is safeguarded against abuse, while using a planetary gear extruder
WO2005102286A1 (en) Method for the production of an abuse-proof, solid form of administration
US20120136021A1 (en) Oxidation-stabilized tamper-resistant dosage form

Legal Events

Date Code Title Description
AS Assignment

Owner name: GRUENENTHAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BARNSCHEID, LUTZ, DR.;REDMER, JESSICA;SCHWIER, SEBASTIAN, DR.;SIGNING DATES FROM 20130307 TO 20130311;REEL/FRAME:034484/0911