WO2013030177A1 - Comprimé résistant à l'abus comprenant de l'oxycodone et du paracétamol - Google Patents

Comprimé résistant à l'abus comprenant de l'oxycodone et du paracétamol Download PDF

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Publication number
WO2013030177A1
WO2013030177A1 PCT/EP2012/066656 EP2012066656W WO2013030177A1 WO 2013030177 A1 WO2013030177 A1 WO 2013030177A1 EP 2012066656 W EP2012066656 W EP 2012066656W WO 2013030177 A1 WO2013030177 A1 WO 2013030177A1
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WO
WIPO (PCT)
Prior art keywords
tablet
weight
oxycodone
layer
gelling
Prior art date
Application number
PCT/EP2012/066656
Other languages
English (en)
Inventor
Céline MALYS
Jean-Baptiste ROCHAIS
Original Assignee
Sanofi
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
Application filed by Sanofi filed Critical Sanofi
Publication of WO2013030177A1 publication Critical patent/WO2013030177A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the invention relates to a tablet formulation based on paracetamol and oxycodone.
  • the invention also relates to a process for preparing said tablet and to the use thereof.
  • analgesics used such as oxycodone
  • narcotics or psychotropic agents which may, in the context of diverted use or misuse, become the subject of drug dependency or abuse.
  • Drug dependency is characterized by the obsessive desire to obtain and to self- administer a substance. Abuse of such substances is defined as excessive and deliberate, permanent or intermittent use having detrimental consequences on the physical or mental health.
  • these analgesics are generally formulated in an oral-use composition, such as a tablet.
  • the analgesics present in the pharmaceutical composition may be extracted chemically under the action of water or other liquids, and may thus be the subject of a diverted use, especially by being administered thereafter generally parenterally in an unauthorized, unsupervised, illegal and dangerous manner.
  • Tablets based on paracetamol and oxycodone exist on the market, in particular the tablets sold under the name Percocet® by the company Endo Pharmaceuticals.
  • the oxycodone present in these tablets may thus be the subject of diverted use and may thus be used, especially after grinding the tablet, dissolving and/or filtering, followed by an extraction of the oxycodone, by drug addicts by administering it by injection, inhalation or orally in solution form.
  • the person thus wishing to divert the use of oxycodone generally seeks to separate the oxycodone from the paracetamol, the latter being hepatotoxic.
  • the Applicant has succeeded in developing a novel formulation of tablets based on these two active agents, which can reduce the risk of abusive and/or diverted use of oxycodone, while at the same time affording the patient a quality of treatment against pain in accordance with his needs and/or comparable to the treatment using the conventional formulations.
  • the Applicant proposes a novel formulation of tablets comprising paracetamol and oxycodone which renders difficult or even impossible separation of the oxycodone from the rest of the tablet and in particular from the paracetamol, thus discouraging the diverted use of oxycodone.
  • the present invention also describes a tablet based on paracetamol and oxycodone which has dissolution and/or pharmacokinetic and/or pharmacological properties comparable to the conventional formulations. Summary of the invention
  • a subject of the present invention is a tablet, characterized in that it comprises at least one active layer comprising paracetamol and oxycodone, and at least one gelling layer comprising hydroxypropylmethylcellulose.
  • the tablet according to the invention renders difficult, or even impossible, the separation of the oxycodone for a diverted use, irrespective of the methods commonly employed for separating oxycodone from the rest of the tablet, and in particular from paracetamol, for instance hot or cold extraction with water or any other suitable extraction liquid.
  • the tablet according to the invention has the advantage of having a release and activity of the active principles that are not impaired by the formulation.
  • the pharmaceutical tablet is advantageously an immediate-release tablet.
  • oxycodone includes oxycodone or a salt thereof.
  • the preferred oxycodone salt is oxycodone hydrochloride.
  • the tablets according to the present invention are of a size suitable for standard oral administration.
  • tablets with a weight of less than 1200 mg and preferably less than 800 mg are preferred.
  • its weight may be between 500 and 1200 mg and advantageously between 600 and 700 mg.
  • novel composition according to the invention thus makes it possible, for assays of active principles that are identical to those of the existing tablets, to have tablets of acceptable sizes for oral administration, despite the addition of constituents that solve the problems indicated above.
  • active layer means a layer comprising the therapeutic agents, namely at least paracetamol and oxycodone.
  • the active layer is prepared especially by mixing paracetamol and oxycodone, and optionally other components, as illustrated, for example, in example 1 .
  • the amount of oxycodone may vary, for example, between 2 and 80 mg (inclusive), and preferably between 2 and 20 mg, and may especially be 2.5; 2.6; 2.7; 2.8.; 3; 3.5; 5; 7.5 or 10 mg.
  • the amount of oxycodone is preferably 2.5 mg in the tablet.
  • the amount of paracetamol may range, for example, between 250 and 650 mg (inclusive), and may especially be 250; 300; 325; 350; 500 or 600 mg.
  • the amount of paracetamol is preferably 325 mg in the tablet.
  • the term "gelling layer" means a layer giving the gelling nature to the tablet.
  • the tablet according to the invention forms a gel under the action of an aqueous medium, such as water or an aqueous solution of an organic acid (for example citric acid or acetic acid) or of a base (for example a sodium bicarbonate or sodium tetraborate solution), or an aqueous-alcoholic solution (for example based on a C1 -C4 alcohol, such as isopropanol or ethanol).
  • an aqueous medium such as water or an aqueous solution of an organic acid (for example citric acid or acetic acid) or of a base (for example a sodium bicarbonate or sodium tetraborate solution), or an a
  • the hydroxypropylnnethylcellulose present in the gelling layer preferably has a viscosity of between 15 000 and 200 000 cp, and advantageously between 75 000 and 140 000 cp (inclusive).
  • cp means centipoises, which is the standard unit of viscosity.
  • the viscosity of hydroxypropylnnethylcellulose is the apparent viscosity measured according to monograph No.0348 relating to the analysis of hypromellose in the European pharmacop/ea (version 7.0).
  • the amount of hydroxypropylnnethylcellulose depends on the characteristics of the tablet, and in particular on the agents and constituents present in the tablet and, of course, on the desired gelling effect. According to one particular embodiment of the invention, the amount of hydroxypropylnnethylcellulose is between 30% and 50% by weight relative to the weight of the gelling layer. More particularly, the amount of hydroxypropylnnethylcellulose is 40% by weight relative to the weight of the gelling layer.
  • the weight ratio of the active layer relative to the gelling layer preferably ranges from 45/55 to 70/30; it may be, for example, 50/50 or 60/40.
  • it is between 55/45 and 65/35; preferably, the ratio is 60/40.
  • the tablet according to the invention may also comprise standard excipients for tablets, including, but in a nonlimiting manner, diluents such as lactose, starches, celluloses, calcium hydrogen phosphate, binders and/or lubricants, optionally glidants agents and optionally disintegrants, such as starch, modified starch, celluloses and/or modified celluloses.
  • diluents such as lactose, starches, celluloses, calcium hydrogen phosphate, binders and/or lubricants, optionally glidants agents and optionally disintegrants, such as starch, modified starch, celluloses and/or modified celluloses.
  • the tablet may also comprise components that can modify the release characteristics of the active agents.
  • the tablet according to the invention has slow release or immediate release of the active agents, preferably immediate release.
  • the tablet according to the invention also comprises, relative to the total weight of the tablet:
  • At least one diluent preferably in a proportion of from 10% to 25% by weight, and/or
  • At least one binder preferably in a proportion of from 1 % to 5% by weight, and/or
  • At least one lubricant preferably in a proportion of from 0.1 % to 3% by weight, and/or
  • At least one glidant preferably in a proportion of from 0.01 % to 1 % by weight, and/or
  • At least one disintegrant preferably in a proportion of from 2% to 10% by weight.
  • the diluent is present in the gelling layer and advantageously in a proportion of between 15% and 20% by weight relative to the total weight of the tablet according to the invention.
  • diluents may be chosen from lactose, starches, celluloses, calcium hydrogen phosphate and a mixture thereof. According to one particularly preferred embodiment of the present invention, the diluent is microcrystalline cellulose.
  • the binder is present in the active layer and advantageously in a proportion of between 1 .5% and 4.0% by weight relative to the total weight of the tablet according to the invention.
  • the binder is advantageously a hydrophilic agent chosen from hydrophilic polymers or hot-melt agents such as cellulose derivatives (hydroxypropylcellulose), povidone (polyvinylpyrrolidone), sucrose, gums, starches, gelatin, macrogols (polyethylene glycols) or a mixture thereof.
  • the binder is polyvinylpyrrolidone (for example Povidone K25 or Povidone K30) and/or pregelatinized starch.
  • the active layer does not comprise any hydroxypropylmethyl cellulose or more generally any gelling agent.
  • the lubricant may be present in the gelling layer, in the active layer or, preferably, in both layers.
  • the amount of lubricant in the tablet is between 0.7% and 3% by weight relative to the total weight of the tablet according to the invention, and in particular in a proportion of from 0.3% to 1 .2% by weight in the gelling layer and in a proportion of from 0.4% to 1 .8% by weight in the active layer.
  • the lubricant is preferably chosen from talc, magnesium stearate, stearic acid, glyceryl monostearate, polyoxyethylene glycols with a molecular weight of from 400 to 7 000 000, hydrogenated castor oil, glyceryl behenate, mono-, bi- or trisubstituted glycerides, sodium stearyl fumarate, sold under the name Pruv® by the company JRS Pharma, and a mixture thereof.
  • the lubricant is magnesium stearate, talc or a mixture thereof.
  • the disintegrant may be present in the gelling layer, in the active layer or, preferably, in both layers.
  • the amount of disintegrant in the tablet is between 2% and 10% by weight relative to the total weight of the tablet according to the invention, and in particular in a proportion of from 1 % to 5% by weight in the gelling layer and/or in a proportion of from 1 % to 5% by weight in the active layer.
  • the disintegrant is chosen in particular from the group consisting of croscarmellose sodium, modified starch and derivatives thereof, crospovidone, sodium carboxymethyl starch, and mixtures thereof.
  • Glidants may also be present in the gelling layer, in the active layer or in both layers, preferably in the gelling layer.
  • the amount of glidants in the tablet is between 0.05% and 0.20% by weight relative to the total weight of the tablet according to the invention, and in particular in a proportion of from 0.05% to 0.20% by weight in the gelling layer.
  • the agents may be chosen especially from colloidal silica or any other silica or silicate, for example the product sold by Degussa under the trade name Aerosil ®, or a mixture thereof.
  • the tablet according to the invention is characterized in that it comprises:
  • At least one diluent which is a microcrystalline cellulose, and/or
  • binder chosen from the group consisting of povidone (K25 and/or K30), pregelatinized starch, and a mixture thereof, and/or
  • At least one disintegrant chosen from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and a mixture thereof, and/or
  • At least one lubricant which is magnesium stearate and/or talc, and/or
  • glidant which is silica.
  • the tablet according to the invention is characterized in that it comprises, relative to the total weight of the tablet:
  • - in the active phase from 0.4% to 2% by weight of oxycodone, from 50% to 60% by weight of paracetamol, from 1 % to 2% by weight of povidone, from 0.5% to 2% of pregelatinized starch, from 1 % to 1 .5% of sodium carboxymethyl starch, from 1 % to 1 .5% of talc, from 0.1 % to 0.15% of magnesium stearate, and
  • - in the gelling phase from 12% to 20% of hydroxypropylmethylcellulose, from 15% to 20% by weight of microcrystalline cellulose, from 3% to 5% by weight of croscarmellose sodium, from 0.1 % to 0.2% of silica and from 0.3% to 0.5% of magnesium stearate.
  • the active layer and the gelling layer are of identical color and appearance, such that separation between these layers is not readily visible by a possible user wishing to divert its use.
  • the tablet comprising at least the two layers advantageously comprises at least one colorant, in at least one of the layers, or in both layers, for example iron oxide (in particular yellow iron oxide) or quinoline yellow, etc.
  • the tablet may also be advantageous for the tablet to comprise, in at least one of the layers, or in both layers, preferably in the gelling layer, at least one nasal irritant, including organic or inorganic acids, salts, ketones, sulfates, bisulfates, persulfates, glycerophosphates, borates, titanates, amino acids or peptides, or a mixture thereof.
  • nasal irritant including organic or inorganic acids, salts, ketones, sulfates, bisulfates, persulfates, glycerophosphates, borates, titanates, amino acids or peptides, or a mixture thereof.
  • Mention may be made in particular of sodium lauryl sulfate, poloxamers, sorbitan monoesters, glyceryl monooleates, or a mixture thereof.
  • sodium lauryl sulfate is used.
  • a coating may be applied to the pre-tableted part consisting of the layers described above.
  • a coated tablet may be particularly advantageous for dissimulating the various layers of the tablet and/or for protecting it against moisture.
  • the tablet according to the invention has a coating.
  • a coated two-layer tablet is particularly preferred.
  • the tablet resulting therefrom may also be subjected in particular to a coating operation, especially by film coating according to operating conditions that are well known to those skilled in the art.
  • the tablet according to the invention is characterized in that it is covered with a film coating.
  • this film coating may comprise at least one component chosen from the group consisting of hypromellose, polyvinyl alcohol, polyethylene glycols, acrylic polymers, titanium dioxide, talc, colorants, and mixtures thereof.
  • a tablet according to the invention that is particularly preferred is an optionally coated two-layer tablet.
  • the tablet according to the invention may comprise more than two layers, namely three layers.
  • a process is proposed for preparing a tablet according to the invention, which comprises the separate preparation of the active layer and of the gelling layer, followed by the assembly of the two layers in a device suitable for manufacturing tablets, optionally followed by the application of a coating using a standard process for coating the tablet thus formed.
  • a tablet with a "sandwich” arrangement may be prepared according to a standard tableting process, in which the first layer is tableted using a suitable composition in powder form and one or more layers are tableted on the first layer or the subsequent layers to form a two-layer or multilayer tablet.
  • the tablet according to the invention may be in various forms, in particular a cylindrical, oblong, elliptical, lenticular, spheroidal, ovoidal or other form.
  • the tablet according to the present invention may be obtained by any standard tableting technique known to those skilled in the art by mixing powders and/or granulation, for example using rotary presses.
  • the components of the tablet according to the invention are mixed together either as a solution or in the form of powders and/or granules, in order then to be optionally dried and then tableted.
  • the mixtures necessary for tableting may be obtained by dry granulation or direct mixing of the constituents.
  • a method is proposed for treating a patient requiring a treatment against pain, in particular occasional, transient or chronic pain, this method comprising the oral administration to said patient of the tablet according to the invention.
  • the invention also relates to the tablet according to the invention for oral use in a method for treating pain, in particular occasional, transient or chronic pain.
  • the invention relates to the tablet according to the invention for use in a therapeutic treatment method, in particular for treating pain, and more specifically occasional, transient or chronic pain, which is directed toward avoiding the diverted use of the oxycodone present in the tablet.
  • the examples that follow illustrate the present invention without, however, limiting its scope. Unless otherwise indicated, the percentages indicated are weight percentages.
  • Oxycodone and yellow iron oxide are predispersed with part of the mixture consisting of the other components of the active layer, including paracetamol. This dispersion is then mixed with the rest of the mixture. The mixture obtained is calibrated on a calibrator of oscillating or rotary type.
  • the mixture is then lubricated with talc and magnesium stearate using an overturning mixer.
  • Preparation of the gelling layer The constituents of the gelling layer are screened on a manual or vibrating screen, and then mixed. The mixture is then lubricated with magnesium stearate using an overturning mixer. The two layers thus prepared are tableted on a two-layer rotary press.
  • a tablet is prepared according to the process of example 1 . Its composition is detailed in Table 1 below. Table 1
  • the hypromellose 100 000 cp was replaced with pregelatinized potato starch, which is another ingredient that can be used as a gelling agent.
  • pregelatinized potato starch which is another ingredient that can be used as a gelling agent.
  • the tablet then obtained, once ground and placed in contact with water, gives insufficient gelling to limit the injection.
  • the gelling layer greatly limits the recovery of the oxycodone: only 14% by weight of the oxycodone present is recovered.
  • volume of water is increased in order to be able to pass through a filter (for example such as a coffee filter) (about 200 ml), then 46% paracetamol and 34% oxycodone are recovered.
  • a filter for example such as a coffee filter
  • the gelling layer thus prevents the practice of cold extraction of the paracetamol.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Emergency Medicine (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une formulation de comprimé à base de paracétamol et d'oxycodone. L'invention concerne également un procédé de préparation dudit comprimé et l'utilisation de celui-ci.
PCT/EP2012/066656 2011-08-29 2012-08-28 Comprimé résistant à l'abus comprenant de l'oxycodone et du paracétamol WO2013030177A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1102623A FR2979242A1 (fr) 2011-08-29 2011-08-29 Comprime contre l'usage abusif, a base de paracetamol et d'oxycodone
FR1102623 2011-08-29

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WO2013030177A1 true WO2013030177A1 (fr) 2013-03-07

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US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
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US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
WO2016170094A1 (fr) 2015-04-24 2016-10-27 Grünenthal GmbH Combinaison inviolable de doses fixes permettant la libération rapide de deux médicaments à partir de particules
WO2016170093A1 (fr) 2015-04-24 2016-10-27 Grünenthal GmbH Combinaison à dose fixe inaltérable présentant une libération rapide de deux médicaments de particules et d'une matrice
WO2016170096A1 (fr) 2015-04-24 2016-10-27 Grünenthal GmbH Combinaison inviolable de doses fixes permettant la libération rapide de deux médicaments à partir de particules différentes
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
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
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
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US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
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US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
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US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form

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US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US9884029B2 (en) 2003-03-26 2018-02-06 Egalet Ltd. Morphine controlled release system
US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
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