AU2006311116A1 - Anti-misuse microparticulate oral pharmaceutical form - Google Patents

Description

Verification of Translation I, Georqes PERIN of CABINET PLASSERAUD Immeuble le Rh6ne-Alpes 235 cours Lafayette 69006 LYON - FRANCE am the translator of PCT Application PCT/EP2006/062627 and I state that the following is a true translation to the best of my knowledge and belief. April 15, 2008 ANTI-MISUSE MICROPARTICULATE ORAL PHARMACEUTICAL FORM Field of the invention 5 The present invention relates to solid microparticulate oral pharmaceutical forms whose composition and structure make it possible to avoid misuse of the pharmaceutical or veterinary active principle (AP) they contain. The active principles (AP) in question are pharmaceutical or veterinary AP, 10 for example those classed in the category of stupefacient products, analgesics or narcotics. Misuse of these pharmaceutical active principles can give rise to drug addiction behavior. In terms of the present disclosure, the expression "AP" denotes both a single active principle and a mixture of several active principles. 15 Microparticulate pharmaceutical form is understood in terms of the present invention as meaning any form in which the AP is contained in microparticles smaller than 1000 ptm. These particles containing the AP can be coated microparticles for modified release of the AP. In the latter case, the microparticles 20 are coated e.g. with a polymer film which controls the rate of release of the AP after oral administration. Presentation of the problem 25 The object of the present invention is to prevent solid oral drugs from being misappropriated for any use other than the therapeutic use(s) officially approved by the competent public health authorities. In other words, the object is to avoid the voluntary or involuntary misuse of solid oral drugs. 30 Misuse is mainly encountered in the following cases: a) addictive behavior (drug addiction, doping), b) criminal behavior (chemical subjection), c) use of a drug in a manner that does not comply with the medical recommen dations (dosage), due to carelessness or because of disabilities affecting the patient. 35 3 analgesics or narcotics. This growing phenomenon is of ever greater concern to the health authorities, especially in the United States and Europe, who are increasingly appealing for the development of pharmaceutical forms that prevent mis appropriation. 5 Prior art Patent US-B-6 696 088 relates to a multiparticulate oral pharmaceutical form that is indicated as being resistant to misuse. It comprises particles of opioid 10 agonist AP in a modified-release form and particles containing an opioid antagonist. The form containing the antagonist is described as releasing less than 36%, and preferably less than 6.2%, of the antagonist AP over a period of 36 h. The two types of particles are interdispersed. When misuse is being practiced, the consequence of crushing the 15 microparticles to extract the opioid AP is to release the AP and its antagonist immediately and concomitantly and thereby to limit the desired effects of the misappropriated opioid. As we understand it, said invention is based on the use of an active substance other than the AP and does not propose, inter alia, a solution for reducing 20 the impact of crushing or reducing the extraction of the AP. Patent application US-A-2003/0068371 describes an oral pharmaceutical formulation comprising an opiate AP (oxycodone), an antagonist of this AP (naloxone) and a gelling agent (e.g. xanthan gum). In particular, said US patent 25 application discloses matrix granules of AP comprising lactose, xanthan gum, povidone and an outer coating based on EUDRAGIT RS 30D®/triacetin/antagonist. The gelling agent is presented as giving the formulation a viscosity such that it cannot be administered nasally or parenterally. As we understand it, this answer is inadequate because, according to said invention, the use of an antagonist is, inter 30 alia, obligatory. Finally, this formulation contains no anti-crushing means, so it can be converted to a pulverulent form and consequently be the subject of misuse by the nasal or oral route. Patent application WO-A-03/013479 describes an oral pharmaceutical form 35 comprising an opiate analgesic and an opiate antagonist (naltrexone) in a 5 inhalation or injection to a therapeutic concentration well below that sought by the misuser. The AP/resin complex takes the form of a matrix. As we understand it, no anti-crushing means is provided in the pharmaceutical form according to said prior art document. Furthermore, this pharmaceutical form contains no means for 5 combating solvent extraction of the AP. It is therefore incapable of preventing solvent extraction of the AP, although the extraction time is longer than the normal release time of the AP. If this oral pharmaceutical form is left in a glass of water for 24 h, virtually all the AP is extracted. 10 Patent applications US-A-2003/0118641 and 2005/0163856 (= WO-A 01/08661) describe oral pharmaceutical formulations for the prolonged release of AP consisting of opioid compounds (analgesics) and their salts. These formulations supposedly prevent misuse by extraction of the AP with common solvents. These anti-misuse formulations do not contain antagonists, although this possibility can be 15 envisaged in order to be even more dissuasive. These formulations comprise a mixture of: - a hydrophilic matrix agent (hydroxyalkyl cellulose) in an amount of 40-65% by weight; - an ion exchange resin (particles smaller than 50 pm in an amount of 5-15% by 20 weight); - and at least one opiate AP. After the incorporation of conventional compression additives, this mixture is converted to tablets. This is therefore a macroscopic matrix system comprising particles of ion 25 exchange resin complexed with the AP, and an anti-extraction means consisting of a viscosifier, preferably hydroxypropyl methyl cellulose. As we understand it, this system is capable of improvement, especially in terms of anti-misuse efficacy. Intercalated patent document WO-A-2005/079760 discloses a pharma 30 ceutical formulation consisting of rubbery microparticles of AP obtained by extrusion, which possess for prolonged release of the AP and have anti-misuse properties. These extruded microparticles comprise a matrix formed of an inert poly(ethyl acrylate/methyl methacrylate) copolymer: EUDRAGIT® NE 30D or NE 40D. This matrix contains the AP (oxycodone), another Eudragit®, RS PO, a 35 plasticizer and a lubricant.

7 - make it possible to associate several AP in one and the same dosage unit, even if these AP are not mutually compatible and/or do not have the same release kinetics; - can exist in forms which can be administered one or more times a day and in which it is possible easily and independently to adjust the release rate and time of 5 different AP. Another object of the invention is to provide novel solid oral drugs whose in vitro dissolution profile is independent of the dose of AP. Another object of the invention is to provide novel solid oral drugs which make it possible to avoid fraudulent misappropriation of the properties of the AP 10 they contain by preventing any conversion of the drug to a form that can be taken orally, nasally and/or by injection (intravenously, subcutaneously, intramuscularly, etc.) outside the therapeutic limits. This would prevent or at least greatly reduce the risks associated with this undesirable behavior. Another object of the invention is to provide novel solid oral drugs that 15 make it possible to avoid misuse while at the same time guaranteeing that the patient undergoing normal follow-up has a quality of treatment and, in particular, a dose that conform to his needs. Another object of the invention is to provide novel solid oral drugs that make it possible to avoid misuse without affecting the pharmacological properties 20 of the drug, without causing the patient who uses the drug normally to run additional risks, and finally without detracting from the patient's comfort when the drug is administered. Another object of the invention is to provide novel solid oral drugs that can be administered one or more times a day and limit the risks of damage to the tissues 25 due to local overconcentrations of AP. Another object of the invention is to provide novel solid oral drugs which can take a variety of galenical forms such as tablets, powder sachets, capsules and the like. Another object of the invention is to provide novel anti-misuse solid oral 30 drugs which are easy and economic to prepare. Brief description of the invention To achieve these objects, it is to the inventors' credit to have reformulated 35 the general problem of the misuse of pharmaceutical forms.

9 coated microparticles of AP so as to avoid misuse. The pharmaceutical form according to the invention solves in particular the main problem presented and meets at least some of the objectives set, in an effective, simple and economic manner, with the aid of physicochemical means. 5 The latter are totally inoffensive to the normal user. They are pharmacologically inert compounds that are approved by the pharmacopeia and by the public health authorities responsible for granting drug marketing authorizations. In one preferred embodiment, the solid oral pharmaceutical form according 10 to the invention contains, in addition to the anti-crushing coating layer (Ra), at least one viscosifier (Vb) that makes it very difficult, if not impossible, to extract the AP contained in the coated microparticles of AP so as to avoid misuse of the AP after liquid extraction. In terms of the present disclosure, the expression "viscosifier" denotes both 15 a single viscosifier and a mixture of several viscosifiers. Detailed description of the invention According to the invention, at least part of the AP is in a modified-release 20 form, namely in the form of coated microparticles for modified release of said AP. The active principles (AP) considered in the present invention are pharmaceutical or veterinary AP, for example those classed in the category of analgesics or narcotics. Misuse of these AP can give rise to addiction behavior. 25 In terms of the present invention, the expression "AP" denotes one active principle or a mixture of several active principles. In terms of the present invention, "microparticulate form" is understood as 30 meaning any pharmaceutical form in which the AP is contained in microparticles smaller than 1000 microns. These particles containing the AP can be microparticles individually coated with a film for modified release of the AP. In the latter case, the microparticles are coated e.g. with a polymer-based film which controls the rate of release of the AP. 35 11 pharmaceutiques nouvelles: aspects technolosique, biopharmaceutique et medical (New pharmaceutical forms: technological, biopharmaceutical and medical aspects) by Buri, Puisieux, Doelker and Benoit, editions Lavoisier 1985, pages 175 to 227. In other words, these coated microparticles preferably each consist of a core 5 comprising AP and a coating comprising at least one coating layer that envelops the core (preferably entirely) and governs the modified release (preferably continuous) of the AP. This release takes place when the coated microparticles of AP are brought into contact with the gastrointestinal juices. The uncoated microparticles of AP (i.e. before coating) can be e.g.: 10 - inert cores covered with at least one layer containing AP; - or mnicroparticles of pure AP; - or granules formed of a matrix of supporting excipients, including the AP. In the case of supported granules, the inert core or support can be 15 composed of sucrose and/or saccharose and/or dextrose and/or lactose and/or a sucrose/starch mixture. The inert core or support can also be a cellulose microsphere or any other particle of pharmaceutically acceptable excipient. Particles of xanthan gum, guar gum, calcium phosphate or calcium carbonate may be mentioned as non-limiting examples of inert supports. Their mean diameter can 20 be between 10 and 200 microns, between 20 and 150 microns or between 50 and 100 microns. These coated microparticles of the "reservoir" type (or individually coated microparticles) can be likened to vehicles for the transport and release of at least 25 one AP in the small intestine or even the large intestine. Examples which may be mentioned of coated microparticles for modified release of the AP are those described in the following patent documents: EP-B 0 709 087 and WO-A-03/030878. 30 Coating on the microparticles of AP Advantageously, the coated microparticles of AP comprise at least one coating layer (Ra), preferably only one coating layer (Ra), which assures the modified release of the AP and simultaneously imparts crushing resistance to the coated microparticles of AP so as to avoid misuse. 35 Particularly preferably, the coating layer (Ra) is designed in such a way that, 13 - polyethylene glycols (PEG), - and mixtures thereof, PVP being particularly preferred; 5 (A3) is selected from the group comprising: - cetyl alcohol esters, - glycerol and its esters, preferably from the following subgroup: acetylated glycerides, glycerol monostearate, glyceryl triacetate and glycerol tributyrate, - phthalates, preferably from the following subgroup: dibutyl phthalate, diethyl 10 phthalate, dimethyl phthalate, dioctyl phthalate, - citrates, preferably from the following subgroup: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate, - sebacates, preferably from the following subgroup: diethyl sebacate, dibutyl sebacate, 15 - adipates, -azelates, - benzoates, - vegetable oils, - fumarates, preferably diethyl fumarate, 20 - malates, preferably diethyl malate, - oxalates, preferably diethyl oxalate, - succinates, preferably dibutyl succinate, - butyrates, - cetyl alcohol esters, 25 - salicylic acid, - triacetin, - malonates, preferably diethyl malonate, - castor oil (this being particularly preferred), - and mixtures thereof; 30 (A4) is selected from the group comprising: - anionic surfactants, preferably from the subgroup comprising alkali metal or alkaline earth metal salts of fatty acids, stearic and/or oleic acid being preferred, - and/or non-ionic surfactants, preferably from the following subgroup: 35 - polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil, 15 mixtures thereof. Another noteworthy characteristic of the coating (Ra) on the coated microparticles is the fact that the coating layer (Ra) represents a fraction by weight 5 Tp, expressed in % by dry weight, based on the total weight of the coated microparticles, such that: Tp _ 15, Tp preferably being between 30 and 60, particularly preferably between 40 and 60 and very particularly preferably between 45 and 55 or about 50. Without wishing to be bound by theory, this relatively high coating rate 10 enables the coating layer (Ra) to assure the modified release of the AP and simultaneously to impart crushing resistance to the coated microparticles of AP so as to avoid misuse. Without implying a limitation, the preferred coated microparticles of AP 15 according to the invention are those having a mean diameter less than or equal to 1000 ptm, preferably of between 50 and 800 4m, particularly preferably of between 100 and 600 p.m and very particularly preferably of between 100 and 300 Itm. Unless indicated otherwise, the diameters of microparticles referred to in the present disclosure are mean diameters by volume. 20 As regards the preparation of the coated microparticles, the techniques that are advantageously used for depositing the coating for modified release of the AP, or depositing the active layer based on the AP, are techniques known to those skilled in the art, for example the technique of spray coating in a fluidized air bed, 25 wet granulation, compaction or extrusion/spheronization. Outer coating In one particular variant of the invention, the coated microparticles for modified release of the AP have an outer coating designed in such a way that, in the 30 manufacture of tablets, it contributes to maintaining a modified release for at least some of said coated microparticles of AP for modified release of the AP. The outer coating is composed of at least one deformable organic constituent with a melting point of between 40 0 C and 120 0 C, preferably of between 45 0 C and 100 0 C. In one preferred variant, the outer coating comprises at least 10% by weight 35 of deformable organic constituent.

17 sensu or any aqueous solution, for example of an organic acid (e.g. acetic acid), saline solutions, sodas or drinks. "Alcohols" are understood as meaning any alcohols taken on their own or in a mixture with one another. "Ketones" are understood as meaning any ketones taken on their own or in a mixture with one 5 another. Particularly preferably, the viscosifier (Vb) is selected from the following groups of polymers: - polyacrylic acids and derivatives thereof, and/or - polyalkylene glycols (e.g. polyethylene glycol), and/or 10 - polyalkylene oxides (e.g. polyethylene oxides), and/or - polyvinylpyrrolidones, and/or - gelatins, and/or - polysaccharides, preferably from the subgroup comprising sodium alginate, pectins, guars, xanthans, carrageenans, gellans and cellulose derivatives (e.g. 15 hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxy methyl cellulose), - and mixtures thereof. According to one modality of the invention, the viscosifier Vb is a polyoxyethylene with a high molecular weight, e.g. with a molecular weight of I 20 million g/mol to 8 million g/mol, for example of 2 million, 5 million or 7 million g/mol. Preferably, the viscosifier Vb, e.g. the high-molecular polyoxyethylene, is included in microparticles distinct from the microparticles of AP. Particularly preferably, the microparticles of AP and the microparticles of 25 viscosifier Vb have a similar size distribution and a similar density and are inseparable by sieving. According to one preferred modality, the viscosifier (Vb) is capable of increasing the viscosity of the liquid used for possible extraction so as to trap the extracted AP in the viscous medium. 30 This viscosifier (Vb) makes it possible to increase the viscosity of the extraction liquid e.g. to beyond 100 mPa.s, preferably 200 mPa.s, particularly preferably beyond 500 mPa.s and very particularly preferably 1000 mPa.s. It is also to the Applicant's credit to have proposed, in one variant, viscosifiers (Vb) that are effective in the case of both aqueous phase extraction and 35 organic solvent extraction. Advantageously, these viscosifiers (Vb) are mixtures of 19 - and mixtures thereof. In alternative embodiments of the invention, at least part of the viscosifier is: - in the free state, i.e. neither contained in nor supported by coated or uncoated 5 microparticles of AP (alternative 1), or - in the form of microparticles that are distinct from the coated or uncoated microparticles of AP (alternative 2). Advantageously, in alternative 2, the microparticles of viscosifier are inseparable from the coated or uncoated microparticles of AP. In terms of the 10 present disclosure, the expression "inseparable" means e.g. inseparable by conventional means such as sieving or centrifugation. In alternative 2, the viscosifier is e.g.: - in and/or on microparticles, - and/or in an outer coating on all or some of the microparticles of AP. 15 Still in alternative 2, the microparticles comprising the viscosifier are preferably physically indiscernible from the microparticles of AP so that they cannot easily be sorted by any appropriate physical means. The microparticles comprising the viscosifier are indiscernible from the microparticles of AP especially by having the same size and/or same density and/or same shape and/or same color. 20 In another alternative, the viscosifier is e.g.: - in and/or on microparticles, - and/or in an outer coating on all or some of the microparticles of AP. In one preferred embodiment, the pharmaceutical form according to the 25 invention is multimicroparticulate. If this pharmaceutical form comprises micro particles of AP (e.g. aAP) and microparticles of viscosifier (Vb), said microparticles preferably have a similar size distribution and a similar density and are preferably inseparable by sieving. Thus the microparticles of viscosifier cannot be separated from the coated or uncoated microparticles of AP. 30 In another preferred embodiment, the pharmaceutical form according to the invention is multimicroparticulate. If this pharmaceutical form comprises microparticles of AP (e.g. aAP) and microparticles of viscosifier (Vb), said micro particles preferably have the same size distribution and the same density and are 35 preferably inseparable by sieving. Thus the microparticles of viscosifier cannot be 21 Sequestering agent Q Obviously, in the case where the microparticulate pharmaceutical form comprises at least one salt of at least one analgesic active principle, those skilled in the art may add at least one sequestering agent to said pharmaceutical form so as to 5 form a slightly soluble complex with the AP in solution in an aqueous or aqueous alcoholic drink. The sequestering agent is e.g. a salt whose ion of opposite polarity to that of the AP is preferably an organic ion. Thus, for a cationic active principle, this sequestering agent is e.g. an organic salt like sodium docusate, or an anionic 10 polymer. The sequestering agent can also be e.g. a salt of an ion exchange resin. In terms of the present invention, a sequestering agent Q is present in the pharmaceutical form in a free form, i.e. non-complexed. "Non-complexed" means that no complex or chemical interaction exists between the sequestering agent Q and the salt of the active principle, AP, in the solid pharmaceutical form. 15 If the AP salt and the sequestering agent Q are present simultaneously in a solvent, e.g. in the case of an illicit attempt to extract the AP, the sequestering agent Q is capable of inducing complexation or a chemical interaction with the AP salt in said solvent. In terms of the present invention, the sequestering agent Q is considered to be "capable of inducing complexation" with the AP salt if the 20 sequestering agent Q is capable of inducing complexation of the AP salt in at least one customary solvent selected from water and aqueous solutions such as water/ ethanol mixtures, alcohol, alcoholic drinks, sodas, vinegar, hydrogen peroxide and mixtures thereof. Advantageously, the sequestering agent Q is capable of inducing complexation of the AP salt in more than one of these customary solvents. 25 The sequestering agents Q used to trap the AP, especially analgesic AP, are inoffensive, even when used regularly. These products are inert from the pharma cological point of view and are approved by the various pharmacopeias and drug registration authorities. In one pharmaceutical form according to the invention, at least one 30 sequestering agent Q is present: - in microparticles devoid of AP, and/or - on microparticles, and/or - in the free state, i.e. neither contained in nor supported by microparticles. Preferably, in one pharmaceutical form according to the invention, the 35 sequestering agent Q is present in a first phase separate from at least one second 23 tetradecylammonium bromide or benzethonium chloride; - cationic polymers such as chitosan and (meth)acrylic copolymers (e.g. Eudragit® RS, Eudragit® RL or Eudragit® E); - polyamino acids, proteins or peptides; 5 - and mixtures thereof. The sequestering agent Q can be an ion exchange resin, preferably a strongly acidic cation exchange resin when the AP 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 separate from a second phase containing the AP. 10 In one embodiment of the invention, the ion exchange resin is e.g. a derivative of a styrene/divinylbenzene copolymer. In one embodiment of the invention, the strongly acidic cation exchange resin will be e.g. a derivative of a sulfonated styrene/divinylbenzene copolymer, such as Amberlite® IRP69, Amberlite® IR69F (Rohm and Haas), Amberlite 200, 15 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 be selected e.g. from derivatives of styrene/divinylbenzene copolymers carrying quaternary ammonium groups, such as Duolite® AP143 (Rohm and Haas), Amberlite IRA958, Amberlite IRP67 (Robinhm and Haas) and DOWEX 22 (Dow). 20 The sequestering agent Q in the form of resin can also be selected from crosslinked methacrylic acid/divinylbenzene copolymers or one of their salts, such as Amberlite® IRP88, Amberlite® IRP64 (Robinhm and Haas) and DOWEX MAC-3 (Dow). The sequestering agent Q in the form of ion exchange resin can also be 25 selected from phenolic polyamines such as Amberlite® IRP58 (Rohm and Haas), and mixtures thereof. In one embodiment of the invention, the sequestering agent Q in the form of ion exchange resin is in a first phase separate from at least one second phase, said second phase comprising the AP salt. For example, the sequestering agent Q in the 30 form of ion exchange resin is contained in microparticles distinct from the micro particles comprising the AP salt. The microparticles of AP and the microparticles of sequestering agent Q in the form of ion exchange resin can be in a form such that they have a similar size distribution, a similar density and are inseparable by sieving. In a first preferred mode of carrying out the invention, the sequestering 35 agent Q is selected from: 25 Advantageously, these microparticles have a similar size distribution and a similar density and are inseparable from one another by sieving. In a first variant, the pharmaceutical form according to the invention cannot 5 be converted to a dry form with immediate release of the AP which can be administered by sniffing. In a second variant, the pharmaceutical form according to the invention cannot be converted to an injectable form with immediate release of the AP. In a third variant, the pharmaceutical form according to the invention 10 comprises modified-release AP and optionally immediate-release AP. This variant can be combined with the first and second variants referred to above, which means that, in a pharmaceutical form containing modified-release AP and immediate release AP, the modified-release AP cannot be converted to a dry form which can be administered by sniffing or to an immediate-release injectable form. 15 In a fourth variant, the pharmaceutical form according to the invention is characterized in that extraction of the AP by chewing and/or crushing is not effective. In a fifth variant, the pharmaceutical form according to the invention is characterized in that it is devoid of AP antagonist(s). 20 In a sixth variant, the pharmaceutical form according to the invention is characterized in that it comprises at least one AP antagonist. With knowledge of the AP used, those skilled in the art can easily determine the appropriate antagonist(s). Of course, any combination of at least two of these six variants is included 25 in the present invention (except combination of the fifth and sixth variants). Active principle(s) The AP used belongs e.g. to at least one of the following families of active substances: amphetamines, analgesics, anorexigenics, antalgics, antidepressants, 30 antiepileptics, antimigraine substances, antiparkinsonism substances, antitussives, anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives, neuroleptics, opiates, psychostimulants, psychotropic substances, sedatives and stimulants. In the case where the AP is an analgesic AP (aAP), it is preferably an opioid. Even more precisely, the AP used is selected from the following 35 compounds: anileridine, acetorphine, acetyl-alpha-methylfentanyl, acetyldihydro- 27 polymorphs and isomers, and mixtures thereof. The following may be mentioned among the anti-inflammatory active principles that can be envisaged: ibuprofen, acetaminophen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, 5 piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, amineoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, their 10 pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers, and mixtures thereof. Even more precisely, the analgesic AP used is selected from the group comprising oxycodone hydrochloride, morphine sulfate, oxymorphone hydro 15 chloride, hydromorphone hydrochloride, hydrocodone hydrochloride and tramadol hydrochloride. In terms of the invention, the expression "pharmaceutical formulation" is understood in the broad sense, i.e. veterinary or dietetic formulations, in particular, 20 are encompassed. According to another of its features, the invention relates to a formulation which is characterized in that it comprises a plurality of microparticles (coated or uncoated microparticles of AP; optionally microparticles of viscosifier) as defined above, e.g. at least 500, preferably from 1,000 to 1,000,000 and particularly 25 preferably from 5,000 to 500,000 microparticles. According to another of its features, the invention relates to a pharmaceutical formulation comprising a plurality of populations of coated microparticles of AP, said populations being distinguished from one another by their release kinetics and/or the AP they contain. 30 Without implying a limitation, it must nevertheless be emphasized that the pharmaceutical formulation according to the invention is of particular value in that it can take the form of a single daily oral dose comprising from 500 to 500,000 microparticles, including the coated microparticles of AP. Advantageously, the pharmaceutical formulation comprising coated micro 35 particles according to the invention is in a galenical form selected from the group 29 Advantageously, the coating layer (Ra) and the viscosifier (Vb), if present, are as defined above. The invention will be explained more clearly by means of the Examples 5 below, given solely by way of illustration, which afford a clear understanding of the invention and demonstrate its different embodiments and/or modes of implemen tation, as well as its different advantages. Description of the Figures 10 Figure 1 shows the dissolution profile in an in vitro reference test (% dissolution D as a function of time T) on the microparticles of Example 1: -E-. Figure 2 shows the dissolution profile in an in vitro reference test (% dissolution D as a function of time T) on the microparticles of Example 1: -0-, 15 and Example 2: (a) ---0---, (b) ---o---, (c) ---*0---, (d) ---A---. Figure 3 shows photographs of the contents of a capsule according to Example 3, observed with the naked eye (A) and under an optical microscope (B). Figure 4 shows the release profile (% by weight of aAP as a function of time in hours) of microcapsules in 0.1 N HC1 (Example 8). 20 Figure 5 shows photographs of the contents of a capsule according to Example 9, observed with the naked eye (A) and under an optical microscope (B). Figure 6 shows the release profile of crushed microparticles (blank triangle) or intact microparticles (ailled square) of Example 9. 25 Examples The reference dissolution test in the Examples which follow is an in vitro dissolution test performed as indicated in the European Pharmacopoeia 5th edition, entitled "Dissolution test for solid oral forms": type II dissolutest performed under 30 SINK conditions, maintained at 37 0 C and stirred at 75 rpm in 900 ml of 0.1 N HCI medium. Example 1: Microparticles of oxycodone HCI according to the invention A mixture of 1600 g of oxycodone HCI, 100 g of Klucel® EF (hydroxy 35 propyl cellulose /Aqualon) and 12.052 g of water is film-coated onto 300 g of inert 31 sieved to between 100 and 600 jtm. The whole is incorporated into a size 0 gelatin capsule. Figure 3 shows photographs of the contents of the capsule, observed with the naked eye (A) and under an optical microscope (B). 5 As shown in Figure 3(A), observed with the naked eye, the microparticles of active principle and the microparticles of viscosifiers are: - indistinguishable, - inseparable by sieving. In the photograph of Figure 3(B) obtained by optical microscopy (note 10 scale), there are only two distinct populations of particles: on the one hand spherical microparticles of oxycodone HCI and microparticles of two viscosifiers, and on the other hand rod-shaped particles of a 3rd viscosifier. Given the very small size of these particles (about 0.2 mm), they cannot be separated from one another. 15 Example 4: Test for syringe extraction of a form according to the invention 200 mg of microparticles prepared in Example 1 (i.e. a dose of 80 mg of oxycodone HC1) are mixed with 90 mg of Klucel I-IF (hydroxypropyl cellulose /Aqualon), 20 mg of PolyOx WSR 303 Sentry (polyethylene oxide /Dow) and 20 mg of Xantural 180 (xanthan /cpKelco) previously sieved to between 100 and 600 20 jmrn. The whole is incorporated into a size 0 gelatin capsule. The capsule is opened and the contents are crushed according to Example 2(a) with a mortar and pestle and then mixed for 10 min with 2.5 ml of extraction liquid at ambient temperature or at the boil. The solution is then taken up with a 2.5 ml syringe (with an 18G needle) through cotton wool serving as a filter. The 25 amount of oxycodone HCl extracted is analyzed by IHPLC or UV and is shown in Table 1. The low extraction yields observed (<20%) are totally dissuasive for potential misusers. 30 Example 5: Test for syringe extraction of a form according to the invention 200 mg of microparticles prepared in Example 1 (i.e. a dose of 80 mg of oxycodone HCI) are mixed with 150 mg of Klucel HXF (hydroxypropyl cellulose /Aqualon), 50 mg of PolyOx WSR 303 Sentry (polyethylene oxide /Dow) and 30 mg of Carbopol 971P (carbomer /BF Goodrich). The mixture is incorporated into a 35 size 00 gelatin capsule.

33 temperature or at the boil. The solution is then taken up With a 2.5 ml syringe (with an 18G needle) through cotton wool serving as a filter. The amount of oxycodone HC1 extracted is analyzed by IHIPLC or UV and is shown in Table 4. The low extraction yields observed (<20%) are totally dissuasive for 5 potential misusers. Example 8: Microparticles of oxycodone HCI according to the invention Step 1: Granules 1615 g of oxycodone and 85 g of povidone (Plasdone ® K29-32 /ISP) are 10 dispersed in a mixture containing 2052 g of water and 1105 g of ethanol. The solution is sprayed onto 300 g of cellulose spheres (Asahi-Kasei) in a Glatt GPCG1 fluidized air bed. Step 2: Anti-crushing microparticles 15 315 g of ethyl cellulose (Ethocel 20 Premium /Dow), 81 g of povidone (Plasdone K29-32 /ISP), 18 g of macrogolglyceroli hydroxystearas (Cremophor RH40 /BASF) and 36 g of castor oil (Garbit huilerie) are solubilized in a mixture composed of 3105 g of acetone and 2070 g of isopropanol. This solution is sprayed onto 450 g of granules (prepared in step 1). 20 The coating represents 50% of the weight of the microparticle and assures that the is released as shown in Figure 4. The release profile is determined under the conditions of the reference dissolution test. Example 9: Contents of a capsule according to the invention 25 230 mg of microparticles obtained in step 2 of Example 8, 100 mg of crushed and sieved Amberlite IR69F (sodium polystyrenesulfonate), 70 mg of sieved Polyox WSR 303 Sentry (polyethylene oxide), 3.8 mg of magnesium stearate and 1.9 mg of Aerosil 200 (colloidal silica) are introduced into a size 0 gelatin capsule. 30 As shown in Figure 5, observed with the naked eye (A) and under an optical microscope (B), the microparticles of active principle and the microparticles of viscosifiers are: - indistinguishable, - inseparable by sieving. 35 35 Solvent Volume (ml) Tap water 100 Tap water with 2 g/1 of NaCI 100 pH 1.2 (HC1) with 2 g/l of NaCI 100 Sprite ® 100 Pepsi-Colao 100 Smirnoff Twisted Apple (5% alcohol) 100 Absolut vodka (40% alcohol) 50 The solution is then taken up and the amount of oxycodone HCI extracted is analyzed by HPLC or UV and is shown in Table 7. 5 The low extraction yields observed, even for long extraction times, are totally dissuasive for potential misusers. Table 1 (Example 4) 10 % oxycodone HCI extracted with the 18G syringe Liquid at ambient temperature Liquid at the boil Tap water 0.2 1 Water/ethanol (60/40 v/v) 3 8 Ethanol 18 1 Table 2 (Example 5) % oxycodone HCI extracted with the 18G syringe Liquid at ambient temperature Liquid at the boil Tap water 1 2 Water/ethanol (60/40 v/v) 4 7 Ethanol 19 8 15 Table 3 (Example 6) % oxycodone HC1 extracted with the 18G syringe Liquid at ambient temperature Liquid at the boil Tap water 1 2 Water/ethanol (60/40 v/v) 5 8 Ethanol 19 9

Claims (19)

1. A solid oral pharmaceutical form, characterized in that: - it contains anti-misuse means, 5 - at least part of the AP it comprises is contained in coated microparticles for modified release of the AP, and - the coated microparticles of AP have a coating layer (Ra) which assures the modified release of the AP and simultaneously imparts crushing resistance to the coated microparticles of AP so as to avoid misuse. 10

2. The pharmaceutical form according to claim 1, characterized in that it comprises at least one viscosifier (Vb) capable of preventing extraction of the AP contained in the coated microparticles of AP for modified release of the AP so as to avoid misuse. 15

3. The pharmaceutical form according to claim 1 or 2, characterized in that it comprises at least one sequestering agent (Q) capable of forming a complex with the AP in solution. 20 4. The pharmaceutical form according to claim 1, 2 or 3, characterized in that the coating layer (Ra) is designed in such a way that, in the event of crushing, it allows maintenance of a modified release of the AP for at least some of the coated microparticles. 25 5. The pharmaceutical form according to any one of the preceding claims, characterized in that the coating layer (Ra) is designed in such a way that, in the event of crushing, it allows maintenance of a modified release for at least 40%, preferably at least 60% and particularly preferably at least 80% of the coated microparticles for modified release of the AP. 30

6. The pharmaceutical form according to any one of the preceding claims, characterized in that the coating layer (Ra) comprises: (Al) at least one film-forming (co)polymer (Al) insoluble in the gastrointestinal juices; 35 (A2) at least one (co)polymer (A2) soluble in the gastrointestinal juices; 39 (A3) is selected from the group comprising: - cetyl alcohol esters, - glycerol and its esters, preferably from the following subgroup: acetylated glycerides, glycerol monostearate, glyceryl triacetate and glycerol tributyrate, 5 - phthalates, preferably from the following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, - citrates, preferably from the following subgroup: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate, - sebacates, preferably from the following subgroup: diethyl sebacate, dibutyl 10 sebacate, - adipates, - azelates, - benzoates, - vegetable oils, 15 - fumarates, preferably diethyl fumarate, - malates, preferably diethyl malate, - oxalates, preferably diethyl oxalate, - succinates, preferably dibutyl succinate, - butyrates, 20 - cetyl alcohol esters, - salicylic acid, - triacetin, - malonates, preferably diethyl malonate, - castor oil (this being particularly preferred), 25 - and mixtures thereof; (A4) is selected from the group comprising: - anionic surfactants, preferably from the subgroup comprising alkali metal or alkaline earth metal salts of fatty acids, stearic and/or oleic acid being preferred, 30 - and/or non-ionic surfactants, preferably from the following subgroup: - polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil, - polyoxyethylene/polyoxypropylene copolymers, - polyethoxylated sorbitan esters, - polyethoxylated castor oil derivatives, 35 - stearates, preferably calcium, magnesium, aluminum or zinc stearates, 41 overcoated microparticles of AP.

13. The pharmaceutical form according to claim 2 and optionally according to any one of the other preceding claims, characterized in that at least one viscosifier 5 (Vb) is selected from those which are soluble in at least one of the following solvents: water, alcohols, ketones and mixtures thereof, said viscosifier being capable of increasing the viscosity of the extraction liquid so as to thwart misuse, especially by injection. 10 14. The pharmaceutical form according to claim 13, characterized in that the viscosifier (Vb) is selected from the following groups of polymers: - polyacrylic acids and derivatives thereof, and/or - polyalkylene glycols (e.g. polyethylene glycol), and/or - polyalkylene oxides (e.g. polyethylene oxides), and/or 15 - polyvinylpyrrolidones, and/or - gelatins, and/or - polysaccharides, preferably from the subgroup comprising sodium alginate, pectins, guars, xanthans, carrageenans, gellans and cellulose derivatives (e.g. hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxy 20 methyl cellulose), - and mixtures thereof.

15. The pharmaceutical form according to claim 13 or 14 in which the viscosifier (Vb) is a polyoxyethylene with a high molecular weight, e.g. with a 25 molecular weight of 1 million g/mol to 8 million g/mol, for example of 2 million, 5 million or 7 million g/mol.

16. The pharmaceutical form according to any one of claims 13 to 15, characterized in that at least one viscosifier (Vb) is present: 30 - in and/or on microparticles, - and/or in an outer coating on all or some of the microparticles of AP, - and/or in the free state, i.e. neither contained in nor supported by microparticles.

17. The pharmaceutical form according to any one of claims 13 to 16, 35 characterized in that the viscosifier (Vb) is capable of increasing the viscosity of the 43 Eudragit® L), crosslinked polyacrylic acids (e.g. Carbopol), carboxymethyl cellulose and derivatives thereof, crosslinked carboxymethyl cellulose and derivatives thereof, and other polysaccharides (e.g. alginate, xanthan gum or gum arabic), and alginate/ (sulfonate) propylene glycol; 5 - monovalent or polyvalent salts such as glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides and acesulfames; - saponified fatty acids such as acetic, succinic, citric, stearic and palmitic acid salts 10 and self-emulsifying glyceryl monooleates; - polyamino acids, proteins or peptides, such as albumins, caseins, globulins and enzymes; - and mixtures thereof. 15 26. The pharmaceutical form according to claim 20 in which the ion of opposite polarity to that of the AP in solution is an organic metal cation or a mixture thereof.

27. The pharmaceutical form according to any one of claims 19 to 23 in which the sequestering agent Q comprises a salt selected from the group comprising: 20 - cationic salts, e.g. of the metals Ca, Fe, Mg or Zn, in the form of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarates, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodides, lactates, oxides, phosphates, trisilicates, salicylates, succinates, sulfonamides or tartrates; -organic cationic salts such as quaternary ammonium salts, particularly trimethyl 25 tetradecylammonium bromide or benzethonium chloride; - cationic polymers such as chitosan and (meth)acrylic copolymers (e.g. Eudragit' RS, Eudragit® RL or Eudragit ® E); - polyamino acids, proteins or peptides; - and mixtures thereof. 30

28. The pharmaceutical form according to any one of claims 19 to 23 in which the sequestering agent Q is a salt of an ion exchange resin, preferably a strongly acidic cation exchange resin when the AP is cationic, or a strongly basic anion exchange resin when the AP is anionic. 35 45 - in the free state, i.e. neither contained in nor supported by microparticles.

37. The pharmaceutical form according to any one of claims 19 to 36 in which the amount of sequestering agent is adjusted in terms of ionic charge in order to 5 complex all or part of the dose of AP contained in the unit form.

38. The pharmaceutical form according to any one of claims 19 to 37 in which the sequestering agent (Q) is in the form of microparticles that are inseparable from the coated or uncoated microparticles of AP. 10

39. The pharmaceutical form according to any one of claims 19 to 38 which comprises microparticles of viscosifier V and/or microparticles of sequestering agent Q, the microparticles of viscosifier V and the microparticles of sequestering agent Q being distinct from the microparticles of AP. 15

40. The pharmaceutical form according to any one of claims 19 to 39 which comprises microparticles of AP as well as microparticles of viscosifier V and/or microparticles of sequestering agent Q, said microparticles having a similar size distribution and a similar density and being inseparable from one another by sieving. 20

41. The pharmaceutical form according to any one of the preceding claims, characterized in that it comprises at least one excipient in the free state, i.e. neither contained in nor supported by microparticles of AP, said excipient contributing to the crushing resistance of the coated microparticles of AP. 25

42. The pharmaceutical form according to claim 41, characterized in that the excipient in the free state is selected from the group comprising: - calcium stearate; - glycerol palmitostearate; 30 - magnesium oxide; - polyalkylene glycols, e.g. polyethylene glycols; - polyvinyl alcohol; - sodium benzoate; - stearic acid; 35 - maize starch; 47 meprodine, beta-methadol, beta-prodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazen, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dioxafetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, 5 diethylthiambutene, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, ethylmethylthiambuten, ethylmorphine, etonitazen, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, 10 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, morpheridine, morphine, myrophine, nalbuphine, narceine, 15 nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene, parafluorofentanyl, pentazocine, pethidine, 20 phenampromide, phenazocine, phenomorphan, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, propanolol, properidine, propirane, race methorphan, racemoramide, racemorphan, remifentanil, sufentanil, thebacon, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, their pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers, and mixtures thereof. 25

49. The pharmaceutical form according to one of the preceding claims, characterized in that the AP used is selected from the group comprising oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride and tramadol hydrochloride. 30

50. The pharmaceutical form according to one of the preceding claims, characterized in that it is devoid of AP antagonist(s).

51. The pharmaceutical form according to any one of claims 1 to 49, 35 characterized in that it comprises at least one AP antagonist.