EP2040685A2 - Forme pharmaceutique orale multimicroparticulaire a liberation prolongee comprenant des moyens anti-mesusage et resistant a l'alcool - Google Patents

Forme pharmaceutique orale multimicroparticulaire a liberation prolongee comprenant des moyens anti-mesusage et resistant a l'alcool

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Publication number
EP2040685A2
EP2040685A2 EP07729498A EP07729498A EP2040685A2 EP 2040685 A2 EP2040685 A2 EP 2040685A2 EP 07729498 A EP07729498 A EP 07729498A EP 07729498 A EP07729498 A EP 07729498A EP 2040685 A2 EP2040685 A2 EP 2040685A2
Authority
EP
European Patent Office
Prior art keywords
microparticles
pharmaceutical form
agent
form according
mixtures
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07729498A
Other languages
German (de)
English (en)
French (fr)
Inventor
Florence Guimberteau
Frédéric DARGELAS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Flamel Ireland Ltd
Original Assignee
Flamel Technologies SA
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 Flamel Technologies SA filed Critical Flamel Technologies SA
Publication of EP2040685A2 publication Critical patent/EP2040685A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/745—Polymers of hydrocarbons
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the field of the present invention is that of the modified-release pharmaceutical dosage forms of medicamentous active principles (PA) intended for oral administration, containing at least one AP, capable of maintaining a modified release of AP in an alcoholic solution, that is, not subject to rapid discharge of the dose in the presence of alcohol; moreover they comprise anti misuse means.
  • PA medicamentous active principles
  • the PAs considered are pharmaceutical and / or veterinary PAs, for example those classified as narcotics, analgesics or narcotics.
  • the abuse of these AP can lead to addictive behaviors.
  • the present invention relates more particularly to pharmaceutical forms of the type referred to in the preceding paragraph and comprising a plurality of reservoir microparticles.
  • the present invention relates more particularly to pharmaceutical forms for which the ingestion of alcohol during administration is disadvised.
  • the object of the present invention is to improve the multimicroparticulate pharmaceutical forms designed to resist attempts of misuse, the improvement of avoiding the patient a rapid discharge of the dose in the presence of a large volume of alcoholic solution.
  • the invention also relates to a process for the preparation of the pharmaceutical forms mentioned above.
  • modified-release dosage forms for administering a drug is well known.
  • they make it possible to better cover the therapeutic need, since the useful plasma concentration in AP can be maintained longer than in the case of instantaneous release forms.
  • they make it possible to limit the height and the number of plasma concentration peaks in PA, which reduces the toxicity of the drug and / or reduces its side effects.
  • the interest of the modified-release forms is, in this respect, particularly marked for active ingredients with a narrow therapeutic window.
  • these systems make it possible, by their increased duration of action, to limit the number of daily intake, which reduces stress for the patient and improves adherence to treatment.
  • a modified release form should therefore ideally be capable of preventing accidental accelerated release of the AP in an alcoholic solution.
  • a modified-release form must be able to prevent the intentional misuse of certain active substances such as opiates, which poses a real public health problem.
  • Intentional misuse is mainly found in the case of drug addiction and chemical servoing. In both cases, people intending to misuse a solid oral drug will usually seek to extract PA from the modified-release form to obtain a fast-acting product.
  • the pharmaceutical form MR must prevent three modes of intentional misuse:
  • obtaining a liquid form from a solid oral drug generally goes through a step of extraction, in aqueous or organic phase, of the targeted PA. This extraction is usually preceded by grinding.
  • the modes of administration 1) by inhalation or 2) by injection are particularly suitable for drug addicts because they are modes which make it possible to accentuate the effects of the AP and which favor its rapid absorption in the organism.
  • the powder obtained by grinding is sucked by the nose or dissolved in water and injected, the desired effects, doping or euphoric, of PA, manifest very rapidly and exacerbated.
  • Mode 3 also constitutes a particularly serious drift which affects adolescents and concerns analgesic PAs, especially morphine and opiate derivatives. From a strong alcoholic drink and an opiate analgesic, including oxycodone, and with some manipulation, it is possible to extract the opiate analgesic, which can then be absorbed by an addict.
  • the misuse of solid oral medications may also be observed when, instead of being swallowed quickly according to the prescription, the drug is chewed before being swallowed, thus bypassing the step of slow disintegration in the stomach and resulting in a discharge of the dose.
  • an MR release form must make it possible to avoid intentional or unintentional misuse of the AP.
  • the MR form must simultaneously exhibit the following four essential properties: a) Do not lead to an accelerated release of AP in an alcoholic solution, such as could occur for example in a patient who accidentally absorbs the drug with a alcoholic drink ; b) be difficult to grind in the form of an immediate release powder, for example to prevent inhalation of the PA; c) be difficult to extract in a small volume of liquid, and thus prevent parenteral injection of PA; d) not lead to the massive solution of PA in an alcoholic beverage or not and thus prevent the oral administration of PA in IR form even after a long contact time.
  • the unpublished application FR 06 50566 describes multimicroparticulate pharmaceutical forms capable of withstanding the accidental discharge of the dose. in the presence of alcohol, particularly to address the concerns of health professionals in the case of accidents caused by this in vivo dose dumping (dumping dose), in patients who have ingested a sustained-release dosage form at the same time as a significant dose of alcohol.
  • dumping dose in patients who have ingested a sustained-release dosage form at the same time as a significant dose of alcohol.
  • These modified release forms possess the property of maintaining the modified release of the PA even in a large volume of alcoholic solution (50 to 900 ml). However, these forms are not designed to withstand attempts to misuse, in particular by grinding a dry form, possibly followed by extraction in a liquid medium.
  • the unpublished application FR 05 53437 describes multimicroparticulate pharmaceutical forms designed to be resistant to misuse, especially intentional misuse. These fraudulent diversions of oral medications involve different stages (grinding, extraction), and said application describes controlled release oral forms comprising anti-misuse means:
  • the coated PA microparticles comprise a coating layer which confers resistance to grinding
  • the pharmaceutical forms of this application contain a viscosifying agent making it very difficult, if not impossible, to extract the PA in a liquid medium;
  • this invention does not propose a technical solution to simultaneously satisfy the four conditions a), b), c) and d) recalled supra.
  • An object of the invention is to provide new solid oral drugs satisfying the specifications mentioned above.
  • PA in an alcoholic solution whose misuse by grinding or after extraction of the PA in a small volume of solvent will be made difficult or impossible.
  • Another object of the invention is to provide novel oral solid drugs, having the following characteristics:
  • Another object of the invention is to provide new solid oral drugs, to prevent the fraudulent diversion of the properties of the PA it contains, making it difficult to administer the drug by the oral, nasal and / or injectable routes. (intravenous, subcutaneous, intramuscular, etc.) outside the therapeutic setting.
  • Another object of the invention is to provide new solid oral drugs, to prevent misuse, while ensuring, for the patient normally followed, a quality of treatment, especially a dose according to his needs.
  • Another object of the invention is to provide a method of manufacturing solid oral drugs resistant to the immediate discharge of the dose of PA in the presence of alcohol and comprising anti-misuse means.
  • modified release form or MR form are synonymous and include: o reservoir systems that is to say the systems where the release of PA is controlled by a coating surrounding the PA.
  • matrix systems in which PA, intimately dispersed in a matrix, for example based on polymer, is released by diffusion and / or erosion.
  • active principle and the abbreviation PA "denote both a single active ingredient that a mixture of several active ingredients.
  • the AP can be in free form or in salt, ester, hydrate, solvate, polymorph, isomer or other pharmaceutically acceptable form;
  • the ingested alcohol can come from different alcoholic beverages or beverages such as beer, wine, cocktails, spirits or their mixtures; in vitro, the term “alcohol” without further precision represents ethanol and the terms "alcoholic solution” or “alcoholic medium” represent an aqueous solution of ethanol;
  • reservoir microparticles refers to microparticles comprising PA and individually coated with at least one coating allowing the modified release of the AP;
  • PA microparticles denotes indifferently reservoir microparticles and / or microparticles comprising PA that are not necessarily coated;
  • microparticles of viscosifying agent means microparticles comprising at least one viscosifying agent and possibly other excipients, excluding PA;
  • quenching agent (English quenching agent) denotes a complexing agent, a deactivating or inactivating agent, a chelator, a precipitating agent, or a scavenger agent capable of interacting with an AP, and disable it;
  • quenching agent microparticles means microparticles comprising at least one sequestering agent and optionally other excipients, excluding AP;
  • microparticles denotes indifferently reservoir microparticles, uncoated PA microparticles, PA microparticles, viscosifying agent microparticles and sequestering agent microparticles, taken alone or as a mixture;
  • modified release means that the release of PA in vitro is such that 75% of the AP is released in a time greater than 0.75 h and preferably greater than 1 h, and more preferably greater than 1, 5 h.
  • a modified release dosage form may, for example, include an immediate release phase and a slow release phase. The modified release can be in particular a prolonged and / or delayed release.
  • Pharmaceutical release forms modified are well known in this field; see for example Remington: The Science and Practice of Pharmacy, 19 th Edition, Mack Publishing Co. Pennsylvania, USA;
  • immediate release means that the release is not of the modified release type and refers to the release by one form of most of the AP in a relatively short time: at least 75% of the AP is released in 0.75 h preferably in 30 minutes;
  • agglomerate or “granule” relates to structures comprising a plurality of microparticles bonded together by an agent D, optionally comprising other excipients, the diameter of the agglomerates or granules being preferably less than 8000 microns;
  • the multimicroparticulate oral pharmaceutical forms according to the invention consist of numerous microparticles whose size is less than one millimeter.
  • the diameters of the microparticles referred to herein are, unless otherwise indicated, mean diameters by volume.
  • These multimicroparticulate forms may be presented and adapted by those skilled in the art in any pharmaceutically acceptable form such as tablets, capsules, sachets, suspensions to be reconstituted;
  • unitary form the pharmaceutical form which contains a dose of PA which may be in the form of, for example, tablets, capsules, sachets, suspensions to be reconstituted;
  • dose dumping or “dose discharge” means an immediate, or significantly accelerated and unintended release of the AP dose after oral ingestion.
  • the pharmaceutical form according to the invention implements harmless physicochemical means (they are pharmacologically neutral compounds, approved as excipients by the various pharmacopoeias and registration authorities) and economic.
  • the approach which has been adopted to measure the resistance of pharmaceutical forms MR to a discharge of the alcohol-induced dose consists in modifying the conventional tests for dissolving MR dosage forms by introducing ethanol into the dissolution medium. for example at a concentration of 10% or 40% (v / v).
  • the order of magnitude of the final volume is 50 to 900 mL.
  • the profile of the desired pharmaceutical form must be adapted to the specifications and depends on the coating of the microparticles. In doing so, it must avoid leading to unwanted behaviors such as: dissolution profiles that are not controllable, in particular the profile is no longer completely controlled by the coating of the microparticles; the loss of the anti-grinding properties of the microparticles of PA; - a discharge of the dose in the presence of alcohol.
  • the inventors were able to reconcile the properties conferred by excipients of different types, to find, by a judicious choice of the nature of each of these excipients (coating excipient, viscosifier, sequestering agent, etc.), their location (in a microparticle, a binder, a granule, etc.) and their content, a formulation that meets the initial specifications.
  • the present invention is directed to an oral pharmaceutical form comprising reservoir-type microparticles, with modified release of at least one AP, not subject to a discharge of the dose in the presence of alcohol, that is to say which is resistant to the immediate discharge of the PA dose in the presence of alcohol, in particular in a large volume and, moreover, whose composition and structure make it possible to avoid the misuse of the PA that said form contains, in particular thanks to anti-misuse means.
  • the anti-misuse means comprise at least anti-grinding means.
  • This pharmaceutical form according to the invention is characterized in that: the means preventing the discharge of the dose of PA in the presence of alcohol comprise at least one agent D which is a pharmaceutically acceptable compound whose speed or capacity to to hydrate or to solvate is superior in an aqueous medium free of alcohol than in alcoholic solution; and at least a portion of the AP is contained in coated microparticles having a coating layer R which provides the modified release of the AP and which at the same time imparts a resistance to grinding to the coated microparticles of PA, to avoid misuse; and optionally at least one viscosifying agent V; and optionally at least one sequestering agent Q.
  • the means preventing the discharge of the dose of PA in the presence of alcohol comprise at least one agent D which is a pharmaceutically acceptable compound whose speed or capacity to to hydrate or to solvate is superior in an aqueous medium free of alcohol than in alcoholic solution; and at least a portion of the AP is contained in coated microparticles having a coating layer R which provides the modified release
  • the oral pharmaceutical form according to the invention is characterized in that the release time of 50% of the PA in an alcoholic solution is not decreased by more than 3 times compared to the release time of 50% of the PA measured in an aqueous medium free of alcohol.
  • the present invention also relates to a process for obtaining an oral solid pharmaceutical form, anti-misuse by grinding and alcohol extraction.
  • the oral pharmaceutical form according to the invention has anti-misuse properties; it comprises reservoir-type microparticles and allows the modified release of the PA both in aqueous dissolution media and in alcoholic solutions.
  • the modified-release coated microparticles of PA are microparticles each coated with at least one coating (comprising for example at least one polymer) deposited according to the techniques known to those skilled in the art.
  • at least one coating comprising for example at least one polymer
  • Buri, et al. New Pharmaceutical Forms
  • the pharmaceutical form according to the invention is multimicroparticulate; it comprises, inter alia, reservoir microparticles with a core comprising the coated PA or film by a coating.
  • This PA heart, or PA microparticle can be:
  • raw (pure) PA in pulverulent form and / or a matrix granule of PA mixed with various other ingredients, and / or a supported granule, such as a neutral carrier, for example cellulose or sugar, covered with at least one layer comprising PA.
  • a neutral carrier for example cellulose or sugar
  • the matrix contains PA and optionally other pharmaceutically acceptable excipients, such as binding agents, surfactants, disintegrants, fillers, pH-controlling or modifying agents (buffers).
  • excipients such as binding agents, surfactants, disintegrants, fillers, pH-controlling or modifying agents (buffers).
  • the layer containing the PA optionally contains other pharmaceutically acceptable excipients, such as binding agents, surfactants, disintegrants, fillers, agents controlling or modifying the pH
  • the neutral carrier can be composed of sucrose and / or sucrose and / or dextrose and / or lactose, and / or sucrose / starch mixture.
  • the neutral carrier may also be a cellulose microsphere or other pharmaceutically acceptable excipient particle.
  • a neutral support mention may be made of particles of xanthan gum, guar gum, calcium phosphate and calcium carbonate.
  • the neutral support has a mean diameter of between 1 and 800 ⁇ m and preferably between 20 and 500 ⁇ m.
  • the PA coated microparticles comprise at least one coating layer R, better still, a single coating layer R, which provides the modified release of the AP and which simultaneously confers grinding resistance to the coated PA microparticles, for avoid misuse.
  • the coating layer R is designed such that it allows, in the case of grinding, the maintenance of a non-immediate release (that is to say modified) for at least a portion of the coated microparticles with modified release of AP.
  • the milling contemplated herein may be, for example, any grinding carried out according to the techniques usually employed by the misusers, namely in particular: mortar / pestle, coffee grinder, crushing between two spoons, crunching / chewing, etc.
  • the coating R is designed such that it allows, in the case of grinding, the maintenance of a modified release for at least 40%, preferably at least 60%, and more preferably still at least 80% of coated microparticles with modified PA release.
  • the anti-grinding coating layer R comprises:
  • At least one (co) polymer A2 is soluble in the liquids of the digestive tract; at least one plasticizer A3;
  • - Al is chosen from the group comprising: o non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, o acrylic polymers, for example copolymers of (meth) acrylic acid and alkyl ester (eg methyl), copolymers of acrylic and methacrylic acid ester carrying at least one quaternary ammonium group (preferably at least one a copolymer of alkyl (meth) acrylate and trimethylammonioethyl methacrylate chloride) and more specifically the products sold under the trade names Eudragit ® RS and / or Eudragit ® RL o polyvinylacetates, o and mixtures thereof;
  • A2 is selected from the group consisting of: nitrogen-containing (co) polymers, preferably in the group comprising poly-acrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams; water-soluble derivatives of cellulose, polyvinyl alcohols (PVA), polyalkylene oxides, preferably ethylene polyoxides (POE), polyethylene glycols (PEG), and mixtures thereof; PVP being particularly preferred;
  • A3 is selected from the group consisting of: esters of cetyl alcohol, glycerol and its esters, preferably in the following subgroup: acetylated glycerides, glycerolmonostearate, glyceryltriacetate, glyceroltributyrate, phthalates, preferably in the following subgroup: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, citrates, preferably in the following subgroup: acetyl tributyl citrate, acetyltriethyl citrate, tributyl citrate, triethyl citrate, sebacates, preferably in the following subgroup: diethyl sebacate, dibutyl sebacate, adipates, azelates benzoates, vegetable oils, fumarates, preferably diethylfumarate, malates, preferably diethylmalate, oxalates, preferably dieth
  • anionic surfactants preferably in the subgroup of alkali or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred, and / or nonionic surfactants, preferably in the polyoxyethylenated oils subgroup, preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene (poloxamer) copolymers, polyoxyethylenated sorbitan esters, polysorbates, or castor oil derivatives polyoxyethylenated, stearates, preferably calcium, magnesium, aluminum or zinc, stearyl fumarates, preferably sodium, o glycerol behenates, o talc, o colloidal silica, o titanium oxide, magnesium oxide, o bentonite, o microcrystalline cellulose, o kaolin, o aluminum silicate, o and their mixtures.
  • anionic surfactants preferably in the subgroup of alkali
  • the coating layer R contains the following components:
  • Al is chosen from the group comprising the non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate,
  • - A2 is selected from the group comprising: • the nitrogenous (co) polymers, preferably from the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl lactams, o • water-soluble derivatives of cellulose, • o polyethylene glycols (PEG), o • and mixtures thereof;
  • the nitrogenous (co) polymers preferably from the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl lactams, o • water-soluble derivatives of cellulose, • o polyethylene glycols (PEG), o • and mixtures thereof;
  • A3 is selected from the group consisting of triethyl citrate, dibutyl sebacate, vegetable oils, castor oil and mixtures thereof;
  • A4 is selected from the group comprising: nonionic surfactants, preferably in the following subgroup: polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene (poloxamer) copolymers, esters polyoxyethylenesorbitan, polysorbates, stearates, preferably magnesium, and mixtures thereof.
  • each component A1, A2, A3 and A4 of the coating layer R its mass m (in% of the total mass A1 + A2 + A3 + A4) satisfies for Al: 10 ⁇ m ⁇ 90, preferably 15 ⁇ m ⁇ 80, and more preferably 60 ⁇ m ⁇ 80; for A2: 2 ⁇ m ⁇ 50, preferably 3 ⁇ m ⁇ 40, and more preferably 5 ⁇ m ⁇ 25; for A3: l ⁇ m ⁇ 30, preferably 2 ⁇ m ⁇ 20, and more preferably 5 ⁇ m ⁇ 15; for A4: 0 ⁇ m ⁇ 40, preferably 0 ⁇ m ⁇ 30, and more preferably 0 ⁇ m ⁇ 20.
  • the coating layer R represents a mass fraction Tp, expressed in% by dry weight, such that: Tp> 15; preferably between 30 and 60, and more preferably between 40 and 60, and more preferably between 45 and 55, or about 50.
  • the coated PA microparticles have a mean diameter by volume of less than or equal to 1000 ⁇ m, preferably between 50 and 800 ⁇ m and, more preferably, between 100 and 600 ⁇ m, and better still, between 100 and 400 ⁇ m. .
  • the diameter of the microparticles is, unless otherwise stated, a mean diameter by volume.
  • the techniques used for the production of PA microparticles are conventional techniques, such as, for example, the spray coating technique in fluidized air bed, the wet granulation, the compacting, the extrusion-spheronization.
  • the pharmaceutical form according to the invention comprises at least one agent D which is a pharmaceutically acceptable compound and whose rate or capacity to hydrate or to be solvated is greater in an aqueous medium free of alcohol than in alcoholic solution. It may be: a compound with a higher solubilization rate in water than in alcoholic solution;
  • the agent D is chosen from the following group of products:
  • Cellulosic derivatives such as, for example:
  • alkyl celluloses (for example hydroxypropylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose), carboxyalkylcelluloses (for example carboxymethylcellulose) and their salts,
  • celluloses binder or microcrystalline
  • Crosslinked carboxyalkylcelluloses crosslinked carboxymethylcelluloses (for example croscarmellose sodium)
  • polyalkylene oxides for example polyethylene oxide or polypropylene oxide.
  • Polysaccharides for example:
  • native starches eg corn, wheat or potato
  • modified starches eg with sodium glycolate
  • Alginates and their salts such as sodium alginate,
  • Clays such as bentonite, laponite and mixtures thereof.
  • agent D is chosen from the following group of products:
  • hydroxyalkylcelluloses for example hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose
  • agent D can be incorporated in various ways, possibly combined with each other, in the pharmaceutical form according to the invention. It can be one of the constituents:
  • agent D is present in the heart of PA, or microparticle not coated with PA.
  • agent D is present in the core of the microparticles at 5 to 70%, preferably 15% to 60% of the total mass of the PA core.
  • the agent D is included in the coating of the microparticles.
  • the agent D can constitute alone a coating layer internal or external to the coating controlling the diffusion. It can also be mixed with the constituents A1, A2, A3 and possibly A4 of the coating which governs the modified release of the AP.
  • the agent D is present in the coating in a proportion of 3 to 30%, preferably 10% to 20% of the total weight of the coating.
  • the following compounds are selected: the polymer A1 is ethylcellulose, the polymer A2 is PVP, the plasticizer A3 is castor oil, A4 is a poloxamer, and the agent D is chosen from guar gum, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and mixtures thereof.
  • the agent D is included in the binder phase of granules or pellets or tablets including the microparticles of PA.
  • the granules, pellets or tablets are obtained by the techniques known to those skilled in the art such as granulation, extrusion or compression.
  • Agent D is present as a mixture with the microparticles, in a proportion of 0.5 to 30% w / w, preferably of 0.5% to 25% w / w, and even more preferably of 1% to 20% w / w. / p, of the total mass of the mixture.
  • the agent D is at least partly in the form of microparticles or, preferably, of granules distinct from those containing the PA.
  • coated microparticles of PA are granulated according to conventional techniques, and granules of the same size and density of agent D are prepared separately, which granules may also contain a viscosifier and / or a sequestering agent (see below).
  • agent D is one of the components of the capsule material that contains the microparticles.
  • the agent D is included in a coating deposited on the capsule containing the microparticles or on the tablet containing the microparticles.
  • the capsule is gelatin-based, and the coating contains sodium carboxymethylcellulose and / or hydroxyethyl cellulose as agent D, preferably 25% w / w agent D relative to to the mass of empty capsules.
  • the viscosifying agent V is chosen from the viscosifiers which are soluble in at least one of the following solvents: water, alcohols, ketones and their mixtures, this agent (s) being capable of increasing the viscosity of the extraction solvent so as to counter misuse, particularly by injection.
  • water is meant herein any aqueous solvent, such as water sensu stricto or any aqueous solution, for example organic acid (eg acetic acid), saline solutions, sodas or beverages.
  • alcohols is meant here all the alcohols taken by themselves or in mixture with each other, and by “ketones” means all the ketones taken alone or mixed with each other.
  • the viscosifying agent V is chosen from the following groups of polymers: poly (meth) acrylic acids and their derivatives, and / or
  • polyalkylene glycols eg polyethylene glycol
  • polyalkylene glycols eg polyethylene glycol
  • alkylene polyoxides eg polyethylene oxide
  • gelatins and / or polysaccharides, preferably in the subgroup comprising: sodium alginate, pectins, guars, xanthans, carrageenans, gellanes and cellulose derivatives (especially hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose),
  • the viscosifying agent V is chosen from:
  • alkylene polyoxides by ethylene oxide
  • cellulose derivatives especially hydroxypropyl cellulose
  • mixtures thereof are cellulose derivatives (especially hydroxypropyl cellulose) and mixtures thereof.
  • the viscosifier V is a polyethylene oxide having a high molecular weight, for example having a molecular weight of 1 million g / mol to 8 million g / mol, for example 2 million, million, or 7 million g / mole.
  • the viscosifying agent V is capable of increasing the viscosity of the liquid used for the possible extraction, so as to trap the extracted PA in the viscous medium.
  • This agent V makes it possible to increase the viscosity of the extraction liquid, for example above 100 mPa.s, preferably 200 mPa.s, and more preferably still above 500 mPa.s, and better still 1000 mPa.s.
  • the viscosifying agent V is effective both in the case of extraction in the aqueous or organic phase; for example agent V is a mixture of hydrophilic and hydrophobic compounds, so as to ensure a high viscosity of the extraction liquid (eg> 100 mPa.s), whether it is aqueous or organic.
  • agent V is adjusted to make the viscosity of 2.5 mL of extraction liquid greater than or equal to 100 mPa.s.
  • at least one viscosifying agent V is present:
  • the viscosifying agent is mainly in the form of microparticles distinct from the microparticles of PA.
  • the viscosity agent microparticles have a comparable density and granulometry.
  • the viscosifier microparticles V and the microparticles of PA have a similar size distribution and a similar density. Thus, they are not separable from PA microparticles, especially by conventional means such as sieving or centrifugation.
  • the pharmaceutical form according to the invention comprises granules containing PA microparticles on the one hand, and granules containing viscosity agent V, optionally combined with the agent D, on the other hand, it is preferable that said granules have a similar size distribution, similar density, similar shape and color.
  • the granules comprising the viscosifying agent and / or the agent D are physically indistinguishable from the PA granules, in order to prevent their sorting by any appropriate physical means.
  • a preferred embodiment of the invention consists in adding to said pharmaceutical form at least a sequestering agent Q.
  • a sequestering agent Q is an agent present in the pharmaceutical form in a free form, that is to say uncomplexed.
  • Non-complexed means that there is no complex or chemical interaction between the sequestering agent Q and the active ingredient salt PA in the solid pharmaceutical form.
  • the sequestering agent Q When the PA salt and the sequestering agent Q are simultaneously in a solvent, for example in the case of a wrong attempt to extract the AP, the sequestering agent Q is capable of inducing a complexation or a chemical interaction with PA salt in said solvent.
  • the sequestering agent Q is considered as "capable of inducing a complexation" with the PA salt when the sequestering agent Q is capable of inducing the complexation of the PA salt in at least one usual solvent selected among water and aqueous solutions, such as water-ethanol mixtures, alcohol, alcoholic beverages, sodas, vinegar, hydrogen peroxide, and mixtures thereof.
  • the sequestering agent Q is capable of inducing a complexation of the PA salt in more than one of these usual solvents.
  • the sequestering agents Q used to trap PA, in particular analgesic, are harmless even for regular use. These are inert products from pharmacological point of view and approved by the different pharmacopoeias and drug registration authorities.
  • At least one sequestering agent Q is present: in microparticles free of PA, and / or
  • the sequestering agent Q is present in a first phase separated by at least a second phase, said second phase containing at least one PA salt.
  • the dosage form comprises PA salt microparticles and separate Q sequestering agent microparticles.
  • said microparticles have a similar size distribution, a similar density and are not separable from each other by sieving.
  • the sequestering agent Q comprises a salt, which contains ions able to form a complex with the PA in solution.
  • these ions are preferably organic ions of opposite polarity to that of PA in solution: if in solution the PA is in anionic form, the sequestering agent Q comprises an organic cation, a metal cation, or a mixture thereof.
  • the sequestering agent Q when the PA in solution is in cationic form, the sequestering agent Q comprises an organic anion.
  • anionic organic salts such as sodium dodecyl sulfate or sodium docusate
  • anionic polymers such as (meth) acrylic copolymers (for example Eudragit® S and Eudragit® L), crosslinked acrylic polyacids (for example Carbopol), carboxymethylcellulose and its derivatives, cross-linked carboxymethylcellulose and its derivatives and other polysaccharides (for example: for example, alginate, xanthan gum or arabic), alginate (sulphonate) propylene glycol; - mono- or polyvalent salts, such as glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;
  • saponified fatty acids such as the salts of acetic acid, succinic acid, citric acid, stearic acid, palmitic acid, and self-emulsifying glyceryl mono-oleates;
  • polyamino acids such as albumins, caseins, globulins and enzymes; - and their mixtures.
  • the ion of opposite polarity to that of the PA in solution is a metal, organic cation, or a mixture thereof.
  • a metal, organic cation, or a mixture thereof for example, the following salts which contain an organic or metallic cation:
  • cationic salts for example metals Ca, Fe, Mg, Zn, in the form of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarates, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodides, lactates, oxides, phosphates, trisilicates, phosphates, salicylates, succinates, sulfonamides, tartrates;
  • metals Ca, Fe, Mg, Zn in the form of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarates, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodides, lactates, oxides, phosphates, trisilicate
  • organic cationic salts such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium chloride;
  • cationic polymers such as chitosan and (meth) acrylic copolymers (for example, Eudragit® RS, Eudragit® RL or Eudragit® E);
  • polyamino acids proteins or peptides
  • the sequestering agent Q may be an ion exchange resin, preferably a strongly acidic cation exchange resin when the PA is cationic or a strongly basic anion exchange resin, when the AP is anionic.
  • such an ion exchange resin is contained in a first phase distinct from a second phase which contains the PA.
  • the ion exchange resin will for example be a derivative of a copolymer of styrene and divinylbenzene.
  • the strongly acidic cation exchange resin will for example be a derivative of a copolymer of styrene and divinylbenzene sulfonic such as Amberlite® IRP69, Amberlite® IR69F (Rohm and Haas) ; Amberlite 200, Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and the like.
  • the strongly basic anion exchange resin will be chosen, for example, from derivatives of styrene and divinylbenzene copolymers bearing quaternary ammonium functional groups, such as Duolite® AP 143 (Rohm and Haas). Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow).
  • the sequestering agent Q in the form of a resin may also be chosen from cross-linked copolymers of methacrylic acid and divinylbenzene or one of their salts, such as Amberlite® IRP88 and Amberlite® IRP64 (Rohm and Haas) DOWEX MAC-3 (Dow).
  • the sequestering agent Q in the form of an ion exchange resin may also be chosen from phenolic polyamines such as Amberlite® IRP58 (Rohm and Haas).
  • the sequestering agent Q in the form of an ion exchange resin is in a first phase separated from at least a second phase, said second phase comprising the PA salt.
  • the sequestering agent Q in the form of an ion exchange resin is contained in microparticles distinct from the microparticles comprising the PA salt.
  • the PA microparticles and Q sequestering agent microparticles in the form of ion exchange resin may be in such a form that they have a similar size distribution, a similar density and are not separable by sieving. .
  • the sequestering agent Q is chosen from:
  • anionic organic salts such as sodium dodecyl sulfate or sodium docusate
  • cationic organic salts such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium chloride;
  • the sequestering agent Q is chosen from:
  • Amberlite® IRP69 Amberlite® IR69F (Rohm and Haas); Amberlite® 200, Amberlite® 200C (Rohm and Haas), or Dowex® 88 (Dow) and mixtures thereof, when PA is cationic;
  • Duolite® AP143 (Rohm and Haas) Amberlite® IRA958, Amberlite® IRP67 (Rohm and Haas) and DOWEX® 22 (Dow), and mixtures thereof, when the PA is anionic.
  • the amount of agent Q is adapted by those skilled in the art by a calculation of the amount of ionic charge necessary to trap all or part of the dose of PA contained in the unitary form.
  • the amount of sequestering agent Q must be such as to complex enough PA so that the remaining amount of free PA in solution is insufficient to achieve the desired effect, in case of illicit use.
  • the amount of sequestering agent Q is sufficient to complex the whole AP of the unit dose.
  • the pharmaceutical form may optionally comprise one or more pharmaceutically acceptable excipients, in the free state, that is to say not contained in, or supported by PA microparticles, said excipient contributing to the resistance of the microparticles of PA coated with grinding.
  • these excipients contributing to the grinding resistance of the coated PA microparticles are chosen from the group comprising:
  • the oral pharmaceutical form according to the invention with modified release of at least one PA both in the aqueous dissolution media and in the alcoholic solutions, is characterized in that the release time of 50% of the PA in alcoholic solution:
  • - is not decreased by more than 3 times compared to the release time of 50% of the PA measured in aqueous medium free of alcohol; - preferably is not decreased by more than 2 times compared to the release time of 50% of the PA measured in aqueous medium free of alcohol;
  • - preferably is not decreased by more than 1.5 times compared to the release time of 50% of PA measured in aqueous medium free of alcohol; preferably is similar to that measured in an aqueous medium, according to similarity factor f 2 defined above;
  • the release time of 50% of the PA in alcoholic solution is greater than the release time of 50% of the AP in an aqueous medium free of alcohol.
  • the pharmaceutical form according to the invention is characterized in that it comprises: a) a PA at least a part of which is contained in microparticles individually coated with a coating R ensuring the modified release of the PA and simultaneously imparting resistance to grinding of the coated PA microparticles.
  • the constituents Al, A2, A3 and A4 of the coating layer R satisfy, in terms of percentage by mass, based on the total mass A1 + A2 + A3 + A4 at the conditions mentioned above.
  • At least one agent D which is present in a proportion of 0.5 to 30% w / w, preferably of 0.5% to 25% w / w, and still more preferably of 1% to 20% w / w , of the total mass of the unitary form; c) optionally at least one viscosifying agent V present in a proportion of from 2 to 400 mg, preferably from 5 to 200 mg, and still more preferably from 10 to 100 mg per unit form; d) optionally at least one sequestering agent Q the amount of which is adjusted in order to trap all or part of the dose of PA contained in the unitary form.
  • the sequestering agent Q is included in a phase or in microparticles separated from the microparticles of AP.
  • the viscosifier V is contained in microparticles separate from the microparticles of AP.
  • the pharmaceutical form according to the invention comprises V-viscosifying agent microparticles and PA microparticles, said microparticles having a similar size distribution, a similar density and not separable from one another by sieving.
  • the coating layer R contains the following components: Al is chosen from the group comprising the non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate,
  • A2 is chosen from the group comprising:
  • Nitrogen-containing (co) polymers preferably in the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams,
  • PEG Polyethylene glycols
  • A3 is selected from the group consisting of triethyl citrate, dibutyl sebacate, vegetable oils, castor oil and mixtures thereof;
  • A4 is chosen from the group comprising: nonionic surfactants, preferably in the following subgroup:
  • Polyoxyethylenated oils preferably polyoxyethylenated hydrogenated castor oil
  • the agent D is chosen from the following group of products: hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose),
  • guar gums guar gums, carrageenans, and mixtures thereof.
  • the viscosifying agent V is chosen from: polyalkylene oxides (for example polyethylene oxide), and / or
  • the viscosifying agent V is a polyethylene oxide having a high molecular weight, for example having a molecular weight of 1 million g / mole to 8 million g / mole, example 2 million, 5 million, or 7 million g / mole.
  • the sequestering agent Q is chosen from:
  • anionic organic salts such as sodium dodecyl sulfate or sodium docusate
  • cationic organic salts such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium chloride
  • ion exchange resins preferably a strongly acidic cation exchange resin or a strongly basic anion exchange resin.
  • the sequestering agent Q is chosen from:
  • a pharmaceutical form according to the invention simultaneously comprises the coating layer R and the agent D of embodiments 1 and 2.
  • the pharmaceutical form further comprises at least one viscosifying agent V according to the method Embodiment 3.
  • the dosage form may contain a sequestering agent Q in modes 4 or 5.
  • the unit pharmaceutical form according to the invention is a tablet comprising: a) a PA at least a part of which is contained in microparticles individually coated with a coating R ensuring the modified release of the PA and conferring simultaneously resistance to grinding coated microparticles of PA
  • each component A1, A2, A3 and A4 of the coating layer R its mass m (in% of the total mass A1 + A2 + A3 + A4) satisfies: for Al: 10 ⁇ m ⁇ 90, preferably 15 ⁇ m ⁇ 80, and more preferably 60 ⁇ m ⁇ 80; for A2: 2 ⁇ m ⁇ 50, preferably 3 ⁇ m ⁇ 40, and more preferably 5 ⁇ m ⁇ 25; for A3: 1 ⁇ m ⁇ 30, preferably 2 ⁇ m ⁇ 20, and more preferably 5 ⁇ m ⁇ 15; for A4: 0 ⁇ m ⁇ 40, preferably 0 ⁇ m ⁇ 30, and more preferably 0 ⁇ m ⁇ 20; b) at least one agent D is present in a mixture with the microparticles in a proportion of 1 to 30% w / w, preferably 2% to 25% w / w, and more preferably still 2% to 20% w / w , of the total mass of
  • the viscosifying agent V is present in a proportion of 2 to 400 mg, preferably 5 to 200 mg, and even more preferably 10 to 100 mg per unit form; d) optionally at least one sequestering agent Q is contained in microparticles separate from the microparticles of PA and viscosifying agent.
  • agent Q is adjusted to trap all or part of the dose of AP contained in the unit form. e) and possibly compressional excipients.
  • the tablet of embodiment 6 comprises at least one sequestering agent Q.
  • the unit pharmaceutical form according to the invention is a capsule comprising: a) an AP, at least a part of which is contained in microparticles individually coated with a coating R ensuring the modified release of the PA and conferring simultaneously resistance to grinding coated microparticles of PA
  • each component A1, A2, A3 and A4 of the coating layer R its mass m (in% of the total mass A1 + A2 + A3 + A4) satisfies: for Al: 10 ⁇ m ⁇ 90, preferably 15 ⁇ m ⁇ 80, and more preferably 60 ⁇ m ⁇ 80; for A2: 2 ⁇ m ⁇ 50, preferably 3 ⁇ m ⁇ 40, and more preferably 5 ⁇ m ⁇ 25; for A3: 1 ⁇ m ⁇ 30, preferably 2 ⁇ m ⁇ 20, and more preferably 5 ⁇ m ⁇ 15; for A4: 0 ⁇ m ⁇ 40, preferably 0 ⁇ m ⁇ 30, and more preferably 0 ⁇ m ⁇ 20; b) at least one agent D which is present in a proportion of 0.5 to 20% w / w, preferably of 0.5% to 15% w / w, and even more preferably of 1% to 10% w / w , the total mass of the unit form c) optional
  • the capsule of embodiment 8 comprises at least one viscosifying agent V.
  • the capsule of embodiment 9 comprises at least one sequestering agent Q.
  • the capsule-type pharmaceutical form comprises V-viscosifying agent microparticles and / or Q-sequestering agent microparticles, the V-viscosifying agent microparticles and the Q-sequestering agent microparticles being distinct from the PA microparticles.
  • the capsule-type pharmaceutical form comprises PA microparticles, as well as V-viscosifiers microparticles and / or Q-sequestering agent microparticles, said microparticles having near-size distributions, near densities, and the like. being not separable from each other by sieving.
  • modes 8 9 and 10 of embodiment of the invention one can refer to modes 1 to 5 embodiment of the invention to determine the nature of the components Al, A2, A3 and A4 of the layer of coating R, that of the agent D, that of the viscosifier V, and possibly that of the sequestering agent Q.
  • the AP used can belong for example to at least one of the families of the following active substances: opiates, analgesics, analgesics, antitussives, anxiolytics, benzodiazepines, anorectic, antidepressants, antiepileptics, anti-migraine, antiparkinsonian, barbiturates, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropics, sedatives, amphetamines, stimulants.
  • active substances opiates, analgesics, analgesics, antitussives, anxiolytics, benzodiazepines, anorectic, antidepressants, antiepileptics, anti-migraine, antiparkinsonian, barbiturates, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropics, sedatives, amphetamines, stimulants.
  • the AP used is chosen from the following compounds: acetorphin, acetylalphamethylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alphaketylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodine, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxy-fentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazene, codeine
  • the analgesic PA implemented is selected from the group consisting of oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride, and tramadol hydrochloride. .
  • the expression "pharmaceutical formulation” is understood in a broad sense, that is to say that includes veterinary or dietetic formulations in particular.
  • the invention is directed to a formulation characterized in that it comprises a plurality of microparticles (PA, coated or uncoated, optionally viscosifying agent) as defined above, for example at less than 500, preferably from 1,000 to 1,000,000, and more preferably from 5,000 to 500,000 microparticles.
  • the invention is directed to a pharmaceutical formulation, comprising a plurality of populations of coated PA microparticles, said populations being distinguished from each other by their release kinetics and / or by the PA they contain.
  • the pharmaceutical form according to the invention may comprise modified release PA microparticles and immediate release PA microparticles.
  • the pharmaceutical formulation according to the invention is particularly interesting in that it can be in the form of a daily oral single dose comprising from 500 to 500,000 microparticles, including the coated PA microparticles.
  • the pharmaceutical formulation comprising coated microparticles according to the invention is in a galenical form chosen from the group comprising in particular: tablets (advantageously orodispersible or gastrodispersible), powders, suspensions, syrups, powders for suspension to be reconstituted or capsules.
  • the pharmaceutical form may also be a monolithic form (for example a tablet).
  • the pharmaceutical form according to the invention is not easily convertible into a dry form which can be administered by nasal aspiration and immediate release of AP.
  • the pharmaceutical form according to the invention is not convertible into an injectable form and to immediate release of AP.
  • the pharmaceutical form according to the invention comprises modified-release PA and optionally immediate-release PA.
  • This variant can be combined with the first and second variants mentioned above.
  • the modified release AP is not convertible into a dry form that can be administered by nasal aspiration or injectable form, and immediate release.
  • the subject of the present invention is also the processes for obtaining the pharmaceutical forms according to the invention as defined above, said processes being broken down into several steps consisting essentially of: a) preparing microparticles not coated with PA by:
  • extrusion / spheronization of PA with possibly one or more pharmaceutically acceptable agent (s) D or excipient (s), and / or; wet granulation of PA with optionally one or more agent (s) D or excipient (s) pharmaceutically acceptable, and / or;
  • the PA reservoir microparticles with agents D, V and Q for setting in capsule or sachet; or - PA reservoir microparticle mixture with optionally one or more agent (s) D, V and Q and pharmaceutically acceptable excipients for obtaining a tablet; this tablet may optionally be coated in a coating turbine with one or more layers containing agent D and / or pharmaceutically acceptable excipients; or - putting in capsule of microparticles reservoirs of PA, V and Q; the capsules may optionally be coated in a turbine or fluidized air bed with one or more agent (s) D and / or pharmaceutically acceptable excipients; or
  • the invention also relates to a method of treating pain comprising administering a pharmaceutical form as described above to a patient in need thereof.
  • the invention furthermore relates to a method for preventing the misuse of an active ingredient, in particular analgesic or opiate, comprising the use of a pharmaceutical form as described above.
  • 1615 g of oxycodone HCl are added with a solution containing 85 g of Methocel E5 (hypromellose / Dow), 2052 g of demineralized water and 1105 g of ethanol. The whole is stirred at 67 ° C. The solution is then sprayed into a Glatt GPCG 1.1 fluidized air bed apparatus on 300 g of Xantural 180 particles (Xanthan gum / Danisco) sieved between 50 and 180 ⁇ m. The recovered product is then screened over 80-300 ⁇ m.
  • Cremophor RH 40 PEG40-hydrogenated castor oil / BASF
  • the weight of the coating represents 45% of the total mass of the microparticle MR of oxycodone HCl.
  • Example 2 Pharmaceutical form according to the unpublished application FR0553437
  • Example 1 55 g of microparticles prepared in Example 1 are mixed with 18 g of Polyox
  • WSR303 polyethylene oxide / Dow sieved between 150 and 300 ⁇ m
  • This capsule is placed in a large volume (500 ml) of 40% ethanol solution and the percentage released after 0.5 and 1 hour of stirring is measured:
  • Example 3 Grinding test on the microparticles of oxycodone HCl.
  • microparticles prepared in Example 1 are lubricated with 1.0% magnesium stearate and 0.5% Aerosil.
  • microparticles at a rate of 197 mg corresponding to a dose of 80 mg of oxycodone HCl, are introduced into a dissolutest, either as such (INTACT), or strongly ground for 2 min by means of a mortar and pestle. (CRUSHED).
  • the results of the dissolution test in 900 ml of 0.1 N HCl (D in%) as a function of time (t in h) of the intact and ground doses are reported in FIG. 1.
  • the dissolution profiles are very close, with a release slightly faster during the first minutes in the case of crushed microparticles; then the profiles are similar.
  • microparticles prepared as example 1 are mixed with 18 g of polyox WSR303 (polyethylene oxide / Dow) sieved between 150 and 300 ⁇ m, 26 g of amberlite IR69F (Rhom & Haas) ground and sieved between 160 and 300 ⁇ m, 0.5 aerosil 200 (colloidal silica / Degussa) and 1 g of magnesium stearate. The mixture is homogenized for 15 minutes.
  • polyox WSR303 polyethylene oxide / Dow
  • amberlite IR69F Ros & Haas
  • 0.5 aerosil 200 colloidal silica / Degussa
  • magnesium stearate 1 g
  • 35 gelatin capsules size 0 (white / white) are each filled with 405 mg of the above mixture.
  • Example 4 In the following misuse tests, the content of a capsule as described in Example 4 is first ground by means of a tablet pulverizer (LGS pill crusher) then placed in the presence of 10mL of solvent and left under stirring 120 min at room temperature.
  • a tablet pulverizer LGS pill crusher
  • the mixture is then removed by means of an insulin syringe through a 0.45 ⁇ m filter.
  • the amounts of oxycodone HCl recovered are analyzed by HPLC. The results of the extractions tests are reported in Table 1.
  • the quantities extracted are less than 15% of the dose.
  • Granule 1582.7 g of oxycodone HCl are added in a solution containing 83.3 g of Plasdone K29 / 32 (povidone / Dow), 2011.1 g of demineralized water and 1082.9 g of ethanol. The whole is stirred at 67 ° C. The solution is then sprayed in a Glatt GPCG 1.1 fluidized air bed apparatus on 300 g of particles of cellulose spheres (Asahi-Kasei). The recovered product is then screened over 80-300 ⁇ m.
  • 450 g of the granules prepared as indicated above are then rolled in a Glatt GPCG 1.1 fluidized air bed apparatus with a solution containing 315 g of Ethocel Premium (ethylcellulose / Dow), 36 g of Plasdone K29 / 32 ( povidone / ISP), 54 g of Lutrol F-68 (Poloxamer 188 / BASF), 45 g of castor oil (Garbit oil mill), 3105 g of acetone and 2070 g of isopropanol.
  • the weight of the coating represents 50% of the total mass of the microparticle MR of oxycodone HCl.
  • 1615 g of oxycodone HCl are added in a solution containing 85 g of Plasdone K29 / 32 (povidone / ISP), 2052 g of demineralised water and 1105 g of ethanol. The whole is stirred at 67 ° C. The solution is then sprayed into a Glatt GPCG 1.1 fluidized air bed apparatus on 300 g of Cellets 90 particles (cellulose spheres / Pharmatrans). The recovered product is then sieved on 80-25 ⁇ m.

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EP07729498A 2006-05-24 2007-05-24 Forme pharmaceutique orale multimicroparticulaire a liberation prolongee comprenant des moyens anti-mesusage et resistant a l'alcool Withdrawn EP2040685A2 (fr)

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FR0604685A FR2901478B1 (fr) 2006-05-24 2006-05-24 Forme pharmaceutique orale multimicroparticulaire a liberation prolongee
PCT/EP2007/055069 WO2007135193A2 (fr) 2006-05-24 2007-05-24 Forme pharmaceutique orale multimicroparticulaire a liberation prolongee comprenant des moyens anti-mesusage et resistant a l'alcool

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WO2007135193A3 (fr) 2008-06-26
CA2651451C (fr) 2013-08-20
FR2901478A1 (fr) 2007-11-30
FR2901478B1 (fr) 2015-06-05
CA2651451A1 (fr) 2007-11-29
CN101453994A (zh) 2009-06-10
WO2007135193A2 (fr) 2007-11-29
JP2009537610A (ja) 2009-10-29
JP5654750B2 (ja) 2015-01-14

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