JP2009537456A - Prevention of misuse fine particle - Google Patents

Abstract

  The present invention relates to a solid fine particle oral pharmaceutical form having a composition and structure that prevents misuse of a pharmaceutically active ingredient (AP) contained therein. An object of the present invention is to prevent improper use of solid oral drugs for any use other than therapeutic use officially approved by a qualified public health organization. In other words, it is intended to prevent misuse due to deliberate or negligent use of solid oral drugs. The present invention ensures that it contains anti-misuse measures, that at least part of the AP it contains is contained in a coated microparticle for modified release of AP, and that the coated microparticle of AP ensures modified release of AP. At the same time, the present invention relates to a solid oral pharmaceutical form characterized by having a coating layer (Ra) that imparts crush resistance to the coated fine particles of AP so as to prevent misuse.

Description

  The present invention relates to solid particulate oral pharmaceutical forms whose composition and structure make it possible to avoid misuse of the pharmaceutical or veterinary active ingredient (AP) they contain.

  Active ingredients (AP) in question are those that fall into the category of pharmaceutical or veterinary drugs AP, such as anesthetics, analgesics or narcotics. Misuse of these pharmaceutically active ingredients can cause drug addiction.

  For the purposes of this disclosure, the expression “AP” means both a single active ingredient and a mixture of several active ingredients.

  Microparticle pharmaceutical form is understood in the context of the present invention to mean any form in which AP is contained in microparticles of less than 1000 μm. Such particles comprising AP may be coated microparticles for modified release of AP. In the latter case, the microparticles are coated with a polymer film that controls the release rate of the AP, for example after oral administration.

<Problem presentation>
The object of the present invention is to prevent misuse of solid oral drugs for any use other than therapeutic use officially approved by a qualified public health organization. In other words, the aim is to avoid misuse due to deliberate or negligent use of solid oral drugs.

Misuse occurs mainly in the following cases.
a) Addiction (drug addiction, doping),
b) criminal behavior (chemical subjection),
c) Use of drugs in a form that does not meet medical recommendations (dose) due to inattention or inability to affect the patient.

In case a. (Or even in case b.), A person trying to misuse a solid oral drug generally attempts to extract the AP from the modified release form to obtain an immediate effect form, and then
-Change to powder form by crushing for inhalation or swallowing,
-Either in a liquid form that can be injected with a syringe or swallowed.

  Preparation of a liquid form from a solid oral drug involves an intermediate step for aqueous or organic extraction of the AP in question. This extraction is generally preceded by grinding.

  The method of administration by inhalation or injection is particularly suitable for drug addicts. This is because these are methods that can further strengthen the influence of AP and facilitate its absorption in the living body in a short time. When the powder obtained by crushing is inhaled or dissolved in water, the desired doping or euphoria of AP appears in a very rapid and intensified form.

  Currently there are also particularly serious undesirable effects affecting teenagers and involving analgesic AP (aAP), especially morphine and opium derivatives. In fact, teenagers prepare vodka cocktails for their peers using oxycodone that they easily extract from tablets with water and alcohol. The method consists in crushing the tablet, pouring the powder into a glass of vodka or water and then waiting for sufficient time to fully extract the morphine derivative, which can subsequently be absorbed.

  A solid oral drug may also be misused by chewing the drug before swallowing instead of swallowing it immediately according to the dose instructions.

  The risks associated with addictive behavior (a.) And criminal activity (b.) Are obvious. Drug misuse by injection is worse and it is pointed out that excipients can cause local tissue necrosis, infections, and respiratory and heart damage.

  With regard to drug misuse associated with inattention and / or patient disability (c.), This can also have serious consequences. For example, chewing a modified release form of AP before swallowing changes the drug to an immediate release form. Thus, at best, the drug will be ineffective after a very short time, and in the worst case it will be toxic.

  Thus, there are clearly significant public health problems related to misuse of drugs, especially solid oral drugs and especially those based on analgesics or narcotics. This growing phenomenon is of greater concern to health institutions in the United States and Europe, which are increasingly appealing, especially for the development of pharmaceutical forms that prevent misuse.

<Prior art>
US Pat. No. 6,696,088 relates to a multiparticulate oral pharmaceutical form that is believed to be less susceptible to misuse. It includes modified release forms of opioid agonist AP particles and particles comprising opioid antagonists. Forms comprising the antagonist are described as releasing less than 36%, preferably less than 6.2% antagonist AP over a 36 hour period. The two types of particles are interdispersed.

  If misused, the micronization of the microparticles to extract opioid AP results in the immediate and simultaneous release of AP and its antagonist, thereby limiting the desired effect of the misused opioid.

  The inventors understand that the invention is based on the use of active substances other than AP, and presents, among other things, a solution for reducing the effects of grinding or reducing the extraction of AP. Absent.

  US patent application US-A-2003 / 0068371 describes an oral formulation comprising an opiate AP (oxycodone), an antagonist of this AP (naloxone) and a gelling agent (eg xanthan gum). In particular, said US patent application discloses matrix granules of AP comprising an outer coating based on lactose, xanthan gum, povidone and EUDRAGIT RS 30D® / triacetin / antagonist. A gelling agent has been shown to impart a viscosity to the formulation that it cannot be administered nasally or parenterally. As we understand, this answer is insufficient. This is because according to the invention, the use of an antagonist is particularly essential. Finally, this formulation does not contain anti-grinding means, so it can be converted to a powder form and as a result can be subject to misuse by the nasal or oral route.

  International patent application WO-A-03 / 013479 describes an oral pharmaceutical form comprising a pharmaceutically effective amount of an opiate analgesic and an opiate antagonist (naltrexone) together with a bitterness enhancer. When a drug addict crushes the tablet, the opioid and its antagonist are released. The opioid effect is therefore neutralized. As we understand, this system does not make it possible, inter alia, to prevent selective extraction of opioids with water without grinding.

  In general, the use of antagonists is not without disadvantages in terms of the medical risks that may be made by the user and the risks of inhibiting the intended therapeutic effect.

  International patent application WO-A-2004 / 054542 discloses a semi-liquid oral pharmaceutical form. It takes the form of capsules (eg gelatin capsules) containing AP in a matrix phase consisting of a water-insoluble highly viscous liquid (sucrose acetic acid isobutyric acid) and a polymer (cellulose acetic acid butyric acid), possibly forming a network in the liquid phase. The formulation can optionally include a compound that modifies the rheology of the pharmaceutical form, and a solvent. By varying the concentration of various compounds and formulations, the authors state that the plasma profile of AP (oxycodone based) administered to dogs can be altered. As we understand, this reference provides, inter alia, a solution to prevent misuse by injection since the viscosity of this formulation is clearly reduced by the addition of small amounts of ethanol. Not.

  US patent application US-A-2003 / 0224051 describes osmotic forms for modified release of oxycodone. This form consists of a tablet comprising a core of oxycodone or a salt thereof, a semipermeable membrane enclosing at least part of the core, and an outlet in the membrane to allow release of oxycodone. This type of tablet allows the opioid to be easily extracted, for example by immersion in water for at least 12 hours. As we understand, this tablet is not a suitable solution to the problem of misuse.

  European patent application EP-A-1 293 209 discloses a misuse-preventing oral pharmaceutical form for sustained release of opioid derivatives (AP) contained in an ion exchange resin. The resulting AP / resin complex makes it possible to limit the plasma concentration obtained after misuse by chewing, inhalation or injection to a much lower therapeutic concentration as required by the misuser. The AP / resin composite takes the form of a matrix. As understood by the present inventors, no means for preventing crushing is provided in the pharmaceutical form according to the prior art document. Furthermore, this pharmaceutical form does not contain means for combating solvent extraction of AP. It therefore does not prevent AP solvent extraction, although the extraction time is longer than the normal release time of AP. When this oral pharmaceutical form is left in a glass of water for 24 hours, virtually all AP is extracted.

US Patent Applications US-A-2003 / 0118641 and 2005/0163856 (= International Patent Publication WO-A-01 / 08661) are oral pharmaceuticals for the sustained release of AP consisting of opioid compounds (analgesics) and their salts. The formulation is described. These formulations probably prevent misuse by extraction of AP using common solvents. The possibility is thought to be even more discouraged, but these misuse prevention formulations do not contain antagonists. These formulations are
-Hydrophilic matrix agent (hydroxyalkylcellulose) in an amount of 40% to 65% by weight;
-Ion exchange resins (particles smaller than 50 μm in an amount of 5% to 15% by weight);
-And at least one opiate AP
A mixture of

  After mixing the usual compression additives, the mixture is processed into tablets.

  This is therefore a macroscopic matrix system comprising particles of ion exchange resin complexed with AP and anti-extraction means consisting of a viscosifier, preferably hydroxypropylmethylcellulose. As understood by the inventors, this system can be improved, particularly with regard to its misuse prevention effect.

  International Patent Publication WO-A-2005 / 079760 to be inserted discloses a pharmaceutical preparation composed of rubbery fine particles of AP obtained by extrusion, which has sustained release of AP and has anti-misuse properties. These extruded microparticles comprise a matrix formed from an inert poly (ethyl acrylate / methyl methacrylate) copolymer: EUDRAGIT® NE 30D or NE 40D. This matrix comprises AP (oxycodone), another Eudragit®, RS PO, plasticizer and lubricant.

  Misuse is prevented by anti-grinding means that only include the rubbery character of the matrix particles for modified release of AP. To our understanding, no means are provided to combat the extraction of AP in a solvent.

As we understand the prior art, none of the previously proposed misuse prevention solutions is sufficient, especially with respect to preventing unauthorized extraction of AP with water, alcohol or other drinkable solvents. is not.
US patent US-B-6 696 088 US patent application US-A-2003 / 0068371 International patent application WO-A-03 / 013479 International patent application WO-A-2004 / 054542 US patent application US-A-2003 / 0224051 European patent application EP-A-1 293 209 US patent application US-A-2003 / 0118641 US patent application US-A-2005 / 0163856 International Patent Publication WO-A-01 / 08661 International Patent Publication WO-A-2005 / 079760 European patent EP-B-0 709 087 International Patent Publication WO-A-03 / 030878 International Patent Application WO-A-03 / 077888 Remington's The science and practice of pharmacy, 19th edition, Mack Publishing Co., Pennsylvania, USA Formes pharmaceutiques nouvelles: aspects technologique, biopharmaceutique et medical (New pharmaceutical forms: technological, biopharmaceutical and medical aspects) by Buri, Puisieux, Doelker and Benoit, editions Lavoisier 1985, pages 175 to 227

<Object of invention>
Under these circumstances, one of the objects of the present invention is to overcome the drawbacks of the prior art.

  Another object of the present invention is preferably without the use of substances other than AP, or AP inhibitors, such as AP antagonists, which are pharmaceutically active and therefore potentially dangerous to the user, especially as described above. For the referenced cases (a.), (B.) And (c.), To provide a novel solid oral drug that makes its misuse difficult if not impossible.

  Another object of the present invention is to avoid misuse, especially for the cases (a.) (B.) (C.) Referred to above, even after `` long-term '' liquid extraction of AP (e.g. analgesics). It is to provide a new solid oral drug that makes it difficult if not possible. For the present disclosure, “long-term” liquid extraction is extraction that lasts longer than 10 minutes.

  Another object of the present invention is to provide a novel solid oral drug that prevents misuse by short-term liquid extraction and / or grinding.

Another object of the present invention is to provide a novel solid oral drug having the following properties: Ie:
-Under normal conditions of administration, these solid oral drugs have a therapeutic effect, for example 12 hours or 24 hours;
-Any attempt to tamper with AP (eg, an analgesic) changes the drug into a form such that rapid absorption of AP in the bloodstream is not possible after it has been ingested.

Another object of the present invention is to
-Can be easily administered to patients who have difficulty swallowing large tablets, e.g. serious patients, infants or children;
-Allows some APs to be combined in one and the same dosage unit, even if some APs are not compatible with each other and / or have the same release kinetics;
-To provide a novel solid oral drug that can be administered once or multiple times a day and can exist in a form that allows the release rate and time of different APs to be adjusted easily and independently It is.

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

  Another object of the present invention is to convert any drug beyond the therapeutic limit into a form that can be taken orally, nasally and / or by injection (intravenous, subcutaneous, intramuscular, etc.). It is to provide a novel solid oral drug that makes it possible to prevent unauthorized abuse of the properties of the APs they contain. This prevents or at least greatly reduces the risks associated with this undesirable behavior.

  Another object of the present invention is to allow a patient undergoing normal follow-up treatment to avoid misuse while simultaneously ensuring that the quality of treatment and, in particular, a dose that meets his needs. It is to provide a novel solid oral drug.

  Another object of the present invention is that it does not affect the pharmacological properties of the drug, and does not endanger the patient who normally uses the drug, and finally comforts the patient when the drug is administered. It is to provide a novel solid oral drug that makes it possible to avoid misuse without sacrificing it.

  Another object of the present invention is to provide a novel solid oral drug that can be administered one or more times per day and can limit the risk of tissue damage due to local overconcentration of AP.

  Another object of the present invention is to provide a novel solid oral drug that can take various galenical forms such as tablets, powder sachets, capsules and the like.

  Another object of the present invention is to provide a novel misuse-proof solid oral drug that is easy and economical to prepare.

  In order to achieve these objectives, it is the inventors' honor to reformulate the general problem of misuse of pharmaceutical forms.

  When different illegal modes of administration of the active ingredient are attempted, grinding the dry form usually appears to be an essential step.

  In case of misuse by nasal administration, the dry pharmaceutical form must first be converted into a fine powder suitable for inhalation through the nose. Grinding the pharmaceutical form is therefore definitely an essential step.

  In the case of misuse by oral administration in sustained release dry form, it is necessary to facilitate the release of the active ingredient by finely grinding the microparticles or tablets.

  In the case of misuse by parenteral administration, AP should first be sufficiently high to avoid injecting excessive amounts, e.g. greater than 1 ml, into the liquid phase, which is actually water or an organic solvent. Need to be extracted. This extraction step is facilitated by a previous step in which the dried form is ground so that the active ingredient can be dissolved or suspended. Furthermore, misuse is possible only after this extraction stage if the viscosity of the liquid is not too high (eg less than or equal to 100 mPa.s).

  Therefore, grinding in dry form is also an essential step for misuse of the pharmaceutical form by parenteral administration.

-The first problem of preventing crushing of systems containing AP (a);
-And the second problem of preventing misuse of AP after its possible extraction (b)
It is the honor of the applicant to reformulate the problem of combating misuse of dry pharmaceutical forms by characterizing

  This novel approach allows applicants to surprisingly and unexpectedly provide APs in the form of coated microparticles for modified release of APs in drug compositions that are required to prevent their misuse. , In some cases, a pharmaceutically acceptable excipient in particulate or non-particulate form that allows the physicochemical mode of action to prevent or even prevent the act of any intentional or negligent misuse It was found that it was appropriate to incorporate a combination of agents.

  Therefore, the present invention mainly includes that it includes a means for preventing misuse, that at least part of the AP it contains is included in the coated microparticles for modified release of AP, and that the coated microparticles of AP are of AP. The present invention relates to a solid oral pharmaceutical form characterized by having a coating layer (Ra) that imparts crush resistance to coated microparticles of AP in order to ensure modified release and at the same time avoid misuse.

  The pharmaceutical form according to the invention solves the major problems indicated, in an effective, simple and economical way, inter alia, using physicochemical means and meets at least some set objectives. The latter is completely harmless to normal users. They are pharmacologically inactive compounds that are approved by the pharmacopoeia and public health authorities responsible for drug marketing authorization.

  In one preferred embodiment, the solid oral pharmaceutical form according to the present invention comprises, in addition to an anti-milling coating layer (Ra), an AP contained in coated microparticles of AP to avoid misuse of AP after liquid extraction. At least one thickener (Vb) that makes it difficult if not impossible to extract.

  For the purposes of this disclosure, the expression “thickener” means both a single thickener and a mixture of several thickeners.

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

  The active ingredients (AP) contemplated in the present invention are those that fall into the category of pharmaceutical or veterinary drugs AP, such as analgesics or narcotics. Misuse of these APs can cause drug addiction.

  In the context of the present invention, the expression “AP” means one active ingredient or a mixture of several active ingredients.

  In the context of the present invention, “particulate form” is understood to mean any pharmaceutical form in which the AP is contained in microparticles less than 1000 microns. These particles containing AP may be microparticles that are individually coated with a film for modified release of AP. In the latter case, the microparticles are coated, for example, with a polymer base film that controls the rate at which AP is released.

  In this disclosure, “modified release form” means a form in which at least a portion of the AP is released at a slower rate compared to the rate of the immediate release form. This portion may be, for example, between 1% and 100%, preferably between 10% and 100% and particularly preferably between 30% and 100%. In particular, the modified release can be lengthened and / or delayed and / or can be in the form of one or more release peaks (pulses). Modified release formulations are well known in the art, see for example, Remington's The science and practice of pharmacy, 19th edition, Mack Publishing Co., Pennsylvania, USA.

  In this disclosure, “immediate release form” means a form that releases the majority of the AP it contains over a relatively short period of time, ie, at least 70% of the AP is 1.4 to 6.8 in an in vitro dissolution test. Is released in 1 hour, preferably 30 minutes, at any pH between.

  All in vitro dissolution profiles quoted in this disclosure are shown in the European Pharmacopoeia No. 4 entitled “Solid Oral Form Dissolution Test”: Type II Dissolution Test with stirring at 75 rpm under SINK conditions at 37 ° C. Obtained as shown in the plate.

  The pharmaceutical formulation according to the invention is therefore a formulation for the modified release of AP.

  In the context of the present invention, “pharmaceutical formulation” should be broadly understood, ie the phrase also includes animal formulations and dietary formulations.

  The pharmaceutical formulation can also include one or more forms for immediate release of AP.

  Advantageously, the pharmaceutical formulation according to the invention is novel in its structure, composition and composition, eg present in the form of a tablet, a powder sachet, a multi-dose reconstitutable suspension powder sachet, or a capsule. can do.

<AP coated fine particles>
Coated microparticles for modified release of AP are advantageously microparticles each coated with at least one coating agent (e.g. comprising at least one polymer) deposited by techniques known to those skilled in the art. is there. For example, the following study can examine this issue. Formes pharmaceutiques nouvelles: aspects technologique, biopharmaceutique et medical (new pharmaceutical forms: technical, biopharmaceutical and medical aspects) by Buri, Puisieux, Doelker and Benoit, editions Lavoisier 1985, pages 175 to 227.

  In other words, these coated microparticles preferably consist of a core each containing an AP and a coating, the coating enveloping the core (preferably completely) and controlling the modified release (preferably continuous) of the AP. Includes a coating layer. This release occurs when the coated microparticles of AP are brought into contact with the gastrointestinal fluid.

Uncoated microparticles of AP (i.e. before coating), for example:
-An inert core covered with at least one layer containing AP;
-Or pure AP particulates;
-Or it may be a granule formed from a matrix of support excipients containing AP.

  In the case of support granules, the inert core or support may be composed of sucrose and / or saccharose and / or dextrose and / or lactose and / or a sucrose / starch mixture. The inert core or support may be cellulose microspheres or any other particle of a pharmaceutically acceptable excipient. Xanthan gum, guar gum, calcium phosphate or calcium carbonate particles can be mentioned as non-limiting examples of inert supports. Their average diameter may be between 10 and 200 microns, between 20 and 150 microns, or between 50 and 100 microns.

  These coated microparticles (or individually coated microparticles) of the “container” type can be compared to transport means for transport and release of at least one AP in the small or even large intestine.

  Mentionable examples of coated microparticles for modified release of AP are those described in the following patent documents: European Patent EP-B-0 709 087 and International Patent Publication WO-A-03 / 030878.

<Coating of AP fine particles>
Advantageously, the coated microparticles of AP have at least one coating layer (Ra), preferably only one, which imparts crush resistance to the coated microparticles of AP to ensure modified release of AP and avoid misuse at the same time. Including a coating layer (Ra).

  Particularly preferably, the coating layer (Ra) is designed to allow non-immediate (i.e. modified) release maintenance due to at least some of the coated microparticles for modified release of AP in the case of grinding. The

  The pulverization expected here is, for example, any pulverization performed by techniques normally used by misusers, i.e., in particular, mortar / grinding, coffee grinder, between two spoons, chewing / chewing etc. It may be.

  In one useful embodiment, the coating layer (Ra), in the case of grinding, is a modification of at least 40%, preferably at least 60% and particularly preferably at least 80% of the coated microparticles for modified release of AP. Designed to allow release maintenance.

Preferably, the anti-crush 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) optionally at least one surfactant and / or lubricant and / or inorganic filler and / or organic filler (A4)
including.

According to a purely illustrative choice of the present 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 (e.g. methyl) esters, copolymers of acrylic and methacrylic acid esters having at least one quaternary ammonium group (preferably alkyl (meth) acrylates and trimethylammonium At least one copolymer of oethyl methacrylate chloride), and more precisely a product marketed under the trademark EUDRAGIT® RS and / or RL,
-Polyvinyl acetate,
-As well as selected from the group comprising mixtures thereof;
(A2) is
A nitrogen-containing (co) polymer from the group comprising preferably polyacrylamide, poly-N-vinylamide, polyvinylpyrrolidone (PVP) and poly-N-vinyllactam,
-Water-soluble cellulose derivatives,
-Polyvinyl alcohol (PVA),
-Polyalkylene oxides, preferably polyethylene oxide (PEO),
-Polyethylene glycol (PEG),
-As well as selected from the group comprising mixtures thereof, PVP being particularly preferred;
(A3) is
-Cetyl alcohol ester,
-Preferably the following subgroups: glycerol and its esters from acetylated glycerides, glycerol monostearate, glyceryl triacetate and glycerol tributyrate,
-Preferably the following subgroups: phthalates from dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,
-Preferably the following subgroups: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, citrate from triethyl citrate,
-Preferably the following subgroups: diethyl sebacate, sebacate from dibutyl sebacate,
-Adipate,
-Azelate,
-Benzoate,
- Vegetable oil,
-Fumarate, preferably diethyl fumarate,
-Malate, preferably diethyl malate,
Oxalate, preferably diethyl oxalate,
-Succinate, preferably dibutyl succinate,
-Butyrate,
-Cetyl alcohol ester,
-Salicylic acid,
-Triacetin,
-Malonate, preferably diethyl malonate,
-Castor oil (this is particularly preferred),
-As well as selected from the group comprising mixtures thereof;
(A4) is
-Anionic surfactants from the subgroup, preferably comprising alkali metal or alkaline earth metal salts of fatty acids (preferably stearin and / or oleic acid),
-And / or preferably the following subgroups:
-Polyethoxylated oil, preferably polyethoxylated hydrogenated castor oil,
-Polyoxyethylene / polyoxypropylene copolymer,
-Polyethoxylated sorbitan ester,
-Polyethoxylated castor oil derivatives,
-Stearates, preferably calcium stearate, magnesium, aluminum or zinc,
-Stearyl fumarate, preferably sodium stearyl fumarate,
-Glycerol behenate,
-Talc powder,
-Colloidal silica,
-Titanium oxide, magnesium oxide,
-Bentonite,
-Microcrystalline cellulose,
-Kaolin,
-Aluminum silicate,
-As well as selected from the group comprising nonionic surfactants from mixtures thereof.

In addition to the qualitative parameters that define the coated microparticles according to the invention, according to an advantageous quantitative aspect, the coating layer (Ra) is based on the following weight percent with respect to the total weight of the coating:
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
Can be specified to include (the sum of percentages equals 100).

In addition, the release rate is, for example:
-By controlling the thickness of the coating (Ra);
-Adjusted by the weight ratio between components A1, A2, A3 and possibly A4 of the coating (Ra).

  Advantageously, the coating on the coated microparticles for modified release of AP includes, inter alia, in addition to the basic components A1, A2, A3 and optionally A4, colorants, pigments, preservatives, flavorings etc. and Other conventional ingredients known to those skilled in the art such as mixtures thereof can be included.

  Another notable feature of the coating (Ra) on the coated microparticles is that the coating layer (Ra) exhibits a weight fraction Tp expressed in dry weight% relative to the total weight of the coated microparticles, such as Tp ≧ 15. The Tp is preferably between 30 and 60, particularly preferably between 40 and 60 and very particularly preferably between 45 and 55 or about 50.

  Without wishing to be bound by theory, this relatively high coverage ratio imparts crush resistance to the coated fine particles of the AP so that the coating layer (Ra) ensures modified release of the AP and at the same time avoids misuse. Is possible.

  Without limitation, preferred coated microparticles of AP according to the invention have an average diameter of 1000 μm or less, preferably between 50 μm and 800 μm, particularly preferably between 100 μm and 600 μm and very particularly preferably between 100 μm and 300 μm. It is.

  Unless otherwise indicated, the diameters of the microparticles referred to in this disclosure are volume average diameters.

  With respect to the preparation of coated microparticles, techniques advantageously used for depositing coatings for modified release of AP, or depositing active layers based on AP, are known to those skilled in the art, such as in a fluidized air bed. Spray coating, wet granulation, compression or extrusion / spheronization.

<External coating>
In one particular variation of the invention, the coated microparticles for modified release of AP maintain at least some modified release of said coated microparticles of AP for modified release of AP in the manufacture of tablets. Has an outer coating designed to contribute. The outer coating consists of at least one deformable organic component having a melting point between 40 ° C. and 120 ° C., preferably between 45 ° C. and 100 ° C.

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

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

  In another variant, the deformable organic component of the outer coating is a fat comprising, for example, hydrogenated vegetable oils, fatty acids, fatty alcohols, fatty acids and / or fatty alcohol esters, polyolefins, and minerals, vegetable, animal or synthetic waxes. Fats or mixtures of fats selected from the group of which are particularly preferred are fatty acid esters such as diglycerides and triglycerides and mixtures thereof, glycerol behenate and hydrogenated castor oil, soybean oil, cottonseed oil and coconut oil .

In one further variation, the outer covering is
-Inorganic fillers such as silica or titanium dioxide, or organic fillers such as microcrystalline cellulose,
-And / or at least one lubricant, such as magnesium stearate or sodium benzoate,
-And / or water-soluble cellulose derivatives, synthetic polymers, preferably at least one hydrophilic polymer such as polyvinylpyrrolidone, acrylic and methacrylic polymers or polyvinyl alcohol (PVA),
-And / or contains at least one surfactant.

  Preferably, the outer coating represents 5% to 50%, preferably 10% to 30% and particularly preferably 20% by dry weight, based on the total weight of the protective coating microparticles of AP. .

  The expression “protective coated microparticles” also includes an outer coating as defined above, ie an outer coating that contributes to the maintenance of at least some modified release of said coated microparticles of AP for the modified release of AP in the manufacture of tablets. Means coated fine particles of AP.

  Further information regarding the outer coating can be found in published international patent application WO-A-03 / 077888.

<Thickener (Vb)>
Preferably, the thickening agent (Vb) is selected from those that are soluble in at least one of the following solvents: water, alcohols, ketones and mixtures thereof, such that the thickening agent prevents misuse, particularly by injection. The viscosity of the extract can be increased.

  “Water” is understood to mean any aqueous solvent such as water in stricto sensu or any aqueous solution of eg an organic acid (eg acetic acid), saline, soda or beverage. “Alcohol” is understood to mean any alcohol used alone or in a mixture with one another. “Ketone” is understood to mean any ketone used alone or in a mixture with each other.

Particularly preferably, the thickener (Vb) is a polymer of the following group:
-Polyacrylic acid and its derivatives, and / or
-Polyalkylene glycols (e.g. polyethylene glycol), and / or
-Polyalkylene oxides (e.g. polyethylene oxide), and / or
-Polyvinylpyrrolidone, and / or
-Gelatin, and / or
-Preferably polysaccharides from the subgroup comprising sodium alginate, pectin, guar, xanthan, carrageenan, gellan and cellulose derivatives (e.g. hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose),
-As well as mixtures thereof.

  According to one aspect of the invention, the thickener Vb has a high molecular weight, e.g. 1 million g / mol to 8 million g / mol, such as 2 million g / mol, 5 million g / mol or 7 million g / mol. Polyoxyethylene having a molecular weight of mol.

  Preferably, the thickener Vb, for example, high molecular weight polyoxyethylene is contained in fine particles different from the fine particles of AP.

  Particularly preferably, the AP microparticles and the thickener Vb microparticles have a similar size distribution and a similar density and cannot be separated by sieving.

  According to one preferred aspect, the thickener (Vb) can increase the viscosity of the liquid used for possible extraction so as to capture the extracted AP in the viscous medium.

  This thickener (Vb) makes it possible, for example, to increase the viscosity of the extract to more than 100 mPa.s, preferably more than 200 mPa.s, particularly preferably more than 500 mPa.s and very particularly preferably 1000 mPa.s. To do.

  In one variant, it is also applicant's honor to propose a thickener (Vb) that is effective in both aqueous phase extraction and organic solvent extraction. Advantageously, these thickeners (Vb) are hydrophilic compounds to ensure that the extract has a high viscosity (e.g., greater than 100 mPa.s), whether it is aqueous or organic. And a mixture of hydrophobic compounds.

  As far as the amount of thickener (Vb) is concerned, this can be easily determined by a person skilled in the art. The amount corresponds to the minimum amount necessary to bring the viscosity of 2.5 ml of the extract to a value of 100 mPa.s or higher.

In some variations that can be combined with each other, in a pharmaceutical form according to the invention, at least one thickener (Vb) is
-In and / or on the microparticles
-And / or during the outer coating of all or part of the microparticles of AP,
-And / or present in a free state, i.e. not contained in and supported by the microparticles.

  Advantageously, at least a portion of the thickener is in the form of particulates that cannot be separated from the coated or uncoated particulates of AP.

<Excipient in free state>
The pharmaceutical form can optionally comprise one or more pharmaceutically acceptable excipients in a free state, i.e. not contained in or carried by the AP microparticles, The excipient contributes to the crushing resistance of the coated fine particles of AP.

Preferably, these excipients that contribute to the crush resistance of the coated microparticles of AP are
- Calcium stearate;
-Glycerol palmitostearate;
-Magnesium oxide;
-Polyalkylene glycols, such as polyethylene glycol;
-Polyvinyl alcohol;
-Sodium benzoate;
- stearic acid;
-Corn starch;
-Talc powder;
-Colloidal silica;
-Zinc stearate, magnesium stearate;
-Stearyl fumarate;
-And selected from the group comprising mixtures thereof.

In an alternative embodiment of the invention, at least a portion of the thickener is:
-In the free state, i.e. not contained in the coated or uncoated microparticles of AP and not supported by the microparticles (alternative 1) or
-It is in the form of fine particles different from the coated or uncoated fine particles of AP (alternative 2)

  Advantageously, in alternative 2, thickener microparticles cannot be separated from coated or uncoated microparticles of AP. For the purposes of this disclosure, the expression “cannot be separated” means that it cannot be separated by conventional means such as, for example, sieving or centrifugation.

In alternative 2, the thickener is for example:
-In and / or on the microparticles
-And / or in the outer coating of all or part of the AP microparticles.

  Further in alternative 2, the microparticles containing the thickener are preferably not easily distinguishable from the AP microparticles because they cannot be easily separated by any suitable physical means. Microparticles containing thickeners are indistinguishable from AP microparticles, in particular by having the same size and / or the same density and / or the same shape and / or the same color.

In another alternative, the thickener is, for example:
-In and / or on the microparticles
-And / or in the outer coating of all or part of the AP microparticles.

  In one preferred embodiment, the pharmaceutical form according to the invention is multimicroparticulate. If this pharmaceutical form comprises AP microparticles (e.g. aAP) and thickener (Vb) microparticles, the microparticles preferably have a similar size distribution and similar density, preferably separated by sieving. I can't. Thus, the thickener microparticles cannot be separated from the coated or uncoated microparticles of AP.

  In another preferred embodiment, the pharmaceutical form according to the invention is multiparticulate. When this pharmaceutical form comprises microparticles of AP (e.g. aAP) and microparticles of thickener (Vb), the microparticles preferably have the same size distribution and the same density, and preferably cannot be separated by sieving. . Thus, the thickener microparticles cannot be separated from the coated or uncoated microparticles of AP.

<Metal sequestering agent Q>
Obviously, if the microparticulate pharmaceutical form contains at least one salt of at least one analgesic active ingredient, it will form a slightly soluble complex with AP in solution in an aqueous or aqueous / alcoholic beverage. A trader can add at least one sequestering agent to the pharmaceutical form.

  The sequestering agent is, for example, a salt in which the ion having the opposite polarity to that of AP is preferably an organic ion. Thus, for cationically active ingredients, the sequestering agent is, for example, an organic salt such as sodium docusate, or an anionic polymer. The sequestering agent may be, for example, a salt of an ion exchange resin.

  In the context of the present invention, the sequestering agent Q exists in free form, i.e. uncomplexed pharmaceutical form. “Uncomplexed” means that there is no complex or chemical interaction between the sequestering agent Q and the salt of the active ingredient, AP, in the solid pharmaceutical form.

  If the AP salt and the sequestering agent Q are present simultaneously in the solvent, for example in the case of illegal attempts to extract AP, the sequestering agent Q is complexed or chemically interacted with the AP salt in the solvent. Can be triggered. In the context of the present invention, the complexation of the AP salt is carried out in at least one conventional solvent selected from water and aqueous solutions such as water / ethanol mixtures, alcohol, alcoholic beverages, soda, vinegar, hydrogen peroxide and mixtures thereof. If the sequestering agent Q can induce, it is considered that the sequestering agent Q “can induce complexation” with the AP salt. Advantageously, the sequestering agent Q can induce complexation of the AP salt in several of these common solvents.

  The sequestering agent Q used to capture AP, especially the analgesic AP, is harmless even when used regularly. These products are also inert from a pharmacological point of view and are approved by various pharmacopoeias and accreditation bodies.

In one pharmaceutical form according to the invention, at least one sequestering agent Q is
-In fine particles without any AP and / or
-On fine particles and / or
-It exists in the free state, ie it is not contained in the microparticles and is not supported by the microparticles.

  Preferably, in one pharmaceutical form according to the invention, the sequestering agent Q is present in a first phase separate from at least one second phase, said second phase comprising at least one AP salt. For example, pharmaceutical forms include AP salt microparticles and a separate sequestering agent Q microparticles. Advantageously, the microparticles have a similar size distribution and a similar density and cannot be separated by sieving.

  Preferably, the sequestering agent Q comprises a salt containing ions that can form a complex with AP in solution. These ions are preferably organic ions having a polarity opposite to that of AP in solution, and when AP is in an anionic form in solution, sequestering agent Q is an organic cation, metal cation or those A mixture of Similarly, when the AP is in cationic form in solution, the sequestering agent Q contains an organic anion.

For example, the following salt containing an organic anion:
-Anionic organic salts such as sodium dodecyl sulfate or sodium docusate;
-(Meth) acrylic copolymers (e.g. Eudragit® S and Eudragit® L), cross-linked polyacrylic acid (e.g. Carbopol), carboxymethyl cellulose and its derivatives, cross-linked carboxymethyl cellulose and its derivatives, and other polysaccharides ( Anionic polymers such as alginate, xanthan gum or gum arabic), and alginate / (sulfonate) propylene glycol;
-Monovalent or polyvalent salts such as glucuronate, citrate, acetate, carbonate, gluconate, succinate, phosphate, glycerophosphate, lactate, trisilicate, fumarate, adipate, benzoate, salicylate, tartrate, sulfonamide and acesulfame;
-Saponified fatty acids such as acetate, succinate, citrate, stearate and palmitate and self-emulsifying glyceryl monooleate;
-Polyamino acids, proteins or peptides such as albumin, casein, globulin and enzymes;
-As well as mixtures thereof.

In another embodiment, the ion having a polarity opposite to that of AP in solution is an organometallic cation or a mixture thereof. For example, the following salts containing organic or metal cations:
-For example, acesulfame, acetate, adipate, benzoate, carbonate, chloride, citrate, fluoride, fumarate, gluconate, glucuronate, glycerophosphate, hydroxide, iododate, iodide, lactate, oxide, phosphate, trisilicate, salicylate, succinate, Cationic salts of metallic Ca, Fe, Mg or Zn in the form of sulfonamides or tartrate;
-Organic cation salts such as quaternary ammonium salts, in particular trimethyltetradecylammonium bromide or benzethonium chloride;
-Cationic polymers such as chitosan and (meth) acrylic copolymers (e.g. Eudragit (R) RS, Eudragit (R) RL or Eudragit (R) E);
-Polyamino acids, proteins or peptides;
-As well as mixtures thereof.

  The sequestering agent Q may be an ion exchange resin, preferably a strongly acidic cation exchange resin when AP is cationic, or a strongly basic anion exchange resin when AP is anionic. Advantageously, such an ion exchange resin is contained in a first phase separate from the second phase comprising AP.

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

  In one embodiment of the invention, the strong acid cation exchange resin is, for example, Amberlite® IRP69, Amberlite IR69F (Rohm and Haas), Amberlite 200, Amberlite 200C (Rohm and Hans) or Dowex 88 (Dow) and the like. Derivatives of sulfonated styrene / divinylbenzene copolymers such as

  In one embodiment of the invention, the strong base anion exchange resin is a fourth such as, for example, Duolite® AP143 (Rohm and Haas), Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow). Selected from derivatives of styrene / divinylbenzene copolymers having quaternary ammonium groups.

  The sequestering agent Q in the form of a resin is a crosslinked methacrylic acid / divinylbenzene copolymer such as Amberlite® IRP88, Amberlite® IRP64 (Rohm and Haas) and DOWEX MAC-3 (Dow) or their It can also be selected from one of the salts.

  The sequestering agent Q in the form of an ion exchange resin can also be selected from phenolic polyamines such as Amberlite® IRP58 (Rohm and Haas), and mixtures thereof.

  In one embodiment of the invention, the sequestering agent Q, which is in the form of an ion exchange resin, is in a first phase separate from at least one second phase, the second phase comprising an AP salt. For example, the sequestering agent Q in the form of an ion exchange resin is contained in fine particles different from the fine particles containing the AP salt. The fine particles of AP and the sequestering agent Q in the form of an ion exchange resin may be in a form such that they have a similar size distribution, similar density, and cannot be separated by sieving.

In a first preferred mode of practicing the invention, the sequestering agent Q is:
-Anionic organic salts such as sodium dodecyl sulfate or sodium docusate;
-Cationic organic salts such as quaternary ammonium salts, in particular trimethyltetradecylammonium bromide or benzethonium chloride;
-And selected from strong acid cation exchange resins or strong base anion exchange resins depending on the polarity of the AP.

In a second preferred mode of practicing the invention, the sequestering agent Q is:
-When AP is cationic, strong acid cation exchange resins Amberlite® IRP69, Amberlite® IR69F (Rohm and Haas), Amberlite 200, Amberlite 200C (Rohm and Haas) or Dowex 88 (Dow), and A mixture of;
-And if the AP is anionic, it is selected from the strong base anion exchange resins Duolite® AP143 (Rohm and Haas), Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow), and mixtures thereof The

  The amount of drug Q is adapted by those skilled in the art by calculating the amount of ionic charge necessary to capture all or part of the dose of AP contained in the unit form. The amount of sequestering agent Q will complex a sufficient amount of AP in case of illegal use, because there will not be enough free AP remaining in solution to achieve the desired effect Need to be able to. Preferably, the amount of sequestering agent Q is sufficient to complex all APs in a unit dose.

  In one variation, the pharmaceutical form may be a unitary form (eg, a tablet).

  In one embodiment, the pharmaceutical form according to the invention comprises thickener V microparticles and / or sequestering agent Q microparticles, preferably thickener V microparticles and sequestering agent Q microparticles. In this embodiment, the thickener V fine particles and the sequestering agent Q fine particles are different from the AP fine particles.

  In another embodiment of the invention, the pharmaceutical form comprises AP microparticles and thickener V microparticles and / or sequestering agent Q microparticles. Preferably, the pharmaceutical form comprises these three types of microparticles in one and the same unit form: AP microparticles, thickener V microparticles and sequestering agent Q microparticles. Advantageously, these microparticles have a similar size distribution and a similar density and cannot be separated from one another by sieving.

  In a first variant, the pharmaceutical form according to the invention cannot be converted into a dry form with an immediate release of AP that can be administered by inhalation through the nose.

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

  In a third variant, the pharmaceutical form according to the invention comprises a modified release AP and optionally an immediate release AP. This variant can be combined with the first and second variants mentioned above, which in a pharmaceutical form comprising modified release AP and immediate release AP, the modified release AP can be administered by snuffing It means that it cannot be changed to dry form or immediate release injection form.

  In a fourth variant, the pharmaceutical form according to the invention is characterized in that the extraction of AP by chewing and / or grinding is not effective.

  In a fifth variant, the pharmaceutical form according to the invention is characterized in that it has no AP antagonist.

  In a sixth variant, the pharmaceutical form according to the invention is characterized in that it comprises at least one AP antagonist. Knowing the AP used, one skilled in the art can readily determine the appropriate antagonist.

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

<Active ingredient>
The APs used are, for example, the following families of active substances: amphetamines, analgesics, anti-appetite drugs, analgesics, antidepressants, antiepileptic drugs, anti-migraine substances, anti-Parkinson substances, antitussives, anxiolytics Belongs to at least one of barbituric acid hypnotics, benzodiazepines, hypnotics, laxatives, neuroleptics, opiates, psychostimulants, psychotropic substances, sedatives and stimulants. When AP is the analgesic AP (aAP), it is preferably an opioid.

  Even more precisely, the AP used is the following compounds: Anileridine, Acetorphine, Acetyl-alpha-methylfentanyl, Acetyldihydrocodeine, Acetylmethadol, Alfentanil, Allylprozin, Alpha-cetylmethadol, Alpha-meprozin, Alpha-prozine, alpha-methadol, alpha-methylfentanyl, alpha-methylthiofentanyl, anireridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxymethyl-3-fentanyl, beta-cetylmethadol, beta -Meprozin, beta-methadol, beta-prozine, vegitramide, buprenorphine, dioxafetil butyrate, clonitazen, cyclazocine, timer, seto Midon, Clonitazen, Codeine, Coca, Cocaine, Codoxime, Dezocine, Dimenoxadol, Dioxafetil Butyrate, Dipipanone, Desomorphine, Dextromolamide, Dextropropoxyphene, Diampromide, Diethylthiambutene, Diphenoxine, Dihydrocodeine, Dihydroe Tolphine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, diphenoxylate, drotevanol, eptazosin, etoheptadine, ethylmethylthiambutene, ethylmorphine, etnitazene, ecgonine, ephedrine, etorphine, ethoxeridine, fentanyl, fretidine, Heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypetidin, isomethadone Ketobemidone, levalorphan, lofentanil, levomethorphan, levomorphamide, levophenacylmorphane, levorphanol, meptazinol, meperidine, metazosin, methadone, methyldesorbin, methyldihydromorphine, methylphenidate, methyl-3-thiofentanyl, Methyl-3-fentanyl, methopone, molamide, morpheridine, morphine, mylofin, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalolphine, normorphine, nicocodine, nicodiocodine, nicomorphine, noracimedol, norcodeine, norpipanone, opium, oxycodone , Oxymorphone, Papaveretam, Phenadoxone, Phenoperidine, Promedol, Properidine, Propyram, Propyl Lopoxyphene, parafluorofentanyl, pentazocine, pethidine, phenampromide, phenazosin, phenomorphan, phenoperidine, forcodine, pimidine, pyritramide, proheptadine, propanolol, propridine, racemetorphan, racemolamide, racemphanil, remifentanil, sufentanil, intebacon, It is selected from thiofentanyl, thirizine, trimeperidine, tramadol, their pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers, and mixtures thereof.

  The pharmaceutical form according to the invention can comprise an analgesic active ingredient (aAP) and at least one further AP different from aAP. This non-analgesic AP is preferably an antidepressant, amphetamine, anorexic drug, non-anesthetic pain killer, antiepileptic drug, anti-migraine substance, anti-parkinsonian substance, antitussive, anxiolytic, barbituric acid hypnosis Drugs, benzodiazepines, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropic substances, sedatives, stimulants, anti-inflammatory agents, their pharmacologically acceptable salts, esters, hydrates, many Selected from forms and isomers, and mixtures thereof.

  Among the possible anti-inflammatory active ingredients are: ibuprofen, acetaminophen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fulbufen, ketoprofen, indoprofen, pyroprofen, carprofen, oxaprozin, Pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, thiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmethine, zomepirac, thiopinac, zidometacin, acemetacin, fenthiazac, clidanac, oxypinac, mefenamic acid, Meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, Mention may be made of isoxicam, their pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers, and mixtures thereof.

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

  In the context of the present invention, the expression “pharmaceutical formulation” is understood in a broad sense, ie inter alia including animal formulations or dietary formulations.

  According to another feature thereof, the present invention relates to a large number of fine particles (AP coated or non-coated) as defined above, for example at least 500 fine particles, preferably 1,000 fine particles to 1,000,000 fine particles and particularly preferably 5,000 fine particles to 500,000 fine particles. Coated fine particles; optionally thickener fine particles).

  According to another feature thereof, the present invention relates to a pharmaceutical formulation comprising a plurality of populations of coated microparticles of AP, said populations being distinguished from each other by their release kinetics and / or the AP they contain.

  Without implying any limitation, the pharmaceutical formulation according to the present invention is particularly useful in that it can take the form of a once daily oral dose containing 500 to 500,000 microparticles, including coated microparticles of AP. That still needs to be stressed.

  Advantageously, pharmaceutical formulations comprising coated microparticles according to the invention comprise tablets (advantageously dispersible in the mouth or stomach), powders, suspensions, syrups, reconstitutable suspension powders, and capsules. It is a galenic form selected from the containing group.

  It is interesting to mix at least two types of coated microparticles of AP that are different in their release kinetics but included in the features that constitute the present invention in one and the same capsule, one and the same powder. Will.

  The present invention further relates to the use of the coated microparticles described above for the manufacture of a novel pharmaceutical formulation, particularly (but without implying a limitation) for the therapeutic treatment of pain.

  The invention further relates to a method of therapeutic treatment, characterized in that there is a method of administering to a patient a pharmaceutical formulation as defined above.

  The present invention further relates to a therapeutic treatment method characterized in that the method comprises taking a pharmaceutical formulation as defined above according to a given dose.

  The invention further relates to a method for the therapeutic treatment of pain, characterized in that it consists in administering to a patient a pharmaceutical formulation as defined above.

  The invention further relates to a method for the therapeutic treatment of pain, characterized in that it consists in taking a pharmaceutical formulation as defined above according to a given dose, wherein the AP used is at least one pain. Stops, including analgesics, for example.

  The invention further relates to a method against AP misuse, characterized in that it consists essentially in using a pharmaceutical form as defined above.

  The invention further relates to a method against AP misuse, characterized in that the method consists essentially in using the coated microparticles of AP for modified release of AP in pharmaceutical form, said microparticles comprising A coating layer (Ra) that imparts crush resistance to the coated fine particles of AP to ensure modified release and at the same time avoid misuse, and in some cases extraction of AP contained in coated fine particles of AP to avoid misuse At least one thickener (Vb) capable of preventing

  Advantageously, the coating layer (Ra) and thickener (Vb), if present, are as defined above.

  The present invention is given solely for the purpose of illustration and provides a clearer understanding of the present invention, more clearly with the following examples that demonstrate its various embodiments and / or modes of implementation, and its various advantages. Explained.

  The reference dissolution test in the examples that follow is a "solid oral dissolution test" performed under SINK conditions maintained at 37 ° C in 900 ml of 0.1 N HCl medium and stirred at 75 rpm: Type II dissolution test In vitro dissolution test carried out as shown in the European Pharmacopoeia 5th edition entitled

Example 1 Oxycodone HCl Fine Particles According to the Present Invention
A mixture of 1600 g oxycodone HCl, 100 g Klucel® EF (hydroxypropylcellulose / Aqualon) and 12.052 g water in GPCG1 fluidized air bed (Glatt®) with 300 g inert cellulose beads (Asahi Kasei) ) Film coat on top. 450 g of the resulting granules were then mixed with 315 g of ethylcellulose (Ethocel 20 Premium / DOW), 81 g of povidone (Plasdone PVP K29 / 32 / ISP), 36 g of castor oil, 18 g of Cremophor RH 40 (macrogol glycerol hydroxystearate). Rate / BASF) and 12.020 g of ethanol.

  This coating represents 50% of the weight of the microparticles and ensures that the active ingredient is released over about 4 hours, as shown in FIG. The release profile is determined under the conditions of the reference dissolution test.

Example 2 Grinding of Oxycodone HCl Fine Particles Prepared in Example 1>
Various methods showing various possible ways of misusing 200 mg of the microparticles prepared in Example 1 (ie, a dose of 80 mg of oxycodone HCl):
(a) By crushing pestle and mortar (250ml) for 2 minutes (about 120 rotations)
(b) by compressing 8 times between two spoons,
(c) By using an "LGS grinder" tablet mill (LGS Health Products, USA)
(d) Grind by using a coffee grinder for 30 seconds.

  The release profile of the milled microparticles is shown in FIG. The release profile is determined under the conditions of the reference dissolution test.

  The release profiles of Example 1 (intact microparticles) and Example 2 (milled microparticles) were calculated as shown by the FDA (Industry SUPAC-MR Guidance: Modified Release Solid Oral Dose Form, page 32) Also similar for the test for f2 similarity coefficient (f2> 50).

  Thus, milling may have little or even no effect on the release of oxycodone from the microparticles.

<Example 3 Appearance of contents of capsule according to the present invention>
200 mg of the microparticles prepared in Example 1 (ie 80 mg dose of oxycodone HCl) were added to the following thickener: 90 mg Klucel HF (hydroxypropylcellulose / Aqualon) pre-screened between 100 μm and 600 μm, Mix with 20 mg PolyOx WSR 303 Sentry (polyethylene oxide / Dow) and 20 mg Xantural 180 (xanthan / cpKelco). The whole is incorporated into a 0 size gelatin capsule.

  FIG. 3 shows a photograph of the contents of the capsules observed under the naked eye (A) and light microscope (B).

As shown in FIG. 3A, which was observed with the naked eye, the fine particles of the active ingredient and the fine particles of the thickener were:
-Cannot be distinguished by sieving,
-Cannot be separated.

  In the photograph of FIG. 3 (B) obtained by light microscopy (note the scale), there are only two distinct particle populations, one of which is oxycodone HCl spherical microparticles and two types of thickening. The fine particles of the agent, and the other are rod-like particles of the third thickener. Given the very small size of these particles (about 0.2 mm), they cannot be separated from each other.

<Example 4 Test for Syringe Extraction in the Form of the Present Invention>
90 mg of Klucel HF (hydroxypropylcellulose / Aqualon), 20 mg of PolyOx WSR 303 Sentry (polyethylene) pre-screened between 100 to 600 μm, 200 mg of the microparticles prepared in Example 1 (ie 80 mg dose of oxycodone HCl). Mix with ethylene oxide / Dow) and 20 mg Xantural 180 (xanthan / cpKelco). The whole is incorporated into a 0 size gelatin capsule.

  The capsule is opened and the contents are ground according to Example 2 (a) using a mortar and pestle and then mixed with 2.5 ml of extract for 10 minutes at ambient temperature or boiling. This solution is then taken through a cotton wool serving as filter paper into a 2.5 ml syringe (with an 18G needle). The amount of oxycodone HCl extracted is analyzed by HPLC or UV and is shown in Table 1.

  The observed low extraction yield (<20%) completely discourages those who can be misused.

<Example 5: Test for extracting a syringe according to the present invention>
200 mg of the microparticles prepared in Example 1 (ie 80 mg dose of oxycodone HCl) was mixed with 150 mg Klucel HXF (hydroxypropylcellulose / Aqualon), 50 mg PolyOx WSR 303 Sentry (polyethylene oxide / Dow) and 30 mg Carbopol 971P. Mix with (Carbomer / BF Goodrich). This mixture is incorporated into a 0 size gelatin capsule.

  The capsule is opened and the contents are ground according to Example 2 (a) using a mortar and pestle and then mixed with 10 ml of extract at ambient temperature or boiling for 10 minutes. This solution is then taken into a 10 ml syringe (with an 18G needle) through absorbent cotton serving as filter paper. The amount of oxycodone HCl extracted is analyzed by HPLC or UV and is shown in Table 2.

  The observed low extraction yield (<20%) completely discourages those who can be misused.

<Example 6: Test for extracting a syringe in the form of the present invention>
150 g Klucel HXF (hydroxypropylcellulose / Aqualon), 50 g PolyOx WSR 303 Sentry (polyethylene oxide / Dow), 30 g Carbopol 971P (carbomer / BF Goodrich) and 10 g povidone (Plasdone PVP K29 / 32 / ISP), Wet granulate with MiPro equipment. The granules are passed through a 100-600 μm sieve.

  250 mg of the resulting granules are added to 200 mg of the microparticles prepared in Example 1 (ie 80 mg dose of oxycodone HCl). This mixture is incorporated into a 0 size gelatin capsule. The capsule is opened and the contents are ground according to Example 2 (a) using a mortar and pestle and then mixed with 10 ml of extract at ambient temperature or boiling for 10 minutes. This solution is then taken into a 10 ml syringe (with an 18G needle) through absorbent cotton serving as filter paper. The amount of oxycodone HCl extracted is analyzed by HPLC or UV and shown in Table 3.

  The observed low extraction yield (<20%) completely discourages possible misusers.

<Example 7 Production of tablets according to the present invention>
200 g of the microparticles prepared in Example 1 were mixed with 90 g of Klucel HF (hydroxypropylcellulose / Aqualon), 20 g of PolyOx WSR 303 Sentry (polyethylene oxide / Dow), 20 g of Xanthural 180 (xanthan / cpKelco), 100 g of lactose. (Tablettose / Meggle GmbH), mixed with 10 g magnesium stearate (Brenntag AG) and 30 g croscarmellose sodium (Ac-Di-Sol / FMC Bipolymer).

  470 mg tablets (ie 80 mg oxycodone dose) are produced using a Korsch reciprocating press.

  The resulting tablets are ground according to Example 2 (a) using a mortar and pestle and then mixed with 2.5 ml of extract at ambient temperature or boiling for 10 minutes. This solution is then taken into a 2.5 ml syringe (with an 18G needle) through absorbent cotton serving as filter paper. The amount of oxycodone HCl extracted is analyzed by HPLC or UV and shown in Table 4.

  The observed low extraction yield (<20%) completely discourages those who can be misused.

Example 8 Oxycodone HCl Fine Particles According to the Present Invention
Process 1: Granule
1615 g oxycodone and 85 g povidone (Plasdone® K29-32 / ISP) are dispersed in a mixture containing 2052 g water and 1105 g ethanol. This solution is sprayed onto 300 g cellulose spheres (Asahi Kasei) in a Glatt GPCG1 fluidized air bed.

Process 2: Anti-grinding fine particles
315 g ethylcellulose (Ethocel 20 Premium / Dow), 81 g povidone (Plasdone K29-32 / 1SP), 18 g macrogol glycerol stearate (Cremophor RH40 / BASF) and 36 g castor oil (Garbit huilerie), 3105 g Solubilize in a mixture consisting of acetone and 2070 g isopropanol. This solution is sprayed onto 450 g of granules (prepared in step 1).

  This coating represents 50% of the weight of the microparticles and ensures that the active ingredient is released as shown in FIG. The release profile is determined under the conditions of the reference dissolution test.

Example 9 Contents of Capsule According to the Present Invention
230 mg of the fine particles obtained in Step 2 of Example 8, 100 mg of ground and screened Amberlite 1R69F (sodium polystyrene sulfonate), 70 mg of screened Polyox WSR 303 Sentry (polyethylene oxide), 3.8 mg of magnesium stearate and 1.9 mg Incorporate mg Aerosil 200 (colloidal silica) into 0 size gelatin capsules.

As shown in FIG. 5, observed with the naked eye (A) and under a light microscope (B), the fine particles of the active ingredient and the fine particles of the thickener are:
-Cannot be distinguished by sieving,
-Cannot be separated.

Example 10 Grinding of the contents of a capsule prepared according to Example 9
The contents of the capsule prepared according to Example 9 are ground for 2 minutes with a mortar and pestle.

  The release profile of the milled microparticles is shown in FIG. This release profile is determined under the conditions of the reference dissolution test.

  The release profiles of intact and ground products are similar. Thus, milling may have little or no effect on the release of oxycodone from the microparticles.

Example 11 Test for Extracting Syringe of Contents of Capsule Prepared according to Example 9>
Open the capsule prepared according to Example 9 and grind the contents with a mortar and pestle for 2 minutes, then mix at ambient temperature (A) or boil (B) with 2.5 ml extract for 10 minutes. . This solution is then taken through a cotton wool serving as filter paper into a 2.5 ml syringe (with 18G or 27G needle). The amount of oxycodone HCl extracted is analyzed by HPLC or UV and is shown in Tables 5 and 6.

  The observed low extraction yield (<20%) completely discourages those who can be misused.

<Example 12: Test for extracting the contents of capsules into a beverage according to Example 9>
Open the capsule prepared according to Example 9 and grind the contents with a mortar and pestle for 2 minutes and then mix with 100 ml non-alcoholic beverage or 50 ml alcoholic beverage as shown in the table below.

  The solution was then collected and the amount of oxycodone HCl extracted was analyzed by HPLC or UV and is shown in Table 7.

  The low extraction yields observed completely discourage those who can be misused, even with long extraction times.

Example 1: Dissolution profile (dissolution% D as a function of time T) in an in vitro reference test of-■-microparticles. Example 1:-■-and Example 2: (a) --- □ ---, (b)-○ ---, (c) --- ● ---, (d)- -▲ --- Dissolution profile (dissolution% D as a function of time T) in an in vitro reference test. 2 is a photograph of the contents of a capsule according to Example 3, observed with the naked eye (A) and under a light microscope (B). Figure 2 is the release profile of microparticles in 0.1 N HCl (wt% AP as a function of time in hours) (Example 8). 10 is a photograph of the contents of a capsule according to Example 9 observed with the naked eye (A) and under a light microscope (B). 9 is a release profile of ground microparticles (blank triangles) or intact microparticles (black squares) of Example 9.

Claims (56)

Including misuse prevention means,
At least part of the active ingredient (AP) included in the pharmaceutical form is contained in the coated microparticles for modified release of AP,
Solid oral pharmaceutical form characterized in that the coated microparticles of AP have a coating layer (Ra) that imparts crush resistance to the coated microparticles of AP in order to ensure modified release of AP and avoid misuse at the same time.   In order to avoid misuse, characterized in that it contains at least one thickener (Vb) that can prevent the extraction of AP contained in the coated microparticles of AP for modified release of AP The pharmaceutical form according to claim 1.   Pharmaceutical form according to claim 1 or 2, characterized in that it comprises at least one sequestering agent (Q) capable of forming a complex with AP in solution.   In the case of pulverization, the coating layer (Ra) is designed to allow the modified release of AP to be maintained for at least a part of the coated microparticles. The pharmaceutical form as described.   In the case of comminution, the coating layer (Ra) is allowed to allow the modified release to be maintained for at least 40%, preferably at least 60%, and particularly preferably at least 80% of the coated microparticles for modified release of AP. The pharmaceutical form according to any one of claims 1 to 4, characterized in that is designed. The coating layer (Ra)
(A1) at least one film-forming (co) polymer (A1) that is insoluble in gastrointestinal fluids;
(A2) at least one (co) polymer (A2) that is soluble in gastrointestinal fluids;
(A3) at least one plasticizer (A3);
(A4) any at least one surfactant and / or lubricant and / or inorganic filler and / or organic filler (A4)
A pharmaceutical form according to any one of claims 1 to 5, characterized in that The coating layer (Ra) is the following (expressed in% by weight 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
A pharmaceutical form according to claim 6, characterized in that (A1) is
A water-insoluble cellulose derivative, preferably ethyl cellulose, and / or cellulose acetate,
Acrylic polymers such as copolymers of (meth) acrylic acid and alkyl (e.g. methyl) esters, copolymers of acrylic and methacrylic esters having at least one quaternary ammonium group (preferably alkyl (meth) acrylates and trimethylammonio) At least one copolymer of ethyl methacrylate chloride), and more precisely a product marketed under the trademark EUDRAGIT® RS and / or RL,
Polyvinyl acetate,
As well as selected from the group comprising mixtures thereof;
(A2) is
Preferably a nitrogen-containing (co) polymer from the group comprising polyacrylamide, poly-N-vinylamide, polyvinylpyrrolidone (PVP), and poly-N-vinyllactam,
Water-soluble cellulose derivatives,
Polyvinyl alcohol (PVA),
Polyalkylene oxide, preferably polyethylene oxide (PEO),
Polyethylene glycol (PEG),
As well as selected from the group comprising mixtures thereof;
(A3) is
Cetyl alcohol ester,
Preferably the following subgroups: acetylated glycerides, glycerol monostearate, glyceryl triacetate, and glycerol from glycerol tributyrate, and esters thereof,
Preferably the following subgroups: phthalates from dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,
Preferably the following subgroups: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, citrate from triethyl citrate,
Preferably the following subgroups: diethyl sebacate, sebacate from dibutyl sebacate,
Adipate,
Azelate,
Benzoate,
Vegetable oil,
Fumarate, preferably diethyl fumarate,
Malate, preferably diethyl malate,
Oxalate, preferably diethyl oxalate,
Succinate, preferably dibutyl succinate,
Butyrate,
Cetyl alcohol ester,
Salicylic acid,
Triacetin,
Malonate, preferably diethyl malonate,
Castor oil (this is particularly preferred),
As well as selected from the group comprising mixtures thereof;
(A4) is
Preferably anionic surfactants from the subgroup comprising alkali metal or alkaline earth metal salts of fatty acids (preferably stearin and / or oleic acid),
And / or preferably the following subgroups:
Polyethoxylated oil, preferably polyethoxylated hydrogenated castor oil,
Polyoxyethylene / polyoxypropylene copolymer,
Polyethoxylated sorbitan ester,
Polyethoxylated castor oil derivative,
Stearate, preferably calcium stearate, magnesium, aluminum or zinc,
Stearyl fumarate, preferably sodium stearyl fumarate,
Glycerol behenate,
Talc powder,
Colloidal silica,
Titanium oxide, magnesium oxide,
Bentonite,
Microcrystalline cellulose,
Kaolin,
Aluminum silicate,
As well as selected from the group comprising nonionic surfactants from mixtures thereof,
The pharmaceutical form according to claim 6 or 7.   The coating layer (Ra) exhibits a ratio such that Tp ≧ 15 by weight Tp expressed as dry weight% relative to the total weight of the coated microparticles, Tp is preferably between 30 and 60, particularly preferably from 40 Pharmaceutical form according to any one of claims 1 to 8, characterized in that it is between 60 and very particularly preferably between 45 and 55 or about 50.   The coated microparticles of AP are characterized by having an average diameter of less than or equal to 1000 μm, preferably between 50 μm and 800 μm, even more preferably between 100 μm and 600 μm, and even more preferably between 100 μm and 300 μm. The pharmaceutical form according to any one of claims 1 to 9.   In the manufacture of tablets, coated microparticles for modified release of AP are designed to contribute to maintaining modified release for at least a portion of said coated microparticles of AP for modified release of AP And wherein the outer coating consists of at least one deformable organic component having a melting point between 40 ° C. and 120 ° C., preferably between 45 ° C. and 100 ° C. To 10. The pharmaceutical form according to any one of 10.   The outer coating is on the order of 5% to 50%, preferably 10% to 30%, and even more preferably 20% by dry weight, based on the total weight of the protective coating particulates of the AP. 12. A pharmaceutical form according to claim 11, characterized in that it is indicated.   At least one thickener (Vb) is selected from those that are soluble in at least one of the following solvents: water, alcohols, ketones, and mixtures thereof, wherein the thickener is particularly misused by injection. 13. A pharmaceutical form according to claim 2 and, optionally, claims 1 and 3 to 12, characterized in that it is possible to increase the viscosity of the extract so as to prevent it. Thickener (Vb) is the next group of polymers:
Polyacrylic acid, and derivatives thereof, and / or polyalkylene glycol (eg polyethylene glycol), and / or polyalkylene oxide (eg polyethylene oxide), and / or polyvinyl pyrrolidone, and / or gelatin, and / or preferably alginic acid Polysaccharides from subgroups, including sodium, pectin, guar, xanthan, carrageenan, gellan, and cellulose derivatives (e.g., hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose),
14. The pharmaceutical form according to claim 13, characterized in that it is selected from:   Thickener (Vb) is a polyoxyethylene having a high molecular weight, for example a molecular weight of 1 million g / mol to 8 million g / mol, for example 2 million g / mol, 5 million g / mol, or 7 million g / mol The pharmaceutical form according to claim 13 or 14, wherein At least one thickener (Vb),
In and / or on the microparticles
And / or during the outer coating of all or part of the AP microparticles,
16. A pharmaceutical form according to any one of claims 13 to 15, characterized in that it exists in a free state, i.e. not contained in and supported by the microparticles.   Increasing the viscosity of the liquid used for possible extraction to a value greater than or equal to 100 mPa.s in an extraction volume of 2.5 ml so that the thickener (Vb) captures the extracted AP in the viscous medium The pharmaceutical form according to any one of claims 13 to 16, characterized in that   The medicament according to any one of claims 13 to 17, characterized in that at least a part of the thickener (Vb) is in the form of microparticles that cannot be separated from the microparticles of coated or uncoated AP. Form.   The sequestering agent Q comprises a salt comprising an ion capable of forming a complex with an extracted AP salt in solution, and optionally any one of claims 1 to 2 and 4 to 18. The pharmaceutical form according to Item.   20. The pharmaceutical form according to claim 19, wherein the ion of the sequestering agent Q is an organic ion having a polarity opposite to that of AP in solution and forms a complex with the extracted AP salt in solution.   21. Pharmaceutical form according to claim 19 or 20, wherein the sequestering agent Q is present in a first phase separate from at least one second phase, said second phase comprising at least one AP salt.   The pharmaceutical form according to any one of claims 19 to 21, comprising fine particles of AP salt and fine particles of sequestering agent Q.   23. The pharmaceutical form according to claim 22, wherein the microparticles have similar size distribution, similar density and cannot be separated by sieving.   21. The pharmaceutical form according to claim 20, wherein the ion having a polarity opposite to that of AP in the solution is an organic anion. The sequestering agent Q is
Anionic organic salts such as sodium dodecyl sulfate or sodium docusate;
(Meth) acrylic copolymers (e.g. Eudragit® S and Eudragit® L), cross-linked polyacrylic acid (e.g. Carbopol), carboxymethyl cellulose and its derivatives, cross-linked carboxymethyl cellulose and its derivatives, and other polysaccharides (e.g. Anionic polymers such as alginate, xanthan gum, or gum arabic), and alginate / (sulfonate) propylene glycol;
Monovalent or polyvalent salts such as glucuronate, citrate, acetate, carbonate, gluconate, succinate, phosphate, glycerophosphate, lactate, trisilicate, fumarate, adipate, benzoate, salicylate, tartrate, sulfonamide, and acesulfame;
Saponified fatty acids such as acetate, succinate, citrate, stearate, and palmitate and self-emulsifying glyceryl monooleate;
Polyamino acids, proteins or peptides such as albumin, casein, globulin, and enzymes;
24. A pharmaceutical form according to any one of claims 19 to 23 comprising a salt selected from the group comprising as well as mixtures thereof.   21. The pharmaceutical form according to claim 20, wherein the ion having a polarity opposite to that of AP in the solution is an organometallic cation or a mixture thereof. The sequestering agent Q is
For example, acesulfame, acetate, adipate, benzoate, carbonate, chloride, citrate, fluoride, fumarate, gluconate, glucuronate, glycerophosphate, hydroxide, iododate, iodide, lactate, oxide, phosphate, trisilicate, salicylate, succinate, sulfone Cationic salt of metal Ca, Fe, Mg or Zn in the form of amide or tartrate;
Organic cation salts such as quaternary ammonium salts, in particular trimethyltetradecylammonium bromide or benzethonium chloride;
Cationic polymers such as chitosan and (meth) acrylic copolymers (e.g. Eudragit® RS, Eudragit® RL or Eudragit® E);
Polyamino acids, proteins or peptides;
24. A pharmaceutical form according to any one of claims 19 to 23 comprising a salt selected from the group comprising as well as mixtures thereof.   24. The sequestering agent Q is an ion exchange resin, preferably a strongly acidic cation exchange resin when AP is cationic, or a salt of a strongly basic anion exchange resin when AP is anionic. Pharmaceutical form as described in any one of these.   29. The pharmaceutical form according to claim 28, wherein the sequestering agent Q is a derivative of a styrene / divinylbenzene copolymer.   29. The pharmaceutical form according to claim 28, wherein the sequestering agent Q is a derivative of a sulfonated styrene / divinylbenzene copolymer.   29. The pharmaceutical form according to claim 28, wherein the sequestering agent Q is a derivative of a styrene / divinylbenzene copolymer having quaternary ammonium groups.   29. The pharmaceutical form according to claim 28, wherein the sequestering agent is a crosslinked methacrylic acid / divinylbenzene copolymer or one of its salts.   29. A pharmaceutical form according to claim 28, wherein the ion exchange resin is a phenolic polyamine. The sequestering agent Q is
Anionic organic salts such as sodium dodecyl sulfate or sodium docusate;
Cationic organic salts such as quaternary ammonium salts, in particular trimethyltetradecylammonium bromide or benzethonium chloride;
34. The pharmaceutical form according to any one of claims 19 to 33, which is selected from strong acid cation exchange resins or strong base anion exchange resins depending on the polarity of AP and AP. Sequestrant Q is:
Strongly acidic cation exchange resins and mixtures thereof when the AP is cationic;
35. The pharmaceutical form according to any one of claims 19 to 34, which is selected from strongly basic anion exchange resins and mixtures thereof when the AP is anionic. At least one sequestering agent Q,
36. Any one of claims 19 to 35, present in the microparticles free from AP and / or on and / or in the free state, i.e. not contained in and supported by the microparticles. The pharmaceutical form according to Item.   37. A pharmaceutical form according to any one of claims 19 to 36, wherein the amount of sequestering agent is adjusted in terms of ionic charge to complex all or part of the dose of AP contained in the unit form. .   38. A pharmaceutical form according to any one of claims 19 to 37, wherein the sequestering agent (Q) is in the form of microparticles that cannot be separated from the coated or uncoated microparticles of AP.   39. Thickener V microparticles and / or sequestering agent Q microparticles, wherein thickener V microparticles and sequestering agent Q microparticles are different from AP microparticles. A pharmaceutical form according to 1.   The fine particles of AP and the fine particles of thickener V and / or sequestering agent Q, wherein the fine particles have a similar size distribution and similar density and cannot be separated from one another by sieving. 40. The pharmaceutical form according to any one of to 39.   Contains at least one excipient in a free state, i.e. not contained in or supported by the AP microparticles, said excipient contributing to the crush resistance of the coated microparticles of AP 41. A pharmaceutical form according to any one of claims 1 to 40, characterized in that Free excipients
Calcium stearate;
Glycerol palmitostearate;
Magnesium oxide;
Polyalkylene glycols such as polyethylene glycol;
Polyvinyl alcohol;
Sodium benzoate;
stearic acid;
Corn starch;
Talc powder;
Colloidal silica;
Zinc stearate, magnesium stearate;
Stearyl fumarate;
42. Pharmaceutical form according to claim 41, characterized in that it is selected from the group comprising and mixtures thereof.   43. Pharmaceutical form according to any one of claims 1 to 42, characterized in that the AP, which can be administered by inhalation through the nose, cannot be changed into a dry form with immediate release.   44. Pharmaceutical form according to any one of claims 1 to 43, characterized in that the AP cannot be changed into an injectable form with immediate release.   45. Pharmaceutical form according to any one of claims 1 to 44, characterized in that it comprises an immediate release AP and / or a modified release AP.   46. Pharmaceutical form according to any one of claims 1 to 45, characterized in that the extraction of AP by chewing and / or grinding is not effective.   AP used is the next family of active substances: amphetamines, analgesics, anti-appetite drugs, analgesics, antidepressants, antiepileptic drugs, anti-migraine substances, anti-Parkinson substances, antitussives, anxiolytics, barbi It belongs to at least one of tool acid hypnotics, benzodiazepines, hypnotics, laxatives, neuroleptics, opiates, psychostimulants, psychotropic substances, sedatives and stimulants. 47. A pharmaceutical form according to any one of.   The AP used is the following compounds: Anileridine, Acetorphine, Acetyl-alpha-methylfentanyl, Acetyldihydrocodeine, Acetylmethadol, Alfentanil, Allylprozin, Alpha-cetylmethadol, Alpha-meprozin, Alpha-prozin, Alpha- Methadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprozine, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxymethyl-3-fentanyl, beta-cetylmethadol, beta-meprozin , Beta-methadol, beta-prozine, vegitramide, buprenorphine, dioxafetil butyrate, clonitazen, cyclazocine, timer, cetobe Don, Clonitazen, Codeine, Coca, Cocaine, Codoxime, Dezocine, Dimenoxadol, Dioxafetil Butyrate, Dipipanone, Desomorphine, Dextromolamide, Dextropropoxyphene, Diampromide, Diethylthiambutene, Diphenoxine, Dihydrocodeine, Dihydroe Tolphine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotevanol, eptazosin, etoheptadine, ethylmethylthiambutene, ethylmorphine, etnitazene, ecgonine, ephedrine, ethylmethylthiambutene, Ethylmorphine, etonitazen, etorphine, ethoxeridine, fentanyl, fretidine, heroin, hydrocodone, hydromolybdenum Rufinol, hydromorphone, hydroxypetidin, isomethadone, ketobemidone, levalorphan, lofentanil, levomethorphan, levomorphamide, levophenacylmorphane, levorphanol, meptazinol, meperidine, metazosin, methadone, methyldesorbin, methyldihydromorphine, methyl Phenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, methopone, molamide, morpheridine, morphine, mylofin, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalolphine, normorphine, nicocodine, nicodicozine, nicomorphine, nor Acimethadol, norcodeine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oki Codon, oxymorphone, papaveretam, phenadoxone, phenoperidine, promedol, properidine, propyram, propoxyphene, parafluorofentanyl, pentazocine, pethidine, phenampromide, phenazosin, phenomorphan, phenoperidine, forcodine, pimidine, pyritramide, proheptazine, propranolol, propranolol Propyran, racemetorphan, racemolamide, racemorphan, remifentanil, sufentanil, thebacon, thebaine, thiofentanyl, thirizine, trimeperidine, tramadol, their pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers 48. The body according to any one of claims 1 to 47, characterized in that it is selected from the body and mixtures thereof. Pharmaceutical forms.   49. The AP used is selected from the group comprising oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride, and tramadol hydrochloride. Pharmaceutical form as described in any one of these.   50. Pharmaceutical form according to any one of claims 1 to 49, characterized in that it has no AP antagonist.   50. Pharmaceutical form according to any one of claims 1 to 49, characterized in that it comprises at least one AP antagonist.   52. The pharmaceutical form according to any one of claims 1 to 51, comprising a plurality of populations of coated microparticles of AP, wherein the populations are distinguished from each other by the release kinetics of the microparticles and / or the AP that the microparticles comprise.   Use of coated microparticles of AP to allow modified release of the AP, wherein the coated microparticles of AP are as defined in claims 1 to 52, for the manufacture of new pharmaceutical formulations.   Use of coated microparticles of AP enabling modified release of the AP, wherein the coated microparticles of AP are as defined in claims 1 to 52, for the manufacture of new pharmaceutical formulations that are active in the treatment of pain .   53. A method against AP misuse, characterized in that it consists essentially in using a pharmaceutical form as defined in any one of claims 1 to 52.   Essentially in the stage of using AP coated microparticles for modified release of AP in pharmaceutical form, said microparticles coated with AP to ensure modified release of AP and at the same time avoid misuse A coating layer (Ra) that imparts pulverization resistance to the fine particles, and in some cases at least one thickener (Vb) that can prevent extraction of AP contained in the coated fine particles of the AP to avoid misuse ), And optionally having at least one sequestering agent (Q) that can prevent extraction of AP contained in the coated microparticles of AP for modified release of AP to avoid misuse , Coating layer (Ra), thickener (Vb), if present, and sequestering agent (Q), if present, as defined in claims 1 to 52 to counter AP misuse Method.