KR20080064905A - Anti-misuse microparticulate oral pharmaceutical form - Google Patents

Abstract

The present invention relates to solid microparticulate oral pharmaceutical forms which have a composition and a structure that prevents the misuse of the active pharmaceutical ingredient (API) contained therein. The aim of the present invention is to prevent the improper use of solid oral drugs for any use other than the therapeutic use(s) officially approved by the appropriate public health authorities. In other words, it is a question of preventing the voluntary or involuntary misuse of solid oral drugs. The invention relates to a solid oral pharmaceutical form, characterized in that it comprises anti-misuse means, in that at least part of the API that it contains is contained in coated microparticles for modified API release, and in that the coated API microparticles comprise a coating layer (Ra), which ensures modified release of the API and which, simultaneously, confers resistance to crushing on the coated API microparticles, so as to prevent misuse.

Description

Misuse Prevention Microparticulate Oral Pharmaceutical Formulations {ANTI-MISUSE MICROPARTICULATE ORAL PHARMACEUTICAL FORM}

The present invention relates to oral microparticulate solid pharmaceutical formulations whose composition and structure prevent the misuse of the pharmaceutical or veterinary active ingredient (AP) they contain.

The active ingredients (AP) in question are those which are classified as pharmaceutical or veterinary AP, such as the category of paralyzing products, anesthetics or narcotics. Misuse of these pharmaceutically active ingredients can cause drug addiction.

As used herein, the expression "AP" refers to both a single active ingredient and a mixture of several active ingredients.

Microparticulate pharmaceutical formulations are understood in the present invention to mean any formulation containing microparticles up to 1000 μm. These particles containing AP may be coated microparticles for modified release of AP. In the latter case, the microparticles are covered, for example, with a polymer film that controls the release rate of the AP after oral administration.

Raise the matter

It is an object of the present invention to prevent the misuse of solid oral drugs for any use other than therapeutically officially approved by the competent health authority. That is, it is an object of the present invention to prevent spontaneous or involuntary misuse of oral solid drugs.

Misuse mainly occurs when:

a) acts of addiction (drug addiction, doping),

b) criminal activity (chemical dependence),

c) Use of the drug in a manner inconsistent with medical recommendations (dosage) due to carelessness or inability to affect the patient.

In the case of a (or even in the case of b), those who misuse oral solid drugs generally extract the AP from the modified release formulation to obtain a rapidly acting formulation and then

-By grinding it into a powder formulation for inhalation or swallowing,

It will change into a liquid formulation so that it can be injected or swallowed by a syringe.

Preparation of liquid formulations from oral solid drugs involves an intermediate step of water soluble extraction or organic extraction of the AP in question. This extraction is usually by milling.

Modes of administration by inhalation or infusion are particularly suitable for drug abusers, because these modes can enhance the effect of AP and are beneficial for absorption by organisms in a short time. When the powder obtained by grinding is inhaled, or dissolved and infused in water, the desired doping or intoxicating effect of the AP appears in a very rapid and violent manner.

Currently, there are particularly seriously undesirable behaviors related to anesthetic APs (aAP), particularly morphine and opiate derivatives, which affect teenagers. In fact, teenagers easily extract oxycodon from tablets with water and alcohol for a party, preparing a cocktail of oxycodone and vodka. This process consists of crushing the tablet and pouring the powder into vodka or water glass and then waiting for a sufficient time for the absorbable morphine derivative to be completely extracted.

Oral solid drugs can also be misused by chewing the drug before swallowing it, instead of swallowing it quickly according to the instructions for administration.

The risks associated with addiction (a) and criminal action (b) are obvious. It is pointed out that misuse of drugs by infusion is more dangerous, ie excipients may be responsible for local tissue necrosis, infections, respiratory disorders and heart disorders.

With regard to drug misuse (c) associated with carelessness and / or patient inability, this may have serious consequences. For example, chewing a modified release formulation of an AP before swallowing changes the drug into an immediate release formulation. Thus, the drug will at best lose its effectiveness after a short time and, in the worst case, will be toxic.

Therefore, there is clearly a serious public health problem associated with drug misuse, in particular solid oral drugs, in particular drugs based on anesthetics or narcotics. This growing phenomenon is of particular interest to health authorities in the United States and Europe, which calls for the development of pharmaceutical formulations to prevent misuse.

Prior art

Patent US-B-6 696 088 relates to multiparticulate oral pharmaceutical formulations which are indicated to resist abuse. It contains particles of opioid agonist AP and particles containing opioid antagonists in modified release formulations. Formulations containing antagonists are described to release up to 36%, preferably up to 6.2%, of antagonist AP for at least 36 hours. The two types of particles are dispersed with each other.

If misused, the microparticles are ground to extract the opioid AP, resulting in immediate and incidental release of the AP and its antagonist to limit the desired effect of the misused opioid.

To the understanding of the present inventors, the present invention is based on the use of an active substance other than AP, and does not propose a solution, in particular to reduce the effect of grinding or to reduce AP extraction.

Patent application US-A-2003 / 0068371 describes an oral pharmaceutical formulation containing an opiate AP (oxycodone), an antagonist (Naloxone) and a gel former (eg xanthan gum) of this AP. In particular, the US patent application discloses a matrix granule of AP containing outer coating, povidone, xanthan gum and lactose, on the basis of EUDRAGIT RS 30D ^® / triacetin / antagonist. Gel formers have been shown to provide viscosity to formulations so that formulations can be administered nasally and parenterally. The inventors understand that this answer is insufficient because the use of antagonists is particularly essential in the invention. Finally, this formulation does not contain any anti-crushing means and can be converted into a powder and misused by nasal or oral route.

Patent application WO-A-03 / 013479 describes oral pharmaceutical formulations containing therapeutically effective amounts of opiate anesthetics and opiate antagonists (naltrexone), and bittering agents. When the drug addict grinds the tablet, the opioid and its antagonist are released. The effect of opioids is then neutralized. To the understanding of the present inventors, it is not possible with this system to inhibit the selective extraction of water and opioids, especially without grinding.

In general, one does not resort to antagonists without disadvantages in terms of possible medical risks operated by the user and the risk of inhibiting the intended therapeutic effect.

Patent application WO-A-2004 / 054542 describes a semi-flow oral pharmaceutical formulation. This probably takes the form of a capsule (eg gelatin capsule) containing AP on a matrix composed of a polymer (cellulose acetate butyrate) and a high viscosity water insoluble liquid (sucrose acetate isobutyrate) forming a network in the liquid phase. The formulation may contain a solvent and a compound that modify the rheology of the pharmaceutical formulation, if necessary. By modifying a compound that is different from the concentration of the formulation, the inventor states that it is possible to modify the plasma profile of the AP (oxycodone based) administered to the dog. To the best of our understanding, this reference does not provide a solution which, in particular, prevents misuse by injection, since the viscosity of this formulation drops sharply even with the addition of small amounts of ethanol.

Patent application US-A-2003 / 0224051 describes osmotic delivery formulations for modified release of oxycodone. The formulation consists of a tablet comprising one of the oxycodone cores or salts thereof, a semipermeable membrane at least partially surrounding the core and an exit orifice in the membrane capable of releasing oxycodone. Tablets of this type can be easily extracted, for example by soaking in water for at least 12 hours. For the understanding of the present inventors, this tablet is not a suitable solution to the problem of misuse.

Patent application EP-A-1293209 describes a misuse preventive oral solid formulation which delays the release of opioid derivatives (AP) contained in ion exchange resins. The resulting AP / resin complex makes it possible to limit plasma concentrations obtained after abuse by chewing, inhalation or injection to therapeutic concentrations below the concentrations sought by the abuser. This AP / resin complex takes the form of a matrix. To the understanding of the present inventors, no pharmaceutical means are provided for pharmaceutical formulations according to the prior art documents. Moreover, the pharmaceutical formulation does not contain any means to prevent AP solvent extraction. Therefore, even if the extraction time is longer than the normal AP release time, solvent extraction of the AP cannot be prevented. If the oral pharmaceutical formulation is placed in a glass of water for 24 hours, most of the drug will be extracted.

Patent applications US-A-2003 / 0118641 and 2005/0163856 (= WO-A-01 / 08661) describe oral pharmaceutical formulations which delay the release of APs consisting of opioid compounds (anesthetics) and salts thereof. have. These formulations seem to prevent misuse by extracting AP with conventional solvents. Although this possibility can be foreseen to flow even further, these anti-misuse formulations do not contain antagonists. These formulations

Hydrophilic matrix preparation (hydroxyalkyl cellulose) in an amount of from 40 to 65% by weight,

Ion exchange resins (particles up to 50 μm in an amount of from 5 to 15% by weight),

Contains a mixture of one or more opiate APs.

After the addition of the usual compression additives, the mixture is converted to tablets.

It is therefore a macroscopic matrix system comprising particles of an ion exchange resin complexed with an AP and an anti-extraction means consisting of a viscosifier, preferably hydroxypropyl methyl cellulose. For the understanding of the present inventors, this system can be improved in particular in terms of the prevention of misuse.

The inserted patent document WO-A-2005 / 079760 describes a pharmaceutical formulation consisting of elastic microparticles of an AP obtained by ejection, which has the property of delaying the release of AP and preventing misuse. These ejected microparticles comprise a matrix formed of an internal poly (ethylacrylate / methyl methacrylate) copolymer, ie EUDRAGIT® NE 30D or NE 40D. This matrix contains AP (oxycodone), another Eudragit®, RS PO, plasticizer and lubricant.

Misuse is prevented by anti-crushing means, which include the elastic characteristics of the matrix particles for the modified release of the AP. For the understanding of the present inventors, there is no means provided to prevent the extraction of AP in the solvent medium.

When the present inventors understand the prior art, none of the anti-naming solutions proposed so far are satisfactory in terms of preventing exploitation of the AP with water, alcohol or other portable solvent.

Purpose of the Invention

Under these circumstances, one of the objects of the present invention is to overcome the insufficiency of the prior art.

Another object of the present invention is, if not impossible, especially in the case of (a) (b) (c) described above, in addition to AP or AP inhibitors such as AP antagonists, which may be dangerous to the user due to pharmaceutical activity. To provide a novel oral solid drug that will be difficult to misuse regardless of the substance.

Another object of the present invention is, if not impossible, a novel oral use, in particular in the case of (a) (b) (c) above, which would be difficult to misuse even after "long-time" liquid extraction of the AP (eg anesthetic). To provide a solid drug. In the present specification, "long time" liquid phase extraction is extraction that lasts 10 minutes or more. Another object of the present invention is to provide a novel oral solid drug which prevents misuse by short-term liquid extraction and / or grinding.

Another object of the present invention is to provide a novel oral solid drug having the following characteristics.

Under ordinary conditions of administration, these oral solid drugs have a therapeutic effect, for example 12 or 24 hours.

Attempts to extract misuse of the AP (eg, anesthetic) will cause the drug to convert into a form in which it is impossible for the AP to be rapidly absorbed into the bloodstream after it is ingested.

Another object of the present invention

-Can be easily administered to patients who have difficulty swallowing large tablets, for example seriously ill patients, infants or children,

It is possible to combine several APs in one or the same dosage unit, even if they are not mutually compatible and / or the release rates are not the same.

To provide a novel oral solid drug, which may exist in a form that can be administered more than once a day, in which it is easy and independent to control the time and release rate of different APs.

Another object of the present invention is to provide a novel oral solid drug whose in vitro dissolution profile is independent of the dosage of AP.

Another object of the present invention is to prevent the conversion of drugs into forms that can be administered orally, nasal and / or injections (intravenously, subcutaneously, intramuscularly, etc.) beyond the therapeutic limits, thereby preventing the nature of the APs they contain. It is a novel oral solid drug that makes it possible to prevent fraudulent misuse. This will prevent or at least greatly reduce the risk associated with undesirable behavior.

It is a further object of the present invention to provide a novel method that makes it possible to ensure that a patient who is undergoing a normal follow-up has a therapeutic dose, in particular a dose consistent with that need while at the same time preventing abuse. It is to provide a solid drug for oral use.

Another object of the present invention is to make it possible to prevent misuse without impairing the patient's stability without administering additional risk to the patient using the drug, usually without affecting the pharmaceutical properties of the drug. It is to provide a novel oral solid drug.

It is yet another object of the present invention to provide a novel oral solid drug that can be administered at least once a day, limiting the risk of tissue damage due to locally concentrated AP.

Another object of the present invention is to provide a novel oral solid drug which can be administered in various herbal forms such as tablets, powder sachets, capsules and the like.

It is yet another object of the present invention to provide an anti-misuse oral solid drug that is easy to manufacture and economical.

Brief Description of the Invention

To achieve this goal, the inventors believe that the general problem of misuse of pharmaceutical formulations needs to be formulated again.

Investigating the different illegal modes of administration of the active ingredients, in fact, the grinding of the dry formulation seems to be usually an essential step.

In case of misuse by nasal administration, the dry pharmaceutical formulation must first be converted into a powder powder suitable for inhalation into the nose. Therefore, grinding of the pharmaceutical formulation is clearly an essential step.

In the case of misuse by oral administration of a delayed release dry formulation, it is necessary to finely grind the microparticles or tablets to facilitate release of the active ingredient.

In the case of misuse by parenteral administration, the AP must first be extracted into a sufficiently high concentration of liquid, in fact water or an organic solvent, in order to avoid being injected into an excessively large volume of, for example, 1 ml or more. This extraction step is facilitated by a preliminary step in which the dry formulation is ground so that the active ingredient can be dissolved or suspended. In addition, after this extraction step, misuse is possible only if the viscosity of the liquid phase is not too high (eg 100 mPa · s or less).

Thus, grinding of the dry formulation is also an essential step for misuse of the pharmaceutical formulation by parenteral administration.

Applicant,

A first problem (a) of preventing the crushing of a system containing AP and

A second problem (b), which prevents misuse of the AP after possible extraction

It is believed that the problem of preventing misuse of dry pharmaceutical formulations needs to be formulated again.

With this new approach, Applicants have surprisingly and unexpectedly employed a combination of coated microparticulate APs, pharmaceutically acceptable excipients, as needed, for spontaneous or involuntary physicochemical modes of action for modified release of APs. It has been found that it is appropriate to incorporate into the compositions of drugs that misuse should be prevented, in the form of microparticles or non-microparticles which makes it possible or even impossible to prevent misuse.

Accordingly, the present invention mainly relates to the fact that it contains a means for preventing misuse, that at least some of the APs it contains are contained in the coated microparticles for modified release of the AP, and that the coated microparticles of the AP It relates to a solid oral pharmaceutical formulation characterized by having a coating layer (Ra) which provides crush resistance to the coated microparticles of the AP to ensure modified release and at the same time prevent misuse.

The pharmaceutical formulations according to the invention solve in particular the main problems presented and fulfill at least part of the set of objectives in an efficient, simple and economic manner with the aid of physicochemical means. The latter is not entirely harmful to the average user. These are pharmaceutically inert compounds approved by public health authorities granting pharmacopoeia and drug marketing permits.

In one preferred embodiment, the oral solid pharmaceutical formulation according to the present invention makes it very difficult to extract the AP contained in the coated microparticles of the AP after liquid extraction, if it is not impossible other than the anti-crushing coating layer (Ra). It contains one or more thickeners (Vb) that prevent misuse of the AP.

As used herein, "thickener" refers to a mixture of both a single thickener and several thickeners.

Detailed description of the invention

According to the invention, at least part of the AP is in the form of a modified release formulation, ie coated microparticles for modified release of the AP.

The active ingredients (AP) of the invention are those which are classified in the category of pharmaceutical or veterinary AP, for example anesthetics or narcotics. Misuse of these APs can cause addiction.

In the present invention, "AP" refers to a mixture of one active ingredient or several active ingredients.

In the present invention, "microparticle formulation" is understood as meaning any pharmaceutical formulation in which the AP contains microparticles of 1000 microns or less. These particles containing AP may be microparticles individually coated with a film for modified release of the AP. In the latter case the microparticles are covered, for example, with a polymer based film that controls the release rate of the AP.

As used herein, "modified release formulation" means a formulation in which at least some of the active ingredient is released at a lower rate than in immediate release formulations. This portion may be between 1 and 100%, preferably between 10 and 100%, and particularly more preferably between 30 and 100%. In particular, the modified release may be in the form of sustained and / or delayed and / or one or more emission peaks (pulses). Modified release formulations are well known in the art. For example, Remington's thesis (The science and practice of pharmacy, 19eme edition, Mack publishing Co. Pennsylvania, USA).

In the present invention, "immediate formulation" refers to a formulation in which the majority of the AP it contains is released by the formulation in a short time, such as between pH 1.4 and 6.8 during in vitro dissolution testing, 70% of the AP is 1 hour, preferably The furnace is released in 30 minutes.

All ex vivo dissolution profiles cited herein are obtained from the European Pharmacopoeia 4th edition, 37 ° C. SINK conditions, under agitation at 75 rpm, type II dissolutest, named “Dissolution Test for Oral Solid Formulations”.

Therefore, the pharmaceutical formulation according to the invention is a formulation for modified release of AP.

In the present invention, "pharmaceutical formulation" is broadly understood, that is to say that the term also encompasses veterinary and nutritional formulations.

This pharmaceutical formulation may also include one or more formulations for immediate release of the AP.

Advantageously, pharmaceutical formulations according to the invention having a new structure, appearance and composition may be present in the form of, for example, tablets, powdered shashes, complex reconstituted suspension powdered shashes or capsules.

AP Cloth microparticles of

The coated microparticles for modified release of AP are advantageously microparticles each coated with one or more coatings (such as including one or more polymers) precipitated by techniques known to those skilled in the art. For example, Buri, Puisieux, Doelker and Benoit, Labrador, 1985, pp. 175-227, Formes pharmaceutiques nouvelles : aspects technologique , biopharmaceutique et medical ( New pharmaceutical forms : technological , biopharmaceutical and medical aspects )].

That is, each of these coated microparticles consists of a core comprising an AP and a coating comprising at least one coating layer surrounding (preferably completely) the core and controlling strain release (preferably continuous) of the AP. good. This release occurs when the coated microparticles of the AP come into contact with the gastrointestinal tract.

Uncoated microparticles of the AP (eg before coating) are, for example,

An inner core covered with one or more layers containing AP or

-Microparticles of pure AP or

Granules that form the matrix supporting the excipients, including the AP.

In the case of support granules, the inner core or support may consist of sucrose and / or sucrose and / or dextrose and / or lactose and / or sucrose / starch mixture. The inner core or support may also be particles of cellulose microspheres or any other pharmaceutically acceptable excipient. Particles of xanthan gum, guar gum, calcium phosphate or calcium carbonate may also be mentioned as non-limiting examples of the internal support. Their average diameter can be 10 to 200 microns, 20 to 150 microns or 50 to 100 microns.

These "storage" type coated microparticles (or individual coated microparticles) may be likened to a carrier for releasing and transporting one or more APs of the small or large intestine.

Examples that may be referred to as coated microparticles for modified release of AP are those described in the patent documents of EP-B-0 709 087 and WO-A-03 / 030878.

AP, microparticle's sheath

Advantageously, one or more cladding layers (Ra), preferably only one, which impart crush resistance to the coated microparticles of the AP while ensuring strain release of the AP to prevent misuse. Covering layer (Ra) of the layer.

Particularly preferably, the coating layer Ra is designed in such a way that non-immediate (ie deformation) is maintained for at least some of the coated microparticles for strain release of the AP upon grinding.

The grinding foreseen herein may be any grinding performed by techniques commonly used by abusers, in particular mortars / minced balls, coffee grinders, between two tablespoons, bite / chew, and the like.

In one important embodiment, the coating layer (Ra), upon pulverization, has a strain release of at least 40%, preferably at least 60% and particularly preferably at least 80% of the coated microparticles for strain release of the AP. It is designed in a way that allows for maintenance.

Specifically, the anti-crushing coating layer Ra

(A1) at least one film-forming (co) polymer (A1) insoluble in gastrointestinal fluids,

(A2) at least one (co) polymer (A2) soluble in gastrointestinal fluids,

(A3) at least one plasticizer (A3),

(A4) at least one surfactant and / or lubricant and / or mineral and / or organic filler (A4) as required.

According to the non-limiting choice and pure description of the invention,

(A1) is

Water-insoluble cellulose derivatives, preferably ethyl cellulose and / or cellulose acetate,

Acrylic polymers such as copolymers of (meth) acrylic acid and alkyl (such as methyl) esters, at least one quaternary ammonium group (preferably at least one of alkyl (meth) acrylates and trimethylammonioethyl methacrylate chloride) Copolymers) to which methacrylic acid esters and acrylic acid esters are bound, more specifically products sold under the trademarks EUDRAGIT®RS and / or RL;

Polyvinyl acetate,

-Mixtures thereof.

(A2) is

Nitrogen-containing (co) polymers, preferably poly-acrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams Containing (co) polymers,

Water-soluble cellulose derivatives,

Polyvinyl alcohols (PVA),

Polyalkylene oxides, preferably polyethylene oxides (PEO),

Polyethylene glycols (PEG),

-Mixtures thereof.

PVP is particularly good.

(A3) is

Cetyl alcohol esters,

Glycerol and esters thereof, preferably glycerol and esters thereof selected from the group consisting of acetylated glycerides, glycerol monostearic acid, glyceryl triacetate and glycerol tributyrate,

Phthalates, preferably phthalates selected from the group consisting of dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,

Citrate, preferably citrate selected from the group consisting of acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate,

Sebacates, preferably sebacates selected from the group consisting of diethyl sebacate, dibutyl sebacate,

-Adipates,

-Azelates,

Benzoic acids,

-Vegetable oils,

Fumaric acids, preferably diethyl fumaric acid,

Maleic acids, preferably diethyl maleic acid,

Oxalic acids, preferably diethyl oxalic acid,

Succinates, preferably dibutyl succinate,

Butyrates,

Cetyl alcohol esters,

Salicylic acid,

Triacetin,

Malonates, preferably diethyl malonate,

-Castor oil (this is especially good),

-Mixtures thereof.

(A4) is

Anionic surfactants, preferably anionic surfactants selected from the group consisting of alkali metal or alkaline earth metal salts of fatty acids (preferably stearic acid and / or oleic acid), and / or

Nonionic surfactants, preferably ie

폴리에톡실화 오일류, 좋기로는 폴리에톡실화 수소화 피마자유와,

Polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil,

폴리옥시에틸렌/폴리옥시프로필렌 공중합체류와,

Polyoxyethylene / polyoxypropylene copolymers,

폴리에톡실화 소르비탄 에스테르류와,

Polyethoxylated sorbitan esters,

폴리에톡실화 피마자유 유도체와,

Polyethoxylated castor oil derivatives,

스테아르산류, 좋기로는 칼슘, 마그네슘, 알루미늄 또는 스테아르산아연류와,

Stearic acid, preferably calcium, magnesium, aluminum or zinc stearate,

스테아릴푸마르산류, 좋기로는 스테아릴푸마르산 나트륨과,

Stearyl fumaric acid, preferably sodium stearyl fumarate,

글리세롤 베헤네이트류와,

Glycerol behenates,

활석과,

Talc,

콜로이드성 규소와,

Colloidal silicon,

산화 티타늄, 산화 마그네슘과,

With titanium oxide, magnesium oxide,

벤토나이트와,

Bentonite,

미세결정성 셀룰로스와,

Microcrystalline cellulose,

고령토와,

Kaolin,

알루미늄 실리케이트와,

With aluminum silicate,

이들의 혼합물로 이루어진 군으로부터 선택되는 비이온성 계면 활성제로 이루어진 군으로부터 선택된다.

Nonionic surfactants selected from the group consisting of mixtures thereof.

In addition to the qualitative parameters defining the microparticles coated according to the invention, a coating layer (Ra) containing the following in weight percent relative to the total amount of coating in an advantageous quantitative manner can be specified.

10 ≦ A1 ≦ 90, preferably 15 ≦ A1 ≦ 80 and particularly preferably 60 ≦ A1 ≦ 80,

5 ≤ A2 ≤ 50, preferably 10 ≤ A2 ≤ 40 and particularly preferably 10 ≤ A2 ≤ 25,

1 ≦ A3 ≦ 30, preferably 2 ≦ A3 ≦ 20 and particularly preferably 5 ≦ A3 ≦ 15,

0 ≦ A4 ≦ 40, preferably 0 ≦ A4 ≦ 30 and particularly preferably 0 ≦ A4 ≦ 20,

The sum of the percentages is 100.

In addition, the release rate is for example

Adjustment of the Ra thickness,

-Controlled in a manner by weight ratio between components A1, A2, A3 and, if necessary, A4 of the coating Ra.

Advantageously, the coating on the coated microparticles for modified release of the AP is in addition to A1, A2, A3 and, if necessary, other essential components known to those skilled in the art, such as in particular colorants, pigments. , Preservatives, fragrances and the like and mixtures thereof.

Another prominent feature of the coating Ra on the coated microparticles is that the weight Tp, ie, Tp ≥ 15, preferably Tp is 30 to 60, in particular the coating layer Ra is expressed in dry weight% relative to the total weight of the coated microparticles. It is preferably the fact that the fragments are 40 to 60 and especially very preferably 45 to 55 or about 50.

Without being supported by theory, this relatively high coating rate allows the coating layer Ra to confer breakage resistance to the coated microparticles of the AP in order to ensure strain release of the AP while preventing misuse.

Without limitation, preferred coated microparticles of the AP according to the invention are those having an average diameter of up to 1000 mm, preferably 50 to 800 mm, particularly 100 to 600 mm and especially very preferably 100 to 300 mm. .

Unless otherwise indicated, the diameters of the microparticles mentioned herein are average diameters relative to volume.

With regard to the preparation of coated microparticles, the techniques advantageous for use in precipitating the coating for modified release of the AP or in precipitating the active layer based on the AP are known to those skilled in the art, such as spray coating in the fluidized air layer. Technology, wet granulation, compression or extrusion / spherization technology.

Outer cloth

In a particular variant of the invention, the coated microparticles for modified release of AP are used to maintain modified release for at least a portion of the dlm of the coated microparticles of AP for modified release of the AP during tablet manufacture. It has an outer sheath designed in a contributing manner. The outer coating consists of at least one deformable organic component having a melting point of 40 to 120 ° C., preferably 45 to 100 ° C.

In one variant, the outer coating comprises at least 10% by weight of deformable organic components.

In particular, in one variant of the invention, the deformable organic component contained in the outer coating is preferably given to polyethylene glycol selected from polyalkylene glycols, in particular having a molecular weight of 6,000 to 20,000 D.

In another variant, the deformable organic component of the outer coating is fat or, for example, hydrogenated vegetable oils, fatty acids, fatty alcohols, fatty acids and / or fatty alcohol esters, polyolefins and minerals, vegetable, animal or It is a mixture of fats selected from the group of fats including synthetic waxes, and especially fatty acid esters such as diglycelides and triglycerides and mixtures thereof, glycerol behenate and hydrogenated castor oil, soybean milk, cottonseed oil and palm oil.

In yet another variant, the outer sheath is

Mineral fillers such as silicon or titanium dioxide, or organic fillers such as microcrystalline cellulose,

And / or one or more lubricants such as magnesium stearate or sodium benzoate,

And / or one or more hydrophilic polymers, such as water-soluble cellulose derivatives, synthetic polymers, preferably polyvinylpyrrolidone, acrylic and methacryl polymers or polyvinyl alcohols (PVA),

And / or at least one surfactant.

Preferably, the outer coating represents 5 to 50 dry weight percent, preferably 10 to 30 dry weight percent and particularly about 20 dry weight percent, relative to the total weight of the overcoated microparticles of the AP.

“Overcoated microparticulates” includes an outer coating as defined above, ie an outer coating that also contributes to maintaining the modified release of at least a portion of the coated microparticles of the AP for modified release of the AP in the manufacture of a tablet. It shows coated microparticles,

Further information on the outer sheath can be found in published patent application WO-A-03 / 077888.

Thickener  ( Vb )

Preferably the thickener (Vb) is selected from those which are soluble in one or more of the following solvents: water, alcohols, ketones and mixtures thereof, wherein the thickener (s) is used to prevent misuse, in particular by abuse In order to increase the viscosity of the extract.

"Water" is understood to mean water or any aqueous solution, such as organic acids (such as acetic acid), salt solutions, soda or beverages, in a narrow sense. "Alcohol" is understood to mean any given alcohols themselves or mixtures with each other. "Ketone" is understood to mean any ketones themselves or mixtures of ketones with each other.

Particularly preferably, the thickener (Vb) is in the following polymer group, ie

Polyacrylic acids and derivatives thereof and / or

Polyalkylene glycols (eg polyethylene glycol) and / or

Polyalkylene oxides (such as polyethylene oxide) and / or

Polyvinylpyrrolidones and / or

Gelatins and / or

Polysaccharides, preferably sodium alginate, pectins, guars, xanthans, carrageenins, gallans and cellulose derivatives (eg hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose) Polysaccharides selected from the group comprising carboxymethyl cellulose)

And mixtures thereof.

According to the mode of the invention, the thickener Vb is, for example, a high molecular weight polyoxyethylene having a molecular weight of 1 to 8 million g / mol, such as 2 million, 5 million or 7 million g / mol.

Preferably, the thickener Vb, such as high molecular weight polyoxyethylene, is included in the ultrafine particles separate from the ultrafine particles of the AP.

Particularly preferably, the microparticles of the AP and the microparticles of the thickener Vb are similar in size distribution and density and cannot be separated into a sieve.

According to one preferred method, the thickener (Vb) can increase the viscosity of the liquid used for extraction to capture the extracted AP in the tacky medium.

This thickener (Vb) is intended to increase the viscosity of the extract, for example up to 100 mPa · s, preferably up to 200 mPa · s, particularly up to 500 mPa · s, particularly very preferably 1000 mPa · s. Make it possible.

Applicants believe that in one variant, an efficient thickener (Vb) was proposed for both aqueous phase extraction and organic solvent extraction. Advantageously, these thickeners (Vb) are mixtures of hydrophilic compounds and hydrophobic compounds to ensure that the extract has a high viscosity (eg 100 mPa · s or more) whether it is an aqueous solution or an organic solution.

As to the amount of thickener (Vb), this can be easily determined by one skilled in the art. This amount corresponds to the minimum amount necessary to bring the viscosity of 2.5 ml of extract to at least 100 mPa · s.

In several variations which can be mixed with one another, at least one thickener (Vb) in the pharmaceutical formulation according to the invention

In and / or on the surface of microparticles and / or

In the outer sheath of all or part of the microparticles of the AP, and / or

Exists in the free state, ie contained in or not supported by the microparticles.

Advantageously, at least some of the thickeners are in the form of microparticles that cannot be separated from the coated or uncoated microparticles of the AP.

Free state excipients

If necessary, the pharmaceutical formulation contains one or more pharmaceutically acceptable excipients in the free state, ie contained in or not supported by the microparticles of the AP, wherein the excipients are ground to the coated microparticles of the AP. Contribute to resistance

Specifically, these excipients that contribute to the grinding resistance of the coated microparticles of the AP are

Calcium stearate,

Glycerol palmitostearate,

Magnesium oxide,

Polyalkylene glycols, such as polyethylene glycols,

Polyvinyl alcohol,

Sodium benzoate,

Stearic acid,

-Cornstarch,

-Talc,

Colloidal silicon,

Zinc stearate, magnesium stearate,

Stearyl fumaric acid,

-Mixtures thereof.

In an alternative embodiment of the invention, at least some of the thickeners

In the glass state, ie contained in or unsupported in the coated or uncovered microparticles of the AP (alternative 1), or

In a microparticulate formulation separate from the coated or uncoated microparticles of the AP (alternative 2).

Advantageously, in alternative 2 the microparticles of the thickener cannot be separated from the coated or uncoated microparticles of the AP. In this specification, the expression “inseparable” means that it cannot be separated by conventional means such as, for example, a sieve or centrifuge.

In alternative 2, the thickener is for example,

In microparticles and / or on the microparticles,

In an outer sheath over some or all of the microparticles of the AP.

In still alternative 2, it is preferred that the microparticles containing a thickener cannot be physically identified with the microparticles of the AP so that they cannot be easily separated by appropriate physical means. Microparticles containing thickeners, in particular, have the same size and / or density and / or shape and / or color and are indistinguishable from the microparticles of the AP.

In another alternative, the thickener is for example,

In microparticles and / or on the microparticles,

And / or in an outer coating over some or all of the microparticles of the AP.

In one preferred embodiment, the pharmaceutical formulation according to the invention is a composite microparticle. If the pharmaceutical formulation contains microparticles of AP (eg, aAP) and thickener (Vb), the microparticles preferably have the same size distribution and the same density and cannot be separated by a sieve. Thus the microparticles of the thickener cannot be separated from the coated or uncovered microparticles of the AP.

In another preferred embodiment, the pharmaceutical formulations according to the invention are multiparticulates. If the pharmaceutical formulation contains microparticles of AP (eg, aAP) and thickener (Vb), the microparticles preferably have the same size distribution and the same density and cannot be separated by a sieve. Thus the microparticles of the thickener cannot be separated from the coated or uncovered microparticles of the AP.

Containment  Q

Obviously, where the microparticulate pharmaceutical formulation contains one or more salts of one or more anesthetic active ingredients, those skilled in the art will appreciate that in order to form a complex with an AP that is slightly soluble in an aqueous alcoholic beverage or aqueous beverage solution, One or more containment agents may be added to the pharmaceutical formulation.

The blocking agent is, for example, a salt in which the ion of the salt whose polarity is opposite to that of the AP is an organic ion. Thus, for cationic active ingredients, these containment agents are organic salts or anionic polymers, such as sodium docusate, for example. The blocking agent may be, for example, an ion exchange resin salt.

In an aspect of the present invention, containment agent Q is in a free pharmaceutical formulation, such as a non-complex. "Non-complex" means that there is no complex or chemical interaction between the active ingredient AP salt and sequestrant Q in the solid pharmaceutical formulation.

If AP salt and sequestrant Q are present simultaneously in a solvent, such as an attempt to illegally extract AP, sequestrant Q may induce chemical interaction or complexation with the AP salt in the solvent. In an aspect of the present invention, the containment agent Q is combined with the AP salt in at least one conventional solvent selected from water and aqueous solutions such as water / ethanol mixtures, alcohols, alcoholic beverages, soda, vinegar, hydrogen peroxide and mixtures thereof. If it can lead to complexation of the blocking agent Q is considered to be "complexing inducing ability" with the AP salt. Advantageously, the containment agent Q can induce complexation of the AP salt in one or more of these conventional solvents.

The containment agent Q, which is used to capture AP, especially anesthetic AP, is not harmful even when used conventionally. These products are inert in pharmaceutical terms and are approved by numerous pharmacopoeia and drug approval authorities.

In one pharmaceutical formulation according to the invention, at least one containment agent Q is

In microparticles without AP, and / or

On microparticles, and / or

It exists in the free state, ie contained in or not supported by the microparticles.

Preferably, in the pharmaceutical formulation according to the invention, said containment agent Q is in a first phase which is separated from at least one second phase, said second phase containing at least one AP salt. For example, the pharmaceutical formulation contains microparticles of AP salt and microparticles of separate containment Q. Advantageously, the microparticles are similar in size distribution and density and cannot be separated into a sieve.

Preferably, the containment agent Q contains a salt containing ions capable of forming a complex with the AP in solution form. These ions are preferably organic ions of opposite polarity to that of the AP in solution form, i.e., if the AP is in an anionic form in solution, the containment Q contains an organic cation, a metal cation or a mixture thereof. Likewise, if the AP is in cationic form in solution, containment agent Q contains an organic anion.

For example, mention may be made of the following salts containing organic anions.

Organic anionic salts, such as sodium dodecyl sulfate or sodium docusate,

(Meth) acrylic copolymers (such as Eudragit ^® S and Eudragit ^® L), crosslinked polyacrylic acids (such as Carbopol), carboxymethylcellulose and derivatives thereof, crosslinked carboxymethylcellulose and derivatives thereof And anionic polymers such as other polysaccharides (such as alginate, xanthan gum or gum arabic) and alginic acid / (sulfonate) propylene glycol,

-Glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipicates ( adipates), monovalent or polyvalent salts such as benzoate, salicylate, tartarate, sulfonamide, acesulfame,

-Saponified fatty acids such as acetates, succinates, citrates, stearates, palmitates and self-emulsifying glyceryl monooleate;

Polyamino acids, proteins or peptides, such as albumin, casein, globulin and enzymes,

And mixtures thereof.

In another embodiment, the ions of opposite polarity to that of the AP in solution form are organometallic cations or mixtures thereof. For example, the following salts containing organic cations or metal cations may be mentioned.

-Acesulfame, acetate, adipic acid, benzoate, carbonate, chloride, citrate, fluoride, fumarate, gluconate, gluconate, glycerophosphate, hydroxides, iodide, iodide, lactate, oxide, Cationic salts such as metal Ca, Fe, Mg or Zn in the form of phosphates, trisilicates, salicylates, succinates, sulfonamides, tartarate salts,

Quaternary ammonium salts, especially organic cationic salts such as trimethyl tetradecyl ammonium bromide or benzetonium chloride,

Cationic polymers such as chitosan and (meth) acrylic copolymers (such as Eudragit ^® RS, Eudragit ^® RL or Eudragit ^® E),

Polyamino acids, proteins or peptides,

And mixtures thereof.

The containment agent Q may be an ion exchange resin, preferably a strong acid cation exchange resin when AP is a cation, or a strong base anion exchange resin when AP is an anion. Advantageously, the ion exchange resin is contained in a first phase separated from a second phase containing AP.

In one embodiment of the present invention, the ion exchange resin is, for example, a derivative of a styrene / divinylbenzene copolymer.

In one embodiment of the present invention, the strong acid cation exchange resin is, for example, Rohm & Haas Company ^{Amberlite ® IRP69, Amberlite ® IR69F,} Amberlite ® 200, Amberlite ® 200C or Dow's Dowex ^® 88 styrene such as / divinylbenzene Will be a derivative of the copolymer.

In one embodiment of the present invention, the strong base anion exchange resin is a styrene / divinylbenzene air bonded to a quaternary ammonium group, such as Duolite ^® AP143, Amberlite ^® IRA958, Amberlite ^® IRP67, or Dowex ^® 22, by Dohm, Rohm & Hass Will be selected from derivatives of the coalescing.

Containment of the resin forms the Q is the Rohm & Hass Company Amberlite ^® IRP88, Amberlite ^® IRP64 and Dow's DOWEX MAC-3, such as cross-linked methacrylic acid / divinylbenzene copolymer, or may be selected from one of the salts thereof, of have.

Q blockers of the ion exchange resin type may be selected from phenol-polyamines, and mixtures thereof, such as Rohm & Hass Company Amberlite ^® IRP58.

In one embodiment, the containment agent Q in the form of an ion exchange resin is present in a first phase that is separated from at least one second phase, the second phase comprising an AP salt. For example, containment agent Q in the form of an ion exchange resin is contained in the microparticles away from the microparticles containing the AP salt. The microparticles of the AP and the microparticles of the containment agent Q in the form of ion exchange resins may be in a form that is similar in size distribution and density and cannot be separated into a sieve.

In a first preferred method of carrying out the invention, the containment agent Q is

Organic anionic salts such as sodium dodecyl sulfate or sodium docusate,

Quaternary ammonium salts, especially organic cationic salts such as trimethyl tetradecyl ammonium bromide or benzetonium chloride,

-Strong base anion exchange resin or strong acid cation exchange resin according to the AP polarity.

In a second preferred method of carrying out the invention, said containment agent Q is

-If the AP is a cation, Amberlite ^® IRP69, Amberlite ^® IR69F, Amberlite 200, Amberlite from Rohm & Haas Strong acid cation exchange resins such as Dowex 88 and mixtures of 200C or Dow

- if the AP is anionic, Rohm & Hass Company Duolite ^® AP143, Amberlite IRA958, are selected from strong base anion exchange resin such as Amberlite IRP67 or Dow's Dowex 22, and mixtures thereof.

The amount of containment Q is employed by those skilled in the art by calculating the amount of ionic charge necessary to capture all or part of the dosage of AP contained in the unit dosage form. The amount of containment Q should be at least complexed with the AP to the extent that the abuser is insufficient to achieve the desired effect with the free AP remaining in the solution, when attempting illegal extraction. At least the amount of containment Q is preferably sufficient to complex all of the AP contained in the unit dosage form.

In one variation, the pharmaceutical formulation may be integral (eg, tablets).

In one embodiment, the pharmaceutical formulation according to the invention contains microparticles of thickener V and / or microparticles of containment Q, preferably microparticles of thickener V and microparticles of containment Q. . In one embodiment, the microparticles of thickener V and the microparticles of containment Q are separated from the microparticles of the AP.

In another embodiment of the present invention, the pharmaceutical formulation contains microparticles of thickener V and / or microparticles of sequestrant Q as well as microparticles of AP. Preferably, the pharmaceutical formulation contains these three types of microparticles, microparticles of AP, microparticles of thickener V and microparticles of containment Q in one and the same unit dosage form. Advantageously, these microparticles are similar in size distribution and density and cannot be separated from each other in a sieve.

In a first variant, the pharmaceutical formulation according to the invention cannot be converted to an immediate release dry formulation of an AP which can be administered by inhalation.

In a second variant, the pharmaceutical formulation according to the invention cannot be converted into an immediate injection formulation of an AP.

In a third variant, the pharmaceutical formulation according to the invention contains a modified release AP and an immediate AP as necessary. This variant can be mixed with the first and second variants described above, which is a pharmaceutical formulation containing a modified release AP and an immediate release AP, wherein the modified release AP is to be administered by inhalation or in an immediate release dosage form. It can not be converted to a dry formulation that can be.

In a fourth variant, the pharmaceutical formulation of the present invention is characterized in that the extraction of AP by chewing and / or grinding is not efficient.

In a fifth variant, the pharmaceutical formulation according to the invention is characterized in that it is free of AP antagonists.

In a sixth variant, the pharmaceutical formulation according to the invention is characterized in that it contains at least one AP antagonist. With the information of the AP used, one skilled in the art can easily determine the appropriate antagonist (s).

Of course, any combination of two or more of these six variants is also included in the present invention (except for the combination of the fifth and sixth modifications).

Active ingredient (s)

The AP used belongs to, for example, one or more of the following collections of active substances.

Amphetamines, anesthetics, appetite suppressants (anorexigenic), analgesics (antalgic), antidepressants, antiepileptics, antimigraine, antiparkinsonants, antitussives, anxiolytics, barbituric acid, benzodiazepines, hypnotics (hypnotiqcs), laxatives ( laxatives), neuroleptics, opiates, psychostimulants, antipsychotics, sedatives and stimulants. If the AP is an anesthetic AP (aAP), it is preferred to be an opioid.

More precisely, the AP used is selected from the following compounds. Aniredine, acetorpine, acetylalpha-methylpentanyl, acetyldihydrocodeine, acetylmethol, alfentanil, allylprodine, alpha-cetylmetholol, alpha-meprodine, alpha-prodine, alpha-methol , Alpha-methylpentanyl, alpha-methylthio-pentanyl, anileridine, atropine, butorpanol, benzetidine, benzylmorphine, beta-hydroxypentanyl, beta-hydroxy-methyl-3-pentanyl, beta-cetyl Metadol, beta-meprodine, beta-methol, beta-prodine, benzitramide, buprenorphine, dioxafetyl butyrate, clonitazene, cyclazosin, cannabis, setobemidon, clonitogen , Codeine, coca, cocaine, codoxime, dezosin, dimenoxadol, dioxafetyl butyrate, dipiphanone, desormorphine, dextromemoramide, dextrosepropoxyphene, diampromide, diethyl thiambutene, Diphenoxine, dihydrocodeine, dihydroetopin, dihydromorphine, dimenox Dol, Dimepeptanol, Dimethylthiambutene, Diphenoxylate, Difipanone, Drotebanol, Eptazosin, Etoheptazine, Ethylmethylthiambutene, Ethylmorphine, Etonithage, Exgonin, Ephedrine, Ephedrine Torpins, ethoxeridines, fentanyl, furretidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypettidine, isometadone, ketobemidone, levallorphane, lofentanil, levome Thorpan, Levomoramide, Levofenacylmorphan, Levorphanol, Citazinol, Meperidine, Metazosin, Methadone, Methyldesorphine, Methyldihydromorphine, Methylphenidate, Methyl-3-thiopentanyl (methyl-3-thiofentanyl), methyl-3-pentanyl, methopone, morphamide, morpheridine, morphine, miropine, nalbuphine, narcane, nicomorphine, norreborganol, normethadon, nallopine, normorphine Nicocodin, nicocodidine, nicomorphine, noasimethadol, norcodine, no Piphanon, opium, oxycodone, oxymorphone, papaveretum, phenadoxin, phenoferidine, promethol, properidine, propiram, propoxyphene parafluoropentanyl, pentazosin, pettidine, phenampromide , Phenazosin, phenomorphan, phenoferidine, polcodine, piminodine, pyritramide, proheptazine, propanolol, properidine, racemetopan, racemoramide, racemopan, remifentanil , Sufentanil, thebacon, thebaine, thiopentanyl, tilidine, trimeperidine, tramadol, pharmaceutically acceptable salts, esters, hydrates, polymorphs and isomers thereof, and mixtures thereof.

The pharmaceutical formulation according to the invention may comprise at least one anesthetic active ingredient (aAP) and at least one additional AP different from aAP. Non-anesthetic APs are antidepressants, amphetamines, anorexics, anesthetics, painkillers, antiepileptics, antimigraines, antiparkinsonants, antitussives, anxiolytics, barbituric acid, benzodiazepines, hypnotics, laxatives, neuroleptics, It is preferred to be selected from the group comprising psychostimulants, antipsychotics, sedatives, stimulants, anti-inflammatory agents, pharmaceutically acceptable salts, esters, hydrates, polymorphs and isomers thereof, and mixtures thereof.

Among the anti-inflammatory active ingredients that may be mentioned, mention may be made of the following. Ibuprofen, Acetaminophen, Diclofenac, Naproxen, Benoxaprofen, Flubiprofen, Phenopropene, Flubufen, Ketoprofen, Indoprofen, Pyroprofen, Carpropene, Oxaprozin, Phra Moprofen, muroprofen, trioxapropene, suprofen, amineoprene, thiapropenic acid, flupropene, bucloxane, indomethacin, sulindac, tolmethine, jomepilac, thiopi Nak, Mapmetacin, Acemetacin, Pentiazac, Klidanac, Oxinac, Mephenam, Meclofenam, Flufenam, Naflumsan, Tolfenamsan, Diflurisal, Flufenisal, Piroxicam ), Sudoxycam or isoxiccam, pharmaceutically acceptable salts, esters, hydrates, polymorphs and isomers thereof, and mixtures thereof.

Even more precisely, the anesthetic AP used is selected from the group consisting of oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride and tramadol hydrochloride.

In the present invention, "pharmaceutical formulation" is understood in the broadest sense, ie, veterinary or nutritional formulations, and especially encompasses the concept.

According to another of its features, the present invention provides a plurality of the above-mentioned microparticles (coated or uncoated microparticles of AP; if necessary, microparticles of thickener), for example, 500 or more, preferably 1,000 to 1,000,000. And particularly preferably 5,000 to 5,00,000.

According to another of its features, the invention relates to pharmaceutical formulations comprising a plurality of populations of coated microparticles of AP, said populations being distinguished from one another by their release rate and / or the AP they contain.

Without limitation, it should nevertheless be emphasized that the pharmaceutical formulations according to the invention are of particular value in that they can be taken in a single oral dosage form daily containing 500 to 500,000 microparticles, including coated microparticles of AP.

Advantageously, the pharmaceutical formulations containing the coated microparticles according to the invention are prepared as tablets (which can advantageously be dispersed in the oral cavity or stomach), powders, suspensions, syrups and capsules which can be reconstituted into suspension powders. Herbal form selected from the group consisting of:

It may be interesting to mix two or more coated microparticles of AP that differ in their release rate but within the main features of the present invention in one and the same capsule, one and the same tablet or one and the same powder.

The invention also relates in particular to the use of the above-mentioned coated microparticles for the preparation of novel pharmaceutical formulations for (without limitation) pain treatment.

The invention also relates to a method of treatment characterized in that it consists in administering a pharmaceutical formulation as described above to a patient.

The invention also relates to a method of treatment characterized in that it consists of ingesting a pharmaceutical formulation as described above according to a predetermined dosage.

The present invention also relates to a method for treating pain characterized in that it consists in administering a pharmaceutical formulation as described above to a patient.

The present invention also relates to a method of treating pain, characterized by ingesting a pharmaceutical formulation as described above according to a predetermined dosage, wherein the AP used comprises one or more pain relief agents, such as anesthetics. .

The invention also relates to a method for preventing misuse of an AP characterized by the essential use of a pharmaceutical formulation as described above.

In addition, the present invention consists essentially of the use of the coated microparticles of the AP for modified release of the AP in a pharmaceutical formulation, wherein the microparticles are coated with the AP to ensure modified release of the AP and at the same time prevent misuse. It has a coating layer (Ra) which imparts crush resistance to the microparticles and at least one thickener (Vb) which can prevent the extraction of the AP contained in the coated microparticles of the AP in order to prevent misuse if necessary. The present invention relates to a method for preventing misuse of an AP.

Advantageously, the coating layer Ra and the thickener Vb, if present, are as described above.

The invention will be explained more clearly through the following examples which clearly illustrate the invention by way of explanation and which illustrate different advantages as well as their different embodiments and / or methods of carrying out the invention.

―의 극미립자들 표면에서의 생체 밖 대조 시험 (시간 T의 기능으로서 용해% D)에 있어서의 용해 프로파일을 나타낸 것이다.1 shows Example 1, that is, Example 1;

Dissolution profile in an ex vivo control test (% dissolution as a function of time T) on the surface of the ultrafine particles.

― 및 실시예 2 즉, (a) ---

---, (b) ---

---, (c) ---

---, (d) ---

---의 극미립자들 표면에서의 생체 밖 대조 시험 (시간 T의 기능으로서 용해% D)에서의 용해 프로파일을 나타낸 것이다.2 shows Example 1, i.

And Example 2, i.e. (a) ---

---, (b) ---

---, (c) ---

---, (d) ---

The dissolution profile in the in vitro control test (% dissolution as a function of time T) on the surface of the microparticles of --- is shown.

Figure 3 shows a photograph of the contents of the capsule according to Example 3 observed with the naked eye (A) and optical microscope (B).

FIG. 4 shows the release profile (wt% of aAP as a function of time in hours) of microcapsules of 0.1 N HCl (Example 8).

5 shows a photograph of the contents of the capsule according to Example 9 under the naked eye (A) and under an optical microscope (B).

FIG. 6 shows the release profile of the ground microparticles (hollow triangle) or intact microparticles (squares) of Example 9. FIG.

The dissolution control test of the Examples described below is an ex vivo dissolution test as indicated in the European Pharmacopoeia 5 edition entitled "Dissolution test for solid oral forms", ie, maintained at 37 ° C. and stirred at 75 rpm in 900 mL of 0.1 N HCl, Type II dissolution test performed under SINK conditions.

Example  1: according to the invention Oxycodone HCl  Microparticles

Oxycodone HCl 1600 g, Klucel ^® EF (hydroxypropyl cellulose / Aqua-alone) in 100 g of water and 12.052 g of a mixture of air GPCG1 fluid bed (Glatt ^®) inside the cellulose beads (Asahi-Kasei), 300 g in the film is coated. 450 g of the resultant granules were then 315 g of ethyl cellulose (Ethocel 20 Premium / DOW), 81 g of povidone (Plasdone PVP K29 / 32 / ISP), 36 g of castor oil, cremophor RH 40 (macrogolglycerololi) The mixture is coated with a mixture of 18 g of macrogolglyceroli hydroxystearas / BASF and 12.020 g of ethanol.

The coating represents 50% by weight of the microparticles and ensures that the active ingredient is released about 4 hours as shown in FIG. 1. The release profile is measured under the conditions of the control dissolution test.

Example  2: Example  Manufactured according to 1 Oxycodone HCl  Crushing of microparticles

200 mg of the microparticles prepared in Example 1 (eg, a dose of 80 mg of oxycodone HCl) is a different method representing misuse in different ways possible, ie

(a) grind vigorously for 2 minutes with pickled balls and mortar (250 ml) (about 120 revolutions),

(b) squeezed eight times between two spoons,

(c) using an "LGS powder mill" tablet mill (LGS Health Products, USA),

(d) use the coffee grinder for 30 seconds

By crushing.

The emission profiles of the ground microparticles are shown in FIG. 2. This release profile is measured under control dissolution test conditions.

The release profiles of Example 1 (intact microparticles) and 2 (crushed microparticles) are similar in terms of testing for the f2 like factor (f2 >> 50) calculated as indicated by the FDA ( Guidance for Industry SUPAC-MR: Modified Release Oral Solid Formulations, p. 32).

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

Example  3: aspects of the contents of the capsule according to the invention

200 mg of microparticles prepared in Example 1 (dose of 80 mg of oxycodone HCl) was added as a thickener, that is, 90 mg of Klucel HF (hydroxypropyl cellulose / Aqualon), PolyOx WSR 303 Sentry (polyethylene oxide / dough) G) 20 mg and 20 mg of Xantural 180 (xanthan / cpKelco) previously filtered to 100 to 600 µm. Fill the whole into size 0 gelatin capsules.

Figure 3 shows a photograph of the contents of the capsule observed with the naked eye (A) and optical microscope (B).

As shown in FIG. 3 (A) visually observed, the microparticles of the active ingredient and the microparticles of the thickener are

-Indistinguishable

-Can not be separated into a sieve.

In the photograph of FIG. 3 (B) observed under an optical scale, there are two distinct populations of particles, one of oxycodone HClDML spherical microparticles and two thickeners, and the other of the third thickener. It is a rod-shaped particle. Because these particles are very small in size (about 0.2 mm) they cannot be separated from each other.

Example  4: injection extraction test of formulations according to the invention

200 mg of the microparticles prepared in Example 1 (dose of 80 mg of oxycodone HCl) were treated with 90 mg of Klucel HF (hydroxypropyl cellulose / aqualon), 20 mg of PolyOx WSR 303 Sentry (polyethylene oxide / dosar) and Mix with 20 mg of Xantural 180 (xanthan / cpKelco) filtered to 100-600 μm. Fill the whole into size 0 gelatin capsules.

The capsule is opened and the contents are pulverized into mortar and mortar according to Example 2 (a), followed by mixing for 10 minutes with 2.5 ml of the extract at ambient temperature or boiling point. The solution is then taken with a 2.5 ml syringe (18G needle) through the raw noodles provided by the filter. The amount of extracted oxycodone HCl is analyzed by HPLC or UV and is shown in Table 1.

The low extraction yield observed (<20%) is to dry up potential abusers completely.

Example  5: injection extraction test of the formulations according to the invention

200 mg of the microparticles prepared in Example 1 (dose of 80 mg of oxycodone HCl) were 150 mg of Klucel HXF (hydroxypropyl cellulose / aqualon), 50 mg of PolyOx WSR 303 Sentry (polyethylene oxide / dough) and Carbopol 971P (carbomer / BF Goodrich) 30 mg. The mixture is filled into size 00 gelatin capsules.

The capsule is opened and the contents are pulverized into a mortar and mortar according to Example 2 (a), followed by mixing for 10 minutes with 10 ml of the extract at ambient temperature or boiling point. The solution is then taken with a 10 ml syringe (18 G needle) through the raw noodles provided by the filter. The amount of oxycodone HCl extracted is shown in Table 2 by HPLC or UV analysis.

The low extraction yield observed (<20%) is to dry up potential abusers completely.

Example  6: injection extraction test of the formulation according to the invention

150 g Klucel HXF (hydroxypropyl cellulose / aqualon), 50 g PolyOx WSR 303 Sentry (polyethylene oxide / dousar), 30 g Carbopol 971P (carbomer / BF Goodrich) and povidone (Plasdone PVP K29 / 32 / ISP) 10 The g is wet granulated in a MiPro instrument. The granules are filtered through a 100 to 600 μm sieve.

250 mg of the resultant granules are added to 200 mg of the microparticles (dosage of oxycodone HCl 80 mg) prepared in Example 1. The whole is filled into size 0 gelatin capsules. The capsule is opened and the contents are pulverized into a mortar and mortar according to Example 2 (a), followed by mixing for 10 minutes with 10 ml of the extract at ambient temperature or boiling point. The solution is then taken with a 10 ml syringe (18 G needle) through the raw noodles provided by the filter. The amount of oxycodone HCl extracted is shown in Table 3 by HPLC or UV analysis.

The low extraction yield observed (<20%) is to dry up potential abusers completely.

Example  7: Preparation of tablets according to the invention

200 mg of the microparticles prepared in Example 1 was added 90 g of Klucel HF (hydroxypropyl cellulose / aqualon), 20 g of PolyOx WSR 303 Sentry (polyethylene oxide / dough), 20 g of Xanthural 180 (xanthan / cpKelco) , 100 g of lactic acid (Tablettose / Meggle GmbH), 10 g of magnesium stearate (Brenntag AG) and 30 g of croscarmellose sodium (Ac-Di-Sol / FMC Bipolymer).

Tablets 470 mg (ie oxycodone dose 80 mg) are prepared using a Korsch reciprocating press.

The tablet thus obtained is pulverized into mortar and mortar according to Example 2 (a) and then mixed with 2.5 ml of the extract at ambient temperature or boiling point for 10 minutes. The solution is then taken with a 2.5 ml syringe (18G needle) through the raw noodles provided by the filter. The amount of oxycodone HCl extracted is shown in Table 4 by HPLC or UV analysis.

The low extraction yield observed (<20%) is to dry up potential abusers completely.

Example  8: according to the invention Oxycodone HCl  Microparticles

Step 1: Granulation

1615 g of oxycodone and povidone ^{(Plasdone ® K29-32 / ISP) 85} g dispersed in 2052 g water and 1105 g of ethanol containing the mixture. The solution is sprayed with 300 g of cellulose spheres (Asahi-Kasei) in a Glatt GPCG1 air fluidized bed.

Stage 2: anti-crushing microparticles

315 g of ethyl cellulose (Ethocel 20 Premium / Dow), 81 g of povidone (Plasdone K29-32 / ISP), 18 g of macrogolglyceroli hydroxystearas (Cremophor RH40 / BASF) and castor oil (Garbit huilerie) 36 g are dissolved in a mixture consisting of 3105 g acetone and 2070 g isopropanol. This solution is sprayed into 450 g of granules (prepared in step 1).

The coating represents 50% by weight of the microparticles and ensures release as shown in FIG. 4. The release profile is measured under control dissolution test conditions.

Example  9: contents of capsule according to the invention

230 mg of the ultrafine particles obtained in step 2 of Example 8, 100 mg of pulverized Amberlite IR69F (polystyrenesulfonate sodium) 100 mg, sifted Polyox WSR 303 Sentry (polyethylene oxide) 70 mg, magnesium stearate 3.8 mg and Aerosil 200 ( 1.9 mg of colloidal silicon) are introduced into a size 0 gelatin capsule.

As shown in FIG. 5 observed with the naked eye (A) and under an optical microscope (B), the microparticles of the active ingredient and the microparticles of the thickener are

-Indistinguishable

-Can not be separated into a sieve.

Example  10: Example  Grinding the contents of the capsules prepared according to 9

The contents of the capsule prepared in Example 9 are ground for 2 minutes with a pestle and mortar.

The emission profile of the stranded microparticles is shown in FIG. 6. This release profile is measured under control dissolution test conditions.

The release profile of the intact and ground commodities is similar. Therefore, grinding has little or no effect on oxycodone release from microparticles.

Example  11: Example  Injection extraction test of capsule contents prepared according to 9

The capsule prepared according to Example 9 is opened and the contents are pulverized with a mortar and mortar for 2 minutes and then mixed with 2.5 ml of the extract at ambient temperature (A) or boiling point (B) for 10 minutes. The solution is then taken with a 2.5 ml syringe (18G needle or 27G needle) through the raw noodles provided by the filter. The amount of extracted oxycodone HCl is shown in Tables 5 and 6 by HPLC or UV analysis.

The low extraction yield observed (<20%) is to dry up potential abusers completely.

Example  12: Within a drink Example  Extraction test of capsule contents according to 9

The capsules prepared according to Example 9 were opened and their contents were ground for 2 minutes in a mortar and mortar and then mixed with 50 ml of an alcoholic beverage or 100 ml of a non-alcoholic beverage as shown in the table below.

menstruum Volume (ml) tap water 100 Tap water with 2 g / l NaCl 100 NaCl 2 g / l and pH 1.2 (HCl) 100 Sprite® 100 Pepsi Cola® 100 Smirnoff Twisted Apple (5% alcohol) 100 Absolute® Vodka (40% alcohol) 50

The solution is then taken up and the amount of oxycodone HCl extracted is shown in Table 7 by HPLC or UV analysis.

The low extraction yield (<20%) observed even in the case of long term extraction is to dry out potential abusers completely.

Table 1 Example 4

Oxycodone HCl% extracted with 18G syringe Liquid at ambient temperature Liquid at boiling point Tap Water / Ethanol (60/40 V / V) Ethanol 0.2 3 18 1 8 1

Table 2 Example 5

Oxycodone HCl% extracted with 18G syringe Liquid at ambient temperature Liquid at boiling point Tap Water / Ethanol (60/40 V / V) Ethanol 1 4 19 2 7 8

Table 3 Example 6

Oxycodone HCl% extracted with 18G syringe Liquid at ambient temperature Liquid at boiling point Tap Water / Ethanol (60/40 V / V) Ethanol 1 5 19 2 8 9

Table 4 Example 7

Oxycodone HCl% extracted with 18G syringe Liquid at ambient temperature Liquid at boiling point Tap Water / Ethanol (60/40 V / V) Ethanol 0.5 4 19 2 10 2

TABLE 5 Amount (%) of AP extracted using a 2.5 ml syringe equipped with a 27G needle (Example 11)

Oxycodone HCl% extracted with 27G syringe Liquid at ambient temperature Liquid at boiling point Tap water / ethanol (60/40 V / V) anhydrous ethanol 0 0 14 1 4 0

TABLE 6 Amount (%) of AP extracted using a 2.5 ml syringe equipped with 18G needle (Example 11)

Oxycodone HCl% extracted with 18G syringe Liquid at ambient temperature Liquid at boiling point Tap water / ethanol (60/40 V / V) anhydrous ethanol 0 3 18 1 8 1

TABLE 7 Amount of AP extracted from different beverages as a function of time (Example 12)

Solvent / extraction time 1 hours 21 hours tap water 8 <45 Tap water with 2 g / l NaCl 8 <45 NaCl 2 g / l and pH 1.2 (HCl) 14 <45 Sprite® 3 <45 Pepsi Cola® 3 <45 Smirnoff Twisted Apple (5% alcohol) 23 <45 Absolute® Vodka (40% alcohol) 24 <45

Claims (56)

Contains misuse prevention means, At least a portion of the contained AP is contained in the coated microparticles for modified release of the AP, Oral solid pharmaceutical formulations characterized in that the coated microparticles of the AP have a coating layer (Ra) which imparts crush resistance to the coated microparticles of the AP to ensure modified release of the AP and at the same time prevent misuse. The pharmaceutical composition of claim 1, which contains at least one thickener (Vb) capable of preventing extraction of the AP contained in the coated microparticles of the AP for modified release of the AP to prevent misuse. Formulation. The pharmaceutical formulation according to claim 1 or 2, which contains at least one sequestrant (Q) capable of forming a complex with the AP in the form of a solution. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the coating layer Ra is designed in such a way as to maintain a modified release of the AP for at least some of the coated microparticles upon grinding. . The coating layer (Ra) according to any one of the preceding claims, wherein the coating layer (Ra) has a strain release upon grinding, at least 40%, preferably at least 60% and particularly preferably 80 of the microparticles coated for strain release of the AP. A pharmaceutical formulation, characterized in that it is designed in such a way as to keep it at or above%. The method according to any one of the preceding claims, wherein the coating layer Ra is (A1) at least one film-forming (co) polymer (A1) insoluble in gastrointestinal fluids, (A2) at least one (co) polymer (A2) soluble in gastrointestinal fluids, (A3) at least one plasticizer (A3), (A4) at least one surfactant and / or lubricant and / or mineral and / or organic filler as required (A4) Pharmaceutical formulations containing a. The method according to claim 6, wherein the coating layer Ra comprises the following components (wt% relative to the total weight of the coating): 10 ≤ A1 ≤ 90, preferably 15 ≤ A1 ≤ 80 and even more preferably 60 ≤ A1 ≤ 80, 5 ≤ A2 ≤ 50, preferably 10 ≤ A2 ≤ 40 and even more preferably 10 ≤ A2 ≤ 25, 1 ≤ A3 ≤ 30, preferably 2 ≤ A3 ≤ 20 and even more preferably 5 ≤ A3 ≤ 15, 0 ≤ A4 ≤ 40, preferably 0 ≤ A4 ≤ 30 and even more preferably 0 ≤ A4 ≤ 20, Pharmaceutical formulations containing a. The method according to claim 6 or 7, (A1), Water-insoluble cellulose derivatives, preferably ethyl cellulose and / or cellulose acetate, Acrylic polymers such as copolymers of (meth) acrylic acid and alkyl (such as methyl) esters, at least one quaternary ammonium group (preferably one of alkyl (meth) acrylates and trimethylammonioethyl methacrylate chloride) Copolymers of methacrylic esters and acrylic esters to which the above copolymers) are bound, and more specifically, the products sold under the trademarks EUDRAGIT ^® RS and / or RL; Polyvinyl acetate, -From the group consisting of mixtures thereof, The above (A2), Nitrogen-containing (co) polymers, preferably polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams Containing (co) polymers, Water-soluble cellulose derivatives, Polyvinyl alcohols (PVA), Polyalkylene oxides, preferably polyethylene oxides (PEO), Polyethylene glycols (PEG), -Selected from the group consisting of mixtures thereof The above (A3), Cetyl alcohol esters, Glycerol and esters thereof, preferably glycerol and esters thereof selected from the group consisting of acetylated glycerides, glycerol monostearic acid, glyceryl triacetate and glycerol tributyrate, Phthalates, preferably phthalates selected from the group consisting of dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, Citrate, preferably citrate selected from the group consisting of acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate, Sebacates, preferably sebacates selected from the group consisting of diethyl sebacate, dibutyl sebacate, -Adipates, -Azelates, Benzoic acids, -Vegetable oils, Fumaric acids, preferably diethyl fumaric acid, Maleic acids, preferably diethyl maleic acid, Oxalic acids, preferably diethyl oxalic acid, Succinates, preferably dibutyl succinate, Butyrates, Cetyl alcohol esters, Salicylic acid, Triacetin, Malonates, preferably diethyl malonate, -Castor oil (this is especially good), -From the group consisting of mixtures thereof, The above (A4) is, Anionic surfactants, preferably anionic surfactants selected from the group consisting of alkali metal or alkaline earth metal salts of fatty acids (preferably stearic acid and / or oleic acid), and / or Nonionic surfactants, preferably,

Polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil,

Polyoxyethylene / polyoxypropylene copolymers,

Polyethoxylated sorbitan esters,

Polyethoxylated castor oil derivatives,

Stearic acid, preferably calcium, magnesium, aluminum or zinc stearate,

Stearyl fumaric acid, preferably sodium stearyl fumarate,

Glycerol behenates,

Talc,

Colloidal silicon,

Titanium oxide, magnesium oxide,

Bentonite,

Microcrystalline cellulose,

Kaolin,

With aluminum silicate,

Nonionic surfactants selected from the group consisting of mixtures thereof Pharmaceutical formulations selected from the group consisting of. The coating layer Ra according to any one of the preceding claims, wherein the coating layer Ra is expressed as dry weight percent of the total weight of the coated microparticles, ie Tp ≥ 15, preferably Tp of 30 to 60, particularly preferably. Pharmaceutical formulation, characterized in that the fragment represents 40 to 60 and particularly very preferably 45 to 55 or about 50. The method according to any one of the preceding claims, wherein the coated microparticles of the AP have an average diameter of 1000 μm or less, preferably 50 to 800 μm, even more preferably 100 to 600 μm and very much more preferably. Pharmaceutical formulations, characterized in that 100 to 300 ㎛. The method of any one of the preceding claims, wherein the coated microparticles for modified release of AP are used to maintain modified release for at least some of the coated microparticles of AP for modified release of the AP during tablet manufacture. Pharmaceutical coating, characterized in that it has an outer coating that is designed in a manner that contributes to the outer coating, wherein the outer coating consists of at least one deformable organic component having a melting point of 40 to 120 ° C., preferably 45 to 100 ° C. 12. The method of claim 11, wherein the outer coating represents from 5 to 50% dry weight, preferably from 10 to 30% and even more preferably about 20% relative to the total weight of the overcoated microparticles of the AP. Pharmaceutical formulation. 3. The at least one thickener (Vb) according to claim 2 and any other of the foregoing, as required, from those soluble in one or more of the following solvents: water, alcohols, ketones and mixtures thereof. Wherein said thickener is capable of increasing the viscosity of the extract to prevent misuse, in particular by misuse by injection. 14. A process according to claim 13, wherein the thickener (Vb) is the next polymer group, i.e. Polyacrylic acids and derivatives thereof and / or Polyalkylene glycols (eg polyethylene glycol) and / or Polyalkylene oxides (such as polyethylene oxide) and / or Polyvinylpyrrolidones and / or Gelatins and / or Polysaccharides, preferably sodium alginate, pectins, guars, xanthans, carrageenins, gallans and cellulose derivatives (eg hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose) Polysaccharides selected from the group comprising carboxymethyl cellulose, Mixtures thereof Pharmaceutical formulation, characterized in that selected from. The method according to claim 13 or 14, wherein the thickener (Vb) is, for example, a high molecular weight polyoxyethylene having a molecular weight of 1 million to 8 million g / mol, such as 2 million, 5 million or 7 million g / mol. Pharmaceutical formulation. The method of claim 13, wherein the one or more thickeners (Vb) are In and / or on the surface of microparticles and / or In the outer sheath of all or part of the microparticles of the AP, and / or A pharmaceutical formulation characterized in that it is present in a free state, ie contained in or not supported by the microparticles. The method according to any one of claims 13 to 16, wherein the thickener (Vb) is used to capture the AP extracted in the viscous medium, so that the viscosity of the liquid used for possible extraction is 100 mPa.s in 2.5 ml of extraction. Pharmaceutical formulations, characterized in that can be increased more than. The pharmaceutical formulation of claim 13, wherein at least a portion of the thickener (Vb) is in the form of microparticles that are inseparable from the coated or uncoated microparticles of the AP. . The pharmaceutical composition according to any one of claims 3 to 20, wherein the containment agent Q contains a salt containing ions capable of forming a complex in the form of a solution with the extracted AP salt. Formulation. The pharmaceutical formulation of claim 19, wherein the ions of the containment agent Q are organic ions that are opposite in polarity to that of the AP in solution form forming a complex in solution form with the extracted AP salt. The pharmaceutical formulation of claim 19 or 20, wherein the containment agent Q is in a first phase that is separated from at least one second phase, and the second phase contains at least one AP salt. The pharmaceutical formulation according to any one of claims 19 to 21, which contains microparticles of the AP salt and microparticles of the containment agent Q. The pharmaceutical formulation of claim 22, wherein the microparticles are similar in size distribution and density and cannot be separated into a sieve. The pharmaceutical formulation of claim 20, wherein the ions of opposite polarity to that of the AP in solution form are organic anions. The method of claim 19, wherein the containment agent Q is Organic anionic salts such as sodium dodecyl sulfate or sodium docusate, (Meth) acrylic copolymers (e.g. Eudragit ^® S and Eudragit ^® L), cross-linked polyacrylic acids (e.g. Carbopol), carboxymethylcellulose and their derivatives, cross-linked carboxymethylcellulose and their Derivatives and other polysaccharides (such as alginates, xanthan gum or gum arabic) and anionic polymers such as alginic acid / (sulfonate) propylene glycol, -Glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipicates ( adipates), monovalent or polyvalent salts such as benzoate, salicylate, tartarate, sulfonamide, acesulfame, Saponified fatty acids such as acetates, succinates, citrates, stearates, palmitates and self-emulsifying glyceryl monooleate; Polyamino acids, proteins or peptides such as albumin, casein, globulin and enzymes, Mixtures thereof A pharmaceutical formulation containing a salt selected from the group consisting of. The pharmaceutical formulation of claim 20, wherein the ions of opposite polarity to that of the AP in solution form are organometallic cations or mixtures thereof. The method of claim 19, wherein the containment agent Q is -Acesulfame, acetate, adipic acid, benzoate, carbonate, chloride, citrate, fluoride, fumarate, gluconate, gluconate, glycerophosphate, hydroxides, iodide, iodide, lactate, oxide, Cationic salts such as phosphates, trisilicates, salicylates, succinates, sulfonamides, tartrates, metals Ca, Fe, Mg or Zn, Quaternary ammonium salts, especially organic cationic salts such as trimethyl tetradecyl ammonium bromide or benzetonium chloride, Cationic polymers such as chitosan and (meth) acrylic copolymers (such as Eudragit ^® RS, Eudragit ^® RL or Eudragit ^® E), Polyamino acids, proteins or peptides, Mixtures thereof A pharmaceutical formulation containing a salt selected from the group consisting of. 24. The method according to any one of claims 19 to 23, wherein said containment agent Q is a salt of an ion exchange resin, preferably a strong acid cation exchange resin when AP is a cation, or a strong base anion exchange resin when AP is an anion. Pharmaceutical formulation. The pharmaceutical formulation of claim 28, wherein the containment agent Q is a derivative of styrene / divinylbenzene copolymer. The pharmaceutical formulation of claim 28, wherein the containment agent Q is a derivative of a sulfonated styrene / divinylbenzene copolymer. The pharmaceutical formulation of claim 28, wherein the containment agent Q is a derivative of a styrene / divinylbenzene copolymer having quaternary ammonium groups bonded thereto. The pharmaceutical formulation of claim 28, wherein the containment agent Q is one of crosslinked methacrylic acid / divinylbenzene copolymers or salts thereof. The pharmaceutical formulation of claim 28, wherein the ion exchange resin is a phenol polyamine. 34. The method of any one of claims 19 to 33, wherein the containment agent Q is Organic anionic salts such as sodium dodecyl sulfate or sodium docusate, Quaternary ammonium salts, especially organic cationic salts such as trimethyl tetradecyl ammonium bromide or benzetonium chloride, -Strong base anion exchange resin or strong acid cation exchange resin according to AP polarity Pharmaceutical formulation. The method of claim 19, wherein the containment agent Q is When the AP is a cation, a strong acid cation exchange resin and mixtures thereof, Strong base anion exchange resins and mixtures thereof when AP is an anion Pharmaceutical formulation. 36. The method of any one of claims 19 to 35, wherein the at least one containment agent Q is Among microparticles without AP, and / or On the surface of the microparticles and / or In a glass state, ie contained in or not supported by microparticles Pharmaceutical formulation as present. 37. The pharmaceutical formulation of any one of claims 19-36, wherein the amount of containment Q is adjusted in terms of ionic charge to complex all or part of the dosage of AP contained in the unit dosage form. . 38. The pharmaceutical formulation according to any one of claims 19 to 37, wherein the containment (Q) is in the form of microparticles that cannot be separated from the coated or uncoated microparticles of the AP. 39. The composition of any one of claims 19-38, wherein the microparticles of thickener V and / or the microparticles of containment Q are contained, the microparticles of thickener V and the microparticles of containment Q are A pharmaceutical formulation that is separate from the microparticles. 40. The microparticles of any one of claims 19-39 contain microparticles of AP as well as microparticles of thickener V and / or microparticles of containment Q, wherein the microparticles have a size distribution and a density. Pharmaceutical formulations, similarly inseparable from each other by a sieve. The method of claim 1, wherein the formulation contains one or more excipients in the free state, ie, contained in or not supported by the microparticles of the AP, wherein the excipient is coated with the AP. A pharmaceutical formulation, characterized in that it contributes to the grinding resistance of the fine particles. The excipient of claim 41, wherein the excipient in free state, Calcium stearate, Glycerol palmitostearate, Magnesium oxide, Polyalkylene glycols, such as polyethylene glycols, Polyvinyl alcohol, Sodium benzoate, Stearic acid, -Cornstarch, -Talc, Colloidal silicon, Zinc stearate, magnesium stearate, Stearyl fumaric acid, Mixtures thereof Pharmaceutical formulations, characterized in that selected from the group consisting of. The pharmaceutical formulation according to any one of the preceding claims, which cannot be converted to an immediate release dry formulation of an AP which can be administered nasal. The pharmaceutical formulation according to any one of the preceding claims, which cannot be converted to an immediate release injection formulation of an AP. The pharmaceutical formulation according to any one of the preceding claims, characterized in that it contains immediate release AP and / or modified release AP. Pharmaceutical formulation according to any one of the preceding claims, characterized in that the extraction of AP by chewing and / or grinding is inefficient. The method according to any one of the preceding claims, wherein the AP used is amphetamines, anesthetics, anorexic, analgic, antidepressant, antiepileptics, antimigraine, antiparkinsonism, antitussive, anxiolytic A pharmaceutical formulation characterized by belonging to at least one of, barbituric acid, benzodiazepines, hypnotiqcs, laxatives, neuroleptics, opiates, psychostimulants, antipsychotics, sedatives and stimulants. The method according to any one of the preceding claims, wherein the AP used is anileridine, acetorpine, acetylalpha-methylpentanyl, acetyldihydrocodeine, acetylmethol, alfentanil, allylprodine, alpha-cetylmethol , Alpha-meprodine, alpha-prodine, alpha-methol, alpha-methylpentanyl, alpha-methylthio-pentanyl, anilridine, atropine, butorpanol, benzetidine, benzylmorphine, beta-hydroxypentanyl , Beta-hydroxy-methyl-3-pentanyl, beta-cetylmethol, beta-meprodine, beta-methol, beta-prodine, benzitramide, buprenorphine, dioxafetyl butyrate, clonitazene , Cyclazosin, cannabis, cetobemidone, clonitogen, codeine, coca, cocaine, cordoxime, dezosin, dimenoxadol, dioxapetylbutyrate, dipipanone, desormorphine, dextromeoramide, dex Tropropoxyphene, Diampromide, Diethyl Thiabutene, Diphenoxine, Dihydro Dane, dihydroetropin, dihydromorphine, dimenoxaldol, dimepeptanol, dimethyl thiambutene, diphenoxylate, dipipanone, drothebanol, epthazocin, etoheptazine, ethylmethyl thiambutene , Ethyl morphine, etonitogen, exonin, ephedrine, etopin, ethylmethylthiabutene, ethyl morphine, etonitogen, etopine, ethoxeridine, fentanyl, furetidine, heroin, hydrocodone, hydromor Pinol, hydromorphone, hydroxypettidine, isometadon, ketobemidone, levalophane, levallorphane, lefentanil, levomethorphan, levomoramide, levofenacylmorphan, levorpanol, meptazinol , Meperidine, metazosin, methadone, methyldesorphine, methyldihydromorphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-pentanyl, metophon, moramide, Morperidine, Morphine, Miropine, Nalbuphine, Narcein, Nicomorphine, Norreborpa , Normetadon, nalophine, normorphine, nicocodine, nicodicodine, nicomorphine, noasimethadol, norcodeine, norreborpanol, normethadon, normorphine, norfipanone, opium, oxycodone, oxymor Von, papaveretum, phenadoxone, phenoferidine, promethol, properidine, propiram, propoxyphene parafluoropentanyl, pentazosin, fetidine, phenapromide, phenazosin, phenomorphan, phenoferri Dean, polcodine, piminodine, pyritramide, propheptazine, propanolol, properidine, propyran, racemetorphan, racemoamide, racemopan, remifentanil, sufentanil, thebacon, The pharmaceutical formulation, characterized in that it is selected from thebaine, thiopentanyl, tilidine, trimeperidine, tramadol, pharmaceutically acceptable salts, esters, hydrates, polymorphs and isomers thereof, and mixtures thereof. The pharmaceutical formulation according to any one of the preceding claims, wherein the AP used is selected from the group consisting of oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride and tramadol hydrochloride. The pharmaceutical formulation according to any one of the preceding claims, wherein the pharmaceutical formulation is free of AP antagonist (s). The pharmaceutical formulation of any one of claims 1-49, wherein the pharmaceutical formulation contains at least one AP antagonist. The pharmaceutical formulation of any one of the preceding claims, comprising a plurality of populations of coated microparticles of AP, said populations being distinguished from one another by the rate of release and / or the AP they contain. Use for the preparation of a novel pharmaceutical formulation of the coated microparticles of the AP described in the foregoing paragraphs for modified release of the AP. Use for the preparation of a new pharmaceutical formulation active in the treatment of pain in the coated microparticles of the AP as described in claims 1-52 for modified release of the AP. 53. A method for preventing misuse of an AP, comprising essentially using the pharmaceutical formulation of any one of claims 1-52. Consisting essentially of the coated microparticles of the AP for modified release of the AP in a pharmaceutical formulation, the microparticles being ground to the coated microparticles of the AP to ensure modified release of the AP and at the same time prevent misuse. One or more thickeners (Vb) capable of preventing the extraction of the AP contained in the coated microparticles of the AP in order to prevent the misuse as necessary, and the misuse as necessary. Contains a containment agent (Q) capable of preventing extraction of the AP contained in the coated microparticles of the AP for strain release of the AP, and the coating agent (Ra), if present, the thickener (Vb). And, if present, said containment agent (Q) as described in claims 1-52.

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