CA2651451A1 - Extended release oral multimicroparticle dosage form - Google Patents

Abstract

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

Description

ORAL PHARMACEUTICAL FORM MULTIMICROPARTICULAR
A PROLONGED RELEASE
Field of the invention The field of the present invention is that of the pharmaceutical forms modified release of medicinal active principles (PA) intended for adminis-oral treatment, containing at least one AP, capable of maintaining a release modified PA in an alcoholic solution, that is to say, not subject to discharge rapid dose in the presence of alcohol; moreover they include means anti misuse.
The PAs considered are pharmaceutical and / or veterinary PAs, by example, those classified as narcotics, painkillers or narcotics. Abuse of these APs can lead to addictive.
The present invention relates more particularly to the pharmaceutical forms type referred to in the preceding paragraph and comprising a plurality of microphone-particle reservoirs. The present invention relates even more especially pharmaceutical forms for which the ingestion of alcohol during administration is not recommended.
The object of the present invention is to improve the pharmaceutical forms.
multimicroparticulate medicines designed to resist attempts to misuse, the improvement in avoiding the patient a rapid discharge of the dose in presence of a large volume of alcoholic solution.
The invention also relates to a method for preparing the forms pharmaceutical products mentioned above.

Context of the invention The interest of modified-release dosage forms for the administration of The treatment of a drug is well known. In particular, they allow better to cover the therapeutic need because the concentration useful plasma in PA can be maintained longer than in the case of release Instant. In addition, they make it possible to limit the height and the number of peaks of PA plasma concentration, which decreases the toxicity of the drug and or reduces its side effects. The interest of modified release forms is, as such, particularly marked for active principles with therapeutic window narrow. By Moreover, these systems make it possible, by their increased duration of action, to limit the number

2 taken daily, which reduces the stress for the patient and improved adherence to treatment Thus, systems have been sought to prolong the action of a drug, and there are many references to this goal. We consult in this respect the work of Buri, Puisieux, Doelker and Benoît: Shapes pharmaceuticals News, Lavoisier 1985, p. 175-227.
However, it appeared that the ingestion of alcohol in parallel with administration of a modified release dosage form (or MR for modified release in English) can lead to accelerated release and potentially dangerous PA in the patient. For PAs such as opioid analgesics, the side effects resulting from the rapid release of a high dose of PA and the Concomitant intake of alcohol leads to serious consequences that can even sometimes put the patient's vital prognosis at risk.
A modified release form should therefore ideally be able to prevent accidental accelerated release of AP in an alcoholic solution.
In addition, a modified release form must be able to intentional misuse of certain active substances such as opiates, which poses a a real public health problem.
Intentional misuse is mainly encountered in the case of mania and chemical enslavement. In both cases, people with intention to misuse a solid oral drug, will usually be employed at extract the PA from the modified release form to obtain a product to action fast.

The pharmaceutical form MR must prevent three modes of misuse intentional:
l. inhalation or oral administration of the form previously put under form an immediate release powder.
2. Parenteral injection of a small volume of fluid containing the extracted PA
of the form MR

3. Oral administration of a drink containing PA in dissolved form.
For cases 2) and 3), obtaining a liquid form from a drug oral solid usually goes through an extraction step, in aqueous phase or organic, of the targeted PA. This extraction is usually preceded by a grinding.
Modes of administration 1) by inhalation or 2) by injection are suitable drug users because they are modes that allow to accentuate kill the effects of AP and promote its rapid absorption into the body.

When the powder obtained by grinding is sucked by the nose or dissolved in of water and injected, the desired effects, doping or euphoric, PA, show very quickly and exacerbated.
Mode 3) is also a particularly serious adolescents and concerns analgesic PAs, especially derivatives opioids and opioids. From a strong alcoholic beverage and a analgé-opiate, especially oxycodone, and with some is possible to extract the opiate analgesic, which can then be absorbed by a addict.
Misuse of solid oral medications may also be observed where, instead of being rapidly swallowed in accordance with the medi-cament is chewed before being swallowed, thus bypassing the slow step disintegration in the stomach and resulting in a discharge of the dose.
Thus, beyond a release profile allowing to extend and / or delay the absorption of AP, an MR release form must be able to avoid the intentional or unintentional misuse of the AP. In particular, the MR form must present simultaneously the following four essential properties:
a) Do not lead to accelerated release of AP in a solution alcohol, such as could occur for example in a patient who accidentally absorb the drug with an alcoholic beverage;
b) be difficult to grind in the form of an immediate release powder, for example to prevent inhalation of PA;
c) be difficult to extract in a small volume of liquid, and thus prevent parenteral injection of PA;
d) not lead to massive solution of PA in a drink alcoholic or not and thus prevent the oral administration of PA in IR form even after a long time of contact.
In order to avoid the massive discharge of the dose in the presence of alcohol, who can result in particular from misuse intentional or not, the application FR 06 50566 no published describes multimicroparticulate pharmaceutical forms capable of resist the accidental discharge of the dose in the presence of alcohol, particular for to address the concerns of health professionals in the face of accidents caused by this discharge of the in vivo dose (the dumping dose), in patients having ingested a sustained-release dosage form at the same time a significant dose of alcohol. These modified release forms possess the property of maintain the modified release of the AP even in a large volume of solution alcoholic (50 to 900 ml). However these forms are not designed to resist

4 attempts to misuse, especially by grinding a dry form, possibly followed by extraction in a liquid medium.
The teaching of this application FR 06 50566 constitutes a progress important because it offers a first solution to the problem a) evoked supra.
However, it does not propose a solution for problems b), c) and d).
The application FR 05 53437 unpublished describes pharmaceutical forms multimicroparticles designed to be particularly resistant to misuse intentional. These fraudulent diversions of oral drugs make intervene different stages (grinding, extraction), and said application describes forms Oral to controlled release comprising anti-misuse means:
the coated PA microparticles comprise a coating layer which confers resistance to grinding;
- in addition the pharmaceutical forms of this application contain an agent viscosity making it very difficult if not impossible to extract the PA
middle liquid;
they may finally contain a sequestering agent.
These forms exhibit resistance to extraction in an aqueous medium or alcoholic low volume (e.g. 2.5 ml). However, these forms are not not adapted to withstand the discharge of the dose that can occur in presence of a large volume of alcoholic medium.
Thus, this invention does not propose a technical solution allowing satisfy simultaneously the four conditions a), b), c) and d) recalled supra.
In this context, it is clear that there is a need for a form modified-release multimicroparticulate pharmaceutical the administration of Oral PA, able, on the one hand, to maintain the modified release of the PA in an alcoholic solution (unintentional or accidental misuse), and other part of resist attempts at intentional misuse.

Objectives of the invention An object of the invention is to provide new solid drugs Oral complying with the specifications mentioned above.
Another object of the invention is to provide new drugs oral solids not leading to a significant acceleration of the release of PA
in an alcoholic solution and having means making misuse of PA
very difficult or impossible.

Another object of the invention is to provide new drugs oral solids, not leading to a significant acceleration of the release from PA in an alcoholic solution whose misuse by grinding or after extraction of PA in a small volume of solvent will be difficult or

5 impossible.
Another object of the invention is to provide new drugs oral solids, having the following characteristics:
- under normal conditions of administration, these solid drugs oral drugs have a therapeutic effect, for example for 12 or 24 hours;
- any attempt at improper extraction of the AP will lead to a release form not immediately or to a product extracted difficult to use, although after Ingestion of the drug, rapid absorption of PA into the circulation blood does will not be possible.
Another object of the invention is to provide new drugs Oral solids, to avoid the fraudulent diversion of properties PA
it contains, making it difficult to administer the drug oral routes, nasal and / or injectable (intravenous, subcutaneous, intramuscular, etc.) out of therapeutic setting.
Another object of the invention is to provide new drugs oral solids, to prevent misuse, while at the same time ensuring, for the sake of patient normally followed, a quality of treatment, in particular a correct dose has his needs.
Another object of the invention is to provide a method of manufacturing Oral solid drugs resistant to immediate discharge of PA dose in presence of alcohol and comprising anti-misuse means.

Definitions In the context of the present disclosure of the invention:
- modified release form or MR form are synonymous and include:
o the reservoir systems, ie the systems where the release of the AP is controlled by a coating surrounding the PA.
matrix systems, in which the PA, intimately dispersed in a matrix, for example based on polymer, is released by diffusion and / or erosion.
- "active ingredient" and the abbreviation "PA" refer to a single principle active than a mixture of several active ingredients. PA can be in free form or under

6 form of salt, ester, hydrate, solvate, polymorph, isomer or other pharmaceutically acceptable forms;
- the ingested alcohol can come from different drinks or beverages alcoholic such beer, wine, cocktails, spirits or their mixtures;
- in vitro, the term "alcohol" without further specification represents ethanol and terms "alcoholic solution" or "alcoholic medium" represents an aqueous solution ethanol;
"reservoir microparticles" means microparticles comprising PA and individually coated with at least one coating allowing the release modified AP;
- "microparticles of PA" indifferently means microparticles reservoirs and / or microparticles comprising PA not necessarily coated;
- "microparticles of viscosifying agent" means microparticles including at less a viscosifying agent and possibly other excipients, to the exclusion of PA;
- "quenching agent" means an agent complexing a deactivating or inactivating agent, a chelator, a precipitating agent, or one again fixative agent (in English, scavenger), likely to interact with an AP and from the disable;
"Sequestering agent microparticles" means microparticles comprising at minus a sequestering agent and possibly other excipients, to the exclusion of PA;
- "microparticles" means indifferently microparticles reservoirs, uncoated microparticles, PA microparticles, microparticles of viscosifying agent and microparticles of sequestering agent, taken alone or in mixed ;
the dissolution profiles in vitro are carried out according to the indications of the European Pharmacopoeia (5th edition, 2.9.3) where the dissolution media classically used are described. To simulate the gastric environment of a subject having absorbed a large amount of alcohol, the dissolution medium is modified by addition ethanol (qs 10% to 40% by volume);
- the term "modified release" means that the release of PA in vitro is as 75% of the AP is released in a time greater than 0.75 h and, preferably, better than 1 h, and more preferably greater than 1.5 h. A pharmaceutical form to modified release may, for example, comprise a release phase immediate and a slow release phase. The modified release may be in particular a extended and / or delayed release. Pharmaceutical release forms

7 modified are well known in this field; see for example Remington: The science and practice ofpharmacy, 19th edition, Mack publishing Co.
Pennsylvania, USA;
- "immediate release" means that the release is not of type release modified and refers to the release by one form of the greater part of the AP
in one relatively short time: at least 75% of the AP is released in 0.75 hours, from preference en30min;
- the similarity between two dissolution profiles is evaluated using the factor of similarity f2 as defined in the document "Quality of products to release amended "of the European Agency for the Evaluation of Medicinal Products, referenced document CPMP / QWP / 604/96 (Annex 3). A value of f2 between 50 and 100 indicate that the two dissolution profiles are similar;
- "agglomerate" or "granule" relates to structures comprising a plurality of microparticles linked together by an agent D, possibly comprising other excipients, the diameter of the agglomerates or granules being preferably less than 8000 m;
the multimicroparticulate oral pharmaceutical forms according to the invention are consisting of many microparticles smaller in size than millimeter.
The diameters of the microparticles discussed in this paper are, unless otherwise indicated, average diameters by volume. These forms multimicroparticles can be presented and adapted by the man of the job in any pharmaceutically acceptable form such as tablets, capsules, sachets, suspensions to be reconstituted;
- by unitary form means the pharmaceutical form which contains a dose of AP which may be in the form of, for example, tablets, capsules, sachets, suspensions to be reconstituted;
- by dose dumping or discharge of the dose or rapid discharge of the dose means immediate release, or significantly accelerated release, and no desired dose of AP after oral ingestion.
Brief description of the invention To achieve the goals they had set for themselves, the inventors had to find some solutions to the various problems listed above and apply them simultaneously to a unique form, since to counter the main modalities of misuse, the pharmaceutical form must be both difficult to crush, and its PA
difficult to extract in different solvents and in different volumes.

8 The pharmaceutical form according to the invention employs physical and harmless chemicals (they are neutral compounds on the plane pharmacological, approved as excipients by the different pharmacopoeias and authorities registration) and economic.
An object of the present invention is to provide a new form multimicroparticulate which has the ability to withstand the discharge of the dose when placed in a large volume of alcohol, moreover this form is able to resist attempts at intentional misuse (crushing, extraction for injection). The approach that has been adopted to measure the resistance of the forms Pharmaceuticals MR at a dose-induced discharge of alcohol consists of modify the conventional tests for the dissolution of pharmaceutical forms MR in introducing ethanol into the dissolution medium, for example at a concentration of 10% or 40% (v / v). The order of magnitude of the final volume is of 50 to 900 mL. For a number of pharmaceutical forms MR, we observe that the co-administration of said form with alcoholic beverages would lead to an unwanted acceleration of the release of the AP.

The profile of the desired pharmaceutical form must be adapted to the charges and depends on the coating of the microparticles. In doing so, avoid to lead to unwanted behaviors such as:
- dissolution profiles that are not controllable, in particular the profile is not more completely controlled by the coating of microparticles the loss of the anti-grinding properties of the microparticles of PA;
- a discharge of the dose in the presence of alcohol.

It is the merit of the Claimant to have discovered that it was possible, by a judicious choice of excipients, their proportions and methods of use in to obtain a formulation that meets the best specifications of the this request.
In other words, the inventors were able to reconcile the properties conferred by excipients of a different nature, to find, by a judicious choice of the nature of each of these excipients (coating excipient, viscosifier, sequestering agent, etc.), their localization (in a microparticle, a binder, a granule, etc.) and their content, a formulation that meets the initial specifications.

9 More specifically, the present invention relates to an oral pharmaceutical form comprising reservoir-type microparticles with modified release from less PA, not subject to a discharge of the dose in the presence of alcohol, that is, tell who resistant to the immediate discharge of the PA dose in the presence of alcohol, particular in a large volume and, moreover, whose composition and structure allow to avoid the misuse of the PA that said form contains, in particular by means of means anti-misuse. In particular, the anti-misuse means comprise at least of the anti-grinding means.
This pharmaceutical form according to the invention is characterized in that - the means preventing the discharge of the dose of PA in the presence of alcohol comprise at least one agent D which is a pharmaceutically active compound acceptable whose speed or ability to hydrate or to solvate is higher in an aqueous medium free of alcohol in alcoholic solution; and at least part of the AP is contained in coated microparticles having a coating layer R which provides the modified release of the AP
and which simultaneously confers on the coated PA microparticles a resistance grinding, to avoid misuse;
and optionally at least one viscosifying agent V;
and possibly at least one sequestering agent Q.
In particular, the oral pharmaceutical form according to the invention is characterized in that that the release time of 50% PA in an alcoholic solution is not decreased by more than 3 times compared to the release time of 50% of AP
measured in an aqueous medium free of alcohol.
The present invention also relates to a process for obtaining a form pharmaceutical oral solid, anti-misuse by grinding and extraction alcoholic.

Brief description of the figures Figure 1: Dissolution of the Microparticles Prepared in Example 3 ^: intact ^: crushed Figure 2: Dissolution of the capsules prepared in Example 4 ^: in 40% EtOH: in HC10.1 N

Figure 3 Dissolution of the tablets prepared in Example 6 ^: in 40% EtOH: in HC10.1 N
Figure 4: Dissolution of the tablets prepared in Example 8 5: in HC10.1 NA: in HC10.1 N / EtOH (90/10 v / v) Figure 5: Dissolution of the tablets prepared in Example 9 in HC10.1 NA: in HC10.1 N / EtOH (90/10 v / v)

Figure 6: Dissolution of the tablets prepared in Example 10 in HC10.1N2: in HC10.1N / EtOH (60/40 v / v) Figure 7: Dissolution of the tablets prepared in Example 12 Aa,: in HC10.1N2: in HC10.1 N / EtOH (80/20 w / w) EtOH is ethanol.

Detailed description of the invention The oral pharmaceutical form according to the invention has anti-misuse; it includes microparticles of type tank and allows the release modified PA in aqueous dissolution media as well as in alcoholic solutions.

Microparticles of coated PA
The coated microparticles with modified PA release are microparticles each coated with at least one coating (for example comprising at least a polymer) deposited according to techniques known to those skilled in the art. We consult on this question for example Buri, et al. : Pharmaceutical Forms New, Lavoisier 1985, p. 175-227 already cited.
The pharmaceutical form according to the invention is multimicroparticulate; she comprises among others reservoir microparticles with a core comprising PA
coated or film coated with a coating. This PA heart, or PA microparticle, can be :
raw (pure) PA in pulverulent form, and / or

11 a matrix granule of PA mixed with various other ingredients, and / or a supported granule, such as a neutral support, for example cellulose or in sugar, covered with at least one layer comprising PA.
In the case of a matrix granulate, the matrix contains the PA and eventually other pharmaceutically acceptable excipients, such as binders, surfactants, disintegrants, fillers, agents controlling or modifying the pH
(Buffer).
In the case of a supported granulate, the layer containing the PA contains eventually other pharmaceutically acceptable excipients, such as binders, surfactants, disintegrants, fillers, agents controlling or modifying the pH
(Buffer). The neutral carrier may be composed of sucrose and / or sucrose and or dextrose and / or lactose, and / or sucrose / starch mixture. The support neutral can also be a cellulose microsphere or any other particle excipient pharmaceutically acceptable. As a non-limiting example of support neutral, we may include particles of xanthan gum, guar gum, calcium, calcium carbonate.

Advantageously, the neutral support has a mean diameter of between 1 and 800 m and preferably between 20 and 500 m.
Coating of PA microparticles Advantageously, the microparticles coated with PA comprise at least a coating layer R, better still, a single layer of coating R, who ensures the modified release of the AP and simultaneously confers a resistance to grinding with coated microparticles of PA, to avoid misuse.
More preferably still, the coating layer R is designed such that so that, in case of grinding, it allows the maintenance of a non immediate (i.e., modified) for at least a portion of the coated microparticles at 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, crushing between two spoons, in crunchy, etc.
According to an interesting embodiment, the coating R is designed so that it allow, in case of grinding, the maintenance of a modified release for at less 40%, preferably at least 60%, and more preferably still at least 80%
coated microparticles with modified release of AP.

12 Preferably, the anti-grinding coating layer R comprises:
at least one (co) film-forming polymer Al that is insoluble in the liquids of the tube digestive;
at least one soluble (co) polymer A2 in the liquids of the digestive tract;
at least one plasticizer A3;
- optionally at least one surfactant and / or a lubricant and / or a charge mineral and / or organic filler A4.
In accordance with a purely illustrative and non-illustrative selection limiting the invention:
Al is selected from the group consisting of:
o 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), ester copolymers of acrylic and methacrylic acid carrying at least one group quaternary ammonium (preferably at least one copolymer of (meth) acrylate and trimethylammonioethyl chloride methacrylate) and more specifically the products marketed under the brands Eudragit RS and / or Eudragit RL
polyvinylacetates, o and their mixtures;

A2 is chosen from the group comprising:
the nitrogenous (co) polymers, preferably in the group comprising the polyunsaturated acrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl lactams, o the water-soluble derivatives of cellulose, polyvinyl alcohols (PVA), the alkylene polyoxides, preferably the ethylene polyoxides (POE), polyethylene glycols (PEG), o and their mixtures;
PVP being particularly preferred A3 is selected from the group consisting of:
o esters of cetyl alcohol,

13 glycerol and its esters, preferably in the following subgroup:
acetylated glycerides, glycerolmonostearate, glyceryltriacetate, glycerol ltributyrate, phthalates, preferably in the following subgroup: dibutyl phthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, o citrates, preferably in the following subgroup:
acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate, the sebacates, preferably in the following subgroup: diethyl sebacate, dibutyl sebacate, o adipates, o azelates, o benzoates, o vegetable oils, fumarates, preferably diethylfumarate, malates, preferably diethyl malate, oxalates, preferably diethyloxalate, succinates, preferably dibutylsuccinate, o butyrates, o esters of cetyl alcohol, malonates, preferably diethyl malonate, castor oil (the latter being particularly preferred), o and their mixtures;

A4 is chosen from the group comprising:
anionic surfactants, preferably in the salt subgroup alkaline or alkaline earth fatty acids, stearic and / or oleic acid being preferred, o and / or nonionic surfactants, preferably in the subgroup of polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers (poloxamer), polyoxyethylenesorbitan esters, polysorbates, o derivatives of polyoxyethylenated castor oil, o stearates, preferably calcium, magnesium, aluminum or zinc, stearyl fumarates, preferably sodium,

14 o the glycerol behenates, o talc, o colloidal silica, titanium oxide, magnesium oxide, o Bentonite, microcrystalline cellulose, o kaolin, o aluminum silicate, o and their mixtures.
According to a preferred variant of the invention, the coating layer R contains the following components:

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

Advantageously, for each component Al, A2, A3 and A4 of the layer of coating R, its mass m (in% of the total mass Al + A2 + A3 + A4) verifies for Al: 10 <_ m <90, preferably 15 <m <80, and more preferably 60 <_m <_80;

for A2: 2 <_ m <_ 50, preferably 3 <_ m <_ 40, and more preferably 5 <_ m <_ 25 for A3: 1 <_ m <_ 30, preferably 2 <_ m <_ 20, and more preferably 5 <_m <_15;
for A4: 0 <_ m <_ 40, preferably 0 <_ m <_ 30, and more preferably <0m <20.

With respect to the total mass of the coated PA microparticles, the coating R represents a mass fraction Tp, expressed in% by dry weight, such that: Tp _ 15; preferably between 30 and 60, and more preferably Between 40 and 60, and more preferably between 45 and 55, or about 50.
Preferably, the coated PA microparticles have a mean diameter of volume less than or equal to 1000 m, preferably between 50 and 800 m, and preferably between 100 and 600 m, and more preferably between 100 and m. The diameter of the microparticles is, unless otherwise stated, a diameter medium in

15 volume.
The techniques used for the manufacture of PA microparticles, are conventional techniques, such as for example the spray technique coating in bed fluidized air, wet granulation, compaction, extrusion-spheronization.

Agent D
The pharmaceutical form according to the invention comprises at least one agent D which is a pharmaceutically acceptable compound and whose rate or capacity at to hydrate or to solvate is superior in aqueous medium free of alcohol that alcoholic solution. It could be :
a compound with a higher solubilization rate in water than in solution alcoholic;
a compound that is soluble in water and insoluble in alcoholic solution;
- or a compound, insoluble in water or alcoholic solution, which swells more or faster in water than in alcoholic solution.
Preferably, the agent D is chosen from the following group of products:
Cellulosic derivatives such as, for example:
= methylcellulose the (hydroxy) (alkyl) celluloses (for example hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), carboxyalkylcelluloses (for example carboxymethylcellulose) and their salts, 0 celluloses (powder or microcrystalline),

16 crosslinked carboxyalkylcelluloses: carboxymethylcelluloses crosslinked (eg croscarmellose sodium), polyalkylene oxides (for example polyethylene oxide or polypropylene oxide).
Polysaccharides, for example:
= native starches (eg corn, wheat or potato) or modified (for example with sodium glycolate), alginates and their salts, such as sodium alginate, = potassium polacrilin, = guar gums, = carrageenans, = pullulans, = the pectins, = chitosans and their derivatives, = and their mixtures, - Proteins, for example:
= gelatin, = albumins, = casein, = lactoglobulins, = and their mixtures Clays such as bentonite, laponite and mixtures thereof.

Even more preferably, agent D is selected from the group of following products:
hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) cellulos and their salts - guar gums, - carrageenans, and their mixtures.
Agent D can be incorporated in different ways, possibly combined between them, in the pharmaceutical form according to the invention. It can be a of the constituents:
the heart of PA (or microparticle not coated with PA):
0 in the neutral support of the microparticles and / or

17 = in the layer containing PA and deposited on the neutral support of microparticles and / or in the granule containing the PA; and or - the coating of the microparticles; and or a mixture with the microparticles:
= either in the binding phase of granules, pellets, tablets including the microparticles of PA and / or = either in a distinct type of microparticle and / or = either in a separate type of granules; and or one of the outer constituents of a monolithic form (for example component capsule, lining a tablet or capsule).

According to a first embodiment of the invention, agent D is present in the heart of PA, or microparticle uncoated PA. Preferably, Agent D
is present in the heart of the microparticles at a rate of 5 to 70%, preference of 15% to 60% of the total mass of the heart of PA.
According to a second embodiment of the invention, agent D is included in the coating of the microparticles. In this case, Agent D may constitute only him a coating layer internal or external to the coating controlling the diffusion.
he can also be mixed with the constituents Al, A2, A3 and possibly A4 of the coating that governs the modified release of the AP. Preferably, the agent D
is present in the coating at a rate of 3 to 30%, preferably from 10% to 20% of the mass Total of the coating. Preferably, the following compounds are chosen: the polymer To the East ethylcellulose, the polymer A2 is PVP, the plasticizer A3 is Castor oil, A4 is a poloxamer, and the agent D is selected from guar gum, hydroxy ethylcellulose, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl sodium cellulose, and mixtures thereof.
According to a third embodiment, the agent D is included in the phase binder of granules or pellets or tablets including microparticles of PA. Granules, pellets or tablets are obtained by the techniques known by the person skilled in the art, for example granulation, extrusion or compression. Agent D is present in a mixture with the microparticles, Reason to 0.5 to 30% w / w, preferably from 0.5% to 25% w / w, and more preferably more 1% to 20% w / w, of the total mass of the mixture.
According to a fourth embodiment, the agent D is at least partially in the form of microparticles or, preferably, granules distinct from those who contain the PA. For example coated microparticles of PA are granulated

18 according to conventional techniques, and separately prepared granules are prepared cut and the same density of agent D, which granules may also contain a viscosifier and / or sequestrant (see below).
According to a fifth embodiment, the agent D is one of the components of the material constituting the capsule which contains the microparticles.
According to a sixth embodiment, the agent D is included in a coating deposited on the capsule containing the microparticles or on the compressed containing the microparticles. For example, the capsule is gelatin-based, and the coating contains sodium carboxymethylcellulose and / or hydroxyethyl cellulose as agent D, preferably in a proportion of 25% w / w agent D
report to the mass of empty capsules.
In the case of the fifth and sixth modes, it will be possible to deposit on the capsule or the tablet a topcoat.
The different embodiments, with regard to the agent D, can be combined between them. In such a case, it is quite possible to incorporate different agents D for each of the embodiments indicated.

Viscosifying agent V
The viscosifying agent V is chosen from viscosifiers which are soluble in at least one of the following solvents: water, alcohols, ketones and their mixtures, this (s) agent (s) being able to increase the viscosity of the extraction solvent so as to upset misuse, particularly by injection. By "water" we mean here everything solvent aqueous, such as water stricto sensu or any aqueous solution, for example acid organic (eg acetic acid), saline solutions, sodas or drinks. By "alcohols" means here all the alcohols taken alone or as a mixture between them, and "ketones" means all the ketones taken on their own or in mix between they.
Preferably, the viscosifying agent V is chosen from the groups of polymers following:
poly (meth) acrylic acids and their derivatives, and / or polyalkylene glycols (eg polyethylene glycol), and / or - alkylene polyoxides (eg polyethylene oxide), and / or polyvinylpyrrolidones, and / or gelatines, and / or the polysaccharides, preferably in the subgroup comprising:
alginate sodium, pectins, guars, xanthans, carrageenans, gellanes and

19 derivatives of cellulose (in particular hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose), - and their mixtures.

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

According to a modality of the invention, the viscosifying agent V is a polyoxide ethylene having a high molecular weight, for example having a weight molecular from 1 million g / mole to 8 million g / mole, for example 2 million, 5 million, or 7 million g / mole.

In a preferred embodiment, the viscosifying agent V is capable of increasing the viscosity of the liquid used for the possible extraction, so as to trap the AP
extracted in the viscous medium. This agent V makes it possible to increase the viscosity of the liquid extraction for example, above 100 mPa.s, preferably 200 mPa.s, and more preferential-still above 500 mPa.s, and more preferably 1000 mPa.s.
According to a variant of the invention, the viscosifying agent V is effective at the times in the case of extraction in aqueous or organic phase; for example agent V is a mixture of hydrophilic and hydrophobic compounds, so as to ensure a strong viscosity of the extraction liquid (eg _ 100 mPa.s), whether this is aqueous or organic.
The amount of agent V is adjusted to make the viscosity of 2.5 mL of liquid extraction greater than or equal to 100 mPa.s.
According to several variants, in the pharmaceutical form according to the invention less a viscosifying agent V is present:
in and / or on microparticles, - and / or in the free state, that is to say, not contained in or supported by, microphone-particles.
Advantageously, the viscosifying agent is mainly in the form of microparticles distinct from PA microparticles. In case the form Pharmaceutical is a divided form (capsule, sachet, suspension with reconstitute), viscosifying agent microparticles have a density and a particle size comparable those of the microparticles of PA. For example, agent microparticles viscosifier V and microparticles of PA, have a size distribution similar and a similar density. Thus, they are not separable from microparticles of PA, especially by conventional means such as sieving or centrifugation.
When the pharmaceutical form according to the invention comprises granules containing microparticles of PA on the one hand, and granules containing agent viscosity V, possibly associated with the agent D, on the other hand, it is preferable that said granules have a similar size distribution, a density similar, a similar shape and color. Thus the granules comprising the agent viscosifying and / or Agent D are physically indistinguishable from the PA granules, in order to to do obstacle to their sorting by any appropriate physical means.

Sequestering Agent Q
In the case where the multimicroparticulate pharmaceutical form comprises at least At least one salt of an active ingredient, or an active ingredient carrying a ionizable function in solution, a preferred embodiment of the invention consists in adding to said at least one sequestering agent Q. The latter is chosen from such so that in the course of an extraction attempt, he forms with PA, in solution aqueous or hydroalcoholic, a poorly soluble complex.

Within the meaning of the present invention, a sequestering agent Q is an agent present in the pharmaceutical form in a free form, i.e. uncomplexed.
"No complex "means that there is no complex or chemical interaction enter the sequestering agent Q and the active ingredient salt PA in the form pharmaceutical solid.
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 PA, the agent sequestering Q is able to induce complexation or chemical interaction with the PA salt in said solvent. For the purposes of the present invention, the agent sequestering Q
is considered "able to induce complexation" with PA salt when the sequestering agent Q is capable of inducing the complexation of the PA salt in at less a common solvent selected from water and aqueous solutions, such as mixtures water-ethanol, alcohol, alcoholic beverages, sodas, vinegar, water oxygenated 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 even for regular use. These are products inert of the

21 pharmacological point of view and approved by the different pharmacopoeias and drug registration authorities.
In a pharmaceutical form according to the invention, at least one agent sequestering 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 pharmaceutical composition comprises microparticles of PA salt and microparticles separate sequestering agent Q. Advantageously, said microparticles they have a distribution of similar size, a similar density and are not separable between they are sieved.
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 of the organic ions of opposite polarity to that of PA in solution: if in solution the PA
is in anionic form, the sequestering agent Q comprises an organic cation, a metal cation, or a mixture thereof. In the same way, when the PA
in solution is in cationic form, the sequestering agent Q comprises an anion organic.
For example, there may be mentioned the following salts which have an organic anion :
anionic organic salts, such as sodium dodecyl sulfate or docusate sodium;
anionic polymers, such as (meth) acrylic copolymers (for example example Eudragit S and Eudragit L), crosslinked acrylic polyacids (e.g.
Carbopol) carboxymethylcellulose and its derivatives, crosslinked carboxymethylcellulose and his derivatives and other polysaccharides (eg alginate, xanthan gum or arabic), alginate (sulfonate) propylene glycol;
mono- or polyvalent salts, such as glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;
saponified fatty acids, such as the salts of acetic acid, succinic acid, citric, stearic, palmitic, and self-emulsifying glyceryl mono-oleates;
polyamino acids, proteins or peptides, such as albumins, caseins, globulins and enzymes;

22 - and their mixtures.

In another embodiment, the ion of opposite polarity to that of the PA in solution is a metal, organic cation, or a mixture thereof. For example, we include the following salts which contain an organic or metallic cation:
cationic salts, for example metals Ca, Fe, Mg, Zn, in the form of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarates, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodide, lactates, oxides, phosphates, trisilicates, phosphates, salicylates, succinate, 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 (eg, Eudragit RS, Eudragit RL or Eudragit E);
polyamino acids, proteins or peptides;
- and their mixtures.

The sequestering agent Q may be an ion exchange resin, preferably a strongly acidic cation exchange resin when the PA is cationic or a strongly basic anion exchange resin, when PA is anionic.
Advantageously, such an ion exchange resin is contained in a first distinct phase of a second phase that contains the PA.
In one embodiment of the invention, the ion exchange resin will be for example a derivative of a copolymer of styrene and divinylbenzene.
In one embodiment of the invention, the strongly acidic resin For example, cation exchanger will be a derivative of a styrene copolymer and of divinylbenzene sulfonic such as Amberlite IRP69, Amberlite IR69F (Rohm and Haas); Amberlite 200, Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and the like.
In one embodiment of the invention, the strongly basic resin anion exchange will for example be selected from the derivatives of copolymers of styrene and divinylbenzene bearing quaternary ammonium functions, as Duolite AP143 (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 crosslinked copolymers of methacrylic acid and divinylbenzene or one of their

23 salts, such as Amberlite IRP88 and Amberlite IRP64 (Rohm and Haas) DOWEX
MAC-3 (Dow).
The sequestering agent Q in the form of an ion exchange resin can also be selected from phenolic polyamines such as Amberlite IRP58 (Rohm and Haas).
The mixtures of these different resins are also conceivable.
According to one embodiment of the invention, the sequestering agent Q in form ion exchange resin, is in a first phase separated from at least a second phase, said second phase comprising PA salt. for example the agent sequestering agent Q in the form of an ion exchange resin, is contained in microparticles distinct from the microparticles comprising PA salt. The microparticles of PA and the microparticles of sequestering agent Q in form of ion exchange resin, may be in such form that they have a distribution of similar size, a similar density and that they are not not separable by sieving.

In a first preferred embodiment of the invention, the agent sequestering Q is selected from:
anionic organic salts, such as sodium dodecyl sulfate or docusate 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 exchange, depending on the polarity of the PA.

In a second preferred embodiment of the invention, the agent sequestering Q is selected from:
- strongly acidic cation exchange resins: Amberlite IRP69 Amberlite IR69F (Rohm and Haas); Amberlite 200, Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and their mixtures, when the PA is cationic;
- strongly basic anion exchange resins: Duolite AP143 (Rohm and Haas) Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX
(Dow), and mixtures thereof, when the AP 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

24 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 insufficient to achieve the desired effect, if used illicit. Of preferably, the amount of sequestering agent Q is sufficient to complex all the PA
unit dose.

Excipient in the free state The pharmaceutical form may optionally include one or more pharmaceutically acceptable excipients, in the free state, i.e.
contents in or supported by PA microparticles, said excipient the resistances of microparticles of PA coated during grinding.
Preferably, these excipients contributing to the grinding resistance of the coated microparticles, are selected from the group consisting of:
calcium stearate;
glycerol palmitostearate;
magnesium oxide;
polyalkylene-e.g. ethylene glycols;
polyvinyl alcohol;
sodium benzoate;
stearic acid;
- corn starch;
- talc;
colloidal silica;
zinc stearate, magnesium;
stearyl fumarate;
- and their mixtures.

Description of the pharmaceutical form Preferably, the oral pharmaceutical form according to the invention, with a release modified from at least one PA both in aqueous dissolution media than in alcoholic solutions, is characterized in that the time of release of 50% of PA in alcoholic solution:
- is not decreased by more than 3 times compared to the release time of 50 % of PA measured in an aqueous medium free of alcohol;

- preferably is not decreased by more than 2 times in relation to the time of release of 50% of the PA measured in aqueous medium free of alcohol;
- preferably is not decreased by more than 1.5 times compared to the time of release of 50% of the PA measured in aqueous medium free of alcohol;
5 - preferably is similar to that measured in aqueous medium, according to factor of similarity f2 defined above;
- even the release time of 50% of the PA in alcoholic solution is greater than release time of 50% PA in aqueous medium free of alcohol.

In general, the pharmaceutical form according to the invention is characterized in what she understands:
a) a PA at least a part of which is contained in microparticles individually coated with a coating R ensuring the modified release of PA and simultaneously conferring resistance to grinding of Coated microparticles. Constituents Al, A2, A3 and A4 of the coating layer R, satisfy, in terms of percentage by mass reported to the total mass Al + A2 + A3 + A4 under the conditions mentioned above.
b) at least one agent D which is present at a level of 0.5 to 30% w / w, preference from 0.5% to 25% w / w, and more preferably still from 1% to 20% w / w, of the Total mass of the unit form;
c) optionally at least one viscosifying agent V present in a proportion of 2 to 400 mg, preferably from 5 to 200 mg, and still more preferably from 10 to 100 mg per unit form;
d) optionally at least one sequestering agent Q whose quantity is adjusted

25 to trap all or part of the dose of PA contained in the form unit.
In a preferred embodiment, the sequestering agent Q is included in a phase or in microparticles separated from the microparticles of PA.

Preferably, the viscosifying agent V is contained in microparticles distinct from the microparticles of AP. Advantageously, the pharmaceutical form according to the invention, comprises microparticles of viscosifying agent V and PA microparticles, said microparticles having a distribution of cut similar, a similar density and not separable from each other by sieving.
According to a mode 1 of embodiment of the invention, the coating layer R
contains the following components:

26 Al is chosen from the group comprising the non-water-soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, A2 is chosen from the group comprising:
the nitrogenous (co) polymers, preferably in the group consisting of polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams, the water-soluble derivatives of cellulose, = polyethylene glycols (PEG), = and their mixtures;
A3 is selected from the group comprising: triethyl citrate, dibutylsébaçate, vegetable oils, castor oil and mixtures thereof;
A4 is chosen from the group comprising: nonionic surfactants, preferably in the following subgroup:
= polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, = ethylene oxide-propylene polyoxide copolymers (Poloxamer), polyoxyethylenesorbitan esters, = polysorbates, stearates, preferably magnesium, = and their mixtures.

According to a mode 2 of embodiment of the invention, the agent D is chosen in the group of products:
hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) celluloses, and their salts - guar gums, - carrageenans, and their mixtures.

According to one embodiment 3 of the invention, the viscosifying agent V is selected among:
- alkylene polyoxides (eg polyethylene oxide), and / or - xanthans and / or cellulose derivatives (especially hydroxypropyl-cellulose)

27 - and their mixtures.
According to a variant of embodiment 3 of the invention, the agent viscosifier V is a polyethylene oxide having a high molecular weight, for example having a weight molecular weight range from 1 million g / mole to 8 million g / mole, for example 2 million, 5 million, or 7 million g / mole.

According to one embodiment 4 of the invention, the sequestering agent Q is chosen from:
anionic organic salts, such as sodium dodecyl sulfate or docusate sodium;
cationic organic salts, such as ammonium salts quaternaries, trimethyl tetradecyl ammonium bromide or benzethonium;
ion exchange resins, preferably a strongly acidic resin exchange of cations or a strongly basic anion exchange resin.
According to one embodiment of the invention, the sequestering agent Q is selected among:
- strongly acidic cation exchange resins: Amberlite IRP69 Amberlite IR69F (Rohm and Haas); Amberlite 200, Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and mixtures thereof, when the PA is cationic;
- strongly basic anion exchange resins: Duolite AP143 (Rohm and Haas) Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow), and mixtures thereof, when the AP is anionic.

These modes 1 to 5 embodiment of the invention can be combined with each other.
In particular, a pharmaceutical form according to the invention comprises simultaneously coating layer R and agent D of embodiments 1 and 2. According to a preferred embodiment, the pharmaceutical form further comprises at least one agent Viscosifier V according to Embodiment 3. Finally, the pharmaceutical form can contain a sequestering agent Q according to modes 4 or 5.

Of course, the final pharmaceutical form according to the invention may be optimized by adding other conventional ingredients and known to man of such as, in particular, dyes, pigments, preservatives, of the flavors, and mixtures thereof.

28 According to a preferred embodiment, the unit dosage form according to the invention is a tablet comprising:
a) a PA at least a part of which is contained in microparticles individually coated with a coating R ensuring the modified release of PA and simultaneously conferring resistance to grinding of coated microparticles For each constituent A1, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass Al + A2 + A3 + A4) verifies:
for AI: 10 <_ m <90, preferably 15 <m <80, and more preferably 60 <_m <_80;
for A2: 2 <_ m <_ 50, preferably 3 <_ m <_ 40, and more preferably 5 <_m <_25;
for A3: 1 <_ m <_ 30, preferably 2 <_ m <_ 20, and more preferably 5 <_m <_15;
for A4: 0 <_ m <_ 40, preferably 0 <_ m <_ 30, and more preferably 0 <_m <_20;
b) at least one agent D is present in a mixture with the microparticles to reason from 1 to 30% w / w, preferably from 2% to 25% w / w, and more preferably still 2% to 20% w / w, of the total mass of the unit form;
c) at least one viscosifying agent V is contained in microparticles distinct from the microparticles of AP. The viscosifying agent V is present at from 2 to 400 mg, preferably from 5 to 200 mg, and more preferably still 10 to 100 mg per unit form;
d) possibly at least one sequestering agent Q is contained in distinct microparticles of PA microparticles and viscosifier.
The amount of agent Q is adjusted to trap all or part of the dose of PA contained in the unitary form.
e) and possibly compressional excipients.

According to one embodiment 7 of the invention, the mode 6 tablet of production, comprises at least one sequestering agent Q.

With regard to modes 6 and 7 of embodiment of the invention, it is possible to report modes 1 to 5 of the invention to determine the nature of the components A1, A2, A3 and A4 of the coating layer R, that of the agent D, that viscosifier V, and optionally that of the sequestering agent Q ,.

29 According to a preferred embodiment, the unit dosage form according to the invention is a capsule comprising:
a) an AP at least part of which is contained in microparticles individually coated with a coating R ensuring the modified release of PA and simultaneously conferring resistance to grinding of coated microparticles For each constituent A1, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass Al + A2 + A3 + A4) verifies:
for Al: 10 <_ m <90, preferably 15 <m <80, and more preferably 60 <_m <_80;
for A2: 2 <_ m <_ 50, preferably 3 <_ m <_ 40, and more preferably 5 <_m <_25;
for A3: 1 <_ m <_ 30, preferably 2 <_ m <_ 20, and more preferably 5 <_m <_15;
for A4: 0 <_ m <_ 40, preferably 0 <_ m <_ 30, and more preferably 0 <_m <_20;
b) at least one agent D which is present at a level of 0.5 to 20% w / w, preference from 0.5% to 15% w / w, and more preferably still from 1% to 10% w / w, of the total mass of the unit form c) optionally at least one viscosifying agent V present in a proportion of 2 to 400 mg, preferably from 5 to 200 mg, and still more preferably from 10 to 100 mg per unit form.
d) optionally at least one sequestering agent Q whose quantity is adjusted in order to trap all or part of the dose of AP contained in the form unit.
According to one embodiment 9 of the invention, the capsule of mode 8 of production, comprises at least one viscosifying agent V.

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

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

Preferably, the capsule-type pharmaceutical form comprises microparticles of PA, as well as microparticles of viscosity agent V and / or microparticles of sequestering agent Q, said microparticles having cut close densities and not separable from each other by sieving.

With regard to modes 8, 9 and 10 of embodiment of the invention, it is possible to himself refer to modes 1 to 5 of embodiment of the invention to determine the nature of components A1, A2, A3 and A4 of the coating layer R, that of the agent D, that Viscosifier V, and optionally that of sequestering agent Q.
Active ingredient The implemented AP may belong for example to at least one of the families of active substances: opiates, analgesics, analgesics, antitussive, anxious lytic, benzodiazepine, anorectic, antidepressant, antiepileptic, anti-migraine, antiparkinsonism, barbiturates, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropics, sedatives, amphetamines, stimulants.

More specifically still, the PA used is chosen from the compounds following acetylphrine, acetylalphamethylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alpha-cetylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodine, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxy-fentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butyrate dioxaphetyl, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazene, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethyl thiambutene, difenoxine, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, 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, norcodine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene para-fluorofentanyl, pentazocine, pethidine, phenampromide, phenophenol, phenorphanine, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, propranolol, properidine, propiram, racemethorphan, racemoramide, racemorphan, remifentanil, sufentanil, thbacone, thebaine, thiofentanyl, tilidine trimperidine, tramadol, and their salts, esters, hydrates, polymorphic and their pharmacologically acceptable isomers, and mixtures thereof.

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

For the purposes of the invention, the expression "pharmaceutical formulation" means in the broad sense that is to say that are included veterinary formulations or particularly dietary.
According to another of its aspects, the invention aims at a formulation characterized in what it comprises a plurality of microparticles (PA, coated or not coated; optionally viscosifying agent) as defined above, by for example, at least 500, preferably 1,000 to 1,000,000, and more preferentially still, from 5,000 to 500,000 microparticles.
According to another of its aspects, the invention aims at a formulation pharmaceutical composition, comprising a plurality of microparticle populations of PA
coated, said populations being distinguished from each other by their kinetics of release and / or by the AP they contain.
Advantageously, the pharmaceutical form according to the invention can include modified release PA microparticles and microparticles of PA immediate release.
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 daily oral dose comprising from 500 to 500,000 microparticles, including coated PA microparticles.
Without this being limiting, the pharmaceutical formulation comprising coated microparticles according to the invention is in a galenic form chosen in the group comprising in particular: tablets (advantageously orodispersible or gastrodispersible), powders, suspensions, syrups, powders for suspension to be reconstituted or capsules.
It may be interesting to mix in one capsule, one tablet or powder, at least two types of coated microparticles of PA having different release kinetics but included in the frame characteristic of the invention.
According to one variant, the pharmaceutical form can also be a form monolithic (eg tablet).
According to a first variant, the pharmaceutical form according to the invention, is not readily convertible into a dry form administrable by aspiration nasal and immediate release of AP.
According to a second variant, the pharmaceutical form according to the invention is not convertible into an injectable and immediate-release form of PA.
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. It means that in a pharmaceutical form that includes modified-release PA and immediate release AP, release is not convertible into a dry form administrable by aspiration nasal or injectable form, and immediate release.

The subject of the present invention is also the processes for obtaining the pharmaceutical forms according to the invention as defined above, said processes consisting of several steps consisting essentially of:
a) preparing uncoated microparticles of PA by:
extrusion / spheronization of PA with possibly one or more agent (s) D
or pharmaceutically acceptable excipient (s), and / or;
wet granulation of PA with possibly one or more agent (s) D or pharmaceutically acceptable excipient (s), and / or;
- compaction of AP with possibly one or more agent (s) D or excipient (s) pharmaceutically acceptable, and / or;
PA sputtering, possibly with one or more agent (s) D or pharmaceutically acceptable excipient (s), in dispersion or in solution in a aqueous or organic solvent on a neutral support or agent D particles, and or ;
sieving of powder or PA crystals;

b) preparing microparticles reservoir of PA by:
- Spraying in a fluidized air bed of a solution or dispersion containing one or several compounds Al, A2, A3 and possibly one or more compounds A4 and or D on the microparticles of PA; the microparticles of AP may have been at prior coated with one or more agents D; PA microparticles coated may optionally be coated with one or more agents D;
c) prepare the final form of the drug by:
granulation and / or extrusion / spheronization of microparticles PA
with D, V and Q agents for capsule or sachet; or - mixture of microparticles tank PA with possibly one or many agent (s) D, V and Q and pharmaceutically acceptable excipients for obtaining a tablet; this tablet may optionally be embedded in a turbine coating by one or more layers containing the agent D and / or excipients pharmaceutically acceptable; or - Put in capsule of microparticles reservoirs of PA, V and Q; the capsules may optionally be embedded in a turbine or fluidised air bed by a or several agent (s) D and / or pharmaceutically acceptable excipients; or - Packing of reservoir microparticles of PA, V and Q with optionally one or more agent (s) D and / or pharmaceutically acceptable excipients acceptable.

The invention also relates to a method of treating pain comprising administration of a pharmaceutical form as described above, to a patient in need.
The invention further relates to a method for preventing the misuse of a principle active, in particular analgesic or opioid, including the implementation of a form pharmaceutical as described 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 its variants of implementation and / or implementation, as well as its different advantages.
EXAMPLES
EXAMPLE 1 Embodiment According to the Invention of Oxycodone Microparticles HC1 Anti-broya2e.

Granulate:
1615 g of oxycodone HC1 are added with a solution containing 85 g of Methocel E5 (hypromellose / Dow), 2052 g of demineralised water and 1105 g ethanol.
The whole is stirred at 67 C. The solution is then sprayed in one Glatt GPCG 1.1 fluidized bed apparatus on 300 g of Xantural 180 (Xanthan gum / Danisco) sifted between 50 and 180 m. The recovered product is then sieved over 80-300 m.

Microparticles:
495 g of the granules prepared above are then film-coated in an apparatus read of Glatt GPCG 1.1 fluidized air with a solution containing 296 g of Ethocel 20 Premium (Ethylcellulose / Dow), 24 g of Plasdone K29 / 32 (povidone / ISP), 49 g of Cremophor RH 40 (PEG40-hydrogenated castor oil / BASF), 41 g castor (Garbit oil mill), 2795 g of acetone and 1863 g of isopropanol.
The mass of the coating represents 45% of the total mass of the microparticle MR
of oxycodone HC1.

Example 2: Pharmaceutical form according to the unpublished application FR0553437 55 g of microparticles prepared in Example 1 are mixed with 18 g of Polyox WSR303 (polyethylene oxide / Dow) sieved between 150 and 300 m, 26 g of Amberlite IR69F (Rhom & Haas) crushed and sieved between 160 and 300 m, 0.5 g Aerosi1200 (colloidal silica / Degussa) and 1 g of magnesium stearate.
405 mg of this mixture is introduced into size 0 gelatin capsules.
This capsule is placed in a large volume (500 ml) of 40% solution ethanol and the percentage released after 0.5 and 1 hour of agitation is measured:

Oxycodone time released (h) (%) 0.5 19 These results show that in the presence of a large amount of solution alcoholic, the amount of oxycodone released is relatively high after one hour.
it may pose a risk to the patient, which is why the applicant has look for develop a slower release form in the presence of alcohol.

Example 3 Bryo2e Test on Oxycodone Microparticles HC1 The microparticles prepared in Example 1 are lubricated with 1.0% of stearate 5 mg and 0.5% Aerosil.
These microparticles, 197 mg corresponding to a dose of 80 mg of oxycodone HC1, are introduced into a dissolutest, either (INTACT), be strongly crushed for 2 minutes with a mortar and pestle (CRUSHED).
The results of the dissolution test in 900 ml of HC10.1 N (D in%) in function of time (t in h) intact and crushed doses are reported in Figure 1.
Profiles of dissolution are very close, with a slightly faster release while the first minutes in the case of crushed microparticles; then the profiles are Similar.
Example 4 Preparation of 2 capsules according to the invention Mixed :
55 g of microparticles prepared in Example 1 are mixed with 18 g of Polyox WSR303 (polyethylene oxide / Dow) sieved between 150 and 300 m, 26 g of Amberlite IR69F (Rhom & Haas) ground and sieved between 160 and 300 m, 0.5 g aerosil 200 (colloidal silica / Degussa) and 1 g of magnesium stearate. The mixture is homogenized for 15 minutes.

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

Coating capsules:
The above capsules are then coated with 16 mg per capsule of Blanose (sodium carboxymethylcellulose / Aqualon) previously dissolved at 6% (m / m) in demineralised water.

Dissolution tests in 900 ml of 0.1N HCl and (40% EtOH, 0.1 N HCl) 60%) are shown in Figure 2. It can be seen that in ethanolic solution, the kinetics of dissolution is considerably slowed down.

EXAMPLE 5 Mesusa2e Test on the Content of the 2-Capsule of Example 4 In the following misuse tests, the contents of a capsule as described in Example 4 is first ground by means of a tablet pulverizer (LGS pill crusher) then brought into the presence of 10 ml of solvent and left stirring.
min to ambient temperature.
The mixture is then removed by means of an insulin syringe through a filter 0.45 m. The quantities of oxycodone HC1 recovered are analyzed by HPLC.
The results of the extractions tests are reported in Table 1.

Table 1 Oxycodone solvent extracted (%) isopropanol170% 0 0.02 diethyl ether ethyl acetate 1.9 ethanol 13.7 acetone 1.1 cooking oil <0.01 The quantities extracted are less than 15% of the dose.

Example 6: Production of tablets according to the invention 10 g of the oxycodone microparticles prepared in Example 1, 5 g of Amberlite IR69F (Rhom & Haas) sieved between 160 and 300 m, 2.5 g Polyox WSR 303, 10 g of Avicel PH 101 (microcrystalline cellulose / FMC), 5 g of Methocel A15 (Methylcellulose / Dow) and 0.25 g of magnesium stearate are mixed and tablets. The mass of the tablets is 655 mg.
The dissolution tests of these tablets in 900 ml of 0.1N HCl and (EtOH 40 %;
HC1 0.1N 60%) are reported in Figure 3. It is found that the release in one alcoholic medium is slower than in an aqueous medium.

Example 7 Production According to the Invention of Oxycodone Microparticles HC1 Anti-broya2e.

Granulate:
1582.7 g of oxycodone HCl are added in a solution containing 83.3 g of Plasdone K29 / 32 (povidone / Dow), 2011.1 g demineralized water and 1082.9 g ethanol. The whole is stirred at 67 C. The solution is then sprayed in a Glatt GPCG fluidized air bed apparatus 1. 1 over 300 g of particles of cellulose spheres (Asahi-Kasei). The recovered product is then sieved on 80-300 m.

Microparticles:
450 g of the granules prepared as indicated above are then film-coated in one Glatt GPCG 1.1 fluidized bed apparatus with a solution containing 315 g of Ethocel 20 Premium (ethylcellulose / Dow), 36 g of Plasdone K29 / 32 (povidone /
ISP), 54 g of Lutrol F-68 (Poloxamer 188 / BASF), 45 g of castor oil (Garbit oil mill), 3105 g of acetone and 2070 g of isopropanol. The mass of the coating represents 50% of the total mass of the microparticle MR oxycodone HC1.

Example 8: Production of tablets according to the invention 11 g of oxycodone microparticles prepared in Example 7, 4 g of Amberlite (Rhom & Haas) sifted between 160 and 300 m, 2 g of Polyox WSR 303, 8 g of talcum (Luzenac 00), 4 g of Methocel A15 (methylcellulose / Dow) and 0.5 g of stearate of magnesium are mixed and then compressed. The mass of the tablets is 590 mg.
The dissolution tests of these tablets in 900 ml of 0.1N HCl and (EtOH 10%;
HC10.1N 90%) are reported in Figure 4. The release rate in a middle containing 10% ethanol is comparable or even slower than that obtained in a purely aqueous medium.

Example 9: Production of tablets according to the invention 11 g of oxycodone microparticles prepared in Example 7, 4 g of Amberlite (Rhom & Haas) crushed and sifted between 160 and 300 m, 2 g pol (ethylene oxide (Polyox WSR 303 / Sentry), 5 g of talc (Luzenac 00), 2 g of methylcellulose (Methocel A15 / Dow), 2 g of hydroxyethylcellulose (Natroso1250G / Aqualon), 3 boy Wut of microcrystalline cellulose (Avicel PH200 / FMC) and 0.5 g of stearate magnesium are mixed and then compressed. The mass of the tablets is 590 mg.
The dissolution tests of these tablets in 900 ml of 0.1N HCl and (EtOH 10%;
HC10.1N 90%) are shown in Figure 5. The release rate in a middle containing 10% ethanol is comparable or even slower than that obtained in a purely aqueous medium.

Example 10: Production of tablets according to the invention 10 g of oxycodone microparticles prepared in Example 1, 5 g of Amberlite (Rhom & Haas) ground and sieved between 160 and 300 m, 2.5 g of polyoxide ethylene (Polyox WSR 303 Sentry), 10 g of microcrystalline cellulose (Avicel PH101 /
FMC) 2.5 g of hypromellose (Methocel E15 / Dow), 2.5 g of hypromellose (Methocel E5 /
Dow), and 0.25 g of magnesium stearate are mixed and then compressed. The mass tablets is 655 mg.

The dissolution tests of these tablets in 900 ml of 0.1N HCl and (40% EtOH;
HC10.1N 60%) are shown in Figure 6.

EXAMPLE 11 Embodiment According to the Invention of Oxycodone Microparticles HC1 anti-broya2e.

Granulate:
1615 g of oxycodone HC1 are added in a solution containing 85 g of Plasdone K29 / 32 (povidone / ISP), 2052 g of demineralized water and 1105 g of ethanol. The all is stirred at 67 ° C. The solution is then sprayed into a device to Glatt GPCG 1.1 fluidized air bed on 300 g of Cellets particles 90 (spheres of cellulose / Pharmatrans). The recovered product is then screened over 80-250 m.

Microparticles:
450 g of the granules prepared above are then film-coated in an apparatus read of Glatt GPCG 1.1 fluidized air with a solution containing 315 g of Ethocel 20 Premium (Ethylcellulose / Dow), 54 g of Plasdone K29 / 32 (povidone / ISP), 27 g of Cremophor RH 40 (PEG40-hydrogenated castor oil / BASF), 54 g castor (Garbit oil mill), 3105 g of acetone and 2070 g of isopropanol.
The mass of the coating represents 50% of the total mass of the microparticle CR
of oxycodone HC1.

EXAMPLE 12: Production of tablets according to the invention 55 mg of oxycodone microparticles prepared as example 11, 20 mg of Amberlite IR69F (Rhom & Haas) sieved 160-300m, 40mg Polyox WSR 303, 120mg of Avicel PH 301 (microcrystalline cellulose / FMC), 10 mg of Methocel A15LV
(methylcellulose / Dow), 5 mg of Klucel HXF (hydroxypropyl cellulose /
Aqualon) 5 mg magnesium stearate, 185 mg Pearlitol SD200 (mannitol / rocket) and 25 mg of sodium bicarbonate (Merck) are mixed and then compressed using a Korsch XP press 1.
These tablets have slower release kinetics in the presence of 20%
of ethanol only in a purely aqueous medium (0.1N HC1) (Figure 7).

Claims (69)

1. Oral pharmaceutical form comprising microparticles of the type tank at modified release of at least one active ingredient (AP), characterized in that what resists the immediate discharge of the PA dose in the presence of alcohol and in this what includes anti-misuse means. 2. The multimicroparticulate pharmaceutical form according to claim 1, characterized in that said anti-misuse means comprise at least anti-grinding means. 3. Pharmaceutical form according to claim 1 or 2, characterized in that:
- the means preventing the immediate discharge of the dose of PA in the presence of alcohol comprise an agent D which is a pharmaceutically active compound acceptable whose speed or ability to hydrate or solvate is greater in middle aqueous alcohol-free only in alcoholic solution; and at least part of the AP is contained in coated microparticles having a coating layer R which provides the modified release of the AP
and which, at the same time, gives the coated PA microparticles resistance at grinding. 4. Pharmaceutical form according to any one of claims 1 to 3 comprising in addition, at least one viscosifying agent V capable of preventing the extraction of the AP
contents in PA coated microparticles with modified release of AP. 5. Pharmaceutical form according to any one of claims 1 to 4 comprising in addition at least one sequestering agent forming, in aqueous solution or hydroalcoholic, a weakly soluble complex with PA. The pharmaceutical form according to claim 3, and optionally one any of the other preceding claims, wherein agent D is selected in the following product group:
cellulosic derivatives such as, for example:
.cndot. methylcellulose, .cndot. (hydroxy) (alkyl) celluloses (for example hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), .cndot. carboxyalkylcelluloses (for example carboxymethylcellulose) and their salts, .cndot. celluloses (powder or microcrystalline), .cndot. crosslinked carboxyalkylcelluloses: carboxymethylcelluloses crosslinked (eg croscarmellose sodium), polyalkylene oxides (for example polyethylene oxide or polypropylene oxide), polysaccharides, for example:
.cndot. native starches (eg corn, wheat or potato) or modified (for example with sodium glycolate), .cndot. alginates and their salts such as sodium alginate, .cndot. potassium polacrilin, .cndot. guar gums, .cndot. carrageenans, .cndot. pullulans, .cndot. pectins, .cndot. chitosans and their derivatives, .cndot. and their mixtures, proteins, for example:
.cndot. gelatin, .cndot. albumins, .cndot. casein, .cndot. lactoglobulins, .cndot. and their mixtures, clays, such as bentonite, laponite, - and their mixtures. The pharmaceutical form according to claim 6, wherein the agent D is selected in the following product group:
hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) celluloses and their salts, - guar gums, - carrageenans, - and their mixtures. The pharmaceutical form according to claim 6 or 7, wherein:
the agent D is a constituent of the heart of PA (or microparticle of PA not coated) is :
.cndot. in the neutral support of each microparticle and / or .cndot. in a layer containing the PA deposited on the neutral support of the microparticle and or .cndot. in a granule containing the PA; and or the agent D is a constituent of the coating of the microparticles of PA; and or the agent D is in mixture with the microparticles; and or agent D is one of the outer constituents of a monolithic form. The pharmaceutical form according to claim 8, wherein agent D
is present in the heart of PA at 5% to 70% w / w, preferably 15%
at 60%
p / p, of the total mass of the heart of PA. The pharmaceutical form according to claim 8 or 9, wherein Agent D
is present in the coating of the microparticles at a rate of 3% to 30% w / w, preferably 10% to 20% w / w, of the total weight of the coating. Pharmaceutical form according to one of Claims 8 to 10, in agent D is present in a mixture with the microparticles, Reason to 0.5% to 30% w / w, preferably 0.5% to 25% w / w, and more preferably again from 1% to 20% w / w, of the total mass of the unit form. 12. Pharmaceutical form according to claim 3, and optionally according to Moon any of the other preceding claims, wherein the R coating comprises:
at least one (co) film-forming polymer A1 that is insoluble in the liquids of the tube digestive;
at least one soluble (co) polymer A2 in the liquids of the digestive tract;
at least one plasticizer A3;
- optionally at least one surfactant and / or a lubricant and / or a charge mineral and / or organic filler A4. Pharmaceutical form according to claim 12, wherein:
A1 is chosen from the group comprising:

.cndot. non-water soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate, .cndot. acrylic polymers, for example acid copolymers (meth) acrylic and alkyl ester (eg methyl) copolymers ester of acrylic and methacrylic acid carrying at least one ammonium group quaternary (preferably at least one copolymer of alkyl (meth) acrylate and trimethylammonioethyl methacrylate chloride) and more specifically the products marketed under the trade names Eudragit ® RS and / or Eudragit ® RL
.cndot. polyvinylacetates, .cndot. and their mixtures;
A2 is chosen from the group comprising:
.cndot. the nitrogenous (co) polymers, preferably in the group consisting of polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and the poly-N-vinyl lactams, .cndot. the water-soluble derivatives of cellulose, .cndot. polyvinyl alcohols (PVA), .cndot. alkylene polyoxides, preferably ethylene polyoxides (POE), .cndot. polyethylene glycols (PEG), .cndot. and their mixtures;
A3 is selected from the group consisting of:
.cndot. esters of cetyl alcohol, .cndot. glycerol and its esters, preferably in the following subgroup:
glycerides acetyl, glyceryl monostearate, glyceryl triacetate, glyceryl tributylate, .cndot. phthalates, preferably in the following subgroup:
dibutyl phthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, .cndot. citrates, preferably in the following subgroup:
acetyltributylcitrate, acetyltriethyl citrate, tributyl citrate, triethyl citrate, .cndot. sebacates, preferably in the following subgroup:
diethyl sebacate, dibutyl, .cndot. adipates, .cndot. azelates, .cndot. benzoates, .cndot. vegetable oils, .cndot. fumarates, preferably diethylfumarate, .cndot. malates, preferably diethyl malate, .cndot. oxalates, preferably diethyloxalate, .cndot. succinates, preferably dibutylsuccinate, .cndot. butyrates, .cndot. esters of cetyl alcohol, .cndot. malonates, preferably diethylmalonate, .cndot. castor oil (the latter being particularly preferred), .cndot. and their mixtures;
A4 is chosen from the group comprising:
.cndot. anionic surfactants, preferably in the subgroup of alkaline salts or alkaline earth fatty acids, stearic and / or oleic acid being preferred, .cndot. and / or nonionic surfactants, preferably in the subgroup next :
.cndot. polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, .cndot. polyoxyethylene-polyoxypropylene (poloxamer) copolymers, .cndot. polyoxyethylenesorbitan esters, .cndot. polysorbates, .cndot. polyoxyethylenated castor oil derivatives, .cndot. stearates, preferably calcium, magnesium, aluminum or of zinc, .cndot. stearyl fumarates, preferably sodium, .cndot. the glycerol behenates, .cndot. talc, .cndot. colloidal silica, .cndot. titanium oxide, magnesium oxide, .cndot. bentonite, .cndot. microcrystalline cellulose, .cndot. kaolin, .cndot. aluminum silicate, .cndot. and their mixtures. The pharmaceutical form according to claim 13, wherein:
A1 is chosen from the group comprising the non-water-soluble derivatives of the cellulose, preferably ethylcellulose and / or cellulose acetate, A2 is chosen from the group comprising:
~ 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, ~ polyethylene glycols (PEG), ~ and their mixtures;
A3 is selected from the group comprising: triethyl citrate, dibutylsébaçate, vegetable oils, castor oil and mixtures thereof;
A4 is chosen from the group comprising: nonionic surfactants, preferably in the following subgroup:
~ Polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, ~ the polyoxyethylene-polyoxypropylene (poloxamer) copolymers, ~ the polyoxyethylenated sorbitan esters, polysorbates, stearates, preferably magnesium, ~ and their mixtures. 15. The pharmaceutical form according to any one of claims 12 to 14, in which for each constituent A1, A2, A3 and A4 of the coating layer R, his mass m (in% of the total mass A1 + A2 + A3 + A4) verifies:
for A1: 10 <= m <= 90, preferably 15 <= m <= 80, and more preferably <= M <= 80;
for A2: 2 <= m <= 50, preferably 3 <= m <= 40, and more preferably <= m <= 25;
for A3: 1 <= m <= 30, preferably 2 <= m <= 20, and more preferably <= M <= 15;
for A4: 0 <= m <= 40, preferably 0 <= m <= 30, and more preferably 0 <= m <= 20. Pharmaceutical form according to one of Claims 12 to 15, in which the coating layer R represents a mass fraction Tp, expressed in percentage 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. Pharmaceutical form according to claim 4, and optionally according to Moon any of the other preceding claims, wherein at least one agent viscosifier V is selected from the viscosifiers soluble in least one solvents: water, alcohols, ketones and their mixtures, this agent viscosifying V being able to increase the viscosity of the extraction solvent so as to upset misuse, particularly by injection. 18. Pharmaceutical form according to claim 4, and optionally according to Moon any of the other preceding claims, wherein the agent viscosifier V
is selected from the following polymer groups:
poly (meth) acrylic acids and their derivatives, and / or polyalkylene glycols (for example polyethylene glycol), and / or polyalkylene oxides (for example of ethylene), and / or polyvinylpyrrolidones, and / or gelatines, and / or the polysaccharides, preferably in the subgroup comprising:
Alginate sodium, pectins, guars, xanthans, carrageenans, gellanes and derived from cellulose (eg hypromellose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose), - and their mixtures. 19. The pharmaceutical form according to claim 18, wherein the agent Viscosifier V is selected from the following groups of polymers:
- alkylene polyoxides (eg polyethylene oxide), and / or - xanthans and / or cellulose derivatives (especially hydroxypropyl-cellulose) - and their mixtures. 20. The pharmaceutical form according to any one of claims 17 to 19, in which at least one viscosifying agent V is present:
- in microparticles, 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 any one of claims 17 to 20, in which the viscosifier V is at least partly in the form of microparticles distinct but non separable PA microparticles 22. Pharmaceutical form according to any one of claims 17 to 21, in the amount of agent V is adjusted to make the viscosity of 2.5 mL
of extraction solvent greater than or equal to 100 mPa.s. 23. Pharmaceutical form according to any one of claims 17 to 22, in which viscosifier V is a polyoxyethylene having a high weight molecular weight, for example having a molecular weight of 1 million g / mol to 8 million g / mol. 24. Pharmaceutical form according to claim 5, 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 salt of PA extracted in solution. 25. The pharmaceutical form according to claim 24, wherein the ions of the sequestering agent Q are organic ions of opposite polarity to that of PA in solution, and which form a complex with PA salt extracted in solution. 26. The pharmaceutical form according to claim 24 or 25, 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. 27. Pharmaceutical form according to any one of claims 24 to 26, comprising PA salt microparticles and agent microparticles sequestering Q. 28. The pharmaceutical form according to claim 27, wherein said microparticles have a similar size distribution, a density similar and are not separable from each other by sieving. 29. The pharmaceutical form according to claim 25, wherein the ion of polarity opposite to that of PA in solution is an organic anion. Pharmaceutical form according to any one of claims 24 to 28, in which the sequestering agent Q comprises a salt selected from the group comprising:
anionic organic salts, such as sodium dodecyl sulfate or docusate sodium;
anionic polymers, such as (meth) acrylic copolymers (for example example Eudragit® S and Eudragit® L), crosslinked acrylic polyacids (for example Carbopol), carboxymethylcellulose and its derivatives, carboxymethylcellulose reticulate and its derivatives and other polysaccharides (e.g., alginate, rubber xanthan or arabic), alginate (sulfonate) propylene glycol;
mono- or polyvalent salts, such as glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;
saponified fatty acids, such as the salts of acetic acid, succinic acid, citric, stearic, palmitic, and self-emulsifying glyceryl mono-oleates;
polyamino acids, proteins or peptides, such as albumins, caseins, globulins and enzymes;
- and their mixtures. The pharmaceutical form according to claim 24 or 25, wherein the ion of opposite polarity to that of PA in solution is a metal cation, organic, or of their mixtures. Pharmaceutical form according to any one of claims 24 to 28, in which the sequestering agent Q comprises a salt selected from the group comprising:
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, succinate, sulfonamides, tartrates;
organic cationic salts, such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium;
cationic polymers, such as chitosan and copolymers (meth) acrylics (eg Eudragit ® RS, Eudragit ® RL or Eudragit ® E);
polyamino acids, proteins or peptides;
- and their mixtures. 33. Pharmaceutical form according to any one of claims 24 to 28, in which the sequestering agent Q is a salt of an ion exchange resin, preference, a strongly acidic cation exchange resin when the PA is cationic, or a strongly basic anion exchange resin, when PA is anionic. 34. The pharmaceutical form according to claim 33, wherein the agent sequestering agent Q is a derivative of a copolymer of styrene and divinylbenzene. The pharmaceutical form according to claim 33, wherein the agent sequestering agent Q is a derivative of a copolymer of styrene and divinylbenzene sulfonic acid. 36. The pharmaceutical form according to claim 33, wherein the agent sequestering agent Q is a derivative of a copolymer of styrene and divinylbenzene carrier of quaternary ammonium functions. 37. The pharmaceutical form according to claim 33, wherein the agent sequestering agent is a crosslinked copolymer of methacrylic acid and divinylbenzene or one of its salts. 38. The pharmaceutical form according to claim 33, wherein the resin Ion exchange is a phenolic polyamine. Pharmaceutical form according to one of Claims 24 to 38, in which sequestering agent Q is chosen from:
anionic organic salts, such as sodium dodecyl sulfate or docusate 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 exchange, depending on the polarity of the PA. 40. Pharmaceutical form according to any one of claims 24 to 39, 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. 41. The pharmaceutical form according to any of claims 24 to 40, in which the amount of sequestering agent is adjusted to complex all or part of the dose of PA contained in the unit form. 42. Pharmaceutical form according to any one of the preceding claims comprising at least one excipient in the free state, that is to say not contained in, nor supported by PA microparticles, said excipient contributing to the resistance to grinding the coated PA microparticles. 43. Pharmaceutical form according to any one of the claims preceding, comprising:
a) a PA at least a part of which is contained in microparticles individually coated with a coating R ensuring the modified release of the PA and simultaneously imparting resistance to grinding of PA microparticles where, for each constituent A1, A2, A3 and A4 of the coating R, its mass m (in% of the total mass A1 + A2 + A3 + A4) verifies:
for A1: 10 <= m <= 90, preferably 15 <= m <= 80, and more preferably <= M <= 80;
for A2: 2 <= m <= 50, preferably 3 <= m <= 40, and more preferably <= m <= 25;
for A3: 1 <= m <= 30, preferably 2 <= m <= 20, and more preferably <= M <= 15;
for A4: 0 <= m <= 40, preferably 0 <= m <= 30, and more preferably 0 <= m <= 20;
b) at least one agent D which is present at a level of 0.5 to 30% w / w, preference of 0.5% to 25% w / w, and more preferably still 1% to 20% w / w, of the mass total of the unitary form;
c) optionally at least one viscosifying agent V present in a proportion of 2 to 400 mg of preferably from 5 to 200 mg, and still more preferably from 10 to 100 mg per form unitary;
d) optionally at least one sequestering agent Q whose quantity is adjusted to to trap all or part of the dose of PA contained in the unitary form, the agent sequestering Q being included in a separate phase distinct from the phase containing the PA salt. 44. The pharmaceutical form according to claim 43, comprising microparticles viscosifying agent V distinct from the microparticles of PA. 45. The pharmaceutical form according to claim 43 or 44, comprising microparticles of viscosifier V and microparticles of PA, said microparticles with similar size distribution, density similar and not being separable from each other by sieving. 46. The pharmaceutical form according to any one of claims 43 to 45, in which the coating layer R contains the following components:
A1 is chosen from the group comprising the non-water-soluble derivatives of the cellulose, preferably ethylcellulose and / or cellulose acetate, A2 is chosen from the group comprising:
.cndot. the nitrogenous (co) polymers, preferably in the group consisting of polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams, .cndot. the water-soluble derivatives of cellulose, .cndot. polyethylene glycols (PEG), .cndot. and their mixtures;
A3 is selected from the group comprising: triethyl citrate, dibutylsébaçate, vegetable oils, castor oil and mixtures thereof;
A4 is chosen from the group comprising: nonionic surfactants, preferably in the following subgroup:
.cndot. polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, .cndot. polyethylene oxide-propylene polyoxide copolymers (Poloxamer), .cndot. polyoxyethylenesorbitan esters, .cndot. polysorbates, .cndot. stearates, preferably magnesium, .cndot. and their mixtures. 47. The pharmaceutical form according to any one of claims 43 to 46, in agent D is selected from the following group of products:
hydroxyalkylcelluloses (for example hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), methylcellulose, carboxy (alkyl) celluloses, and their salts - guar gums, - carrageenans, and their mixtures. 48. The pharmaceutical form according to any one of claims 43 to 47, in which viscosifier V is chosen from:
- alkylene polyoxides (eg polyethylene oxide), and / or - xanthans and / or cellulose derivatives (especially hydroxypropyl-cellulose) - and their mixtures. 49. The pharmaceutical form according to any one of claims 43 to 48, in which sequestering agent Q is chosen from:
anionic organic salts, such as sodium dodecyl sulfate or docusate sodium;
cationic organic salts, such as ammonium salts quaternaries, trimethyl tetradecyl ammonium bromide or benzethonium;
ion exchange resins, preferably a strongly acidic resin exchange of cations or a strongly basic anion exchange resin. 50. The pharmaceutical form according to any one of claims 43 to 49, 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 PA is anionic. 51. The pharmaceutical form according to any one of claims 43 to 50, who is present in a tablet unit form, comprising:
a) a PA at least a part of which is contained in microparticles individually coated with a coating R ensuring the modified release of PA and simultaneously conferring resistance to grinding of microparticles of PA coated, where for each component A1, A2, A3 and A4 the coating layer R, its mass m (in% of the total mass A1 + A2 + A3 + A4) checks for A1: 10 <= m <= 90, preferably 15 <= m <= 80, and more preferably <= M <= 80;
for A2: 2 <= m <= 50, preferably 3 <= m <= 40, and more preferably <= m <= 25;

for A3: 1 <= m <= 30, preferably 2 <= m <= 20, and more preferably <= m <= 15;
for A4: 0 <= m <= 40, preferably 0 <= m <= 30, and more preferably 0 <= m <= 20;
b) at least one agent D is present in a mixture with the microparticles to reason from 1 to 30% w / w, preferably from 2% to 25% w / w, and more preferably still 2% to 20% w / w, of the total mass of the unit form;
c) at least one viscosifying agent V contained in microparticles separate microparticles of PA, at a rate of 2 to 400 mg, preferably from 5 to 200 mg, and even more preferably from 10 to 100 mg, per unit form, d) possibly at least one sequestering agent Q contained in distinct microparticles of PA microparticles and viscosifier;

the amount of sequestering agent being adjusted in ionic charge, in order to trap all or part of the dose of PA contained in the unit form;
e) optionally compressional excipients. 52. The pharmaceutical form according to claim 51, comprising at least one agent sequestering Q. 53. Pharmaceutical form according to any one of Claims 43 to 50, who is present in a unitary capsule form, comprising:
a) an AP at least part of which is contained in microparticles individually coated with a coating R ensuring the modified release of PA and simultaneously conferring resistance to grinding of coated PA microparticles and where for each constituent A1, A2, A3 and A4 of the coating layer R, its mass m (in% of the total mass A1 + A2 + A3 + A4) checks for A1: 10 <= m <= 90, preferably 15 <= m <= 80, and more preferably <= M <= 80;
for A2: 2 <= m <= 50, preferably 3 <= m <= 40, and more preferably <= M <= 25;
for A3: 1 <= m <= 30, preferably 2 <= m <= 20, and more preferably <= M <= 15;
for A4: 0 <= m <= 40, preferably 0 <= m <= 30, and more preferably 0 <= m <= 20; 54 b) at least one agent D, which is present at 0.5 to 20% w / w, preference from 0.5% to 15% w / w, and more preferably still from 1% to 10% w / w, of the total mass of the unit form;
c) optionally at least one viscosifying agent V contained in Separate microparticles of PA microparticles, 2 to 400 mg, preferably from 5 to 200 mg, and still more preferably from 10 to 100 mg, per unit form, d) possibly at least one sequestering agent Q contained in distinct microparticles of PA microparticles and viscosifier;

the amount of sequestering agent being adjusted in ionic charge, in order to trap all or part of the dose of PA contained in the unit form.

54. The pharmaceutical form according to claim 53, comprising at least one agent viscosifier V. 55. The pharmaceutical form according to claim 53 or 54, comprising at least a sequestering agent Q. 56. The pharmaceutical form according to any one of claims 53 to 55, comprising V-viscosifiers microparticles and / or microparticles of sequestering agent Q, the microparticles of viscosity agent V and the microparticles of sequestering agent Q being distinct from the microparticles of PA. 57. The pharmaceutical form according to any one of claims 53 to 56, comprising PA microparticles, as well as agent microparticles viscosifier V and / or microparticles of sequestering agent Q, said microparticles with similar size distribution, density similar and not being separable from each other by sieving. 58. The pharmaceutical form according to claim 42, wherein the excipient in the state free is selected from the group consisting of:
calcium stearate;
- glyceryl behenate glycerol palmitostearate;
magnesium oxide;
polyalkylene glycols and preferably polyethylene glycols;
polyvinyl alcohol;

sodium benzoate;
stearic acid;
- corn starch;
- talc;
colloidal silica;
zinc stearate, magnesium stearate;
stearyl fumarate;
- and their mixtures. 59. Pharmaceutical form according to any one of the preceding claims characterized in that the coated PA microparticles have a diameter medium in volume less than or equal to 1000 μm, preferably between 50 and 800 μm and, more preferably between 100 and 600 μm, and more preferably between 100 and 400 μm. 60. Pharmaceutical form according to any one of the preceding claims comprising at least:
PA microparticles coated with a grinding resistant coating;
an ion exchange resin;
polyoxyethylene;
- methylcellulose. 61. Pharmaceutical form according to any one of the preceding claims comprising at least:
PA microparticles coated with a grinding resistant coating;
an ion exchange resin;
polyoxyethylene;
methylcellulose;
hydroxyethylcellulose. 62. Pharmaceutical form according to claim 53, characterized in that himself present in the form of a capsule coated with a carboxyl-based agent D
sodium methylcellulose. 63. Pharmaceutical form according to claim 53, characterized in that himself present in the form of a capsule coated with a hydroxyethyl-based agent D

cellulose. 64. Pharmaceutical form according to any one of the claims preceding, comprising modified release PA microparticles and microparticles of PA immediate release. 65. Pharmaceutical form according to any one of the claims preceding, 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. 66. Pharmaceutical form according to any one of the claims preceding, wherein the active ingredient is selected from the following families:
opiates, analgesics, analgesics, antitussives, anxiolytics, benzodiazepines, appetite suppressants, antidepressants, antiepileptics, anti-migraine, antiparkinsonian, barbiturates, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropics, sedatives, amphetamines, stimulants. 67. Pharmaceutical form according to any one of the claims preceding, wherein the active ingredient is selected from the group consisting of:
acetorphine, acetylalphamethylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alpha-cetylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodine, anileridine, atropine butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, bêtaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazene, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethyl-thiambutene, difenoxine, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydro-morphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramid, morphine, morphine, myrophin, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene fluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenorpheridine, pholcodine, piminodine, piritramide, proheptazine, propranolol, properidine, propiram, racemethorphan, racemoramide, racemorphane, remifentanil, sufentanil, thbacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and their salts, esters, hydrates, polymorphs and their pharmacologically acceptable isomers, and mixtures thereof. 68. Pharmaceutical form according to any one of the claims preceding, wherein the analgesic BP is selected from the group consisting of oxycodone hydrochloride, morphine sulphate, hydrochloride oxymorphone, hydromorphone hydrochloride, hydrocodone hydrochloride, and tramadol hydrochloride. 69. Process for obtaining a pharmaceutical form according to any one of the preceding claims, in several steps consisting essentially of:
a) preparing hearts (uncoated microparticles) of AP by:
extrusion / spheronization of PA with possibly one or more agent (s) D
or pharmaceutically acceptable excipient (s), and / or;
wet granulation of PA with possibly one or more agent (s) D or pharmaceutically acceptable excipient (s), and / or;
- compaction of AP with possibly one or more agent (s) D or excipient (s) pharmaceutically acceptable, and / or;
PA sputtering, possibly with one or more agent (s) D or pharmaceutically acceptable excipient (s), in dispersion or in solution in a aqueous or organic solvent on a neutral support or agent D particles, and or ;
sieving of powder or PA crystals;
b) preparing microparticles reservoir of PA by:
- Spraying in a fluidized air bed of a solution or dispersion containing one or several compounds A1, A2, A3 and possibly one or more compounds A4 and or D on the microparticles of PA; the microparticles of AP may have been at prior coated with one or more agents D; PA microparticles coated may optionally be coated with one or more agents D;

c) prepare the final form of the drug by:
granulation and / or extrusion / spheronization of microparticles PA
with D, V and Q agents for capsule or sachet; or - mixture of microparticles tank PA with possibly one or many agent (s) D, V and Q and pharmaceutically acceptable excipients for obtaining a tablet; this tablet may optionally be embedded in a turbine coating by one or more layers containing the agent D and / or excipients pharmaceutically acceptable; or - Put in capsule of microparticles reservoirs of PA, V and Q; the capsules may optionally be embedded in a turbine or fluidised air bed by a or several agent (s) D and / or pharmaceutically acceptable excipients; or - Packing of reservoir microparticles of PA, V and Q with optionally one or more agent (s) D and / or pharmaceutically acceptable excipients acceptable.