US20100015223A1 - Crush-Resistant Tablets Intended to Prevent Accidental Misuse and Unlawful Diversion - Google Patents

Crush-Resistant Tablets Intended to Prevent Accidental Misuse and Unlawful Diversion Download PDF

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US20100015223A1
US20100015223A1 US12/224,374 US22437407A US2010015223A1 US 20100015223 A1 US20100015223 A1 US 20100015223A1 US 22437407 A US22437407 A US 22437407A US 2010015223 A1 US2010015223 A1 US 2010015223A1
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tablets
matrix
compression
tablet
active ingredient
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Vincent Cailly-Dufestel
Catherine Herry
Johnatan Bacon
Pascal Oury
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Ethypharm SAS
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Ethypharm SAS
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    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K9/2095—Tabletting 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • the present invention concerns insoluble matrix tablets having very high crush resistance.
  • the present invention also concerns the method to obtain said tablets and their use for sustained-release, oral administering of the active ingredients, and in particular of psychotropic active ingredients.
  • the phenomenon of accidental misuse may assume several aspects. First, it may arise from failure to heed administering conditions. It may happen that the tablet, intended to be swallowed, is accidentally chewed by the patient. The consequences of full or partial destruction of the tablet whose structure is intended to delay the release of the active ingredient, can prove to be dangerous and even fatal for the patient (excess dosage leading overdose). This is the reason why the leaflet supplied with the drug OxyContin® LP specifically states that ⁇ The tablets must be swallowed whole without being chewed>>.
  • the leaflet supplied with OxyContin® LP indicates in the list of contraindications that the consumption of alcohol is to be avoided with this drug.
  • Drug abuse also affects other classes of therapeutic drugs, in particular benzodiazepines (Rohypnol®), and to a lesser extent certain neurological treatments (Artane® Antiparkinson drug).
  • Rohypnol® benzodiazepines
  • Artane® Antiparkinson drug benzodiazepines
  • the tablet or capsule containing the active ingredients of interest is reduced to a fine powder using any possible means available to the drug addict, in particular a mortar or lighter, even simply by chewing or biting the tablet.
  • the rough powder obtained which necessarily contains the excipients initially present in the pharmaceutical form, can then be dissolved in a small volume of liquid (a few millilitres) sometimes previously heated and/or to which an acid is added for certain active ingredients present in base form (brown heroin, base morphine).
  • the liquid obtained can then be roughly filtered to limit the entry of large particles into the bloodstream, using a cigarette filter for example, before it is injected via intravenous route.
  • the active ingredient then becomes immediately available in the bloodstream, since there is no longer any excipient to delay its release, giving rise to an immediate psychotropic effect sought by drug addicts.
  • Abuse by inhalation also consists of crushing the pharmaceutical form until a sufficiently fine powder is obtained to render the active ingredient accessible to the micro-vessels of the intranasal mucous membrane.
  • the action of the sustained-release excipients, designed for oral administration is fully ineffective and the expected immediate psychotropic effect is able to be achieved.
  • Drug abuse is also accompanied by numerous health risks related directly to injection or inhalation of the excipients and of non-purified crush residues, little or ill-filtered and non-sterile.
  • Recent studies report that some tampered tablets are sometimes dissolved directly in the syringe, then injected without any prior filtering, this practice being directly responsible for numerous deaths through pulmonary embolism.
  • the addition of acids in non-sterile liquid form (lemon juice) to the crush residues is apparently also responsible for the transmission of bacterial or mycosal pathologies (candidiasis).
  • one approach consists of associating the active ingredient in one same pharmaceutical form with an agent capable of limiting the psychotropic effect when the formulation is taken by parenteral route.
  • Patent EP 0 185 472 describes an oral formulation of buprenorphine also containing an effective dose of naloxone, which acts as competing antagonist at the morphone receptors. Since naloxone has only very slight bio-availability via oral route, it little hinders the analgesic action of buprenorphine when the medicinal product is administered conventionally per os. On the other hand, when subject to abuse by parenteral route, naxolone becomes fully available and inhibits the analgesic action of buprenorphine. With this type of chemical association, however, the oral pharmaceutical form remains crushable and soluble in an aqueous medium.
  • patent application US 2003/0143269 describes a pharmaceutical form in which the opioid and the antagonist are interdispersed so that the antagonist is “sequestered” in a compartment preventing it from being released when the medicinal product is taken normally by oral route.
  • the product is tampered with by crushing, deterioration of the structure leads to mixing of the two active agents and to inhibition of the sought after psychotropic effect.
  • patent application US 2003/0068392 describes a pharmaceutical form in which the opioid agent is associated not only with an antagonist, but also with an irritant agent sequestered in a closed compartment. Tampering with the pharmaceutical form inevitably leads to release of the irritant. This form therefore requires the association of three active agents, and the creation of compartmented areas, which makes its manufacture complex and more costly than a simple pharmaceutical form such as a tablet.
  • patent application US 2005/0281748 teaches the manufacture of an oral dosage pharmaceutical form in which the opioid agent of interest is modified so as to increase its lipophilicity, by forming a salt between the active agent and one or more fatty acids.
  • This pharmaceutical form allows the sustained release of the active ingredient when it is taken by oral route, since the enzymes of the gastrointestinal tract gradually break down the groups of fatty acids, releasing the active ingredient as and when they are broken down.
  • any physical tampering of the pharmaceutical form releases microparticles of active ingredient coated with an insoluble layer, preventing the immediate release of the active ingredient in an aqueous medium.
  • Said formulation requires chemical conversion of the active ingredient.
  • Patent application US 2003/0118641 describes an oral dosage form of opioid with sustained release, in which the active opioid ingredient is associated with a hydrophilic polymer matrix and a cationic resin. Since the resin carries opposite charges to the active ingredient, it binds to this ingredient within the polymer matrix, preventing its extraction.
  • Said pharmaceutical form renders the active compound inseparable from the excipients responsible for its sustained release in the body, even if usually available solvents are used (hot water, alcohol, vinegar, hydrogen peroxide, etc. . . . ).
  • Said gels also have the capacity to resist extraction of oxycodone in the presence of an alcohol or acid, the active ingredient remaining trapped in the network formed by the gelling agent.
  • gel-containing pharmaceutical forms are complex formulations, which firstly require the use of high viscosity liquids at industrial level, giving rise to restricted handling, and secondly entail major restrictions with regard to packaging (use of bottles of vials), which is not the case with tablets.
  • Patent EP 0 974 355 describes tablets obtained by granulating a hydrosoluble vitamin mixed with at least one additive of saccharide type, in the presence of a conventional polymer binder such as HPMC for example. Said tablets, intended for swift release of the hydrosoluble vitamin in the body, have high hardness strength, in the order of 20 to 30 kp/cm 2 (kiloponds/cm 2 ), which is equivalent to hardness values of approximately 1.96 to 2.94 MPa. Although relatively hard and consisting of more than 90% hydrosoluble vitamin and of excipients that are also hydrosoluble (HPMC, saccharides), these tablets disintegrate rapidly in the body (disintegration time in the region of 10 to 15 minutes). Said tablets are firstly fully unsuitable for sustained release of the active ingredient, and secondly are easily dissolved in an aqueous medium, making them unfit for use as pharmaceutical form for substances which may be given abuse.
  • Patent EP 0 933 079 describes matrix tablets having a crush resistance varying from around 1 MPa (1 N/mm 2 ) up to 10 MPa. Said tablets are obtained from a treated starch powder that can be directly compressed. However, these tablets are intended for the rapid release of active ingredients, since they have a relatively short disintegration time in an aqueous medium, in the order of approximately 6 to 7 minutes. Owing to their rapid disintegration in an aqueous medium these tablets, here again, cannot be used to convey active ingredients which are liable to be given abuse and which are intended to be released over long time periods.
  • Patent EP 0 997 143 describes the production of bi-convex matrix tablets of very high hardness (up to 1.1 MPa i.e. around 11 kp/cm 2 ) and with a friability of less than 1%, obtained after compressing a matrix consisting chiefly of a compressible, disintegratable carbohydrate (generally mannitol) and a binder. Said chewable tablets, even if they have very high hardness in the solid state, dissolve in an aqueous medium and after a very short period of time in the mouth, and therefore rapidly release the active ingredient into the body.
  • this special grade of ethylcellulose is water-insoluble, limiting the diffusion of liquids and hence release of the active ingredient in the body. Release of the active ingredient is achieved slowly since the tablets obtained from this model show a release profile in which less than 80% of the active ingredient is released after 24 hours.
  • Matrix tablets having very strong crush resistance are also described in the work by Pontier et al. (Pontier et al. Journal of European Ceramic Society, 22 (2002)). In particular, the authors show that it is possible to obtain very hard matrix tablets using mineral excipients of the calcium phosphate family, such as tricalcium phosphate or hydroxyapatite, by direct compression. For example, from a tricalcium phosphate powder, previously granulated then compressed under compression forces in the order of 300 MPa, it is possible to obtain tablets whose crush resistance (tensile strength) can reach 6.5 MPa.
  • this article does not give any information on the capacity of such tablets to release one or more active ingredients over an extended period of time, nor the capacity of such pharmaceutical structures to remain intact in an aqueous medium.
  • Said tablets also have the capability of releasing theophylline in an aqueous medium over a long period of time (60% of active ingredient released in 8 hours) by gradual diffusion through the matrix pores.
  • this article does not allow any conclusion to be drawn on the capacities of said tablets to remain intact in an aqueous medium, and hence to resist abuse by crushing in a liquid medium.
  • Patent application US 2005/0031546 concerns an abuse-deterrent pharmaceutical form containing one or more active ingredients liable to give rise to addiction, and at least one synthetic or natural polymer necessarily having a tensile strength of at least 500 N.
  • the only polymer specifically described is ethylene polyoxide having a molecular weight of 7 000 000 optionally associated with an xanthane gum.
  • These tablets can be prepared using a method which comprises a compression step preceded by a heat exposure step, concomitant with a heat exposure step or followed by a heat exposure step. Therefore the heat exposure step is necessary to obtain the desired hardness. This step, even if of short duration, is firstly not applicable to heat-sensitive active ingredients and secondly requires the use of special equipment and extra energy consumption which contributes towards increasing the cost of the process.
  • the applicant has unexpectedly found a novel, solid, oral pharmaceutical formulation prepared simply in the form of sustained-release matrix tablets, that are both insoluble and ultra-hard. With said tablets, it is possible to prevent the phenomenon of accidental misuse and to curb and even eliminate the phenomenon of drug abuse.
  • the subject-matter of the invention is therefore water-insoluble matrix tablets, capable of releasing one or more active ingredients into the body over extended periods, preferably over periods of more than 12 hours and further preferably more than 20 hours, containing at least one active ingredient which may be the subject of drug abuse dispersed in a compression matrix, said matrix consisting of at least one excipient chosen from the group comprising sustained-release, water-insoluble, pH-independent polymers, mineral excipients and their mixtures, the quantity of said excipient and the compression conditions being chosen so that said tablets have a crush resistance of at least 4 MPa, advantageously at least 6 MPa.
  • the compression conditions do not necessarily entail a heating step of the mixture to be compressed, or of the compression tooling either before or during the actual compression step.
  • the tablets conforming to the invention are used to produce pharmaceutical forms capable of releasing the active ingredient or ingredients they contain, in particular opioid agents, over a period of 24 hours, making it possible for these active ingredients to be taken once-a-day.
  • the terms deliberate misuse or drug abuse are used to designate any intentional deterioration of pharmaceutical forms.
  • the notion of drug abuse concerns reducing the tablets to powder, then inhaling this powder or dissolving it in a small quantity of liquid for its parenteral injection.
  • the term matrix tablet is used to designate a tablet whose inner structure is homogeneous and identical from the core towards the periphery of the tablet. Therefore the tablets of the present invention consist of a homogeneous mixture of active ingredient in powder or granule form and of a compression matrix containing at least one excipient chosen from the group comprising sustained-release, water-insoluble, pH-independent polymers, mineral excipients and their mixtures.
  • compression matrix is used to designate all the excipients which take part in the cohesion of the tablet.
  • Said compression matrix is both water-insoluble and has a certain permeability (hydrophilic matrix) or a porous network (inert matrix) responsible for gradual release of the active ingredient, which does not vary in relation to the pH conditions of the medium.
  • compression mixture>> in the present application is used to designate all the constituents of the tablet (the active ingredient or ingredients, whether granulated or not, and the constituents of the compression matrix) before their compression into tablet form.
  • Hardness characterizes the tensile strength of the tablet under a diametral-compression test. A round tablet is placed between two jaws, one of which is fixed and the other mobile. Hardness corresponds to the force applied by the mobile jaw which causes rupture of the tablet into two more or less equal parts. It is expressed in Newtons (N) ou Kilonewtons (kN) (see European Pharmacopoeia: ref: 01/2005:20908).
  • Crush resistance is inferred from measurement of hardness: it is a parameter which takes into account the surface area of the tablet exposed to the force, and corresponds to strength per unit surface area expressed in Pascals (Pa) ou Megapascals (MPa), 1 MPa corresponding to 1 Newton per mm 2 .
  • Crush resistance is a parameter of particular interest to compare the behaviour of tablets with different surface areas, since it does not require recourse to the parameter of tablet size. Its calculation formula is the following (as per ⁇ Determination of tablet strength by the diametral-compression test>>. Fell, J. T.; Newton, J. M. J. Pharm. Sci., 59 (5): 688-691 (1970)):
  • Rd is the diametral tablet breaking load (in MPa)
  • D is the diameter of the tablet (in mm)
  • H is the thickness of the tablet (in mm).
  • the expression ⁇ sustained-release>> polymers is used to designate polymers routinely used in the pharmaceutical industry to control the release of an active ingredient into its dissolution medium.
  • the sustained-release polymers used are water-insoluble, which means that release of the active ingredient into the surrounding medium occurs exclusively via a phenomenon of simple diffusion, with no erosion or gradual disintegration of the polymer.
  • These polymers effectively have certain permeability vis-á-vis the surrounding medium, responsible for gradual diffusion of the active ingredient out of the polymer matrix. Therefore the lower the permeability of the polymer, the more the diffusion of the active ingredient is sustained.
  • the expression pH-independent polymers is used to designate those polymers capable of forming a permeable network or matrix, and whose permeability is not influenced by the pH of the surrounding medium.
  • the tablets of the invention are also practically insoluble in an aqueous medium, even at low pH (pH ⁇ 3). These characteristics make them difficult to administer via parenteral route.
  • the sustained-release, water-insoluble, pH-independent polymers of the present invention belong to the group comprising cellulose derivatives, the mixture of microcrystalline cellulose and [polyvinyl acetate/polyvinylpyrrolidone (80:20)] (sold under the trade name Kollidon SR®) and the mixture of microcrystalline cellulose and [poly(ethylacrylate/methylmethacrylate/trimethylamonioethyl methacrylate chloride) (1:2:0.2)].
  • excipients present in the compression matrix of the tablets conforming to the present invention advantageously represent between 40 and 100 weight % of the total weight of said matrix, advantageously 50 to 90 weight % of the total weight of the matrix.
  • the compression matrix consists of a (1:1) mixture of two polymers, advantageously it consists of a (1:1) mixture of microcrystalline cellulose and of the mixture [polyvinyl acetate/polyvinylpyrrolidone to a proportion of 80:20 (sold under the trade name Kollidon SR®)], or a mixture of microcrystalline cellulose and [polyethylacrylate/methylmethacrylate/trimethyl-amonioethyl methacrylate chloride in proportions of (1:2:0.2)].
  • these two polymers each represent a weight proportion in the order of 40% of the total weight of said compression matrix.
  • the compression matrix can advantageously, in addition to the excipients of the compression matrix, contain one or more excipients intended to promote the conducting of the compression process such as anti-adherent agents e.g. colloidal silica, talc, magnesium stearate, Polyethylene Glycol (PEG) or calcium stearate, or to promote cohesion of the tablets on compressing such as binders conventionally used for this purpose, in particular starches, cellulose derivatives, or fillers, lubricants, plasticizers, bulking agents, or sweeteners or colouring agents.
  • anti-adherent agents e.g. colloidal silica, talc, magnesium stearate, Polyethylene Glycol (PEG) or calcium stearate
  • binders conventionally used for this purpose, in particular starches, cellulose derivatives, or fillers, lubricants, plasticizers, bulking agents, or sweeteners or colouring agents.
  • these excipients are used conventionally to the proportion of 0.1 to 10 weight % of the total weight of the compression matrix, preferably between 0.5 and 5 weight %.
  • the antagonist is advantageously chosen from the group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine and naluphine, these different compounds each being either in a pharmaceutically acceptable form, in particular a base or salt, or solvated form.
  • These antagonists are present in doses conventionally used, in particular to the proportion of 0.5 to 100 mg per tablet.
  • the tablets conforming to the invention are therefore of particular interest as reservoirs for active ingredients which may be given drug abuse, and which are intended to be released into the body over periods of more than 8 hours, preferably more than 12 hours, and further preferably more than 20 hours.
  • the active ingredients contained in the tablets of the invention can be present in any form known to those skilled in the art, in particular in powder, crystal or granule form.
  • the tablets conforming to the invention may contain one or more active ingredients which may be of any type.
  • active ingredients are chosen which are intended to be controllably released into the body i.e. over periods of at least 8 hours and preferably more than 12 hours, further preferably more than 20 hours.
  • the tablets of the invention are used to produce once-a-day pharmaceutical dosage forms.
  • the tablets of the invention are fully adapted for the sustained release of active ingredients which may be given drug abuse and/or more generally any active ingredients whose rapid or immediate release into the body caused by tampering with the pharmaceutical form could be dangerous or fatal for the consumer.
  • the tablets conforming to the invention are preferably used for the sustained release of active ingredients belonging to the family of psychotropic agents i.e. capable of acting on the psyche by stimulating, tranquillizing or hallucinogenic effects.
  • the active ingredients which can be used under the present invention are preferably derivatives and/or alkaloids of opium, whether natural or synthetic, such as codeine, narceine, noscapine and their salts.
  • the active ingredients which can be used in the invention also belong to the group comprising morphine, its derivatives and their salts, in particular morphinenes such as pholcodine, nalorphine, codeine, dihydrocodeine, hydromorphone, and morphinanes such as buprenorphine, butorphanol, dextromethorphane, nalbufine, naltrexone, naloxone, nalmefene, hydrocodone, oxymorphone and oxycodone, and in general all analogs of morphine and all morphine analgesics such as fentanyl, tramadol, apomorphine and etorphine.
  • morphinenes such as pholcodine, nalorphine, codeine, dihydrocodeine, hydromorphone, and morphinanes such as buprenorphine, butorphanol, dextromethorphane, nalbufine,
  • the present invention also relates to alkaloid derivatives, whether natural or synthetic, having a psychotropic effect such as cocaine or heroin.
  • the present invention also relates to any substances currently used for therapeutic purposes to treat addiction to opiate drugs and/or as substitution and disintoxication treatment, such as methadone and buprenorphine for example, highly subject to drug abuse.
  • the present invention can also be considered for all other therapeutic classes of medicinal products that are currently the subject of drug abuse, in particular neuroleptics, tranquillizers, hypnotics, analgesics, anxiolytics, and in particular the class of benzodiazepines.
  • the active ingredient(s) in the tablets of the invention can represent between 5 and 70 weight % of the total weight of the tablet.
  • the active ingredient(s) represent 10 to 50 weight % of the total weight of the tablet.
  • the active ingredient(s) can be added directly to the mixture to be compressed, coated on carriers (to obtain microgranules) or wet- or dry-granulated (to obtain granules).
  • the depositing (coating) method of the active ingredient is a conventional method known to those skilled in the art and may vary in relation to the type, quantity and fragility of the active ingredient(s) to be deposited. Therefore depositing (coating) can be made by spraying a solution or suspension of the active ingredient(s) onto the surface of the neutral carrier, or by spraying the active ingredient(s) in powder form onto the surface of the carrier previously moistened with a binder solution.
  • the granules of active ingredient(s) may also be obtained by dry or wet granulation of the active ingredients of interest, generally in the presence of at least one binding agent and optionally a wetting agent, depending on techniques, here again well known to those skilled in the art.
  • the granules thus obtained are mixed with the excipients of the compression matrix, and the mixture is then compressed.
  • the exceptional hardness of the tablets conforming to the invention can be obtained without it being necessary to apply a heating step, before or during compression, either to the mixture to be compressed (compression matrix and active ingredient) and/or to the compression tooling (press).
  • the granules containing the active ingredient(s) of interest have a diameter allowing a good compression yield, i.e. generally between 100 and 600 ⁇ m.
  • the active ingredient is mixed directly with the excipients forming the compression matrix, then the mixture is directly compressed.
  • Another possible embodiment of the invention consists of mixing the active ingredient with the excipient(s) of the compression matrix, then dry- or wet-granulating this mixture to obtain directly compressible granules.
  • the tablets conforming to the invention can be of any shape and size allowing tablets of high hardness to be obtained.
  • the total surface area of the tablet is less than 150 mm 2 .
  • the present invention is therefore suitable for the production of tablets with either low or high doses of active ingredient.
  • the tablets can be film-coated with an outer coating which those skilled in the art will know how to adapt in relation to needs and the intended function of this coating.
  • the outer coating can be applied for the purpose of protecting the active ingredient, if it is a labile active ingredient sensitive to the low pH values of the gastric medium for example, in which case the term gastroresistant coating is used.
  • the outer coating can be applied to further delay diffusion of the active ingredient through the matrix.
  • different grades of ethylcellulose can be used, or of methacrylic polymers well known to the skilled person.
  • Said coating can therefore consist of a mixture of one or more excipients of different type known to those skilled in the art, used either alone or in a mixture for the different functions listed above.
  • excipient(s) used for coating are applied in a manner known to those skilled in the art, in the necessary quantity to obtain the desired function(s).
  • the present invention also concerns the method to manufacture the tablets of the invention.
  • This method comprises the following steps:
  • Compression is performed on a rotary compressing machine with pre-compression station.
  • the compression parameters must be chosen so that the hardness of the tablets obtained is adapted to the present invention. However, it is not necessary to apply any heating step either before and/or during compression to the mixture to be compressed or to the compression tooling, for the purpose of achieving the exceptional hardness observed with the tablets of the invention.
  • the applied compression forces lie between 10 kN and 160 kN, advantageously between 30 kN and 80 kN. They are chosen to be compatible with the punch material and so that they can be used at industrial production rates, whilst allowing tablets to be obtained whose tensile strength is greater than 4 MPa, and preferably greater than 6 MPa.
  • FIG. 1 gives the dissolution profile in phosphate buffer medium pH 6.8 (monopotassium phosphate/disodium phosphate) of 40 mg oxycodone HCI tablets, non-film coated, obtained according to example 1.
  • FIG. 2 gives the dissolution profile at pH 6.8 of non-film coated, 40 mg oxycodone HCI tablets, obtained according to example 2.
  • FIG. 3 gives the dissolution profile in phosphate buffer medium pH 6.8 (monopotassium phosphate/disodium phosphate) of tablets conforming to example 2, film-coated with a layer of ethylcellulose EC30 D, which have undergone curing under the conditions of example 3.
  • phosphate buffer medium pH 6.8 monopotassium phosphate/disodium phosphate
  • FIG. 4 gives the comparative dissolution profiles of oxycodone matrix tablets according to the invention in an ethanol-free 0.1 N HCl medium, and in a 0.1 N HCl medium containing 40% ethanol such as measured according to example 4.
  • FIG. 5 illustrates the dissolution profiles of oxycodone matrix tablets conforming to the invention in two dissolution media of different pH (1.2 and 6.8) following the operating mode described in example 4.
  • FIG. 6 illustrates the 24-hour dissolution profiles of 40 mg oxycodone tablets according to the invention, after a storage period in alu/alu blister packs under accelerated stability conditions of 1 month, 2 months, 3 months and 6 months under the conditions of example 4.
  • FIG. 7 illustrates the 24-hour dissolution profiles of 20 mg oxycodone tablets conforming to the invention, after a storage period in HDPE bottles with a desiccant under conditions of accelerated stability of 1 month, 2 months and 3 months.
  • FIG. 8 gives the plasma profiles of oxycodone after once-a-day administration of 40 mg oxycodone tablets conforming to the invention, and 40 mg oxycodone tablets of the reference product OxyContin®, according to example 4.
  • FIG. 9 illustrates the 24-hour dissolution profile, at pH 6.8, of ultra-hard, non-coated tablets of oxycodone and naloxone, according to example 5.
  • FIG. 11 illustrates the dissolution profiles observed with tablets conforming to the invention ( ⁇ QD>>) and tablets of the reference product OxyContin® (ref) at pH 6.8, for whole tablets, tablets cut in half or crushed tablets ( ⁇ in pieces>>)
  • FIG. 12 gives the dissolution profile of microgranules of hydromorphone in an aqueous medium (0.1 N HCl) under three conditions of dissolution: without ethanol, in the presence of 20% ethanol and in the presence of 40% ethanol, for 4 hours according to the conditions of example 9.
  • FIG. 13 gives the dissolution profile of microgranules of morphine sulphate in a dissolution medium of pH 6.8 without ethanol, at pH 6.8 in the presence of 20% ethanol, and at pH 6.8 in the presence of 40% ethanol for 12 hours, according to example 10.
  • FIG. 14 illustrates comparative dissolution tests between ultra-hard tablets of morphine sulphate conforming to the invention, and commercially available tablets of morphine sulphate (Avinza®)) in the presence of: A) 20% ethanol in 0.1 N HCl medium, or B) 40% ethanol in 0.1 N HCl medium, according to example 10.
  • the granules are obtained by wet granulation of the active ingredient (oxycodone HCl, batch N° DV000165; McFarlan Smith, England) and hydroxypropylmethylcellulose (HPMC grade Pharmacoat® 606, Brenntag) which acts as binder. Granulation is conducted in a fluidised bed (GCPG-1, Wurster, Glatt, Germany) by bottom-spraying a solution of the binder (HPMC) onto the active ingredient in powder form.
  • active ingredient oxygen trihydroxypropylmethylcellulose
  • HPMC grade Pharmacoat® 606, Brenntag hydroxypropylmethylcellulose
  • Oxycodone is added to the fluidised bed and placed in sustentation.
  • the binder solution is sprayed onto the powder which aggregates to form granules.
  • Water is progressively removed by evaporation and after a final drying step.
  • the final drying step in an oven (16 hours at 60° C.) is conducted to obtain an acceptable final water content (less than 6%).
  • phase 1 corresponds to spraying of the first 175 g of solution
  • phase 2 corresponds to spraying of the remaining 185 g:
  • the granules obtained after the fluidised bed step have the characteristics indicated in Table 3.
  • a pre-mixture of microcrystalline cellulose (Avicel® PH102, FMC) and precipitated silica (Sylo ⁇ d® 244, Keyser & Mc Kay) is formed in a cubic mixer (AR 401, Erweka) for 2 min at 40 rpm.
  • the mixture of polyvinylacetate/povidone (80:20) (Kollidon® SR, BASF) and the oxycodone granules prepared as described under step 1.1 are added to the pre-mixture and homogenisation is conducted in the cubic mixer for 15 minutes at 40 rpm.
  • the lubricant magnesium stearate, Quimdis
  • intended to limit sticking and friction during compression is added to the preceding mixture using the mixing parameters: 5 minutes at 40 rpm.
  • the quantity of oxycodone granules used is determined with a view to producing tablets containing 40 mg oxycodone.
  • the characteristics of the tablets obtained are summarized in Table 5.
  • the mean values correspond to the mean calculated for 20 tablets.
  • the tablets obtained following Example 1 have very high crush resistance, 6 Mpa, and zero friability, without there being any need to heat the matrix constituents or the compression press before or during compression.
  • the tablets obtained according to Example 1 have hardness and friability characteristics which make them practically unbreakable, meaning that they are excellent candidates for a pharmaceutical medium which can limit abuse thereof by crushing.
  • Measurement of the dissolution of the tablets obtained in Example 1 is performed in 900 mL of dissolution medium buffered at pH 6.8, (monopotassium phosphate/disodium phosphate) using the rotating paddle method with a paddle rotating speed of 100 rpm (Type II paddle apparatus in accordance with the American Pharmacopoeia USP 24).
  • the dissolution medium is continuously analysed by chromatography (HPLC) with UV detection. For each sample, measurement is performed on at least three vessels.
  • the applicant sought to determine the influence of the quantity of binder used during the granulation step on the dissolution profile of the tablets.
  • Example 2 The tablets obtained following Example 2 show very strong crush resistance, equal to 6 Mpa, and zero friability. No heating step before or during compression was necessary to obtain tablets of such hardness.
  • the quantity of binder used has little influence on the release kinetics which extend over 24 h.
  • Example 2 an assessment is made of the influence of an outer coating applied to the oxycodone tablets obtained following Example 2.
  • no heating step was applied either to the mixture to be compressed or to the compression tooling, whether before or during the actual compression.
  • This sub-coat is intended to improve the surface condition of the tablets. It consists of a mixture of HPMC (Pharmacoat® 603), an anti-foaming agent (Simethicone, Dow Corning), a lubricant (micronised talc, Luzenac (Univar) and anti-static agent (Syloid 244, Keyser & McKay), the HPMC representing a weight gain of 3% relative to the total weight of the uncoated tablets.
  • HPMC Puracoat® 603
  • an anti-foaming agent Sithoxymethylcellulose
  • a lubricant micronised talc
  • Luzenac Luzenac
  • anti-static agent Syloid 244, Keyser & McKay
  • This sub-coating is performed in conventional manner in a perforated pan (Trislot).
  • Coating is conducted using an aqueous dispersion of ethylcellulose (Aquacoat® ECD-30, FMC) the proportion of ethylcellulose representing 2.87 weight % of the total weight of the coated tablets.
  • the proportion of the different excipients is given in Table 10.
  • no specific heating step of the tablets was performed, either before or during application of the sub-coat or the actual coating.
  • Coated, sustained-release, 40 mg oxycodone tablets are prepared (technical batch n° XCOX5111).
  • the oxycodone is first granulated in a fluidised air bed (GPCG1) in the presence of water and a binding agent (HPMC 606).
  • GPCG1 fluidised air bed
  • HPMC 606 binding agent
  • a pre-mixture of microcrystalline cellulose (Avicel® PH102, FMC) and precipitated silica (Sylo ⁇ d® 244, Keyser & Mc Kay) is formed in a cubic mixer (AR 401, Erweka) for 2 min at 40 rpm.
  • the polyvinylacetate/povidone mixture (80:20) (Kollidon® SR, BASF) and the oxycodone granules are added to the previous pre-mixture and homogenization is conducted in a cubic mixer for 15 minutes at 40 rpm.
  • the lubricant magnesium stearate, Quimdis
  • intended to limit adherence and compression friction is added to the previous mixture according to the mixing parameters: 3 minutes at 40 rpm.
  • the quantity of granules used is determined so as to manufacture tablets containing 40 mg oxycodone.
  • Compression is performed in conventional manner without either the mixture to be compressed or the compression tooling being subjected to a heating step, whether before or during the actual compression step.
  • the tablets containing 40 mg oxycodone obtained after this step have the following characteristics which are given in Table 13:
  • the tablets conforming to the invention have very high crush resistance, of more than 5 MPa.
  • oxycodone granules are prepared in a high shear granulator.
  • the mixture to be compressed is prepared as described for Examples 1 and 2.
  • the tablets are compressed on a SVIAC PR12 rotary compressor, using oblong punches of different sizes depending on the doses to be manufactured, under a compression force in the order of 10 to 15 kN.
  • the tablets thus manufactured all have excellent crush resistance, which is greater than 6 Mpa irrespective of their size, even though at no time during the process was it necessary to heat the constituents of the tablets or the compression tooling to increase their hardness and resistance.
  • the ⁇ bare>> tablets containing 40 mg of active ingredient after the compression step are then coated with a coating intended to delay their release profile into the body.
  • Coating of the tablets is conducted in a perforated pan (Trislot).
  • Coating uses an aqueous dispersion of ethylcellulose (Aquacoat® ECD-30, FMC) the proportion of ethylcellulose representing 2.87 weight % of the total weight of the coated tablets.
  • Aquacoat® ECD-30, FMC aqueous dispersion of ethylcellulose
  • a curing step of the coating film is carried out in an oven at 60° C. for 24 h.
  • the tablets thus manufactured all have excellent crush resistance, which is greater than 6 MPa irrespective of their size.
  • the tablets of the invention maintain a sustained-release dissolution profile.
  • Dissolution medium of pH 6.8 Dissolution medium of pH 1.2
  • the tablets conforming to the invention maintain a constant sustained-release profile.
  • These tablets can therefore be considered to be pH-independent, imparting thereto a particular advantage insofar as they can be used as vectors for any of type of active ingredient which is to be released over an extended time.
  • coated tablets containing 40 mg oxycodone obtained following the above-described method, are examined with regard to stability in order to determine their reaction to storage.
  • the tablets are stored for 6 months under accelerated stability conditions in accordance with ICH standards in force (45° C.; 75% humidity) in two types of packs: a) Al/Al aluminium blister pack, and b) HDPE bottles (high density polyethylene) in the presence of a desiccant.
  • ICH standards in force (45° C.; 75% humidity) in two types of packs: a) Al/Al aluminium blister pack, and b) HDPE bottles (high density polyethylene) in the presence of a desiccant.
  • the tablets conforming to the invention are therefore stable and show a dissolution profile which is both pH-independent and independent of the presence (even strong presence) of alcohol in the dissolution medium.
  • the 40 mg tablets prepared in this example are also tested in vivo to determine the plasma profile of oxycodone in patients receiving said tablets.
  • a clinical trial (Algorithme, Canada, n° OXY/24018/001) was conducted in 12 healthy, fasting, male and female volunteers separated into two semi-groups. Each semi-group was successively given the two treatments (tablets of the invention and reference product) after an intermediate period without any treatment (wash-out period).
  • the reference product used in this trial was OxyContin®, a sustained-release oxycodone tablet taken twice a day, also containing a dose of 40 mg. (batch N°121777, expiry date April 2007, Purdue).
  • the plasma profiles obtained show that there is no loss of bio-availability of the active ingredient, despite a decrease in Cmax.
  • these matrix tablets containing oxycodone according to the invention have a plasma profile after once-a-day administration in man, such that the ratio of AUC ⁇ observed with these tablets to the AUC ⁇ value observed with OxyContin® extended release tablets having the same dosage, lies within the bioequivalence interval of 80 to 125%.
  • Tablets conforming to the invention are prepared by associating two active ingredients: oxycodone and naloxone.
  • the tablets are produced in the same manner as in Example 4 (granulation of oxycodone in a high shear granulator). They do not undergo any heat treatment either before, during or after compression.
  • Dissolution tests are conducted, as in the preceding examples, under the following conditions: Type II paddle apparatus/100 rpm/medium pH 6.8/volume of dissolution medium: 900 mL/assay by continuous UV spectrophotometry at 225 nm/vessel width: 10 mm.
  • the profile is given FIG. 8 .
  • the aim of this test is to produce tablets conforming to the invention in which mineral excipients are used as chief ingredient of the compression matrix.
  • Tablets are prepared containing oxycodone and dicalcium phosphate dihydrate (Emcompress®) to replace the excipients of Kollidon SR® and Avicel PH 102® type used in the preceding examples.
  • Emcompress® dicalcium phosphate dihydrate
  • the preparation method is identical to the one described in Example 1 (granulation of oxycodone then physical mixing with the powdered excipients of the compression mixture).
  • the tablets so obtained are then placed in a dissolution medium.
  • the dissolution conditions are the following: Type II paddle apparatus; paddle rotating speed: 100 rpm; medium pH 6.8; volume of dissolution medium: 900 ml; continuous UV at 225 nm; vessel 10 mm.
  • the dissolution profile of the reference product is close to that targeted for the bare tablet i.e. without a sustained-release coating, whereas the profile of the tablet of the invention ( ⁇ QD>>) is close to that targeted for a sustained-release tablet.
  • the profile of the oxycodone in the crushed ⁇ QD>> tablet, conforming to the invention, remains a sustained-release profile.
  • the tested tablets are also evaluated regarding the extraction of their active ingredient for injection.
  • the Stéribox® contains:
  • the tested extraction medium is the water supplied with the Stéribox®, in the maximum available volume (2 ml).
  • the operating mode used for extraction is the one described in the leaflet supplied with the Stéribox®:
  • very hard, non-coated tablets are produced conforming to the invention, which contain hydromorphone, an alkaloid derived from morphine having powerful analgesic action used to treat pain and hence subject to drug abuse.
  • Microtablets 3 mm in diameter are prepared containing a dose of 3 mg hydromorphone.
  • composition of the tablets is summarized in Table 28 below.
  • the hydromorphone is first mixed with the excipients forming the compression mixture (Avicel PH102, Kollidon® SR and silica) after a screening step intended to remove large-size particles and other aggregates.
  • Mixing uses a dry process in a conventional blender (V Blender) for 20 minutes.
  • the powdered magnesium stearate is then added to the mixture and the whole is again mixed for 2 to 5 minutes. Compression of the final mixture obtained is obtained by direct compression of the mixture on a 6-station, Sviac RT6 rotary press, using extra-deep concave punches 3 mm in diameter.
  • the applied compression force is 17.8 KN.
  • the hardness of the tablets obtained is greater than 108 N, i.e. a crush resistance of more than 6.8 MPa and with zero friability.
  • the dissolution profile of the tablets prepared in this manner is measured by 12-hour UV spectrophotometry under three conditions:
  • the dissolution conditions are as follows: Type II paddle apparatus; paddle rotating speed: 100 rpm; volume of dissolution medium: 500 ml; 37° C.; filter 45 ⁇ m, automatic sampling (closed circuit) at sampling times of 5, 15, 30, 45, 60, 120, 180 and 240 minutes. UV analysis at 280 nm with 1.0 cm cells; 10 tablets of hydromorphone are deposited in each vessel (equivalent to 30 mg/vessel).
  • First microgranules of morphine sulphate are prepared by coating neutral particles of size 500 to 600 ⁇ m using a binding agent: HPMC.
  • Compression of the final mixture obtained is carried out on a tablet press (PR-12, Sviac) using round punches 10 mm in diameter and a compression force of 26.1 kN.
  • the dissolution profile of the tablets prepared according to the invention is measured by 12-hour UV spectrophotometry at pH 6.8 under three conditions
  • the dissolution results are shown FIG. 13 .
  • the tablets conforming to the invention have a sustained-release profile which is not affected by the presence of ethanol in the dissolution medium. These tablets therefore have major resistance to alcohol, imparting a distinct advantage to the tablets of the invention over other commercially available, sustained-release morphine sulphate tablets.
  • Comparative dissolution tests were conducted on tablets prepared according to the invention and on commercially available morphine sulphate tablets (Avinza®).
  • the dissolution method used was the same as the one described previously, with the sole exception that the dissolution medium is a 0.1N HCl medium. Two conditions were tested: 0.1 N HCl medium in the presence of 20% ethanol (A) and 0.1N HCl medium in the presence of 40% ethanol (B).
  • the dissolution results are shown FIG. 14 .
  • the commercially available product shows a very rapid dissolution profile and is not a sustained-release form. Additionally, it has low alcohol tolerance since the dissolution rate increases with the quantity of alcohol present in the medium.
  • the dissolution rate of the tablet according to the invention is not modified by the presence of alcohol in the medium.

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Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050031546A1 (en) * 2003-08-06 2005-02-10 Johannes Bartholomaus Abuse-proffed dosage form
US20050236741A1 (en) * 2004-04-22 2005-10-27 Elisabeth Arkenau Process for the production of an abuse-proofed solid dosage form
US20060039864A1 (en) * 2004-07-01 2006-02-23 Johannes Bartholomaus Abuse-proofed oral dosage form
US20060188447A1 (en) * 2005-02-04 2006-08-24 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20060193914A1 (en) * 2005-02-04 2006-08-31 Judy Ashworth Crush resistant delayed-release dosage forms
US20070003616A1 (en) * 2003-12-24 2007-01-04 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20070048228A1 (en) * 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US20070183980A1 (en) * 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Dosage form that is safeguarded from abuse
US20080312264A1 (en) * 2004-07-01 2008-12-18 Grunenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US20090004267A1 (en) * 2007-03-07 2009-01-01 Gruenenthal Gmbh Dosage Form with Impeded Abuse
US20090202634A1 (en) * 2008-01-25 2009-08-13 Grunenthal Gmbh Pharmaceutical dosage form
US20110187017A1 (en) * 2010-02-03 2011-08-04 Grunenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US8409616B2 (en) 2003-11-26 2013-04-02 Acura Pharmaceuticals, Inc. Extended release opioid abuse deterrent compositions and methods of making same
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US20140322321A1 (en) * 2011-12-06 2014-10-30 Ethypharm Tablet capable of combatting misuse by injection
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US8927025B2 (en) 2010-05-11 2015-01-06 Cima Labs Inc. Alcohol-resistant metoprolol-containing extended-release oral dosage forms
US8951555B1 (en) 2000-10-30 2015-02-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9060976B2 (en) * 2001-08-06 2015-06-23 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
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
US9233073B2 (en) 2010-12-23 2016-01-12 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
WO2016043698A1 (en) * 2014-09-15 2016-03-24 Inspirion Delivery Technologies, Llc Orally administrable compositions and methods of deterring abuse by intranasal administration
US9616030B2 (en) 2013-03-15 2017-04-11 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9616029B2 (en) 2014-03-26 2017-04-11 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid 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
US9707224B2 (en) 2013-10-31 2017-07-18 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
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
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
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
US9974751B2 (en) 2006-09-15 2018-05-22 Cima Labs Inc. Abuse resistant drug formulation
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
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10420726B2 (en) 2013-03-15 2019-09-24 Inspirion Delivery Sciences, Llc Abuse deterrent compositions and methods of use
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
US10688054B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release morphine, method of use and method of making
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10729685B2 (en) 2014-09-15 2020-08-04 Ohemo Life Sciences Inc. Orally administrable compositions and methods of deterring abuse by intranasal administration
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US11324707B2 (en) 2019-05-07 2022-05-10 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
US11992468B2 (en) 2019-05-07 2024-05-28 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024430A1 (en) 2001-09-21 2003-03-27 Egalet A/S Morphine polymer release system
EP2957281A1 (de) 2001-09-21 2015-12-23 Egalet Ltd. Polymer-freigabe-system
DE602004031096D1 (de) 2003-03-26 2011-03-03 Egalet As Morphin-system mit kontrollierter freisetzung
FR2898056B1 (fr) 2006-03-01 2012-01-20 Ethypharm Sa Comprimes resistant a l'ecrasement destines a eviter le detournement illicite
CA2687192C (en) 2007-06-04 2015-11-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
FR2946533A1 (fr) 2009-06-12 2010-12-17 Ethypharm Sa Reduction des fluctuations plasmatiques d'opioides.
WO2010149169A2 (en) 2009-06-24 2010-12-29 Egalet A/S Controlled release formulations
FR2949061B1 (fr) 2009-08-12 2013-04-19 Debregeas Et Associes Pharma Microgranules flottants
FR2949062B1 (fr) * 2009-08-12 2011-09-02 Debregeas Et Associes Pharma Nouvelles formulations pharmaceutiques contre le mesusage des medicaments
US20110150989A1 (en) * 2009-12-22 2011-06-23 Mallinkckrodt Inc. Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans
CN101843596B (zh) * 2010-03-26 2012-07-25 中国人民解放军广州疗养院 盐酸美沙酮分散片及其制备方法
CA2877183A1 (en) 2012-07-06 2014-01-09 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
CA2919892C (en) 2013-08-12 2019-06-18 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9770514B2 (en) 2013-09-03 2017-09-26 ExxPharma Therapeutics LLC Tamper-resistant pharmaceutical dosage forms
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
CA2910865C (en) 2014-07-15 2016-11-29 Isa Odidi Compositions and methods for reducing overdose
EP3169315B1 (de) 2014-07-17 2020-06-24 Pharmaceutical Manufacturing Research Services, Inc. Missbrauchssichere flüssigkeitsfülldosierform mit unmittelbarer freisetzung
AU2015336065A1 (en) 2014-10-20 2017-05-04 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US20160256452A1 (en) * 2015-03-06 2016-09-08 Develco Pharma Schweiz Ag Composition Of Opioid Receptor Antagonists For Use In Treatment Of Constipation With Highly Increased Whole Gut Transit Time
WO2017151571A1 (en) * 2016-02-29 2017-09-08 First Time Us Generics Llc Abuse deterrent soft chewable drug formulations
CA2937365C (en) 2016-03-29 2018-09-18 F. Hoffmann-La Roche Ag Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same
CN107811985B (zh) * 2016-09-13 2021-05-28 四川科瑞德制药股份有限公司 一种抗癫痫缓释制剂及其制备方法与用途
CN112451493B (zh) * 2020-12-04 2022-06-28 江苏恩华药业股份有限公司 一种防滥用的羟考酮口服缓释片及其制备方法

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773955A (en) * 1970-08-03 1973-11-20 Bristol Myers Co Analgetic compositions
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US4874614A (en) * 1985-03-25 1989-10-17 Abbott Laboratories Pharmaceutical tableting method
US4935245A (en) * 1987-01-24 1990-06-19 Basf Aktiengesellschaft Pulverulent, water-dispersible preparation of a sparingly water-soluble pharmaceutical active compound and its preparation
US5747058A (en) * 1995-06-07 1998-05-05 Southern Biosystems, Inc. High viscosity liquid controlled delivery system
US5952005A (en) * 1993-03-30 1999-09-14 Pharmacia & Upjohn Aktiebolag Controlled release preparation for administering morphine
US6245357B1 (en) * 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US20010038852A1 (en) * 2000-03-29 2001-11-08 Karl Kolter Solid oral dosage forms with delayed release of active ingredient and high mechanical stability
US20020068392A1 (en) * 2000-12-01 2002-06-06 Pt Plus Co. Ltd. Method for fabricating thin film transistor including crystalline silicon active layer
US6413536B1 (en) * 1995-06-07 2002-07-02 Southern Biosystems, Inc. High viscosity liquid controlled delivery system and medical or surgical device
US20020143269A1 (en) * 2001-03-30 2002-10-03 Neuenfeldt Eric Matthew Method and device to reduce needle insertion force
US20030004177A1 (en) * 2001-05-11 2003-01-02 Endo Pharmaceuticals, Inc. Abuse-resistant opioid dosage form
US20030118641A1 (en) * 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US6592901B2 (en) * 2001-10-15 2003-07-15 Hercules Incorporated Highly compressible ethylcellulose for tableting
US20050281748A1 (en) * 2004-06-12 2005-12-22 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US20060193914A1 (en) * 2005-02-04 2006-08-31 Judy Ashworth Crush resistant delayed-release dosage forms
US20070003616A1 (en) * 2003-12-24 2007-01-04 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8430346D0 (en) 1984-11-30 1985-01-09 Reckitt & Colmann Prod Ltd Analgesic compositions
GB8728294D0 (en) 1987-12-03 1988-01-06 Reckitt & Colmann Prod Ltd Treatment compositions
DE9109852U1 (de) 1991-08-09 1991-12-12 CGS Gesellschaft für Entwicklung und Projektierung elektronischer Systeme mbH, 2000 Hamburg Vorrichtung zur Härteprüfung von Tabletten
CA2126441C (en) * 1991-12-30 1999-12-21 David F. Erkoboni Microcrystalline cellulose spheronization composition
JP4098376B2 (ja) 1996-09-05 2008-06-11 ビーエーエスエフ ソシエタス・ヨーロピア 錠剤特性の優れた水溶性ビタミン組成物およびその製造法
DE19709663A1 (de) * 1997-03-10 1998-09-17 Basf Ag Verwendung von redispergierbaren Polymerpulvern oder Polymergranulaten als Bindemittel zur Herstellung von festen pharmazeutischen Darreichungsformen
GB9802201D0 (en) 1998-02-03 1998-04-01 Cerestar Holding Bv Free-flowable directly compressible starch as binder,disintegrant and filler for compresion tablets and hard gelatine capsules
US6270790B1 (en) 1998-08-18 2001-08-07 Mxneil-Ppc, Inc. Soft, convex shaped chewable tablets having reduced friability
SG83757A1 (en) * 1999-12-09 2001-10-16 Wing Thye Lum Powder composition and method for polishing stone
NZ520554A (en) 2000-02-08 2005-08-26 Euro Celtique S Tamper-resistant oral opioid agonist formulations
DE10014588A1 (de) 2000-03-27 2001-10-04 Basf Ag Wirkstoffhaltige Schwimmformen enthaltend Polyvinylacetat und Polyvinylpyrrolidon, deren Verwendung und Herstellung
UA81224C2 (uk) * 2001-05-02 2007-12-25 Euro Celtic S A Дозована форма оксикодону та її застосування
US6708626B2 (en) * 2001-06-11 2004-03-23 Kobe Steel, Ltd. Double-walled damping structure
US7141250B2 (en) * 2001-08-06 2006-11-28 Euro-Celtique S.A. Pharmaceutical formulation containing bittering agent
US7332182B2 (en) 2001-08-06 2008-02-19 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
DE102004032051A1 (de) * 2004-07-01 2006-01-19 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform
DE10336400A1 (de) * 2003-08-06 2005-03-24 Grünenthal GmbH Gegen Missbrauch gesicherte Darreichungsform
EA011374B1 (ru) 2004-01-06 2009-02-27 Панацея Биотек Лимитед Нераспадающаяся твёрдая композиция для перорального применения с высокой дозой растворимых в воде лекарственных средств
FI1765303T4 (fi) * 2004-07-01 2023-01-31 Väärinkäytöltä suojattu oraalinen tabletti
AT8586U1 (de) 2005-06-29 2006-10-15 Lannacher Heilmittel Orale retardformulierung sowie verfahren zu ihrer herstellung
FR2898056B1 (fr) 2006-03-01 2012-01-20 Ethypharm Sa Comprimes resistant a l'ecrasement destines a eviter le detournement illicite

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773955A (en) * 1970-08-03 1973-11-20 Bristol Myers Co Analgetic compositions
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US4874614A (en) * 1985-03-25 1989-10-17 Abbott Laboratories Pharmaceutical tableting method
US4935245A (en) * 1987-01-24 1990-06-19 Basf Aktiengesellschaft Pulverulent, water-dispersible preparation of a sparingly water-soluble pharmaceutical active compound and its preparation
US5952005A (en) * 1993-03-30 1999-09-14 Pharmacia & Upjohn Aktiebolag Controlled release preparation for administering morphine
US6413536B1 (en) * 1995-06-07 2002-07-02 Southern Biosystems, Inc. High viscosity liquid controlled delivery system and medical or surgical device
US5747058A (en) * 1995-06-07 1998-05-05 Southern Biosystems, Inc. High viscosity liquid controlled delivery system
US6245357B1 (en) * 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US20010038852A1 (en) * 2000-03-29 2001-11-08 Karl Kolter Solid oral dosage forms with delayed release of active ingredient and high mechanical stability
US20030118641A1 (en) * 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US20020068392A1 (en) * 2000-12-01 2002-06-06 Pt Plus Co. Ltd. Method for fabricating thin film transistor including crystalline silicon active layer
US20020143269A1 (en) * 2001-03-30 2002-10-03 Neuenfeldt Eric Matthew Method and device to reduce needle insertion force
US20030004177A1 (en) * 2001-05-11 2003-01-02 Endo Pharmaceuticals, Inc. Abuse-resistant opioid dosage form
US6592901B2 (en) * 2001-10-15 2003-07-15 Hercules Incorporated Highly compressible ethylcellulose for tableting
US20070003616A1 (en) * 2003-12-24 2007-01-04 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20050281748A1 (en) * 2004-06-12 2005-12-22 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US20060193914A1 (en) * 2005-02-04 2006-08-31 Judy Ashworth Crush resistant delayed-release dosage forms

Cited By (151)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10076516B2 (en) 1999-10-29 2018-09-18 Purdue Pharma L.P. Methods of manufacturing oral dosage forms
US9675611B1 (en) 1999-10-29 2017-06-13 Purdue Pharma L.P. Methods of providing analgesia
US9669024B2 (en) 1999-10-29 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9669022B2 (en) 1999-10-29 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9320717B2 (en) 1999-10-29 2016-04-26 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9278074B2 (en) 1999-10-29 2016-03-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9056107B1 (en) 1999-10-29 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8980291B2 (en) 1999-10-29 2015-03-17 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9669023B2 (en) 2000-10-30 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9517236B2 (en) 2000-10-30 2016-12-13 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9023401B1 (en) 2000-10-30 2015-05-05 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9056052B1 (en) 2000-10-30 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9060940B2 (en) 2000-10-30 2015-06-23 Purdue Pharma L.P. Controlled release hydrocodone
US9198863B2 (en) 2000-10-30 2015-12-01 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10022368B2 (en) 2000-10-30 2018-07-17 Purdue Pharma L.P. Methods of manufacturing oral formulations
US9682077B2 (en) 2000-10-30 2017-06-20 Purdue Pharma L.P. Methods of providing analgesia
US9205055B2 (en) 2000-10-30 2015-12-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9572804B2 (en) 2000-10-30 2017-02-21 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9572805B2 (en) 2000-10-30 2017-02-21 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9526724B2 (en) 2000-10-30 2016-12-27 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9205056B2 (en) 2000-10-30 2015-12-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8951555B1 (en) 2000-10-30 2015-02-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9504681B2 (en) 2000-10-30 2016-11-29 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9289391B2 (en) 2000-10-30 2016-03-22 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9387173B2 (en) 2001-08-06 2016-07-12 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9387174B2 (en) 2001-08-06 2016-07-12 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9517207B2 (en) 2001-08-06 2016-12-13 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US10130586B2 (en) 2001-08-06 2018-11-20 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US10206881B2 (en) 2001-08-06 2019-02-19 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US9060976B2 (en) * 2001-08-06 2015-06-23 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
US10537526B2 (en) 2001-08-06 2020-01-21 Purdue Pharma L.P. Pharmaceutical formulation containing gelling agent
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
US20080311049A1 (en) * 2003-08-06 2008-12-18 Grunenthal Gmbh Abuse-proof dosage form
US8420056B2 (en) 2003-08-06 2013-04-16 Grunenthal Gmbh Abuse-proofed dosage form
US20080247959A1 (en) * 2003-08-06 2008-10-09 Grunenthal Gmbh Form of administration secured against misuse
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US20070183980A1 (en) * 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Dosage form that is safeguarded from abuse
US20060193782A1 (en) * 2003-08-06 2006-08-31 Johannes Bartholomaus Abuse-proofed dosage form
US20070048228A1 (en) * 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal 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
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
US8637540B2 (en) 2003-11-26 2014-01-28 Acura Pharmaceuticals Compositions for deterring abuse of opioid containing dosage forms
US8822489B2 (en) 2003-11-26 2014-09-02 Acura Pharmaceuticals Abuse deterrent compositions and methods of making same
US9492443B2 (en) 2003-11-26 2016-11-15 Acura Pharmaceuticals, Inc. Abuse deterrent compositions and methods of making same
US8409616B2 (en) 2003-11-26 2013-04-02 Acura Pharmaceuticals, Inc. Extended release opioid abuse deterrent compositions and methods of making same
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
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
US20080317854A1 (en) * 2004-04-22 2008-12-25 Grunenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US20050236741A1 (en) * 2004-04-22 2005-10-27 Elisabeth Arkenau Process for the production of an abuse-proofed solid dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US20080312264A1 (en) * 2004-07-01 2008-12-18 Grunenthal 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
US20060039864A1 (en) * 2004-07-01 2006-02-23 Johannes Bartholomaus Abuse-proofed oral dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
US20060193914A1 (en) * 2005-02-04 2006-08-31 Judy Ashworth Crush resistant delayed-release dosage forms
US20100151028A1 (en) * 2005-02-04 2010-06-17 Grunenthal Gmbh Crush resistant delayed-release dosage forms
US20060188447A1 (en) * 2005-02-04 2006-08-24 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US10675278B2 (en) 2005-02-04 2020-06-09 Grünenthal GmbH Crush resistant delayed-release dosage forms
US20080311187A1 (en) * 2005-02-04 2008-12-18 Grunenthal Gmbh Crush resistan delayed-release dosage form
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US9572803B2 (en) 2006-09-15 2017-02-21 Cima Labs Inc. Abuse resistant drug formulation
US9974751B2 (en) 2006-09-15 2018-05-22 Cima Labs Inc. Abuse resistant drug formulation
US9216176B2 (en) 2006-09-15 2015-12-22 Cima Labs Inc. Abuse resistant drug formulation
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US20090004267A1 (en) * 2007-03-07 2009-01-01 Gruenenthal Gmbh Dosage Form with Impeded Abuse
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US10688055B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences, Llc Abuse resistant forms of extended release morphine, method of use and method of making
US10729657B2 (en) 2007-08-13 2020-08-04 Ohemo Life Sciences Inc. Abuse resistant forms of extended release morphine, method of use and method of making
US11291634B2 (en) 2007-08-13 2022-04-05 OHEMO Life Sciences, Inc. Abuse resistant forms of extended release oxymorphone, method of use and method of making
US11285112B2 (en) 2007-08-13 2022-03-29 Oheno Life Sciences, Inc Abuse resistant forms of immediate release oxymorphone, method of use and method of making
US11278500B2 (en) 2007-08-13 2022-03-22 OHEMO Life Sciences, Inc. Abuse resistant forms of extended release hydrocodone, method of use and method of making
US11191730B2 (en) 2007-08-13 2021-12-07 Ohemo Life Sciences Inc. Abuse resistant forms of immediate release hydromorphone, method of use and method of making
US11045422B2 (en) 2007-08-13 2021-06-29 Oheno Life Sciences, Inc. Abuse resistant drugs, method of use and method of making
US10736851B2 (en) 2007-08-13 2020-08-11 Ohemo Life Sciences Inc. Abuse resistant forms of extended release morphine with oxycodone, method of use and method of making
US10736850B2 (en) 2007-08-13 2020-08-11 Ohemo Life Sciences Inc. Abuse resistant oral opioid formulations
US10736852B2 (en) 2007-08-13 2020-08-11 OHEMO Life Sciences, Inc. Abuse resistant oral opioid formulations
US10729656B2 (en) 2007-08-13 2020-08-04 Ohemo Life Sciences Inc. Abuse resistant forms of immediate release oxycodone, method of use and method of making
US10688054B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release morphine, method of use and method of making
US10702480B2 (en) 2007-08-13 2020-07-07 OHEMO Life Sciences, Inc. Abuse resistant forms of extended release morphine, method of use and method of making
US10695298B2 (en) 2007-08-13 2020-06-30 Inspirion Delivery Sciences, Llc Abuse resistant forms of extended release hydromorphone, method of use and method of making
US10688053B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences, Llc Abuse resistant forms of extended release hydrocodone, method of use and method of making
US10688051B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release oxycodone, method of use, and method of making
US10688052B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release oxymorphone, method of use and method of making
US20090202634A1 (en) * 2008-01-25 2009-08-13 Grunenthal Gmbh Pharmaceutical dosage form
US8383152B2 (en) 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal 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
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10493033B2 (en) 2009-07-22 2019-12-03 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10155044B2 (en) 2009-09-30 2018-12-18 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US20110187017A1 (en) * 2010-02-03 2011-08-04 Grunenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US8927025B2 (en) 2010-05-11 2015-01-06 Cima Labs Inc. Alcohol-resistant metoprolol-containing extended-release oral dosage forms
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9707180B2 (en) 2010-12-23 2017-07-18 Purdue Pharma L.P. Methods of preparing tamper resistant solid oral dosage forms
US9895317B2 (en) 2010-12-23 2018-02-20 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US9233073B2 (en) 2010-12-23 2016-01-12 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10864164B2 (en) 2011-07-29 2020-12-15 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10987309B2 (en) * 2011-12-06 2021-04-27 Ethypharm Tablet capable of combatting misuse by injection
US20140322321A1 (en) * 2011-12-06 2014-10-30 Ethypharm Tablet capable of combatting misuse by injection
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US9730885B2 (en) 2012-07-12 2017-08-15 Mallinckrodt Llc Extended release, abuse deterrent pharmaceutical compositions
US11096887B2 (en) 2012-07-12 2021-08-24 SpecGx LLC Extended release, abuse deterrent pharmaceutical compositions
US10485753B2 (en) 2012-07-12 2019-11-26 SpecGx LLC Extended release, abuse deterrent pharmaceutical compositions
US9320796B2 (en) 2012-11-30 2016-04-26 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10688184B2 (en) 2012-11-30 2020-06-23 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US11857629B2 (en) 2012-11-30 2024-01-02 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10441657B2 (en) 2012-11-30 2019-10-15 Abuse Deterrent Pharmaceuticals, Llc Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10420726B2 (en) 2013-03-15 2019-09-24 Inspirion Delivery Sciences, Llc Abuse deterrent compositions and methods of use
US10195152B2 (en) 2013-03-15 2019-02-05 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US11571390B2 (en) 2013-03-15 2023-02-07 Othemo Life Sciences, Inc. Abuse deterrent compositions and methods of use
US9616030B2 (en) 2013-03-15 2017-04-11 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10517832B2 (en) 2013-03-15 2019-12-31 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10751287B2 (en) 2013-03-15 2020-08-25 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US11207318B2 (en) 2013-10-31 2021-12-28 Clexio Biosciences Ltd. Immediate release abuse-deterrent granulated dosage forms
US9707224B2 (en) 2013-10-31 2017-07-18 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
US9757371B2 (en) 2013-10-31 2017-09-12 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
US11844796B2 (en) 2013-10-31 2023-12-19 Clexio Biosciences Ltd. Immediate release abuse-deterrent granulated dosage forms
US10568881B2 (en) 2013-10-31 2020-02-25 Clexio Biosciences Ltd. Immediate release abuse-deterrent granulated dosage forms
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US9980917B2 (en) 2014-03-26 2018-05-29 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
US9616029B2 (en) 2014-03-26 2017-04-11 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US10729685B2 (en) 2014-09-15 2020-08-04 Ohemo Life Sciences Inc. Orally administrable compositions and methods of deterring abuse by intranasal administration
WO2016043698A1 (en) * 2014-09-15 2016-03-24 Inspirion Delivery Technologies, Llc Orally administrable compositions and methods of deterring abuse by intranasal administration
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11324707B2 (en) 2019-05-07 2022-05-10 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine
US11992468B2 (en) 2019-05-07 2024-05-28 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine

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