RU2339365C2 - Drug dosage form, protected from unintended application - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention relates to drug forms domain, particularly to thermoformed by extrusion without colour altering, protected from unintended application, dosage form, which includes active substance, potentially subject to non-medical abuse, and auxiliaries; it also contains synthetic or natural polymer with at least 500 N breaking strength. Moreover production method for such drug form is described.

EFFECT: providing of protection from non-medical internal applications.

35 cl, 1 dwg, 1 tbl, 1 ex

Description

The present invention relates to improperly protected, thermoformed by extrusion without changing the color of the dosage form, which along with one or more active substances (A), which are potentially the object of their non-medical use, as well as possible physiologically compatible excipients (B) contains at least one synthetic or natural polymer (B) and optionally at least one wax (G) and in which component (B) and possibly the component present nt (D) have a breaking strength of at least 500 N, and also relates to a method for preparing such, the inventive dosage form.

Many of the pharmaceutical active ingredients, along with their extremely high effectiveness, which they show with indications appropriate for their use, are potentially also the object of their non-medical use, i.e. they can be used to cause effects that are not appropriate for their intended purpose. Examples of such substances include opiates, which are highly effective painkillers used for severe and very severe pains, and which are often used by addicted to or abusing people to cause such intoxication, euphoric conditions.

For non-medical use of such substances, the corresponding dosage forms containing them, for example tablets or capsules, are crushed, for example, in a mortar, the active substance is extracted from the powder obtained in this way using mainly aqueous liquid and the resulting solution, sometimes after filtering it through cotton or cellulose administered parenterally, usually intravenously. When the active substance is introduced into the body in this way, compared with the oral administration of the active substance for non-medical purposes, its intake ("inflow") into the body is additionally accelerated with the achievement of the desired result, namely the so-called quick "arrival" or "high". A similar onset of “high” is also achieved with nasal administration, i.e. when sniffing, powdered dosage form. Since oral retard dosage forms that contain active substances that are potentially the object of their non-medical use, even when taken orally in intentionally large amounts, usually do not lead to the required rapid onset of high, such dosage forms are also subjected to non-medical use the active substances contained in them are crushed and the active substances are extracted from them.

To prevent non-medical use of active ingredients in US 4070494 it was proposed to add a swellable substance to the dosage form. When water is added to extract the active substance, such a substance swells, forming a gel that binds the active substance, the amount of which in the filtrate separated from the gel, as a result, is only at an insignificant level.

Another approach to preventing the non-medical use of active substances by their parenteral administration into the body is proposed in WO 95/20947, which describes a multilayer tablet that individually contains in its different layers an active substance that is potentially the object of its non-medical use, and at least at least one gelling agent.

Another approach to preventing the non-medical use of active substances by their parenteral administration into the body is proposed in WO 03/015531 A2. This publication describes a dosage form containing an analgesic opioid and dye as an aversive (disgusting) agent. Thanks to such a dye, the dosage form when performing unacceptable manipulations with it is painted in a color at which a person should refrain from further use of such a dosage form.

Another well-known possibility, which is intended to complicate the non-medical use of active substances, is to add to the dosage form antagonists of active substances, for example, naloxone or naltexone in the case of opioids, or agents that cause physiological protective reactions, for example, Ipecacuanha root, otherwise called emetic root.

Since, however, dosage forms containing an active substance suitable for non-medical use, in order to be able to be introduced into the body for non-medical purposes, in most cases, as before, it is necessary to grind it into powder, the present invention was based on the task of complicating the previous non-medical use of the active substance grinding the dosage form containing it into powder with usually available improvised means, respectively, to prevent such a grinding the use of the dosage form and thereby offer a solid dosage form for the potentially active substances of non-medical use, which, if used for its intended purpose, would exhibit the required therapeutic effect, but the active substances contained in it could not be converted into a suitable for non-medical administration into the body form by simply grinding such a dosage form into a powder.

This problem is solved using the invention, which is protected from misuse, thermoformed by extrusion without changing the color of the dosage form, which along with one or more active substances (A), which are potentially the object of their non-medical use, contains at least one synthetic or a natural polymer (B) and optionally at least one wax (G) and in which component (B) and possibly present component (G) have a fracture resistance of at least at least 500 N.

By using polymers with the indicated minimum fracture resistance (measured by the procedure described below), preferably in quantities such that the dosage form has the same minimum fracture resistance of at least 500 N, it is possible to prevent the dosage form from being pulverized by conventional improvised means and thereby significantly complicate, respectively, stop its subsequent use for other purposes.

This is due to the fact that without sufficient grinding of the dosage form, the possibility of parenteral, especially intravenous, safe introduction of the active substance contained in it into the body or the extraction of the active substance contained in it, lasts too long, respectively, when it is taken orally for non-medical purposes rapid onset of “high” due to the lack of spontaneous release of the active substance from it.

By grinding the dosage form into powder according to the present invention, it is meant to be powdered by conventional, available improvised means, such as, for example, a mortar and pestle, hammer, mallet or other common means, which allow the application of appropriate force to grind solid materials into powder .

Accordingly, the dosage form according to the invention is suitable for preventing the use of active ingredients, preferably pharmaceutical active substances, which are potentially the object of their non-medical use, for other purposes, by parenteral, nasal and / or oral administration to the body.

Pharmaceutical active substances that are potentially the object of their non-medical use, as well as their applicable amounts and methods for their preparation, are known to specialists in this field and may be present in the dosage form according to the invention as such, in the form of their corresponding derivatives, especially esters or ethers , or in the form of corresponding physiologically compatible compounds, primarily in the form of their respective salts or solvates, as well as in the form of racemates or stereoisomers in. The dosage form according to the invention is also suitable for administration of several pharmaceutical active substances into the body in its composition. In a preferred embodiment, however, the dosage form of the invention comprises only one specific active ingredient.

The dosage form according to the invention is particularly suitable for preventing the non-medical use of at least one pharmaceutical active substance selected from the group consisting of opioids, tranquilizers, preferably benzodiazepines, barbiturates, stimulants and other narcotic drugs.

The dosage form of the invention is most suitable for preventing the non-medical use of an opioid, tranquilizer or other drug selected from the group comprising N- {1- [2- (4-ethyl-5-oxo-2-tetrazolin-1-yl) ethyl ] -4-methoxymethyl-4-piperidyl} propionanilide (alfentanil), 5,5-diallyl barbituric acid (allobarbital), allylprodin, alpha-prodin, 8-chloro-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine (alprazolam), 2-diethylaminopropiophenone (ampepramone), (±) -α-methylphenethylamine (amphetamine), 2- (α-methylphenethylamino) -2-f enylacetonitrile (amphetaminyl), 5-ethyl-5-isopentyl barbituric acid (amobarbital), anileridine, apocodein, 5.5-diethyl barbituric acid (barbital), benzyl morphine, bezitramide, 7-bromo-5- (2-pyridyl) , 4-benzodiazepin-2 (3H) -one (bromazepam), 2-bromo-4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-ƒ] [1,2,4] triazolo [ 4,3-a] [1,4] diazepine (brotizolam), 17-cyclopropylmethyl-4,5α-epoxy-7α [(S) -1-hydroxy-1,2,2-trimethylpropyl] -6-methoxy-6 , 14-endo-ethanomorphinan-3-ol (buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl -2H-1,4-benzodiazepin-3-yl) d imethylcarbamate (camazepam), (1S, 2S) -2-amino-1-phenyl-1-propanol (cathine / D-norpsevdoephedrine), 4-oxide 7-chloro-N-methyl-5-phenyl-3H-1,4 -benzodiazepin-2-ylamine (chlordiazepoxide), 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepin-2,4 (3H, 5H) -dione (clobazam), 5- (2-chlorophenyl ) -7-nitro-1H-1,4-benzodiazepin-2 (3H) -one (clonazepam), clonitazene, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4- benzodiazepine-3-carboxylic acid (chlorazepate), 5- (2-chlorophenyl) -7-ethyl-1-methyl-1H-thieno [2,3-e] [1,4] diazepin-2 (3H) -one ( clotiazepam), 10-chloro-11b- (2-chlorophenyl) -2,3,7,11b-tetrahydrooxazolo [3,2-d] [1,4] benzodiazepin-6 (5H) -one (cloxazolam), (- ) -methyl- [3β-benzoi hydroxy-2β (1αH, 5αH) -tropanecarboxylate] (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol (codeine), 5- (1-cyclohexenyl) -5- ethyl barbituric acid (cyclobarbital), cyclorphan, ciprenorphine, 7-chloro-5- (2-chlorophenyl) -1H-1,4-benzodiazepin-2 (3H) -one (delorazepam), desomorphine, dextromoramide, (+) - (1) -benzyl-3-dimethylamino-2-methyl-1-phenylpropyl) propionate (dextropropoxyphene), deocin, diampromide, diamorphone, 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiatepine-2 (3H) -one (diazepam), 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine), 4,5α-epoxy-17-methyl-3,6a-morphinanediol (dihydromorphine), dim enoxadol, dimeheptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, (6aR, 10aR) -6,6,9-trimethyl-3-pentyl-6a, 7,8,10a-tetrahydro-6H-benzo [c] chromene-1-ol ( dronabinol), eptazocine, 8-chloro-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine (estazolam), ethoheptazine, ethylmethylthiambutene, ethyl [7-chloro- 5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate] (ethyloflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7- morphinen-6α-ol (ethylmorphine), ethonitazene, 4,5α-epoxy-7α- (1-hydroxy-1-methylbutyl) -6-methoxy-17-methyl-6,14-endo-ethenomorphinan-3-ol (ethorphine ), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (phencamphamine), 7- [2- (α-methylphenethylamino) ethyl] theophylline) (phenethillin), 3- (α-methylphenethylamino) propionitrile (fenproporex), N- (1-phenethyl-4-piperidyl) propionanilide (fentanyl) 7-chloro-5- (2-fluorophenyl) -1-methyl-1H-1,4-benzodiazepin-2 (3H) -one (fludiazepam), 5- (2-fluorophenyl) -1-methyl-7-nitro 1H-1,4-benzodiazepin-2 (3H) -one (flunitrazepam), 7-chloro-1- (2-diethylaminoethyl) -5- (2-fluorophenyl) -1H-1,4-benzodiazepine-2 (3H) -one (flurazepam), 7-chloro-5-phenyl-1- (2,2,2-trifluoroethyl) -1H-1,4-benzodiazepin-2 (3H) -one (galazepam), 10-bromo-11b- (2-fluorophenyl) -2,3,7,11b-tetrahydro [1,3] oxazolo [3,2-d] [1,4] benzodiazepine-6 (5H) -one (haloxazolam), heroes n, 4,5a-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone (hydromorphone), hydroxypetidine, isomethadone, hydroxymethylmorphinan, 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H- [1,3] oxazino [3,2-d] [1,4] benzodiazepine-4,7 (6H) -dione (ketazolam), 1- [4- (3-hydroxyphenyl) -1-methyl-4-piperidyl] -1-propanone (ketobemidone), (3S, 6S) -6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)), (-) - 6-dimethylamino-4,4-diphenyl-3-heptanone (levomethadone), (-) - 17-methyl-3-morphinanol (levorphanol), levofenacylmorphan, lofentanil, 6- ( 2-chlorophenyl) -2- (4-methyl-1-piperazinyl methylene) -8-nitro-2H-imidazo [1,2-a] [1,4] benzodiazepin-1 (4H) -one (loprazolam), 7-chloro-5- (2-chlorophenyl) -3-hydroxy- 1H-1,4-benzodiazepin-2 (3H) -one (lorazepam), 7-chloro-5- (2-chlorophenyl) -3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2 (3H) -one (lormetazepam), 5- (4-chlorophenyl) -2,5-dihydro-3H-imidazo [2,1-a] isoindol-5-ol (mazindole), 7-chloro-2,3-dihydro-1 -methyl-5-phenyl-1H-1,4-benzodiazepine (medazepam), N- (3-chloropropyl) -α-methylphenethylamine (mefenorex), meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate), meptazinol, metazocine, methylmorphine, N, α-dimethylphenethylamine (methamphetamine), (±) -6-dimethylamino-4,4-diphenyl-3- eptanone (methadone), 2-methyl-3-o-tolyl-4 (3H) -quinazolinone (methaqualone), methyl [2-phenyl-2- (2-piperidyl) acetate] (methylphenidate), 5-ethyl-1- methyl 5-phenylbarbituric acid (methylphenobarbital), 3,3-diethyl-5-methyl-2,4-piperidinedione (methiprilon), methopone, 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine (midazolam), 2- (benzhydrylsulfinyl) acetamide (modafinil), 4,5α-epoxy-17-methyl-7-morphinene-3,6a-diol (morphine), myrofin, (±) -trans-3- (1,1-dimethylheptyl) -7,8,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b, d] pyran-9 ( 6αH) -one (nabilon), nalbuphen, nalorphine, narcein, nicomorphine, 1-meth l-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2 (3H) -one (nimetazepam), 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2 (3H) -one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2 (3H) -one (nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normetadone), normorphine , norpipanone, coagulated juice of plants belonging to the species Papaver somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2 (3H) -one (oxazepam), (cis-trans ) -10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo [3,2-d] [1,4] benzodiazepine-6- (5H) -one (oxazolam), 4, 5a-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, rast plants and parts of plants belonging to the species Papaver somniferum (including the subspecies setigerum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone (pernoline), 1,2,3,4,5,6-hexahydro-6.11 -dimethyl-3- (3-methyl-2-butenyl) -2,6-methano-3-benzazocin-8-ol (pentazocine), 5-ethyl-5- (1-methylbutyl) barbituric acid (pentobarbital), ethyl (1-methyl-4-phenyl-4-piperidinecarboxylate) (petidine), phenadoxone, phenomorphine, phenazocine, phenoperidine, piminodine, folcodein, 3-methyl-2-phenylmorpholine (phenmethrazine), 5-ethyl-5-phenylbarbituric acid ( ), α, α-dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1- (2-propynyl) -1H-1,4 -benzodiazepin-2 (3H) -one (pinazepam), α- (2-piperidyl) benzhydryl alcohol (pipradrol), 1 '- (3-cyano-3,3-diphenylpropyl) [1,4'-bipiperidine] -4 '-carboxamide (pyritramide), 7-chloro-1- (cyclopropylmethyl) -5-phenyl-1H-1,4-benzodiazepin-2 (3H) -one (prazepam), profadol, proheptazine, promedol, properidine, propoxyphene, N - (1-methyl-2-piperidinoethyl) -N- (2-pyridyl) propionamide, methyl {3- [4-methoxycarbonyl-4- (N-phenylpropanamido) piperidino] propanoate} (remifentanil), 5-sec-butyl- 5-ethylbarbituric acid (secbutabarbital), 5-allyl-5- (1-methylbutyl) barbituric acid (secobarbital), N- {4-methoxymethyl-1 - [2- (2-thienyl) ethyl] -4-piperidyl} propionanilide (sufentanil), 7-chloro-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepin-2 (3H) -one (temazepam) , 7-chloro-5- (1-cyclohexenyl) -1-methyl-1H-1,4-benzodiazepin-2 (3H) -one (tetrazepam), ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1 -carboxylate) (tilidine (cis and trans)), tramadol, 8-chloro-6- (2-chlorophenyl) -1-methyl-4H- [1,2,4] triazolo [4,3-a] [1, 4] benzodiazepine (triazolam), 5- (1-methylbutyl) -5-vinyl barbituric acid (vinylbital), (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (1R, 2R , 4S) -2- [dimethylamino) methyl-4- (n-fluorobenzyloxy) -1- (m-methoxyphenyl) cyclohexanol, (1R, 2R) -3- (2-dimet amylaminomethylcyclohexyl) phenol, (1S, 2S) -3 (3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentane- 3-ol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, preferably in the form of a racemate, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl-2 - (4-isobutylphenyl) propionate, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl-2- (6-methoxynaphthalen-2-yl) propionate, 3- (2-dimethylaminomethylcyclohex-1-enyl) phenyl-2- ( 4-isobutylphenyl) propionate, 3- (2-dimethylaminomethylcyclohex-1-enyl) phenyl-2- (6-methoxynaphthalen-2-yl) propionate, 3- ( 2-Dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ether RR-SS) -2-acetoxy-4-trifluoromethylbenzoic acid, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ether (RR-SS) -2-hydroxy-4-trifluoromethylbenzo acids, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ether (RR-SS) -4-chloro-2-hydroxybenzoic acid, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ether (RR-SS) -2 -hydroxy-4-methylbenzoic acid, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ether (RR-SS) -2-hydroxy-4-methoxybenzoic acid, 3- (2-dimethylaminomethyl-1-hydro cyclohexyl) phenyl ether (RR-SS) -2-hydroxy-5-nitrobenzoic acid, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ether (RR-SS) -2 ', 4'-difluoro-3-hydroxydiphenyl- 4-carboxylic acids, as well as the corresponding stereoisomeric compounds, their corresponding derivatives, especially amides, esters or ethers, and their physiologically compatible compounds, especially their salts and solvates, most preferably hydrochlorides.

The dosage form according to the invention is particularly suitable for preventing non-medical use of an opioid active substance selected from the group consisting of oxycodone, hydromorphone, morphine, tramadol and their physiologically compatible derivatives or compounds, preferably their salts and solvates, preferably their hydrochlorides.

The dosage form of the invention is also most suitable for preventing non-medical use of an opioid active substance selected from the group consisting of (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (2R, 3R) - 1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol, (1R, 2R) -3- (2-dimethylaminopetylcyclohexyl) phenol, their physiologically compatible salts, preferably hydrochlorides, physiologically compatible enantiomers, stereoisomers, diastereomers and racem mats and their physiologically compatible derivatives, preferably ethers, esters and amides.

These compounds, respectively, methods for their preparation are described in applications EP-A-693475, respectively, EP-A-780369. Accordingly, these publications are incorporated into this description by reference and form part of it.

At least one synthetic or natural polymer (B) with a fracture resistance, measured in accordance with the procedure described below in the present description, of at least 500 N, is used to give the required dosage form of the invention of the invention. at least one polymer selected from the group consisting of polyalkylene oxides, preferably polymethylene oxide, polyethylene oxide and polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, their copolymers and mixtures of at least two of these polymers. High molecular weight, thermoplastic polyalkylene oxides are preferred. Most preferred are high molecular weight polyethylene oxides with a molecular weight determined by rheological measurements of at least 0.5 million, preferably from at least 1 to 15 million. The viscosity of such polymers at 25 ° C. when measured in a 5% by weight aqueous solution with using a Brookfield viscometer, the RVF model (spindle No. 2, rotation speed 2 rpm) is from 4,500 to 17,600 cP, when measured with a 2% by weight aqueous solution using the indicated viscometer (spindle No. 1, respectively 3, speed rotation of 10 rpm) is from 400 to 4000 cP, respectively, when measured in a 1% by weight aqueous solution using the specified viscometer (spindle No. 2, rotation speed 2 rpm), is from 1650 to 10,000 cP.

Such polymers are preferably used in the form of powders. They can be soluble in water.

In order to impart the required fracture resistance to the dosage form according to the invention, it is additionally possible to use, in addition, at least one natural or synthetic wax (G) with a fracture resistance, measured in accordance with the methodology described below, of at least 500 N. while waxes with a softening temperature of at least 60 ° C. Carnauba wax and beeswax are more preferred. Carnauba wax is most preferred. Carnauba wax is a natural wax that is obtained from the leaves of carnauba (wax palm) and whose softening temperature is at least 80 ° C. With the additional use of the wax component, it is used together with at least one polymer (B) in such quantities that the resistance of the dosage form to destruction is at least 500 N.

Component (B) is preferably used in an amount of from 20 to 99.9 wt.%, More preferably in an amount of at least 30 wt.%, Most preferably in an amount of at least 40 wt.%, Based on the total weight of the dosage form.

As auxiliary substances (B), auxiliary substances commonly used in the preparation of solid dosage forms can be used. In a preferred embodiment, these include plasticizers, such as polyethylene glycol, excipients that affect the release of the active substance, preferably hydrophobic or hydrophilic, more preferably hydrophilic, polymers, most preferably hydroxypropyl cellulose, and / or antioxidants. Suitable antioxidants are ascorbic acid, butylhydroxyanisole, butylhydroxytoluene, salts of ascorbic acid, monothioglycerol, phosphoric acid, vitamin C, vitamin E and its derivatives, sodium bisulfite, most preferably butylhydroxytoluene (BgTg) or BGT.

The antioxidant is preferably used in an amount of from 0.01 to 10 wt.%, More preferably from 0.03 to 5 wt.%, Based on the total weight of the dosage form.

The dosage forms according to the invention are distinguished by the fact that, due to their hardness, it is impossible to grind them into powder with the usual available means, such as a mortar and pestle. Thus, the possibility of non-medical use of the active substances contained in them by their oral, parenteral, especially intravenous, or nasal administration into the body is almost completely excluded. At the same time, the dosage forms proposed in the invention in order to prevent any possible improper use of them in one of the preferred options may contain, as auxiliary substances (B), additional hindering, respectively preventing non-medical use of the active substances included in their composition.

Thus, in particular, the dosage form according to the invention, which is protected from improper use, along with one or more active substances that are potentially the object of their non-medical use, at least one polymer (B) that increases its hardness and possibly at least one wax (D) may also contain as auxiliary substances (B) at least one of the following components (a) - (e):

(a) at least one irritating nasal cavity and / or pharynx substance,

(b) at least one viscosity increasing agent (thickener), which, when extracted from the dosage form using the minimum amount of aqueous liquid, forms a gel, which, when added to the additional amount of aqueous liquid, is preferably visually distinguishable,

(c) at least one antagonist for each of the active substances that are potentially the object of their non-medical use,

(g) at least one emetic.

(e) at least one dye as an aversive,

(e) at least one bitter substance.

Each of the above components (a) to (e) is individually suitable for additional protection of the dosage form of the invention against misuse. So, in particular, component (a) is preferably used to protect the dosage form from non-medical use of the active substance contained in it by nasal, oral and / or parenteral, preferably intravenous, administration to the body, component (b) is preferably used to prevent non-medical the use of the active substance by its parenteral, mainly intravenous, and / or nasal administration into the body, component (c) is preferably used for protection against non-medical use of the active substance by its nasal and / or parenteral, mainly intravenous, administration to the body, component (g) is preferably used to protect against non-medical use of the active substance by its parenteral, mainly intravenous and / or oral and / or nasal in the body, component (e) is preferably used as a visual repellent to protect against non-medical use of the active substance so its oral or parenteral administration, and component (e) is preferably used for the protection of non-medical use of the active substance through its oral or nasal administration into the body. Proposed in the invention the use of at least one of the above components in addition to the remaining ingredients of the dosage forms proposed in the invention further complicates their misuse.

In one embodiment, the dosage form of the invention may also comprise a combination of two or more components (a) to (e), preferably a combination of components (a), (b) and optionally (c) and / or (e) and / or (e), respectively, from components (a), (b) and optionally (d) and / or (e) and / or (e).

In another embodiment, the dosage form of the invention may contain all components (a) to (e).

If the dosage form according to the invention contains component (a) that protects it from improper use, then all those substances that, when they are properly ingested through the nasal cavity and / or pharynx provokes a response of the body, which either manifests itself in the occurrence of such unpleasant sensations, for example, burning, that further desire disappears or it becomes impossible to continue the introduction of appropriate guide the active substance into the body or at a physiological level prevents reception of the particular active substance, for example manifested in an increased allocation nasal secretion or sneezing. The usually irritating nasal cavity and / or pharynx of the substance and when administered parenterally, especially intravenously, into the body cause very unpleasant sensations up to the appearance of unbearable pain, discouraging any desire or making it impossible to further introduce the corresponding active substance into the body.

The most suitable substances for irritating the nasal cavity and / or pharynx are those substances that cause burning, itching, sneezing, increased secretion, or at least have two such irritating effects. Appropriate substances and their commonly used amounts are known to those skilled in the art or can be determined by simple preliminary experiments.

The basis of the irritating nasal cavity and / or pharynx of the substance used as component (a) is preferably one or more irritating ("burning") substances from at least one medicinal or food-containing plant or one or more parts of such a plant containing it (them).

Corresponding medicinal or food plants containing irritating substances are known to those skilled in the art and are described, for example, in the book Pharmazeutische Biologic - Drogen und ihre Inhaltsstoffe, Prof. Dr. Hildebert Wagner, 2nd, revised, ed., Gustav Fischer Verlag, Stuttgart-New York, 1982, cc.82 et seq. The relevant sections of this book are hereby incorporated into this description by reference and are part of it.

By dosage form is meant a separate, appropriately separable, single dosage form (dosage unit), such as, for example, a tablet or capsule.

In a preferred embodiment, to the dosage form according to the invention, one or more irritating substances can be added as component (a) from at least one corresponding medicinal or food plant containing it (s) selected from the group comprising Allii sativi Bulbus, Asari Rhizoma s. Herba, Calami Rhizoma, Capsici Fructus (capsicum), Capsici Fructus acer (cayenne pepper), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructusapae (pepper) Semen, Zedoariae Rhizoma and Zingiberis Rhizoma, most preferably from the group consisting of Capsici Fructus (capsicum), Capsici Fructus acer (cayenne pepper) and Piperis nigri Fructus (pepper).

By irritating substances from medicinal or food-containing plants containing them are preferably meant o-methoxy (methyl) phenolic compounds, acid amides, mustard oils or sulfide compounds or their derivatives.

At least one irritating substance from the medicinal or food-containing plants containing it is most preferably selected from the group consisting of myristicin, elemicin, isoeugenol, α-asaron, safrol, ginjiroles, xanthorizole, capsaicinoids, preferably capsaicin, capsaicin derivatives such as N- vanillyl-9E-octadecenamide, dihydrocapsaicin, nordigidrocapsaicin, homocapsaicin, norkapsaicin and nomorkapsaicin, piperin, preferably trans piperin, glucosinolates, preferably based on non-volatile mustard mas l, most preferably based on n-Hydroxybenzylated mustard oil containing metilmerkaptogruppy metilsulfonilirovannogo mustard oil or mustard oil, and derivatives thereof.

In a preferred embodiment, the content of parts of the corresponding medicinal or edible plants containing irritating substances in the dosage form according to the invention can be from 0.01 to 30 wt.%, Most preferably from 0.1 to 0.5 wt.%, in terms of the entire mass of the dosage form. When using one or more irritating substances from the corresponding medicinal or food plants, the content of such (their) substance (s) in the dosage form proposed in the invention should preferably be from 0.001 to 0.005 wt.%, Calculated on its entire weight.

Another way to prevent the use of the dosage form proposed in the invention for other purposes is to add at least one viscosity-enhancing agent to it as another component (b) that prevents the non-medical use of the active ingredient in the dosage form and which is extracted from the medicinal product form using the minimum amount of aqueous liquid required, preferably in the form of an aqueous extract, forms a gel, safe administration which in the body is unlikely and which in the preferred embodiment, when added to an additional amount of aqueous liquid remains visually distinguishable.

The expression "visually distinguishable" according to the present invention means that the gel containing the active ingredient containing the active ingredient when formed by adding the minimum amount of aqueous liquid, when it is added, preferably with an injection needle, to the additional amount of aqueous liquid with a temperature of 37 ° C practically does not dissolve in it and retains its integrity and does not lend itself to simple dispersion, after which its parenteral, especially intravenous, safe administration would be possible body. In a preferred embodiment, such a gel should remain visually discernible for at least one minute, more preferably for at least ten minutes.

Increasing the viscosity of the extract leads to a deterioration in its passage through the needle, respectively, its injectability, or even completely makes its injection impossible. The gel that remains visually distinguishable when it is added to an additional amount of aqueous liquid, for example, when injected into the blood, first retains the shape of an almost continuous filament, which, although it is crushed by mechanical action on relatively small fragments, however, cannot be dispersed or even dissolved, after which it would be possible parenteral, especially intravenous, safe introduction of such a gel into the body. Thus, in combination with at least one other possible component (a), (c) - (e), the use of a gel-forming component (b), due to its similar property, additionally leads to an unpleasant burning sensation, vomiting, imparting to or withdrawing from a dosage form an unpleasant taste extract and / or giving the dosage form or extract extracted from it a repellent appearance.

Therefore, intravenous administration of an appropriate gel with a high probability would lead to blockage of blood vessels and thereby cause serious harm to health.

To test one or another viscosity-enhancing agent for its suitability for use in the dosage form of the invention, as an ingredient (b), the active substance is mixed with a viscosity-increasing agent and suspended in 10 ml of water at a temperature of 25 ° C. If at the same time a gel is formed that meets the above conditions, then the corresponding viscosity-enhancing agent is suitable for use in the dosage forms of the invention in order to further prevent, accordingly prevent the non-medical use of the active substances contained in them.

When component (b) is added to the dosage form of the invention, it is preferable to use one or more viscosity-enhancing agents selected from the group consisting of microcrystalline cellulose with 11 wt.% Sodium carboxymethyl cellulose (Avicel ^® RC 591), sodium salt of carboxymethyl cellulose ( Blanose ^® , CMC-Na С300Р, Frimulsion BLC-5 ^® , Tyiose С300Р ^® ), polyacrylic acid (Carbopol ^® 980 NF, Carbopol ^® 981), locust bean gum (Cesagum ^® LA-200, Cesagum ^® LID / 150, Cesagum ^® LN-1), pectins, preferably from citrus fruits or apples (Cesap ectin ^® HM Medium Rapid Set), waxy maize starch (C * Gel 04201 ^® ), sodium alginate (Frimulsion ALG (E401) ^® ), guar gum (Frimulsion BM ^® , Polygum 26 / 1-75 ^® ), ι-carrageenan ( Frimulsion D021 ^® ), karaya gum, gellan gum (Kelcogel F ^® , Kelcogel LT100 ^® ), galactomannan (Meyprogat 150 ^® ), packaging gum (Polygum 43/1 ^® ), propylene glycol alginate (Protanal-Ester SD-LB ^® ), sodium hyalate , tragant, container gum (Vidogum SP 200 ^® ), velan gum (K1A96), which is a polysaccharide obtained enzymatically, and xanthan gum (Xantural 180 ^® ).

Xanthan gums are most preferred. The designations in parentheses are trade names under which the relevant materials are marketed. In order to comply with the above conditions, the viscosity-enhancing agent (a) is generally sufficient to use in an amount of from 0.1 to 20% by weight, most preferably from 0.1 to 15% by weight, based on the total weight of the dosage form.

The content of viscosity-enhancing agents when used as component (b) in the dosage form of the invention should preferably be at least 5 mg in terms of each single dosage form, i.e. for each dosage unit.

In the most preferred embodiment of the present invention, as a component (b), those viscosity increasing agents are used which, when extracted from the dosage form with a minimum amount of aqueous liquid, form a gel with air bubbles in its volume. Such gels look cloudy externally, serving as an additional visual warning that keeps them from parenteral administration.

A viscosity-enhancing agent that, when a minimum amount of aqueous liquid is added, forms a gel, in some cases, component (B) can also serve.

The viscosity-enhancing agents and other ingredients of the dosage form of the invention may also be spatially separated from one another.

The dosage form proposed in the invention for the prevention of its misuse and for protection against such misuse may further contain component (c), namely: one or more antagonists of the active substance, respectively, active substances, which are potentially their object (their) non-medical use, and in a preferred embodiment, the antagonist (s) is present (s) in the dosage form of the invention spatially separate from its other ingredients, etc. and its intended use has no effect.

Appropriate antagonists for the prevention of non-medical use of active substances are known to specialists in this field and may be contained in the proposed dosage form as such either in the form of corresponding derivatives, especially esters or ethers, or in the form of corresponding physiologically compatible compounds, especially in the form their salts or solvates.

The composition of the dosage form containing the opioid as the active substance, it is preferable to include an antagonist selected from the group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorfin or nalufin, in each case, optionally in the form of a corresponding physiologically compatible compound, especially in the form base, salt or solvate. Suitable antagonists, if component (c) is provided for in the composition of the dosage form proposed in the invention, is used in an amount of at least 1 mg, more preferably in an amount of 3 to 100 mg, most preferably in an amount of 5 to 50 mg, based on one dosage form, i.e. per dosage unit.

The composition of the dosage form according to the invention containing a stimulant as an active substance preferably comprises an antipsychotic antagonist, preferably at least one compound selected from the group consisting of haloperidol, promethacin, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazin , chlorprotixin, zuclopentixol, flupentixol, protipendil, zotepine, benperidol, pipamperone, melperone and bromperidol.

These antagonists are preferably included in the composition of the dosage form according to the invention in the usual therapeutic dosage known to those skilled in the art, and most preferably in a dosage that is 2-3 times higher than the usual dosage per dosage unit.

The dosage form according to the invention for preventing its misuse and for protecting against such misuse may also contain component (g), which is at least one emetic, which should preferably be present in the dosage form according to the invention spatially separate from its other ingredients and when used for its intended purpose, should not show any action in the body.

Appropriate emetics for preventing non-medical use of the active substance are known to specialists in this field and may be contained in the dosage form according to the invention as such either in the form of corresponding derivatives, especially esters or ethers, or in the form of corresponding physiologically compatible compounds, especially in the form of their salts or solvates.

In the composition of the dosage form according to the invention, it is in a preferred embodiment possible to use an emetic agent based on one or more substances contained in the root of ipekacuan (emetic root), preferably based on the emethine contained therein, and described, for example, in the book Pharmazeutische Biologic - Drogen and ihre Inhaltsstoffe ", Prof. Dr. Hildebert Wagner, 2nd, revised, publ., Gustav Fischer Verlag, Stuttgart, New York, 1982. The relevant sections of this book are hereby incorporated by reference and incorporated into it.

In a preferred embodiment, the dosage form according to the invention may contain, as component (g), an emetin emetic, preferably in an amount of at least 3 mg, more preferably at least 10 mg, most preferably in an amount of at least 20 mg, based on one dosage form , i.e. per dosage unit.

Similarly, in another preferred embodiment, apomorphine, preferably in an amount of not less than 3 mg, more preferably not less than 5 mg, most preferably not less than 7 mg, can be used as an emetic in the dosage form of the invention in order to protect it from misuse; based on one dosage unit.

If the dosage form proposed in the invention contains component (e) as another excipient that prevents its use for other purposes, then such a dye, when trying to extract the active substance from the dosage form for its parenteral, mainly intravenous, administration to the body, gives the corresponding aqueous the solution has an intense color, which can cause a visual repellent effect. Such a change in color prevents the non-medical use of the active substance and by ingestion, which is usually preceded by aqueous extraction of the active substance from the dosage form containing it. The corresponding dyes, as well as the quantities in which they are required to be used to achieve the desired visual repellent effect, are discussed in WO 03/015531, the relevant sections of which are hereby incorporated by reference and are part of it.

If the dosage form according to the invention contains, as yet another component (e) that prevents its improper use, the addition of at least one bitter substance to the dosage form, due to the deterioration in the taste of the dosage form caused by it, further prevents the non-medical use of active substance by its oral and / or nasal administration into the body.

The corresponding bitter substances, as well as their quantities necessary to achieve the desired effect, are described in application US 2003/0064099 A1, the relevant sections of which are hereby incorporated by reference and are part of it. As bitter substances, it is preferable to use aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol, aromatic substances of fruits, preferably aromatic substances of citrons, oranges, lemons, grapefruits or a mixture of aromatic substances of these fruits, and / or denatonium benzoate ( Bitrex ^® ). Especially preferred is denatonium benzoate.

The solid dosage form of the invention is suitable for oral, vaginal or rectal, preferably oral, administration. In a preferred embodiment, the dosage form of the invention is not a film form. The dosage form according to the invention can be presented in a dispersed (loose) form, preferably in the form of microtablets, microcapsules, micropellets, granules, spheroids, grains or pellets, optionally packaged in capsules or compressed into tablets, and is preferably intended for oral use . In a preferred embodiment, the size, or polydispersity, of said microtablets, microcapsules, micropellets, granules, spheroids, grains or pellets ranges from 0.1 to 3 mm, most preferably from 0.5 to 2 mm. Depending on the type and required properties of the dosage form for its preparation in some cases, you can also use the usual excipients (B).

Proposed in the invention is protected from improper use of the dosage form is made by thermoforming using an extruder without changing the color of the extrudate.

To determine the degree of discoloration caused by such thermoforming, the color of the mixture of the starting components included in the dosage form is first determined, but without the addition of a coloring component, for example a colored pigment or a component having its own color (such as α-tocopherol). This composition is then thermoformed according to the invention, carrying out all stages of the process, including cooling the extrudate, in an inert gas atmosphere. For comparison, the same composition is thermoformed in the same way, but not in an inert gas atmosphere. Next, determine the color of both prepared from the same initial composition of the dosage forms, one of which was obtained in accordance with the invention, and the other for comparative purposes. The color atlas Munsell Book of Color, published in 1966 by Munsell Color Company Baltimore, Maryland, USA, is used to determine coloration. If the thermoformed dosage form in accordance with the invention has a color with identification number N 9.5 /, and the maximum has a color with identification number 5Y 9/1, then the thermoforming process is classified as not accompanied by a color change. If the dosage form after thermoforming has a color defined by the Atlas of Munsell Book of Color with identification number 5Y 9/2 or more, then the thermoforming process is classified as accompanied by a color change.

When creating the invention, it was unexpectedly found that the solid dosage forms protected against improper use by the method proposed in the invention do not exhibit any color change classified according to the method described above, if the entire process of their preparation is carried out in an inert gas atmosphere, preferably nitrogen, using an extruder for their thermoforming.

In accordance with this, another object of the present invention is a method of preparing proposed in the invention is protected against misuse of dosage forms, characterized in that

1) components (A), (B), (C) and possibly used component (D) are mixed with each other, and mixed with them or, if necessary, mixed separately with the addition of component (B) and possibly used component (D), possibly used additional components (a) - (e),

2) the resulting mixture or the resulting mixture is heated in the extruder at least to the softening temperature of component (B) and, by applying force, it is extruded through the outlet of the extruder,

3) the still plastic extrudate is divided into separate parts from which the dosage forms are formed, or

4) dosage forms are formed from the cooled and, if necessary, newly heated extrudate separated into separate parts, carrying out steps 2) and 3) and optionally steps 1) and 4) in an inert gas atmosphere, preferably nitrogen.

The mixing of the components in step 1) can also occur already in the extruder.

For mixing components (A), (B), (C) and possibly (D), as well as mixing with them, respectively separately mixing possible additional components (a) - (e) and, if necessary, components (B) and possibly used component (G) is used, respectively, in each case, a known mixer is used. Such a mixer may be, for example, a roller mixer, a vibratory mixer, a shear mixer or a forced mixer.

Component (B) and optionally used component (D) are preferably combined with an antioxidant before mixing them with the remaining components according to the invention. For this purpose, both components (B) and (D) can be mixed with an antioxidant, for which, in a preferred embodiment, the antioxidant is dissolved or suspended in an easily volatile solvent, the resulting solution, respectively, the resulting suspension is then mixed with the component (B) and possibly used component until homogeneity (D) and finally, the solvent is removed by drying, preferably in an inert gas atmosphere.

For the preparation of the dosage forms proposed in the invention, which contain dosage subunits with additional preventive and, accordingly, hindering the non-medical use of their active ingredients, the components obtained in stage 1) of the mixture can be extruded together or separately.

In any case, heated (s) in the extruder to at least the softening temperature of component (B), and preferably the molten (s) mixture (s) is extruded from the extruder through its head with at least one channel.

For the implementation of the proposed invention, the method is preferable to use conventional extruders, most preferably single or double screw extruders.

In the preferred embodiment, the extruder should have at least two temperature zones, in the first of which, adjacent to the loading and possibly provided mixing zone, the mixture is heated to at least the softening temperature of component (B). The flow rate of the moldable mixture in a preferred embodiment is from 2.0 to 8.0 kg / h.

After heating to at least the softening temperature of component (B), the molten mixture is moved by the worm in the extruder, continues to be homogenized, compressed, compressed accordingly, reaching a minimum pressure of 5 bar, preferably at least 10 bar, immediately before exiting the die, and depending on the number of channels (holes) in the extrusion head is extruded through it in the form of an extrudate or extrudates. The extruder can be equipped with a head with any channel profile, respectively channels in it. Thus, in particular, the channel or channels in the extrusion head can (round) have a circular section, preferably with a diameter of 0.1 to 15 mm, an oblong section, preferably with a maximum longitudinal length of 21 mm and a transverse length of 10 mm, or an oval section. It is preferable to use an extrusion die with a channel or channels of circular cross section. The extruder used may have a heated or cooled housing. Appropriate temperature control of the extruder body, i.e. heating or cooling depends on the average temperature of the extrudable mixture (product temperature), which (temperature) should be not less than the softening temperature of component (B), but should not exceed the temperature above which an unacceptable change in the properties of the processed active substance, which is potentially an object, can occur its non-medical use. With this in mind, the temperature of the extrudable mixture is preferably maintained below 180 ° C, more preferably below 150 ° C, but not lower than at least the softening temperature of component (B).

After extrusion of the molten mixture and, if necessary, cooling of the obtained extrudate or extrudates, it is preferable to grind it (them). Such grinding, in the preferred embodiment, may consist in cutting the extrudates with flying or rotating knives, water-jet cutters, wires, blades or laser cutters.

For the intermediate, respectively final storage of the extrudate or divided into separate parts of the extrudate, respectively, of the finished dosage forms proposed in the invention does not require the creation of an inert gas atmosphere.

Separated into separate parts, the extrudate can be granulated or tableted by conventional methods to finalize the dosage form. In another embodiment, the rod-shaped extrudate can not be divided into separate parts, but can be calendared by passing through rolls rotating in mutually opposite directions, which have profile recesses located on their lateral surfaces, giving the extrudate in such a way a profile that corresponds to the final contour dosage form, preferably tablets, then separated from the rest of the extrudate by conventional methods.

In the event that the extrudate or the extrudate divided into separate parts is not immediately subjected to molding to give it a profile that corresponds to the final form of the dosage form, but first cooled for intermediate storage, further processing of the extrudate after such intermediate storage must be carried out in an inert gas atmosphere , preferably nitrogen, which you want to save from the moment of heating the intermediate stored extrudate until the completion of its mastication and final form formulations of a dosage form.

The force applied in the extruder to at least the plasticized mixture is set by controlling the rotation speed and selecting the geometry of the conveying device (worm) in the extruder, as well as by selecting the size of the outlet of the extruder to a value at which the pressure in the extruder, preferably before the direct extrusion of the plasticized mixture, reaches the required for this level. The extrusion parameters necessary to obtain a dosage form with a fracture resistance of at least 500 N can be determined for each specific composition by conducting simple preliminary experiments.

In a further preferred embodiment, the dosage form according to the invention is presented in the form of a tablet, capsule or in the form of an oral osmotic therapeutic system (POTS), preferably when using at least one additional, non-intended use of the dosage form component (a) - (e) .

When component (c) and / or component (g) and / or component (e) are included in the composition of the dosage form proposed in the invention, each of them must be used in such a form or in such a low dosage that, when using the dosage form for its intended purpose, practically completely eliminate the possibility of manifestation by him of harming the patient or reducing the effectiveness of the active substance of the action.

When component (g) and / or component (e) is included in the composition of the dosage form proposed in the invention, the dosage of each of them must be selected so that when using the dosage form for its intended purpose by ingestion, it does not cause any negative reaction of the body. If the prescribed dosage of these components is exceeded, if the dosage form is used for other purposes, they cause nausea, respectively, urge to vomit, respectively, unpleasant taste sensations. The specific dose of component (g) and / or component (e) at which the patient, when used for its intended purpose by oral administration, remains tolerant of each of these components, can be determined by conducting simple preliminary experiments.

If, however, to protect the dosage form proposed in the invention from improper use, regardless of the almost complete impossibility of grinding it into powder, component (c) and / or component (d) and / or component (e) are used, then each of such components it is preferable to use in such a high dosage that, when the dosage form is not used for its intended purpose, it exhibits a pronounced negative effect. In a preferred embodiment, compliance with this condition is achieved by spatial separation of at least the active substance, respectively, of the active substances from component (c) and / or component (d) and / or component (e), preferably by including the active substance, respectively, of the active substances in the composition of at least one metered subunit (X), and component (c) and / or component (g) and / or component (e) - in the composition of at least one other metered subunit (Y), in which components (c) , (g) and (e) when applying the dosage form for its intended purpose, they do not show when taken orally and / or when they enter the body, and in both dosed subunits identical other components of the dosage form are used, especially component (B) and possibly the component used ( D).

When at least two components (c) and (d), respectively (e) are included in the dosage form of the invention, they can be contained in the same dosage subunit (Y) or in different dosage subunits (Y). In a preferred embodiment, all components (c), (d) and (e), when used, are included in the same dosage subunit (Y).

Dosage subunits according to the present invention are understood to be solid forms, each of which, along with conventional, well-known auxiliary substances, contains the active substance (s), at least one polymer (B) and optionally used component (D) and, if necessary, at least at least one of the possible components (a) and / or (b) and / or (e), respectively, each of which contains at least one polymer (C) and possibly used component (D) and the antagonist (s) and / or vomiting agent (s) and / or lump component (e) and / or component (e) and, if necessary, at least one of the possibly used components (a) and / or (b). It should be noted that each of the above dosed subunits is prepared as described above.

A significant advantage associated with the separation in the proposed dosage form of the active substances from components (c), respectively (d), respectively (e) by including those and others in the composition of different dosage subunits (X) and (Y) is that that when the dosage form is used for its intended purpose, component (c) and / or component (d) and / or component (e), when ingested and / or ingested, are practically not released from the dosed subunits containing them or only released from them in so ma in small amounts in which they do not show any harmful effect to the patient or reduce the effectiveness of the treatment, or when passing through the patient’s body, they are released from the dosed subunits containing them only in those places where they are not resorbed to a sufficient extent for the manifestation of their action. In a preferred embodiment, component (c) and / or component (d) and / or component (e), when used as directed, are practically not released into the patient’s body or are not felt by him.

It is obvious to a person skilled in the art that these conditions described above may vary depending on the particular components (c), (d) and / or (e) used, as well as on the composition and type of the dosage units, respectively, of the dosage form. Optimal for each specific dosage form, its composition and type can be determined by conducting simple preliminary experiments. Of decisive importance is only the inclusion in the composition of each specific dosage subunit of the polymer (B) and, if necessary, component (D) and its preparation as described above.

If, contrary to expectations, the similar dosage form proposed in the invention, which contains component (c) and / or component (e) and / or component (d) and / or component (e) in dosed subunits (Y), is successful for non-medical use grind the active substance into powder and extract the active substance from it with a suitable extractant, then along with the active substance the corresponding component (c) and / or (e) and / or (e) and / or (d) will be obtained form in which it is impossible to separate it from the simple way the active substance, and therefore when applying the extract obtained from the dosage form, primarily when it is administered orally and / or parenterally, it will exert its effect upon ingestion and / or ingestion, moreover, one of the components (c) and / or (g) and / or (e) will additionally cause a corresponding negative reaction of the body, and component (e), when trying to extract the active substance, will cause a visually repulsive color change and thus prevent the use of drug forms for other purposes.

The dosage form proposed in the invention with a spatial separation of the active substance, respectively, of the active substances from components (c), (d) and / or (d), preferably due to the inclusion of, respectively, both of them in the composition of different dosage subunits, can have the most diverse structure, while the corresponding dosage subunits can have any spatial arrangement relative to each other in the dosage form according to the invention, subject to the above lovy regarding release of component (c) and / or the component (g).

It is obvious to a person skilled in the art that component (a) and / or component (b), when used accordingly and in their use in the dosage form of the invention, can preferably be included in the composition of not only each of the respective dosage subunits (X) and ( Y), but also of the independent dosage subunits corresponding to the dosage subunits (X) and (Y), provided that the preparation form of such independent dosage subunits does not adversely affect the protection of the dosage form from applied I and not intended to release the active substance during application of the dosage form for its intended purpose and contains in its composition the polymer (B) and optionally used component (D), and these subunits themselves dosage to achieve the desired hardness is obtained in the manner described above.

In one preferred embodiment, the dosage subunits (X) and (Y) constituting the dosage form of the invention are presented in dispersed form, preferably in the form of microtablets, microcapsules, micropellets, granules, spheroids, grains or pellets, and the dosage subunit ( X), and the dosed subunit (Y) must have the same form, i.e. appearance so that the metered subunit (X) cannot be separated from the metered subunit (Y), for example, by mechanical sorting. In a preferred embodiment, the size of said microtablets, microcapsules, micropellets, granules, spheroids, grains or pellets ranges from 0.1 to 3 mm, most preferably from 0.5 to 2 mm.

Dosage subunits (X) and (Y), presented in dispersed form, in the preferred embodiment, can also be packaged in capsules or compressed into tablets, while the final stage of preparation of the dosage form should ensure the preservation of the dosage subunits (X) and (Y) in the finished dosage form.

The corresponding dispersed metered subunits (X) and (Y) must not only have an identical external shape, but must also be visually indistinguishable from one another so that they cannot be separated from each other by simple sorting. To do this, for metered subunits of both types, for example, identical coatings can be applied, which, along with a similar function consisting in giving metered subunits of both types of the same appearance, can perform other functions, for example, retard the release of one or more active substances or give metered subunits of each particular type are resistant to the action of gastric juice.

From dispersed dosage subunits by suspension in pharmaceutically acceptable suspending agents, suspensions or suspensions may also be prepared in oral formulations.

In another preferred embodiment of the present invention, the dosed subunits (X) and (Y) are proposed to be layered relative to each other.

In this embodiment, the layers of the dosage subunits (X) and (Y) are preferably arranged relative to each other in the dosage form according to the invention, vertically or horizontally, while one or more layers of the dosage subunits (X) and one or several layers of metered subunits (Y), and therefore, along with the preferred sequence of arrangement of layers of type (X) - (Y), respectively (X) - (Y) - (X) any other sequence of arrangement of layers is possible, including e and in combination with layers containing component (a) and / or component (b).

Also preferred is the dosage form of the invention in which the dosage subunit (Y) forms a core that is completely enclosed in a shell of the dosage subunit (X) and which can be separated from it by a separation layer (Z). It is preferable to use the same structure in the above dispersed forms, in which case both dosed subunits (X) and (Y), as well as the separation layer (Z) provided between them, which in its hardness must satisfy the requirements of the invention, are prepared in the same dispersed form.

In a further preferred embodiment, the dosage subunit (X) forms a core in the dosage form of the invention enclosed in a shell of a dosage subunit (Y) that has at least one channel leading from the core of the dosage form to its surface.

Between the dosage subunit (X) layer and the dosage subunit (Y) layer, the dosage form of the invention for spatially separating the dosage subunit (X) from the dosage subunit (Y) may have one or more separation layers (Z), preferably one the separation layer (Z), which in some cases can be formed by swelling material.

The dosage form according to the invention with at least partial vertical or horizontal arrangement of the layers of the dosage subunits (X) and (Y), as well as the possible separation layer (Z) between them, should preferably be in the form of a tablet or a laminate.

Moreover, in the most preferred embodiment, the free surface of the metered subunit (Y) is completely and in some cases at least part of the free surface of the metered subunit (subunits) (X), as well as in some cases at least part of the free surface possibly provided for ( s) of the separation (s) layer (s) (Z) can be coated with at least one preventing the release of component (c) and / or component (e) and / or component (d) and / or (e) component barrier layer ( Z '). Such a barrier layer (Z ') in its hardness must also satisfy the requirements of the invention.

Also particularly preferred is the dosage form according to the invention with vertical or horizontal arrangement of layers of metered subunits (X) and (Y) and at least one “push” layer (p) located between them (p) (p) as well as the possibly provided separation layer (Z), in which all the free surfaces of the metered subunits (X) and (Y), the “push” layer and the possibly provided separation layer (Z) of the layered structure are coated semipermeable coated em (E) which is permeable to the medium in which the active ingredient is released, i.e., usually for physiological fluid, but generally not permeable to the active substance and to component (c) and / or component (d) and / or component (e) and which has at least one opening for release in the area of the dosed subunit (X) active substance.

The corresponding dosage form, which is known as the oral osmotic therapeutic system (POTS), as well as materials suitable for its manufacture, and methods for its manufacture are described, inter alia, in US Pat. Nos. 4,612,008, 4,765,989, and 4,783,337. the present description is by reference and form part of it.

In a further preferred embodiment, the dosage unit (X) in the dosage form of the invention is in the form of a tablet in which its lateral face and optionally one of both main surfaces are coated with a barrier layer (Z ') containing component (c) and / or component (g ) and / or component (e).

It is obvious to a person skilled in the art that the auxiliary substances used in each case for the preparation of the dosage form according to the invention, which are included in the dosage unit (s) (X), respectively (Y), as well as the possibly provided release agent (s) (s) layer (s) (Z) and / or barrier (s) layer (s) (Z '), are selected depending on the location of these subunits and layers in the dosage form proposed in the invention, on the intended route of its introduction into the body, as well as dependent and from a particular substance used as a possibly contemplated component (a) and / or component (b) and / or component (e) and as component (c) and / or component (d) and / or component (e). Materials having the properties required in each case are known to those skilled in the art.

When a dosage subunit (Y) is enclosed in a dosage form according to the invention in an enclosure preventing the release of component (c) and / or component (g) and / or component (e) from it, preferably in the form of a barrier layer, it is possible to prepare such a dosage subunit use the usual materials known to those skilled in the art, provided that at least one polymer (B) and possibly component (D) are included in its composition to comply with the hardness requirements of the invention arno form.

If the use of an appropriate barrier layer (Z ') to prevent the release of component (c) and / or component (d) and / or component (e) is not provided, then the materials for the preparation of metered subunits (Y) should be selected so that practically completely exclude the release of the corresponding component (c) and / or component (g) from the dosed subunit (Y). In the preferred embodiment, to comply with this requirement, you can use the following materials, which can be used to form a barrier layer.

Preferred materials in this regard include materials selected from the group consisting of alkyl celluloses, hydroxyalkyl celluloses, glucans, scleroglucans, mannans, xanthan gums, copolymers of poly [bis (n-carboxyphenoxy) propane and sebacic acid, preferably in a molar ratio of 20:80 (manufactured under the name Polifeprosan 20 ^®), carboxymethyl cellulose, cellulose ethers, cellulose esters, nitrocelluloses, polymers based on (meth) acrylic acid and esters thereof, polyamides, polycarbonates, polyalkylenes, polialkilengl coli, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls, polyglycolides, polysiloxanes and polyurethanes and copolymers thereof.

Materials suitable for preparing metered subunits (Y) include materials selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate (low, medium or high molecular weight cellulose acetate, cellulose acetate, cellulose, cellulose acetate , cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sodium sulfate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, poligeksilmetakrilat, poliizodetsilmetakrilat, polylauryl, polifenilmetakrilat, polymethyl acrylate, poliizopropilakrilat, poliizobutilakrilat, polioktatdetsilakrilat, polyethylene, low density polyethylene, high density polyethylene, polypropylene, polyethylene, polyethylene oxide, polyethylene terephthalate, polyvinyl alcohol, polivinilizobutilovy ether, polyvinyl acetate and polyvinyl chloride.

The copolymers most suitable for use for the above purposes include copolymers selected from the group consisting of copolymers of butyl methacrylate and isobutyl methacrylate, copolymers of high molecular weight methyl vinyl ester and maleic acid, maleic acid methyl vinyl ester, maleic acid malide ester and maleic acid imide amide amide vinylidene as well as copolymers of vinyl alcohol and vinyl acetate.

Other materials most suitable for the barrier layer include starch-filled polycaprolactone (WO 98/20073), aliphatic polyetheramides (DE 19753534 A1, DE 19800698 A1, EP 0820698 A1), aliphatic and aromatic pre-ether urethanes (DE 19822979), polyhydroxyalkanoates total polyhydroxybutyrates and polyhydroxyvaleriates, casein (DE 4309528), polylactides and copolylactides (EP 0980894 A1). These publications are accordingly included in the present description by reference and form part of it.

The above materials can, if necessary, be used in admixture with other usual excipients known to those skilled in the art, preferably excipients selected from the group consisting of plasticizers, glidants, antioxidants, for example glycerol monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil , glycerol palmitostearate, glycerol behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearino hydrochloric acid, sodium stearate, talc, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols, polyalkylene glycols and their derivatives.

If there is a separation layer (Z) in the dosage form according to the invention, it, as well as a dosage subunit (Y) not enclosed in a shell, is preferably made from the materials mentioned above for the barrier layer. It is obvious to a person skilled in the art that it is also possible to control the release of the active substance, respectively component (c) and / or component (g) from the corresponding dosage subunit, by varying the thickness of the separation layer.

The dosage form of the invention is a dosage form with a controlled release of the active substance from it. Moreover, in a preferred embodiment, it is suitable for twice daily administration in a patient.

In addition, the dosage form according to the invention may be a retard form with at least partially delayed (retarded) release of one or more active substances from it, which are potentially the object of their non-medical use and the retardation of the release of which can be achieved using conventional methods known to those skilled in the art in the field of materials and methods, for example, due to the introduction of the active substance in the matrix delaying its release or due to nan Oran one or more release delaying coatings it. However, with the controlled release of the active substance, the above conditions should always be ensured, i.e., for example, when using the dosage form for its intended purpose, the almost complete release of the active substance, respectively, of the active substances from it should be completed before it is possible component (c) and / or component (g) contained in it begin to show their negative effect on the body. In addition, the addition of materials delaying the release of active substances should not reduce the necessary hardness of the dosage form.

The controlled release of the active substance from the dosage form of the invention is preferably achieved by incorporating the active substance into the matrix. Matrix excipients control the release of active substances. The matrix-forming materials can be, for example, hydrophilic gel-forming materials, the release of active substances from which occurs predominantly as a result of diffusion, or hydrophobic materials, the release of active substances from which occurs mainly as a result of diffusion from pores in the matrix.

Physiologically compatible hydrophilic materials known to those skilled in the art can be used as matrix forming materials. As the hydrophilic matrix-forming materials, it is preferable to use polymers, most preferably cellulose ethers, cellulose esters and / or acrylic resins. Particularly preferred matrix forming materials include ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) acrylic acid and / or its derivatives, such as its salts, amides or esters.

Similarly, it is preferable to use hydrophobic materials such as hydrophobic polymers, waxes, fats, long chain fatty acids, fatty alcohols, or the corresponding esters or ethers or mixtures of these materials as matrix forming materials. Particularly preferred hydrophobic materials for use as matrices include mono- or diglycerides of C ₁₂ -C ₃₀ fatty acids and / or C ₁₂ -C ₃₀ fatty alcohols and / or waxes or mixtures of these materials.

It is also possible to use mixtures of the above hydrophilic and hydrophobic materials as matrix forming materials.

In addition, component (B), as well as the possibly provided component (D), which according to the invention are used to give the dosage form the necessary fracture resistance of at least 500 N, can already serve as additional matrix-forming materials.

The dosage form according to the invention, when it is intended for oral administration, can preferably also have a coating resistant to the action of gastric juice, which dissolves depending on the pH of the medium in which the active substance is released from the dosage form. In the presence of such a coating, the dosage form according to the invention passes through the stomach without dissolving in it and begins to dissolve and release the active substance only in the intestine. In a preferred embodiment, the gastric juice resistant coating should dissolve at a pH in the range of 5 to 7.5.

Appropriate materials and methods used to retard the release of active substances, as well as to apply coatings resistant to the action of gastric juice, are known, for example, from the book "Coated Pharmaceutical Dosage Forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials", Kurt N. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st ed., Medpharm Scientific Publishers, 1998. Accordingly, this publication is incorporated herein by reference and forms part of .

Method for determination of fracture resistance

To test the suitability of a particular material for use as component (B) or (D) from the material being tested at a temperature equal to at least its softening temperature, determined by the DSC diagram of the material, a tablet is pressed with a pressing force of 150 N with a diameter of 10 mm and a thickness (height) of 5 mm. Then, in accordance with the method for determining the resistance of tablets to destruction, published in the European Pharmacopoeia of the 1997 edition, ss. 143, 144, method No. 2.9.8, using the equipment described below, determine the resistance of the tablets made in this way to destruction. As measuring equipment, a Zwick type Zwick Z 2.5 material testing machine is used with a maximum developed force Fmax of 2.5 kN, with a cross travel of a maximum of 1150 mm and set using an adjusting mechanism consisting of a column and a lead screw , with a free rear working space of 100 mm, with a test speed adjustable from 0.1 to 800 mm / min, and the testControl software. For measurements, use a punch with screw-in inserts and a cylinder (10 mm in diameter) and a dose with a maximum measured force of Fmax 1 kN, with a diameter of 8 mm, with measurement accuracy according to ISO 7500-1, corresponding to class 0.5, starting from 10 N, and class , 1 starting from 2 N, and with a verification certificate M issued by the manufacturer according to DIN 55350-18 (calculated by the Zwick methodology, the maximum total force Fmax 1.45 kN) (all equipment from Zwick GmbH & Co. KG, Ulm, Germany, with the following order numbers: BTC-FR 2.5 TH.D09 for test oh the machine, BTC-LC 0050N. P01 for the dose meter and BO 70,000 S06 for the centering device).

The drawing, which is attached to the description, in an extremely simplified form schematically shows a device for measuring the resistance of tablets to fracture and, in particular, shows the adjustment device used (6) for aligning the position of tablets (4) before and during the measurement. To take measurements, a tablet (4) is placed between the upper pressure plate (1) and the lower pressure plate (3) of the device for applying a load, not shown in the drawing, and fixed using two two-piece clamps (2), each of which, after setting the required to fix and center the analyzed tablet, the distances (5) are firmly connected to the upper, respectively lower pressure plate (not shown). To adjust the distance (5), both parts of each of the clamps can be moved or moved apart in the horizontal direction by moving along the corresponding pressure plate on which they are mounted.

Tablets are also resistant to destruction under the influence of a certain mechanical load, which, when a given force is applied, are not destroyed, but in some cases are plastically deformed.

The measurement method described above, which can test not only tablets, but also dosage forms different from them, determined the resistance of the proposed dosage forms to destruction.

The invention is illustrated below by way of example. All the explanations discussed in this example are for illustrative purposes only and do not limit the scope of the invention (see table).

Components Amount per tablet Total amount Tramadol hydrochloride 100.0 mg 1495.0 g Polyethylene oxide, NF, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals) 167.8 mg 2,508.6 g Hydroxypropyl methylcellulose, 100,000 mPa • s 33.5 mg 500.8 g Polyethylene glycol (PEG 6000) 33.5 mg 500.8 g Butylhydroxytoluene (BHT) 0.2 mg 3.0 g total weight 335.0 mg 5008.2 g

The indicated amount of BHT was dissolved in ethanol (96%) to give a 7.7% (by weight) ethanol solution. This solution was first stirred for 30 minutes in a high-speed mixer with 150 g of polyethylene oxide, after which the remaining amount of polyethylene oxide was added and mixed for another 30 minutes. Then, the resulting mixture was dried at 40 ° C for 12 hours. All other components were added to this dried mixture and stirred for 15 minutes in a gravity mixer. The resulting powder mixture was supplied in metered amounts to an extruder. For extrusion, a twin-screw extruder of the Micro 27 GL 40 D type from Leistritz (Nuremberg, Germany) with a spindle diameter of 18 mm was used. In the extruder, worms with blunt ends were used, the hexagonal recesses under the corresponding key were closed with plugs. As an extrusion head, a heated head with a circular channel and a diameter of 8 mm was used. The whole process was carried out in a nitrogen atmosphere.

The following parameters were used for extrusion:

worm speed 100 rpm performance 4 kg / h product temperature 125 ° C extruder body temperature 120 ° C

The still hot extrudate was cooled in a nitrogen atmosphere. Biplane tablets were separated from the cooled extrudate.

The resistance of the tablets to destruction was determined by the method described above. When exposed to tablets with a force of 500 N, no destruction occurred. In addition to this, it was impossible to grind the tablets with a hammer or with a mortar and pestle.

The cooled extrudate, respectively, 10 tablets separated from it, had a color with the identification number Munsell Book of Color with identification number N 9.5 /, which indicated that there was no discoloration of the dosage form prepared according to the invention when it was thermoformed using an extruder .

Claims (35)

1. A dosage form which is protected from misuse, thermoformed by extrusion without discoloration, characterized in that it, along with one or more active substances (A), which are potentially the object of their non-medical use, as well as possible physiologically compatible excipients (B ) contains at least one synthetic or natural polymer (B) and optionally at least one wax (G), wherein component (B) and possibly present component (G) are contained dosage form in quantities such that its breaking strength is at least 500 N. 2. The dosage form according to claim 1, characterized in that it is presented in the form of a tablet. 3. The dosage form according to claim 1, characterized in that it is presented in dispersed form, preferably in the form of microtablets, micropellets, granules, spheroids, grains or pellets, optionally compressed into tablets or packaged in capsules. 4. The dosage form according to claim 1, characterized in that it contains as polymer (B) at least one polymer selected from the group consisting of polyethylene oxide, polymethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers and mixtures thereof, preferably polyethylene oxide. 5. The dosage form according to claim 1, characterized in that the polyethylene oxide (B) has a molecular weight of at least 0.5 million 6. The dosage form according to claim 5, characterized in that the polyethylene oxide (B) has a molecular weight of at least 1 million 7. The dosage form according to claim 6, characterized in that the molecular weight of polyethylene oxide (B) is from 1 to 15 million 8. The dosage form according to claim 1, characterized in that it contains as wax (G) at least one natural, semi-synthetic or synthetic wax with a softening temperature of at least 60 ° C. 9. Dosage form according to claim 8, characterized in that the wax (G) is carnauba wax or beeswax. 10. The dosage form according to claim 1, characterized in that the active substance (A) is at least one active substance selected from the group consisting of opioids, tranquilizers, stimulants, barbiturates and other narcotic drugs. 11. The dosage form according to claim 1, characterized in that it further comprises at least one of the following components a) -e): (a) at least one irritating nasal cavity and / or pharynx substance, (b) at least one viscosity-enhancing agent which, when extracted from the dosage form using the minimum amount of aqueous liquid, forms a gel, which preferably is visually distinguishable when added to the additional aqueous liquid, (c) at least one antagonist for the active substance, respectively, for active substances that are potentially the object of their non-medical use, (g) at least one emetic, (e) at least one dye as an aversive, (e) at least one bitter substance. 12. The dosage form according to claim 11, characterized in that the irritating substance used as component (a) causes burning, itching, the urge to sneeze, increased secretion, or at the same time has at least two such irritating effects. 13. The dosage form according to claim 11, characterized in that the basis of the irritating substance used as component (a) is one or more irritating substances from at least one medicinal or food plant containing it (them). 14. The dosage form according to item 13, wherein the irritant drug or food plant is at least one medicinal or food plant selected from the group consisting of Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (capsicum), Capsici Fructus acer (cayenne pepper), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructus (pepper), Sineminapenienapenimenapenimenapenimenapenimeni Zedoariae Rhizoma and Zingiberis Rhizoma, most preferably at least one drug or drink e food plant selected from the group consisting of Capsici Fructus (capsicum), Capsici Fructus acer (cayenne pepper) and Piperis nigri Fructus (pepper). 15. The dosage form according to claim 13, characterized in that the irritating substance from the medicinal or edible plant containing it is presented in the form of an o-methoxy (methyl) phenolic compound, an acid amide, mustard oil or sulfide compound, or is a derivative of one of these compounds. 16. The dosage form according to item 13, wherein the annoying substance from the medicinal or food plant containing it is at least one substance selected from the group consisting of myristicin, elemicin, isoeugenol, β-asaron, safrole, ginjiroli , xanthorizole, capsaicinoids, preferably capsaicin, piperine, preferably trans piperine, glucosinolates, preferably based on non-volatile mustard oils, most preferably based on n-hydroxybenzylated mustard oil, containing metilmerkaptogruppy present metilsulfonilirovannogo mustard oil or mustard oil, and one of derivatives thereof. 17. The dosage form according to claim 11, characterized in that component (b) is at least one viscosity increasing agent selected from the group comprising microcrystalline cellulose with 11 wt.% Sodium carboxymethyl cellulose (Avicel ^® RC 591), sodium carboxymethyl cellulose salt (Blanose ^® , CMC-Na С300Р ^® , Frimulsion BLC-5 ^® , Tyiose C300 P ^® ), polyacrylic acid (Carbopol ^® 980 NF, Carbopol ^® 981), locust bean gum (Cesagum ^® LA-200, Cesagum ^® LID / 150, Cesagum ^® LN-1), citrus fruits or apples pectins (Cesapectin ^® HM Medium Rapid Set), waxy maize starch (C * Gel 04201 ^® ), sodium alginate (Frimulsion ^® ALG (E401) ^® ), guar gum (Frimulsion BM ^® , Polygum 26 / 1-75 ^® ), ι-carrageenan (Frimulsion D021 ^® ), karaya gum, gellan gum (Kelcogel F ^® , Kelcogel LT100 ^® ), galactomannan (Meyprogat 150 ^® ), container gum (Polygum 43/1 ^® ), propylene glycol alginate (Protanal-Ester SD-LB ^® ), apple pectin, sodium hyaluronate, tragant, container gum (Vidogum SP 200 ^® ), velan gum (K1A96), which is a polysaccharide obtained enzymatically, and xanthan gum (Xantural 180 ^® ). 18. The dosage form according to claim 11, characterized in that component (c) is at least one opioid antagonist selected from the group consisting of naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorfin, nalufin and the corresponding physiologically compatible compound, primarily a base, salt or solvate. 19. The dosage form according to claim 11, characterized in that component (c) is at least one antipsychotic as a stimulant antagonist, preferably selected from the group consisting of haloperidol, promethacin, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine , chlorprotixin, zuclopentixol, flupentixol, protipendil, zotepine, benperidol, pipamperone, melperone and bromperidol. 20. The dosage form according to claim 11, characterized in that the basis of the emetic agent used as component (g) is one or more substances contained in the root of ipecacuanh (emetic root), preferably the emetin contained therein and / or apomorphine . 21. The dosage form according to claim 11, characterized in that component (d) is at least one physiologically compatible dye. 22. The dosage form according to claim 11, characterized in that component (e) is at least one bitter substance selected from the group comprising aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol and mixtures thereof , fruit flavors, preferably citron, oranges, lemons, grapefruit flavors, and mixtures of at least two of these fruit flavors, denatonium benzoate, and mixtures of at least two of these bitter substances. 23. The dosage form according to claim 11, characterized in that the active substance, respectively, the active substances (A) are spatially separated from component (c) and / or component (d) and / or component (e), preferably do not directly contact with said (s) component (s), while preferably the active substance, respectively, the active substance is contained (-at) in at least one dosed subunit (X), and component (c) and / or component (g) and / or component (e) in at least one other dosed subunit (Y), in which component (c) and / or component (d) and / or component (e) do not, when used as directed, when directed into the body, respectively, when ingested, their effect. 24. The dosage form according to claim 1, characterized in that it is a retard form with at least partially retardable release of at least one active substance contained therein. 25. The dosage form according to paragraph 24, wherein each of the active substances (A), which are potentially the object of their non-medical use, is present in the matrix retarding its release. 26. Dosage form according to claim 25, characterized in that component (B) and / or possibly present component (D) also serve as a material forming a retarding active substance matrix. 27. A method of preparing a dosage form according to one of claims 1 to 26, characterized in that 1) components (A), (B), (C) and possibly used component (D) are mixed with each other, and mixed with them or, if necessary, mixed separately with the addition of component (B) and possibly used component (D), possibly used additional components (a) - (e), 2) the resulting mixture or the resulting mixture is heated in the extruder at least to the softening temperature of component (B) and, by applying force, it is extruded through the outlet of the extruder, 3) the still plastic extrudate is divided into separate parts from which the dosage forms are formed, or 4) dosage forms are formed from the cooled and, if necessary, newly heated extrudate separated into separate parts, carrying out steps 2) and 3) and optionally steps 1) and 4) in an inert gas atmosphere. 28. The method according to item 27, wherein the mixing of the components in stage 1) occurs already in the extruder in an inert gas atmosphere. 29. The method according to item 27, wherein the mixture obtained in stage 1) is extruded together or separately. 30. The method according to item 27, wherein the mixture obtained in stage 1), respectively, obtained in stage 1) of the mixture is extruded from the extruder through its head with at least one channel. 31. The method according to item 27, wherein the extrudate is divided into separate parts by cutting or chopping. 32. The method according to item 27, wherein the extrudate is obtained in the form of a rod, which is subjected to molding by calendering by passing through rolls rotating in mutually opposite directions, which on their side surfaces have opposed profile recesses, and then are divided into separate parts. 33. The method according to item 27, wherein the extrudate is divided into separate parts is subjected to granulation or tabletting. 34. The method according to item 27, wherein the nitrogen is used as an inert gas. 35. The dosage form according to claim 1, obtained by the method according to one of paragraphs.27-34.