KR20140090222A - Anti-misuse microparticulate oral pharmaceutical form - Google Patents

Abstract

The present invention relates to oral solid microparticle pharmaceutical formulations, whose composition and structure make it possible to prevent misuse of the pharmaceutically active ingredient (AP) they contain.
The object of the present invention is to prevent misuse of oral solid drugs for any purpose other than the therapeutic use (s) formally approved by the health authority. That is, the object of the present invention is to prevent spontaneous or involuntary misuse of oral solid drugs.
The present invention includes misuse prevention means that at least some of the APs contained therein are contained in the coated microparticles for deformation release of AP and the AP coated microparticles ensure the deformation release of AP and at the same time, (Ra) which imparts crushing resistance to the coated microparticles of the AP to prevent the formation of microcapsules.

Description

{ANTI-MISUSE MICROPARTICULATE ORAL PHARMACEUTICAL FORM}

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

The active ingredient (AP) in question is a pharmacy or veterinary AP, for example, those that are categorized into the category of paralyzing product, narcotic or drug. Misuse of these pharmacologically active ingredients can lead to drug addiction.

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

The microparticulate pharmaceutical formulations are understood to mean any formulations containing AP in the microparticles of 1000 microns or less in the present invention. These particles containing AP may be coated microparticles for modified release of AP. In the latter case, the microparticles are coated with a polymeric film that, for example, regulates the release rate of AP after oral administration.

Raising the issue

It is an object of the present invention to prevent an oral solid drug from being misused for any purpose other than the therapeutic use officially approved by the public health authority. That is, an object of the present invention is to prevent spontaneous or involuntary misuse of oral solid drugs.

Misuse occurs mainly in the following cases.

a) addiction (drug addiction, doping),

b) criminal activity (chemical dependency),

c) Due to inattention or inability to affect the patient, use the drug in a manner that does not conform to the medical recommendation (dose).

In the case of a (or even in the case of b), those who wish to misuse the oral solid drug will generally be able to extract AP from the modified release formulation to obtain a rapid acting formulation,

- grinding it to be inhaled or swallowed and changing it into a powdered formulation,

- This will be converted to a liquid formulation so that it can be injected or swallowed by a syringe.

Preparing liquid formulations from oral solid drugs involves an intermediate step of aqueous extraction or organic extraction of the AP in question. This extraction is generally by grinding.

The mode of administration by inhalation or infusion is particularly suitable for drug abuse since these methods can enhance the effectiveness of AP and are beneficial for the bioavailability in a short time. When the pulverized powder is injected into the nose or dissolved in water, the desired doping or pickling effect of AP appears in a very rapid and intense manner.

Currently, there are particularly seriously undesirable behaviors that affect teenagers, anesthetic AP (aAP), particularly morphine and opioid derivatives. In fact, teens can easily extract oxycodone from tablets with water and alcohol for the party, and prepare oxycodone and vodka cocktails. This process consists of comminuting the tablet, pouring the powder into a board or a water bath, and then waiting for a sufficient period of time for the morphine derivative, which can be absorbed, to be completely extracted.

Oral solid drugs can be misused by chewing the drug before swallowing it instead of swallowing them promptly according to the administration guide.

The risks associated with addiction (a) and criminal activity (b) are obvious. Misuse of medication by injection is indicated as being more dangerous, that is, excipients may be responsible for local tissue necrosis, infection, respiratory and cardiac disorders.

With regard to drug abuse (c) related to carelessness and / or patient inability, this may have serious consequences. For example, chewing a modified release formulation of AP prior to swallowing changes the drug to an immediate release formulation. Therefore, the drug should be good and lose its effect after a short time, and in the worst case it will become toxic.

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

Prior Art

Patent US-B-6 696 088 relates to multiparticulate oral pharmaceutical formulations indicated as inhibiting abuse. It contains particles of the opioid agonist AP in the modified release formulation and particles containing an opioid antagonist. Formulations containing antagonists are described to release less than 36%, preferably less than 6.2%, of the antagonist AP over a period of 36 hours. Two types of particles are dispersed to each other.

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

As we understand, the invention is based on the use of active materials other than AP, and in particular does not suggest a solution to reduce the impact of grinding or reduce AP extraction.

The patent application US-A-2003/0068371 describes an oral pharmaceutical formulation containing an opiate AP (oxicondone), an antagonist of this AP (naluxone) and a gel-forming agent (e.g. xanthan gum). In particular, the aforementioned US patent application discloses matrix granules of AP containing an outer coating, povidone, xanthan gum and lactose based on EUDRAGIT RS 30D ^® / triacetin / antagonist. Gel formers are proposed to provide viscosity to the formulation such that the formulation can not be administered parenterally or parenterally. As the present inventors understand, this answer is insufficient because the use of an antagonist in the above invention is particularly essential. Finally, this formulation does not contain any anti-crushing means and can be converted to a powder and misused by the expense or oral route.

The patent application WO-A-03/013479 describes an oral pharmaceutical formulation containing a therapeutically effective amount of an opiate anesthetic and an opioid antagonist (naltrexone), and a bittering agent. When a drug addict crushes the tablet, the opioid and its antagonist are released. The effect of the opioid is then neutralized. As the present inventors understand, it is not possible with this system to inhibit the selective extraction of opioids using water, especially without pulverization.

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

The patent application WO-A-2004/054542 describes semi-flow oral pharmaceutical formulations. This takes the form of capsules (e.g., gelatin capsules) containing AP on a matrix, possibly composed of a polymer forming a network in liquid phase (cellulose acetate butyrate) and a high viscosity water insoluble liquid (sucrose acetate isobutyrate). The formulation may contain a solvent and a compound that, if necessary, modifies the rheology of the pharmaceutical formulation. By modifying compounds that differ from the concentration of the formulation, the inventor states that the plasma profile of the AP (oxycodone base) administered to the dog can be modified. It is understood by the present inventors that this reference does not provide a solution to prevent misuse by injection, especially since the viscosity of the formulation rapidly drops even with the addition of small amounts of ethanol.

The patent application US-A-2003/0224051 describes an osmotic delivery formulation for the modified release of oxycodone. The formulation is comprised of a tablet comprising a core of oxycodone or a salt thereof, a semi-permeable membrane at least partially surrounding the core, and an exit orifice in the film capable of releasing oxycodone. This type of tablet can be easily extracted, for example, by immersion in water for at least 12 hours. As the present inventors understand, this tablet is not an appropriate solution to the misuse problem.

The patent application EP-A-1293209 describes a solid preparation for oral administration for the sustained release of an opioid derivative (AP) contained in an ion exchange resin. The resultant AP / resin complex makes it possible to limit the plasma concentration obtained after chewing, inhalation or insufflation by injection to a therapeutic concentration below the concentration sought by the abuser. This AP / resin composite takes the form of a matrix. As the present inventors have appreciated, there is no anti-crushing means provided in the pharmaceutical formulations according to the prior art documents. Moreover, this pharmaceutical formulation does not contain any means of preventing AP solvent extraction. Therefore, even if the extraction time is longer than the normal AP release time, the solvent extraction of AP can not be prevented. If this oral pharmaceutical formulation is left in the water for 24 hours, most of the AP will be extracted.

Patent applications US-A-2003/0118641 and 2005/0163856 (= WO-A-01/08661) describe oral pharmaceutical formulations for sustained release of AP consisting of opioid compounds (anesthetics) and salts thereof have. These formulations appear to prevent misuse by extracting AP with conventional solvents. Although these possibilities may be predicted to be much more pessimistic, these misuse-preventive formulations do not contain antagonists. These formulations

- a hydrophilic matrix formulation (hydroxyalkylcellulose) in an amount of from 40 to 65% by weight,

- an ion exchange resin (particles of 50 탆 or less in an amount of 5 to 15% by weight)

- a mixture of at least one opiate agent AP.

After adding a conventional crushing additive, the mixture is converted to a tablet.

Therefore, this is a macroscopic matrix system comprising particles of AP complexed with AP and a means of extraction comprising a viscosifier, preferably hydroxypropyl methylcellulose. As understood by the present inventors, this system can be improved particularly in view of the misuse prevention effect.

The inserted patent document WO-A-2005/079760 describes a pharmaceutical formulation consisting of an extruded micro-particulate of AP obtained by extrusion, which maintains the sustained release of AP and prevents misuse. These extruded microparticles include an inert poly (ethyl acrylate / methyl methacrylate) copolymer, i.e. a matrix formed of EUDRAGIT® NE 30D or NE 40D. This matrix contains AP (oxycodone), another Eudragit (R), RS PO, plasticizer and lubricant.

Misuse is inhibited by anti-crushing means that include the elastic characteristics of the matrix particles for modified release of AP. As the present inventors understand, there is no provision for preventing the extraction of AP from the solvent medium.

When the present inventors understand the prior art, none of the anti-abuse solutions proposed so far are particularly unsatisfactory in preventing abuse of AP with solvents suitable for water, alcohol or other drinking.

Object of the invention

Under such circumstances, one of the objects of the present invention overcomes the inadequacies of the prior art.

It is another object of the present invention to provide a pharmaceutical composition for preventing or treating a substance other than AP which may be dangerous to the user due to its pharmaceutical activities, Is to provide a novel oral solid drug that will not be used even with inhibitors and will not be difficult to misuse.

It is a further object of the present invention to provide a new oral dosage form which will be difficult, even if not misusable, even after the "prolonged" liquid phase extraction of the AP (e.g. anesthetic) ≪ / RTI > In this specification, "long time" liquid extraction is an extraction that lasts more than 10 minutes. It is still another object of the present invention to provide a novel oral solid drug which prevents misuse by short-term liquid extraction and / or pulverization.

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

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

An attempt to misuse an AP (e.g., anesthetic) will cause the drug to switch to a form that is unable to rapidly absorb AP into the bloodstream after it is ingested.

Another object of the present invention is to provide

- can be easily administered to patients who are difficult to swallow large-sized tablets, such as seriously ill patients, infants or children,

- It is possible to bind several APs in one or the same dosage unit, even if they can not be used in combination and / or the release behavior is not the same

Which can be present in a form that can be administered more than once a day, and in this form it is easy and independent to modulate the release time and rate of release of the different APs.

It is a further object of the present invention to provide novel oral solid pharmaceuticals wherein the in vitro dissolution profile is independent of AP dose.

Another object of the present invention is to prevent the conversion of the drug into a form that can be administered orally, intranasally, and / or by injection (intravenous, subcutaneous, intramuscular, etc.) beyond the therapeutic limit, And to provide a novel oral solid drug which makes it possible to prevent unjust misuse. This will prevent or at least greatly reduce the risk associated with undesirable behavior.

It is a further object of the present invention to provide a novel and novel therapeutic agent that enables the patient experiencing the usual follow-up to ensure that the patient has a quality of care, To provide a solid drug for oral use.

It is a further object of the present invention to provide a pharmaceutical composition which does not normally affect the pharmaceutical properties of the drug and which does not present any additional risk to the patient using the drug and which makes it possible to prevent misuse And to provide a novel oral solid drug.

It is a further object of the present invention to provide novel oral solid pharmaceuticals that can be administered at least once a day, limiting the risk of tissue damage due to topically enriched AP.

It is a further object of the present invention to provide novel oral solid pharmaceuticals which can be administered in a variety of herbal forms such as tablets, powdered sachets, capsules and the like.

It is still another object of the present invention to provide a novel solid oral drug for prevention of misuse which is easy to manufacture and economical.

Brief Description of the Invention

To achieve this goal, we believe that the general problem of misuse of pharmaceutical formulations should be formulated again.

If we examine the different illegal dosing regimens of the active ingredient, in fact, milling of the dry formulation is likely to be an essential step.

In the case of misapplication by expedient administration, the dry pharmaceutical formulation should first be converted to a fine powder suitable for nasal inhalation. Therefore, pulverization of pharmaceutical formulations is clearly an essential step.

In the case of misuse by oral administration of a sustained-release dry formulation, it is necessary to finely pulverize the microparticles or tablets to promote the release of the active ingredient.

In the case of misuse by parenteral administration, the AP must first be extracted into a sufficiently high concentration of the liquid phase, in fact, water or a liquid phase which is an organic solvent, in order to prevent it from being injected in excessively large volumes, e.g. This extraction step is facilitated by a preliminary step wherein the dry formulation is milled so that the active ingredient can be dissolved or suspended. Further, after this extraction step, misuse can only be performed when the viscosity of the liquid phase is not too high (for example, 100 mPa.s or less).

Therefore, pulverization of dry formulations is also an essential step for misuse of the pharmaceutical formulations by parenteral administration.

The applicant,

The first problem (a) and the second problem

- a second problem (b) that prevents misuse of AP after possible extraction

We believe that the problem of preventing misuse of dry pharmaceutical formulations should be formulated again.

With this new approach, the Applicant has surprisingly and unexpectedly discovered that the combination of AP with a coated microparticulate form for modified release of AP, and a pharmaceutically acceptable excipient, if necessary, allows the physicochemical mode of action to be any voluntary or involuntary It has been found that it is appropriate to incorporate into the composition of the drug which should be prevented from being misused, in the form of a fine particle or a non-particulate, which makes it possible or even impossible to prevent misuse.

Therefore, the present invention is primarily intended to be applicable to the case where it contains misapplication measures and that at least some of the APs it contains are contained in the coated microparticles for the modified release of AP, Characterized in that it has a coating layer (Ra) which imparts crushing resistance to the AP coated microparticles in order to ensure deformation release and at the same time prevent misuse.

The pharmaceutical formulations according to the present invention specifically address at least some of the objectives set out in an efficient, simple and economical manner with the aid of physico-chemical means, solving the main problems presented. The latter is entirely harmless to normal users. These are pharmacologically inert compounds approved by the public health authority to award pharmacopeia and drug sales licenses.

In one preferred embodiment, the oral solid pharmaceutical formulation according to the present invention makes it very difficult, if not impossible, to extract AP contained in AP coated microparticles in addition to the anti-crush coating layer (Ra) (Vb) which prevents misuse of the thickener (Vb).

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

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, at least part of the AP is in the form of a modified release formulation, i.e. a coated extreme particulate for modified release of the AP.

The active ingredients (AP) of the present invention are those that fall into the category of pharmaceutical or veterinary APs, e.g., anesthetics or drugs. Misuse of these APs can cause addiction.

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

In the present invention, "the ultrafine particle formulation" is understood to mean any pharmaceutical formulation in which the AP is contained in the ultrafine particles of 1000 microns or less. These particles containing AP may be the ultrafine particles individually coated with a film for the modified release of AP. In the latter case, the extreme microparticles are coated with a polymeric base film which controls the release rate of, for example, AP.

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

In the present invention, "immediate-release formulation" refers to a formulation in which most of the AP contained therein is released in a relatively short period of time, such as between pH 1.4 and 6.8 during in vitro dissolution testing, at least 70% Lt; / RTI > within 30 minutes.

All extracellular dissolution profiles cited herein are obtained from a type II dissolutest, "dissolution test for oral solid formulations", which is carried out under stirring conditions at 75 rpm under the 37 ° C SINK conditions of the European Pharmacopoeia 4 plate .

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

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

The pharmaceutical formulations may also include one or more formulations for rectal administration of AP.

Advantageously, the pharmaceutical formulations according to the present invention, which are novel in structure, appearance and composition, can be in the form of, for example, tablets, powdered shakers, multi-dose reconstitutable suspending powders, shakes or the like.

AP Cloth Very fine particles

It is advantageous that the coated extreme microparticles for the modified release of AP are microparticles each coated with one or more coatings (including, for example, one or more polymers) deposited by techniques known to those skilled in the art. For example, the beak (Buri), puree siuk switch (Puisieux), also elkeo (Doelker) and Benoit (Benoit), edition 1985's in large Rab, 175-227 plane, book [Formes pharmaceutiques nouvelles : aspects technologique , biopharmaceutique et medical ( New pharmaceutical forms : technological , biopharmaceutical and medical These questions can be explained in terms of aspects .

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

The uncoated microparticles of the AP (e.g., before coating)

An inert core coated with at least one layer containing AP or

- pure AP microparticles or

RTI ID = 0.0 > AP-containing < / RTI > excipient.

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

These coated " reservoir "-coated microparticles (or individually coated microparticles) may be analogous to a carrier for releasing and transporting one or more APs of the small intestine or colon.

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

AP of Of very fine particles  covering

Advantageously, the coated microparticles of AP are coated with one or more coating layers (Ra), preferably only 1 < RTI ID = 0.0 > (Ra) of the layer.

Particularly preferably, the coating layer (Ra) is designed in such a way that non-instantaneous (i. E., Deformation release) is maintained for at least some of the coated microparticles for deformation release of AP during milling.

The milling to be foreseen in this specification may be any milling which is usually performed by a technique used by an abuser, in particular by a milling / grinding machine, a coffee grinder, between two spoons, bite / chewing, and the like.

In one important embodiment, the coating layer (Ra) has a modi fi ed release of at least 40%, preferably at least 60% and particularly preferably at least 80% of the coated microparticles for deformation release of AP at the time of milling It is designed in such a way as to allow maintenance.

Preferably, the anti-crush coating layer (Ra)

- (A1) at least one film-forming (co) polymer (A1) insoluble in gastric juice, and

- (A2) at least one (co) polymer (A2) soluble in the gastric juice, and

- (A3) at least one plasticizer (A3)

- (A4) optionally, one or more surfactants and / or lubricants and / or minerals and / or organic fillers (A4).

According to a purely non-limiting selection of the present invention,

(A1)

- water-insoluble cellulose derivatives, preferably ethylcellulose and / or cellulose acetate,

-Acrylic polymers such as copolymers of (meth) acrylic acid and alkyl (e.g. methyl) esters, copolymers of methacrylic esters and acrylic esters with at least one quaternary ammonium group bonded (preferably alkyl (meth) acrylates And trimethylammonioethyl methacrylate chloride), and more particularly to products sold under the trademarks EUDRAGITRS and / or RL,

- polyvinylacetate salts,

- mixtures thereof.

(A2)

Nitrogen-containing (co) polymers, preferably nitrogen, selected from the group consisting of poly-acrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) Containing (co) polymerized product,

- a water-soluble cellulose derivative,

- polyvinyl alcohols (PVA),

- polyalkylene oxides, preferably polyethylene oxide (PEO)

- polyethylene glycols (PEG),

- mixtures thereof.

PVP is particularly good.

(A3)

- cetyl alcohol esters,

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

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

- a citric acid salt selected from the group consisting of citric acid salts, preferably acetyl tributyl citrate, acetyltriethyl citrate, tributyl citrate, triethyl citrate,

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

- adipic acid salts,

- azelates,

- benzoic acids,

- Vegetable oil,

- fumaric acids, preferably diethyl fumaric acid,

Maleic acid, preferably diethyl maleic acid,

- oxalic acids, preferably diethyl oxalic acid,

- succinates, preferably dibutyl succinate,

- Butyrates,

- cetyl alcohol esters,

- Salicylic acid,

- triacetin,

- malonates, preferably diethyl malonate,

- castor oil (which is particularly good)

- mixtures thereof.

(A4)

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

- Nonionic surfactants, preferably

폴리에톡실화 오일류, 좋기로는 폴리에톡실화 수소화 피마자유와,

Polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil,

폴리옥시에틸렌/폴리옥시프로필렌 공중합체류와,

Polyoxyethylene / polyoxypropylene copolymer,

폴리에톡실화 소르비탄 에스테르류와,

Polyethoxylated sorbitan esters,

폴리에톡실화 피마자유 유도체와,

Polyethoxylated castor oil derivatives,

스테아르산류, 좋기로는 스테아르산칼슘, 스테아르산마그네슘, 스테아르산알루미늄 또는 스테아르산아연과,

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

스테아릴푸마르산류, 좋기로는 스테아릴푸마르산 나트륨과,

Stearyl fumaric acid, preferably sodium stearyl fumarate,

글리세롤 베헤네이트류와,

Glycerol behenate,

활석과,

Talc,

콜로이드성 규소와,

Colloidal silicon,

산화 티타늄, 산화 마그네슘과,

Titanium oxide, magnesium oxide,

벤토나이트와,

Bentonite,

미세결정성 셀룰로스와,

Microcrystalline cellulose,

고령토와,

Kaolin,

알루미늄 실리케이트와,

Aluminum silicate,

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

Nonionic surfactants selected from the group consisting of mixtures thereof.

In addition to the qualitative parameters defining the coated microparticles according to the invention, a coating layer (Ra) containing, by weight, based on the total amount of coating, according to an advantageous quantitative approach, may be embodied.

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

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

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

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

The sum of the percentages is 100.

Also, the release rate may be, for example,

- adjustment of the coating (Ra) thickness,

- the proportion of components A1, A2, A3 and optionally A4 in the coating (Ra).

Advantageously, the coating on the coated microparticles for the modified release of AP can comprise, in addition to the essential components of A1, A2, A3 and optionally A4, other conventional components known to the person skilled in the art such as colorants, , Preservatives, perfumes, and the like, and mixtures thereof.

Another remarkable feature of the coating (Ra) on the coated polar microparticles is the fact that the coating layer (Ra) represents the weight fraction Tp expressed as dry weight% based on the total weight of the coated microparticles such as Tp > = 15, Tp is preferably 30 to 60, particularly preferably 40 to 60, and very particularly preferably 45 to 55 or about 50.

This relatively high coverage rate is believed to cause the coated layer (Ra) to impart pulverization resistance to the AP coated microparticles in order to ensure the deformation release of the AP while at the same time preventing misuse.

Without limitation, the preferred coated microparticles of the AP according to the invention have an average diameter of less than 1000 [mu] m, preferably 50 to 800 [mu] m, particularly preferably 100 to 600 [mu] m and particularly preferably 100 to 300 [ .

Unless otherwise indicated, the diameter of the microparticles referred to herein is the average diameter to volume.

With respect to the preparation of coated microparticles, techniques which are advantageous for use in precipitating a coating for the modified release of AP or for precipitating an active layer based on AP are known to those skilled in the art, such as spray coating Technology, wet granulation, compression or extrusion / spheronization techniques.

Outer cloth

In a particular variation of the invention, the coated microparticles for modified release of AP contribute to maintaining a modified release of at least a portion of the coated microparticles of AP for modified release of the AP during tablet preparation It has an outer coating designed in such a way that The outer coating consists of at least one deformable organic component having a melting point of from 40 to 120 캜, preferably from 45 to 100 캜.

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

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

In another variant, the deformable organic component of the outer covering is selected from the group consisting of hydrogenated vegetable oils, fatty acids, fatty alcohols, fatty acids and / or fatty alcohol esters, polyolefins and minerals, vegetable, animal or synthetic waxes , Fatty acid esters such as diglycerides and triglycerides and mixtures thereof, glycerol behenate and hydrogenated castor oil, soy milk, cottonseed oil and palm oil.

In a further alternative variant, said outer covering

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

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

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

- and / or at least one surfactant.

Suitably, the outer coating represents from 5 to 50% by dry weight, preferably from 10 to 30% by dry weight, and especially preferably about 20% by dry weight, based on the total weight of the AP coated protective microparticles.

"Protective coated polar microparticles" are APs that also include outer coatings as defined above, i.e., outer coatings that contribute to maintaining the modified release of at least a portion of the coated polar microparticles of AP for modified release of AP Coated microparticles.

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

Thickener  ( Vb )

Preferably, the thickener (Vb) is selected from those which are soluble in at least one of the following solvents: water, alcohols, ketones and mixtures thereof, said thickener (s) being used to prevent misuse, The viscosity of the extract can be increased.

"Water" is understood to mean any aqueous solvent, such as water, in the narrow sense, or any aqueous solution, such as an organic acid (such as acetic acid), saline solution, soda or beverage. "Alcohol" is understood to mean any given alcohol itself or a mixture with one another. "Ketone" is understood to mean any ketone itself or a mixture of ketones with one another.

Particularly preferably, the thickener (Vb) is a polymer of the following formula

- polyacrylic acids and their derivatives and / or

Polyalkylene glycols (e.g., polyethylene glycol) and / or

Polyalkylene oxide (such as polyethylene oxide) and / or

Polyvinylpyrrolidone and / or

- Gelatines and / or

Polysaccharides, preferably sodium alginate, pectins, guars, xanthans, caragenes, gellans and cellulose derivatives (such as hydroxypropylmethylcellulose, methylcellulose, hydroxyethyl Cellulose, carboxymethylcellulose), polysaccharides selected from the group comprising < RTI ID = 0.0 >

- and mixtures thereof.

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

Preferably, the thickener Vb, such as a high molecular weight polyoxyethylene, is included in the ultra fine particles which are different from the extremely fine particles of AP.

Particularly preferably, the polar microparticles of AP and the thickener Vb are similar in size distribution and density and can not be separated by screening.

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

The thickener (Vb) is capable of increasing the viscosity of the extract to, for example, greater than 100 mPa.s, preferably greater than 200 mPa.s, particularly preferably greater than 500 mPa.s, particularly preferably greater than 1000 mPa.s .

Applicants believe, in one variant, proposed an efficient thickener (Vb) in the case of both aqueous extraction and organic solvent extraction. Advantageously, these thickeners (Vb) are a mixture of hydrophilic compounds and hydrophobic compounds to ensure that the extract has a high viscosity (e.g., greater than 100 mPa.s), whether it is an aqueous solution or an organic solution.

With respect to the amount of the thickener (Vb), this can be easily determined by a person skilled in the art. The amount corresponds to the minimum amount required to bring the viscosity of the extract to 2.5 m < 2 >

In some variations where they can be mixed with one another, in the pharmaceutical formulation according to the invention, one or more thickeners (Vb)

- on and / or on the surface of the fine particles, and / or

- in the outer coating of all or part of the AP microparticles, and / or

- It is present in the glassy state, that is, contained in the nano-particles or not supported by the nano-particles.

Advantageously, at least a portion of the thickener is in the form of a microparticle that can not be separated from the coated or uncoated microparticles of the AP.

Excipients in glass form

If desired, the pharmaceutical formulations may contain one or more pharmaceutically acceptable excipients in the free state, i.e. in the state of being contained in, or not carried by, the microparticles of the AP, said excipients being selected from the group consisting of pulverization It contributes to resistance.

Advantageously, these excipients, which contribute to the crushing resistance of AP coated microparticles,

- calcium stearate,

- palmitostearic acid glycerol,

- Magnesium oxide,

Polyalkylene glycols such as polyethylene glycols,

- polyvinyl alcohol,

- sodium benzoate,

- Stearic acid,

- Corn starch,

- talc,

- colloidal silicon,

- zinc stearate, magnesium stearate,

- stearyl fumaric acid,

- mixtures thereof.

In an alternative embodiment of the present invention, at least a portion of the thickener

- in a free state, i.e. in a state not contained in or supported by the microparticles coated or uncoated with AP (Alternative 1), or

- A very fine particulate formulation (Alternative 2) that is distinct from AP coated or uncoated microparticles.

Advantageously, in alternative 2, the thickener microparticles can not be separated from the AP coated or uncoated microparticles. As used herein, the expression "not separable" means that it can not be separated by conventional means such as, for example, a sieve or centrifuge.

In alternative 2, the thickener is, for example,

- in and / or on the fine particulate, and / or

- some or all of the AP microparticles are in the outer envelope.

Still in Alternative 2, the polar microparticles containing the thickener should not be physically identifiable with the AP microparticles so that they can not be easily separated by appropriate physical means. The fine particles containing the thickener are especially unidentifiable with the polar microparticles of the AP because they have the same size and / or density and / or shape and / or color.

In another alternative, the thickener may be, for example,

- On and / or on the fine particulate,

- and / or within the outer envelope on some or all of the polar particulate of the AP.

In one preferred embodiment, the pharmaceutical formulation according to the invention is a multiparticulate. If the pharmaceutical formulation contains the microparticles of the AP microparticles (e.g., aAP) and the thickener (Vb), the microparticles preferably have similar size distributions and similar densities, and can not be separated by sieves. Thus, the thickener microparticles can not be separated from the AP coated or uncoated microparticles.

In another preferred embodiment, the pharmaceutical formulation according to the present invention is a multiparticulate. If the pharmaceutical formulation contains the microparticles of the AP microparticles (e.g., aAP) and the thickener (Vb), the microparticles preferably have the same size distribution and the same density, and can not be separated by the sieve. Thus, the thickener microparticles can not be separated from the AP coated or uncoated microparticles.

Blockade agent  Q

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

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

In the context of the present invention, the sequestering agent Q is present in the form of a free-of-charge, e.g., a complex, in free form. A "non-complex" means that there is no complex or chemical interaction between the active ingredient AP salt and the sequestering agent Q in the solid pharmaceutical formulation.

If the AP salt and sequestering agent Q are present simultaneously in the solvent, such as attempting to illegally extract AP, the sequestering agent Q may induce a chemical interaction or complexation with the AP salt in the solvent. In the context of the present invention, the sequestering agent Q is selected from the group consisting of AP salts and / or salts thereof in one or more conventional solvents selected from water and aqueous solutions such as water / ethanol mixtures, alcohols, alcoholic drinks, soda, vinegar, hydrogen peroxide, The blocking agent Q is deemed to have "ability to induce complexation" with the AP salt. Advantageously, said sequestrant Q can induce the complexation of the AP salt in one or more of these conventional solvents.

Blockade Q, used to capture APs, especially anesthetic APs, is not harmful even when used regularly. These products are inactive from a pharmacological standpoint and approved by numerous pharmacopoeial and drug approval authorities.

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

- in the AP-free, fine particulate, and / or

- on top of the fine particulate, and / or

- exist in the glassy state, that is, contained in the nano-particles or not supported by the nano-particles.

Preferably, in the pharmaceutical formulation according to the invention, said sequestering agent Q is present in a first phase separated from at least one second phase, said second phase containing at least one AP salt. For example, the pharmaceutical formulation contains the microparticles of the AP salt and the microparticles of the sequestering agent Q. Advantageously, the ultra fine particles are similar in size distribution and density and can not be separated by sieving.

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

For example, the following salts containing organic anions may be mentioned.

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

- (meth) acrylate copolymer (e.g. Eudragit ^® S and Eudragit ^® L), cross-linked polyacrylic acids (e.g. Carbopol (Carbopol)), carboxymethylcellulose and derivatives thereof, cross-linked carboxymethyl cellulose and derivatives thereof And other polysaccharides (such as alginate, xanthan gum or gum arabic) and alginic acid / (sulfonate) propylene glycol,

Glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfam, and the like,

- saponified fatty acids such as acetate, succinate, citrate, stearate, palmitate and self-emulsifying glyceryl monooleate,

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

- and mixtures thereof.

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

The present invention also relates to a method for producing an aqueous solution containing an organic acid such as acesulfame, acetate, adipate, benzoate, carbonate, chloride, citrate, fluoride, fumarate, gluconate, gluconate, glycerophosphate, hydroxide, iodate, Metal salts in the form of phosphates, trisilicates, salicylates, succinates, sulphonamides, or tartrates, cationic salts such as Ca, Fe, Mg or Zn,

- quaternary ammonium salts, in particular organic cation salts such as tetradecyltrimethylammonium bromide or benzethonium chloride,

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

- polyamino acids, proteins or peptides,

- and mixtures thereof.

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

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

In one embodiment of the present invention, the strong acid cation exchange resin is a sulfonated styrene / di (meth) acrylate such as, for example, Amberlite ^® IRP69, Amberlite ^® IR69F, Amberlite ^® 200, Amberlite ^® 200C from Rohm & Haas or Dowex ^® 88 from Dow. Vinyl benzene copolymer.

In one embodiment of the present invention, the strong base anion exchange resin is Rohm & Hass Company Duolite ^® AP143, Amberlite ^® IRA958, Amberlite ^® IRP67 or Dow's Dowex ^® 22 such as a quaternary ammonium group bonded styrene / divinylbenzene air ≪ / RTI >

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

Blocking agent Q in the form of ion exchange resin may be selected from phenol polyamines such as Amberlite ^® IRP 58 from Rohm & Hass, and mixtures thereof.

In one embodiment, said sequestering agent Q in the form of an ion exchange resin is present in a first phase separated from at least one second phase, said second phase comprising an AP salt. For example, the blocker Q in the form of an ion-exchange resin is contained in the nano-particles different from the nano-particles containing the AP salt. The polystyrene microparticles of the AP and the blocker Q of the ion exchange resin type may have a similar size distribution and density and can not be separated by the constitution.

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

- an organic anion salt such as sodium dodecyl sulfate or sodium docusate,

- a quaternary ammonium salt, especially tetradecyltrimethylammonium bromide or benzethonium chloride,

- It is selected according to AP polarity from strong base anion exchange resin or strong acid cation exchange resin.

In a second preferred method of carrying out the present invention, the containment agent Q comprises

When AP is a cation, Amberlite ^® IRP69, Amberlite ^® IR69F, Amberlite 200, Amberlite ^{® from} Rohm & 200C or Dowex 88 from Dow, and mixtures thereof,

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

The amount of sequestering agent Q is employed 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 dosage form. The amount of sequestrant Q should at least be capable of complexing with AP to an insufficient extent to obtain the desired effect with the glass AP remaining in solution when attempting illegal extraction. At least the amount of sequestrant Q is sufficient to complex all of the APs contained in the unit dose.

In one variation, the pharmaceutical formulation may be an integral (e.g., tablet) formulation.

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

In another embodiment of the present invention, the pharmaceutical formulation contains the microparticles of AP as well as the microparticles of thickener V and / or the microparticles of Q. Suitably, the pharmaceutical formulations contain these three types of polar particulates, i.e., the AP microparticles, the thickener V microparticles and the Q sequestering microparticles in one identical unit dosage form. Advantageously, these ultra fine particles are similar in size distribution and density and can not be separated from each other by sieving.

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

In a second variant, the pharmaceutical formulation according to the present invention can not be converted to an AP, i.e. a square injection formulation.

In a third variant, the pharmaceutical formulation according to the invention contains modified release AP and optionally immediate AP. This variant can be mixed with the first and second variants described above, which is a pharmaceutical formulation containing modified release AP and immediate AP, wherein said modified release AP is a dry formulation, It can not be converted into a injectable formulation.

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

In a fifth variant, the pharmaceutical formulation according to the invention is characterized by the absence of an AP antagonist.

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

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

The active ingredient (s)

The APs used belong, for example, to one or more of the following set of active substances.

(Eg, amphotericin, anesthetic, anorexigenic, antalgic, antidepressant, antiepileptics, anti-migraine, antiparkinsonian, antihypertensive, anxiolytic, barbituric acid, benzodiazepines, hypnotics, laxatives, neuroleptics, opiates, psychostimulants, psychotropic drugs, sedatives and irritants. If the AP is an anesthetic AP (aAP), it is preferable to be an opioid.

More precisely, the AP used is selected from the following compounds. Alpha-methadol, alpha-methadol, alpha-methadol, alpha-methadol, alpha-methadone, alpha-methadone, , Alpha-methyl-fentanyl, alpha-methylthio-fentanyl, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxypentanyl, But are not limited to, metadol, beta- metaprodine, beta-methadol, beta-prodin, beztramide, buprenorphine, dioxapelletylbutyrate, clonitazene, cyclolazocine, cannabis, But are not limited to, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, codeine, cocaine, cocaine, Diphenoxine, dihydrocodeine, dihydroetorphine, dihydro morphine, dimenoxy But are not limited to, styrene, dimethephenol, dimethyl thiambutene, diphenoxylate, dipiphenone, dorothenol, eptasosin, etheptazine, ethylmethyl thiambutene, ethylmorphine, ethonitazene, exonine, ephedrine, But are not limited to, thiophene, etorphine, fentanyl, furutidine, heroin, hydrocodone, hydro- morphinol, hydro- morphone, hydroxypethidine, isomethadone, ketobemidone, levallorphane, Methylphenidate, methyl-3-thiopentanyl, thiophene, levomoramide, levopene acylmorphan, levorphanol, 멥tazinol, meperidine, metazocine, methadone, methyldisorbin, methyl-3-thiofentanyl, methyl-3-fentanyl, methone, morpholine, morpholine, morphine, myrropine, nalbuphine, narsine, nicomorphine, norebrelpanol, , Nicocordine, nicodicodine, nicodormine, noracymetadol, norcodaine, noradrenaline A prodrug, a prodrug, a propylpyridine, a propylphenol, a parafluoropentanyl, a pentazocine, a petidine, a phenanthroline, Amide, racemorphan, remy amide, phenanthoxine, phenomorphan, phenopyridine, polycodine, piminodine, pyritramide, propheptazine, propanolol, propellidine, Fentanyl, sufentanil, tebacon, tebine, thiopentanyl, tilidine, tmeperidine, tramadol, pharmaceutically acceptable salts, esters, hydrates, polyamorphs and isomers thereof, and mixtures thereof.

The pharmaceutical formulations according to the invention may comprise one or more anesthetic active ingredients (aAP) and aAP and one or more additional APs. The non-brittle AP may be used in combination with an antidepressant, amphetamine, anorexics, non-emetic painkillers, antiepileptics, anti-migraine agents, anti-parkinsonics, A pharmaceutically acceptable salt, ester, hydrate, polymorph and isomer thereof, and a mixture thereof, in combination with a pharmaceutically acceptable carrier, diluent, excipient, excipient, psychostimulant, psychotropic drug, sedative, stimulant, antiinflammatory agent.

Of the anti-inflammatory active ingredients that may be included, the following may be mentioned. But are not limited to, ibuprofen, acetaminophen, diclofenac, naproxen, beroxaprofen, fluorevifropen, fenoprofen, fluvufen, ketoprofen, indoprofen, pyroprofen, But are not limited to, methoxycinnamic acid, methoxycinnamic acid, methoxycinnamic acid, methoxycinnamic acid, methoxycinnamic acid, (Methionine), napromic acid, tolpenamic acid, diflurisal, flupenisal, piroxicam (fenoxycarboxylic acid, fenoxycarboxylic acid, piroxicam, a poison cam or an ischemic cam, pharmaceutically acceptable salts, esters, hydrates, polymorphs and isomers thereof, and mixtures thereof.

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

In the present invention, "pharmaceutical formulation" is understood as broad meaning, i.e., veterinary or nutritional formulations, and is a particularly encompassing concept.

According to another of its features, the present invention is characterized in that the above-mentioned plurality of fine grains (the coated or uncoated fine grains of the AP, the fine grained fine grains of the thickening agent if necessary) are mixed with, for example, at least 500, And particularly preferably from 5,000 to 500,000 of the formulation.

According to another of its characteristics, the present invention relates to a pharmaceutical formulation comprising a plurality of clusters of AP microparticles, said population being distinguished from one another by their release kinetics and / or by the AP they contain.

It should be emphasized that the pharmaceutical formulations according to the invention are nonetheless of particular value in that they can be taken once a day oral dosage form containing 500 to 500,000 microparticles, including coated microparticles of AP .

Advantageously, the pharmaceutical formulations containing the coated microparticles according to the present invention comprise a tablet (advantageously dispersed orally or topically), a powder, a suspension, a syrup, a reconstitutable suspension powder and a capsule ≪ / RTI >

It may be interesting to mix two or more of the coated microparticles of the AP within the main features of the invention, although their release behavior is different, to one and the same capsule, one and the same tablet or one and the same powder.

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

The present invention also relates to a therapeutic treatment method characterized in that the patient is administered a pharmaceutical formulation as described above.

The present invention also relates to a therapeutic treatment method characterized in that it is constituted by ingesting the pharmaceutical formulation as described above according to a predetermined dose.

The present invention also relates to a method of treating pain, characterized in that the patient is administered a pharmaceutical formulation as described above.

The present invention also relates to a method of treatment of pain characterized by ingesting a pharmaceutical formulation as described above according to a predetermined dose, wherein the AP used comprises at least one pain reliever, such as an anesthetic agent .

The invention also relates to a method for preventing misuse of AP characterized in that it consists essentially of using a pharmaceutical formulation as described above.

In addition, the present invention consists essentially of using coated microparticles of AP for modified release of AP as pharmaceutical formulations, which ensure the modified release of AP and, at the same time, (Ra) which imparts crushing resistance to the fine particles and at least one thickening agent (Vb) which can prevent the extraction of AP contained in the AP coated fine particles to prevent misuse as required And more particularly to a method for preventing abuse of an AP.

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

The present invention will be more clearly understood through the following examples, which are intended to provide a clear understanding of the invention and to explain the different embodiments thereof and / or their methods of implementation, by way of illustration.

―의 극미립자의 생체 밖 대조 시험에 있어서의 용해 프로파일 (시간 T의 함수로서 용해% D)을 나타낸 것이다.
도 2는 실시예 1 즉, ―

― 및 실시예 2 즉, (a) ---

---, (b) ---

---, (c) ---

---, (d) ---

---의 극미립자의 생체 밖 대조 시험에서의 용해 프로파일 (시간 T의 기능으로서 용해% D)을 나타낸 것이다.
도 3은 실시예 3에 따른 캡슐의 내용물을 육안 (A) 및 광학 현미경 (B)하에 관찰한 사진을 나타낸 것이다.
도 4는 0.1 N HCl 중의 극미립자(실시예 8)의 방출 프로파일 (시간의 함수로서 aAP의 중량%)을 나타낸 것이다.
도 5는 실시예 9에 따른 캡슐의 내용물을 육안 (A) 및 광학 현미경 (B)하에 관찰한 사진을 나타낸 것이다.
도 6은 실시예 9의 분쇄된 극미립자들 (속이 빈 삼각형) 또는 본래 그대로의 극미립자들 (사각형)의 방출 프로파일을 나타낸 것이다.FIG.

- dissolution profiles (dissolution% D as a function of time T) in an in-vitro control experiment of the microparticles.
Fig. 2 is a graph showing the results of Example 1,

- and Example 2, that is, (a) ---

---, (b) ---

---, (c) ---

---, (d) ---

(Solubility% D as a function of time T) in an in vitro control experiment of the microparticles.
3 is a photograph showing the contents of the capsule according to Example 3 observed under a naked eye (A) and an optical microscope (B).
Figure 4 shows the release profile (wt% of aAP as a function of time) of the microparticles (Example 8) in 0.1 N HCl.
5 is a photograph of the content of the capsule according to Example 9 observed under the naked eye (A) and the optical microscope (B).
Figure 6 shows the emission profile of the pulverized nano-particles (hollow triangle) or intact nano-particles (quadrangle) of Example 9.

The dissolution control test of the examples described below is an in vitro dissolution test as outlined in European Pharmacopoeia 5 edition entitled " Dissolution test for solid oral forms ", i.e., maintenance at 37 DEG C and stirring at 900 rpm in 75 mL of 0.1 N HCl, Lt; RTI ID = 0.0 > SINK < / RTI > conditions.

Example  1: According to the present invention Oxycodone HCl Very fine particles

Oxycodone HCl 1600 g, Klucel ^® EF (hydroxypropyl cellulose / Aqua sialon) 100 g, and a mixture of water 12.052 g The GPCG1 air fluid bed (Glatt ^®) coating film on a 300 g inert cellulose beads (Asahi-Kasei) in a. Then 450 g of the resulting granules were 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 macrogolglyceroli hydroxystearas / BASF) and 12.020 g of ethanol.

The coating represents 50 wt% of the microparticles and ensures that the active ingredient is released for about 4 hours as shown in Fig. The release profile is measured under the conditions of a controlled dissolution test.

Example  2: Example  1 Oxycodone HCl Of very fine particles  smash

200 mg of the microparticles prepared in Example 1 (e. G., A dose of 80 mg oxycodone HCl) were administered in different ways, which represent possible misuse in different ways,

(a) Grinding (120 revolutions) intensely for 2 minutes with a jellyfish and a mortar (250 ml)

(b) 8 squeezes between 2 spoons,

(c) Using "LGS Powder" refiner (LGS Health Products, USA)

(d) Using a coffee grinder for 30 seconds

Lt; / RTI >

The emission profiles of the pulverized nano-particles are shown in Fig. This release profile is measured under reference dissolution test conditions.

The release profiles of Example 1 (intact microparticles as is) and 2 (microparticles pulverized) are similar in terms of testing for the f2-like factor (f2 > 50) calculated by the FDA Guidance for Industry SUPAC-MR: Solid formulations for modified release oral, p. 32).

Thus, milling has little or even no effect in releasing oxycodone from the microparticles.

Example  3: Aspects of contents of capsules according to the present invention

200 mg of the microparticles prepared in Example 1 (dose of 80 mg of oxycodone HCl) were mixed with 90 mg of a thickener, namely Klucel HF (hydroxypropyl cellulose / Aqualon) previously diluted to 100 to 600 탆, PolyOx WSR , 20 mg of 303 Sentry (polyethylene oxide / DOOSA) and 20 mg of Xantural 180 (xanthan / cpKelco). The whole is filled into size 0 gelatin capsules.

3 shows photographs of the contents of the capsules observed under the naked eye (A) and the optical microscope (B).

As shown in FIG. 3 (A), which is observed with the naked eye, the ultrafine particles of the active component and the ultrafine particles of the thickener

- can not distinguish,

- can not be separated by constitution.

In the photograph of FIG. 3 (B) observed with an optical microscope, there are two distinct groups of particles, one being spherical microparticles of oxycodone HCl and the other of the two thickening agents, and the other being a third thickener Of the particles. Since these particles are very small in size (about 0.2 mm) they can not be separated from each other.

Example  4: injection extraction test of the formulation according to the present invention

200 mg of the microparticles prepared in Example 1 (dosage of 80 mg of oxycodone HCl) were mixed with 90 mg of Klucel HF (hydroxypropyl cellulose / acacalone) which had been previously sieved to 100 to 600 탆, PolyOx WSR 303 Sentry (polyethylene oxide / 20 mg) and 20 mg of Xantural 180 (xanthan / cpKelco). The whole is filled into size 0 gelatin capsules.

The capsules are opened and the contents are pulverized according to the procedure of Example 2 (a) and then mixed with 2.5 ml of the extract at ambient temperature or boiling point for 10 minutes. Then, the solution is taken through a fresh-water surface provided with a filter into a 2.5 ml syringe (18G needle). The amount of extracted oxycodone HCl was analyzed by HPLC or UV and is shown in Table 1.

The observed low extraction yield (< 20%) is to discontinue the potential abuser completely.

Example  5: injection extraction test of the formulation according to the present invention

200 mg of the microparticles prepared in Example 1 (dose of 80 mg of oxycodone HCl) were mixed with 150 mg of Klucel HXF (hydroxypropylcellulose / acaron), 50 mg of PolyOx WSR 303 Sentry (polyethylene oxide / And mixed with 30 mg of 971P (carbomer / BF Goodrich). The mixture is filled into size 0 gelatin capsules.

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

The observed low extraction yield (< 20%) is to discontinue the potential abuser completely.

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

, 50 g of PolyOx WSR 303 Sentry (polyethylene oxide / DOWA), 30 g of Carbopol 971P (carbomer / BF Goodrich) and 10 g of Povidone (Plasdone PVP K29 / 32 / ISP) 10 g of Klucel HXF (hydroxypropylcellulose / g is wet granulated in the MiPro device. The granules are sieved to 100 to 600 μm and filtered.

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

The observed low extraction yield (< 20%) is to discontinue the potential abuser completely.

Example  7: Preparation 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 / acaron), 20 g of PolyOx WSR 303 Sentry (polyethylene oxide / DOWA), 20 g of Xanthural 180 (xanthan / cpKelco) , 100 g of lactic acid (Tablettose / Meggle GmbH), 10 g of magnesium stearate (Brenntag AG) and 30 g of croscarmellose sodium (Ac-Di-Sol / FMC Bipolymer).

A 470 mg tablet (i.e., an oxycodone dose of 80 mg) is prepared using a Korsch reciprocating press.

The tablets thus obtained are pulverized in a mortar and mortar according to Example 2 (a), and then mixed with 2.5 ml of the extract at ambient temperature or boiling point for 10 minutes. Then, the solution is taken through a fresh-water surface provided with a filter into a 2.5 ml syringe (18G needle). The amount of extracted oxycodone HCl was analyzed by HPLC or UV and is shown in Table 4.

The observed low extraction yield (< 20%) is to discontinue the potential abuser completely.

Example  8: According to the present invention Oxycodone HCl Very fine particles

Step 1: Granulation

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

Step 2: Anti-crushed fine particles

31 g of ethylcellulose (Ethocel 20 Premium / Dow), 81 g of povidone (Plasdone K29-32 / ISP), 18 g of macrogolglyceroli hydroxystearas (Cremophor RH40 / BASF) and 25 g of Garbit huilerie 36 g is dissolved in a mixture consisting of 3105 g of acetone and 2070 g of isopropanol. This solution is sprayed with 450 g of granules (made in step 1).

The coating represents 50% by weight of the microparticles and ensures that the active ingredient is released as shown in Fig. The release profile is measured under controlled dissolution test conditions.

Example  9: Contents of the capsules according to the present invention

230 mg of the fine particles obtained in Step 2 of Example 8, 100 mg of pulverized Amberlite IR69F (polystyrene sulfonate sodium), 70 mg of sieved Polyox WSR 303 Sentry (polyethylene oxide), 3.8 mg of magnesium stearate and 200 mg of Aerosil 200 (Colloidal silicon) is introduced into size 0 gelatin capsules.

As shown in Fig. 5 observed under the naked eye (A) and the optical microscope (B), the ultrafine particles of the active component and the ultrafine particles of the thickener

- can not distinguish,

- can not be separated by constitution.

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

The contents of the capsules prepared in Example 9 were pulverized for 2 minutes with a mortar and pestle.

The emission profile of the pulverized nano-particles is shown in Fig. This release profile is measured under reference dissolution test conditions.

The release profile of the intact and crushed goods is similar. Thus, milling has little or no effect in releasing oxycodone from the microparticles.

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

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

The observed low extraction yield (< 20%) is to discontinue the potential abuser completely.

Example  12: In the beverage Example  9 Extraction test of capsule contents according to

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

Then, the amount of oxycodone HCl extracted from the solution was analyzed by HPLC or UV, and it is shown in Table 7.

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

Example 4
The oxycodone HCl extracted with 18G syringe% Liquid at ambient temperature Liquid at boiling point tap water
Water / ethanol (60/40 V / V)
ethanol 0.2
3
18 One
8
One

Example 5
The oxycodone HCl extracted with 18G syringe% Liquid at ambient temperature Liquid at boiling point tap water
Water / ethanol (60/40 V / V)
ethanol One
4
19 2
7
8

Example 6
The oxycodone HCl extracted with 18G syringe% Liquid at ambient temperature Liquid at boiling point tap water
Water / ethanol (60/40 V / V)
ethanol One
5
19 2
8
9

Example 7
The oxycodone HCl extracted with 18G syringe% Liquid at ambient temperature Liquid at boiling point tap water
Water / ethanol (60/40 V / V)
ethanol 0.5
4
19 2
10
2

Amount (%) of AP extracted using a 2.5 ml syringe equipped with a 27G needle (Example 11)
Oxycodone HCl extracted with 27G syringe% Liquid at ambient temperature Liquid at boiling point tap water
Water / ethanol (60/40 V / V)
Anhydrous ethanol 0
0
14 One
4
0

Amount of AP (%) extracted using a 2.5 ml syringe with 18G needles (Example 11)
The oxycodone HCl extracted with 18G syringe% Liquid at ambient temperature Liquid at boiling point tap water
Water / ethanol (60/40 V / V)
Anhydrous ethanol 0
3
18 One
8
One

Amount (%) of AP extracted from different beverages as a function of time (Example 12) Solvent / extraction time 1 hours 21 hours tap water 8 <45 Tap water containing 2 g / l NaCl 8 <45 PH 1.2 (HCl) containing 2 g / l NaCl &lt; RTI ID = 0.0 &gt; 14 <45 Sprite® 3 <45 PepsiCo ® 3 <45 Smirnoff Twisted Apple (5% alcohol) 23 <45 Absolute® Vodka (40% alcohol) 24 <45

Claims (1)

- means for preventing misuse,
At least a part of the active ingredient contained is contained in the microparticles coated for the modified release of the active ingredient,
Characterized in that the coated microparticles of the active ingredient have a coating layer (Ra) which imparts crushing resistance to the coated microparticles of the active ingredient, while at the same time ensuring a modified release of the active ingredient, Formulation.

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