FR2901478A1 - MULTIMICROPARTICULATED ORAL PHARMACEUTICAL FORM WITH PROLONGED RELEASE - Google Patents

Abstract

A modified release multimicroparticulate pharmaceutical form capable of maintaining the modified release of the active ingredient in an alcoholic solution and resisting attempts at misuse.

Description

-2- number of daily holds, which decreases the constraint for the

  patient and improves adherence to treatment. Thus, systems for prolonging the action of a drug have been sought, and there are many references to this purpose. In this regard, consult the work of Buri, Puisieux, Doelker and Benoît: Forms Pharmaceutiques Nouvelles, Lavoisier 1985, p. 175-227. However, it has been found that the ingestion of alcohol in parallel with the administration of a modified release dosage form (MR) can lead to the accelerated and potentially dangerous release of PA in the patient. For PAs such as opioid analgesics, the side effects following the rapid release of a high dose of AP and the concomitant intake of alcohol lead to serious side effects that may even be life-threatening for the patient. A modified release form should therefore ideally be capable of preventing accidental accelerated release of the AP in an alcoholic solution. In addition, 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 drug MR must prevent three modes of intentional misuse: 1. inhalation or oral administration of the form previously put into the form of an immediate release powder. 2. Parenteral injection of a small volume of liquid containing the AP extracted from the MR form 3. Oral administration of a beverage containing PA in dissolved form. For cases 2) and 3), 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 AP and which promote its rapid absorption into the body. When the powder obtained by grinding is sucked by the nose or dissolved in water and injected, the desired effects, doping or euphoric, 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: in the case of a monolithic matrix tablet, a discharge of the dose occurs. Thus, beyond a release profile for prolonging and / or delaying the absorption of PA, an MR release form must make it possible to avoid intentional or unintentional misuse of the AP. In particular, 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 the parenteral injection of AP., d) not lead to the massive solution of the PAd in an alcoholic beverage or not and thus prevent the oral administration of the AP. in IR form even after a long contact time. In order to avoid the massive discharge of the dose in the presence of alcohol, which may result especially from intentional or unintentional misuse, 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. 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

  -4- attempts to misuse, especially by grinding a dry form, possibly followed by extraction in a liquid medium. The teaching of this application FR 06 50566 constitutes an important advance since it proposes a first solution to the problem a) mentioned above.

  However, it does not propose a solution for problems b), c) and d). 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 ; in addition, the pharmaceutical companies of this application contain a viscosifying agent: making it very difficult, if not impossible, to extract the PA in a liquid medium; they may finally contain a sequestering agent. These forms exhibit resistance to extraction in aqueous or alcoholic medium of low volume (for example 2.5 ml). However, these forms are not adapted to withstand the discharge of the dose that can occur in the presence of a large volume of alcoholic medium. Thus, this invention does not propose a technical solution to simultaneously satisfy the four conditions a), b), c) and d) recalled supra. In this context, it is clear that there is a need for a modified-release microparticulate pharmaceutical form for the administration of oral PA, able, on the one hand, to maintain the modified release of AP in a solution. alcoholic (unintentional or accidental misuse), and on the other hand, to resist attempts of intentional misuse.

  OBJECTIVES OF THE INVENTION It is an object of the invention to provide novel oral solid drugs that meet the above-mentioned specification.Another object of the invention is to provide novel oral solid drugs that do not lead to acceleration. Significant release of PA in an alcoholic solution and having means making misuse of PA very difficult or impossible.Another object of the invention is to provide new oral solid drugs, not leading to a significant acceleration of the release. in an alcoholic solution whose misuse will be made difficult or impossible, by grinding or after extraction of the PA in a small volume of solvent Another object of the invention is to provide new solid oral drugs, having the following characteristics: - under normal conditions of administration, these oral solid drugs have a therapeutic effect apeutical, for example for 12 or 24 hours; - Any attempt at improper extraction of the AP will lead to a non-immediate release form or to a extracted product that is difficult to use, so that after ingestion of the drug, rapid absorption of the AP into the bloodstream will not be possible. 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, consistent with 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.

  Definitions For the purpose of the present disclosure of the invention: - 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 the PA, intimately dispersed in a matrix, for example based on polymer, is released by diffusion and erosion. "active principle" and the abbreviation "PA" denote both a single active ingredient and a mixture of several active ingredients. The AP may be in free form or in the form of salt, ester, hydrate, solvate, polymorph, isomers or other pharmaceutically acceptable forms; 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 specification represents ethanol and the terms "alcoholic solution" or "alcoholic medium" represent an aqueous solution of ethanol; "reservoir microparticles" means microparticles comprising PA and individually coated with at least one coating allowing the modified release of the AP; "AP microparticles" denotes indifferently microparticles reservoirs and / or microparticles comprising PA not necessarily coated; "Viscosifying agent microparticles" refers to microparticles comprising at least one viscosifying agent and optionally other excipients, excluding AP; "quenching agent" (English quenching agent) means 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; "Sequestering microparticles" means microparticles comprising at least one sequestering agent and optionally other excipients, excluding AP; "Microparticles" means either reservoir microparticles, uncoated PA microparticles, PA microparticles, viscosifier microparticles and sequestering agent microparticles, taken alone or as a mixture; the dissolution profiles in vitro are carried out according to the indications of the European Pharmacopoeia (5th edition, ≈2.9.3) where the dissolution media conventionally used are described. To simulate the gastric medium of a subject having absorbed a large amount of alcohol, the dissolution medium is modified by adding ethanol (q.s.p. 10% to 40% by volume); the term "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. Modified release dosage forms are well known in the art; see for example Remington: The Science and Practice of Pharmacy, 1901 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 at 0. 75 h, preferably 30 min; the similarity between two dissolution profiles is evaluated using the similarity factor f2 as defined in the "Quality of modified-release products" document of the European Agency for the Evaluation of Medicinal Products, referenced document CPMP / QWP / 604/96 (Annex 3). A value of f2 between 50 and 100 indicates that the two dissolution profiles are similar; "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 gm; 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; by unitary form is meant 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-unloading or rapid dose-discharge means an immediate, or significantly accelerated, and unintended release of the AP dose after oral ingestion. Brief description of the invention

  To achieve the objectives they had set for themselves, the inventors had to find solutions to the various problems listed above and apply them simultaneously to a single form. since to counter the main methods of misuse, the pharmaceutical form must be both difficultly grindable, and its PA difficult to extract in different solvents and in different volumes. The pharmaceutical form according to the invention uses harmless physico-chemical means (they are pharmacologically neutral compounds, approved as excipients by the various pharmacopoeias and registration authorities) and economic.

  An object of the present invention is to provide a new multimicroparticulate form which has the ability to withstand the discharge of the dose when placed in a large volume of alcohol, furthermore this form is able to withstand attempts to misuse intentional (grinding, extraction for injection). 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. For a number of pharmaceutical forms MR, it is observed that the co-administration of said form with alcoholic beverages would lead to an unwanted acceleration of the release of the AP.

  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.

  It is the merit of the Applicant to have discovered that it was possible, by a judicious choice of excipients, their proportions and their modes of implementation, to obtain a formulation that meets the best specifications of the present In other words, 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.

  More specifically, 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 means -9-anti-misuse. In particular, 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 part of the AP is contained in coated microparticles comprising a coating layer R which provides the modified release of the AP and which, at the same time, gives the coated microparticles of PE resistance to grinding, in order to avoid misuse; and optionally at least one viscosifying agent V; and possibly at least one sequestering agent Q.

  In particular, 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.

Brief description of the figures

  Figure 1: Dissolution of microparticles prepared in Example 3 ^: intact ^: crushed

  2: Dissolution of the capsules prepared in Example 4: in 40% EtOH: in 0.1 N HCl

  3: Dissolution of the tablets prepared in Example 6: in 40% EtOH: in 0.1 N HCI

  Figure 4: Dissolution of the tablets prepared in Example 8: in 0.1 N HCl: in 0.1 N HCl / EtOH (90/10 v / v)

  Figure 5: Dissolution of the tablets prepared in Example 9 in 0.1 N HCl A: in 0.1 N HCl / EtOH (90/10 v / v)

  Figure 6: Dissolution of the tablets prepared in Example 10: in 0.1 N HCl: in 0.1 N HCl / EtOH (60/40 v / v)

EtOH is ethanol.

  Detailed description of the invention

  The oral pharmaceutical form according to the invention has antimesusage properties; it comprises reservoir-type microparticles and allows the modified release of the PA both in aqueous dissolution media and in alcoholic solutions. 15

  Coated Microparticles of PA Coated microparticles with modified release of AP are microparticles each coated with at least one coating (comprising for example at least one polymer) deposited according to techniques known to those skilled in the art. For example, Buri, et al. : Pharmaceutical Forms News, Lavoisier 1985, p. 175-227 already cited. The pharmaceutical form according to the invention is multimicroparticulate; it comprises, inter alia, reservoir microparticles with a core comprising PA coated or film-coated with a coating. This PA core, or PA microparticle, may be: raw (pure) PA in powder form, and / or - a matrix granule of PA mixed with various other ingredients, and / or - a supported granulate, such as a neutral carrier, for example cellulose or sugar, covered with at least one layer comprising PA. In the case of a matrix pellet, the matrix contains PA and optionally other pharmaceutically acceptable excipients, such as binding agents, surfactants, disintegrants, fillers, pH-controlling or modifying agents (buffers). In the case of a supported granule, the neutral carrier may 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. By way of non-limiting example of neutral support, mention may be made of particles of xanthan gum, guar gum, calcium phosphate and calcium carbonate.

  Advantageously, the neutral support has a mean diameter of between 1 and 800 m and preferably between 20 and 500 m.

  Coating of the Microparticles of PA Advantageously, the microparticles coated with PA 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 microparticle resistance to grinding. coated PA, to avoid misuse. More preferably still, 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.

  According to an interesting embodiment, 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. Preferably, the anti-grinding coating layer R comprises: at least one (co) film-forming polymer A1 insoluble in the liquids of the digestive tract; at least one soluble (co) polymer A2 in the digestive tract liquids; at least one plasticizer A3; optionally at least one surfactant and / or a lubricant and / or a mineral filler and / or an organic filler A4. According to a purely illustrative and nonlimiting selection of the invention: Al is chosen from the group comprising: o non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, acrylic polymers, for example copolymers of (meth) acrylic acid and of alkyl ester (for example methyl), copolymers of acrylic and methacrylic acid ester carrying at least one quaternary ammonium group ( preferably at least one copolymer of alkyl (meth) acrylate and methacrylate chloride) and more specifically the products Eudragit RS and / or Eudragit RL the polyvinylacetates, 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 sub-group: acetylated glycerides, glycerolmonostearate, glyceryl triacetate, glycerol tributrate, phthalates, preferably in the following sub-group: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, citrates, preferably in the following subgroup: acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate, sebacates, preferably in the sub-group; the following group: diethyl sebacate, dibutyl sebacate, adipates, azelates, benzoates, vegetable oils, fumarates, preferably diethyl fumarate, malates, preferably diethyl malate, oxalates, and the like; , preferably diethyloxalate, succinates, preferably dibutylsuccinate, butyrates, trimethylammonioethylcommercialized under es 0 o

  Esters of cetyl alcohol, malonates, preferably diethyl malonate, castor oil (the latter being particularly preferred), and mixtures thereof; A4 is selected from the group consisting of: anionic surfactants, preferably in the subgroup of alkali or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred, or nonionic surfactants, preferably in the subgroup of polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene (poloxamer) copolymers, polyoxyethylenated sorbitan esters, polysorbates, derivatives of polyoxyethylenated castor, o stearates, preferably calcium, magnesium, aluminum or zinc, o stearyl fumarates, preferably sodium, o behenate glycerol, o talc, o colloidal silica, o oxide titanium, magnesium oxide, bentonite, microcrystalline cellulose, kaolin, aluminum silicate, and mixtures thereof.

  According to a preferred variant of the invention, the coating layer R contains the following components:

  Al is selected from the group consisting of non-water-soluble derivatives of cellulose, preferably ethyl cellulose and / or cellulose acetate, A2 is selected from the group consisting of: nitrogen-containing (co) polymers, preferably in the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams, o the water-soluble derivatives of cellulose, o polyethylene glycols (PEG), o and their mixtures, wherein A3 is selected from the group consisting of triethyl citrate, dibutyl sebacate, vegetable oils, castor oil and mixtures thereof, wherein A4 is selected from the group consisting of nonionic surfactants, preferably in the sub-group; the following group: polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene (poloxamer) copolymers, sorbitanpolyoxyethylenated esters, polysorbates, stearates, preferably magnesium, and mixtures thereof.

  Advantageously, for each component A1, A2, A3 and A4 of the coating layer R, its mass ni (in% of the total mass Al + A2 + A3 + A4) satisfies for Al: 10 ≤.m 90, preferably 15 m 80, and more preferably 60Sm80; for A2: 2 m 50, preferably 3 m 40, and more preferably 5 m 25; for A3: 1 mM 30, preferably 2 m 20, and more preferably 5 m 15; for A4: 0 m 40, preferably 0 m 30, and more preferably 0m520.

  With respect to the total mass of the coated PA microparticles, 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. Preferably, the coated PA microparticles have a volume average diameter of less than or equal to 1000 m, preferably between 50 and 800 m and more preferably between 100 and 600 m, and more preferably 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, fluidized air bed spray coating technique, wet granulation, compacting, extrusion-spheronization. Agent D The pharmaceutical form according to the invention comprises at least one agent D which is a pharmaceutically acceptable compound and whose rate or ability 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; a compound soluble in water and insoluble in alcoholic solution; or a compound, insoluble in water or in alcoholic solution, which swells more or more rapidly in water than in alcoholic solution. Preferably, the agent D is chosen from the following group of products: Cellulosic derivatives such as, for example: • methylcellulose • (hydroxy) (alkyl) celluloses (for example hydroxypropylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose), • carboxyalkylcelluloses (for example carboxymethylcellulose) and their salts, celluloses (powder or microcrystalline), crosslinked carboxyalkylcelluloses: crosslinked carboxymethylcelluloses (for example croscarmellose sodium), polyalkylene oxides (for example polyethylene oxide or polypropylene oxide). Polysaccharides, for example: native starches (for example corn, wheat or potato) or modified starches (for example with sodium glycolate), alginates and their salts, such as sodium alginate, • potassium polacrilin, • guar gums, • carrageenans, • pullulans, • pectins, • chitosans and their derivatives, • and their mixtures, Proteins, for example: • gelatin, • albumins, • casein, • lactoglobulins,

  And clays thereof such as bentonite, laponite and mixtures thereof.

  Even more preferably, the agent D is selected from the following group of products: hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) celluloses and their salts, guar gums, carrageenans, and mixtures thereof. The 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: of the PA core (or microparticle not coated with PA): in the neutral support of the microparticles and / or in the layer containing the PA and deposited on the neutral support of the microparticles and / or in the granule containing the PA; and / or coating the microparticles; and / or a mixture with the microparticles: either in the binding phase of granules, pellets, tablets including PA microparticles and / or in a distinct type of microparticles and / or in a distinct type of granules ; and / or one of the outer constituents of a monolithic form (e.g., capsule component, coating of a tablet or capsule).

  According to a first embodiment of the invention, the agent D is present in the PA core, or uncoated microparticle of PA. Preferably, the agent D is present in the core of the microparticles in a proportion of 5 to 70%, preferably 15% to 60% of the total mass of the PA core. According to a second embodiment of the invention, the agent D is included in the coating of the microparticles. In this case, 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. Preferably, the agent D is present in the coating in an amount of 3 to 30%, preferably 10 to 20% of the total weight of the coating. Preferably, 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. According to a third embodiment, 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. According to a fourth embodiment, the agent D is at least partly in the form of microparticles or, preferably, of granules distinct from those containing the PA. For example, the coated PA microparticles 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). .

  In a fifth embodiment, agent D is one of the components of the capsule material that contains the microparticles. According to a sixth embodiment, the agent D is included in a coating deposited on the capsule containing the microparticles or on the tablet containing the microparticles. For example, the capsule is gelatin-based, and the coating contains sodium carboxymethylcellulose and / or hydroxyethyl cellulose as agent D. Preferably at 25% w / w agent D compared to the mass of empty capsules. In the case of the fifth and sixth modes, one can deposit on the capsule or tablet a topcoat.

  The different embodiments, with regard to the agent D, can be combined with one another. In such a case, it is quite possible to incorporate different agents D for each of the embodiments indicated.

  Viscosifying Agent V The viscosifying agent V is chosen from viscosifiers which are soluble in at least one of the following solvents: water, alcohols, ketones and mixtures thereof, this agent (s) being capable of increasing the viscosity of the extraction solvent so as to counter misuse, particularly by injection. By "water" is meant here any solvent

  Aqueous medium, such as water in the strict sense or any aqueous solution, for example organic acid (eg acetic acid), saline solutions, soda or beverages. By "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. Preferably, the viscosifying agent V is chosen from the following groups of polymers: poly (meth) acrylic acids and their derivatives, and / or polyalkylene glycols (for example polyethylene glycol), and / or polyalkylene oxides ( eg polyethylene oxide), and / or polyvinylpyrrolidones, and / or 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), and mixtures thereof.

  Advantageously, according to a preferred variant of the invention, the viscosifying agent V is chosen from: polyalkylene oxides (by ethylene oxide), and / or xanthans and / or cellulose derivatives ( especially hydroxypropyl cellulose) - and mixtures thereof.

  According to one embodiment of the invention, 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.

  According to a preferred embodiment, 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. According to one variant of the invention, 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 (e.g., 100 mPa ·%), whether aqueous or organic. The amount of agent V is adjusted to make the viscosity of 2.5 mL of extraction liquid greater than or equal to 100 mPa.s.

  According to several variants, in the pharmaceutical form according to the invention at least one viscosifying agent V is present: in and / or on microparticles, and / or in the free state, that is to say not contained in nor supported by microparticles.

  Advantageously, the viscosifying agent is mainly in the form of microparticles distinct from the microparticles of PA. In the case where the pharmaceutical form is a divided form (capsule, sachet, suspension to be reconstituted), the viscosity agent microparticles have a density and a particle size comparable to those of the microparticles of AP. For example, 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. When 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. Thus, 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.

  Sequestering agent Q In the case where the multimicroparticulate pharmaceutical form comprises at least one salt of an active ingredient, or an active ingredient bearing an ionizable function in solution, a preferred embodiment of the invention consists in adding to said form at least one sequestering agent Q. The latter is chosen so that during an extraction attempt, it forms with the PA, in aqueous or aqueous-alcoholic solution, a poorly soluble complex. For the purposes of the present invention, 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. When the PA salt and the sequestering agent Q are simultaneously in a solvent, for example in the case of an unlawful attempt to extract the AP, the sequestering agent Q is capable of inducing a complexation or a reaction. chemical interaction with PA salt in said solvent. For the purpose of the present invention, 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. Advantageously, 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 pharmacologically inert products approved by the different pharmacopoeias and drug registration authorities.

  In a pharmaceutical form according to the invention, at least one sequestering agent Q is present: in microparticles free of AP, and / or on microparticles, and / or in the free state, that is, not contained in or supported by microparticles.

  Preferably, in a pharmaceutical form according to the invention, 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. For example, the dosage form comprises PA salt microparticles and separate Q sequestering agent microparticles. Advantageously, said microparticles have a similar size distribution, a similar density and are not separable from each other by sieving.

  Preferably, 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. In the same way, when the PA in solution is in cationic form, the sequestering agent Q comprises an organic anion. For example, there may be mentioned the following salts which have 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), carboxyethylcellulose and its derivatives, crosslinked carboxymethylcellulose and its derivatives and other polysaccharides ( for example, alginate, xanthan gum or arabic), alginate (sulfonate) 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, proteins or peptides, such as albumins, caseins, globulins and enzymes; and their mixtures.

  In another embodiment, the ion of opposite polarity to that of the PA in solution is a metal, organic cation, or a mixture thereof. For example, mention may be made of the following salts which contain an organic or metal 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; 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; - and their mixtures.

  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. Advantageously, such an ion exchange resin is contained in a first phase distinct from a second phase which contains PA.

  In one embodiment of the invention, the ion exchange resin will for example be a derivative of a copolymer of styrene and divinylbenzene. In one embodiment of the invention, the strongly acidic acid 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. In one embodiment of the invention, the strongly basic anion exchange resin will for example be chosen from derivatives of styrene and divinylbenzene copolymers bearing quaternary ammonium functions, such as Duolite AP143 (Rohm and Haas) Amberlite IRA958 , Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow). The resin sequestering agent Q may also be selected from crosslinked copolymers of methacrylic acid and divinylbenzene or a salt thereof, 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 mixtures of these different resins are also conceivable. According to one embodiment of the invention, 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. For example, 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. .

  In a first preferred embodiment of the invention, 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; strongly acidic cation exchange resins or strongly basic anion exchange resins, depending on the polarity of the PA.

  In a second preferred embodiment of the invention, the sequestering agent Q is chosen from:

  The strongly acidic cation exchange resins: Amberlite IRP69, Amberlite IR69F (Rohm and Haas); Amberlite 12,200, Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and mixtures thereof, when the PA is cationic; strongly basic anion exchange resins: Duolite AP143 (Rohm and Haas) Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow), and mixtures thereof, when the AP 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 AP contained in the unit 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. Preferably, the amount of sequestering agent Q is sufficient to complex the whole AP of the unit dose.

Excipient, free state

  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 coated PA microparticles. grinding. Preferably, these excipients contributing to the grinding resistance of the coated PA microparticles are selected from the group consisting of: calcium stearate; glycerol palmitostearate; magnesium oxide; polyalkylene-e.g. ethylene glycols; [polyvinyl alcohol; Sodium benzoate; stearic acid; corn starch; talcum; colloidal silica; Zinc stearate, magnesium; stearyl fumarate and mixtures thereof.

  Description of the pharmaceutical form

  Preferably, 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 alcohol solution: it 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, it 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, no more than 1.5% is lost in relation to the release time of 50% of the PA measured in an alcohol-free aqueous medium; is preferably similar to that measured in aqueous medium, according to similarity factor f, defined above; or even the release time of 50% of the PA in alcoholic solution is greater than the release time of 50% of the PA in aqueous medium free of alcohol.

  In general, 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 Al + A2 + A3 + A4 at the conditions mentioned above. b) 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.

  In a preferred embodiment, the sequestering agent Q is included in a phase or in microparticles separated from the microparticles of AP. Preferably, the viscosifying agent V is contained in microparticles distinct from the microparticles of AP. Advantageously, 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.

  According to one embodiment of the invention, the coating layer R contains the following components: Al is chosen from the group comprising non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, A2 is selected from the group consisting of: • nitrogen-containing (co) polymers, preferably in the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams, • derivatives water-soluble cellulose, • polyethylene glycols (PEG), • 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 consisting of: nonionic surfactants, preferably in the following subgroup: polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, polyethylene oxide-propylene polyoxide copolymers (poloxamines) r), • polyoxyethylenated sorbitan esters, • polysorbates, • stearates, preferably magnesium, • and mixtures thereof.

  According to a method of embodiment of the invention, the agent D is chosen from the following group of products: hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) celluloses, and their salts guar gums, carrageenans, and mixtures thereof.

  According to one embodiment of the invention, the viscosifying agent V is chosen from: alkylene polyoxides (for example polyethylene oxide), and / or xanhans and / or cellulose derivatives (in particular hydroxypropyl cellulose) and mixtures thereof. According to a variant of the embodiment 3 of the invention, the viscosifying agent 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, example 2 million, 5 million, or 7 million g / mole.

  According to one embodiment 4 of the invention, 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.

  According to one embodiment of the invention, the sequestering agent Q is chosen from: - strongly acidic cation exchange resins: Amberlite IRP69, Amberlite IR69F (Rohm and Haas); Amberlite 200, Amberlite 200C (Rohm and Haas), or Dowex: 88 (Dow) and mixtures thereof, when the PA is cationic; strongly basic anion exchange resins: Duolite AP143 (Rohm and Haas) Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow), and mixtures thereof, when the AP is anionic.

  These modes 1 to 5 embodiment of the invention can be combined with each other. In particular, a pharmaceutical form according to the invention simultaneously comprises the coating layer R and the agent D of embodiments 1 and 2. According to one preferred variant, the pharmaceutical form further comprises at least one viscosifying agent V according to Embodiment 3. Finally, the pharmaceutical form may contain a sequestering agent Q according to modes 4 or 5. Of course, the final pharmaceutical form according to the invention may be optimized by adding other conventional ingredients. and known to those skilled in the art, such as, in particular, dyes, pigments, preservatives, flavors, and mixtures thereof.

  A preferred embodiment, the unit dosage 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, a grinding resistance of the coated PA microparticles For each component A 1, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass Al + A2 + A3 + A4) satisfies: for Al : 10 m 90, preferably 15 m 80, and more preferably 60m80; for A2: 2 μm 50, preferably 3 μm, and more preferably 55 μm; 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%, the total mass of the unit form; C) at least one viscosifying agent V is contained in microparticles separate from the microparticles of AP. 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. The amount of agent Q is adjusted to trap all or part of the dose of AP contained in the unit form. e) and possibly compressional excipients.

  According to one embodiment of the invention, the tablet of Embodiment 6 comprises at least one sequestering agent Q.

  With regard to modes 6 and 7 of embodiment of the invention, reference may be made to embodiments 1 to 5 of the invention to determine the nature of the components A1, A2, A3 and A4 of the layer. coating R, that of the agent D, that of the viscosifier V, and optionally that of the sequestering agent Q ,.

  According to a preferred embodiment, 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 At the same time, a resistance to grinding of the coated PA microparticles For each component A1, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass Al + A2 + A3 + A4) satisfies: for Al: 10 m 90, preferably 15 m <80, and more preferably 605m <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 <m515; For A4: 0 m 40, preferably 0 m 30, and more preferably 0mS20; 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 weight of the unit 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. According to an embodiment of the invention, the capsule of the embodiment 8 comprises at least one viscosifying agent V.

  According to one embodiment of the invention, the capsule of embodiment 9 comprises at least one sequestering agent Q.

  Advantageously, the capsule-type pharmaceutical form comprises V-viscosifier microparticles and / or Q-sequestering agent microparticles, the V-viscosifying microparticles and the Q-sequestering agent microparticles being distinct from the microparticles. of PA.

  Preferably, the capsule-type pharmaceutical form comprises PA microparticles, as well as V-viscosifier microparticles and / or Q-sequestering agent microparticles, said microparticles having near-size distributions, close densities and no not separable from each other by sieving.

  With regard to 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.

  Active principle The AP used can belong for example to at least one of the following families of active substances: opiates, analgesics, analgesics, antitussives, anxiolytics, benzodiazepines, anorectic, antidepressants, antiepileptics, antimigraine, antiparkinsonian, barbiturates, hypnotics, laxatives, neuroleptics, psychostimulants., psychotropic, sedative, amphetamines, stimulants.

  More specifically still, the AP used is chosen from the following compounds: acetorphin, acetylalphamethylfentanyl, acetyl dihydrodecine, acetylmethadol, alfentanil, allylprodine, alphaketylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthiofentanyl, alphaprodine, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazene, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethylthiambutene, difenoxine, dihydrocodeine, dihydromorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol. eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomorarnide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydro-morphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morphine, morphine, myrophin, nalbuphine, narceine, nicomorphine , norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracidethanol, norcodine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene para-fluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenorporidine, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, propranolol, properidine, propiram, racemethorphan, racemoramide, racemorphan, remifentanil, sufentanil, thbacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and their salts, their pharmacologically acceptable esters, hydrates, polymorphs and isomers, and mixtures thereof.

  More specifically, the analgesic PA used is selected from the group consisting of oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride, and tramadol hydrochloride. .

  For the purposes of the invention, the expression "pharmaceutical formulation" is understood in the broad sense, that is to say that includes veterinary or dietary formulations in particular. According to another of its aspects, 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 least 500, preferably from 1,000 to 1,000,000, and more preferably from 5,000 to 500,000 microparticles. According to another of its aspects, 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 kinetics of release and / or by the PA they contain. . Advantageously, the pharmaceutical form according to the invention may comprise modified release PA microparticles and immediate release PA microparticles. Without wishing to be limiting, it should nevertheless be emphasized that the pharmaceutical formulation according to the invention is particularly advantageous in that it may be in the form of a daily oral single dose comprising from 500 to 500 000 microparticles, including the microparticles of PA coated. Without this being limiting, the pharmaceutical formulation comprising coated microparticles according to the invention is in a galenic form selected from the group comprising in particular: tablets (advantageously orodispersible or gastrodispersible), powders, suspensions, syrups , powders for suspension to be reconstituted or capsules. It may be advantageous to mix in the same capsule, the same tablet or the same powder, at least two types of microparticles coated with PA having different release kinetics but included in the characteristic framework of the invention.

  According to one variant, the pharmaceutical form may also be a monolithic form (for example a tablet).

  According to a first variant, the pharmaceutical form according to the invention is not convertible into a dry form that can be administered by nasal aspiration and with immediate release of AP. According to a second variant, the pharmaceutical form according to the invention is not convertible into an injectable form and to immediate release of AP. According to a third variant, 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. This means that in a dosage form that includes modified release PA and immediate release AP, 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 stages consisting essentially of: a) preparing hearts (uncoated microparticles) of PA by: extrusion / spheronization of PA with optionally one or more pharmaceutically acceptable agent (s) D or excipient (s), and / or; wet granulation of PA with optionally one or more pharmaceutically acceptable agent (s) D or excipient (s), and / or; compaction of AP with optionally one or more pharmaceutically acceptable agent (s) D or excipient (s), and / or; spraying PA, optionally with one or more agent (s) D or excipient (s) pharmaceutically acceptable, dispersed or dissolved in an aqueous or organic solvent on a neutral carrier or agent D particles, and / or; - 32 - sieving of powder or PA crystals; b) preparing PA reservoir microparticles by: fluidized bed airing of a solution or dispersion containing one or more compounds A1, A2, A3 and optionally one or more compounds A4 and / or D on the microparticles of PA; ; the microparticles of PA may have been previously coated with one or more agents D; the coated PA microparticles may optionally be coated with one or more D agents; c) preparing the final form of the drug by: granulating and / or extruding / spheronizing PA reservoir microparticles with D, V and Q agents for capsule or sachet; or a mixture of PA reservoir microparticles with optionally one or more D, V and Q agent (s) 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 gelatinization of reservoir microparticles 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 bagging reservoir microparticles of PA, V and Q optionally with one or more D-agent (s) and / or pharmaceutically acceptable excipients.

  The invention also relates to a method of treating pain comprising administering a pharmaceutical treatment as described above to a patient in need thereof.

  The invention further 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. The invention will be better explained by the following examples, given by way of illustration and to understand the invention and to highlight its variants and / or implementation, as well as its various advantages.

35 EXAMPLES

  EXAMPLE 1 Production According to the Invention of Microparticles of Oxycodone HC1 Anti-Grinding Granulated: 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 in a Glatt G1.1 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.

  Microparticles 495 g of the granules prepared above are then film-coated in a Glatt G1.1 fluidized air bed apparatus with a solution containing 296 g of Ethocel Premium (Ethylcellulose / Dow), 24 g of Plasdone K29 / 32 ( povidone / ISP), 49 g of Cremophor RH 40 (PEG40-hydrogenated castor oil / BASF), 41 g of castor oil (Garbit oil mill), 2795 g of acetone and 1863 g of isopropanol. The weight of the coating represents 45% of the total mass of the microparticle MR oxycodone HCI. Example 2: Pharmaceutical form according to the unpublished application FR0553437 20 55 g of microparticles: Prepared cules in 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) crushed and sieved between 160 and 300 m, 0.5 g of Aerosil 200 (colloidal silica / Degussa) and 1 g of magnesium stearate. 405 mg of this mixture is introduced into size 0 gelatin capsules. 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. These results show that in the presence of a large amount of alcoholic solution, the amount of oxycodone released is relatively high after one hour. This may present a risk for the patient, which is why the Applicant has sought to develop a slower release form in the presence of alcohol. Example 3: Grinding test on oxycodone HCl microparticles.

  The microparticles prepared in Example 1 are lubricated with 1.0% magnesium stearate and 0.5% Aerosil. These 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 HCI (D in%) as a function of the time (t in h) of the intact and milled doses are reported in FIG. 1. The dissolution profiles are very close, with slightly faster release during the first minutes in the case of crushed microparticles; then the profiles are similar. Example 4: Preparation of capsules according to the invention

  Mixture: 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, 26 g of amberlite IR69F (Rhom & Haas) crushed and sieved between 160 and 300 m, 0.5 g of aerosil 200 (colloidal silica / Degussa) and 1 g of magnesium stearate. The mixture is homogenized for 15 minutes.

  Capsules: 35 gelatin capsules size 0 (white / white) are each filled with 405 mg of the above mixture.

  Coating capsules: The above capsules are then coated with 16 mg per capsule of Blanose 7LF (sodium carboxymethylcellulose / Aqualon) previously dissolved at 6% (m / m) in demineralised water. Dissolution tests in 900 ml of 0.1N HCI and (40% EtOH, 0.1N 60% HCl) are reported in Figure 2. It is found that in ethanolic solution, the kinetics of dissolution is considerably slowed down. Example 5: Misuse Test on the Content of the Capsule of 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 brought into contact with 10 ml of solvent and left stirring for 120 min at room temperature. The mixture is then removed by means of an insulin syringe through a 0.45 m filter. The amounts of oxycodone HC1 recovered are analyzed by HPLC. The results of the extractions tests are reported in Table 1.

  Table 1 Solvent Oxycodone extracted (%) isopropanol 70% 0 diethyl ether 0.02 ethyl acetate 1.9 ethanol 13.7 acetone 1.1 cooking oil <0.01 The amounts extracted are less than 15% of the dose. Example 6: Production of tablets according to the invention

  10 g of the oxycodone microparticles prepared in Example 1, 5 g of Amberlite IR69F (Rhom & Haas) sieved between 160 and 300 m, 2.5 g of Polyox WSR 303, 10 g of Avicel PH 101 (microcrystalline cellulose / FMC), 5 g of Methocel A15 (methylcellulose / Dow) and 0.25 g of magnesium stearate are mixed and then compressed. The mass of the tablets is 655 mg. The dissolution tests of these tablets in 900 ml of 0.1N HCl and (40% EtOH, 0.1N 60% HCl) are reported in Figure 3. It is found that the release in an alcoholic medium is slower than in an aqueous medium. EXAMPLE 7 Embodiment According to the Invention of Anti-Grinding Oxycodone HCl Microparticles

  Granule: - 1582.7 g of oxycodone HC1 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 G1.1 fluidized air bed apparatus on 300 g of cellulose sphere particles (Asahi-Kasei). The recovered product is then screened over 80-300 m.

  Microparticles: 450 g of the granules prepared as indicated above are then film-coated in a Glatt G1.l fluidized air-milk 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 mass of the coating represents 50% of the total mass of the microparticle MR oxycodone HC1.

  Example 8: Production of tablets according to the invention

  11 g of oxycodone microparticles prepared in Example 7, 4 g of Amberlite IR69F (Rhom & Haas) sieved between 160 and 300 m, 2 g of Polyox WSR 303, 8 g of talc (Luzenac 00), 4 g of Methocel A15 (methylcellulose / Dow) and 0.5 g of magnesium stearate are mixed and then compressed. The mass of the tablets is 590 mg.

  The dissolution tests of these tablets in 900 ml of 0.1N HCl and (EtOH 10%, 0.1N HCl 90%) are reported in FIG. 4. The release rate in a medium containing 10% ethanol is comparable or even slower than that obtained in a purely aqueous medium.

  Example 9 Production of tablets according to the invention 11 g of oxycodone microparticles prepared in Example 7, 4 g of Amberlite IR69F (Rhom & Haas) ground and sieved between 160 and 300 m, 2 g of pol (oxide of ethylene (Polyox WSR 303 / Sentry), 5 g of talc (Luzenac 00), 2 g of methylcellulose (Methocel A15 / Dow), 2 g of hydroxyethylcellulose (Natrosol 250G / Aqualon), 3 g of microcrystalline cellulose (Avicel PH200 / FMC) and 0.5 g of magnesium stearate are mixed and compressed The mass of the tablets is 590 mg The dissolution tests of these tablets in 900 ml of 0.1N HCl and (EtOH 10%; HCl 0, 1N 90%) are reported in Figure 5. The release rate in a medium containing 10% ethanol is comparable to or even slower than that obtained in a purely aqueous medium Example 10: Production of tablets according to the invention 10 g of oxycodone microparticles prepared in Example 1, 5 g of Amberlite IR69F (Rhom & Haas) crushed and sieved between 160 and 300 m, 2.5 g of polyethylene oxide (Polyox WSR 303 Sentry), 10 g of microcrystalline cellulose (Avicel PH101 / FMC), 2.5 g of hypromellose (Methocel E15 / Dow), 2, 5 g of hypromellose (Methocel E5 / Dow), and 0.25 g of magnesium stearate are mixed and then compressed. The mass of the tablets is 655 mg. The dissolution tests of these tablets in 900 ml of 0.1N HCl and (EtOH 40%, 0.1N HCl 60%) are shown in Figure 6.15.

Claims (69)

  An oral pharmaceutical form comprising microparticles of the reservoir type, with modified release of at least one active ingredient (AP), characterized in that it resists the immediate discharge of the dose of AP in the presence of alcohol and in that it includes anti-misuse means.   2. The multimicroparticulate pharmaceutical form according to claim 1, characterized in that said anti-misuse means comprise at least anti-grinding means.   Pharmaceutical form according to claim 1 or 2, characterized in that: the means preventing the immediate discharge of the dose of PA in the presence of alcohol comprise an 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 PA microparticles.   4. Pharmaceutical form according to any one of claims 1 to 3 further comprising at least one viscosifying agent V capable of preventing the extraction of PA contained in the coated PA microparticles modified release of PA.   5. Pharmaceutical form according to any one of claims 1 to 4 further comprising at least one sequestering agent forming, in aqueous or aqueous-alcoholic solution, a poorly soluble complex with PA. 30   The pharmaceutical form according to claim 3, and optionally any one of the preceding claims, wherein the agent D is selected from the following group of products: cellulosic derivatives such as for example: methylcellulose, (hydroxy) (alkyl) celluloses (eg hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose), • carboxyalkylcelluloses (eg carboxymethylcellulose) and their salts, • celluloses (powder or microcrystalline), • crosslinked carboxyalkylcelluloses: crosslinked carboxymethylcelluloses (for example croscarmellose sodium), polyalkylene oxides (for example polyethylene oxide or polypropylene oxide), polysaccharides, for example: • native starches (for example corn, wheat or potato) or modified starches (for example with sodium glycolate), • alginates and their salts such as sodium alginate, 10 • potassium polacrilin, guar gums, carrageenans, pullulans, pectins, chitosans and their derivatives, and mixtures thereof, proteins, for example: gelatin, albumins, • casein, • lactoglobulins, • and mixtures thereof, clays such as bentonite, laponite, and mixtures thereof. 25   The pharmaceutical form according to claim 6, wherein the agent D is selected from the following group of products: hydroxyalkylcelluloses (eg hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) celluloses and their salts , guar gums, carrageenans, and mixtures thereof. 35   The pharmaceutical form according to claim 6 or 7, wherein: agent D is a component of the PA core (or uncoated PA microparticle), that is: in the neutral support of each microparticle and or in a layer containing the PA deposited on the neutral support of the microparticle and / or in a granule containing the PA; and / or agent I) is a constituent of the coating of PA microparticles; and / or agent I) is in admixture with the microparticles; and / or agent I) is one of the outer constituents of a monolithic form.   9. The pharmaceutical form according to claim 8, wherein agent D is present in the heart of PA at 5% to 70% w / w, preferably 15% to 60% w / w, of the total mass of the heart of PA.   The pharmaceutical form according to claim 8 or 9, wherein agent D is present in the microparticle coating at 3% to 30% w / w, preferably 10% to 20% w / w , the total mass of the coating.   The pharmaceutical form according to any one of claims 8 to 10, wherein agent D is present in admixture with the microparticles at a level of 0.5% to 30% w / w, preferably 0.5% % to 25% w / w, and more preferably still from 1% to 20% w / w, of the total mass of the unit form.   Pharmaceutical form according to claim 3, and optionally according to any one of the preceding claims, wherein the coating layer R comprises: at least one (co) film-forming polymer Al insoluble in the liquids of the digestive tract; at least one soluble (co) polymer A2 in the digestive tract liquids; at least one plasticizer A3; optionally at least one surfactant and / or a lubricant and / or a mineral filler and / or an organic filler A4.   The pharmaceutical form according to claim 12, wherein: Al is selected from the group consisting of: • water-insoluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, • acrylic polymers, by for example, copolymers of (meth) acrylic acid and of alkyl ester (for example methyl), copolymers of acrylic and methacrylic acid ester carrying at least one ammonium-41-quaternary group (preferably at least one copolymer). alkyl (meth) acrylate and trimethylammonioethyl methacrylate chloride) and more specifically the products sold under the trade names Eudragit RS and / or Eudragit RL • polyvinylacetates, • and mixtures thereof; A2 is selected from the group consisting of: • nitrogen-containing (co) polymers, preferably in the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams, • derivatives water-soluble cellulose, • polyvinyl alcohols (PVA), • polyalkylene oxides, preferably ethylene polyoxides (POE), • polyethylene glycols (PEG), • and mixtures thereof; A3 is selected from the group consisting of: • esters of cetyl alcohol, • glycerol and its esters, preferably in the following sub-group: acetylated glycerides, glycerolylostearate, glyceryltriacetate, glyceryltributrate, • 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, oils vegetable oils, fumarates, preferably diethyl fumarate, malates, preferably diethyl malate, oxalates, preferably diethyl oxalate, succinates, preferably dibutyl succinate, butyrates, esters of cetyl alcohol, Malonates, preferably diethyl malonate, castor oil (the latter being particularly preferred), and mixtures thereof; A4 is selected from the group consisting of: • anionic surfactants, preferably in the subgroup of alkali or alkaline earth fatty acid salts, stearic and / or oleic acid being preferred, • and / or nonionic surfactants, ionic, preferably in the following subgroup: • polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, • polyoxyethylenepolyoxypropylene (poloxamer) copolymers, • polyoxyethylenated sorbitan esters, • polysorbates, • derivatives of polyoxyethylenated castor oil, • stearates, preferably calcium, magnesium, aluminum or zinc, • stearyl fumarates, preferably sodium, • glycerol behenates, • talc, • colloidal silica, • titanium oxide, magnesium oxide, bentonite, microcrystalline cellulose, kaolin, aluminum silicate, and mixtures thereof.   The pharmaceutical form according to claim 13, wherein: Al is selected from the group consisting of water-insoluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, A2 is selected from the group consisting of: the nitrogen-containing (co) polymers, preferably in the group comprising the polyacrylamides, the poly-N-vinylamides, the polyvinylpyrrolidones (PVP) and the poly-N-vinyl-lactams, the water-soluble derivatives of the cellulose, or the polyethylenes; 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 consisting of: nonionic surfactants, preferably in the following subgroup: polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene (poloxamer) copolymers polyoxyethylenesorbitan esters, polysorbates, stearates, preferably magnesium, and mixtures thereof.   15. Pharmaceutical form according to any one of claims 12 to 14, wherein for each constituent Al, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass Al + A2 + A3 + A4) verifies: for Al: 10 m 90, preferably 15 m S 80. and more preferably 60 <m80; for A2: 5 m <25; for A3: 5 <<<15; for A4: 0m520.   Pharmaceutical form according to any one of claims 12 to 15, in which the coating layer R represents a mass fraction Tp, expressed as a percentage by dry weight relative to the total mass of the coated microparticles, such that: Tp 15; preferably between 30 and 60, and even more preferably between 40 and 60, and more preferably between 45 and 55 or about 50.   Pharmaceutical form according to Claim 4, and optionally according to any one of the preceding claims, in which at least one viscosifying agent V is chosen from viscosifiers which are soluble in at least one of the following solvents: water, alcohols, ketones and their mixtures, this viscosifying agent V being able to increase the viscosity of the extraction solvent so as to counter misuse, particularly by injection.   The pharmaceutical form according to claim 4, and optionally according to any one of the preceding claims, wherein the viscosifying agent V is selected from the following groups of polymers: poly (meth) acrylic acids and their derivatives, and or polyalkylene glycols (for example polyethylene glycol), and / or polyalkylene oxides (for example ethylene), and / or polyvinylpyrrolidones, and / or 2 m <50, preferably 3 m 40 and more preferably 1 to <30, preferably 25 to 20, and more preferably 0 to 40, preferably 0 to 30, and more preferably to gelatin, and / or polysaccharides, preferably in the subgroup comprising: sodium alginate, pectins, guars, xanthans, carrageenans, gellanes and cellulose derivatives (for example hypromellose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose), - and their melas nge.   The pharmaceutical form according to claim 18, wherein the viscosifying agent V is selected from the following groups of polymers: - alkylene polyoxides (eg polyethylene oxide), and / or - xanthans and / or cellulose derivatives (especially hydroxypropyl cellulose) and mixtures thereof.   The pharmaceutical form according to any one of claims 17 to 19, wherein at least one viscosifier V is present in microparticles, and / or on microparticles, and / or in the free state, i.e., not contained in or supported by microparticles.   21. The pharmaceutical form as claimed in any one of claims 17 to 20, in which the viscosifying agent V is at least partly in the form of distinct but non-separable microparticles of the microparticles of PA.   22. The pharmaceutical form according to any one of claims 17 to 21, wherein the amount of agent V is adjusted to make the viscosity of 2.5 mL of the extraction solvent greater than or equal to 100 mPa.s. 30   23. The pharmaceutical form according to any one of claims 17 to 22, wherein the viscosifier V is a polyoxyethylene having a high molecular weight, for example having a molecular weight of 1 million g / mol to 8 million g / mol. 35   24. The pharmaceutical form according to claim 5, and optionally any one of the preceding claims, wherein the sequestering agent Q comprises a salt, which contains ions capable of complexing with the PA salt extracted in solution. 25- 45 -   25. The pharmaceutical form according to claim 24, wherein the ions of the sequestering agent Q are organic ions of opposite polarity to that of the PA in solution, and which form a complex with the PA salt extracted in solution.   The pharmaceutical form according to claim 24 or 25, wherein 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. 10   27. The pharmaceutical form according to any one of claims 24 to 26, comprising PA salt microparticles and Q sequestering agent microparticles.   28. The pharmaceutical form according to claim 27, wherein said microparticles have a similar size distribution, a similar density and are not separable from each other by sieving.   The pharmaceutical form of claim 25, wherein the ion of opposite polarity to that of the PA in solution is an organic anion. 20   30. The pharmaceutical form according to any of claims 24 to 28, wherein the sequestering agent Q comprises a salt selected from the group consisting of: 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, crosslinked carboxymethylcellulose and its derivatives and other polysaccharides (for example, alginate, xanthan gum or arabic), alginate (sulfonate) 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, succinic, citric, stearic and palmitic acids, and self-emulsifying glyceryl mono-oleates; polyamino acids, proteins or peptides, such as albumins; , caseins, globulins and enzymes; and their mixtures.   The pharmaceutical form of claim 24 or 25, wherein the ion of opposite polarity to that of the AP in solution is an organic metal cation, or a mixture thereof.   The pharmaceutical form according to any one of claims 24 to 28, wherein the sequestering agent Q comprises a salt selected from the group consisting of: 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; organic cationic salts, such as quaternary ammonium compounds, in particular tri methyl 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; - and their mixtures.   The pharmaceutical form according to any one of claims 24 to 28, wherein the sequestering agent Q is a salt of 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 PA is anionic.   34. The pharmaceutical form according to claim 33, wherein the sequestering agent Q is a derivative of a copolymer of styrene and divinylbenzene.   The pharmaceutical form of claim 33, wherein the sequestering agent Q is a derivative of a copolymer of styrene and divinylbenzene sulfonic acid.   36. The pharmaceutical form according to claim 33, wherein the sequestering agent Q is a derivative of a styrene-divinylbenzene copolymer bearing quaternary ammonium functions.   37. The pharmaceutical form according to claim 33, wherein the sequestering agent is a crosslinked copolymer of methacrylic acid and divinylbenzene, or a salt thereof.   The pharmaceutical form of claim 33, wherein the ion exchange resin is a phenolic polyamine.   39. The pharmaceutical form according to any one of claims 24 to 38, wherein the sequestering agent Q is selected 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; strongly acidic cation exchange resins or strongly basic anion exchange resins, depending on the polarity of the PA.   40. The pharmaceutical form according to any one of claims 24 to 39, wherein at least one sequestering agent Q is present: in microparticles free of PA, and / or on microparticles, and / or in free state, that is to say not contained in or supported by microparticles. 25   41. The pharmaceutical form according to any one of claims 24 to 40, wherein the amount of sequestering agent is adjusted to complex all or part of the dose of PA contained in the unit form.   42. The pharmaceutical form according to any of the preceding claims comprising at least one excipient in the free state, i.e., not contained in, or supported by, PA microparticles, said excipient contributing to the resistance. grinding coated microparticles of PA.   43. The pharmaceutical form as claimed in any one of the preceding claims, comprising: a) a PA at least a portion of which is contained in microparticles individually coated with an R coating providing the modified release of the AP and simultaneously conferring resistance to grinding microparticles of PA5-48-coated, where for each constituent Al, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass Al + A2 + A3 + A4) verifies: for Al: 90 m, preferably 15 m 80, and more preferably 60 mS 80; for A2: 2 m 50, preferably 3 m <40, and more preferably 5 <mS25; for A3: 1 S m 30, preferably 2 m 20, and more preferably 5 m <15; for A4: 0 <_ m <_ 40, preferably 0 S m <_ 30, and more preferably 10 0≤m_ <20; b) at least one agent D which is present at a level of 0.5 to 30% w / w, preferably from 0.5% to 25% w / w, and more preferably still from 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 to trap all or part of the dose of PA contained in the unit form, the sequestering agent Q being included in a separate phase distinct from the phase containing the salt of PA.   44. The pharmaceutical form according to claim 43, comprising V-viscosifiers microparticles distinct from the microparticles of PA. 25   45. The pharmaceutical form according to claim 43 or 44, comprising microparticles of viscosifier V and microparticles of PA, said microparticles having a similar size distribution, a similar density and not separable from each other by sieving. 30   46. The pharmaceutical form according to any one of claims 43 to 45, wherein the coating layer R contains the following components: Al is selected from the group consisting of non-water-soluble derivatives of cellulose, preferably ethylcellulose and or cellulose acetate, A2 is selected from the group consisting of: • nitrogenous (co) polymers, preferably in the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N -vinyl-lactams, • water-soluble derivatives of cellulose, • polyethylene glycols (PEG), • 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; polyethylene oxide-propylene oxide polyoxide copolymers; poloxamer), polyoxyethylenesorbitan esters, polysorbates, stearates, preferably magnesium, and mixtures thereof.   47. The pharmaceutical form as claimed in any one of claims 43 to 46, in which the agent D is chosen from the following group of products: hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) celluloses, and their salts - guar gums, carrageenans, and mixtures thereof.   48. The pharmaceutical form according to any one of claims 43 to 47, wherein the viscosifier V is selected from: polyalkylene oxides (eg polyethylene oxide), and / or xanthans and / or or cellulose derivatives (especially hydroxypropyl cellulose) and mixtures thereof.   49. The pharmaceutical form according to any one of claims 43 to 48, wherein 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. 50. A pharmaceutical form according to any one of claims 43 to 49, wherein the sequestering agent Q is selected from: - strongly acidic cation exchange resins and mixtures thereof, when the PA is cationic - strongly basic exchange resins anions and mixtures thereof when the AP is anionic.   51. The pharmaceutical form according to any one of claims 43 to 50, which is in tablet unit form, comprising: a) a PA at least a portion of which is contained in microparticles individually coated with an R-coating; the modified release of the AP and simultaneously conferring resistance to grinding of the coated PA microparticles, where for each component A1, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass Al + A2 + A3 + A4) satisfies for A1: 10 <nn 90, preferably 15 S m 80, and more preferably 60 m 80; for A2: 2-50 m, preferably 3 m S 40, and more preferably 25 mS 25; for A3: 1 m <_ 30, preferably 2 _ <m 20, and more preferably 5m <_15; for A4: 0 m 40, preferably 0 to 30 m, and more preferably 0SmS20; 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 p, of the total mass of the unit form; c) at least one viscosifying agent V contained in microparticles separate from the microparticles of AP, in a proportion of 2 to 400 mg, preferably from 5 to 200 mg, and more preferably still from 10 to 100 mg, per unit form, ) at least one sequestering agent Q contained in microparticles separate from the microparticles of PA and of viscosifying agent, the quantity of sequestering agent being adjusted in ionic charge so as to trap all or part of the dose of AP contained in the unitary form; e) optionally compressional excipients.   52. The pharmaceutical form according to claim 51, comprising at least one sequestering agent Q.   53. The pharmaceutical form according to any one of claims 43 to 50, which is in a unitary capsule form, 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 AP and simultaneously conferring resistance to grinding coated microparticles of PA and where for each constituent Al, A2, A3 and A4 of the coating layer R, its mass rn (in% of the total mass Al + A2 + A3 + A4) satisfies for A] _: 10 5 m 5 90, preferably 15 m 5 80, and more preferably 60_5m5 80; for A2: 2: 5 m 5 50, preferably 35 m _ <40, and more preferably 55m_525; for A3: 1: 5 m 5, preferably 25 m 2, and more preferably 55 m 515; for A4: 0 5 m 5 40, preferably 0 5 m 5 30, and more preferably 0-5 m -520; b) at least one agent D, which is present at from 0.5 to 20% w / w, preferably from 0.5% to 15% w / w, and more preferably still from 1% to 10% w / w, the total mass of the unit form; c) optionally at least one viscosifying agent V contained in microparticles separate from the microparticles of AP, in a proportion of 2 to 400 mg, preferably from 5 to 200 mg, and still more preferably from 10 to 100 mg, per unit form, ) optionally at least one sequestering agent Q contained in microparticles separate from the microparticles of PA and viscosifying agent; the amount of sequestering agent being adjusted in ionic charge so as to trap all or part of the dose of AP contained in the unitary form.   54. The pharmaceutical form according to claim 53, comprising at least one viscosifying agent V.   55. The pharmaceutical form according to claim 53 or 54, comprising at least one sequestering agent Q.   56. A pharmaceutical form according to any one of claims 53 to 55, comprising microparticles of viscosifier V and / or microparticles of sequestering agent Q, the viscosifying agent microparticles V and the sequestering agent microparticles Q being distinct from the microparticles of AP.   57. The pharmaceutical form according to any one of claims 53 to 56, comprising PA microparticles, as well as V-viscosifying microparticles and / or Q-sequestering agent microparticles, said microparticles having a similar size distribution. , a similar density and not separable from each other by sieving.   58. The pharmaceutical form according to claim 42, wherein the free excipient is selected from the group consisting of: calcium stearate glyceryl behenate glycerol palmitostearate; magnesium oxide; polyalkylene glycols and preferably polyethylene glycols; polyvinyl alcohol; sodium benzoate; stearic acid; corn starch; talcum; colloidal silica; zinc stearate, magnesium stearate; stearyl halate; and their mixtures.   59. Pharmaceutical form according to any one of the preceding claims, characterized in that 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.   60. A pharmaceutical form according to any one of the preceding claims comprising at least: PA microparticles coated with a grinding resistant coating; an ion exchange resin; polyoxyethylene; methylcellulose.   61. Pharmaceutical form according to any one of the preceding claims comprising at least: microparticles of PA coated with a grinding resistant coating; an ion exchange resin; polyoxyethylene; methylcellulose; hydroxyethylcellulose.   62. Pharmaceutical form according to claim 53, characterized in that it is in the form of a capsule coated with a D-agent based on sodium carboxymethylcellulose.   63. Pharmaceutical form according to claim 53, characterized in that it is in the form of a capsule coated with a D agent based on hydroxyethyl cellulose.   64. The pharmaceutical form according to any one of the preceding claims, comprising modified release PA microparticles and immediate release PA microparticles.   Pharmaceutical form according to any one of the preceding claims, 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.   66. Pharmaceutical form according to any one of the preceding claims, in which the active principle is chosen from the following families: opiates, analgesics, analgesics, antitussives, anxiolytics, benzodiazepines, anorectics, antidepressants, anti-epileptics, anti-migraine, antiparkinsonian, barbiturates, hypnotics , laxatives, neuroleptics, psychostimulants, psychotropics, sedatives, amphetamines, stimulants.   Pharmaceutical form according to any one of the preceding claims, in which the active principle is chosen from the group consisting of: acetorphin, acetylalphamethylfentanyl, acetyl dihydrocreine, acetylmethadol, alfentanil, allylprodine, alphaketylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodin, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxymethyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, cetobemidone. clonitazene, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethyl-thiambutene, difenoxine, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydromorphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morphine, morphine, myrophin, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracidethanol, norcodine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene parafluorofentanyl, pentazocine, pethidine phenampromide, phenazocine, phenorpocin, phenorpocin, phenorpocin, phenorpocin, phenorporidine, propenolol, propiridine, propiramine, propirolol, racemethorphan, racemoramide, racemorphane, remifentanil, sufentanil, thecacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and their salts, esters, their hydrates, their polymorphs and their pharmacologically acceptable isomers, and their mixtures.   68. The pharmaceutical form according to any of the preceding claims, wherein the analgesic PA is selected from the group consisting of oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrochloride, and the like. hydrocodone, and tramadol hydrochloride.   69. Process for obtaining a pharmaceutical form according to any one of the preceding claims, in several steps consisting essentially of: a) preparing hearts (uncoated microparticles) of AP by: extrusion / spheronization of PA with optional one or more pharmaceutically acceptable agent (s) D or excipient (s), and / or; wet granulation of PA with optionally one or more pharmaceutically acceptable agent (s) D or excipient (s), and / or; compaction of AP with optionally one or more pharmaceutically acceptable agent (s) D or excipient (s), and / or; spraying PA, optionally with one or more pharmaceutically acceptable agent (s) D or excipient (s), in dispersion or in solution in an aqueous or organic solvent on a neutral support or particles of agent D, and / or; sieving of powder or PA crystals; B) preparing PA reservoir microparticles by: fluidized air bed spraying with a solution or dispersion containing one or more compounds A1, A2, A3 and optionally one or more compounds A4 and / or D on the microparticles PA; the microparticles of PA may have been previously coated with one or more agents D; the coated PA microparticles may optionally be coated with one or more D agents; c) preparing the final form of the drug by: granulating and / or extruding / spheronizing PA reservoir microparticles with D, V and Q agents for capsule or sachet; or a mixture of PA reservoir microparticles with optionally one or more D, V and Q agent (s) 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 capsules capsule microparticles of PA, V and Q; the capsules 30 may optionally be coated in a turbine or fluidized air bed with one or more agent (s) 1) and / or pharmaceutically acceptable excipients; or bagging reservoir microparticles of PA, V and Q optionally with one or more agent (s) D and / or pharmaceutically acceptable excipients. 35