Connect public, paid and private patent data with Google Patents Public Datasets

Abuse-proofed oral dosage form

Download PDF

Info

Publication number
US20080248113A1
US20080248113A1 US12140470 US14047008A US2008248113A1 US 20080248113 A1 US20080248113 A1 US 20080248113A1 US 12140470 US12140470 US 12140470 US 14047008 A US14047008 A US 14047008A US 2008248113 A1 US2008248113 A1 US 2008248113A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
form
dosage
preferably
according
invention
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
US12140470
Inventor
Johannes Bartholomaus
Heinrich Kugelmann
Elisabeth Arkenau-Maric
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
    • A61K9/2031Organic 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
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • 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
    • 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
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2068Compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • 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
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893Tablet coating processes

Abstract

The present invention relates to an abuse-proofed, oral dosage form with controlled opioid-release for once daily administration, characterised in that it comprises at least one opioid with potential for abuse (A), at least one synthetic or natural polymer (C), optionally delayed-release matrix auxiliary substances, physiologically acceptable auxiliary substances (B), optionally a wax (D) and optionally at least one delayed-release coating, component (C) or (D) in each case exhibiting a breaking strength of at least 500 N, preferably of at least 1000 N.

Description

  • [0001]
    The present invention relates to an abuse-proofed oral dosage form with controlled opioid release for once daily administration, comprising at least one opioid with potential for abuse (A), at least one synthetic or natural polymer (C), optionally delayed-release matrix auxiliary substances, optionally physiologically acceptable auxiliary substances (B), optionally a wax (D) and optionally a delayed-release coating, component (C) or (D) in each case exhibiting a breaking strength of at least 500 N, preferably of 1000 N.
  • [0002]
    The name opioids is taken according to the invention to mean compounds which interact with at least one opioid receptor. In particular, with the exception of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, the physiologically acceptable salts or derivatives thereof, opioids are taken to mean those compounds which exhibit a potential for abuse.
  • [0003]
    Preferably, opioids are used for combating pain. To this end, analgesics are frequently used in long-term treatment, for example in the case of chronic pain or pain caused by tumours. In long-term treatment, in particular, it is important to enable the patient to enjoy a good quality of life. The measures which improve the quality of life of a patient include dosage forms which allow once daily administration. However, because of the relatively large quantity of opioid, such dosage forms, which provide delayed release of the active ingredient, are particularly attractive to the abuser who wishes to induce the desired state of narcosis or euphoria as quickly as possible.
  • [0004]
    Since, however, delayed-release dosage forms containing opioids with potential for abuse do not usually give rise to the kick desired by the abuser when taken orally even in abusively high quantities, these dosage forms for example in the form of tablets or capsules are also comminuted, e.g. ground, and sniffed by the abuser for the purpose of abuse or the active ingredients are extracted from the powder obtained in this way by means of an aqueous liquid and the resultant solution is administered parenterally, in particular intravenously, optionally after filtration through cotton wool or cellulose wadding. This type of administration produces even more accelerated increase in opioid levels than with oral or nasal abuse, with the result desired by the abuser, namely the “kick” or “rush”.
  • [0005]
    U.S. Pat. No. 4,070,494 proposed adding a swellable agent to the dosage form in order to prevent abuse. When water is added to extract the opioid, this agent swells and ensures that the filtrate separated from the gel contains only a small quantity of active ingredient.
  • [0006]
    The multilayer tablet disclosed in WO 95/20947 is based on a similar approach to preventing parenteral abuse, said tablet containing the opioid with potential for abuse and at least one gel former, each in different layers.
  • [0007]
    WO 03/015531 A2 discloses another approach to preventing parenteral abuse. A dosage form containing an analgesic opioid and a dye as an aversive agent is described therein. The colour released by tampering with the dosage form is intended to discourage the abuser from using the dosage form which has been tampered with.
  • [0008]
    Another known option for complicating abuse involves adding to the dosage form an antagonist to the opioid, such as for example naloxone or naltexone, or compounds which cause a physiological defense response, such as for example ipecacuanha (ipecac) root, or bitter substances.
  • [0009]
    However, since in most cases of abuse of dosage forms with delayed-release of an opioid, it is still necessary to pulverise the dosage form, it was the object of the present invention to complicate or prevent the pulverisation preceding abuse of the dosage form comprising the means conventionally available for potential abuse and accordingly to provide a dosage form with controlled release of opioids with potential for abuse which ensures the desired therapeutic effect when correctly administered once daily, but from which the opioids cannot be converted into a form suitable for abuse simply by pulverisation.
  • [0010]
    This object was achieved by the preparation of the abuse-proofed oral dosage form, according to the invention, with controlled release of at least one opioid for once daily administration, which dosage form comprises, in addition to at least one opioid and/or at least one of the physiologically acceptable compounds thereof, preferably salts or derivatives, preferably esters or ethers, with potential for abuse (A), at least one synthetic or natural polymer (C), optionally delayed-release matrix auxiliary substances, optionally physiologically acceptable auxiliary substances (B), optionally a wax (D), and optionally at least one delayed-release coating, component (C) or (D) in each case exhibiting a breaking strength of at least 500 N, preferably of 1000 N.
  • [0011]
    By using components (C) and optionally (D) with the stated minimum breaking strength, preferably in such quantities that the dosage form also exhibits such a minimum breaking strength, pulverisation of the dosage form with conventional means and thus subsequent abuse, preferably nasal or parenteral abuse, may be complicated considerably or prevented.
  • [0012]
    Preferably, the components (C) and optionally (D) are present in such quantities that the dosage form exhibits a breaking strength of at least 500 N, preferably of at least 1000 N.
  • [0013]
    Without sufficient comminution of the dosage form, non-hazardous parenteral, in particular intravenous or nasal administration is impossible or extraction of the active ingredient takes the abuser too long, or no or an inadequate kick is obtained on abusive oral administration, since spontaneous release does not occur.
  • [0014]
    According to the invention, comminution is taken to mean pulverisation of the dosage form with conventional means which are available to an abuser, such as for example a pestle and mortar, a hammer, a mallet or other usual means for pulverisation by application of force.
  • [0015]
    The dosage form according to the invention is thus suitable for preventing parenteral, nasal and/or oral abuse of opioids with potential for abuse.
  • [0016]
    Opioids with potential for abuse are known to the person skilled in the art, as are the dosages thereof to be used and processes for the production thereof, and may be present in the dosage form according to the invention as such, in the form of the corresponding derivatives thereof, 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, as racemates or stereoisomers. The dosage form according to the invention is also suitable for the administration of a plurality of opioids. Preferably it is used to administer to humans or mammals, preferably to humans, a particular opioid for combating pain for a duration of at least 24 hours.
  • [0017]
    The dosage forms according to the invention are very particularly suitable for preventing the abuse of an opioid which is selected from the group consisting of N-{1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide (alfentanil), allylprodine, alphaprodine, anileridine, bemidone, benzylmorphine, bezitramide, 17-cyclopropylmethyl-4,5a-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol (buprenorphine), butorphanol, carfentanil, clofedanol, clonitazene, (−)-methyl-[3β-benzoyloxy-2β(1aH,5aH)-tropane carboxylate] (cocaine), 4,5a-epoxy-3-methoxy-17-methyl-7-morphinen-6a-ol (codeine), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate (dextropropoxyphene), dezocine, diampromide, diamorphone, 4,5a-epoxy-3-methoxy-17-methyl-6a-morphinanol (dihydrocodeine), 4,5a-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, dihydromorphone, eptazocine, ethoheptazine, ethylmethylthiambutene, 4,5a-epoxy-3-ethoxy-17-methyl-7-morphinen-6a-ol (ethylmorphine), etonitazene, 4,5-epoxy-7-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol (etorphine), fenpipramide, N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl), heroin, 4,5-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5a-epoxy-3-hydroxy-17-methyl-6-morphinanone (hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan, 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol), (−)-6-dimethylamino-4,4-diphenol-3-heptanone (levomethadone), (−)-17-methyl-3-morphinanol (levorphanol), levophenacylmorphane, levoxemacin, lofentanil, meperidine, 2-methyl-2-propyltrimethylene dicarbamate, meptazinol, metazocine, methadone, methylmorphine, metapon, 3-methylfentanyl, 4-methylfentanyl, 4,5a-epoxy-17-methyl-7-morphinen-3,6a-diol (morphine), myrophine, nalbuphene, nalorphine, narceine, nicomorphine, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone), normorphine, norpipanone, the exudation from plants belonging to the species Papaver somniferum (opium), 4,5a-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, plants and parts of plants belonging to the species Papaver somniferum (including the subspecies setigerum) (Papaver somniferum), papaveretum, 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol (pentazocine), ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate) (pethidine), phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine, pholcodeine, 1′-3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide (piritramide), proheptazine, promedol, properidine, propoxyphene, methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]-propanoate} (remifentanil), N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide (sufentanil), ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine, cis and trans), tramadol, (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-isobutoxy-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-trifluoromethyl-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-dimethylaminomethyl-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 together with corresponding stereoisomeric compounds, in each case the corresponding derivatives thereof, in particular amides, esters or ethers, and in each case the physiologically acceptable compounds thereof, in particular the salts and solvates thereof, particularly preferably hydrochlorides.
  • [0018]
    The dosage form according to the invention is particularly suitable for preventing abuse of an opioid active ingredient selected from among the group comprising oxycodone, hydromorphone, morphine, tramadol and the physiologically acceptable derivatives or compounds thereof, preferably the salts and solvates thereof, preferably the hydrochlorides thereof.
  • [0019]
    Furthermore, the dosage form according to the invention is particularly suitable for preventing the abuse of an opioid active ingredient selected from among the group comprising (2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, the physiologically acceptable salts thereof, preferably hydrochlorides, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and the physiologically acceptable derivatives thereof, preferably ethers, esters or amides.
  • [0020]
    These compounds and the process for the production thereof are described in EP-A-693475 and EP-A-780369 respectively. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
  • [0021]
    The dosage in the delayed-release dosage form is selected such that once daily administration is ensured. The corresponding dosages are known to the person skilled in the art.
  • [0022]
    In order to achieve the necessary breaking strength of the dosage form according to the invention, at least one synthetic, semi-synthetic or natural polymer (C) is used which has a breaking strength, measured using the method disclosed in the present application, of at least 500 N, preferably of 1000 N. Preferably, at least one polymer is selected for this purpose from among the group comprising polyalkylene oxides, preferably polymethylene oxides, polyethylene oxides, polypropylene oxides, polyolefins, preferably polyethylenes, polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes, polymethacrylates, the copolymers thereof, and mixtures of at least two of the stated polymer classes or polymers. Particularly preferably, a water-soluble or water-swellable polymer is used. The polymers are distinguished by a molecular weight of at least 0.5 million, preferably of at least 1 million to 15 million, determined by rheological measurement. Particularly preferably suitable are thermoplastic polyalkylene oxides, such as polyethylene oxides, with a molecular weight of at least 0.5 million, preferably of at least 1 million to 15 million, determined by rheological measurement. The polyethylene oxides have a viscosity at 25° C. of 4500 to 17600 cP, measured on a 5 wt. % aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt. % aqueous solution using the stated viscosimeter (but with spindle no. 1 or 3/rotational speed 10 rpm) or of 1650 to 10000 cP, measured on a 1 wt. % aqueous solution using the stated viscosimeter (but with spindle no. 2/rotational speed 2 rpm).
  • [0023]
    The polymers are preferably used as powder to produce the dosage form according to the invention.
  • [0024]
    Moreover, in addition to the above-stated polymers, at least one natural, semi-synthetic or synthetic wax (D) with a breaking strength, measured using the method disclosed in the present application, of at least 500 N, preferably of 1000 N, may additionally be used to achieve the necessary breaking strength of the dosage form according to the invention. Waxes with a softening point of at least 60° C. are preferred. Carnauba wax and beeswax are particularly preferred. Carnauba wax is very particularly preferred. Carnauba wax is a natural wax which is obtained from the leaves of the carnauba palm and has a softening point of at most 90° C. When additionally using the wax component, the latter is used together with at least one polymer (C), preferably a polyethylene oxide, in such quantities that the dosage form exhibits a breaking strength of at least 500 N, preferably of 1000 N, measured using the method stated in the present application.
  • [0025]
    The dosage forms according to the invention are distinguished in that, they cannot be pulverised using conventional comminution tools, such as grinders, due to their hardness. Oral, parenteral, in particular intravenous, or nasal abuse is complicated a very great deal thereby, if not ruled out altogether. However, in order to prevent any possible abuse of the dosage forms according to the invention, in a preferred embodiment, the dosage forms according to the invention may contain further abuse-complicating or -preventing agents as auxiliary substances (B).
  • [0026]
    Thus, the abuse-proofed dosage form according to the invention may comprise, in addition to at least one opioid, at least one polymer (C) and optionally at least one wax (D), at least one of the following components (a)-(f) as auxiliary substances (B):
    • (a) at least one substance which irritates the nasal passages and/or pharynx,
    • (b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, preferably as an aqueous extract obtained from the dosage form, forms a gel which preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid,
    • (c) at least one antagonist for the present opioids with potential for abuse,
    • (d) at least one emetic,
    • (e) at least one dye as an aversive agent,
    • (f) at least one bitter substance.
  • [0033]
    The components (a) to (f) are each suitable on their own as additional protection of the dosage form according to the invention against abuse. Accordingly, component (a) is preferably suitable for proofing the dosage form against nasal, oral and/or parenteral, preferably intravenous, abuse, component (b) is preferably suitable for proofing against parenteral, particularly preferably intravenous and/or nasal abuse, component (c) is preferably suitable for proofing against nasal and/or parenteral, particularly preferably intravenous, abuse, component (d) is preferably suitable for proofing against parenteral, particularly preferably intravenous, and/or oral and/or nasal abuse, component (e) is suitable as a visual deterrent against oral or parenteral abuse and component (f) is suitable for proofing against oral or nasal abuse. Through the co-use of at least one of the above-stated components, it is possible to complicate abuse even more effectively for the dosage forms according to the invention.
  • [0034]
    In one embodiment, the dosage form according to the invention may also comprise two or more of components (a)-(f) in a combination, preferably in the combinations (a), (b) and optionally (c) and/or (f) and/or (e) or (a), (b) and optionally (d) and/or (f) and/or (e).
  • [0035]
    In another embodiment, the dosage form according to the invention may comprise all of components (a)-(f).
  • [0036]
    If the dosage form according to the invention comprises component (a) as additional protection against abuse, substances which irritate the nasal passages and/or pharynx which may be considered according to the invention are any substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the abuser that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding opioid(s) and/or opiate(s), for example due to increased nasal secretion or sneezing. These substances which conventionally irritate the nasal passages and/or pharynx may also bring about a very unpleasant sensation or even unbearable pain when administered parenterally, in particular intravenously, such that the abuser does not wish to or cannot continue taking the substance.
  • [0037]
    Particularly suitable substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Appropriate substances and the quantities thereof which are conventionally to be used are known per se to the person skilled in the art or may be identified by simple preliminary testing.
  • [0038]
    The substance which irritates the nasal passages and/or pharynx of component (a) is preferably based on one or more constituents or one or more plant parts of at least one hot substance drug.
  • [0039]
    Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in “Pharmazeutische Biologie—Drogen und ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
  • [0040]
    One or more constituents of at least one hot substance drug selected from the group consisting of Allii sativi bulbus (garlic), Asari rhizoma curn herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Japanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root), particularly preferably from the group consisting of Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigri fructus (pepper) may preferably be added as component (a) to the dosage form according to the invention.
  • [0041]
    The constituents of the hot substance drugs preferably comprise o-methoxy(methyl)phenol compounds, acid amide compounds, mustard oils or sulfide compounds or compounds derived therefrom.
  • [0042]
    Particularly preferably, at least one constituent of the hot substance drugs is selected from the group consisting of myristicin, elemicin, isoeugenol, a-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids, preferably capsaicin, capsaicin derivatives, such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzyl mustard oil, methylmercapto mustard oil or methylsulfonyl mustard oil, and compounds derived from these constituents.
  • [0043]
    The dosage form according to the invention may preferably contain the plant parts of the corresponding hot substance drugs in a quantity of 0.01 to 30 wt. %, particularly preferably of 0.1 to 0.5 wt. %, in each case relative to the total weight of the dosage unit. If one or more constituents of corresponding hot substance drugs are used, the quantity thereof in a dosage unit according to the invention preferably amounts to 0.001 to 0.005 wt. %, relative to the total weight of the dosage unit. A dosage unit is taken to mean a separate or separable administration unit, such as for example a tablet or a capsule.
  • [0044]
    Another option for preventing abuse of the dosage form according to the invention consists in adding at least one viscosity-increasing agent as a further abuse-preventing component (b) to the dosage form, which, with the assistance of a necessary minimum quantity of an aqueous liquid, preferably as an aqueous extract obtained from the dosage form, forms a gel which is virtually impossible to administer safely and preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid
  • [0045]
    For the purposes of the present application, visually distinguishable means that the opioid- or opiate-containing gel formed with the assistance of a necessary minimum quantity of aqueous liquid, when introduced, preferably with the assistance of a hypodermic needle, into a further quantity of aqueous liquid at 37° C., remains substantially insoluble and cohesive and cannot straightforwardly be dispersed in such a manner that it can safely be administered parenterally, in particular intravenously. The material preferably remains visually distinguishable for at least one minute, preferably for at least 10 minutes.
  • [0046]
    Increasing the viscosity to a gel makes it more difficult or even impossible for it to be passed through a needle or injected. If the gel remains visually distinguishable, this means that the gel obtained on introduction into a further quantity of aqueous liquid, for example by injection into blood, initially remains in the form of a largely cohesive thread, which, while it may indeed be broken up mechanically into smaller fragments, cannot be dispersed or even dissolved in such a manner that it can safely be administered parenterally, in particular intravenously. In combination with at least one further present component (a), (d) to (f), this additionally leads to unpleasant burning, vomiting, bad flavour and/or visual deterrence.
  • [0047]
    Intravenous administration of such a gel would most probably result in obstruction of blood vessels, associated with serious damage to the health of the abuser.
  • [0048]
    In order to verify whether a viscosity-increasing agent is suitable as component (b) for use in the dosage form according to the invention, the opioid(s) and/or opiate(s) is(are) mixed with the viscosity-increasing agent and suspended in 10 ml of water at a temperature of 25° C. If this results in the formation of a gel which fulfills the above-stated conditions, the corresponding viscosity-increasing agent is suitable for additionally preventing or averting abuse of the dosage forms according to the invention.
  • [0049]
    If component (b) is added to the dosage form obtained by the process according to the invention, preferably one or more viscosity-increasing agents are used, which are selected from the group comprising microcrystalline cellulose with 11 wt. % carboxymethylcellulose sodium (Avicel® RC 591), carboxymethylcellulose sodium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 P®), polyacrylic acid (Carbopol® 980 NF, Carbopol® 981), locust bean flour (Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1), pectins, preferably from citrus fruits or apples (Cesapectin® HM Medium Rapid Set), waxy maize starch (C*Gel 04201®), sodium alginate (Frimulsion ALG (E401)®), guar flour (Frimulsion BM®, Polygum 26/1-75®), iota-carrageenan (Frimulsion D021®), karaya gum, gellan gum (Kelcogel F®, Kelcogel Lγ100®), galactomannan (Meyprogat 150®), tara stone flour (Polygum 43/1®), propylene glycol alginate (Protanal-Ester SD-LB®), sodium-hyaluronate, tragacanth, tara gum (Vidogum SP 200®), fermented polysaccharide welan gum (K1A96), xanthans such as xanthan gum (Xantural 180®). Xanthans are particularly preferred. The names stated in brackets are the trade names by which the materials are known commercially. In general, a quantity of 0.1 to 5 wt. %, relative to the total quantity of the dosage form, of the stated viscosity-increasing agent(s) is sufficient to fulfill the above-stated conditions.
  • [0050]
    The component (b) viscosity-increasing agents, where provided, are preferably present in the dosage form according to the invention in quantities of =5 mg per dosage unit, i.e. per administration unit.
  • [0051]
    In a particularly preferred embodiment of the present invention, the viscosity-increasing agents used as component (b) are those which, preferably by extraction from the dosage form with the necessary minimum quantity of aqueous liquid, form a gel which encloses air bubbles. The resultant gels are distinguished by a turbid appearance, which provides the potential abuser with an additional optical warning and discourages him/her from administering the gel parenterally.
  • [0052]
    The component (C) may also optionally serve as an additional viscosity-increasing agent, which forms a gel with the assistance of a necessary minimum quantity of aqueous liquid.
  • [0053]
    It is also possible, to arrange the viscosity-increasing component and the other constituents of the dosage form according to the invention spatially separately from one another.
  • [0054]
    Moreover, in order to discourage and prevent abuse, the dosage form according to the invention may furthermore comprise component (c), namely one or more antagonists for the opioid(s) and/or opiate(s) with potential for abuse, wherein the antagonist is preferably spatially separated from the remaining constituents of the dosage form according to the invention and, when correctly used, do not exert any effect.
  • [0055]
    Suitable antagonists for preventing the abuse of opioids are known per se to the person skilled in the art and may be present in the dosage form according to the invention 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.
  • [0056]
    The antagonist used is preferably selected from the group comprising naloxone, naltrexone, nalmefene, nalide and nalmexone, 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. The corresponding antagonists, where component (c) is provided, are preferably used in a quantity of =1 mg, particularly preferably in a quantity of 3 to 100 mg, very particularly preferably in a quantity of 5 to 50 mg per dosage form, i.e. per administration unit.
  • [0057]
    The dosage form according to the invention preferably comprises the antagonist component in a conventional therapeutic dose known to the person skilled in the art, particularly preferably in a quantity of twice to three times this dose per administration unit.
  • [0058]
    If the combination for additional discouragement and prevention of abuse of the dosage form according to the invention comprises component (d), it may comprise at least one emetic, which is preferably present in a spatially separated arrangement from the other components of the dosage form according to the invention and, when correctly used, is intended not to exert its effect in the body.
  • [0059]
    Suitable emetics for additionally preventing abuse of an opioid are known per se to the person skilled in the art and may be present in the dosage form according to the invention 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.
  • [0060]
    An emetic based on one or more constituents of ipecacuanha (ipecac) root, preferably based on the constituent emetine may preferably be considered for the dosage form according to the invention, as are, for example, described in “Pharmazeutische Biologie—Drogen und ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New York 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
  • [0061]
    The dosage form according to the invention may preferably comprise the emetic emetine as component (d), preferably in a quantity of =3 mg, particularly preferably of =10 mg and very particularly preferably in a quantity of =20 mg per dosage form, i.e. administration unit.
  • [0062]
    Apomorphine may likewise preferably be used as an emetic for additional abuse-proofing, preferably in a quantity of preferably =3 mg, particularly preferably of =5 mg and very particularly preferably of =7 mg per administration unit.
  • [0063]
    If the dosage form according to the invention contains component (e) as a further abuse-preventing auxiliary substance, the use of such a dye brings about an intense coloration of a corresponding aqueous solution, in particular when the attempt is made to extract the opioid(s) for parenteral, preferably intravenous administration, which coloration may act as a deterrent to the potential abuser. Oral abuse, which conventionally begins by means of aqueous extraction of the opioid(s), may also be prevented by this coloration. Suitable dyes and the quantities required for the necessary deterrence may be found in WO 03/015531, wherein the corresponding disclosure should be deemed to be part of the present disclosure and is hereby introduced as a reference.
  • [0064]
    If the dosage form according to the invention contains component (f) as a further abuse-preventing auxiliary substance, this addition of at least one bitter substance and the consequent impairment of the flavour of the dosage form additionally prevents oral and/or nasal abuse.
  • [0065]
    Suitable bitter substances and the quantities effective for use may be found in US-200310064099, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference. Suitable bitter substances are preferably aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, preferably aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate (Bitrex®)). Denatonium benzoate is particularly preferably used.
  • [0066]
    To ensure once daily administration, the dosage form according to the invention comprises the opioid (s) and/or opiate(s) with potential for abuse at least in part in delayed-release form, wherein the delayed release of the active ingredient may be achieved with the assistance of conventional materials and processes known to the person skilled in the art, for example by embedding the opioid(s) in a delayed-release matrix or by applying one or more delayed-release coatings. Opioid release must, however, be controlled such that the above-stated conditions are fulfilled in each case, for example that, in the event of correct administration of the dosage form, the opioid(s) are virtually completely released before the optionally present component (c) and/or (d) can exert an impairing effect. In particular, release of the opioid must ensure analgesic action for at least 24 hours.
  • [0067]
    If release of the opioid(s) from the dosage form according to the invention is controlled with the assistance of at least one delayed-release coating, the delayed-release coating may consist of conventional materials known to the person skilled in the art.
  • [0068]
    In a preferred embodiment of the dosage form according to the invention, the delayed-release coating is preferably based on a water-insoluble, optionally modified natural and/or synthetic polymer or on a natural, semi-synthetic or synthetic wax or on a fat or a fatty alcohol or on a mixture of at least two of the above-stated components.
  • [0069]
    To produce a delayed-release coating, the water-insoluble polymers preferably comprise poly(meth)acrylates, particularly preferably poly(C1-4)-alkyl(meth)acrylates, poly(C1-4)-dialkylamino-(C1-4)-alkyl(meth)acrylates and/or the copolymers thereof, very particularly preferably copolymers of ethyl acrylate and methyl methacrylate with a molar ratio of monomers of 2:1 (Eudragit NE30D®), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium methyl methacrylate chloride with a molar ratio of monomers of 1:2:0.1 (Eudragit RS®), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium methyl methacrylate chloride with a molar ratio of monomers of 1:2:0.2 (Eudragit RL®) or a mixture of at least two of these above-stated copolymers. These coating materials are commercially obtainable as 30 wt. % aqueous latex dispersions, i.e. as Eudragit RS30D®, Eudragit NE30D® or Eudragit RL30D® and are preferably also used as such as coating material.
  • [0070]
    Polyvinyl acetates optionally in combination with further auxiliary substances may likewise preferably be used as water-insoluble polymers for the production of a delayed-release coating for the dosage forms according to the invention. These are commercially obtainable as aqueous dispersions containing 27 wt. % of polyvinyl acetate, 2.5 wt. % of povidone and 0.3 wt. % of sodium lauryl sulfate (Kollicoat SR 30 D®).
  • [0071]
    In a further preferred embodiment, the delayed-release coatings for the dosage form according to the invention are based on water-insoluble cellulose derivatives, preferably alkylcelluloses such as for example ethylcellulose, or cellulose esters, such as for example cellulose acetate. The coatings of ethylcellulose or cellulose acetate are preferably applied from an aqueous pseudolatex dispersion. Aqueous ethylcellulose pseudolatex dispersions are commercially obtainable as 30 wt. % dispersions (Aquacoat®) or as 25 wt. % dispersions (Surelease®).
  • [0072]
    If the delayed-release coating is based a water-insoluble, optionally modified natural and/or synthetic polymer, the coating dispersion or solution may comprise, in addition to the corresponding polymer, a conventional physiologically acceptable plasticiser known to the person skilled in the art, in order to reduce the necessary minimum film temperature.
  • [0073]
    Suitable plasticisers are for example lipophilic diesters from an aliphatic or aromatic dicarboxylic acid with C6-C40 and an aliphatic alcohol with C1-C8, such as for example dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic esters of citric acid, such as triethyl citrate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate, polyethylene glycols, propylene glycol, esters of glycerol, such as for example triacetin, Myvacet® (acetylated mono- and diglycerides, C23H44O5 to C25H47O7), medium-chain triglycerides (Miglyol®), oleic acid or mixtures of at least two of the stated plasticisers. Aqueous dispersions of Eudragit RS® and optionally Eudragit RL® preferably contain triethyl citrate.
  • [0074]
    Preferably, a delayed-release coating for the dosage form according to the invention contains plasticisers in quantities of 5 to 50 wt. %, particularly preferably of 10 to 40 wt. % and very particularly preferably of 10 to 30 wt. %, relative to the quantity of polymer used. In individual cases, for example for cellulose acetate, it is also possible to use larger quantities of plasticisers.
  • [0075]
    Moreover, a delayed-release coating may comprise further conventional auxiliary substances known to the person skilled in the art, such as for example slip agents, preferably talcum or glycerol monostearate, colouring pigments, preferably iron oxides or titanium dioxide, or surfactants, such as for example Tween 80®.
  • [0076]
    The release profile obtained for the opioid(s) may furthermore be adjusted by conventional options known to the person skilled in the art, such as for example the thickness of the coating or by the use of further auxiliary substances as constituents of the coating. Suitable auxiliary substances are for example hydrophilic or pH-dependent pore formers, such as for example sodium carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, lactose, polyethylene glycol or mannitol or water-soluble polymers, such as for example polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • [0077]
    The dosage forms according to the invention for release of the opioid(s) may additionally also comprise a coating which is resistant to gastric juices, which dissolves in pH-dependent manner. This coating makes it possible to ensure that the dosage forms according to the invention pass through the stomach undissolved and the opioid(s) is (are) not released until it (they) reach(es) the intestine.
  • [0078]
    The coating resistant to gastric juices is preferably based on methacrylic acid/alkyl methacrylate copolymers, preferably methyl methacrylate, such as methacrylic acid or ethylene methacrylate copolymers with a molar ratio of the particular monomers of 1:1 to 1:2, such as Eudragit L® Eudragit S®, Eudragit L30D-55®, Eudragit FS®.
  • [0079]
    A delayed-release coating may be applied by conventional methods known to the person skilled in the art, such as for example by spraying of solutions, dispersions or suspensions, by melt methods or by powder application methods. The solutions, dispersions or suspensions may be used in the form of aqueous or organic solutions or dispersions. Aqueous dispersions are preferably used in this connection. Organic solvents which may be used are alcohols, for example ethanol or isopropanol, ketones, such as for example acetone, esters, for example ethyl acetate, wherein alcohols and ketones are preferably used. The coating methods are known from the prior art, for example H. Sucker, Georg Thieme Verlag, 1991, pages 347 et seq. They are hereby introduced as a reference and are accordingly deemed to be part of the disclosure.
  • [0080]
    If the dosage form according to the invention is in multiparticulate form, the delayed-release coating is preferably applied in such a manner that the multiparticulate forms containing the opioid(s) are coated, after the production thereof, with the particular polymers and optionally further auxiliary substances from aqueous and/or organic media, preferably from aqueous media, with the assistance of the fluidised bed method and the coating is preferably simultaneously dried at conventional temperatures in the fluidised bed.
  • [0081]
    A poly(meth)acrylate-based coating is preferably dried at temperatures in the range from 30 to 50° C., particularly preferably from 35 to 45° C. For cellulose-based coatings, such as for example ethylcellulose, drying preferably proceeds at a temperature in the range from 50 to 80° C., particularly preferably in the range from 55 to 65° C. If necessary, drying may additionally be followed by a temperature controlled treatment in order to obtain a stable release profile.
  • [0082]
    Delayed release of the active ingredient from the dosage form according to the invention may also be achieved by embedding the opioid(s) in a delayed-release matrix.
  • [0083]
    Materials which may be used for a delayed-release matrix are preferably physiologically acceptable, hydrophilic polymers, preferably cellulose ethers, cellulose esters and/or acrylic resins. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the salts, amides or esters thereof, are particularly preferably used.
  • [0084]
    Where hydrophobic compounds are used as the delayed-release matrix, fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof may be used. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof are particularly preferably used as hydrophobic compounds.
  • [0085]
    It is also possible to use mixtures of the above-stated hydrophilic and hydrophobic matrix materials.
  • [0086]
    Component (b) as a viscosity-increasing agent may preferably also serve as a material for a delayed-release matrix, if this is permitted by the structure of the dosage form according to the invention.
  • [0087]
    Component (C) and the optionally present component (D), which serve to obtain the breaking strength of at least 500 N, preferably of 1000 N, which is necessary according to the invention, may optionally also serve as additional delayed-release matrix materials.
  • [0088]
    Corresponding delayed-release compounds and methods for the delayed release of the dosage forms according to the invention 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 corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
  • [0089]
    The dosage form according to the invention may assume multiparticulate form, preferably the form of microtablets, micropellets, granules, spheroids, beads or pellets, optionally packaged in capsules or press-moulded into tablets. The multiparticulate forms preferably have a size or size distribution in the range from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm. Depending on the desired dosage form, conventional auxiliary substances (B) are optionally also used for the formulation of the dosage form.
  • [0090]
    In a particularly preferred embodiment, the dosage form according to the invention assumes the form of a tablet, a capsule or is in the form of an oral osmotic therapeutic system (OROS), preferably if at least one further abuse-preventing component (a)-(f) is also present.
  • [0091]
    The abuse-proofed, solid dosage form according to the invention is preferably produced by mixing components (A), (C) and optionally (D), optionally at least one of the additional abuse-preventing components (a)-(f) and optionally further auxiliary substances (B), in particular the delayed-release matrix compounds, and, with preceding or simultaneous exposure to heat, forming the resultant mixture, optionally after pelletisation, into the dosage form by application of force.
  • [0092]
    Pelletisation may be performed by a melt method or by wet pelletisation.
  • [0093]
    Mixing of components (A), (C) and optionally (D) and of the optionally present further components (a)-(f) and optionally the further auxiliary substances (B), in particular the delayed-release matrix compounds, may proceed 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.
  • [0094]
    The resultant mixture is preferably directly formed into the dosage form according to the invention by application of force with preceding or simultaneous exposure to heat. The mixture may, for example, be formed into tablets by direct tabletting. In direct tabletting with preceding exposure to heat, the material to be press-moulded is heated immediately prior to tabletting at least to the softening temperature of component (C) and then pressed.
  • [0095]
    The resultant mixture of components (A), (C), optionally (D), the optionally present components (a) to (f) and optionally further auxiliary substances (B), in particular the delayed-release matrix compounds, may also first be pelletised and then formed into the dosage form according to the invention by application of force with preceding or simultaneous exposure to heat.
  • [0096]
    It is also possible to form the resultant mixture containing one or more opioid(s) with potential for abuse (A) and optionally physiologically acceptable auxiliary substances (B), such as components (a) to (f) and optionally the delayed-release matrix compounds and at least one synthetic or natural polymer (C) and optionally a wax (D), into the dosage form by application of force, optionally to singulate the formed articles and optionally in each case to grade them by size and, after or during heating to at least the softening point of component (C), to expose them to force until the formed articles exhibit a breaking hardness of at least 500 N, preferably of 1000 N, optionally to provide them with a cover, which optionally has delayed-release properties, and optionally to mix all the formed articles together again.
  • [0097]
    If components (c) and/or (d) and/or (f) are present in the dosage form according to the invention, care must be taken to ensure that they are formulated in such a manner or are present in such a low dose that, when correctly administered, the dosage form is able to bring about virtually no effect which impairs the patient or the efficacy of the opioid(s).
  • [0098]
    If the dosage form according to the invention contains component (d) and/or (f), the dosage must be selected such that, when correctly orally administered, no negative effect is caused. If, however, the intended dosage of the dosage form is exceeded inadvertently, in particular by children, or in the event of abuse, nausea or an inclination to vomit or a bad flavour are produced. The particular quantity of component (d) and/or (f) which can still be tolerated by the patient in the event of correct oral administration may be determined by the person skilled in the art by simple preliminary testing.
  • [0099]
    If, however, irrespective of the fact that the dosage form according to the invention is virtually impossible to pulverise, the dosage form containing the components (c) and/or (d) and/or (f) is provided with protection, these components should preferably be used at a dosage which is sufficiently high that, when abusively administered, they bring about an intense negative effect on the abuser. This is preferably achieved by spatial separation of at least the opioid(s) from components (c) and/or (d) and/or (f), wherein the opioid(s) is/are present in at least one subunit (X) and components (c) and/or (d) and/or (f) is/are present in at least one subunit (Y), and wherein, when the dosage form is correctly administered, components (c), (d) and (f) do not exert their effect on taking and/or in the body and the remaining components of the formulation, in particular component (C), are identical.
  • [0100]
    If the dosage form according to the invention comprises at least 2 of components (c) and (d) or (f), these may each be present in the same or different subunits (Y). Preferably, when present, all the components (c) and (d) and (f) are present in one and the same subunit (Y).
  • [0101]
    In the case of spatial separation into subunit(s) (X) and subunits (Y) and irrespective of the arrangement of these subunits in the dosage form, a subunit (X) contains the active ingredient in delayed-release form, such that said active ingredient ensures controlled release with once daily administration.
  • [0102]
    For the purposes of the present invention, subunits are solid formulations, which in each case, apart from conventional auxiliary substances known to the person skilled in the art, contain the opioid(s), at least one polymer (C) and optionally at least one of the optionally present components (a) and/or (b) and/or (e) or in each case at least one polymer (C) and the antagonist(s) and/or emetic(s) and/or component (e) and/or component (f) and optionally at least one of the optionally present components (a) and/or (b) and optionally the delayed-release matrix compounds. Care must here be taken to ensure that each of the subunits is formulated in accordance with the above-stated process.
  • [0103]
    One substantial advantage of the separated formulation of the opioid(s) from components (c) or (d) or (f) in subunits (X) and (Y) of the dosage form according to the invention is that, when correctly administered, components (c) and/or (d) and/or (f) are hardly released on taking and/or in the body or are released in such small quantities that they exert no effect which impairs the patient or therapeutic success or, on passing through the patient's body, they are only liberated in locations where they cannot be sufficiently absorbed to be effective. When the dosage form is correctly administered, preferably hardly any of components (c) and/or (d) and/or (f) is released into the patient's body or they go unnoticed by the patient.
  • [0104]
    The person skilled in the art will understand that the above-stated conditions may vary as a function of the particular components (c), (d) and/or (f) used and of the formulation of the subunits or the dosage form. The optimum formulation for the particular dosage form may be determined by simple preliminary testing. What is vital is that each subunit contains the polymer (C) and has been formulated in the stated manner.
  • [0105]
    Should, contrary to expectations, the abuser succeed in comminuting such a dosage form according to the invention, which comprises components (c) and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose of abusing the opioid(s) and obtain a powder which is to be extracted with a suitable extracting agent, not only the opioid(s) but also the particular component (c) and/or (e) and/or (f) and/or (d) will be obtained in a form in which it cannot readily be separated from the opioid(s), such that when the dosage form which has been tampered with is administered, in particular by oral and/or parenteral administration, it will exert its effect immediately on taking and/or in the body combined with an additional negative effect on the abuser corresponding to component (c) and/or (d) and/or (f) or, when the attempt is made to extract the active ingredient, the coloration will act as a deterrent and so prevent abuse of the dosage form.
  • [0106]
    A dosage form according to the invention, in which the opioid(s) is/are spatially separated from components (c), (d) and/or (e), preferably by formulation in different subunits, may be formulated in many different ways, wherein the corresponding subunits may each be present in the dosage form according to the invention in any desired spatial arrangement relative to one another, provided that the above-stated conditions for the release of components (c) and/or (d), on the one hand, and for release of the opioid, namely controlled release for once daily administration, on the other, are fulfilled.
  • [0107]
    The person skilled in the art will understand that component(s) (a) and/or (b) which are optionally also present may preferably be formulated in the dosage form according to the invention both in the particular subunits (X) and (Y) and in the form of independent subunits (Y′) corresponding to subunits (X) and (Y), provided that neither the abuse-proofing nor the opioid release over 24 hours in the event of correct administration is impaired by the nature of the formulation and the polymer (C) is included in the formulation and formulation is carried out in accordance with the above-stated processes.
  • [0108]
    In a preferred embodiment of the dosage form according to the invention, subunits (X) and (Y) are present in multiparticulate form, wherein microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets are preferred and the same form, i.e. shape, is selected for both subunit (X) and subunit (Y), such that it is not possible to separate subunits (X) from (Y) by mechanical selection. The multiparticulate forms are preferably of a size in the range from 0.1 to 3 mm, preferably of 0.5 to 2 mm.
  • [0109]
    The subunits (X) and (Y) in multiparticulate form may also preferably be packaged in a capsule or be press-moulded into a tablet, wherein the final formulation in each case proceeds in such a manner that the subunits (X) and (Y) are also retained in the resultant dosage form.
  • [0110]
    The multiparticulate subunits (X) and (Y) of identical shape should also not be visually distinguishable from one another so that the abuser cannot separate them from one another by simple sorting. This may, for example, be achieved by the application of identical coatings which, apart from this disguising function, may also incorporate further functions, such as, for example, controlled release of one or more opioid(s) or provision of a finish resistant to gastric juices on the particular subunits.
  • [0111]
    In a further preferred embodiment of the present invention, subunits (X) and (Y) are in each case arranged in layers relative to one another.
  • [0112]
    The layered subunits (X) and (Y) are preferably arranged for this purpose vertically or horizontally relative to one another in the dosage form according to the invention, wherein in each case one or more layered subunits (X) and one or more layered subunits (Y) may be present in the dosage form, such that, apart from the preferred layer sequences (X)-(Y) or (X)-(Y)-(X), any desired other layer sequences may be considered, optionally in combination with layers containing components (a) and/or (b).
  • [0113]
    Another preferred dosage form according to the invention is one in which subunit (Y) forms a core which is completely enclosed by the delayed-release subunit (X), wherein a separation layer (Z) may be present between said layers. Such a structure is preferably also suitable for the above-stated multiparticulate forms, wherein both subunits (X) and (Y) and an optionally present separation layer (Z), which must satisfy the hardness requirement according to the invention, are formulated in one and the same multiparticulate form.
  • [0114]
    In a further preferred embodiment of the dosage form according to the invention, the subunit (X) forms a core, which is enclosed by subunit (Y), wherein the latter comprises at least one channel which leads from the core to the surface of the dosage form.
  • [0115]
    The dosage form according to the invention may comprise, between one layer of the subunit (X) and one layer of the subunit (Y), in each case one or more, preferably one, optionally swellable separation layer (Z) which serves to separate subunit (X) spatially from (Y).
  • [0116]
    If the dosage form according to the invention comprises the layered subunits (X) and (Y) and an optionally present separation layer (Z) in an at least partially vertical or horizontal arrangement, the dosage form preferably takes the form of a tablet, a coextrudate or a laminate.
  • [0117]
    In one particularly preferred embodiment, the entirety of the free surface of subunit (Y) and optionally at least part of the free surface of subunit(s) (X) and optionally at least part of the free surface of the optionally present separation layer(s) (Z) may be coated with at least one barrier layer (Z′) which prevents release of component (c) and/or (e) and/or (d) and/or (f). The barrier layer (Z′) must also fulfill the hardness conditions according to the invention.
  • [0118]
    Another particularly preferred embodiment of the dosage form according to the invention comprises a vertical or horizontal arrangement of the layers of subunits (X) and (Y) and at least one push layer (p) arranged therebetween, and optionally a separation layer (Z), in which dosage form the entirety of the free surface of the layer structure consisting of subunits (X) and (Y), the push layer and the optionally present separation layer (Z) is provided with a semipermeable coating (E), which is permeable to a release medium, i.e. conventionally a physiological liquid, but substantially impermeable to the opioid(s) and to component (c) and/or (d) and/or (f), and wherein this coating (E) comprises at least one opening for release of the opioid(s) in the area of subunit (X).
  • [0119]
    A corresponding dosage form is known to the person skilled in the art, for example under the name oral osmotic therapeutic system (OROS), as are suitable materials and methods for the production thereof, inter alia from U.S. Pat. No. 4,612,008, U.S. Pat. No. 4,765,989 and U.S. Pat. No. 4,783,337. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
  • [0120]
    An osmotic dosage form containing an analgesic opioid and a dye as an aversive agent is likewise known to the person skilled in the art from the prior art (WO 03/015531). The tablet core preferably consists of two layers, an opioid-containing layer and a push layer, wherein the push layer contains the dye as the aversive agent. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
  • [0121]
    In a further preferred embodiment of the claimed invention, the subunit (X) of the dosage form according to the invention is in the form of a tablet, the edge face and optionally one of the two main faces of which is covered with a barrier layer (Z′) containing component (c) and/or (d) and/or (f).
  • [0122]
    The person skilled in the art will understand that the auxiliary substances of the subunit(s) (X) or (Y) and of the optionally present separation layer(s) (Z) and/or of the barrier layer(s) (Z′) used in formulating the dosage form according to the invention will vary as a function of the arrangement thereof in the dosage form according to the invention, the mode of administration and as a function of the particular opioid, of the optionally present components (a) and/or (b) and/or (e) and of component (c) and/or (d) and/or (f), while maintaining release of the active ingredient over 24 hours. The materials which have the requisite properties are in each case known per se to the person skilled in the art.
  • [0123]
    If release of component (c) and/or (d) and/or (f) from subunit (Y) of the dosage form according to the invention is prevented with the assistance of a cover, preferably a barrier layer, the subunit may consist of conventional materials known to the person skilled in the art, providing that it contains at least one polymer (C) to fulfill the hardness condition of the dosage form according to the invention.
  • [0124]
    If a corresponding barrier layer (Z′) is not provided to prevent release of component (c) and/or (d) and/or (f), the materials of the subunits should be selected such that release of the particular component (c) and/or (d) from subunit (Y) is virtually ruled out.
  • [0125]
    The materials which are stated below to be suitable for production of the barrier layer may preferably be used for this purpose. Preferred materials are those which are selected from the group comprising alkylcelluloses, hydroxyalkylcelluloses, glucans, scleroglucans, mannans, xanthans, copolymers of poly[bis(p-carboxyphenoxy)propane:sebacic acid], preferably in a molar ratio of 20:80 (marketed under the name Polifeprosan 20®), carboxymethylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, polymers based on (meth)acrylic acid and the esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls, polyglycolides, polysiloxanes and polyurethanes and the copolymers thereof.
  • [0126]
    Particularly suitable materials may be selected from the group comprising methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate (of low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate, sodium cellulose sulfate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, polyoctatdecyl acrylate, polyethylene, low density polyethylene, high density polyethylene, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinyl chloride.
  • [0127]
    Particularly suitable copolymers may be selected from the group comprising copolymers of butyl methacrylate and isobutyl methacrylate, copolymers of methyl vinyl ether and maleic acid of high molecular weight, copolymers of methyl vinyl ether and maleic acid monoethyl ester, copolymers of methyl vinyl ether and maleic anhydride and copolymers of vinyl alcohol and vinyl acetate.
  • [0128]
    Further materials which are suitable for formulating the barrier layer are starch-filled polycaprolactone (WO98/20073), aliphatic polyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1), aliphatic and aromatic polyester urethanes (DE 19822979), polyhydroxyalkanoates, in particular polyhydroxybutyrates, polyhydroxyvalerates, casein (DE 4 309 528), polylactides and copolylactides (EP 0 980 894 A1). The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
  • [0129]
    The above-stated materials may optionally be blended with further conventional auxiliary substances known to the person skilled in the art, preferably selected from the group consisting of glyceryl monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearic acid, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and the derivatives thereof.
  • [0130]
    If the dosage form according to the invention comprises a separation layer (Z′), said layer, like the uncovered subunit (Y), may preferably consist of the above-stated materials described for the barrier layer. The person skilled in the art will understand that release of the opioid(s) and/or opiate(s) or of component (c) and/or (d) from the particular subunit may be controlled by the thickness of the separation layer.
  • [0131]
    Method for Determining Breaking Strength
  • [0132]
    In order to verify whether a polymer or a wax may be used as component (C) or (D) respectively, the polymer or wax is press-moulded to form a tablet with a diameter of 10 mm and a height of 5 mm using a force of 150 N at a temperature which at least corresponds to the softening point of the polymer or wax and is determined with the assistance of a DSC diagram of the polymer or wax. Using tablets produced in this manner, breaking strength is determined with the apparatus described below in accordance with the method for determining the breaking strength of tablets published in the European Pharmacopoeia 1997, page 143, 144, method no. 2.9.8. The apparatus used for the measurement is a “Zwick Z 2.5” materials tester, Fmax=2.5 kN, draw max. 1150 mm with the setup comprising a column and a spindle, clearance behind of 100 mm, a test speed of 0.1800 mm/min and testControl software. Measurement was performed using a pressure piston with screw-in inserts and a cylinder (diam. 10 mm), a force transducer, (Fmax. 1 kN, diameter=8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M to DIN 55350-18, Zwick gross force Fmax=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany).
  • [0133]
    The tablets deemed to be resistant to breaking under a specific load include not only those which have not broken but also those which may have suffered plastic deformation under the action of the force.
  • [0134]
    The breaking strength of the dosage forms according to the invention is determined using the same measurement method.
  • [0135]
    The invention is explained below with reference to Examples. These explanations are given merely by way of example and do not restrict the general concept of the invention.
  • EXAMPLE 1
  • [0136]
    a) Production of an Abuse-Proofed Tablet Containing Oxycodone
  • [0137]
    The quantities of oxycodone hydrochloride, polyethylene oxide powder and hydroxypropylmethylcellulose (Metholose 90 SH 100 000) as the delayed-release matrix material listed in Table 1 were mixed in a free-fall mixer. The tabletting tool, which consists of die, top punch and bottom punch with a diameter of 10 mm, was heated to 90° C. in a heating cabinet. 600 mg portions of the powder mixture were press-moulded by means of the heated tool, the pressure being maintained for at least 15 seconds.
  • [0000]
    TABLE 1
    Complete
    Components Per tablet batch
    Oxycodone HCl  80.0 mg  40.0 g
    Polyethylene oxide, NF, MW 7 000 000 470.0 mg 235.0 g
    (Polyox WSR 303, Dow Chemicals)
    Hydroxypropylmethylcellulose 100 000 mPas  50.0 mg  25.0 g
    (Metholose 90 SH 100 000)
    Total weight 600.0 mg 300.0 g
  • [0138]
    The breaking strength of the tablets is determined using the above-described method. No breakage occurred when a force of 500 N was applied. The tablets could not be comminuted using a hammer, nor with the assistance of a pestle and mortar.
  • [0139]
    In Vitro Release from the Tablets Produced According to a)
  • [0140]
    In vitro release of oxycodone hydrochloride from the tablets produced according to a) was determined in a paddle stirrer apparatus with sinker according to the method described in the European Pharmacopoeia. The temperature of the release medium was 37° C. and the rotational speed of the stirrer 75 min−1. The release medium used was intestinal juice, pH 6.8. The quantity of oxycodone hydrochloride released in each case into the dissolution medium at any one time was determined by spectrophotometry. The percentage released quantity, relative to the total quantity of oxycodone hydrochloride, at each point in time is shown in Table 2.
  • [0000]
    TABLE 2
    Time, minutes Released quantity, wt. %
    30 11
    240 40
    480 61
    720 76
    1080 92
    1440 97

Claims (25)

1. An abuse-proofed oral dosage form with controlled opioid release for once daily administration, comprising at least one opioid with potential for abuse (A) and/or one of the physiologically acceptable compounds or derivatives thereof, at least one synthetic or natural polymer (C), optionally delayed-release auxiliary substances, optionally physiologically acceptable auxiliary substances (B), optionally a wax (D) and optionally at least one delayed-release coating, wherein the at least one opioid with potential for abuse (A) is selected from the group consisting of oxymorphone, hydromorphone, morphine and physiologically acceptable compounds and derivatives thereof, and wherein the dosage form exhibits a breaking strength of at least 500 N.
2. A dosage form according to claim 1, wherein the opioid is at least one opioid selected from among the group consisting of hydromorphone, morphine, the stereoisomers thereof, the enantiomers thereof, the diastereomers thereof in any desired mixtures, the physiologically acceptable compounds thereof, and the derivatives thereof.
3. (canceled)
4. A dosage form according to claim 1, which is in the form of a tablet.
5. A dosage form according to claim 1, which is in multiparticulate form.
6. A dosage form according to claim 1, wherein the polymer (C) is at least one polymer selected from among the group consisting of polyethylene oxides, polyethylenes, polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes, polyacrylates, and the copolymers thereof.
7. A dosage form according to claim 6, wherein the polyethylene oxide is of high molecular weight.
8. A dosage form according to claim 6, wherein the polymer (C) is a water-soluble or water-swellable polymer.
9. A dosage form according to claim 1, wherein the wax (D) is at least one natural, semi-synthetic or synthetic wax with a softening point of at least 60° C.
10. A dosage form according to claim 9, wherein the wax (D) is carnauba wax or beeswax.
11. A dosage form according to claim 1, wherein the component(s) (C) and optionally (D) are present in such quantities that the dosage form exhibits a breaking strength of at least 1000 N.
12. A dosage form according to claim 1, wherein the at least one opioid with a potential for abuse (A) is present in a delayed-release matrix.
13. A dosage form according to claim 12, wherein component (C) and/or component (D) also serves as an additional delayed-release component.
14. A dosage form according to claim 1, which comprises a delayed-release coating.
15. A dosage form according to claim 1, which comprises at least one of the following components (a)-(f) as the auxiliary substance (B):
(a) at least one substance which irritates the nasal passages and/or pharynx,
(b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel which optionally remains visually distinguishable when introduced into a further quantity of an aqueous liquid,
(c) at least one antagonist for each of the opioids with potential for abuse,
(d) at least one emetic,
(e) at least one dye as an aversive agent, and
(f) at least one bitter substance.
16. A dosage form according to claim 15, which comprises at least one polymeric viscosity-increasing agent selected from among the group consisting of carboxymethylcellulose sodium, polyacrylic acid, locust bean flour, pectin, waxy maize starch, alginate, guar flour, iota-carrageenan, karaya gum, gellan gum, galactomannan, tara stone flour, propylene glycol alginate, hyaluronate, tragacanth, tara gum, fermented polysaccharide welan gum and xanthan.
17. A dosage form according to claim 16, wherein component (C) serves as an additional viscosity-increasing agent.
18. A process for the production of a dosage form according to claim 1, which comprises:
(1) mixing components (A), (C), optionally (B) and optionally (D) and optionally delayed-release matrix compounds to form a mixture, and
(2) forming the mixture, optionally after pelletisation, into the dosage form by application of force optionally with preceding or simultaneous exposure to heat and optionally providing the dosage form with a delayed-release coating.
19. A process according to claim 18, wherein pelletisation is performed by a melt method.
20. A process according to claim 18, wherein pelletisation is performed by wet pelletisation.
21. A process for the production of a dosage form according to claim 1, which comprises:
(1) forming a mixture containing components (A), (C), optionally (B) and optionally (D) and optionally delayed-release matrix compounds into formed articles by application of force,
(2) optionally singulating the formed articles and optionally in each case grading by size, and
(3) exposing the formed articles to force, after or during heating to at least the softening point of component (C), until the formed articles exhibit a breaking hardness of at least 500 N, and
(4) optionally providing the formed articles with an optionally delayed-release coating and optionally mixing the formed articles together again.
22. A dosage form obtained by a process according to claim 18.
23. A dosage form according to claim 1, wherein the physiologically acceptable compounds and derivatives are salts, solvates, esters, ethers and amides.
24. A dosage form obtained by a process according to claim 21.
25. A method of treating pain comprising administering to a patient in need thereof a effective amount to treat pain of at least one opioid with potential for abuse (A) selected from the group consisting of oxymorphone, hydromorphone, morphine and physiologically acceptable compounds and derivatives thereof, wherein said at least one opioid with potential for abuse (A) is administered to said patient in the form of a dosage form according to claim 1.
US12140470 2004-07-01 2008-06-17 Abuse-proofed oral dosage form Abandoned US20080248113A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
DE200410032049 DE102004032049A1 (en) 2004-07-01 2004-07-01 Abuse-proofed, oral dosage form
US10890763 US20060002860A1 (en) 2004-07-01 2004-07-14 Abuse-proofed oral dosage form
DE102004032049.7 2005-07-01
US12140470 US20080248113A1 (en) 2004-07-01 2008-06-17 Abuse-proofed oral dosage form

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12140470 US20080248113A1 (en) 2004-07-01 2008-06-17 Abuse-proofed oral dosage form
US14143487 US20140112989A1 (en) 2004-07-01 2013-12-30 Abuse-proofed oral dosage form
US15057161 US20170209378A9 (en) 2004-07-01 2016-03-01 Abuse-proofed oral dosage form

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10890763 Division US20060002860A1 (en) 2004-07-01 2004-07-14 Abuse-proofed oral dosage form

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14143487 Continuation US20140112989A1 (en) 2004-07-01 2013-12-30 Abuse-proofed oral dosage form

Publications (1)

Publication Number Publication Date
US20080248113A1 true true US20080248113A1 (en) 2008-10-09

Family

ID=35508085

Family Applications (8)

Application Number Title Priority Date Filing Date
US10890763 Abandoned US20060002860A1 (en) 2004-07-01 2004-07-14 Abuse-proofed oral dosage form
US12140470 Abandoned US20080248113A1 (en) 2004-07-01 2008-06-17 Abuse-proofed oral dosage form
US13897746 Abandoned US20130251643A1 (en) 2004-07-01 2013-05-20 Abuse-proofed oral dosage form
US14143487 Pending US20140112989A1 (en) 2004-07-01 2013-12-30 Abuse-proofed oral dosage form
US14795900 Pending US20150313845A1 (en) 2004-07-01 2015-07-10 Abuse-proofed oral dosage form
US15057161 Pending US20170209378A9 (en) 2004-07-01 2016-03-01 Abuse-proofed oral dosage form
US15059730 Pending US20160184295A1 (en) 2004-07-01 2016-03-03 Abuse-proofed oral dosage form
US15255534 Pending US20160367549A1 (en) 2004-07-01 2016-09-02 Abuse-proofed oral dosage form

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10890763 Abandoned US20060002860A1 (en) 2004-07-01 2004-07-14 Abuse-proofed oral dosage form

Family Applications After (6)

Application Number Title Priority Date Filing Date
US13897746 Abandoned US20130251643A1 (en) 2004-07-01 2013-05-20 Abuse-proofed oral dosage form
US14143487 Pending US20140112989A1 (en) 2004-07-01 2013-12-30 Abuse-proofed oral dosage form
US14795900 Pending US20150313845A1 (en) 2004-07-01 2015-07-10 Abuse-proofed oral dosage form
US15057161 Pending US20170209378A9 (en) 2004-07-01 2016-03-01 Abuse-proofed oral dosage form
US15059730 Pending US20160184295A1 (en) 2004-07-01 2016-03-03 Abuse-proofed oral dosage form
US15255534 Pending US20160367549A1 (en) 2004-07-01 2016-09-02 Abuse-proofed oral dosage form

Country Status (6)

Country Link
US (8) US20060002860A1 (en)
CN (1) CN101027044B (en)
DE (1) DE102004032049A1 (en)
DK (1) DK1765303T3 (en)
ES (1) ES2402192T3 (en)
RU (1) RU2396944C2 (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US8114384B2 (en) 2004-07-01 2012-02-14 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
WO2012058695A2 (en) * 2010-10-29 2012-05-03 Najib Babul Compositions of (-)-17-(cyclobutylmethyl) morphinan-3, 14-diol
US8192722B2 (en) 2003-08-06 2012-06-05 Grunenthal Gmbh Abuse-proof dosage form
US8383152B2 (en) * 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US8486449B2 (en) 2008-12-16 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8486448B2 (en) 2007-12-17 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US8808745B2 (en) 2001-09-21 2014-08-19 Egalet Ltd. Morphine polymer release system
US8815289B2 (en) 2006-08-25 2014-08-26 Purdue Pharma L.P. Tamper resistant dosage forms
US8877241B2 (en) 2003-03-26 2014-11-04 Egalet Ltd. Morphine controlled release system
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
US9044402B2 (en) 2012-07-06 2015-06-02 Egalet Ltd. Abuse-deterrent pharmaceutical compositions for controlled release
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9301918B2 (en) 2013-03-15 2016-04-05 Mallinckrodt Llc Abuse deterrent solid dosage form for immediate release with functional score
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9694080B2 (en) 2001-09-21 2017-07-04 Egalet Ltd. Polymer release system
US9730885B2 (en) 2012-07-12 2017-08-15 Mallinckrodt Llc Extended release, abuse deterrent pharmaceutical compositions
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
WO2017189947A1 (en) * 2016-04-28 2017-11-02 Ascent Pharmaceuticals, Inc. Pharmaceutical dosage forms
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
DK1842533T3 (en) * 2003-08-06 2013-05-27 Gruenenthal Gmbh Dosage protected against abuse
DE10361596A1 (en) * 2003-12-24 2005-09-29 Grünenthal GmbH A process for preparing a secured against misuse dosage form
DE102004020220A1 (en) * 2004-04-22 2005-11-10 Grünenthal GmbH A process for preparing a secured against misuse, solid dosage form
DE102004032049A1 (en) * 2004-07-01 2006-01-19 Grünenthal GmbH Abuse-proofed, oral dosage form
DE102004032103A1 (en) * 2004-07-01 2006-01-19 Grünenthal GmbH Abuse-proofed, oral dosage form
DE102005005446A1 (en) * 2005-02-04 2006-08-10 Grünenthal GmbH Unbreakable dosage forms with delayed release
DE102005005449A1 (en) * 2005-02-04 2006-08-10 Grünenthal GmbH A process for preparing a secured against misuse dosage form
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
WO2007056142A3 (en) * 2005-11-02 2007-11-08 Najib Babul Methods of preventing the serotonin syndrome and compositions for use therefor
US8329744B2 (en) * 2005-11-02 2012-12-11 Relmada Therapeutics, Inc. Methods of preventing the serotonin syndrome and compositions for use thereof
US20100172989A1 (en) * 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
US20090317355A1 (en) * 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20090082466A1 (en) * 2006-01-27 2009-03-26 Najib Babul Abuse Resistant and Extended Release Formulations and Method of Use Thereof
US20080020032A1 (en) * 2006-07-21 2008-01-24 Michael Crowley Hydrophobic abuse deterrent delivery system for hydromorphone
WO2008134071A1 (en) * 2007-04-26 2008-11-06 Theraquest Biosciences, Inc. Multimodal abuse resistant extended release formulations
US20080292665A1 (en) * 2007-05-25 2008-11-27 Kulli John C Simple mechanical procedure and product for deterring substance abuse
DE102007025858A1 (en) 2007-06-01 2008-12-04 Grünenthal GmbH A process for preparing a Arzneimitteldarreichungsform
US20090022798A1 (en) * 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
DE102007039043A1 (en) 2007-08-17 2009-02-19 Grünenthal GmbH star Hub
JP2011511782A (en) 2008-02-12 2011-04-14 アボット・ラボラトリーズAbbott Laboratories Extended release hydrocodone acetaminophen and its related methods and applications
US8372432B2 (en) * 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
WO2009114648A1 (en) * 2008-03-11 2009-09-17 Depomed Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
EP2143336A1 (en) * 2008-07-08 2010-01-13 Alsiano A/S Powdered chewing gum compositions, the use thereof and a method for preparing such compositions
WO2010066034A8 (en) * 2008-12-12 2010-08-19 Paladin Labs Inc. Narcotic drug formulations with decreased abuse potential
US9056054B2 (en) * 2009-06-25 2015-06-16 Elite Laboratories, Inc. Abuse resistant oral dosage forms
ES2560210T3 (en) * 2009-07-22 2016-02-17 Grünenthal GmbH Dosage form resistant to manipulation for opiádes sensitive to oxidation
CN102596252A (en) * 2009-08-31 2012-07-18 蒂宝制药公司 Gastric retentive pharmaceutical compositions for immediate and extended release of acetaminophen
US8597681B2 (en) 2009-12-22 2013-12-03 Mallinckrodt Llc Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
US9198861B2 (en) 2009-12-22 2015-12-01 Mallinckrodt Llc Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
ES2643291T3 (en) 2010-12-22 2017-11-22 Purdue Pharma L.P. Forms of controlled release dosage with tamper proof coated
CA2822769C (en) 2010-12-23 2016-10-04 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US8741885B1 (en) 2011-05-17 2014-06-03 Mallinckrodt Llc Gastric retentive extended release pharmaceutical compositions
US8658631B1 (en) 2011-05-17 2014-02-25 Mallinckrodt Llc Combination composition comprising oxycodone and acetaminophen for rapid onset and extended duration of analgesia
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
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
JP6208261B2 (en) 2013-02-05 2017-10-04 パーデュー、ファーマ、リミテッド、パートナーシップPurdue Pharma L.P. Tampering resistant pharmaceutical preparations
US20140271896A1 (en) 2013-03-15 2014-09-18 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
CA2955229A1 (en) 2014-07-17 2016-01-21 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form

Citations (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3806603A (en) * 1969-10-13 1974-04-23 W Gaunt Pharmaceutical carriers of plasticized dried milled particles of hydrated cooked rice endosperm
US3865108A (en) * 1971-05-17 1975-02-11 Ortho Pharma Corp Expandable drug delivery device
US4002173A (en) * 1974-07-23 1977-01-11 International Paper Company Diester crosslinked polyglucan hydrogels and reticulated sponges thereof
US4014965A (en) * 1972-11-24 1977-03-29 The Dow Chemical Company Process for scrapless forming of plastic articles
US4070494A (en) * 1975-07-09 1978-01-24 Bayer Aktiengesellschaft Enteral pharmaceutical compositions
US4200704A (en) * 1978-09-28 1980-04-29 Union Carbide Corporation Controlled degradation of poly(ethylene oxide)
US4207893A (en) * 1977-08-29 1980-06-17 Alza Corporation Device using hydrophilic polymer for delivering drug to biological environment
US4427681A (en) * 1982-09-16 1984-01-24 Richardson-Vicks, Inc. Thixotropic compositions easily convertible to pourable liquids
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4667013A (en) * 1986-05-02 1987-05-19 Union Carbide Corporation Process for alkylene oxide polymerization
US4744976A (en) * 1984-07-23 1988-05-17 Zetachron, Inc. Erodible matrix for sustained release bioactive composition
US4892778A (en) * 1987-05-27 1990-01-09 Alza Corporation Juxtaposed laminated arrangement
US5004601A (en) * 1988-10-14 1991-04-02 Zetachron, Inc. Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith
US5082668A (en) * 1983-05-11 1992-01-21 Alza Corporation Controlled-release system with constant pushing source
US5126151A (en) * 1991-01-24 1992-06-30 Warner-Lambert Company Encapsulation matrix
US5200197A (en) * 1989-11-16 1993-04-06 Alza Corporation Contraceptive pill
US5211892A (en) * 1990-07-20 1993-05-18 L'oreal Process for the compaction of a powder mixture providing an absorbent or partially friable compact product and the product obtained by this process
US5508042A (en) * 1991-11-27 1996-04-16 Euro-Celtigue, S.A. Controlled release oxycodone compositions
US5593694A (en) * 1991-10-04 1997-01-14 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release tablet
US5601842A (en) * 1993-09-03 1997-02-11 Gruenenthal Gmbh Sustained release drug formulation containing a tramadol salt
US5620697A (en) * 1992-12-31 1997-04-15 Orion-Yhtyma Oy Method for preparing matrix-type pharmaceutical compositions through ultrasonic means to accomplish melting
US5707636A (en) * 1994-08-03 1998-01-13 Saitec S.R.L. Apparatus and method for preparing solid forms with controlled release of the active ingredient
US5866164A (en) * 1996-03-12 1999-02-02 Alza Corporation Composition and dosage form comprising opioid antagonist
US5908850A (en) * 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
US6228863B1 (en) * 1997-12-22 2001-05-08 Euro-Celtique S.A. Method of preventing abuse of opioid dosage forms
US6235825B1 (en) * 1998-03-05 2001-05-22 Mitsui Chemicals, Inc. Polylactic acid resin composition and film therefrom
US6245357B1 (en) * 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US6248737B1 (en) * 1994-07-23 2001-06-19 Gruenenthal Gmbh 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects
US6340475B2 (en) * 1997-06-06 2002-01-22 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
US6348469B1 (en) * 1995-04-14 2002-02-19 Pharma Pass Llc Solid compositions containing glipizide and polyethylene oxide
US6355656B1 (en) * 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
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
US6375957B1 (en) * 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US6399100B1 (en) * 1997-08-01 2002-06-04 Elan Corporation, Plc Controlled release pharmaceutical compositions containing tiagabine
US20030008409A1 (en) * 2001-07-03 2003-01-09 Spearman Steven R. Method and apparatus for determining sunlight exposure
US20030044464A1 (en) * 1999-08-31 2003-03-06 Iris Ziegler Sustained-release, oral pharamaceutical forms of formulation
US6534089B1 (en) * 1996-04-05 2003-03-18 Alza Corporation Uniform drug delivery therapy
US20030064099A1 (en) * 2001-08-06 2003-04-03 Benjamin Oshlack Pharmaceutical formulation containing bittering agent
US20030068276A1 (en) * 2001-09-17 2003-04-10 Lyn Hughes Dosage forms
US20030069263A1 (en) * 2001-07-18 2003-04-10 Breder Christopher D. Pharmaceutical combinations of oxycodone and naloxone
US20030068392A1 (en) * 2001-08-06 2003-04-10 Richard Sackler Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
US20030068370A1 (en) * 2001-08-06 2003-04-10 Richard Sackler Pharmaceutical formulation containing irritant
US20030068375A1 (en) * 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US20030068371A1 (en) * 2001-08-06 2003-04-10 Benjamin Oshlack Pharmaceutical formulation containing opioid agonist,opioid antagonist and gelling agent
US6547997B1 (en) * 1997-11-28 2003-04-15 Abbot Laboratories Method for producing solvent-free noncrystalline biologically active substances
US6562375B1 (en) * 1999-08-04 2003-05-13 Yamanouchi Pharmaceuticals, Co., Ltd. Stable pharmaceutical composition for oral use
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
US6569506B1 (en) * 1998-08-27 2003-05-27 Chevron Chemical Company Llc Oxygen scavenging packaging
US20030104052A1 (en) * 2001-10-25 2003-06-05 Bret Berner Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
US20030104053A1 (en) * 2001-10-25 2003-06-05 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US20030118641A1 (en) * 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US20030124185A1 (en) * 2001-08-06 2003-07-03 Benjamin Oshlack Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent
US20040010000A1 (en) * 2002-04-29 2004-01-15 Ayer Atul D. Methods and dosage forms for controlled delivery of oxycodone
US6699503B1 (en) * 1992-09-18 2004-03-02 Yamanuchi Pharmaceutical Co., Ltd. Hydrogel-forming sustained-release preparation
US20040052844A1 (en) * 2002-09-16 2004-03-18 Fang-Hsiung Hsiao Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins
US20040052731A1 (en) * 2002-07-05 2004-03-18 Collegium Pharmaceuticals, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US6723343B2 (en) * 1999-08-31 2004-04-20 Gruenenthal Gmbh Pharmaceutical tramadol salts
US6753009B2 (en) * 2002-03-13 2004-06-22 Mcneil-Ppc, Inc. Soft tablet containing high molecular weight polyethylene oxide
US20040126428A1 (en) * 2001-11-02 2004-07-01 Lyn Hughes Pharmaceutical formulation including a resinate and an aversive agent
US20050012067A1 (en) * 2003-07-14 2005-01-20 Magic Plastics, Inc. Axially actuated drain valve for pools and spas
US20050031546A1 (en) * 2003-08-06 2005-02-10 Johannes Bartholomaus Abuse-proffed dosage form
US20050095291A1 (en) * 2000-02-08 2005-05-05 Benjamin Oshlack Tamper-resistant oral opioid agonist formulations
US20050106249A1 (en) * 2002-04-29 2005-05-19 Stephen Hwang Once-a-day, oral, controlled-release, oxycodone dosage forms
US20060004034A1 (en) * 2002-11-11 2006-01-05 Gruenenthal Gmbh Spirocyclic cyclohexane compounds
US20060002859A1 (en) * 2004-07-01 2006-01-05 Elisabeth Arkenau Process for production of an abuse-proofed solid dosage form
US20060002860A1 (en) * 2004-07-01 2006-01-05 Johannes Bartholomaus Abuse-proofed oral dosage form
US7074430B2 (en) * 1993-05-10 2006-07-11 Euro-Celtique S.A. Controlled release tramadol tramadol formulation
US20070003616A1 (en) * 2003-12-24 2007-01-04 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20070020335A1 (en) * 2005-07-07 2007-01-25 Farnam Companies, Inc. Sustained release pharmaceutical compositions for highly water soluble drugs
US7201920B2 (en) * 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
US20070092573A1 (en) * 2005-10-24 2007-04-26 Laxminarayan Joshi Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist
US7214385B2 (en) * 2001-08-06 2007-05-08 Thomas J. Gruber Pharmaceutical formulation containing dye
US20080069871A1 (en) * 2006-07-21 2008-03-20 Vaughn Jason M Hydrophobic abuse deterrent delivery system
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
US20090017121A1 (en) * 2001-10-25 2009-01-15 Bret Berner Gastric retained gabapentin dosage form
US7674800B2 (en) * 2004-03-30 2010-03-09 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone
US20100092553A1 (en) * 2005-11-10 2010-04-15 Flamel Technologies anti-misuse microparticulate oral pharmaceutical form
US20110020454A1 (en) * 2008-03-13 2011-01-27 Rosa Lamarca Casado Novel dosage and formulation
US7939543B2 (en) * 2005-03-04 2011-05-10 Purdue Pharma L.P. Method of reducing α, β unsaturated ketones in opioid compositions
US20110159100A1 (en) * 2009-06-24 2011-06-30 Egalet A/S Formulations and methods for the controlled release of active drug substances
US20120034171A1 (en) * 2003-08-06 2012-02-09 Gruenenthal Gmbh Abuse-proofed dosage form
US20120059065A1 (en) * 2010-09-02 2012-03-08 Grünenthal GmbH Tamper Resistant Dosage Form Comprising An Anionic Polymer
US20120065220A1 (en) * 2010-09-02 2012-03-15 Grunenthal Gmbh Tamper Resistant Dosage Form Comprising An Anionic Polymer
US20120135071A1 (en) * 2002-06-17 2012-05-31 Grunenthal Gmbh Abuse-proofed dosage form
US20120136021A1 (en) * 2009-07-22 2012-05-31 Grunenthal Gmbh Oxidation-stabilized tamper-resistant dosage form
US8192722B2 (en) * 2003-08-06 2012-06-05 Grunenthal Gmbh Abuse-proof dosage form

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2210071A1 (en) * 1971-03-09 1972-09-14
US3966747A (en) * 1972-10-26 1976-06-29 Bristol-Myers Company 9-Hydroxy-6,7-benzomorphans
DE2822324C3 (en) * 1978-05-22 1981-02-26 Basf Ag, 6700 Ludwigshafen
US4992279A (en) * 1985-07-03 1991-02-12 Kraft General Foods, Inc. Sweetness inhibitor
US5198226A (en) * 1986-01-30 1993-03-30 Syntex (U.S.A.) Inc. Long acting nicardipine hydrochloride formulation
US4892889A (en) * 1986-11-18 1990-01-09 Basf Corporation Process for making a spray-dried, directly-compressible vitamin powder comprising unhydrolyzed gelatin
EP0277092B1 (en) * 1987-01-14 1992-01-29 Ciba-Geigy Ag Therapeutic system for slightly soluble active ingredients
US5396269A (en) * 1991-02-20 1995-03-07 Hitachi, Ltd. Television telephone
DE4227385A1 (en) * 1992-08-19 1994-02-24 Kali Chemie Pharma Gmbh pancreatin
EP0654263B1 (en) * 1993-11-23 2002-01-23 Euro-Celtique S.A. Method for preparing a sustained release composition
ES2132589T3 (en) * 1994-05-18 1999-08-16 Lannacher Heilmittel Preparation oral delayed effect.
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
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
EP2065055A1 (en) * 1996-06-26 2009-06-03 Board of Regents, The University of Texas System Holt-melt extrudable pharmaceutical formulation
DE69731114D1 (en) * 1996-11-05 2004-11-11 Novamont Spa contain Biologiscgh abbaure polymer compositions, starch and a thermoplastic polymer
US5948787A (en) * 1997-02-28 1999-09-07 Alza Corporation Compositions containing opiate analgesics
US6344535B1 (en) * 1997-12-03 2002-02-05 Bayer Aktiengesellschaft Polyether ester amides
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
CA2379987A1 (en) * 1999-07-29 2001-02-08 Roxane Laboratories, Inc. Opioid sustained-released formulation
EP1207866B1 (en) * 1999-08-31 2004-10-13 Grünenthal GmbH Delayed-action form of administration containing tramadol saccharinate
US20020015730A1 (en) * 2000-03-09 2002-02-07 Torsten Hoffmann Pharmaceutical formulations and method for making
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
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
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
US20030044458A1 (en) * 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
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
FR2833838B1 (en) * 2001-12-21 2005-09-16 Ellipse Pharmaceuticals Method of manufacturing a tablet including a morphine-like analgesic and compresses obtained
WO2003094812A1 (en) * 2002-05-13 2003-11-20 Endo Pharmaceuticals Inc. Abuse-resistant opioid solid dosage form
DE10250083A1 (en) 2002-06-17 2003-12-24 Gruenenthal Gmbh Abuse-proofed dosage form
DE10250084A1 (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
DE10250087A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Abuse-proofed dosage form
US20050186139A1 (en) * 2002-10-25 2005-08-25 Gruenenthal Gmbh Abuse-proofed dosage form
US20040091528A1 (en) * 2002-11-12 2004-05-13 Yamanouchi Pharma Technologies, Inc. Soluble drug extended 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
DE102004019916A1 (en) * 2004-04-21 2005-11-17 Grünenthal GmbH secured against misuse medicated plaster
DE102004032103A1 (en) * 2004-07-01 2006-01-19 Grünenthal GmbH Abuse-proofed, oral dosage form
US20060064009A1 (en) * 2004-09-21 2006-03-23 Webler William E Vessel imaging devices and methods
DE102007011485A1 (en) * 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with impeded abuse
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
WO2011009602A1 (en) * 2009-07-22 2011-01-27 Grünenthal GmbH Hot-melt extruded controlled release dosage form

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3806603A (en) * 1969-10-13 1974-04-23 W Gaunt Pharmaceutical carriers of plasticized dried milled particles of hydrated cooked rice endosperm
US3865108A (en) * 1971-05-17 1975-02-11 Ortho Pharma Corp Expandable drug delivery device
US4014965A (en) * 1972-11-24 1977-03-29 The Dow Chemical Company Process for scrapless forming of plastic articles
US4002173A (en) * 1974-07-23 1977-01-11 International Paper Company Diester crosslinked polyglucan hydrogels and reticulated sponges thereof
US4070494A (en) * 1975-07-09 1978-01-24 Bayer Aktiengesellschaft Enteral pharmaceutical compositions
US4207893A (en) * 1977-08-29 1980-06-17 Alza Corporation Device using hydrophilic polymer for delivering drug to biological environment
US4200704A (en) * 1978-09-28 1980-04-29 Union Carbide Corporation Controlled degradation of poly(ethylene oxide)
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4427681A (en) * 1982-09-16 1984-01-24 Richardson-Vicks, Inc. Thixotropic compositions easily convertible to pourable liquids
US5082668A (en) * 1983-05-11 1992-01-21 Alza Corporation Controlled-release system with constant pushing source
US4744976A (en) * 1984-07-23 1988-05-17 Zetachron, Inc. Erodible matrix for sustained release bioactive composition
US4806337A (en) * 1984-07-23 1989-02-21 Zetachron, Inc. Erodible matrix for sustained release bioactive composition
US4667013A (en) * 1986-05-02 1987-05-19 Union Carbide Corporation Process for alkylene oxide polymerization
US4892778A (en) * 1987-05-27 1990-01-09 Alza Corporation Juxtaposed laminated arrangement
US5004601A (en) * 1988-10-14 1991-04-02 Zetachron, Inc. Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith
US5200197A (en) * 1989-11-16 1993-04-06 Alza Corporation Contraceptive pill
US5211892A (en) * 1990-07-20 1993-05-18 L'oreal Process for the compaction of a powder mixture providing an absorbent or partially friable compact product and the product obtained by this process
US5126151A (en) * 1991-01-24 1992-06-30 Warner-Lambert Company Encapsulation matrix
US5593694A (en) * 1991-10-04 1997-01-14 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release tablet
US5508042A (en) * 1991-11-27 1996-04-16 Euro-Celtigue, S.A. Controlled release oxycodone compositions
US6699503B1 (en) * 1992-09-18 2004-03-02 Yamanuchi Pharmaceutical Co., Ltd. Hydrogel-forming sustained-release preparation
US5620697A (en) * 1992-12-31 1997-04-15 Orion-Yhtyma Oy Method for preparing matrix-type pharmaceutical compositions through ultrasonic means to accomplish melting
US7074430B2 (en) * 1993-05-10 2006-07-11 Euro-Celtique S.A. Controlled release tramadol tramadol formulation
US5601842A (en) * 1993-09-03 1997-02-11 Gruenenthal Gmbh Sustained release drug formulation containing a tramadol salt
US6248737B1 (en) * 1994-07-23 2001-06-19 Gruenenthal Gmbh 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects
US5707636A (en) * 1994-08-03 1998-01-13 Saitec S.R.L. Apparatus and method for preparing solid forms with controlled release of the active ingredient
US6348469B1 (en) * 1995-04-14 2002-02-19 Pharma Pass Llc Solid compositions containing glipizide and polyethylene oxide
US5908850A (en) * 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
US6355656B1 (en) * 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US5866164A (en) * 1996-03-12 1999-02-02 Alza Corporation Composition and dosage form comprising opioid antagonist
US6534089B1 (en) * 1996-04-05 2003-03-18 Alza Corporation Uniform drug delivery therapy
US6340475B2 (en) * 1997-06-06 2002-01-22 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
US20020051820A1 (en) * 1997-06-06 2002-05-02 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
US6399100B1 (en) * 1997-08-01 2002-06-04 Elan Corporation, Plc Controlled release pharmaceutical compositions containing tiagabine
US6547997B1 (en) * 1997-11-28 2003-04-15 Abbot Laboratories Method for producing solvent-free noncrystalline biologically active substances
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
US6235825B1 (en) * 1998-03-05 2001-05-22 Mitsui Chemicals, Inc. Polylactic acid resin composition and film therefrom
US6245357B1 (en) * 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US6569506B1 (en) * 1998-08-27 2003-05-27 Chevron Chemical Company Llc Oxygen scavenging packaging
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
US6562375B1 (en) * 1999-08-04 2003-05-13 Yamanouchi Pharmaceuticals, Co., Ltd. Stable pharmaceutical composition for oral use
US6723343B2 (en) * 1999-08-31 2004-04-20 Gruenenthal Gmbh Pharmaceutical tramadol salts
US20030044464A1 (en) * 1999-08-31 2003-03-06 Iris Ziegler Sustained-release, oral pharamaceutical forms of formulation
US20110097404A1 (en) * 2000-02-08 2011-04-28 Purdue Pharma L.P. Tamper-resistant oral opioid agonist formulations
US20050095291A1 (en) * 2000-02-08 2005-05-05 Benjamin Oshlack Tamper-resistant oral opioid agonist formulations
US20030118641A1 (en) * 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US20030008409A1 (en) * 2001-07-03 2003-01-09 Spearman Steven R. Method and apparatus for determining sunlight exposure
US20030069263A1 (en) * 2001-07-18 2003-04-10 Breder Christopher D. Pharmaceutical combinations of oxycodone and naloxone
US20030068370A1 (en) * 2001-08-06 2003-04-10 Richard Sackler Pharmaceutical formulation containing irritant
US20030068375A1 (en) * 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US20030068371A1 (en) * 2001-08-06 2003-04-10 Benjamin Oshlack Pharmaceutical formulation containing opioid agonist,opioid antagonist and gelling agent
US20120108622A1 (en) * 2001-08-06 2012-05-03 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US20030124185A1 (en) * 2001-08-06 2003-07-03 Benjamin Oshlack Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent
US20090081287A1 (en) * 2001-08-06 2009-03-26 Purdue Pharma L.P. Pharmaceutical Composition Containing Gelling Agent
US7214385B2 (en) * 2001-08-06 2007-05-08 Thomas J. Gruber Pharmaceutical formulation containing dye
US7157103B2 (en) * 2001-08-06 2007-01-02 Euro-Celtique S.A. Pharmaceutical formulation containing irritant
US20030068392A1 (en) * 2001-08-06 2003-04-10 Richard Sackler Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
US20030064099A1 (en) * 2001-08-06 2003-04-03 Benjamin Oshlack Pharmaceutical formulation containing bittering agent
US20030068276A1 (en) * 2001-09-17 2003-04-10 Lyn Hughes Dosage forms
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
US6723340B2 (en) * 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US20030104053A1 (en) * 2001-10-25 2003-06-05 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US20030104052A1 (en) * 2001-10-25 2003-06-05 Bret Berner Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
US20030133985A1 (en) * 2001-10-25 2003-07-17 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data
US20090017121A1 (en) * 2001-10-25 2009-01-15 Bret Berner Gastric retained gabapentin dosage form
US20040126428A1 (en) * 2001-11-02 2004-07-01 Lyn Hughes Pharmaceutical formulation including a resinate and an aversive agent
US6753009B2 (en) * 2002-03-13 2004-06-22 Mcneil-Ppc, Inc. Soft tablet containing high molecular weight polyethylene oxide
US20050106249A1 (en) * 2002-04-29 2005-05-19 Stephen Hwang Once-a-day, oral, controlled-release, oxycodone dosage forms
US20040010000A1 (en) * 2002-04-29 2004-01-15 Ayer Atul D. Methods and dosage forms for controlled delivery of oxycodone
US20120135071A1 (en) * 2002-06-17 2012-05-31 Grunenthal Gmbh Abuse-proofed dosage form
US20040052731A1 (en) * 2002-07-05 2004-03-18 Collegium Pharmaceuticals, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
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
US20040052844A1 (en) * 2002-09-16 2004-03-18 Fang-Hsiung Hsiao Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins
US20060004034A1 (en) * 2002-11-11 2006-01-05 Gruenenthal Gmbh Spirocyclic cyclohexane compounds
US20050012067A1 (en) * 2003-07-14 2005-01-20 Magic Plastics, Inc. Axially actuated drain valve for pools and spas
US8114383B2 (en) * 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US20120034171A1 (en) * 2003-08-06 2012-02-09 Gruenenthal Gmbh Abuse-proofed dosage form
US20120107250A1 (en) * 2003-08-06 2012-05-03 Gruenenthal Gmbh Abuse-proofed dosage form
US20050031546A1 (en) * 2003-08-06 2005-02-10 Johannes Bartholomaus Abuse-proffed dosage form
US8192722B2 (en) * 2003-08-06 2012-06-05 Grunenthal Gmbh Abuse-proof dosage form
US7201920B2 (en) * 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
US20090005408A1 (en) * 2003-12-24 2009-01-01 Grunenthal Gmbh Process for the production of an abuse-proofed dosage form
US20070003616A1 (en) * 2003-12-24 2007-01-04 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US7674799B2 (en) * 2004-03-30 2010-03-09 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US7683072B2 (en) * 2004-03-30 2010-03-23 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone
US7674800B2 (en) * 2004-03-30 2010-03-09 Purdue Pharma L.P. Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone
US20060002860A1 (en) * 2004-07-01 2006-01-05 Johannes Bartholomaus Abuse-proofed oral dosage form
US20060002859A1 (en) * 2004-07-01 2006-01-05 Elisabeth Arkenau Process for production of an abuse-proofed solid dosage form
US7939543B2 (en) * 2005-03-04 2011-05-10 Purdue Pharma L.P. Method of reducing α, β unsaturated ketones in opioid compositions
US20070020335A1 (en) * 2005-07-07 2007-01-25 Farnam Companies, Inc. Sustained release pharmaceutical compositions for highly water soluble drugs
US20070092573A1 (en) * 2005-10-24 2007-04-26 Laxminarayan Joshi Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist
US20100092553A1 (en) * 2005-11-10 2010-04-15 Flamel Technologies anti-misuse microparticulate oral pharmaceutical form
US20080069871A1 (en) * 2006-07-21 2008-03-20 Vaughn Jason M Hydrophobic abuse deterrent delivery system
US20110020454A1 (en) * 2008-03-13 2011-01-27 Rosa Lamarca Casado Novel dosage and formulation
US20110159100A1 (en) * 2009-06-24 2011-06-30 Egalet A/S Formulations and methods for the controlled release of active drug substances
US20120136021A1 (en) * 2009-07-22 2012-05-31 Grunenthal Gmbh Oxidation-stabilized tamper-resistant dosage form
US20120065220A1 (en) * 2010-09-02 2012-03-15 Grunenthal Gmbh Tamper Resistant Dosage Form Comprising An Anionic Polymer
US20120059065A1 (en) * 2010-09-02 2012-03-08 Grünenthal GmbH Tamper Resistant Dosage Form Comprising An Anionic Polymer

Cited By (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8808745B2 (en) 2001-09-21 2014-08-19 Egalet Ltd. Morphine polymer release system
US9707179B2 (en) 2001-09-21 2017-07-18 Egalet Ltd. Opioid polymer release system
US9694080B2 (en) 2001-09-21 2017-07-04 Egalet Ltd. Polymer release system
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US8877241B2 (en) 2003-03-26 2014-11-04 Egalet Ltd. Morphine controlled release system
US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US8192722B2 (en) 2003-08-06 2012-06-05 Grunenthal Gmbh Abuse-proof dosage form
US8420056B2 (en) 2003-08-06 2013-04-16 Grunenthal Gmbh Abuse-proofed dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US8309060B2 (en) 2003-08-06 2012-11-13 Grunenthal Gmbh Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US8114384B2 (en) 2004-07-01 2012-02-14 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US9486413B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
US9770416B2 (en) 2006-08-25 2017-09-26 Purdue Pharma L.P. Tamper resistant dosage forms
US8815289B2 (en) 2006-08-25 2014-08-26 Purdue Pharma L.P. Tamper resistant dosage forms
US8821929B2 (en) 2006-08-25 2014-09-02 Purdue Pharma L.P. Tamper resistant dosage forms
US9763886B2 (en) 2006-08-25 2017-09-19 Purdue Pharma L.P. Tamper resistant dosage forms
US8846086B2 (en) 2006-08-25 2014-09-30 Purdue Pharma L.P. Tamper resistant dosage forms
US9775808B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US8894987B2 (en) 2006-08-25 2014-11-25 William H. McKenna Tamper resistant dosage forms
US8894988B2 (en) 2006-08-25 2014-11-25 Purdue Pharma L.P. Tamper resistant dosage forms
US8911719B2 (en) 2006-08-25 2014-12-16 Purdue Pharma Lp Tamper resistant dosage forms
US9763933B2 (en) 2006-08-25 2017-09-19 Purdue Pharma L.P. Tamper resistant dosage forms
US9775809B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9775811B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9775812B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9492393B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9545380B2 (en) 2006-08-25 2017-01-17 Purdue Pharma L.P. Tamper resistant dosage forms
US9492391B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9084816B2 (en) 2006-08-25 2015-07-21 Purdue Pharma L.P. Tamper resistant dosage forms
US9095614B2 (en) 2006-08-25 2015-08-04 Purdue Pharma L.P. Tamper resistant dosage forms
US9095615B2 (en) 2006-08-25 2015-08-04 Purdue Pharma L.P. Tamper resistant dosage forms
US9101661B2 (en) 2006-08-25 2015-08-11 Purdue Pharma L.P. Tamper resistant dosage forms
US9492389B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9492392B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US8834925B2 (en) 2006-08-25 2014-09-16 Purdue Pharma L.P. Tamper resistant dosage forms
US9492390B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9775810B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9486412B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
US9770417B2 (en) 2006-08-25 2017-09-26 Purdue Pharma L.P. Tamper resistant dosage forms
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
US8486448B2 (en) 2007-12-17 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8691270B2 (en) 2007-12-17 2014-04-08 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8920833B2 (en) 2007-12-17 2014-12-30 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8920834B2 (en) 2007-12-17 2014-12-30 Paladin Labs Inc. Misuse preventative, controlled release formulation
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US8383152B2 (en) * 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US8486449B2 (en) 2008-12-16 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8927013B2 (en) 2008-12-16 2015-01-06 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8927014B2 (en) 2008-12-16 2015-01-06 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8685447B2 (en) 2008-12-16 2014-04-01 Paladin Labs Inc. Misuse preventative, controlled release formulation
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
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
WO2012058695A2 (en) * 2010-10-29 2012-05-03 Najib Babul Compositions of (-)-17-(cyclobutylmethyl) morphinan-3, 14-diol
WO2012058695A3 (en) * 2010-10-29 2014-05-15 Najib Babul Compositions of (-)-17-(cyclobutylmethyl) morphinan-3, 14-diol
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9044402B2 (en) 2012-07-06 2015-06-02 Egalet Ltd. Abuse-deterrent pharmaceutical compositions for controlled release
US9730885B2 (en) 2012-07-12 2017-08-15 Mallinckrodt Llc Extended release, abuse deterrent pharmaceutical compositions
US9301918B2 (en) 2013-03-15 2016-04-05 Mallinckrodt Llc Abuse deterrent solid dosage form for immediate release with functional score
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9713611B2 (en) 2014-09-12 2017-07-25 Recro Gainesville, LLC Abuse resistant pharmaceutical compositions
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
US9452163B2 (en) 2014-09-12 2016-09-27 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US9486451B2 (en) 2014-09-12 2016-11-08 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
WO2017189947A1 (en) * 2016-04-28 2017-11-02 Ascent Pharmaceuticals, Inc. Pharmaceutical dosage forms

Also Published As

Publication number Publication date Type
US20160367549A1 (en) 2016-12-22 application
US20140112989A1 (en) 2014-04-24 application
US20160184295A1 (en) 2016-06-30 application
US20130251643A1 (en) 2013-09-26 application
US20170209378A9 (en) 2017-07-27 application
CN101027044B (en) 2012-01-11 grant
ES2402192T3 (en) 2013-04-29 grant
US20060002860A1 (en) 2006-01-05 application
RU2007103707A (en) 2008-11-20 application
RU2396944C2 (en) 2010-08-20 grant
US20150313845A1 (en) 2015-11-05 application
DK1765303T3 (en) 2013-03-25 grant
DE102004032049A1 (en) 2006-01-19 application
US20160175256A1 (en) 2016-06-23 application
CN101027044A (en) 2007-08-29 application

Similar Documents

Publication Publication Date Title
US7201920B2 (en) Methods and compositions for deterring abuse of opioid containing dosage forms
US20040224020A1 (en) Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats
US20110038930A1 (en) Hot-melt extruded pharmaceutical dosage form
US20120059065A1 (en) Tamper Resistant Dosage Form Comprising An Anionic Polymer
US20070259045A1 (en) Alcohol Resistant Dosage Forms
US20080031901A1 (en) Sustained release monoeximic formulations of opioid and nonopioid analgesics
US20090004267A1 (en) Dosage Form with Impeded Abuse
US20100098758A1 (en) Abuse-Resistant Dosage Form
US20120065220A1 (en) Tamper Resistant Dosage Form Comprising An Anionic Polymer
US8192722B2 (en) Abuse-proof dosage form
US20080075771A1 (en) Hydrophilic opioid abuse deterrent delivery system using opioid antagonists
US20070065365A1 (en) Abuse-resistant transdermal system
US20120202838A1 (en) Drug formulations
US20080152595A1 (en) Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20070231268A1 (en) Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20050152843A1 (en) Abuse-proofed dosage form
US9492391B2 (en) Tamper resistant dosage forms
US20060177380A1 (en) Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20080317854A1 (en) Process for the production of an abuse-proofed solid dosage form
US8075872B2 (en) Abuse-proofed dosage form
US20120141583A1 (en) Alcohol resistant dosage forms
US20090005408A1 (en) Process for the production of an abuse-proofed dosage form
US20070183980A1 (en) Dosage form that is safeguarded from abuse
WO2007087452A2 (en) Abuse resistant and extended release formulations and method of use thereof
US20130129826A1 (en) Tamper-resistant oral pharmaceutical dosage form comprising opioid antagonist and/or aversive agent, polyalkylene oxide and anionic polymer

Legal Events

Date Code Title Description
AS Assignment

Owner name: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT

Free format text: CONFIRMATORY GRANT OF SECURITY INTEREST IN UNITED STATES PATENTS (EXCLUSIVELY LICENSED PATENTS);ASSIGNOR:ENDO PHARMACEUTICALS INC.;REEL/FRAME:025456/0172

Effective date: 20101130

AS Assignment

Owner name: MORGAN STANLEY SENIOR FUNDING, INC., AS ADMINISTRA

Free format text: SECURITY INTEREST IN EXCLUSIVELY LICENSED PATENTS;ASSIGNOR:ENDO PHARMACEUTICALS INC.;REEL/FRAME:026561/0978

Effective date: 20110617

AS Assignment

Owner name: ENDO PHARMACEUTICALS INC., PENNSYLVANIA

Free format text: RELEASE OF SECURITY INTEREST IN EXCLUSIVELY LICENSED PATENTS RECORDED AT REEL/FRAME 25456/172;ASSIGNOR:JPMORGAN CHASE BANK N.A., AS ADMINISTRATIVE AGENT;REEL/FRAME:026577/0357

Effective date: 20110617

AS Assignment

Owner name: ENDO PHARMACEUTICALS SOLUTIONS INC., PENNSYLVANIA

Free format text: RELEASE OF PATENT SECURITY INTEREST IN EXCLUSIVELY LICENSED PATENTS;ASSIGNOR:MORGAN STANLEY SENIOR FUNDING, INC., AS ADMINISTRATIVE AGENT;REEL/FRAME:032380/0157

Effective date: 20140228

AS Assignment

Owner name: ENDO PHARMACEUTICALS INC., PENNSYLVANIA

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF RECEIVING PARTY IN RELEASE OF PATENT SECURITY INTERESTIN EXCLUSIVELY LICENSED PATENTS PREVIOUSLY RECORDED ON REEL 032380 FRAME 0157. ASSIGNOR(S) HEREBY CONFIRMS THE RELEASE OF SECURITY INTEREST IN EXCLUSIVELY LICENSED PATENTS.;ASSIGNOR:MORGAN STANLEY SENIOR FUNDING, INC., AS ADMINISTRATIVE AGENT;REEL/FRAME:032513/0255

Effective date: 20140228