CA2627058A1 - Anti-misuse microparticulate oral pharmaceutical form - Google Patents

Abstract

The field of the present invention is that of pharmaceutical forms microparticulate oral substances whose composition and structure prevent the misuse of the pharmaceutical active ingredient (PA) they contain. The object of the present invention is to prevent the diversion of oral solid medicines, for any other use than the use or therapeutic uses officially approved by the health authorities competent public health. In other words, it's about avoiding misuse voluntary or involuntary oral solid drugs. The invent ion an oral and solid pharmaceutical form, characterized in that it has anti-misuse means, in that at least a part of the AP that it includes is contained in coated microparticles, modified release of PA, and in that the coated PA microparticles comprise a layer coating (Ra), which ensures the modified release of the AP and which, simultaneously, confers resistance to grinding with PA microparticles coated, to avoid misuse.

Description

ORAL PHARMACEUTICAL FORM
ANTI-MEASURING MICROPARTICLE

Field of the invention The field of the present invention is that of pharmaceutical forms oral solid microparticles whose composition and structure to avoid the misuse of the pharmaceutical or veterinary active ingredient (PA) they contain.
The active ingredients considered (PA) are pharmaceutical PAs or veterinarians, for example those classified in the category of narcotics, painkillers or narcotics. Abuse of these pharmaceutical active ingredients can give place to addictive behaviors.
For the purposes of this presentation, the term "PA" refers both to a single principle active, a mixture of several active ingredients.
By microparticulate pharmaceutical form is meant within the meaning of this invention any form in which the AP is contained in microparticles size less than 1000 m. These particles containing PA may be microparticles coated with modified release of AP. In the latter case, the microparticles coated are, for example, coated with a polymer film which controls the speed of release of PA
after oral administration.

Position of the problem The object of the present invention is to prevent the diversion of oral solid medicinal products, for any purpose other than the use or the uses therapeutic officially approved by the competent public health authorities. In other terms, it is a question of avoiding the intentional or involuntary misuse solid drugs Oral.

Misuse is mainly encountered in the following cases:
a) addictive behavior (drug addiction, doping), b) criminal behavior (chemical enslavement).
(c) use of a drug in a manner inconsistent with the recommendations medical (dosage), inadvertently or due to disability affecting the patient.

2 In the case a. (in the case of b.), persons intending to to make a misuse of the solid, oral drug, will usually seek to extract the PA of the modified release form to obtain a fast-acting form, then to the to put :
- in a pulverulent form by grinding so as to be inhaled or swallowed, - either in a liquid form that can be injected with a syringe or swallowed.
Obtaining a liquid form from a solid oral drug requires a aqueous or organic extraction step of the targeted PA. This extraction is usually preceded by grinding.
Modes of administration by inhalation or by injection are suitable drug users because they are modes that allow accentuate the effects of AP and that promote its absorption into the body on short times.
When the powder obtained by grinding is sucked by the nose or dissolved in water and injected, the desired effects, doping or euphoric, of PA, manifest very quickly and exacerbated.
There is also currently a particularly serious drift that affects adolescents with regard to analgesic PAs (PAa), especially derivatives opioids and opioids. Indeed, teenagers are preparing for their holidays, a cocktail of vodka with oxycodone, which they extract easily with water and the alcohol. This process involves grinding the tablet and pouring the powder into a glass of vodka or water and then wait long enough to extract completely derivatives of morphine, which can then be absorbed.
Misuse of solid oral medications may also be observed when the drug is chewed before being swallowed, instead of being swallowed quickly accordance at the dosage.
The risks associated with addictive (a.) And criminal (b.) Behaviors are obvious. We recall that injecting drug misuse is an aggravating factor:
excipients may be responsible for local tissue necrosis, infections, unrest respiratory and cardiac.
Regarding deviations (c.) From the use of a medicine related to inattention and / or patient's disabilities, they can also have consequences serious. By example, chewing before swallowing of modified-release forms of AP, Transform the drug into an immediate release form. So, the least of risk is that the drug becomes ineffective after a very long time short, and the worse, it becomes toxic.
There is clearly a serious public health problem related to misuse of the medicinal products, and in particular solid oral medicinal products, in particular those

3 analgesics or narcotics. This growing phenomenon worries more in addition to health authorities, particularly in the United States and Europe, which are calls to development of pharmaceutical forms for the prevention of diversions.

Prior art US-B-6 696 088 discloses an oral pharmaceutical form multiparticulate, indicated as resistant to misuse. This one includes opioid agonist PA particles in a modified release form and particles comprising an opioid antagonist. The form containing the antagonist is described as releasing less than 36% and even more preferentially less than 6.2% of the PA
antagonist over a period of 36h. Both types of particles are interspersed.
The fact, during a practice of misuse, to grind the microparticles to in extracting the opioid PA results in immediate release and concomitant the PA and its antagonist and thus limit the desired effects of the opioid hijacked.
According to our understanding, this invention is based on the use of a substance other than the PA and does not propose, among other things, a solution to the impact of grinding or reduce the extraction of the AP.
The patent application US-A-2003/0068371 describes a pharmaceutical formulation oral formulation comprising an opiate PA (oxycodone), an antagonist of this PA (naloxone) and one gelling agent (eg xanthan gum). In particular, this US request discloses Matrix granules of PA comprising lactose, xanthan gum, povidone and an overcoating based on EUDRAGIT RS 30D / triacetin / antagonist. The agent gelling is presented as conferring on the formulation a viscosity such that it does not can not be administrable nasally and parenterally. According to our understanding, this parade is not sufficient since, in accordance with this invention, the use of a antagonist is between other compulsory. Finally, this formulation does not include any means grinding, can therefore be put into powder form and, therefore, be the subject of a Misuse by nasal or oral route.

The patent application WO-A-03/013479 describes an oral pharmaceutical form comprising an opiate analgesic and an opiate antagonist (naltrexone) quantity pharmaceutically effective, as well as a bitterness promoter. When the drug addict crushes the tablet, the opioid and its antagonist are released.
The opioid effect is

4 then neutralized. According to our understanding, this system does not allow between other to prevent the selective extraction of the opioid with water, without grinding.

In general, the use of antagonists is not devoid disadvantages, in the light of any medical risks that may be incurred by users and risks inhibition of the intended therapeutic effect.

Patent Application WO-A-2004/054542 describes an oral pharmaceutical form semiliquid. It comes in the form of a capsule (for example gelatin) comprising PA in a matrix phase composed of a strong liquid viscosity (sucrose acetate isobutyrate) insoluble in water and a polymer (cellulose acetate butyrate) to form a network in the liquid phase. The formulation can eventually include a compound modifying the rheology of the pharmaceutical form and a solvent.
By playing on the different compounds and concentration of the formulation, the authors declare to be able to modify the plasma profiles of PA (oxycodone base) administered to dogs. According to our understanding, this reference does not provide any solution for interfering, inter alia, with injectable misuse, all the more so less than the viscosity of this formulation drops sharply with small additions ethanol.

The patent application US-A-2003/0224051 describes an osmotic form to modified release of oxycodone. This form consists of a tablet comprising a heart of oxycodone or one of its salts, a semi-permeable membrane wrap at least partly the heart, an outlet port provided in the membrane and allowing the release of oxycodone. This type of tablet allows easy extraction of opioid, by immersion in water for, eg, at least 12 hours. According to our understanding, this tablet is not a suitable solution to the problem of misuse.

Patent Application EP-A-1 293 209 discloses an oral pharmaceutical form solid anti-misuse, sustained release of an opioid derivative (PA) content in ion exchange resin. The PA / resin complex thus obtained makes it possible to limit the plasma concentration obtained after misuse by chewing, inhalation or injection, at a therapeutic concentration well below that sought by the author of misuse. The PA / resin complex is in matrix form. according to our understanding, no anti-grinding means is provided in the form pharmaceutical according to this earlier document. Moreover, this pharmaceutical form has no anti-solvent extraction means of PA. It can not therefore prevent a Solvent extraction of PA, provided that the extraction time is longer long as the normal time of PA release. If this oral pharmaceutical form is left in a glass of water for 24h, almost all of the PA is extracted.

Applications US-A-2003/0118641 and 2005/0163856 (= WO-A-01/08661)

Describe oral pharmaceutical formulations with sustained release of PA trained by opioid compounds (analgesics) and their salts. These formulations are sensible prevent misuse by extraction of PA, using common solvents. These formulations anti-misuse do not contain antagonists, although this possibility is feasible to be even more dissuasive. These formulations comprise a mixture:
a hydrophilic matrix agent (hydroxyalkylcellulose) at a rate of 40-65%
in weight ;
- an ion exchange resin (particles smaller than 50 m in size) reason of 5-15% by weight);
and at least one opiate PA.
After adding conventional compression additives, this mixture is put under made of tablets.
It is therefore a macroscopic matrix system comprising particles of ion exchange resin complexed with PA and anti-extraction means formed by a viscosifier, preferably hydroxypropyl methylcellulose. According to our understanding, this system is perfectible especially in terms of anti-misuse effectiveness.
Interlay document WO-A-2005/079760 discloses a formulation pharmaceutical composition consisting of microparticles of rubbery PA, obtained by extrusion, equipped with the extended release of the AP and anti-properties misuse. These extruded microparticles comprise a matrix formed by a poly (ethylacrylate, methylmethacrylate) neutral copolymer: EUDRAGIT NE 30D or BORN
40D. This matrix contains the PA (oxycodone) another Eudragit RS PO, a plasticizer and a lubricant.
The prevention of misuse is achieved by an anti-grinding means that holds only to the rubbery character of the release matrix particles modified from PA. According to our understanding, no means anti-extraction of PA in medium solvent is not planned.

According to our understanding of the prior art, none of the anti-misuse proposed until now is not satisfactory, especially in terms of prevention of the improper extraction of PA, using water, alcohol or other solvents drinkable.

6 Objectives of the invention In these circumstances, one of the objectives of the present invention is to fill in the deficiencies of the prior art.
Another object of the invention is to provide new drugs solid oral disorders, the misuse of which will be made difficult or impossible, cases (a.) (b.) (c.) mentioned above, and this-preferably- without resorting to substances, other than PA, which can be pharmaceutically active and therefore dangerous for users, even inhibitory of PA, such as, for example, PA antagonists.
Another object of the invention is to provide new drugs solid oral disorders, the misuse of which will be made difficult or impossible, cases (a.) (b.) (c.) mentioned above, even after a "long" liquid extraction of PA (by analgesic example). For the purposes of this paper, a "long" extraction liquid, is a extraction for more than 10 minutes.
Another object of the invention is to provide new drugs solid oral agents preventing misuse by short liquid extraction and / or grinding.
Another object of the invention is to provide new drugs solid oral, having the following characteristics:
- under normal conditions of administration, these oral solid drugs have a therapeutic effect, for example for 12 or 24 hours;
- any attempt at improper extraction of the AP (eg analgesic) will cause the transformation of the medicinal product into a form such as after ingestion of drug, rapid absorption of PA into the bloodstream will not be possible.
Another object of the invention is to provide new drugs solid Oral:
- easily administered to patients who have difficulty swallowing big tablets, that is to say for example seriously ill patients, infants or children;
- allowing to associate several PA, in one and the same unit dosage, even if these PAs are not compatible with each other and / or do not have the same kinetics of release;
- may exist in manageable forms one or more times by day and in which it is possible to easily and independently adjust the speed and time to release of different PAs.
Another object of the invention is to provide new drugs solid oral doses, whose in vitro dissolution profile is independent of the dose of PA.
Another object of the invention is to provide new drugs solid to avoid the fraudulent diversion of PA properties they

7 contain, by preventing any transformation of the drug giving access to catches oral, nasal and / or injectable (intravenous, subcutaneous, intramuscular ...) outside the therapeutic setting. In doing so the risks associated with these drifts would be prevented or at least greatly reduced.
Another object of the invention is to provide new drugs solid to avoid misuse, while ensuring for the patient normally monitored, a quality of treatment, in particular a dose, consistent with its needs.
Another object of the invention is to provide new drugs solid to avoid misuse, without affecting the properties pharmacological drug, and without putting the patient at additional risk using normally the drug and finally without harming the comfort of the latter when administration.
Another object of the invention is to provide new drugs solid Oral, administered once or several times a day and limiting the risks degradation tissues due to local overconcentration of AP.
Another object of the invention is to provide new drugs solid oral forms, which may be in various galenic forms, such as tablets, sachets of powder, capsules and the like.
Another object of the invention is to provide new drugs solid Oral, anti-misuse and whose preparation is easy and economical.

Brief description of the invention To achieve these objectives, the inventors had the merit of restating the general problem of the misuse of pharmaceutical forms.
If we examine the various modes of illicit administration of a principle active he It appears that the crushing of the dry form is, most of the time, a step obliged.
In the case of misuse by nasal administration, the pharmaceutical form must first be converted into a powder form able to aspiration. The grinding of the pharmaceutical form is therefore a step obliged.
In the case of misuse by oral administration of a dry form to release prolonged, it is necessary to accelerate the release of the active ingredient by finely grinding the microparticles or the tablet.
In the case of misuse by parenteral administration, it is necessary to first extract the PA in a liquid phase, in practice water or WO 2007/05437

8 PCT / EP2006 / 062627 organic solvents, and this at a sufficiently high concentration for to avoid to inject too high volumes, for example greater than 1 ml. This step extraction is facilitated by a preliminary step of grinding the dry form in order to allow the dissolution or suspension of the active ingredient. In addition, after this phase extraction, misuse is only possible if the viscosity of the liquid is not not too high (eg less than or equal to 100 mPa.s).
Thus, the grinding of a dry form is also a necessary step for the misuse of said pharmaceutical form by parenteral administration.
It is the merit of the Claimant to have reformulated the problem of the struggle against the misuse of dry pharmaceutical forms, distinguishing - a main problem (a) of preventing crushing of the system containing the PA;
- and a secondary problem (b) of prevention of the misuse of PA after its extraction possible.
This new approach allowed him to discover, surprisingly and unexpectedly, that it is appropriate to involve in the composition of the drug which one seeks to prevent misuse, PA in the form of microparticles coated with modified release of AP and, optionally, a combination of excipients pharmaceutically acceptable, in microparticulate or non-microparticulate form and whose fashion physicochemical action can thwart or even make impossible, any act voluntary or not of misuse.

Thus, the invention relates primarily to a form pharmaceutical oral and solid, characterized in that it comprises anti-misuse means, in that least part of the AP that it contains is contained in microparticles coated, with modified release of AP, and that the coated PA microparticles behave a coating layer (Ra), which provides the modified release of the PA and which, simultaneously, confers resistance to grinding with microparticles PA
coated, to avoid misuse.
The pharmaceutical form according to the invention solves in particular the problem main laid down and satisfies at least part of the objectives laid down, so effective, simple and economic, using physicochemical means. These are totally harmless to the normal user. These are neutral (inert) compounds on the plan pharmacological, approved by the pharmacopoeia and the health authorities public responsible for issuing authorizations for placing medicinal products on the market.
According to a preferred embodiment, the oral and solid pharmaceutical form according to the invention comprises, in addition to the anti-grinding coating layer (Ra), at less an agent

9 viscosifier (Vb) to make it very difficult, or even prevent, PA extraction contained in the coated PA microparticles, to avoid the misuse of PA
after one liquid extraction.
As used herein, the term "viscosifying agent" also refers to well one only viscosifier, a mixture of several viscosifiers.

Detailed description of the invention According to the invention, at least a part of the PA is in a form to modified release, namely in the form of microparticles coated with modified release said PA.

The active ingredients (PA) considered in the present invention are PAs pharmaceutical or veterinary products, for example those classified in the category of the painkillers or narcotics. The misuse of these PAs can give rise to addictive behaviors.

For the purposes of the present invention, the expression PA designates a principle active or still a mixture of several active ingredients.

By microparticulate form is meant in the sense of the present invention any form in which the PA is contained in microparticles of cut less than 1000 microns. These particles containing PA may be microparticles individually coated with a film leading to the modified release of the PA. In this In the latter case, the coated microparticles are, for example, coated with film-based polymer controlling the release rate of PA.

By "modified release form" is meant in this disclosure a form wherein at least a fraction of the PA is released at a lower rate at speed of an immediate release form. This fraction can be, for example between 1 and 100%, preferably between 10 and 100%, and even more preferably between 30 and 100%. A modified release may be extended and / or delayed in particular and / or form of one or more release peaks (pulses). Formulations to release modified are well known in this field; see for example Remington: The science and practice ofpharmacy, 19th edition, Mack Publishing Co. Pennsylvania, USA.

By "immediate release form" is meant in this disclosure a form which releases most of the amount of AP it contains into one time relatively brief: at least 70% of the AP is released in 1 hour, preferably in thirty minutes, at any pH between 1.4 and 6.8 in a dissolution test.
vitro.
All the in vitro dissolution profiles discussed in this presentation, are made according to the indications of the European Pharmacopoeia 4th edition entitled:
"Dissolution test of solid oral forms": Dissolutest type II
carried out SINK conditions at 37 C and stirred at 75 rpm.
The pharmaceutical formulation according to the invention is therefore a formulation

10 modified release of AP.
For the purposes of the invention, "pharmaceutical formulation" must be understood meaning wide, that is to say that this term also includes the formulations veterinarians and dietary.
This pharmaceutical formulation may further comprise one or more immediate release forms of AP.

Advantageously, the pharmaceutical formulation according to the invention, which is new in its structure, presentation and composition, may exist by example in the form of a tablet, a sachet of powder, a sachet of powder for multidose suspension to be reconstituted or capsule.

Microparticles of coated PA
The coated microparticles with modified PA release are, advantageously microparticles each coated with at least one coating (comprising by example at least one polymer) deposited according to the techniques known to man art.
For example, see the publication Pharmaceutical forms news: technological, biopharmaceutical and medical aspects of Buri, Puisieux Doelker and Benoit, published by Lavoisier 1985, pages 175 to 227.
In other words, these coated microparticles are preferably formed each of a core comprising PA and a coating comprising at least one layer wrapping coating (preferably entirely) the heart and governing the release modified (preferably continuous) PA. This release occurs when the PA coated microparticles are brought into contact with the liquid of the gastrointestinal tract intestinal.
Microparticles of uncoated PA (ie before coating), may be example:
neutral hearts covered with at least one layer containing PA;

11 - or microparticles of pure PA;
- or granules formed by a matrix of carrier excipients including the PA.
In the case of a supported granulate, the neutral core or support may be composed of sucrose and / or sucrose and / or dextrose and / or lactose, and / or blending sucrose / starch.
The neutral core or support may also be a cellulose microsphere or other pharmaceutically acceptable excipient particle. As an example limiting neutral support, there may be mentioned particles of xanthan gum, guar gum, of calcium phosphate, calcium carbonate.Their average diameter can be understood between 10 and 200 microns, or between 20 and 150 microns or between 50 and 100 microns.
These coated microparticles of the "reservoir" type (or microparticles individually coated) may be assimilated to vehicles transportation and the release of at least one PA, in the small intestine or even in the fat intestine.
As examples of coated microparticles with modified release of PA, mention may be made of those described in the following patent documents: EP-B-0 709 087 and WO-A-03/030878.

Coating of PA microparticles Advantageously, the microparticles coated with PA comprise at least one coating layer (Ra), better still, a single coating layer (Ra), who assures the modified release of the AP, which simultaneously confers resistance to grinding coated microparticles, to avoid misuse.
More preferably still, the coating layer (Ra) is designed to such so that, in case of grinding, it allows the maintenance of a non immediate (ie a modified release of AP) for at least a portion of the microparticles coated modified release of AP.
The grinding envisaged here can be for example any grinding carried out according to the techniques usually used by misusers, know including: mortar / pestle, coffee grinder, between two spoons, in crunchy, etc.
According to an interesting embodiment, the coating layer (Ra) is designed to such so that, in case of grinding, it allows the maintenance of a release modified for at minus 40%, preferably at least 60%, and more preferably still at less than 80%
coated microparticles with modified release of AP.
Preferably, the anti-grinding coating layer (Ra) comprises:
- (A1) at least one (co) film-forming polymer (A1) insoluble in the liquids of tract gastrointestinal;

12 - (A2) at least one (co) polymer (A2) soluble in the liquids of the tract gastrointestinal intestinal;
- (A3) at least one plasticizer (A3);
- (A4) optionally at least one surfactant and / or lubricant and / or charge mineral and / or organic (A4).
In accordance with a purely illustrative and non-illustrative selection limiting the invention:
(Al) is selected from the group consisting of:
the non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, acrylic polymers, for example acid copolymers (meth) acrylic and alkyl ester (eg methyl), copolymers of acrylic acid ester and methacrylic carrier of at least one quaternary ammonium group (preferably at least one a copolymer of alkyl (meth) acrylate and trimethylammonioethyl chloride methacrylate) and more specifically the products marketed under the brand names EUDRAGIT RS and / or RL
polyvinylacetates, - and their mixtures;

(A2) is selected from the group consisting of:
the nitrogenous (co) polymers, preferably in the group comprising the polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl lactams, the water-soluble derivatives of cellulose, polyvinyl alcohols (PVA), alkylene polyoxides, preferably ethylene polyoxides (POE), polyethylene glycols (PEG), - and their mixtures;
PVP being particularly preferred (A3) is selected from the group consisting of:
esters of cetyl alcohol, glycerol and its esters, preferably in the following subgroup:
acetylated glycerides, glycerolmonostearate, glyceryl triacetate, glycerol tributrate, phthalates, preferably in the following subgroup: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate,

13 citrates, preferably in the following subgroup:
acetyltributylcitrate, acetyltriethyl citrate, tributyl citrate, triethyl citrate, the sebacates, preferably in the following subgroup: diethyl sebacate, dibutyl, - adipates, azelates - benzoates, - vegetable oils, fumarates, preferably diethylfumarate, malates, preferably diethyl malate, oxalates, preferably diethyloxalate, succinates, preferably dibutylsuccinate, - butyrates, esters of cetyl alcohol, - salicylic acid, - triacetin, malonates, preferably diethyl malonate, castor oil (the latter being particularly preferred), - and their mixtures;
(A4) is selected from the group consisting of:
anionic surfactants, preferably in the subgroup of salts alkaline or alkaline-earth fatty acids, stearic and / or oleic acid being preferred, and / or nonionic surfactants, preferably in the subgroup next :
polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenesorbitan esters, polyoxyethylenated castor oil derivatives, stearates, preferably of calcium, magnesium, aluminum or zinc, stearyl fumarates, preferably sodium, - the glycerol behenates, - talc, - colloidal silica, titanium oxide, magnesium oxide, - bentonite, microcrystalline cellulose,

14 - kaolin, aluminum silicate, - and their mixtures.

Beyond the qualitative parameters of definition of coated microparticles according to the invention, it may be specified that, in accordance with a quantitative of advantageous embodiment, the coating layer (Ra) comprises, in% by weight compared to the total mass of the coating:
<_ Al <90, preferably 15 <Al <80, and more preferably still 60 <1><80;
5 <_ A2 <_ 50, preferably 10 <_ A2 <_ 40, and more preferably still 10 <_A2 <_25;
1 <_ A3 <_ 30, preferably 2 <_ A3 <_ 20, and more preferably still 5A3 <_15;
0 <_ A4 <40, preferably 0 <A4 <30, and more preferably still 0A4 <_20;
the sum of the percentages being equal to 100.
Moreover, the release speed is regulated for example in the way next - by controlling the thickness of the coating (Ra);
- by the weight ratios between the components A1, A2, A3 and possibly A4, from coating (Ra).
Advantageously, the coating of the coated microparticles with release modified PA may include, in addition to the essential constituents A1, A2, A3 and possibly A4, other conventional ingredients known to those skilled in the art, such as in particular, dyes, pigments, preservatives, flavors ... and mixtures thereof.

Another remarkable characteristic of the coating (Ra) of the microparticles the coating layer (Ra) represents a fraction Tp, expressed in% by dry weight relative to the total mass of microparticles coated, such as: Tp _ 15; preferably between 30 and 60, and more preferentially still between 40 and 60, and more preferably between 45 and 55 or about 50.
Without wishing to be bound by the theory, this rate of coating relatively important allows the coating layer (Ra) to ensure the modified release of the AP
and, simultaneously, to confer resistance to grinding with microparticles PA
coated, to avoid misuse.

Without this being limiting, preference is given according to the invention to coated microparticles which have an average diameter less than or equal to 1000 m, preferably between 50 and 800 m and more preferably included between 100 and 600 m, and better still, between 100 and 300 m.
The microparticle diameters discussed in this paper are, unless otherwise indicated, average diameters by volume.

With regard to the preparation of coated microparticles, techniques advantageously used for depositing the coating allowing the release Modified PA or the deposition of the active layer based on the PA, are known techniques those skilled in the art, such as for example the technique of spray coating in air bed fluidized, wet granulation, compaction, extrusion-spheronization.

overcoat

According to one particular variant of the invention, the microparticles coated modified release of AP includes an overcoating designed so that the Overcoating is used in the manufacture of tablets to maintain a release modified for at least a portion of said coated microparticles of PA
release modified PA. The overcoating is composed of at least one organic constituent deformable having a melting temperature between 40 C and 120 C, of preferably between 45 C and 100 C.
According to a preferred variant, the overcoating comprises at least 10% by weight of deformable organic constituent.
In particular, according to a variant of the invention, the organic constituent deformable included in the overcoat is selected from polyalkylene glycols, the polyethylene glycols having a molecular weight of 6000 to 20000 D, being particularly preferred.
According to another variant, the deformable organic component of the overcoating is a body fat or mixture of fatty substances, for example selected from the group of fat body comprising: hydrogenated vegetable oils, fatty acids, alcohols fatty esters of fatty acids and / or fatty alcohol, polyolefins and mineral waxes, plant, animal or synthetic fatty acid esters such as di and triglycerides and their mixtures, glycerol behenate and hydrogenated castor oils, of soy, cotton and palm being particularly preferred.
According to a further variant, the overcoating comprises:
a mineral filler such as silica or titanium dioxide by example or a organic filler such as microcrystalline cellulose for example,

16 and / or at least one lubricant such as magnesium stearate or benzoate Sodium for example, and / or at least one hydrophilic polymer such as the water-soluble derivatives of the cellulose, synthetic polymers preferably polyvinylpyrrolidone, polymers acrylics and methacrylics, or polyvinyl alcohols (PVAs), and / or at least one surfactant.
Preferably, the overcoating is 5 to 50%, preferably 10 to 30%.
%
and more preferably still of the order of 20% by weight on a dry basis of total mass of supercoated PA microparticles.
Supercoated microparticles denote a microparticle of coated PA, further comprising a supercoat as defined above, i.e.
over-coating that during the manufacture of tablets, to maintain a modified for at least a part of said coated microparticles of PA coated with release modified PA.
Additional information on the over-coating can be found in the published patent application WO-A-03/077888 Viscosifying agent (Vb) Preferably, the viscosifying agent (Vb) is chosen from the agents viscosifiers soluble in at least one of the following solvents: water, alcohols, ketones and their mixtures, this agent (s) being able to increase the viscosity of the extraction liquid in a way to counteract misuse, particularly by injection.
By "water" is meant any aqueous solvent, such as water stricto sensu or any aqueous solution, for example organic acid (eg acetic acid), saline solutions, sodas or drinks. "Alcohols" means all the alcohols taken at alone or in mix between them. By "ketones" we mean all the ketones taken from them alone or in mixture between them.
Even more preferably, the viscosifying agent (Vb) is chosen from groups of polymers:
acrylic polyacids and their derivatives, and / or polyalkylene glycols (eg polyethylene glycol), and / or polyalkylene oxides (eg ethylene), and / or polyvinylpyrrolidones, and / or gelatines, and / or the polysaccharides, preferably in the subgroup comprising:
alginate sodium, pectins, guars, xanthans, carrageenans, gellans and derivatives cellulose (eg hydroxypropylmethylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose),

17 - and their mixtures.
According to a modality of the invention, the viscosifying agent Vb is a polyoxyethylene having a high molecular weight, for example having a molecular weight of 1 million g / mole at 8 million g / mole, for example 2 million, 5 million, or 7 million g / mol.
Preferably, the viscosifying agent Vb, for example high polyoxethylene weight molecule, is included in microparticles, distinct from microparticles of PA.
More preferably, the microparticles of PA and the microparticles agent viscosifier Vb have a near size distribution, a density close and are not separable by sieving.
According to a preferred modality, the viscosifying agent (Vb) 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 viscosifying agent (Vb) makes it possible to increase the viscosity of the liquid extraction for example, above 100 mPa.s, preferably 200 mPa.s, and more preferably still beyond 500 mPa.s, and more preferably 1000 mPa.s.
It is also the merit of the plaintiff to propose, in a variant, of the viscosifiers (Vb) effective both in the case of aqueous phase or as an organic solvent. Advantageously, these viscosifying agents (Vb) are of the mixtures of hydrophilic compounds and hydrophobic compounds, so as to ensure a high viscosity (greater than 100 mPa.s for example) of the extraction liquid, whether aqueous or organic.
As regards the quantity of viscosifying agent (Vb), it is easily ascertainable by the skilled person. This quantity corresponds to the minimum quantity necessary for make the viscosity of 2.5 mL of extraction fluid at a higher value or equal to 100 mPa.s.
According to several variants that can be combined with each other, in the form according to the invention, at least one viscosifying agent (Vb) is present:
in and / or on microparticles, and / or in a super-coating of all or some of the microparticles of PA, - and / or in the free state, that is to say, not contained in, nor supported by microparticles.
Advantageously, the viscosifying agent is at least partly in the form of non-separable microparticles of coated or uncoated PA microparticles coated.
Excipients in the free state The pharmaceutical form may optionally include one or more pharmaceutically acceptable excipients, in the free state, i.e.
contained in nor

18 supported by PA microparticles, said excipient contributing to the resistances microparticles of PA coated with grinding.
Preferably, these excipients contributing to the resistance to grinding of coated microparticles, are selected from the group consisting of:
calcium stearate;
glycerol palmitostearate;
magnesium oxide;
polyalkylene eg ethylene glycols;
polyvinyl alcohol;
sodium benzoate;
stearic acid;
- corn starch;
- talc;
colloidal silica;
zinc stearate, magnesium;
stearyl fumarate;
- and their mixtures.

According to alternative embodiments of the invention, the viscosifying agent - is at least partly in the free state, that is to say, not contained in, nor supported by coated or uncoated microparticles (alternative 1), - is at least partly in the form of microparticles distinct from microparticles of PA coated or uncoated (alternative 2).
Advantageously, in alternative 2, the agent microparticles viscosifier are are not separable coated microparticles or uncoated PA. At sense of In this presentation, the term "non-separable" means, for example, no separable by conventional means, such as sieving or centrifugation.
In the alternative 2.1, the viscosifying agent is, for example - in and / or on microparticles and / or in a super-coating of all or part of the microparticles of AP.
Still in this alternative 2, it is preferable that the microparticles comprising the viscosifying agent are physically indistinguishable from microparticles of PA, and this to prevent their sorting by any appropriate physical means.
The microparticles comprising the viscosifying agent are indistinguishable from microparticles of PA, in particular because they are of the same size and / or density and / or even shape and / or color.

19 In another alternative, the viscosifying agent is, for example:
in and / or on microparticles, and / or in a super-coating of all or part of the microparticles of AP.

According to a preferred embodiment, the pharmaceutical form according to the invention is multimicroparticulate. It is best that when this form pharmaceutical includes PA microparticles (eg PAa) and agent microparticles viscosifier (Vb), said microparticles have a near size distribution, a density close and they are not separable by sieving. Thus, agent microparticles viscosifier are not separable coated microparticles or uncoated PA.

According to another preferred embodiment, the pharmaceutical form according to the invention is multimicroparticulate. It is best that when this form pharmaceutical composition comprises PA microparticles (eg PAa) and microparticles viscosifying agent (Vb), said microparticles have the same distribution of size, the same density and that they are not separable by sieving. Thus, microparticles viscosifying agent are not separable from the coated PA microparticles or not coated.

Sequestering Agent Q
Of course, in the case where the multimicroparticulate pharmaceutical form comprises at least one salt of at least one active ingredient analgesic, the man of the job can add to said pharmaceutical form, at least one sequestering agent forming, in solution in an aqueous or hydroalcoholic beverage, a weakly complex soluble with the PA.
The sequestering agent is, for example, a salt whose ion of opposite polarity to that of PA, is preferably an organic ion. So, for an active ingredient cationic, this agent sequestering agent is, for example, an organic salt such as sodium docusate, or a anionic polymer. The sequestering agent may also for example be a salt a resin ion exchange.
For the purpose of the present invention, a sequestering agent Q is a present agent in the pharmaceutical form in a free form, that is to say uncomplexed. "No complex"
means that there is no complex or chemical interaction between the sequestering agent Q and the salt of active ingredient PA in the solid pharmaceutical form.
When PA salt and sequestering agent Q are simultaneously present in a solvent, for example in the case of an unlawful attempt to extract the AP, the agent sequestering Q is able to induce complexation or chemical interaction with salt PA in said solvent. For the purposes of the present invention, the agent sequestering Q is considered "capable of inducing complexation" with PA salt when the agent sequestering agent Q is capable of inducing the complexation of the PA salt in at least one solvent standard chosen from water and aqueous solutions, such as mixtures water-ethanol, Alcohol, alcoholic beverages, sodas, vinegar, hydrogen peroxide, and their mixtures.
Advantageously, the sequestering agent Q is capable of inducing a complexation of the PA salt in more than one of these usual solvents.
Sequestering agents Q used to trap PA, especially analgesic are harmless including for regular use. These are inert products from point of view 10 pharmacological and approved by the different pharmacopoeias and authorities registration of medicines.
In a pharmaceutical form according to the invention, at least one sequestering agent Q
is present :
in microparticles free of PA, and / or On microparticles, and / or - in the free state, that is to say, not contained in, nor supported by microparticles.
Preferably, in a pharmaceutical form according to the invention, the agent sequestering Q is present in a first phase separated from at least one second phase, said second phase containing at least one PA salt. For example, the form

The pharmaceutical composition comprises microparticles of PA salt and agent microparticles separate sequestering Q. Advantageously, said microparticles have a distribution of close size, the near density and are not separable from each other by sieving.
Preferably, the sequestering agent Q comprises a salt, which contains ions capable of forming a complex with the PA in solution. These ions are preferably ions organic polarity opposite to that of PA in solution: if in solution PA is under anionic form, the sequestering agent Q comprises an organic cation, a cation metallic, or a mixture thereof. In the same way, when the PA in solution is under 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 docusate of sodium;
anionic polymers, such as (meth) acrylic copolymers (for example example Eudragit S and Eudragit L), crosslinked acrylic polyacids (e.g.
Carbopol), the carboxymethylcellulose and its derivatives, crosslinked carboxymethylcellulose and its derivatives and other polysaccharides (for example, alginate, xanthan gum or arabic), alginate-(sulfonate) propylene glycol;

21 mono- or polyvalent salts, such as glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarate, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;
saponified fatty acids, such as the salts of acetic acid, succinic acid, citric, stearic, palmitic, 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 an organic metal cation, or a mixture thereof. For example, we will mention the salts following that contain an organic or metallic cation:
cationic salts, for example metals Ca, Fe, Mg, Zn, in the form of of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarate, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodides, lactates, oxides, phosphates, trisilicates, phosphates, salicylates, succinates, sulfonamides, tartrates;
organic cationic salts, such as quaternary ammonium salts, in trimethyl tetradecyl ammonium bromide or benzethonium;
cationic polymers, such as chitosan and copolymers (Meth) acrylic (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 resin strongly acidic cation exchange when the PA is cationic or a resin strongly basic anion exchange, when the AP is anionic. Advantageously, a such ion exchange resin is contained in a separate first phase of a second phase that contains the PA.
In one embodiment of the invention, the ion exchange resin is for example a derived from a copolymer of styrene and divinylbenzene In one embodiment of the invention, the strongly acidic resin exchange of cations will be for example a derivative of a copolymer of styrene and divinylbenzene sulfonic acid such as Amberlite IRP69, Amberlite IR69F (Rohm and Haas);
Amberlite 200,1'Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and Similar.
In one embodiment of the invention, the strongly basic resin exchange of anions will for example be chosen from styrene copolymer derivatives and of divinylbenzene carrying quaternary ammonium functions, such as Duolite

22 (Rohm and Haas) Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow).
The sequestering agent Q in the form of a resin may also be chosen from the copolymers crosslinked methacrylic acid and divinylbenzene or a salt thereof, 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 can also be chosen from phenolic polyamines such as Amberlite IRP58 (Rohm and Haas);
and their mixtures.
According to one embodiment of the invention, the sequestering agent Q in form of resin ion exchanger, is in a first phase separated from at least a second phase, said second phase comprising PA salt. For example the sequestering agent Q under form of ion exchange resin, is contained in microparticles distinct from microparticles comprising PA salt. PA microparticles and microparticles of sequestering agent Q in the form of an ion exchange resin, may be in a form such that they have a near size distribution, a close density and that they are not separable by sieving.
In a first preferred embodiment of the invention, the agent sequestering Q is chosen from:
anionic organic salts, such as sodium dodecyl sulfate or docusate of sodium;
cationic organic salts, such as ammonium salts quaternaries, trimethyl tetradecyl ammonium bromide or benzethonium;
- strongly acidic cation exchange resins or resins strongly basic anion exchangers, according to the polarity of the PA.
In a second preferred embodiment of the invention, the agent sequestering Q
is chosen from:
the 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 IR.A958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow), and their mixtures, when the PA is anionic.

The quantity of agent Q is adapted by those skilled in the art by a calculation of the quantity in ionic charge necessary to trap all or part of the dose of PA contained in the unitary form. The quantity of sequestering agent Q must be such that it allows complex enough PA so that the remaining amount of free PA in solution is

23 insufficient to achieve the desired effect, if used illegally. Of preferably, the amount of sequestering agent Q is sufficient to complex the entire PA of the unit dose.

According to one variant, the pharmaceutical form can also be a form monolithic (tablet eg).

According to one embodiment, the pharmaceutical form according to the invention comprises Viscosifier agent microparticles and / or agent microparticles sequestering Q, preferably V-viscosifiers microparticles and agent microparticles Sequestering Q. In this embodiment, the agent microparticles viscosifier V and the microparticles of sequestering agent Q are distinct from the microparticles of PA.
According to another embodiment of the invention, the pharmaceutical form comprises microparticles of PA, as well as agent microparticles viscosifier V
and / or microparticles of sequestering agent Q. Preferably, the form pharmaceutical includes these three types of microparticles, that is to say PA microparticles, microparticles of viscosifying agent V and agent microparticles sequestering Q, in the same unitary form. Advantageously, these microparticles have a distribution of close size, close density and are not separable from each other by sieving.

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 suction and release immediate PA.
According to a second variant, the pharmaceutical form according to the invention is not not convertible into an injectable form and immediate release of AP.
According to a third variant, the pharmaceutical form according to the invention comprises modified release PA and optionally release PA
immediate.
This variant can be combined with the first and second variants mentioned above above. This means that in a pharmaceutical form that has PA to release modified and immediate release AP, the modified release PA is not not convertible into a dry form that can be administered by nasal aspiration or in a form injectable, and immediate release.
According to a fourth variant, the pharmaceutical form according to the invention is characterized in that extraction of the PA by chewing and / or grinding is not not efficient.
According to a fifth variant, the pharmaceutical form according to the invention is characterized in that it is free of PA antagonist agent (s).
According to a sixth variant, the pharmaceutical form according to the invention is characterized in that it comprises at least one agent (s) antagonist (s) of the PA.
In

24 knowing the PA implemented, the skilled person can easily determine the one or suitable antagonistic agents.
Naturally, any combination of at least two of these six variants is included in the present invention (except for the combination of the fifth and sixth variants).

Active subtances) The implemented PA belongs for example to at least one of the families of active substances: amphetamines, analgesics, anorectics, analgesics, antidepressants, antiepileptics, anti-migraine, antiparkinsonian, antitussives, anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives, neuroleptics, opiates, psychostimulants, psychotropic drugs, sedatives, stimulants. In the case where the PA is a PA analgesic (PAa), it is preferably an opioid.
More specifically still, the PA used is chosen from the compounds following: anileridine, acetorphine, acetylalphamethylfentanyl, Acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodine, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butyrate dioxaphetyl, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazene, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethyl-thiambutene, difenoxin, 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, methyldihydro-morphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morphine, morphine, myrophin, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodin, nicomorphine, noracymethadol, norcodeine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene para-fluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenomorphan, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, propanolol, properidine, propiram, racemethorphan, racemoramide, racemorphane, remifentanil, sufentanil, thebacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and their salts, esters, hydrates, polymorphs and their isomers Pharmacologically acceptable, and mixtures thereof.
The pharmaceutical form according to the invention may comprise at least one principle analgesic active ingredient (PAa) and at least one additional PA different from PAa. This PA no analgesic is preferably selected from the group consisting of:
depressants, amphetamines, anorexics, non-pain relievers, anti-inflammatory drugs, epileptics, 10 anti-migraine, anti-Parkinsonian, anti-tussive, anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropics, sedatives, stimulants, agents anti-inflammatory agents, and their salts, esters, hydrates, polymorphs and their pharmacologically acceptable isomers, and mixtures thereof.
Among the antiinflammatory active principles that can be envisaged, mention may be made :
ibuprofen, acetaminophen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, amineoprofen, acid tiaprofenic, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetine, zomepirac, tiopinac, Zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, acid meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and their salts, their esters, their hydrates, their polymorphs and their pharmacologically acceptable isomers, and their mixtures.

More specifically still, the analgesic PA implemented is selected in the group consisting of oxycodone hydrochloride, morphine sulphate, hydrochloride oxymorphone, hydromorphone hydrochloride, hydrocodone hydrochloride, and tramadol hydrochloride.

For the purposes of the invention, the expression "pharmaceutical formulation" means broad meaning that is to say that are included veterinary formulations or diet especially.
According to another of its aspects, the invention aims at a formulation characterized in this that it comprises a plurality of microparticles (PA, coated or not coated;
optionally viscosifying agent) as defined above, for example example, at least 500, preferably from 1,000 to 1,000,000, and more preferably still from 5,000 to 500,000 microparticles.

26 According to another of its aspects, the invention aims at a formulation pharmaceutical, comprising a plurality of populations of coated PA microparticles, said populations differing from each other by their release kinetics and / or by the PA
they contain.
Without being limiting, it must nevertheless be emphasized that the formulation pharmaceutical composition according to the invention is particularly interesting in that she can present as a single oral daily dose of 500 to 500 microparticles, including coated PA microparticles.
Advantageously, the pharmaceutical formulation comprising microparticles coated according to the invention is in a galenic form chosen from the group comprising: tablets (advantageously orodispersible or gastrodispersible), powders, suspensions, syrups, powders for suspension reconstitute or capsules.
It can be interesting to mix in the same capsule, the same tablet or the same powder, at least two types of microparticles coated with PA having of the kinetics of release different but included in the frame characteristic of the invention.

The invention also relates to the use of coated microparticles described above for the manufacture of new pharmaceutical formulations, in particular particular, but not exclusively in the context of the therapeutic treatment against pain.
The invention also relates to a method of therapeutic treatment characterized in this it consists in administering to the patient the pharmaceutical formulation as as defined above above.
The invention also relates to a method of therapeutic treatment characterized in this that it consists of an ingestion according to a specific posology, of the formulation pharmaceutical as defined above.
The invention also provides a method of therapeutic treatment against pain characterized in that it consists in administering to the patient the formulation pharmaceutical as defined above.
The invention also provides a method of therapeutic treatment against pain characterized in that it consists of ingestion according to a dosage determined, of the pharmaceutical formulation as defined above, the PA used including at less an anti-pain, for example an analgesic.

27 The invention also relates to a method for controlling the misuse of PA, characterized in that it essentially consists of implementing a form pharmaceutical as defined above.
The invention also relates to a method for controlling the misuse of PA, characterized in that it consists essentially of implementing in a form pharmaceutical composition, coated microparticles with modified release of the PA and having a coating layer (Ra), which provides the modified release of the PA and who, simultaneously, confers grinding resistance to the microparticles of PA
coated to avoid misuse; and optionally at least one viscosifying agent (Vb) fit for prevent the extraction of the AP contained in the coated PA microparticles, to avoid misuse.
Advantageously, the coating layer (Ra) and the viscosifying agent (Vb) eventual are as defined above.

The invention will be better explained by the following examples, given only at illustration and to understand the invention and to make stand out variants of implementation and / or implementation, as well as its different advantages.

Description of figures Figure 1 shows the dissolution profile in a reference test (%
of dissolution D as a function of time T) in vitro microparticles of Example 1: - ~ -.
Figure 2 shows the dissolution profile in a reference test (%
of dissolution D as a function of time T) in vitro microparticles of Example 1: - ~ -and example 2: (a) --- ~ ---, (b) --- o ---, (c) --- 0 ---, (d) --- ~ --- .
Figure 3 shows (A) a photograph of an observation with the naked eye and (B) under an optical microscope the contents of a capsule according to Example 3.
Figure 4 shows the release profile (% by weight PAa based of time in hours) of microcapsules in 0.1N HC1 (Example 8).
Figure 5 shows (A) a photograph of an observation with the naked eye and (B) under an optical microscope the contents of a capsule according to Example 9.
Figure 6 shows the release profile of crushed microparticles (rod empty) or intact (solid square) of Example 9.

28 Examples The reference dissolution test in the examples which follow is a test of in vitro dissolution performed according to the indications of the pharmacopoeia European 5th edition entitled: "Trial of the dissolution of solid oral forms": dissolutest type II
performed under SINK conditions maintained at 37 C and stirred at 75 rpm in 900 ml of IHC10.1N medium.

Example 1 Microparticles of Oxycodone HC1 According to the Invention A mixture of 1600g of oxycodone HCI, 100g of Klucel EF (Hydroxypropyl cellulose / Aqualon) and 12052g of water is film coated on 300g of inert balls of cellulose (Asahi-Kasei) in a fluidized air bed GPCG1 (Glatt). 450g of granules thus obtained are then coated with a mixture composed of 315 g of ethylcellulose (Ethocel Premium / DOW), 81g of povidone (Plasdone PVP K29 / 32 / ISP), 36g of castor, 18g of Cremophor RH 40 (Macrogolglyceroli hydroxystearas / BASF) and 12020g ethanol.
The coating represents 50% of the mass of the microparticle and ensures release of the active ingredient over approximately 4 hours, as shown in Figure 1. The profile of release is performed under the conditions of the reference dissolution test.

EXAMPLE 2 Grinding of Oxycodone HC1 Microparticles Prepared According to example 1 200 mg of microparticles prepared in Example 1 (a dose of 80 mg of Oxycodone HC1) are milled according to different methods, which represent various possibilities of misuse:
(a) with pestle and mortar (250mL) ground strongly for 2 minutes (-120 rotations) (b) pressing 8 times between two spoons (c) with a LGS pulverizer Tablet Crusher (LGS Health Products USA) (d) with a coffee grinder for 30 seconds.
The release profiles of the crushed microparticles are reported in the figure 2.
The release profile is carried out under the conditions of the dissolution test reference.
The release profiles of Example 1 (intact microparticles) and of example 2 (ground microparticles) are similar in the sense of the similarity f2 (f2> 50) calculated according to FDA guidance (Guidance for Industry SUPAC-MR:
Modified release solid oral dosage forms p. 32).

29 Thus, grinding has little or no effect on the release of oxycodone from microparticles.

Example 3 Aspect of the Content of a Capsule According to the Invention 200 mg of microparticles prepared in Example 1 (a dose of 80 mg of Oxycodone HC1) are mixed with the following viscosifiers: 90mg from Klucel HF (hydroxypropylcellulose / Aqualon), 20mg of PolyOx WSR 303 Sentry (polyoxide ethylene / Dow) and 20mg of Xantural 180 (xanthan / cpKelco) beforehand Thames between 100 and 600 m. The whole is incorporated in a gelatin capsule of size 0.
Figure 3 shows the photographs of an observation with the naked eye (A) and under Optical microscope (B) of the capsule contents.
As shown in Figure 3 (A), with the naked eye, the principle microparticles active and the microparticles of viscosifying agents are:
- not distinguishable, - not separable by sieving.
In the photograph of Figure 3 (B) obtained by light microscopy (Pay attention to scale), only two particle populations can be distinguished: on the one hand, of the spherical microparticles of Oxycodone HC1 and microparticles of two agents viscosifiers, and secondly, particles in the form of rods of a third agent viscosifier. Given the very small size of these particles (approximately 0.2 mm), they do not are not separable from each other.

Example 4: Syringe extraction test of a form according to the invention 200 mg of microparticles prepared in Example 1 (a dose of 80 mg of Oxycodone HC1) are mixed with 90mg of Klucel HF (hydroxypropylcellulose / Aqualon), 20mg of PolyOx WSR 303 Sentry (polyethylene oxide / Dow) and 20mg of Xantural 180 (xanthan / cpKelco) previously sieved between 100 and 600 m. The all is incorporated in a size 0 gelatin capsule.
The capsule is opened and the contents are ground according to Example 2 (a) using a mortar and pestle and then mix 10 min at room temperature or boiling, in 2.5mL of extraction liquid. The solution is then removed by means of a Syringe 2.5mL with a 18G needle through a hydrophilic cotton as a filter.
The rate oxycodone HC1 extract is analyzed by HPLC or UV and reported in the table 1.
The low extraction yields (<20%) observed are totally dissuasive for misuse candidates.

Example 5: Syringe extraction test of a form according to the invention 200 mg of microparticles prepared in Example 1 (a dose of 80 mg of Oxycodone HC1) are mixed with 150mg of Klucel HXF
(hydroxypropyl / Aqualon), 50mg PolyOx WSR 303 Sentry (polyethylene oxide / Dow) and 30mg of Carbopol 971P (carbomer / BF Goodrich). The mixture is incorporated in a capsule in gelatin of size 00.
The capsule is opened and the contents are ground according to Example 2 (a) using a mortar and pestle and then mix 10 min at room temperature or boiling, in 10 ml of extraction liquid. The solution is then removed by means of a Syringe 10mL with a 18G needle through a hydrophilic cotton as a filtered. The rate oxycodone HC1 extract is analyzed by HPLC or UV and reported in the table 2.
The low extraction yields (<20%) observed are totally dissuasive for misuse candidates.

Example 6: Syringe extraction test of a form according to the invention 150g of Klucel HXF (Hydroxypropylcellulose / Aqualon), 50g of PolyOx WSR 303 Sentry (poly (ethylene oxide / Dow) 30g of Carbopol 971P (carbomer / BF
Goodrich) and 10g of povidone (Plasdone PVP K29 / 32 / ISP) are granulated by granulation wet on a MiPro device. The granules are screened over 100-600 m.
250 mg of the granules thus obtained are added to 200 mg of microparticles prepared in Example 1 (ie a dose of 80 mg of Oxycodone HCl). The whole thing is integrated in a size 0 gelatin capsule. The capsule is opened and the contents is ground according to Example 2 (a) using a mortar and pestle and mixing 10 min.
temperature ambient or boiling, in 10 mL of extraction liquid. The solution is then Taken by means of a 10mL syringe with a 18G needle through a cotton hydrophilic as a filter. The oxycodone HC1 content extracted is analyzed by HPLC or UV and reported in Table 3.
The low extraction yields (<20%) observed are totally dissuasive for misuse candidates.
Example 7 Manufacture of a Tablet According to the Invention 200 g of microparticles prepared in Example 1 are mixed with 90 g of Klucel HF (hydroxypropylcellulose / Aqualon), 20g PolyOx WSR 303 Sentry (poly (ethylene oxide / Dow), 20g Xanthural 180 (xanthan / cpKelco), 100g of Lactose (Tablettose / Meggle GmbH), 10g of magnesium stearate (Brenntag AG) and 30g of croscarmellose sodium (Ac-Di-Sol / FMC Bipolymer).

470 mg tablets (a dose of 80 mg oxycodone) are manufactured in using an alternative Korsch press.
The tablet obtained is ground according to Example 2 (a) by means of a mortar and a pestle and then mix lOmin at room temperature or boil in 2.5 mL of liquid extraction. The solution is then removed using a syringe of 2.5mL with a 18G needle through a hydrophilic cotton as a filter. The rate of oxycodone HC1 extract is analyzed by HPLC or UV and reported in Table 4.
The low extraction yields (<20%) observed are totally dissuasive for misuse candidates.
Example 8 Microparticles of Oxycodone HCI According to the Invention Step 1: Granulated 1615 g of oxycodone and 85 g of Povidone (Plasdone K29-32 / ISP) are dispersed in a mixture containing 2052 g of water and 1105 g of ethanol. The solution is sprayed on 300 g of cellulose spheres (Asahi-Kasei) in a fluidized air bed Glatt GPCG1.

Step 2: Anti-grinding microparticles 315 g of ethylcellulose (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 oil mill) are solubilized in a mixture composed of 3105 g acetone and 2070 g of isopropanol. This solution is sprayed on 450 g of granule (prepared in step 1).
The coating represents 50% of the mass of the microparticle and ensures the release as shown in Figure 4. The release profile is realized in the conditions of reference dissolution test.

Example 9 Content of a capsule according to the invention 230 mg of microparticles obtained after step 2 of Example 8, 100 mg Amberlite IR69F (sodium polystyrene sulfonate), crushed and sieved, 70 mg from Polyox WSR 303 Sentry (polyethylene oxide) sieved, 3.8 mg of magnesium stearate and 1.9 mg of Aerosi1200 (colloidal silica) are introduced into a gelatin capsule of size 0.
As shown in Figure 5, with the naked eye (A) and the light microscope (B), the microparticles of active ingredient and the microparticles of viscosifying agents are :
- not distinguishable, - not separable by sieving.

EXAMPLE 10 Grinding of the Content of a Capsule Prepared According to Example 9 The contents of the capsule prepared in Example 9 are milled for 2 minutes at ugly mortar and pestle.
The release profiles of the crushed microparticles are reported in the figure 6.
The release profile is carried out under the conditions of the dissolution test reference.
The release profiles of the intact and crushed product are Similar. So, grinding has little or no effect on the release of oxycodone from microparticles.
Example 11: Syringe extraction test of the contents of a prepared capsule according to example 9.
A capsule prepared according to Example 9 is opened and the contents are ground 2 minutes by means of a mortar and pestle and mixed 10 min at room temperature (A) or boiling (B) in 2.5 mL of extraction liquid. The solution is then taken from using a 2.5mL syringe with either a 18G needle or a needle from 27G to through a hydrophilic cotton as a filter. The rate of oxycodone HC1 extract is analyzed by HPLC or UV and reported in Tables 5 and 6.

The low extraction yields (<20%) observed are totally dissuasive for misuse candidates.

Example 12 Extraction Test in Beverages of the Content of a Capsule According to example 9 A capsule prepared according to Example 9 is opened and the contents are ground 2 minutes by means of a mortar and pestle and then mixed in 100 mL of non alcoholic or 50 ml of alcoholic beverage as shown in the table below:

Solvent Volume (ml) Tap water 100 Tap water with 2g / 1 NaC1 100 pH1.2 (HC1) with 2g / 1 NaCl 100 Sprite 100 Pepsi-Cola 100 Smirnoff Twisted Apple (5% alcohol) 100 Absolut vodka (40% alcohol) 50 The solution is then removed and the level of oxycodone HC1 extracted is analyzed by HPLC or UV and reported in Table 7.

The low extraction yields observed even for durations extraction are completely dissuasive for misuse candidates.
Table 1 (Example 4) % Oxycodone HC1 extracted with 18G syringe Temperature liquid Liquid to boil ambient at the tap 0.2 1 with Ethanol (60/40 v / v) 3 8 thanol 18 1 Table 2 (Example 5) % Oxycodone HC1 extracted with 18G syringe Temperature liquid Liquid to boil ambient at the tap 1 2 with Ethanol (60/40 v / v) 4 7 thanol 19 8 Table 3 (Example 6) % Oxycodone HC1 extracted with 18G syringe Temperature liquid Liquid to boil ambient at the tap 1 2 with Ethanol (60/40 v / v) 5 8 thanol 19 9 Table 4 (Example 7) % Oxycodone HCl extracted with 18G syringe Temperature liquid Liquid to boil ambient at the tap 0.5 2 with Ethanol (60/40 v / v) 4 10 thanol 19 2 Table 5: Amount of PA Extracted (%) Using a 2.5mL Syringe equipped a 27G needle (example 11) % Oxycodone HCl extracted with 27G syringe Liquid at room temperature Liquid at boiling point at the tap 0 1 Ethanol (60/40 v / v) 0 4 absolute thanol 14 0 Table 6: Amount of PA Extracted (%) Using a 2.5mL Syringe equipped an 18G needle (example 11) % Oxycodone HC1 extracted with 18G syringe Liquid at room temperature Liquid at boiling point at the tap 0 1 with Ethanol (60/40 v / v) 3 8 absolute thanol 18 1 Table 7: Amount of PA extracted (%) from different beverages during time (example 12) Solvent / extraction time 1h 21h Tap water 8 <45 Tap water with 2g / 1 NaCl 8 <45 pH1.2 (HCl) with 2g / 1 NaCl 14 <45 Sprite 3 <45 Pepsi-Cola 3 <45 Smirnoff Twisted Apple (5% 23 <45 alcohol) Absolut vodka (40% alcohol) 24 <45

Claims (56)

1. Oral and solid pharmaceutical form, characterized in that:
it includes anti-misuse means, - at least part of the AP that it comprises is contained in microparticles coated, modified release PA, the coated PA microparticles comprise a coating layer (Ra), who ensures the modified release of the AP and simultaneously confers a resistance to grinding with coated microparticles of PA, to avoid misuse. 2. Pharmaceutical form according to claim 1, characterized in that comprises at least one viscosifying agent (Vb) capable of preventing the extraction of PA content in PA coated microparticles with modified release of PA, for avoid misuse. Pharmaceutical form according to claim 1 or 2, characterized in that what comprises at least one sequestering agent (Q) capable of forming a complex with the PA in solution. Pharmaceutical form according to claim 1, 2 or 3, characterized in that that the covering layer (Ra) is designed in such a way that, in case of grinding, the maintenance of a modified PA release, for at least some of the microparticles coated. Pharmaceutical form according to any one of the preceding claims, characterized in that the coating layer (Ra) is designed so that what allow, in case of grinding, the maintenance of a modified release for at minus 40%, of preferably at least 60%, and more preferably still at least 80% of the coated microparticles with modified PA release. 6. Pharmaceutical form according to any one of the preceding claims, characterized in that the coating layer (Ra) comprises:
(A1) at least one (co) film-forming polymer (A1) insoluble in the liquids of tract gastrointestinal;
(A2) at least one (co) polymer (A2) soluble in the liquids of the gastrointestinal tract intestinal;
(A3) at least one plasticizer (A3);

(A4) optionally at least one surfactant and / or lubricant and / or a charge mineral and / or organic (A4). Pharmaceutical form according to claim 6, characterized in that the layer of coating (Ra) comprises (in% by weight relative to the total mass of the coating):
<= A1 <= 90, preferably 15 <= A1 <= 80, and more preferentially still 60 <= A1 <= 80;
5 <= A2 <= 50, preferably 10 <= A2 <= 40, and more still preferably 10 <= A2 <= 25;
1 <= A3 <= 30, preferably 2 <= A3 <= 20, and more preferentially still 5 <= A3 <= 15;
0 <= A4 <= 40, preferably 0 <= A4 <= 30, and more preferentially still 0 <= A4 <= 20. The pharmaceutical form according to claim 6 or 7, wherein:
(A1) is selected from the group consisting of:
the non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, acrylic polymers, for example acid copolymers (meth) acrylic and alkyl ester (eg methyl), copolymers of acrylic acid ester and methacrylic carrier of at least one quaternary ammonium group (preferably at least one a copolymer of alkyl (meth) acrylate and trimethylammonioethyl chloride methacrylate) and more specifically the products marketed under the brand names EUDRAGIT ® RS and / or RL
polyvinylacetates, - and their mixtures;

(A2) is selected from the group consisting of:
the nitrogenous (co) polymers, preferably in the group comprising the polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl lactams, the water-soluble derivatives of cellulose, polyvinyl alcohols (PVA), alkylene polyoxides, preferably ethylene polyoxides (POE), polyethylene glycols (PEG), - and their mixtures;

(A3) is selected from the group consisting of:
- esters of cetyl alcohol glycerol and its esters, preferably in the following subgroup:
acetylated glycerides, glycerolmonostearate, glyceryl triacetate, glycerol tributrate, phthalates, preferably in the following subgroup: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, citrates, preferably in the following subgroup:
acetyltributylcitrate, acetyltriethyl citrate, tributyl citrate, triethyl citrate, the sebacates, preferably in the following subgroup: diethyl sebacate, dibutyl, - adipates, azelates - benzoates, - vegetable oils, fumarates, preferably diethylfumarate, malates, preferably diethyl malate, oxalates, preferably diethyloxalate, succinates, preferably dibutylsuccinate, - butyrates, esters of cetyl alcohol, - salicylic acid, - triacetin, malonates, preferably diethyl malonate, castor oil (the latter being particularly preferred), - and their mixtures;

(A4) is selected from the group consisting of:
anionic surfactants, preferably in the subgroup of salts alkaline or alkaline-earth fatty acids, stearic and / or oleic acid being preferred, and / or nonionic surfactants, preferably in the subgroup next :
polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenesorbitan esters, polyoxyethylenated castor oil derivatives, stearates, preferably of calcium, magnesium, aluminum or zinc, stearyl fumarates, preferably sodium, - the glycerol behenates, - talc, - colloidal silica, titanium oxide, magnesium oxide, - bentonite, microcrystalline cellulose, - kaolin, aluminum silicate, - and their mixtures. Pharmaceutical form according to any one of the preceding claims, characterized in that the coating layer (Ra) represents a fraction mass Tp, expressed in% by dry weight relative to the total mass of the microparticles coated, such that: Tp> = 15; preferably between 30 and 60, and more preferably still between 40 and 60, and more preferably between 45 and 55, or about 50. 10. Pharmaceutical form according to any one of the claims preceding, characterized in that the coated PA microparticles have a diameter lower middle or equal to 1000 μm, preferably between 50 and 800 μm and, even more, between 100 and 600 microns, and better still, between 100 and 300 microns. 11. Pharmaceutical form according to any one of the claims preceding, characterized in that the coated microparticles with modified release of PA comprise an overcoating designed so that the overcoating contributes, during the manufacture of tablets, to maintain a modified release for at least part of the said coated PA microparticles with modified PA release, said overcoating being composed of at least one deformable organic constituent having a temperature of melting between 40 ° C and 120 ° C, preferably between 45 ° C and 100 ° C. Pharmaceutical form according to Claim 11, characterized in that the over-coating represents from 5 to 50%, preferably from 10 to 30%, and more preferably still in the order of 20% by dry weight of the total mass of PA microparticles overcoated. Pharmaceutical form according to claim 2, and optionally according to Moon any of the other preceding claims, characterized in that less an agent viscosifier (Vb) is selected from the viscosifiers soluble in least one of solvents: water, alcohols, ketones and their mixtures, this agent being able to increase the viscosity of the extraction liquid so as to counter the misuse especially by injectable route. Pharmaceutical form according to claim 13, characterized in that the agent Viscosifier (Vb) is selected from the following groups of polymers:
acrylic polyacids and their derivatives, and / or polyalkylene glycols (eg polyethylene glycol), and / or polyalkylene oxides (eg ethylene), and / or polyvinylpyrrolidones, and / or gelatines, and / or the polysaccharides, preferably in the subgroup comprising:
alginate sodium, pectins, guars, xanthans, carrageenans, gellans and derivatives cellulose (eg hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose), - and their mixtures. The pharmaceutical form according to claim 13 or 14, wherein the agent viscosifier (Vb) is a polyoxyethylene having a high molecular weight, by example having a molecular weight of 1 million g / mole to 8 million g / mole, example 2 million, 5 million, or 7 million g / mole. Pharmaceutical form according to one of Claims 13 to 15, characterized in that at least one viscosifying agent (Vb) is present - in and / or on microparticles and / or in a super-coating of all or some of the microparticles of PA, - and / or in the free state, that is to say, not contained in, nor supported by microparticles. Pharmaceutical form according to one of Claims 13 to 16, characterized in that the viscosifying agent (Vb) is capable of increasing the viscosity of the liquid used for the eventual extraction to a value greater than or equal to 100 mPa.s in a extraction volume of 2.5 mL, so as to trap the extracted PA in the medium viscous. 18. Pharmaceutical form according to any one of claims 13 to 17, characterized in that the viscosifying agent (Vb) is at least partly made of non-separable microparticles of coated or uncoated PA microparticles coated. 19. The pharmaceutical form according to claim 3, and optionally according to Moon any of the other preceding claims, wherein the agent sequestering Q
comprises a salt, which contains ions capable of forming a complex with the PA salt extract in solution. The pharmaceutical form according to claim 19, wherein the the agent sequestering Q are organic ions of opposite polarity to that of PA in solution, and who form a complex with the PA salt extracted in solution. 21. The pharmaceutical form according to claim 19 or 20, wherein the agent sequestering Q is present in a first phase separated from at least one second phase, said second phase containing at least one PA salt. 22. Pharmaceutical form according to any one of claims 19 to 21, comprising PA salt microparticles and Q. sequestering agent microparticles. 23. The pharmaceutical form according to claim 22, wherein said microparticles have a near size distribution, a close density and are not separable between they are sieved. 24. The pharmaceutical form according to claim 20, wherein the ion of polarity opposite to that of PA in solution is an organic anion. 25. Pharmaceutical form according to any one of claims 19 to 23, in which the sequestering agent Q comprises a salt selected from the group consisting of:
anionic organic salts, such as sodium dodecyl sulfate or docusate of sodium;
anionic polymers, such as (meth) acrylic copolymers (for example example Eudragit® S and Eudragit® L), crosslinked acrylic polyacids (eg example Carbopol), the 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, fumarate, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;
saponified fatty acids, such as the salts of acetic acid, succinic acid, citric, stearic, palmitic, and self-emulsifying glyceryl mono-oleates;

polyamino acids, proteins or peptides, such as albumins, caseins, globulins and enzymes;
- and their mixtures. 26. The pharmaceutical form according to claim 20, wherein the ion of polarity opposite to that of PA in solution is a metal cation, organic, or a of their mixtures. Pharmaceutical form according to any one of claims 19 to 23, in which 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, iodide, 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 copolymers (Meth) acrylic (for example, Eudragit ® RS, Eudragit ® RL or Eudragit ® E);
polyamino acids, proteins or peptides;
- and their mixtures. 28. 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 resin strongly cationic acid exchange when the PA is cationic, or a resin strongly basic anion exchange, when PA is anionic. The pharmaceutical form according to claim 28, wherein the agent sequestering Q
is a derivative of a copolymer of styrene and divinylbenzene. 30. The pharmaceutical form according to claim 28, wherein the agent sequestering Q
is a derivative of a copolymer of styrene and divinylbenzene sulfonic acid. 31. The pharmaceutical form according to claim 28, wherein the agent sequestering Q
is a derivative of a copolymer of styrene and divinylbenzene functions quaternary ammoniums. The pharmaceutical form according to claim 28, wherein the agent sequestering is a crosslinked copolymer of methacrylic acid and divinylbenzene, or one of its salts. The pharmaceutical form according to claim 28, wherein the resin exchange of ions is a phenolic polyamine. Pharmaceutical form according to any one of claims 19 to 33, in which sequestering agent Q is chosen from:
anionic organic salts, such as sodium dodecyl sulfate or docusate of sodium;
cationic organic salts, such as quaternary ammonium salts, in trimethyl tetradecyl ammonium bromide or benzethonium;
- strongly acidic cation exchange resins or resins strongly basic anion exchangers, according to the polarity of the PA. Pharmaceutical form according to any one of claims 19 to 34, in which sequestering agent Q is chosen from:
the strongly acidic cation exchange resins and their mixtures, when the PA is cationic;
strongly basic anion exchange resins and mixtures thereof, when the PA
is anionic. Pharmaceutical form according to any one of claims 19 to 35, in which at least one sequestering agent Q is present:
in microparticles free of PA, and / or - on microparticles, and / or - in the free state, that is to say, not contained in, nor supported by microparticles. Pharmaceutical form according to one of claims 19 to 36, in which the amount of sequestering agent is adjusted in ionic charge for complexing everything or part of the dose of PA 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 non-microparticles separable from microparticles of PA coated or uncoated. 39. Pharmaceutical form according to any one of claims 19 to 38, comprising Viscosifier agent microparticles and / or agent microparticles sequestering Q, V-viscosifying agent microparticles and agent microparticles sequestering Q
being distinct from the microparticles of PA. 40. Pharmaceutical form according to any one of claims 19 to 39, comprising microparticles of PA, as well as microparticles of viscosifying agent V and / or microparticles of sequestering agent Q, said microparticles having a distribution of close size, close density and not separable from each other by sieving. 41. Pharmaceutical form according to any one of the claims preceding, characterized in that it comprises at least one excipient in the free state, that is to say, no contained in or supported by PA microparticles, said excipient contributing to the resistance of coated microparticles to grinding. 42. The pharmaceutical form according to claim 41, characterized in that excipient in the free state is selected from the group consisting of:
calcium stearate;
glycerol palmitostearate;
magnesium oxide;
polyalkylene eg ethylene glycols;
polyvinyl alcohol;
sodium benzoate;
stearic acid;
- corn starch;
- talc;
colloidal silica;
zinc stearate, magnesium;
stearyl fumarate;
- and their mixtures. 43. Pharmaceutical form according to any one of the claims preceding, characterized in that it is not convertible into a dry form administrable by Nasal suction and immediate release of AP. 44. Pharmaceutical form according to any one of the claims preceding, characterized in that it is not convertible into an injectable form and release immediate PA. 45. Pharmaceutical form according to any one of the claims preceding, characterized in that it comprises immediate release PA and / or PA
release changed. 46. Pharmaceutical form according to any one of the claims preceding, characterized in that the extraction of PA by chewing and / or grinding, is not effective. 47. Pharmaceutical form according to one of the preceding claims, characterized in what the PA implemented belongs to at least one of the families of active substances amphetamines, analgesics, anorectics, analgesics, antidepressants, antiepileptics, anti-migraine, antiparkinsonian, antitussive, anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives, neuroleptics, opiates, psychostimulants, psychotropic, sedative, stimulants. 48. Pharmaceutical form according to one of the preceding claims, characterized in the PA used is chosen from the following compounds:
anileridine, acetorphin, acetylalphamethylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodine, anileridine, atropine butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, ketobemidone 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, methyldihydro-morphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morphine, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodin, nicomorphine, noracymethadol, norcodeine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene para-fluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenomorphan, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, propanolol, properidine, propiram, racemethorphan, racemoramide, racemorphan, remifentanil, sufentanil, thebacon, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and their salts, their esters, their hydrates, their polymorphs and their pharmacologically acceptable isomers, and their mixtures. 49. Pharmaceutical form according to one of the preceding claims, characterized in what the AP used is chosen from the group consisting of hydrochloride of oxycodone, morphine sulphate, oxymorphone hydrochloride, hydrochloride hydromorphone, hydrocodone hydrochloride, and hydrochloride tramadol. 50. Pharmaceutical form according to one of the preceding claims, characterized in it is free of PA antagonist (s). 51. Pharmaceutical form according to any one of claims 1 to 49, characterized in that it comprises at least one PA antagonist agent. 52. Pharmaceutical form according to one of the preceding claims, including a plurality of populations of coated PA microparticles, said populations distinguishing one from the other by their release kinetics and / or by the PA they contain. 53. Use of coated microparticles of PA allowing release modified said PA, the coated PA microparticles being as defined in the claims for the manufacture of new pharmaceutical formulations. 54. Use of coated microparticles of PA allowing release modified said PA, the coated PA microparticles being as defined in the claims 1 at 52, for the manufacture of new active pharmaceutical formulations in the therapeutic treatment against pain. 55. A method for controlling the misuse of PA, characterized in that is essentially to implement a pharmaceutical form as defined in one any of claims 1 to 52. 56. A method for controlling the misuse of PA, characterized in that is essentially to be used in a pharmaceutical form, microparticles of PA coated, modified release PA and having a layer of coating (Ra), which ensures the modified release of the AP and which simultaneously confers a resistance to grinding with coated microparticles of PA, to avoid misuse; and eventually at least one viscosifying agent (Vb) capable of preventing the extraction of the AP contained in the coated microparticles, to avoid misuse; and possibly at minus one sequestering agent (Q) able to prevent the extraction of the AP contained in the microparticles coated PA with modified PA release, to avoid misuse; the layer of coating (Ra), optional viscosifier (Vb) and sequestering agent (Q) possible being as defined in claims 1 to 52.