Degradation-resistant dosage form with delayed release of oxycodone hydrochloride

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form contains oxycodone hydrochloride as a physiologically active substance (A), optionally one or more physiologically combined excipients (B), a synthetic or natural polymer (C) and optionally natural, semisynthetic or synthetic wax (D).

EFFECT: dosage form of oxycodone hydrochloride possess degradation resistance of at least 400 N to less than 500 N, and releases max 99% of oxycodone hydrochloride in the physiological conditions after 5 h.

14 cl, 7 dwg, 17 ex

 

The present invention relates to a dosage form for introduction into the body in its composition of oxycodone hydrochloride as a physiologically active substance (A), which is mechanically stable and therefore does not lend itself at all or can be measured only with great difficulty grinding by conventional methods, such as grinding with a hammer or mallet, milling, grinding in a mortar and other methods. Proposed in the invention of the dosage form is characterized by at least partially sustained-release profile from it physiologically active substance (A) of oxycodone hydrochloride in physiological conditions.

Numerous physiologically active (active) substances such as food additives, drugs and other similar substances, produced in the form of repository drugs, i.e. drugs, which unlike traditional drugs (for example, the so-called drugs with immediate release of these active substances) of physiologically active substances are released into the body slowly over a relatively long period of time, which often amounts to several hours. Thanks to this slow release of physiologically active substances from medicinal forms, on the one hand, and their gradual transformation in the organization is the mechanism in the course of metabolism, accordingly, the gradual elimination from the body, on the other hand, the concentration entering the body physiologically active substance in the blood plasma is maintained at a more or less constant level. As a consequence, in most cases it is possible to reduce the number taken by the patient for one day dosage forms application, which is often sufficient to take only one or two times a day.

The use of repository drugs in certain cases can also reduce the degree of manifestation of side effects of physiologically active substances. For example, for certain drugs is characterized by greater inherent side effects, when the concentration of the medicinal substance in the blood plasma is at least temporarily stored above a certain limit. Therefore, these drug substances, particularly in those cases when it is desirable to take only two or three times a day, practically not suitable for their introduction into the body as part of the preparations immediate-release of these active substances. For this reason, these medicinal substances are usually injected into the body as part of repository drugs that provide a continuous release of these active substance over a relatively ol the term period of time and do not allow short-term increase in the concentration of active substance in the blood plasma to an unacceptably high level.

Repository of drugs (repository dosage forms) usually contain a physiologically active substance embedded in controlling or regulating its release matrix and/or provided with a film coating, controlling or regulating the release of physiologically active substances.

However, some patients, particularly elderly patients often have difficulty with the ingestion of solid forms of application, such as tablets, gelatin capsules and others. Swallowing such solid dosage forms (application forms), these patients can often poperhnutsja them, and as a result, they sometimes develops sustainable reflex aversion to such forms of application.

To solve this problem have been developed various devices, allowing them to crush or grind into powder solid dosage forms (the so-called "shredders"tablets). In homes for the elderly, for example, solid dosage forms, such devices grinds caring for elderly staff. In this case, in order to avoid difficulties with swallowing tablets long term care people take the drug form is not in the form of solid tablets or other solid forms application and in powdered form.

However, dosage forms is, represents a repository of drugs, should not be subjected to grinding using such devices. This is due to the fact that grinding repository dosage form usually leads to the destruction of its internal structure responsible for the slow release of the active substance, and, as a consequence, the disappearance of the slow release of the active substance effect. Grinding repository application forms accompanied by the shortening of the diffusion paths contained in them physiologically active substances and/or elimination of diffusion barriers. For example, after grinding repository of drugs, which slow the release of it physiologically active substance must provide a film coating, it is not at all, and only part of the resulting solid particles and occupies only a small percentage of the area of their surface. For this reason, after receipt of such powdered dosage forms all source contained within a physiologically active substance is often released from it in a relatively short time, from which the concentration of the physiologically active substance in the blood plasma over a relatively short period of time abruptly increases and reaches a relatively high level. Thereby repository Ave is parathas, which the source was designed for prolonged action, turn to drugs with immediate release of these physiologically active substances.

However, depending on the physiological activity of the active substance similar too rapid release and, accordingly, the too rapid increase of its concentration in the blood plasma to unacceptably high levels can cause serious side effects, and in some cases can even lead to death of the patient. As examples of active substances, the flow into the body in excessive amounts potentially associated with a similar risk of harm to the patient's health or even death, can be called ANTIPARKINSONISM funds, ANTIEPILEPTICS, antidiabetics, antihypertensive drugs, antiarrhythmic agents and other.

Usually people grinding repository dosage forms for themselves or for other people who are not aware of such risks. In practice, the known deaths of patients, presumably caused by taking their repository of drugs, powdered nurses, respectively caregivers. More detailed information on this issue can be found, for example, J.E. Mitchell. Oral Dosage Forms That Should Not Be Crushed: 2000 Update, published in Hospital Pharmacy, 2000, is H. Miller and others You Crush or Not to Crush, Izd-vo Nursing, 2000, in R. Grittith and other Tablet Crushing and the law: the implications for nursing, Prof. Nurse, 2003, J.G. Schier and others Fatality from administration of labetalol and crushed extended-release nifedipine, Ann. Pharmacotherapy, 2003, in A. James. The legal and clinical implications of crushing tablet medication. Nurse Times, 100(50), 2005, S. 28-29 and R. Cornish. Avoid the Crush: hazards of medication administration in patients with dysphagia or a feeding tube, CMAJ, 172(7), 2005, S. 871-872.

Repository of drugs can be fraught with danger for young children. Thus, in particular, children often cannot distinguish between solid dosage forms from sweets. In the case of children of such forms of application, for example, inadvertently left their parents in an apartment in an easily accessible place, there is a danger that children will accept such dosage forms for sweets, take them in your mouth and chew. If the concern repository preparations containing the drug substance in the dosage, adult, in this case, only the high content of medicinal substance in the repository the drug is for a child with danger of overdose. However, this danger is magnified when chewed dosage forms, the effect of slow release of drug substance from which the result vanishes, since in this case the medicinal substance, which besides the fact that it is already in the repository form when the change in high dosage, yet in too many get into the body in a substantially shorter time interval, as an adult man could be associated with a significant threat to his health, and for the child in General can have much more serious consequences.

Chewing repository of drugs can lead to overdose contained physiologically active substances and in the adult. Thus, in particular, sometimes adults quite consciously chew dosage form, as they are often not knowing the type and purpose of the repository of the drug, expect a rapid onset of action.

One of the famous features, aimed at reducing the risks associated with the grinding of repository drugs, is in the Appendix to the form of application of antagonists, i.e. counteracting means, or compounds that cause physiological protective reactions, and physiological effects of such additives must be shown only in the reception shredded dosage forms. However, the disadvantage of this approach is that the release of physiologically active substances, however, is not a slow character, and another contained in the application form physiologically active substance, for example, a counter tool, create is no additional load on the body or causes its protective response as, for example, vomiting.

Based on the foregoing, in the pharmaceutical industry, there remains a need in the application forms with delayed release of these active substances, which (dosage form) would reduce the risk of overdose and thus would allow to renounce the use of their composition opposing funds or other similar funds.

The present invention was based on the task to offer dosage form, which would have advantages over the known prior art forms application. This dosage form should provide a slow release of her physiologically active substances, but should also reduce the risk of overdose, primarily due to improper handling and improper of its application, in particular grinding, grinding, grinding in a mortar, etc.

With the invention it has been unexpectedly found that the above problem can solve dosage form that contains a physiologically active substance (s) (component (A)), optionally one or more physiologically compatible auxiliary substances (B) (component (B)), a synthetic or natural polymer (C) (component (C)) and do not necessarily natural, semi-synthetic or synthetic wax (D) (component (D)) and the possession is T. resistance to fracture of at least 400 N, preferably at least 420 N, more preferably at least 440 N, especially preferably at least 460 N, most preferably at least 480 N, especially at least 500 N, and which under physiological conditions to at least partially slowly releases a physiologically active substance (A). In accordance with that proposed in the invention of the pharmaceutical form contains a physiologically active substance (A) with at least partially delayed its release.

Proposed in the invention of the dosage form in a wide temperature range has mechanical strength, i.e. along with a relatively high resistance to fracture under certain conditions has sufficient hardness and toughness, and therefore almost impossible to crushing or grinding into powder by grinding, grinding in a mortar, pounding with a hammer, etc. and grinding using commercially available devices for grinding into powder traditional forms application. However, this effect is not necessarily due to the hardness of the dosage form. Thus, in particular, the presence of the proposed invention the dosage form and relatively high toughness though and allows you to deform proposed in the invention of the medicinal form of PR is the application of an external mechanical impact, for example, a hammer, but does not allow its fragmentation into several small fragments. The proposed invention in dosage form cannot be crushed, even if it is pre-cooled, the purpose of which is to increase its fragility, for example, when cooled to temperatures below -25°C or below -40°C or when cooled in liquid nitrogen.

The result is an effect of slow release of the physiologically active substance of the proposed invention the dosage form and effectively prevents the possibility of overdose due to improper handling of the dosage form and its improper use.

Preferred properties proposed in the invention forms application, including, in particular, and their mechanical properties cannot be obtained automatically by processing components (A), (B), optionally (B) and optionally (D) any other traditional methods of cooking applications. Moreover, in the preparation of application forms is usually required to select the appropriate equipment and configure the appropriate settings, first of all, pressure/stress, temperature and time. To get the dosage form with the required properties can only exposing the components in the preparation of medicinal Faure is s impact sufficient pressure for a sufficient temperature for a sufficient period of time. In other words, even when using traditional equipment for compliance with the criteria is usually an appropriate approval process parameters.

Under a slow release according to the invention mainly refers to a release profile, when the physiologically active substance to provide more prolonged therapeutic action is released from the dosage form over a prolonged period of time at a lower frequency of reception of the dosage form. A similar effect is achieved primarily oral. The expression "at least partially delayed release" is used according to the invention to denote any form of application that provide the modified allocation contained in them physiologically active substances. Under the forms used mainly refers to dosage forms coated or uncoated, which for purposeful change of speed or place of release of these physiologically active substances are produced using special excipients or special methods or by using both of these possibilities in their combination.

Proposed in the invention the dosage form from the point of view of the prot the project process the release of these physiologically active substances in time are divided into the following types: dosage forms with delayed release or detention". "extended release", "delayed release"), dosage form with stepped or gradual release ("repeat action release"), pharmaceutical form prolonged release (). "prolonged release") and dosage forms with uniformly slow release ("sustained release"). In Russian literature, all such applications are called forms with prolonged action.

In the context of the present description under "deferred or delayed release" preferably refers to the release of a physiologically active substance, starting with a delay for a specified, finite period of time (time lag), after which the release of the physiologically active substance is unimpeded. Under "step or phased release" preferably refers to the initial release of the first partial quantity of the physiologically active substance with the subsequent release of at least one of the following partial amounts. Under "slow release" preferably refers to the release of a physiologically active substance with a reduced speed in order to maintain its therapeutic efficacy, reduce toxicity or other therapeutic purposes. By "uniformly prolonged high what opozdaniem" preferably refers to a continuous release of a physiologically active substance over a relatively long period of time to reduce the frequency of administration of the medicine. More detailed information on the forms application with a similar release profiles of these active substances can be found, for example, Knwoing. Lehrbuch der Pharmazeutischen Technologie, 6th ed., publishing house WVG Stuttgart, 1999 and in the European Pharmacopoeia.

In one preferred options after 5 hours of the proposed invention the dosage form under physiological conditions is released at most 99%, preferably a maximum of 90%, more preferably 75%, especially preferably a maximum of 50%, and most preferably a maximum of 40%, especially at most 30%, substance (A). In a particularly preferred variant of dosage form in this case contains no tramadol hydrochloride or oxycodone hydrochloride, more preferably does not contain opioid [N02A] (value code "N02A see below). The release of the physiologically active substance from the dosage form preferably be determined in accordance with standard methods described in the European Pharmacopoeia, preferably in the above example 1 conditions.

In a preferred embodiment, the physiologically active substance (s) released from the proposed invention the dosage form under physiological conditions in the amount of from 0.1 to 75 wt.% after 30 min, in an amount of from 0.5 to 95 wt.% after 240 min, in an amount of from 1 to 100 wt.% after 480 min and in an amount of from 2.5 to 100 wt.% after 720 minutes

The following table presents 5 other preferred release profiles of physiologically active substances of the invention the dosage form [data in wt.% released component (A)]:

Time [h]No. 1No. 2No. 3No. 4No. 5
10-300-500-5015-2520-50
20-400-750-7525-3540-75
43-553-9510-9530-4560-95
810-6510-10035-10040-6080-100
1220-7520-100 55-10055-7090-100
1630-8830-10070-10060-75
2450-10050-100>90
36>80>80

Features of release of the physiologically active substances of the invention forms application preferably practically should not depend on the pH of the medium in which it is released physiologically active substances (environmental release), i.e. the profile release in artificial gastric juice preferably should mostly match the profile of the release in an artificial environment that mimics gastric juice. The difference between the two release profiles at any point in time measurements preferably should not exceed 20%, more preferably 15%, mainly 10%, particularly preferably 7.5%, and most preferably of 5.0%, above the powers of 2.5%.

Proposed in the invention of the dosage form preferably should have a uniform profile of the release of her physiologically active substances. While the profile of release of the physiologically active substance (A) should preferably be uniform in all the individual forms of use (i.e. when comparing two forms of application, prepared the same way) and/or within a single dosage form (i.e. when comparing two separate parts of one and the same pharmaceutical form). The comparison between the two samples with the weight of preferably 500 mg difference between the total released from each of these amounts of the active substance at any point in time measurements in a preferred embodiment, should not exceed 20%, preferably 15%, more preferably 10%, particularly preferably 7.5%, and most preferably of 5.0%, primarily of 2.5%.

The profile of release of the physiologically active substance of the proposed invention the dosage form preferably should remain stable during storage, preferably, after storage for 3 months at elevated temperature, for example at 37°C, in tightly closed containers. In this regard, the expression "stable storage" means that when compared to the social profile of release of the physiologically active substance with a profile of its release after storage of the difference between the two release profiles of physiologically active substances at any time measurements should not exceed 20%, preferably 15%, more preferably 10%, particularly preferably a maximum of 7.5%, most preferably of 5.0%, primarily of 2.5%.

The use of certain polymers in appropriate quantities and in appropriate conditions according to the invention allows to give the form of the application of fracture resistance of at least 400 N, preferably at least 420 N, more preferably at least 440 N, especially preferably at least 460 N, most preferably 480 N, especially at least 500 N (fracture resistance measured by the following method, and preferred according to the invention by a method for determining the resistance to fracture is a modification of the method described in European Pharmacopoeia, edition 5.0, s, section 2.9.8, and entitled "Resistance to Crushing of Tablets" ("the Resistance of tablets to destruction")). In this way effectively to prevent crushing, for example, grinding into powder, conventional dosage forms, respectively improvised means.

Under the crushing or grinding of the dosage form according to the present invention assumes its grinding to a powder using a standard available available tools such as mortar and pestle, a hammer, stake the carcass or other common means, allowing with a corresponding effort to cut solid materials in powder, and above all with the help of specially developed for this purpose devices (shredders tablets), while the share of possibly formed during such grinding of fine fraction (particles with a size of 0.3 mm or less) should not exceed 5 wt.%.

Thus, the proposed invention in a pharmaceutical form suitable to prevent overdose of physiologically active substances, especially food additives and drugs manufactured in the form of repository drugs. You can refuse inclusion in the proposed invention the dosage form opposing means, irritants and other funds for similar purposes. Along with overdose prevention of physiologically active substances and the associated risks for the patient proposed in the invention the dosage form remain, furthermore, all other advantages of repository medication, as example of which can be called a uniform release of these physiologically active substances for over a maximum of ±7.5%, and particularly preferably a maximum of ±5.0 percent, most preferably a maximum of ±2,5%, primarily a maximum of ±1,0%.

Proposed in the invention of the dosage form is great for what is next, a relatively homogeneous distribution of the physiologically active substance (A) its volume. In a preferred embodiment, the amount of the component (A) in two parts of the dosage form with the volume of 1.0 mm3vary between a maximum of ±10%, more preferably a maximum of ±7.5%, and particularly preferably a maximum of ±5.0 percent, most preferably a maximum of ±2,5%, primarily a maximum of ±1,0%.

The total mass of the proposed invention the dosage form should preferably be from 0.01 to 1.5 g, more preferably from 0.05 to 1.2 g, particularly preferably from 0.1 to 1.0 g, most preferably from 0.2 to 0.9 g, especially from 0.25 to 0.8,

In a preferred embodiment of the proposed invention in dosage form contains at least the polymer (C)selected from the group comprising polyalkylene, preferably polyethylenoxide, polyethylene oxide or polypropyleneoxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, polymeric fatty gidrokshikislotu, such as a copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate (Biopol®), polymer hydroxyvalerenic acid, polycaprolactone, polyvinyl alcohol, polyetherimide, poliatilenaksida, Polyglactin, polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide, polylactide, Polyacetal (for example, polysaccharides, optionally with modified side chains), polylactides the ID, polylactam, polyglycolide, complex poliorcetes, polyanhydride, block copolymers of polyethylene glycol and polybutylene terephthalate (Polyactive®), polyanhydride (polifeprosan, Polifeprosan), copolymers and mixtures of at least two of these polymers.

Preferred high molecular weight thermoplastic polyalkylene, especially polyethylene oxide, polypropyleneoxide or (block)copolymers. Particularly preferred high molecular weight polyalkylene, especially polyethylene oxides with molecular weight, preferably mass-average molecular mass (Mwor srednevozrastnoe molecular weight (Mη)at least 0,5×106g/mol, a long period of time and which are not so simply change for the worse.

To make the proposed invention in the form of application required resistance to destruction using at least one synthetic or natural polymer (C), the presence of which is mainly due to the increased resistance of the dosage form destruction. The resistance of the dosage form destruction, measured in accordance with presented below in this description of technique is at least 400 N, preferably at least 420 N, more preferably at least 440 N, especially preferably at mere N, most preferably at least 480 N, especially at least 500 N. In one of the preferred options the resistance of the dosage form destruction is at least 500 N, preferably of at least 600 N, more preferably at least 700 N, mainly of at least 800 N, especially preferably at least 900 N, most preferably at least 1000 N, primarily at least 1100 N.

The proposed invention in dosage form, along with their high resistance to degradation in the preferred embodiment is characterised by the presence of other mechanical properties, such as its hardness, toughness, resistance to rebound and/or its modulus of elasticity, which under certain conditions are maintained even at low temperatures (for example, at temperatures below -24°C or below -40°C or when cooled in liquid nitrogen).

In one of the preferred options proposed in the invention, the dosage form has a density of at least 0,80 or at least 0,85 g/cm3preferably at least 0.90 or at least 0.95 g/cm3especially preferably at least 1,00, at least of 1.05 or at least 1.10 g/cm3most preferably a density in the range from 0.80 to 1.35 g/cm3 primarily from 0.95 to 1.25 g/cm3.

Proposed in the invention of the dosage form is marked by a relatively homogeneous distribution of density volume. In a preferred embodiment, the densities of the two parts of the dosage form with the volume of 1.0 mm3vary between a maximum of ±10%, more preferably preferably at least 1.0×106g/mol, more preferably at least a 2.5×106g/mol, particularly preferably at least 5,0×106g/mol, most preferably at least 7,5×105g/mol, or 7.5×106g/mole, especially at least 10×106g/mol, preferably from 1.0×106up to 15×106g/mol. Appropriate methods for determining the molecular mass Mwaccordingly Mηwell known. The molecular mass Mηpreferably be determined by rheological measurements, a molecular mass Mwby gel chromatography (GPC) on reasonable phases.

The viscosity of the polymer (B) at 25°C. when measured at 5%by weight aqueous solution of the polymer by using a Brookfield viscometer, model RVF spindle # 2, speed 2 rpm), preferably should be between 4500 to 176,000 MPa·s (CPs)when measured at 2%by weight aqueous solution of the polymer using the specified viscometer (n is using spindle No. 1, 3 when the speed of rotation of 10 rpm) should be from 400 to 4000 MPa·s (CP), respectively, when measured at 1%by weight aqueous solution of the polymer using the specified viscometer with spindle No. 2 at speed 2 rpm) must be from 1650 to 10000 MPa·s (CP).

For preparation of the proposed invention the dosage form of the polymer (C) preferably used in powder form. It can be soluble in water.

The polymer (C) preferably used in the amount of at least 20 wt.%, more preferably at least 30 wt.%, especially preferably at least 40 wt.%, most preferably at least 50 wt.%, first of all, at least 60 wt.%, in terms of the whole mass of the dosage form. In one of the preferred options the polymer is used in an amount of from 20 to 49 wt.% in terms of the whole mass of the dosage form.

One of the proposed invention in a pharmaceutical form suitable for introduction into the body in its composition of several physiologically active substances (As). Preferably, however, to include in the composition of the dosage form only one particular physiologically active substance (A), preferably a food additive or drug substance (active pharmaceutical ingredient).

Mass fraction of Phys is logicheskie active substance (A) in terms of the whole mass offered in the invention, the dosage form preferably should be from 0.01 to 95 wt.%, more preferably from 0.5 to 80 wt.%, particularly preferably from 1.0 to 70 wt.%, most preferably from 5.0 to 60 wt.%, first of all, from 10 to 50 wt.%. In one preferred options mass fraction of physiologically active substances in the proposed invention in the form of application exceeds 20 wt.%.

In one of the preferred options proposed in the invention, the dosage form does not contain possessing psychotropic action of the substance. Professionals in this field are well aware of what substances have a psychotropic effect. Psychotropic effect, i.e. specific effects on mental function, usually have substances affecting mental processes. Thus, substances with a psychotropic action can affect mood, rendering it either raising or lowering the action. In the context of the present description to substances with a psychotropic action are primarily opioids, stimulants, sedatives (barbiturates and benzodiazepines) and other drugs. In the preferred embodiment, under the substances with a psychotropic action refers to substances, when introduced into the body is first of all not on purpose (mainly for non-medical purposes) is accelerated in comparison with their ingestion label receipt ("inflow") de the corresponding substances in the body to achieve the desired result, namely, the onset of the so-called quick "rush" or "high." Similar rapid onset of "buzz" is achieved, for example, when natalina the introduction, i.e. when nochange, powdered dosage forms containing the substance with psychotropic action. Under the substances with a psychotropic action preferably refers to those substances which (in the appropriate dosage with the content in the appropriate form of application and when introduced into the body in an equitable way) have on the mental activity of the person and/or perception of reality such effects, which in principle due to the possibility of their use not for medical purposes.

Listed below are some opiates, opioids, tranquilizers, or other narcotic substances, which are substances with psychotropic effects and therefore it is preferable not to include in the proposed invention the dosage form: Alfentanil, allobarbital, allylprodine, Alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital, Anileridine, apocodeine, barbitala, amidon, benzylmorphine, Bezitramide, bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil, Katin/D-norpseudoephedrine, chlordiazepoxide, clobazam, chlophedianol, clonazepam, clonitazene, cloris the Pat, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphine, diazepam, Dihydrocodeine, dihydromorphine, dihydromorphine, dimenoxadol, dimethiconol, dimethylthiambutene, dioxaphetyl, Dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethylotest, Ethylmorphine, etonitazene, Etorphine, fencamfamin, fenetylline, fineframe, fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, hydroxymethylation, ketazolam, Ketobemidone, levacetylmethadol (LAAM), levomethadone, Levorphanol, levophenacylmorphan, levoxyl, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepama, mefenorex, meperidine, meprobamate, metapan, meptazinol, metazocine, methylmorphine, methamphetamine, methadone, methaqualone, 3-methylpentyl, 4-methylpentyl, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, morphine, mirfin, nabilone, nalbuphine, nalorfin, Narain, Nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, Normethadone, normorphine, norpipanone, opium, oxazepam, oksazolov, oxycodone, Oxymorphone, Papaver somniferum (poppy hypnotic), papaveretum, parolin, pentazocine, pen is Barbital, pethidine, phenadoxone, phenomorphan, phenazocine, Phenoperidine, piminodine, pholcodeine, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piritramid, prazepam, profadol, proheptazine, promedol, properidine, propoksifen, Remifentanil, secbutabarbital, secobarbital, Sufentanil, temazepam, tetrazepam, tilidin (CIS and TRANS), tramadol, triazolam, vinylbital, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(n-forbindelse)-1 -(m-methoxyphenyl)yclohexanol, (1R,2R)-3-(2-dimethylaminomethylene)phenol, (1S,2S)-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, 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-methoxynaphthalene-2-yl)propionate, 3-(2-dimethylaminomethylene-1-enyl)-phenyl 2-(4-isobutyl-phenyl)-propionate, 3-(2-dimethylaminomethylene-1-enyl)phenyl-2-(6-methoxynaphthalene-2-yl)propionate, 3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl ether (RR-SS)-2-acetoxy-4-trichoroethylene acid, 3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl ether (RR-SS)-2-hydroxy-4-trichoroethylene acid, 3-(2-what emailmyname-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-hydroxycyclohexyl)phenyl ether (RR-SS)-2-hydroxy-5-nitrobenzoic acid, 3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)phenyl ether (RR-SS)-2',4'-debtor-3-hydroxybiphenyl-4-carboxylic acid and the corresponding stereoisomeric compounds, in each case, their respective derivatives, physiologically compatible enantiomers, stereoisomers, diastereomers and racemates and the physiologically compatible derivatives, for example, ethers, esters or amides, and in each case their respective physiologically compatible compounds, especially their salts and solvate, such as hydrochloride.

In the structure proposed in the invention the dosage form is most preferable not to include a substance selected from the group including opioids [A07DA, N01, N02A, R05DA, R05FA], barbiturates [N01AF, N01AG, N03AA], a derivative of benzodiazepine [N03AE], a treatment for opiate dependence [N07BC], anxiety [N05B], hypnotics and sedatives [N05C], psychoactive agents; agents used to treat syndrome of impaired attention hyperactivity disorder (ADHD) and nootropic agents [N06B], protivore the major tools [AA], tools for weight loss, except for nutritional tools [AA], muscle relaxants Central action [MV] and antidotes [V03AB]. Specified in square brackets denote correspond with ATC-code used by who for the classification of medicinal substances (preferably in January 2005 Gili 2006). More detailed information about ATC-codes can be found, for example, U., Fricke, J. Günther. Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen für den deutschen Arzneimittelmarkt: Methodik der ATC-Klassifikation und DDD Festlegung. ATC-Index mit DDD-Angaben, Izd-vo Wissenschaftliches Institut der AOK, as well as in the Swiss Pharmaceutical Society, Index Nominum: International Drug Directory, published by CRC Press, 18th ed. (31 January 2004).

In one of the preferred options proposed in the invention, the dosage form does not contain a compound selected from the group including

(1) analgesic tools, such as aspirin, acetaminophen, diflunisal (diflunisal) and others,

(2) anesthetics, such as lidocaine, procaine, benzocaine, xylocaine and others,

(3) anti-arthritis remedies and anti-inflammatory drugs such as phenylbutazone, indomethacin, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone, probenecid, cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac and its salts and its corresponding sulfide, and the others who motivaatorite and anti-inflammatories

(4) anti-asthma drugs, such as theophylline, ephedrine, beclomethasone dipropionate, epinephrine and others,

(5) disinfectants used for infections of the urinary tract, such as sulfamethoxazole, trimethoprim, nitrofurantoin, norfloxacin and others,

(6) anticoagulants, such as heparin, bishydroxycoumarin, warfarin, and others,

(7) anti-convulsants, such as diphenylhydantoin, diazepam, and others,

(8) antidepressants, such as amitriptyline, chlordiazepoxide, perphenazine, protriptyline, imipramine, doxepin, and others,

(9) substances suitable for the treatment of diabetes to regulate blood sugar, such as insulin, tolbutamide, tolazamide, somatotropin, acetohexamide, hlorpropamid and others,

(10) anti-cancer drugs such as adriamycin, fluorouracil, methotrexate, asparaginase and others,

(11) antipsychotics, such as prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, triptorelin, perphenazine, amitriptyline, triflupromazine and others,

(12) antihypertensives, such as spironolactone, hydrochlorothiazide methyldopa, hydralazine, clonidine, chlorthiazide, deserpidine, timolol, propanolol, metoprolol, prazosin hydrochloride, reserpine and the other,

(13) muscle relaxants such as matalan, danbolt, cyclobenzaprin, Methocarbamol, diazepam, succinylcholine and others,

(14) Antiprotozoal tools, such as chloramphenicol, chloroquine, trimethoprim and sulfamethoxazole

(15) spermicides, such as nonoxynol,

(16) an antibacterial agent, such as beta-laktamovogo antibiotics, tetracyclines, chloramphenicol, neomycin, cefoxitin, thienamycin, gramicidin, bacitracin, sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone, Kalinicheva acid and its analogues, as well as antimicrobial combination of floodline and pentosidine,

(17) antihistmine tools and anti funds, such as perilipin, chlorpheniramine (for example, chlorpheniramine maleate, tetrahydrozoline, antazoline,

(18) antiparasitic tools, such as ivermectin,

(19) antiviral agents such as acyclovir and interferon,

(20) antifungal agents, amebicide, trihomonatsidnym funds or Antiprotozoal agents such as, for example, polyoxyethyleneglycol, alkylarylsulfonate, oksikhinolinata, miconazole nitrate, sulfanilamide, candicidin, sulfisoxazole, nizatidine, clotrimazole, metronidazole, and others, and

(21) losoxantrone, theophylline or β-hydroxic Tefillin (etofillin), diphenhydramine, according to its hydrochloride, diltiazem, respectively, its hydrochloride and diphenylether(adenosine).

In another preferred embodiment of the proposed invention in dosage form does not contain irritating the nasal cavity and/or pharynx substances, i.e. substances which, when appropriate ingested through the nose and/or throat provoke a reaction of the body, which either manifests itself in the occurrence of such unpleasant sensations, such as burning sensation that disappears further desire or becomes impossible to continue the introduction of the corresponding active substance in the body, or on a physiological level, preventing the receiving of the corresponding active substance, for example, is manifested in the increased secretion of nasal secretion or sneezing. As an example, irritating the nasal cavity and/or pharynx substances are those substances that cause a burning sensation, an itch, the urge to sneeze, increased secretions, or both have at least two such annoying actions. The relevant substances and their commonly used well-known in this field. Thus, in particular, the basis of some irritating the nasal cavity and/or pharynx substance is one or more annoying ("burning") of substances containing the drug is whether edible plants or containing one or more of its(their) parts of such plants. Relevant medicinal or edible plants that contain irritating substances, known to specialists in this field and are described, for example, in the book "Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe", Prof. Dr. Hildebert Wagner, 2nd, revised ed., published by Gustav Fischer Verlag, Stuttgart-New York, 1982, c. 82 and forth. The relevant sections of this book are hereby incorporated into the present description by reference and are a part of it.

In the structure proposed in the invention, the dosage form preferably further include antagonists of physiologically active substances (A), preferably antagonists of psychotropic substances, primarily antagonists of opioids. Appropriate antagonists or other physiologically active substance (S) known to specialists in this field and can be represented as such or in the form of corresponding derivatives, especially complex or ethers, or in the form of corresponding physiologically compatible compounds, primarily in the form of their salts or solvate. In the structure proposed in the invention, the dosage form preferably not include antagonists selected from the group comprising naloxone, naltrexone, nalmefene, naled, naloxon, nalorfin and Malutin, in each case optionally in the form of corresponding physiologically compatible compounds, primarily in the form of the establishment, salt or MES, and do not include neuroleptic agent, for example, a compound selected from the group including haloperidol, promethazine, fluphenazine (fluphenazine), perphenazine, levomepromazine, thioridazine, persin, chlorpromazine, chlorprothixene (chlorprothixene), zuclopenthixol (zuclopenthixol), flupentixol (flupenthixol), prothipendyl (prothipendyl), zotepine, benperidol (benperidol), pipamperone (pharmaron), melperone (malpura) and bromperidol.

In addition, the proposed invention in dosage form preferably should not contain emetic agent. Appropriate material resources known to specialists in this field and can be represented as such or in the form of corresponding derivatives, especially complex or ethers, or in the form of corresponding physiologically compatible compounds, primarily in the form of their salts or solvate. In the structure proposed in the invention, the dosage form preferably not include emetic agent on the basis of one or more substances contained in the root of ipecac (gag root), for example, on the basis of the contained emetinom, and are described, for example, in the book "Pharmazeutische Biologie - Drogen and ihre Inhaltsstoffe", Prof. Dr. Hildebert Wagner, 2nd, revised ed., published by Gustav Fischer Verlag, Stuttgart, New York, 1982. The relevant sections of this book hereby incorporated vnastoyaschee description as a reference and are a part of it. Proposed in the invention of the dosage form preferably should not contain apomorphine as a vomiting agent.

Proposed in the invention of the dosage form preferably should not also contain a bitter substance. Relevant bitter substances, as well as necessary to achieve the desired effect of the number described in the application US 2003/0064099, relevant sections of which are hereby incorporated in the present description by reference and are a part of it. As an example, bitter substances can be called aromatic oils, such as peppermint oil, eucalyptus oil, oil of bitter almond, menthol, aromatic substances of fruits, such as aromatic substances dei Cedri, oranges, lemons, grapefruits or a mixture of aromatic substances specified fruits, and/or benzoate, dentonia.

Thus proposed in the invention, the dosage form preferably contains no substances with a psychotropic action, nor irritating the nasal cavity and/or pharynx substances or antagonists physiologically active substance (A), neither the material resources nor bitter substances.

In one of the preferred options proposed in the invention, the dosage form comprises a physiologically active substance (A) the food additive. Dietary supplements contain the advantages of the NGO one or more nutrients in a concentrated, dosed, not typical for food. Food supplements are intended to Supplement the daily diet in those cases where appropriate nutrients enter the body of a man used them as food in insufficient quantities, respectively, when it is desirable that the additional flow in the body. Food additive is preferably selected from the group comprising vitamins, minerals, trace elements, enzymes, fatty acids, amino acids and antioxidants. Particularly preferred dietary supplements include vitamins, Pro-vitamins and their derivatives, primarily retinol, calcitriol, tocopherol, phylloquinone, thiamine, Riboflavin, folic acid, Niacin (primarily nicotinamide), Pantothenic acid, pyridoxal, cobalamin, L-ascorbic acid, biocytin, Biotin, and carotenoids.

In another preferred embodiment of the proposed invention in dosage form comprises a physiologically active substance (S) drug substance (active pharmaceutical ingredient), causing the possibility of using the dosage form as a drug and determining its biological activity. As a medicinal substances in the proposed invention in the form of application in principle can use is shared by all known medicinal substance, which may be present in the proposed invention in the form of application as such, in the form of their derivatives, especially complex or ethers, or in the form of corresponding physiologically compatible compounds, primarily in the form of corresponding salts or solvate, in the form of racemates or in the form enriched in one or more stereoisomers (enantiomers or diastereomers).

In a particularly preferred embodiment of the proposed invention in dosage form contains one substance (A) or more substances (A) from the group, including

- preparations for the treatment and prevention of digestive diseases and diseases associated with metabolic disorders [And]above all dental treatment [A01], tools for treatment and prevention of diseases associated with impaired acidity [A02]means for treatment and prevention of functional disorders of the gastrointestinal tract [A03], antagonists of serotonin NT3receptors [AAA], antihistamines [AAV], for the treatment of liver and biliary tract [A], laxatives [A06], intestinal antimicrobial and anti-inflammatory remedies [AA], intestinal adsorbents (chelators) [AV], electrolytes with carbohydrates [AS], intestinal anti-inflammatory drugs [AE], against the diarrhoeal microorganisms [A07F], tools, promoting digestion, including enzyme preparations [a]means for treatment of diabetes [a10], vitamins [A11], mineral supplements [A12], anabolic agent for systemic use [A14] and appetite stimulants [A15],

- preparations for the treatment and prevention of diseases of blood and blood-forming organs [In], especially anticoagulants (antithrombotic tools) [V], hemostatic [V], stimulators of hematopoiesis [V] and other hematological tools [W],

- preparations for the treatment and prevention of diseases of the cardiovascular system [S], first means for treatment of heart disease [C01], antihypertensive [C02], diuretics [S], peripheral vasodilators [s], angioprotectors [s], hypertensive tools [SA], β-blockers [From 07], calcium channel blockers [COS], means affecting the renin-angiotensin [from 09], and lipid-lowering means [C10],

- preparations for the treatment of skin diseases [D]first of all antifungal agents for systemic use [D01B], remedies for psoriasis treatment for systemic use [D05B], tools for systemic treatment of acne [D10B],

- preparations for the treatment and prevention of diseases of the urogenital organs and sex hormones [G]first of all antiseptics and antimicrobial agents for the treatment of gynecolo the systematic diseases [G01], uterotonics funds (cash, enabling clan activities) [G02A], tokoliticheskoe tools-sympathomimetics (sympathomimetics, suppressing tribal activities) [G02CA], inhibitors of prolactin secretion [G02CB], hormonal contraceptives for systemic use [G03] and tools for the treatment of urological diseases [G04],

- hormonal drugs for systemic use, excluding sex hormones and insulins [N], especially the hypothalamic-pituitary hormones and their analogues [H01], corticosteroids for systemic use [H02], drugs for the treatment of diseases of the thyroid gland [H03], hormones of the pancreas [N] and hormones for the treatment of diseases of the parathyroid gland (means for the regulation of calcium homeostasis) [N],

- antimicrobial agents for systemic use [J], primarily antibiotics for systemic use [J01], antifungal agents for systemic use [J02], remedies against mycobacteria [J04], antivirals for systemic use [J05], immune sera and immunoglobulins [J06] and vaccines [J07],

- antineoplastic and immunomodulating agents [L], especially anti-cancer drugs [L01], tools for endocrine therapy system [L02], Immunostimulants [L03] and immunosuppressants [L04],

- preparations for the treatment and prevention of sableman the th of the musculoskeletal system [M], first of all, anti-inflammatory and Antirheumatic drugs [M01], muscle relaxants peripheral actions [MA], muscle relaxants Central action [MS], protivopodagricakih tools [M04] and means for the treatment of bone disease [M05],

- preparations for the treatment and prevention of diseases of the nervous system [N], especially salicylic acid and its derivatives [N02BA], pyrazolones [N02BB], anilines [N02BE], ergot alkaloids [N02CA], derivatives of corticosteroids [N02CB], selective serotonin agonists 5HT1receptors [N02CC], derived as [N03AB], derivatives of oxazolidine [N03AC], derivatives of succinimide [N03AD]derived carboxamide [N03AF], derivatives of fatty acids [N03AG], ANTIPARKINSONISM funds [N04], antipsychotics [N05A], antidepressants [N06A], for the treatment of dementia [N06D], parasympathomimetic [N07A] and anti-vertigo [N07C],

- antiparasitic tools, insecticides and repellents [P], primarily Antiprotozoal tools [P01], deworming drugs [P02] and tools for combating ectoparasites, including protivochesotocnaya tools, insecticides and repellents [P03],

- preparations for the treatment and prevention of diseases of the respiratory tract [R], primarily nasal drugs [R01], a treatment for diseases of the throat and pharynx [R02], tools for lichenification of respiratory diseases [R03], expectorants, excluding combinations with antitussive means [R05C], and antihistamines for systemic use [R06],

- preparations for the treatment and prevention of diseases of the sense organs [S]primarily means for otological treatment [S02],

- General nutritional tools [V06] and radiotherapy tools [V10],

where is given in square brackets denote in this case correspond to the ATC-codes used by who for the classification of medicinal substances (preferably in January 2005 or 2006).

In a preferred embodiment of the proposed invention in dosage form contains one or more physiological active substance (A)selected from the group comprising 4-aminomethylbenzoic acid, abacavir, abamectin, abciximab, abbandon, abrin, acamprosate, acarbose, acebutolol, aceclidine, aceclofenac, acetazolam, acemetacin, acenocoumarol, acetazolamide, acetoacetic acid, acetyldigoxin, acetylaminophenol, acetylcysteine, β-acetyldigoxin, acetylcysteine, acetylsalicylic acid, acetylthiocholine, acyclovir, acipimox, acitretin, aclarubicin, aconitin, acriflavine chloride, acrivastine, actinoquinol, acylaminoacyl, adalimumab, adapalen, adefovir, adefovir dipivoxil, adenosine, adenosintriphosphate, adenosine osvat, adepitan, adrenaline, Austin, agalsidase-alpha, agalsidase-beta, agaricina acid, aymalin, alanine, albendazole, alkorani, aldeslakin, aldosterone, alemtuzumab, alendronate acid, alphacalcidol, alfuzosin, angelkat F, alitretinoin, alizapride, allantoin F, allopurinol, allisoncarolinet, almatret F, almotriptan, α-acetyldigoxin, alprenolol, alprostadil, alteplase, aluminum glycinate F, aluminum hydroxide F, aluminum phosphate F, aluminum reformat, amantadine, Amazon, Ambroxol, ambulinia bromide, formic acid, amikacin, amidopirin, amidotrizoate acid, amifostine, amikacin, amiloride, aminouksusnoy acid, aminoglutetimid, aminophylline, aminoaciduria, amiodarone, amisulpride, amitriptyline, amlodipine, amorolfine, amoxicillin, amphotericin b, ampicillin, APV, amylmetacresol, amyl nitrate, anagrelide, anakinra, anastrozole, ancrod, anistreplase, antazoline, antitrombin III, apomorphine, apraclonidine, either aprepitant, aprindine, Aprotinin, arcitumomab, arginine, aripiprazole, arsenic trioxide, artemether (Artemether), articaine, ascorbic acid, asparagine, L-asparaginase, aspartic acid, atazanavir, atenolol, Atomoxetine, atorvastatin, atosiban, atovaquone (atobahn), atricure, atricure besilate, atropine, auranofin, azapropazone, azathioprine, azelaic acid, azelastin, azidothymidine, AZ is thromycin, azlotillin, aztreonam, N2-alalalalalalala, paraaminosalicilovaya acid, bacampicillin, bacitracin, baclofen, balsalazide, bambuterol, Bamyan, bamipine, barbexaclone, barium sulfate F, barnidipine, basiliximab, batroxobin, becaplermin, beclomethasone, bendamustine (bendamustine), befunolol, bemiparin, benactyzine, benazepril, benzilan, bendazac, bendroflumethiazide, benperidol (benperidol), benproperine, benserazida, Bensberg, benzathine, benzatropine, benzbromarone, benzocaine, benzoyl peroxide, benzilan, benzydamine, benzylpenicillin, benzylpenicillin, betacarotene, betahistine, betahistine, betamethasone, bethanechol, betaxolol, bethanechol chloride, satiated, bevacizumab, bexarotene, bezafibrat, bebensee bromide, bikalutamid, BILSAT, bifonazole, bimatoprost, biperiden, bisoprolol, bivalirudin, bleomycin, factors VII, VIII, IX, X and XIII, Barnaby, bornapril, bortezomib, bosentan, botulinum toxin type b, brimonidine, brinzolamide, brivudin, Bromhexine, parlodel, bromperidol, brompheniramine, brotizolam, budesonide, budipine, bufexamac, buflomedil, bumetanide, bunazosin, Burenin, bupivacaine, bupranolol, bupropion, buserelin, buspirone, busulfan, butylamine, butanilicaine butenafine, buritama, butirosin, butizide, butylscopolamine, 5-harkerware, the inhibitor of C1-esterase, cabergoline, cadexomer and Odin, efedrin, callpath the IOL, calcitonin, calcitriol, camylofin, candesartan, cilexetil, canrenoate acid, capecitabine, capreomycin, capsaicin, captopril, carazolol, Carbajal F, carbamazepine, carbasalate calcium, carbenoxolone, carbidopa, carbimazol, carbinoxamine, carboplatin, Karlukovo acid, carmustin, caroverine, carteolol, carvedilol, caspofungin, cefaclor, cephalo-Smoking, cephalexin, tsefaloridin, cefamandole, Cefazolin, cefdinir, cefepime, zeitmeister, cefixime, cefodizime, cefoperazone, Cefotaxime, cefotiam, cefoxitin, cefpirome, cefpodoxime, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime, Ceftriaxone, cefuroxime, celecoxib, celiprolol, certoparin, cetirizine, cetrimide, cerimonia bromide, cetrorelix, cetuximab, pyridinium, chenodesoxycholic acid, quinidine, quinine, quinine-iron citrate F, quinine tannat F, chlorambucil, chloramphenicol, chlorbutanol, chlorexidine, chloridazon, chlorobutanol, chloroquine, chloroxylenol, chlorphenamine, chlorphenesin, chlorphenoxamine, chlorpromazine, chlorprothixene (chlorprothixene), chlorthalidone, chlortetracycline, chlorzoxazone, choline, chondroitin sulfate, alpha hCG stimulation, hCG stimulation, chrysarobin, chymotrypsin, ciclesonide, cicletanine, ciclopirox, cyclosporine, cidofovir, cilastatin, cilazapril, cimetidine, cinacalcet, cinchocaine, Cinnarizine, tsinelas the pam, ciprofloxacin, cisapride, cisatracurium besilate, cisplatin, citalopram, citicoline, cladribine, clarithromycin, clavulanic acid, clemastin, clenbuterol, clindamycin, kliohinol, clobetasol, clobetasone, clobutinol, clocortolone, clodronate acid, clofibrate, clomiphene, clomipramine, clonazepam, clonidine, clopamide, clopidogrel, claustebola acetate, botulinum Clostridium, clotrimazole, Klochikhin, clozapine, kokarboksilazu, colchicine, cholecalciferol, colesevelam, colestipol, cholestyramine, colfosceril palmitate, colistin, Collyrium Zinci F (collyria zinc F), corticorelin, corticotropin, cortisone, cresol, croconazole, cromoglicic acid, crotamiton, trifluoro, coumarin derivatives, cyanamide, cyanocobalamin, cyclizine, cyclobutyl, cyclopentolate, cyclophosphamide, cycloserine, cyproheptadine at, cyproteron, cysteine, cytarabine, 2,4-dichlorobenzoyl alcohol, 2-Diethylaminoethanol, dacarbazine, daclizumab, dactinomycin, dalfopristin, dalteparin, danaparoid, danazol, dantrolene, dapiprazole, Dapsone, darbepoetin alpha, darifenacin, daunorubicin, deanol, deanol (debolaz, Deanolace), dacarbazine, dictateur F, deferiprone, deferoxamine, delapril, demeclocycline, denamarin, depreotide, decaline, desflurane, desipramine, desirudin, deslanoside, desloratadin, desmaninae, desmopressin, desogestrel, desoximetasone, desoksiribonukleaza, detime, DEXA is tazon, dexchlorpheniramine, dexibuprofen, dexketoprofen, dexrazoxane, dextran, dextromethorphan, diacerein, diacetylmorphine, dibenzepin, dibotermin alpha, diclofenac, diclofenamide, didanosine, dienestrol, dienoguest, diethylstilbestrol, difloxacin, diflucortolone, diflunisal, digitoxin, digoxin, digitalin, dihydroergocornine, dihydroergocristine, dihydroergocryptine, digidroergotamin, dihydroergotoxine, dihydrotachysterol, Diisopropylamine, Dikili clorazepate, diltiazem, dimenhydrinate, dimaranan, dimercaprol, dimethylsulfoxide, dimetindene, disodium Selenite, dinoprost, dinoprostone, diosmin, diphenhydramine, Diphenoxylate, diphenylpyraline, dipivefrin, diprophylline, dipyridamole, disopyramide, dinitrogen oxide, distigmine, disulfiram, dithranol, dixyrazine, D-norpseudoephedrine, dobezilata calcium, dobutamine, docetaxel, dofetilide, dolasetron, domperidone, donepezil, dopamine, dopexamine, dornase alpha, dorzolamide, dosulepin, doxapram, doxazosin, doxepin, doxorubicin, doxycycline, doxylin, drofenik, droperidol, drospirenone, drotrecogin alpha, DULOXETINE, dutasteride, dydrogesterone, N,N'-dihydroxyethylene, Bastin, econazole, ecothiopate iodide, efalizumab, efavirenz, eflornithine, iron(III)ammonium citrate F, iron oxide superparamagnetic particles, elcatonin, eletriptan, emedastine, Amarone, Amarone karrah the NAT, emetine, emtricitabine, enalapril, enalaprilat, enflurane, enfuvirtide, enoxacin, enoxaparin, entacapone, ephedrine, ephedrine racephedrine, epinastine, epinephrine, epirubicin, eplerenone, epoetin Alfa, epoetin beta, epoetin Delta, epoprostenol, eprazinone, eprosartan, eptacog alpha, eptifibatide, eptotermin alpha, erdosteine, ergocalciferol, ergometrine, ergotamine, ertapenem, erythromycin, ESCITALOPRAM, esmolol, esomeprazole, estradiol, estramustine, estriol, estrone, etakrinova acid, etamivan, etanercept, ethacridine, ethambutol, ethaverine, levonorgestrel, ethisterone, ethosuximide, etidronate acid, etilefrine, etodolac, etofenamate, etofibrate, etofillin, etomidate, etonogestrel, etoposide, etoricoxib, everolimus, actomyosin, exemestane, ezetimibe, 3-vertirosan, famciclovir, famotidine, felbamate, felbinac, felodipine, fenbufen, fendilin, fenofibrate, fenoterol, fenticonazole, fexofenadin, fibrinogen, fibrinolizin, filgrastim, finasteride, flavoxate, flecainide, Flucloxacillin, fluconazole, fludarabine, fludeoxyglucose [18F], fludrocortisone, flufenacet, flumazenil, flumetazon, flunarizin, flunisolide, fluoqinolona acetonide, pertinent, fluocortolone, fluphenazine (fluphenazine), fluorescein dilaurate, fluorescein sodium, fluorometholone (formation), fluorouracil, Portofino acid, Persian, flook ethyl, fluoxetine, flupentixol, fluphenazine, flupirtine, flupredniden, flurbiprofen, flutamide, fluticasone, flutrimazole, fluvastatin, fluvoxamine, polynovo acid, follitropin Alfa, follitropin beta, folic acid, fomepizole, fomivirsen, fondaparinux, formestane, formoterol, fosamprenavir, foscarnet, fosfestrol, fosfomicin, fosinopril, fosphenytoin, fotemustine, framycetin, frovatriptan, fulvestrant, furosemide, fusafungine, guidikova acid, phytic acid, gabapentin, gadobenate acid, gadobutrol, gadodiamide, gadopentetate acid, gadoteridol, gadoterate acid, gadoteridol acid meglumine, galaxytool acid, galantamine, gallopamil, ganciclovir, ganirelix, Gatifloxacin, gemcitabine, gemfibrozil, gentamicin, heparin, gestodene, glatiramer, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, glikvidon, glisoxepide, glucagon, glutamine, glutamic acid, glycopyrronium, glycopyrrolate bromide, glycyrrhetic acid, gonadorelin, goserelin, gramicidin, granisetron, grepafloxacin, griseofulvin, G-strophanthin, guaiacol, guanethidine, guanfacine,13S-urea, 4-hydroxybutiric acid, halcinonide, halofantrine, halometasone, haloperidol halothane, heme, hematoporphyrin, heparin, hepatitis b vaccine, heptaminol, hexobarbital, geksobendin, geksoprenalin, histamine, is histidin, gomatropin, homogenising, albumin human, hyaluronidase, hydralazine, hydrastinine, hydroquinone, hydrochlorothiazide, hydrocortisone, hydrotalcite F, hydroxocobalamin, hydroxycarbamide, hydroxychloroquine, hydroxyzin, hydroxylamine, hydroxyprogesterone, hydroxyzine, hymecromone, ibandronate acid, ibopamine, ibritumomab tiuxetan, ibuprofen, ibutilide, idarubitsin, ifosfamide, iloprost, imatinib, imatinib mesilate, imidapril, imiglucerase, imipenem, imipramine, imiqimod (imiquimod), immunology, Indianapolis, indapamide, indinavir, indium chloride [111In], indobufen, indomethacin, indoramin, infliximab, inosine, insulin, insulin aspart, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, interferon alpha, interferon alpha-2b, interferon of alfacon-1, interferon beta, interferon beta-1A, interferon beta-1b, interferon gamma, iobitridol, iodine, yodamid, iodixanol, ioflupane [123I], iohexol, iomeprol, iopamidol, iopentol, iopromide, yasargil, iotrolan, eurocinema acid, ioversol, ioxaglate acid, ioxithalamate, ipratropium, irbesartan, irinotecan, isepamicin, isoamyl, isoconazole, isoflurane, isoleucine, isoniazid, isonicotinoyl acid, izoprenalin, isosorbide, isoagglutinin acid, isotretinoin, isoxsuprine, isradipine (isradipine), Itraconazole, jozamitsin, potassium perman is Anat, kallidinogenase, kanamycin, kavain, Cabazon, ketamine, ketoconazole, Ketoprofen, Ketorolac, ketotifen, collagenase, creosote, labetalol, lacidipine, lactitol, lamivudine, lamotrigine, lanreotide, lansoprazole, laronidase, latanoprost, Leflunomide, lenograstim, lepirudin, lercanidipine, letrozole, leucine, leiprorelina, levallorphan, levamisole, levetiracetam, levobunolol, levobupivacaine, levocabastine, levocetirizine, levodopa, levofloxacin, levofolinate calcium, levomepromazine, levomethadyl, levonorgestrel, levonorgestrel, " levosimendan", levothyroxine, lidocaine, lincomycin, lindane, linezolid, liotironin, lisinopril, lisuride, lobelin, lodoxamide, lofepramine, lomefloxacin, lomustin, lonazolac, loperamide, lopinavir, loratadine, lorazepam oxide, lornoxicam, losartan, loteprednol, lovastatin, lumefantrin, lutropin alpha, lymecycline, lynestrenol, lypressin, lysine, magaldrate F, magnesium pidolate, magnesium L-aspartate, mangafodipir, manidipine, maprotiline, mebendazole, mebeverine, meclofenoxate provided cloxapen, meclozine, medrogestone, medroxyprogesterone, mefenamicacid, mefloquine, megestrol, melagatran, melitracen, melperone (malpura), melphalan, memantine, menadione, mepacrine, mepartricin, mephenytoin mepindolol, mepivacain, mepyramine, mequinol, mercaptamine, mercaptopurine, Meropenem, mesalazine, meso, mesterolone, Maxim is d, matuklasan, Metamizole, methamphetamine, Methenolone, Methenolone acetate, Metformin, methantheline, methazolamide, methenamine, methionine, methohexital, methotrexate, 5-methoxypsoralen, 8-methoxypsoralen, methyl-5-aminolevulinat, methylpentene bromide, methyldopa, methylergometrine, methylprednisolone, methylrosaniline, methyltestosterone, metalline chloride, methysergide, metildigoxin, metipranolol, metoclopramide, metoprolol, meteksan (matrixes), metronidazole, meksiletin, mezlocillin, mianserin, miconazole, midodrin, mifepristone, miglitol, miglustat, milnacipran, milrinone, miltefosine, minocycline, Minoxidil, mirtazapine, misoprostol, mitobronitol, mitomycin, mitotane, mitoxantrone, mevacore chloride, miwakuriyu, mizolastine, moclobemide, moexipril, molgramostim, molsidomin, mometazon, monochloracetic acid, montelukast, moroctocog alpha, moxaverine, moxifloxacin, moxonidine, mupirocin, mycophenolate mofetil, nadifloxacin, nandrolone decanoate, nadroparin calcium, naftidrofuryl, naftifine, nalbuphine, naled, nalmefene, naloxone, naloxone, naltrexone, nalbuphine, nafazolina, 2-naphthol, naproxen, naratriptan, nateglinide, sodium aurothiomalate, sodium phenylbutyrate, sodium fluoride, sodium hyaluronate, sodium iodide [131I], sodium molybdate [99Mo], sodium phenylbutyrate, N-butyl-P-aminobenzoate, N-butylscopolamine b is Omid, nebivolol, nedocromil, nefazodone, nefopam, nelfinavir, neomycin, neostigmine, neostigmine the methyl sulfate, netilmicin, nevirapine, N-heptyl-2-phenylglycinol, nicardipine, nicergoline, nicetime, Nikolin, Nicolosi, nicorandil, nicotine, nicotinic aldehyde, nicotinamide, nicotine resinate, nicotinic acid, esters of nicotinic acid, nicotinebuy alcohol, nifedipine, niflumova acid, nifuratel, nilvadipine, nimesulide, nimodipine, nimorazole, nimustine (nyastatin), nisoldipine, nitisinone, nitrendipin, nitric monoxide, nitrofurantoin, nitroglycerin, nizatidine, N-methylephedrine, nonacog alpha, nonivamide, norepinephrine, norelgestromin, norepinephrine, norethisterone, norfenefrine, norfloxacin, norgestimate, norgestrel, nortriptyline, noscapine, nystatin, obidoxime chloride, OCTAFLUOROPROPANE, oktokog alpha, octogen, octreotide, odansetron, ofloxacin, olaflur F, olanzapine, olmesartan medoxomil, olopatadine, olsalazine, omeprazole, omoconazole, ondansetron, opipramol, oral vaccine against cholera, ortsiprenalin, orlistat, argipressin, orphenadrine, oseltamivir, osteogenic protein-1: Bmp-7, oxaprozin, oxatomide, oxcarbazepine, oxedrine tartrate, oxetacaine, oxiconazole, oxilofrine, Oxytropis, 2-oxo-3-methylmalonyl acid, 2-oxo-3-methylvaleramide acid, 2-oxo-3-phenylpropionate acid, 2-oxo-4-methylvaleramide is islote, oxprenolol, oxybuprocaine, oxybutinin, oksifedrin, Oxymetazoline, oxytetracycline, oxytocin, paclitaxel, palinavir, palivizumab, palonosetron, pamidronovu acid, pancuronium (pankhuri), pantoprazole, papaverine, paracetamol, paraldehyde is recommended, parecoxib, paricalcitol, parnaparin, paromomycin, paroxetine, pefloxacin, pegfilgrastim, peginterferon Alfa, pegvisomant, pemetrexed, penbutolol, penciclovir, penfluridol, penicillamine, pentaerythrityl TETRANITRATE, pentamidine, pentetrazol, pentetreotide, pentosan polysulphate sodium, pentoxifylline, pentoxyverine, persin, perchloro acid, purpleyin, partisipant, perflutren, pergolid, perindopril, perphenazine, phenacetin, fenamate, venison, phenazopyridine, Pheniramine, phenol, phenolphthalein, phenoxybenzamine, dentists, phenprocoumon, phentolamine, phenylalanine, phenylbutazone, phenylephrine, phenylpropanolamine, phenyltoloxamine, phenytoin, phloroglucin, pholedrine, phthalylsulfathiazole, physostigmine, fitomenadion, phytosterol, picric acid, pilocarpine, pimecrolimus, pimozide, Pinnawela bromide, pindolol, pioglitazone, pipamperone, piazetta, pipecuronium bromide, piperidou acid, pipenzolate, piperacillin, piperidine, piracetam, pirarubicin, pirbuterol, pirenzepine, piritramid, piroxicam, pivmecillinam, pizotifen, podophyllotoxin, the floor is decanol, polycarbophil, polyestradiol phosphate, polymyxin B, polymyxin-B, polystyrenesulfonate acid, porfimer, primulin, primaly bitartrate, pramipexol, pranoprofen, prasterone, pravastatin, prazepam, prazosin, prednicarbate, prednisolone, prednisone, pregabalin, proglumetacin (proglumetacin), pridinol, prilocain, primaquine, primidone, procaine, procaine amide, procarbazine, procarbazine, procyclidine, progesterone, proglumetacin, proglumide, proguanil, Proline, promethazine, propacetamol, propafenone, propranolol, propicillin, propiverine, propofol, propranolol, propylthiouracil, propifenazona, Protamine, Protamine sulfate protein C, prothipendyl (prothipendyl), prothrombin, protionamide, protirelin, proxymetacaine, proxyphylline, pseudoephedrine, pulmonal, Pyrantel, pyrazinamide, pyridostigmine, mestinon bromide, pyridoxine, a 3-pyridinemethanol, pyrimethamine, pyrithione zinc, pyritinol, pyragollole, pirwani, Erwinia embonate, mercury imidachloprid, quetiapine, chinagrid, inapril, inupristin, rabeprazole, racecadotril, racephedrine, raloxifene, raltitrexed, ramipril, ranitidine, rasagiline, rasburicase, raubasine, reboxetine, Repaglinide, reproterol, reserpine, resorcinol, reteplase, retinol, reviparin, ribavirin, Riboflavin, rifabutin, rifampicin, rifamycin, rifaximin, rilmenidine, riluzole, rimexolone, risedronate acid, risperi is he, ritonavir, rituximab, rivastigmine, rizatriptan, rocuronium bromide, rofecoksib, ropinirole, ropivacaine, rosiglitazone, mercury sulfide red F, roksatidina, roxithromycin, salbutamol, salicylic acid, salmeterol, nitric acid, nitrous acid, silverin, samarium [153Sm] lexidronam, saquinavir, sulfur hexafluoride, scopolamine, selegiline, selenium sulfide, series, sermorelin, sertaconazole, sertindole, sertraline, sevelamer, sevoflurane, sibutramine, silver chloride F, sildenafil, silibinin, simvastatin, sirolimus, solifenacin, formaldehyde solution, somatostatin, growth hormone, sotalol, spalinowy acid, spartein, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptodornase, streptokinase, streptomycin, strontium ranelate, strontium chloride, strychnine, sucralfate F, sulbactam, sulesomab, sulfacetamide, sulfadiazine, sulfadimetoksin, sulfaguanidine, sulfamethazine, sulfamethoxazole, sulfamethoxydiazine, sulfometuron, sulfanilamide, sulfasalazin, sulfathiazole, sulfisomidine, sulindac, sulodexide, sulfur hexafluoride, sulpiride, sulprostone, sultamicillin, Altium, sumatriptan, suxamethonium, tacalcitol, tacrolimus tadalafil tamoxifen, tamsulosin, tasonermin, taurolidine, tazarotene, tazobactam, tegafur, teicoplanin, telithromycin, telmisartan], temozolomide, tanecka the ABC, teniposide, tenofovir, tenofovir disoproxil, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, teriparatide, terizidone, terlipressin, testosterone, testosterone propionate, testosterone undecanoate, tetracaine tetrakozaktid, tetracycline, tetrafluoroborate -1+tetrofosmin, tetryzoline, thallium chloride [201TL], theobromine, adrenalin, theophylline, tiamazol, thiamine, tietilperazin, thiocolchicoside, thiopental, thioridazine, thiotepa, threonine, thrombin, thrombokinase, thymol, thyrotropin alpha, tiagabine, tianeptine, tiaprid, tibolone, ticlopidine, tiludronic acid, timolol, Tinzaparin, tioconazole, tioguanin, Tiotropium bromide, tirilazad, tirofiban, tibouren, tizanidine, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide, tolkapon, typenamespace, tolmetin, tolperison, tolterodine, topiramate, topotecan, torasemid, toremifene, tramazoline, trandolapril, tranexamic acid, tranilcipromin, trapidil, trastuzumab, travoprost, trazodone, tretinoin, triamcinolone, triamcinolone acetonide, triamteren, trichloroacetic acid, triterpenoid, trifluoperazine, triflupromazine, trihexyphenidyl, trimebutine, trimekain, trimegestone, Trimetazidine, trimethoprim, trimipramine, tripelenamine, triprolidine, triptorelin, tritoqualine, trofosfamide, tromantadine, trometamol, Tropicamide, tropisetron, tropi, tryptophan, that is ikurrina chloride, tulobuterol, tyloxapol, tyrosine, tyrothricin, unoprostone, rapid, urapidil, urokinase, ursodeoxycholic acid, valacyclovir, valdecoxib, valganciclovir, valine, alprenolol acid, valsartan, vancomycin, vardenafil, vecuronium (vacarme), vecuronium bromide, venlafaxine, verapamil, verteporfin, vigabatrin, viloxazine, vinblastine, vincamine, vincristine, vindesine, vinorelbine, Vinpocetine, vicidin, voriconazole, satumomab, hydrogen peroxide, ksantinola nicotinate, ximelagatran, xipamide, Xylometazoline, yohimbine, yttrium90Y chloride, zalcitabine, zaleplon, zanamivir, zidovudine, zinc acetate dehydrate, zinc chloride, zinc citrate, zinc sulfate, ziprasidone, zofenopril, zoledronic acid, zolmitriptan, zolpidem, zolpidem tartrate, zonisamide, zopiclone, zotepine and zuclopenthixol (zuclopenthixol).

The above connection is marked principally by their international nonproprietary names (INNS) and is well known to specialists. More detailed information about these physiologically active substances can be found, for example, International Nonproprietary Names (INN) for Pharmaceutical Substances, World Health Organisation (WHO).

In one of the preferred options proposed in the invention, the dosage form contains one or more physiologically active substance (A)selected from the group comprising 1,1-(3-dimethylamine is-3-phenylenedimethylene)-6-fluoro-1,3,4,9-tetrahydropyrido[3,4-b]indole, primarily in the form of hemitartrate, 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, primarily in the form of citrate, and 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-toroidal, first in the form of hemitartrate. These compounds are known from the prior art (see WO 2004/043967, WO 2005/066183).

To make the proposed invention in the form of application required resistance to the destruction of it, in addition, optionally contain at least one natural, semi-synthetic or synthetic wax (D) (component (D)). It is preferable to use a wax with a softening temperature at least 50°C., more preferably at least 55°C., particularly preferably at least 60°C., most preferably at least 65°C., especially at least 70°C. Especially preferred Carnauba wax and beeswax. The most preferred Carnauba wax. Carnauba wax is a natural wax obtained from the leaves of the Carnauba (wisconsni palm trees) and a softening temperature which is at least 80°C. a Wax component with its additional use preferably be used in conjunction with at least one polymer (C) in such quantities that the resistance offered to the invention the medicament is military forms of destruction was at least 400 N, preferably at least 500 N.

As auxiliary substances (B) one can use the well-known, commonly used in the preparation of solid forms of the excipients. In the preferred embodiment, these include plasticizers such as triacetin and polyethylene, preferably low molecular weight polyethylene glycol, excipients that affect the release of active substance, preferably a hydrophobic or hydrophilic, preferably hydrophilic polymers, most preferably hypromellose and/or antioxidants. As materials for the formation of slowing down the release of physiologically active substances (prolonging) matrix, it is preferable to use hydrophilic polymers, particularly preferably ethers, cellulose, esters of cellulose and/or acrylic resin. It is most preferable to use as materials for the formation of slowing down the release of physiologically active substance matrix ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or its derivatives such as its salts, amides or esters.

For use as suitable antioxidants ascorbic acid, butalgital anisol (BHA), equivalent (OSH), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and its derivatives, sodium bisulfite, most preferably equivalent or butylhydroxyanisole and α-tocopherol.

The antioxidant is preferably used in an amount of from 0.01 to 10 wt.%, more preferably from 0.03 to 5 wt.%, in terms of the whole mass of the dosage form.

Proposed in the invention dosage forms are distinguished by the fact that their thanks to their resistance to destruction cannot be crushed into powder normal available means at hand, such as the mortar and pestle. Thus almost completely eliminated the possibility of overdose is contained in them physiologically active substances. However, proposed in the invention the dosage form to further improve their resistance to destruction may contain as excipients (B) additional increase fracture resistance of the tool.

Proposed in the invention of the dosage form in the preferred embodiment, is a solid dosage form suitable for oral, vaginal or rectal, preferably oral administration. In a preferred embodiment of the proposed invention in dosage form does not t aetsa film. In yet another preferred embodiment of the proposed invention in dosage form presented in the form of tablets, capsules or in the form of an oral osmotic therapeutic system (POTS).

In a more preferred embodiment of the proposed invention in dosage form presented in the form of tablets.

The proposed invention in dosage form can be represented in the dispersion (solids), preferably in the form of microtablets, microcapsules, micropellets, granules, spheroids, pellets or pellets, not necessarily packaged in capsules or compressed into tablet form, preferably for oral administration. In such dispersed forms of the individual particles as such, as well as perhaps made of them, the tablet preferably should also have a resistance to the destruction of at least 400 N.

In a preferred embodiment, the particle size, respectively, the polydispersity of these dispersed forms of application lies in the range from 0.1 to 3 mm, most preferably from 0.5 to 2 mm depending on the desired properties of the dosage form for its preparation in some cases you can also optionally use the usual auxiliary substances (B).

The proposed invention in dosage form can be prepared asnami ways, which are described in more detail below. Accordingly, the invention relates also to the application forms, prigotavlivaemy these methods.

Cooking method proposed in the invention the dosage form in the preferred embodiment is that

(a) mix between a component (A)may be used, the component (B), component (b) and possibly used component (G),

(b) obtained in stage (a) the mixture is optionally subjected to preliminary molding, preferably by thermal impact on her and/or by application to her efforts, and the supplied amount of heat should preferably be sufficient to heat the component (C) to the temperature of its softening,

(C) mixture is allowed to harden by heat on it and by the application thereto efforts to supply this heat to the mixture during and/or before the application for her efforts in sufficient quantity to heat the component (B) at least up to the temperature of its softening,

(g) the solidified mixture, if necessary, divided into separate parts,

(d) optionally molded dosage form and

(e) if necessary, put on her film coating.

Heat can lead to a mixture by direct heating or by heating by ultrasound. For application to the mixture in the Elijah and/or for forming from her dosage forms can be used, for example, the installation for direct tabletting or acceptable extruders, primarily dvuhjarusnye (twin-screw) extruder or planetary roller extruders.

The following are the preferred methods of preparation proposed in the invention the dosage form.

Method 1

In this embodiment of the proposed invention in dosage form preferably prepared without the use of an extruder, which in the preferred embodiment, component (A)may be used, the component (B), component (b) and possibly used component (G) is mixed among themselves and from the mixture obtained, in some cases, after granulation, by application of force with the prior or simultaneous heat molded dosage form.

In the preparation of the dosage form in such a way to heating and application efforts are not using an extruder.

For mixing the component (A)may be used of the component (B), component (b) and may be used of the component (D) use a known mixer. Such a mixer may represent, for example, rotating the mixer, vibromaster working with the creation of shear forces mixer or mixer forced mixing.

The resulting mixture is preferably directly settlement is e its preparation by application of force with the prior or simultaneous heat molded proposed in the invention of the dosage form. So, for example, of a mixture by direct tabletting can be molded tablets. With the direct pelletizing with simultaneous heat moldable mixture using a tablet form, i.e. the lower (stationary) punch, the upper (movable) of the punch and die is heated at least up to the softening temperature of the polymer component (C) and pressed. With the direct pelletizing with pre-heat moldable material is heated immediately prior to pelletizing at least up to the softening temperature of the component (b) and then pressed using a tablet form.

For example, in tablet form, consisting of a lower die, the upper punch and the matrix of the powder mixture, excerpted portions 300 mg, can be extruded at a temperature of 80°C tablets with a diameter of 10 mm and a radius of curvature of convex surfaces 8 mm, while maintaining the applied mixture to a pressing force of, for example, of 2 kN or 4 kN, within, for example, 15 S.

The mixture of component (A)may be used of the component (B), component (b) and may be used of the component (G) can also first be pelletized and then molded from the obtained granulate by application of force with the prior or simultaneous t is ploym the impact of the proposed invention in dosage form.

Each application efforts molding its action remain up until the dosage form reaches a hardness at which its resistance to fracture is at least 400 H, 420 N., 440, 460 N or 480 N, preferably at least 500 N.

The granulation can be carried out by the method of wet granulation or pelletization of the melt in a known granulators.

Each of the above stages of the preparation method proposed in the invention the dosage form, first stage heating and simultaneous or subsequent application of force, perform without the use of the extruder.

Method 2

In this embodiment of the proposed invention in dosage form prepared by thermoforming using an extruder without the changes the color of the extrudate.

To determine the extent caused by such thermoforming discoloration first determine the color of the mixture of initial components included in the dosage form, but without the addition of give color component, for example, a color pigment or with its own color component (such as α-tocopherol). This composition is then subjected according to the invention thermoforming parts, carrying out all stages of the process, including cooling the extrudate, in the atmosphere of inert gas. For comparison, t is coy same composition is subjected to thermoforming the same way but not in the atmosphere of inert gas. Next, determine the color of both prepared from the same original compositions of applications, one of which was received in accordance with the invention, and the other for comparative purposes. To determine the color use satin colors "Munsell Book of Colour", published in 1966 by the company Munsell color Company, Baltimore, Columbia, Maryland, USA. If obtained in accordance with the invention by thermoforming dosage form has a color ID 9,5 N/, and the maximum color ID 5Y 9/1, thermoforming process are classified as mesoprosodes change color. If the dosage form after thermoforming is defined according to the Atlas of flowers "Munsell Book of Colour" color ID 5Y 9/2 or more, thermoforming process is regarded as accompanied by a colour change.

With the invention it has been unexpectedly found that its proposed dosage forms do not show any classified by the method described above color change, if the whole process of their preparation is carried out in an atmosphere of inert gas, preferably nitrogen, using thermoforming extruder.

This proposed invention, the preparation method proposed in the invention forms application differs in that

1) component (A)may be used, the component (B), component (b) and possibly used component (G) is mixed among themselves,

2) the resulting mixture is heated in the extruder at least up to the softening temperature of the component (b) and by application of force ekstragiruyut outlet of the extruder,

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

4) of the cooled and if necessary, re-heated is divided into separate parts of the extrudate is formed into the dosage form, while stage 2) and (3) and optional stage 1) and 4) in an atmosphere of inert gas, preferably nitrogen.

The mixture of components in stage 1) may also occur already in the extruder.

For mixing the component (A)may be used of the component (B), component (b) and may be used of the component (G) can also be used a known mixer. Such a mixer may represent, for example, rotating the mixer, vibromaster working with the creation of shear forces mixer or mixer forced mixing.

Component (b) and possibly used component (G) before mixing with the other components according to the invention is preferably combined with the antioxidant. To this end both components (C) and (D) you shall be mixed with the antioxidant, in the preferred embodiment, the antioxidant is dissolved or suspended in a volatile solvent, the resulting solution, respectively, the resulting slurry is then to homogeneity mixed with component (b) and may be used by the component (G) and finally by drying, preferably in an atmosphere of inert gas, to remove the solvent.

Heated in the extruder at least up to the softening temperature of component (C), and preferably the molten mixture is extruded from the extruder through his head with at least one channel.

For carrying out the invention the method according to this option, you must use the appropriate extruder, preferably a worm (roll) extruders, particularly preferably dvuhjarusnye (twin-screw) extruder.

The extrusion is preferably carried out in a mode in which the degree of swelling (increase in cross-sectional dimension) of the extrudate after extrusion preferably should not exceed 50%, which means that, for example, using an extrusion head with the diameter of the outlet 6 mm extrudate must have a maximum diameter of 9 mm, More preferably the degree of swelling of the extrudate should not exceed 40%, particularly preferably 35%, most preferably 30%, especially 25%. When creating the invention of neojidan is installed, what at too a high mechanical load on the extrudable material in the extruder, there is a significant increase in the transverse dimensions of the extrudate, which leads to undesirable oscillation properties, especially mechanical properties of the extrudate.

In a preferred embodiment, the extruder must be at least two temperature zones, the first of which, adjacent to the boot and possibly prescribed mixing zone, the mixture is heated at least up to the softening temperature of the component (B). Consumption moldable mixture in the preferred embodiment, is from 2.0 to 8.0 kg/h

After heating the mixture to at least the softening temperature of component (C), the molten mixture is moved in the extruder his worm or worms, continues to gomogeniziruetsya, komprimerede, respectively sealed, just before reaching the exit of the extrusion head of a minimum pressure of 5 bar, preferably at least 10 bar, and depending on the number of channels (holes) in the extrusion head squeezed through it in the form of one or several of the extrudates. The extruder can be equipped with a head with any profile of the channel, respectively, of the channels in it. Thus, in particular, the channel, respectively, the channels in the extrusion head may(-the ut) to have a round cross-section, preferably a diameter of from 0.1 to 15 mm, oblong cross-section, preferably with a maximum longitudinal length of 21 mm and a transverse length of 10 mm or oval cross-section. It is preferable to use an extruder die with a channel, respectively channels of circular cross section. Used according to the invention, the extruder may be heated or cooled case. The corresponding temperature control housing of the extruder, i.e. heating or cooling depends on the average temperature of the extrudable mixture (product temperature), which (temperature) must not be lower than the softening temperature of component (C), but must not exceed the temperature above which can happen invalid change the properties of the processed physiologically active substance (A). With this in mind, the temperature of the extrudable mixture is preferably kept below 180°C, more preferably below 150°C, but not lower than at least the softening temperature of the component (B).

After extrusion of the molten mixture, and optionally cooling the resulting extrudate, respectively, of the obtained extrudates his(their) preferably be split into separate parts. This separation of the extrudate(s) into separate parts in the preferred embodiment, may be his(their) cutting volatile or in adaushkina knives, waterjet cutters, wires, blades or laser cutters.

For the interim, so the final storage of the extrudate or divided into separate parts of the extrudate, respectively, are provided in the invention forms application does not require the creation of an atmosphere of inert gas.

Divided into separate parts extrudate conventional methods can be subjected to granulation or pelletizing to give the form of the implementation of the final geometric shape. In another embodiment, having the form of a rod extrudate can not be divided into separate parts, and be calandrinia passing through rotating in mutually opposite directions rolls, which on their side surfaces are placed against each other profile deepen, bringing the extrudate in this way a profile that corresponds to the final contour dosage forms, preferably tablets, then separated from the rest of the extrudate by conventional methods.

In the case when the extrudate or divided into separate parts of the extrudate is not immediately subjected to molding to give it a profile that corresponds to the final shape of the dosage form, and is first cooled to the intermediate store, after further processing of the extrudate must p is boditi in the atmosphere of inert gas, preferably nitrogen, which is required to keep from heating the stored intermediate extrudate until the completion of its softening and final molding from him the dosage form.

The force applied in the extruder to at least by plasticized mixture, set the speed control and the selection of the geometry of the conveying device (worm) in the extruder, and by choosing the dimensions of the outlet of the extruder so that the pressure in the extruder is preferably immediately prior to extrusion by plasticized mixture has reached the necessary level. The extrusion parameters required to obtain the dosage form of resistance to the destruction of at least 400 N, preferably at least 500 N, can be determined for each specific composition of conduct simple preliminary experiments.

For extrusion can be used, for example, dvuhseriynyy extruder type Micro 27 GL 40 D company Leistritz (Nuremberg) worms diameter 18 mm you can use worms with eccentric ends. As the extrusion head, you can use a heated extrusion head with a channel of circular or annular cross-section and a diameter of 8 mm, the Whole process should be carried out in a nitrogen atmosphere. For EXT is usii you can use the following parameters: speed worms: 100 rpm capacity: 4 kg/h, the product temperature: 125°C housing temperature of the extruder: 120°C.

Method 3

In this embodiment, for the preparation of the proposed invention the dosage form of heat down to the moldable mixture by heating up ultrasound.

To do this, first prepare a homogeneous mixture of at least component (a) and component (B) (performing the function of the binder). To this mixture, you can add other excipients, such as fillers, plasticizers, slip agents or dyes. As the plasticizer, it is preferable to use low molecular weight polyethylene glycol.

The process of mixing can be carried out in conventional mixers. As examples, rotary mixers, also known as gravitational, drum or rotary mixers, container mixers, eccentric faucets (faucets with Ren wheel or swing faucets, respectively mixers type "drunken barrel") or vibronically working with the creation of shear forces faucets, mixers forced mixing, mixers mixer with lemasney blades, planetary mixers, kneading-type mixer with a Z-shaped blades, mixers with sigmaprime blades, centrifugal mixers or mixers intense action

The choice of type of mixer is determined inter alia by the flowability of the mixed material and the forces of cohesion in him.

The mixture is then subjected to molding. The mixture is preferably subjected to molding, preferably by compression or molding, during or after exposure to ultrasound.

When exposed to the mixture with ultrasound is most preferable to provide direct contact between it and the sonotrode of an ultrasonic device. In the preparation of dosage forms that proposed in the invention method, it is preferable to use an ultrasonic device, schematically shown in figure 1.

In figure 1 the position 1 labeled press, allowing you to develop the necessary pressing force applied to the moldable mixture, position 2 indicated Converter, position 3 marked power, position 4 marked the sonotrode, position 5 indicated matrix for shaping, position 6 marked the bottom punch, the position of the 7 designated plate-base or base plate, and the positions (8) and (9) indicate, respectively, the ultrasonic generator and the control system is an ultrasonic device. These positions belong exclusively to 1.

To the mixture, it is preferable to effect ultrasonic vibrations with a frequency ranging from 1 kHz to 2 MHz, more PR is doctitle from 15 to 40 kHz. The influence of ultrasound on the mixture should continue until softening of the polymer (B). In a preferred embodiment, the duration of exposure of the ultrasound into the mix is a few seconds, especially preferably from 0.1 to 5, most preferably from 0.5 to 3 C.

The effect on the mixture with ultrasound and the Annex thereto the necessary efforts to provide a uniform supply to her energy, which creates conditions for rapid and homogeneous sintering. In this way receive a dosage form, which have resistance to the destruction of at least 400 N, preferably at least 500 N, and which thus cannot be crushed into powder.

At the stage of molding the mixture upon completion of the process of mixing can be pelletized and then molded from the obtained pellets, influencing them by ultrasound and applying to them the necessary effort, dosage forms, such as tablets.

The granulation can be carried out in known machines and apparatus (granulators).

When the granulation method of wet granulation as a granulating liquid, you can use water or aqueous solutions, such as, for example, water-ethanol or water-isopropanol solutions.

The mixture or prepared from the granules can also be used for further forming podvergayuschimsya in the molten state, to which the mixture is exposed to ultrasound with application to her efforts melted and then ekstragiruyut through the extrusion head. Thus obtained extrudates or thus obtained extrudate by using known devices to be divided into separate parts required length (measured pieces). Then thus obtained separate molded workpiece can be subjected to further processing, if necessary, when exposed to ultrasound and application efforts in dosage forms with final geometry.

Such final shaping with getting ready applications it is preferable to carry out the appropriate forms with the application the required effort.

The above-described molded workpiece can also be obtained by calendering method, which first mixture, respectively prepared from the granules plasticity, affecting ultrasound and putting the necessary effort, and then ekstragiruyut through the extrusion head. The resulting extrudate is passed between two rotating in mutually opposite directions shaped rollers, preferably with the necessary effort, bringing the extrudate thus the final profile.

As mentioned above,a finished dosage form formed of a mixture, preferably from a powder mixture containing a physiologically active substance (a) and the polymer (B) with resistance to the destruction of at least 400 N, preferably at least 500 N, by direct compaction by application thereto of the respective efforts with prior or concurrent exposure to this mixture with ultrasound. Apply the mixture to force the maximum corresponds to the force, which is usually used for molding applications, for example, tablets, respectively, for the crushing of granular materials in extruded products with the corresponding final geometry.

Proposed in the invention method can also produce multi-layered tablets.

When manufacturing such a multilayer tablets effects of ultrasound and appropriate efforts should be subjected to at least one layer which contains a physiologically active substance (A).

Apply mixture to the required effort, you can also use worms extruder or calender rolls. It is preferable to produce the dosage form by direct pressing of the powder mixture consisting of the components of the dosage form, or relevant, obtained from the mixture of granules, preferably with simultaneous or prior exposure to with the offer or pellets ultrasound. Similar effects of ultrasound continue to softening of the polymer (C), which usually requires from less than 1 up to a maximum of 5 C.

As the press in this embodiment can be used, for example, pneumatic press Branson WPS 94-003 (firm Branson Ultraschall, Dietzenbach, Germany) with a flat working (pressure) surface, and as the ultrasonic generator you can use the analog generator (2000 watt) Branson PG-220A, 94-001 (firm Branson Ultraschall) with a sonotrode with a diameter of 12 mm, it is possible to use a matrix with a diameter of 12 mm, the bottom of which forms the bottom punch with a flat working surface with a diameter of 12 mm, Plastication can be performed with the following parameters: frequency: 20 kHz, amplitude: 50%, air force: 250 N. The effect on the mixture with ultrasound preferably with simultaneous application of appropriate forces with the help of the sonotrode can take, for example, 0.5 C.

Method 4

In this embodiment, for the preparation of the proposed invention the dosage form component (A), component (b) and possibly used component (G), and probably used auxiliary substances (B), such as antioxidants, plasticizers and/or retarding the release of physiologically active substances (prolonging) excipients, process on planetary roller extruder.

The planetary-roller EXT Edery known and are described inter alia in the Handbook Handbuch der Kunststoff-Extrusionstechnik I (1989), "Grundlagen", Chapter 1.2 "Klassifizierung von Extrudern" ("Classification of extruders"), S. 4-6. The relevant sections of this publication is hereby incorporated into this description by reference and should be considered as part of it.

Following application of the planetary roller extruder for preparation of the proposed invention the dosage form of the method according to this variant is illustrated with reference to figure 2 and 3. All such explanations are purely illustrative and do not limit the scope of the invention.

Figure 2 planetary roller extruder is shown in longitudinal section, and figure 3 planetary roller extruder is shown in cross section, illustrating the principle of its action.

Figure 2 shows the planetary roller extruder, which can be used for the formulation proposed in the invention by the method according to this variant. This extruder has a shaft 1, which is in the direction of movement of the extrudable mixture of the above components is first made in the form of feed worm 5, and then executed in the form of a Central screw nut 3 planetary roller extruder. Around the center of the worm 3 in the preferred embodiment, there are from three to seven planetary worms 4, which, in turn, is surrounded by a casing B. Below with reference to figure 2 is considered the preferred process sentence is the service of the pharmaceutical dosage form proposed in the invention method by extruding its components using a planetary roller extruder. Extrudable components in the arrow 2 direction to go in the dispenser 7, dosed them in the area of supply of the worm 5 and further due to its rotation (drive not shown) are moved them in the direction of a Central screw nut 3. Obviously, the mixing of raw materials (components) may occur in the area of feed screw nut. However, the components of the dosage form can also be pre-blended and serve dispenser 7 the mixture in the feeding area of the worm 5. The feed worm mixture is conveyed further through the feeding part of the planetary roller extruder. As a result of heating to at least the softening temperature of the component (B) mixture is melted and then the molten mixture enters the Central area of the worm, i.e. extrusion part where it is due to the interaction between a Central screw nut 3 and the planetary worms 4 moves them further, continues to gomogeniziruetsya, komprimerede, respectively compacted and depending on the number of channels (holes) in the extrusion head 8 is extruded through it in the form of one or several of the extrudates. The extruder can be equipped with a head with any profile of the channel, respectively, of the channels in it. Thus, in particular, the channel, respectively, the channels in the extrusion head is E. may(may) have a round cross-section, preferably a diameter of from 0.1 to 15 mm, oblong cross-section, preferably with a maximum longitudinal length of 21 mm and a transverse length of 10 mm or oval cross-section. The extrusion head may be made in the form of a slit head. It is preferable to use an extruder die with a channel, respectively, channels, round, oval or oblong cross-section. I used according to the invention the planetary roller extruder, the housing 6, as well as the Central worm can be made to be heated or cooled. The corresponding temperature control housing of the extruder and/or the Central worm, i.e. heating or cooling depends on the average temperature of the extrudable mixture, which temperature must be not lower than the softening temperature of component (C), but must not exceed the temperature above which can happen invalid change the properties of the processed physiologically active substance (A). With this in mind, the temperature of the extrudable mixture is preferably kept below 180°C, more preferably below 150°C, but not lower than at least the softening temperature of the component (B). The above positions are purely to 2 and 3.

After extrusion of the molten mixture, and optionally cooling the resulting extra the ATA, accordingly, the obtained extrudates his(their) were split into separate parts that are not shown in figure 2. This separation of the extrudate(s) into separate parts in the preferred embodiment, may be his(their) cutting volatile or rotating blades, water-jet cutters, wires, blades or laser cutters.

The extrudates after their separation into separate parts, preferably on a separate part of the discoid form, if necessary, subjected to further cooling and then in some cases, if necessary, re-heating is subjected to molding, giving them the final geometric shape of the finished dosage form.

Such molding, for example, tablets may be in the transmission and thereby the crushing plastic extrudate between two driven in rotation in mutually opposite directions rollers, which on their side surfaces are placed against each other and serve primarily to the softening of the die cavities, the profile of which corresponds to the final shape of the tablets.

In addition, after the separation of the extrudates into separate parts can also be molded from each of them tablets, using a matrix that can be performed heated, and at least the Dean forming punch. For this purpose, the extrudate is preferably divided into separate cylindrical pellets. Such granules or other get in dispersed form or in particulate form, such as pellets or spheroids, in addition to pressing of these tablets can also be packaged in capsules and in this form to use in future as prepared proposed in the invention by way of the dosage form.

In another preferred embodiment, obtained by extrusion through an extrusion head with multiple channels extrudates can optionally after cooling by weave or twist similar to the production of ropes combined into one harness greater compared to separate extrudates thickness. In the following, this harness can be processed by its division into separate parts and molding, if necessary, to soften by wetting acceptable solvent or by heating to the softening temperature of the polymer (b) and optionally with subsequent removal of the solvent, in the same way as described above for processing individual extrudates.

Figure 3 shows a planetary roller extruder cross section. In this extruder rotating around the Central screw nut 3 is at least three, as shown in the drawing example, six PLA is Yarnykh worms 4, lateral (screw) surface 41 which communicate, at first, with lateral (screw) surfaces 31 of the Central screw nut 3 and, secondly, with lateral (screw) surfaces 61 inside the housing 6 of the planetary roller extruder. During the rotation of the Central screw nut 3 and the rolling of the respective lateral (screw) surfaces one on each of the other planetary worms 4 rotates around its own axis as indicated by arrow 42 toward and around the center of the worm 3 in the arrow 43 direction. It provides necessary according to the invention, compression, respectively, the seal used according to the invention mixtures of preparing dosage forms. The above positions are purely to 2 and 3.

If necessary, you can use the planetary roller extruder having not only one extrusion part, but at least one more part in which optionally may also occur degassing extrudable mixture.

Proposed in the invention the method according to this variant can be performed in batch or continuous mode, preferably in a continuous mode.

As the extruder in this embodiment can be used, for example, a planetary roller extruder type BCG 1 firm LBB Bohle (Ennigerloh, Germany) with four planetary worms and extrusion head with a diameter of 8 mm. the Components of the extrudable mixture, respectively ready extrudable mixture can gravimetrically dosed in such an extruder with a flow rate of 3.0 kg/h Extrusion can be performed, for example, when the rotational speed of 28.6 rpm and when the product temperature of about 88°C.

Method 5

In this embodiment, for the preparation of the proposed invention the dosage form of at least components (a) and component (B), and component (G) and optionally used auxiliary substances (B), such as antioxidants, plasticizers and/or retarding the release of physiologically active substances, excipients, processed into dosage form with addition of a solvent component (C), i.e. the polymer (or polymers (B).

For this component (A)may be used, the component (B), component (b) and possibly used component (G) is mixed among themselves and from the mixture obtained after adding the solvent, and optionally after granulation is formed into dosage form.

For mixing the component (A)may be used of the component (B), component (b) and may be used of the component (D) use a known mixer. Such a mixer may represent, for example, the filing mixer, vibromaster working with the creation of shear forces mixer or mixer forced mixing.

The solvent of the polymer (B) add at least in such quantities that ensure uniform hydration of the mixture components of the dosage form.

As a solvent of the polymer (B) it is preferable to use an aqueous solvent such as water, mixtures of water and aliphatic alcohols, preferably alcohols with C1-C6esters, ethers, hydrocarbons, most preferably distilled water, alcohols, short-chain, such as methanol, ethanol, isopropanol, butanol or aqueous solutions of alcohols.

The solvent is preferably added with stirring. After adding the solvent evenly moistened them the mass is dried. Drying is preferably conducted by means of supplying heat to the mixture by heating to a temperature at which excluded the change in its color. This temperature can be determined by simple preliminary experiments.

Before or after drying, the mixture can be divided into individual portions, preferably on separate portions, each of which corresponds to the mass of a single dosage form. From these individual portions after appropriate drying then formed into dosage forms.

For such molded who I am, it is preferable to use a tablet press.

Another possible method of moistening the mixture components of the dosage form is in the separation of the mixture before the addition thereto of a solvent in individual portions, preferably in the distribution of the mixture separate portions according to the forms in subsequent dispersion in a liquid dispersant under stirring and then adding a solvent. Component (C) must be insoluble in the dispersant, which must be miscible with the solvent.

As the dispersant, it is preferable to use hydrophilic solvents, such as aliphatic alcohols, ketones, esters. Particularly preferable to use alcohols with a short chain.

Another possible method of moistening the mixture components of the dosage form is the introduction of a mixture of a solvent in the form of foam. For such foaming of the solvent, it is preferable to use a rotating high frequency mixer, preferably with the addition of conventional stabilizers foam. For use as such stabilizers are suitable, for example, hydrophilic polymers such as hypromellose.

Foamed solvent preferably also enter into the mixture components of the dosage form during the mixing process preferably results in a granular mass.

Such granular annoy mass before or after its division into individual portions, preferably on separate portions, each of which corresponds to the mass of a single dosage form, being dried and then formed her dosage forms.

Drying and molding preferably by the method described above. When preparing proposed in the invention the dosage form of the method according to this variant to the mixture of its components, the solvent can also be added in such quantities, in which are formed suitable for molding paste.

Like pasta before or after drying, you can perform the above-described method, can be divided into individual portions, each of which, after drying and, if necessary, after further division into smaller portions, each of which corresponds to the mass of a single dosage form, processed by molding or plastic deformation in the dosage form.

For individual portions can be shaped in the form of rods or bars which can be obtained by using sieves or Kegel machine. Such rods after drying is preferably divided into separate parts and mould of these dosage forms. For such molding is preferable to use a tablet press, the forming rolls or equipped with rollers forming belt conveyors.

In addition, the paste can also be processed in p is oski sheet material (planar structure) and then after drying to cut down from it dosage forms.

The paste should preferably be processed in the extruder, which depending on the type of extrusion heads, respectively, form channels it allows to obtain the above rods or flat sheet materials, which by their felling or cutting, respectively stamping divided into separate parts. These separate parts then by the above-described molding, plastic deformation or cutting can be processed into finished dosage forms. Appropriate devices for performing such operations are well known.

Proposed in the invention the method according to this variant can be performed in continuous or batch mode.

To the mixture components of the dosage form, the solvent can also be added to the amount at which the dissolution occurs at least a polymer component (B). The resulting solution or the resulting dispersion/suspension is preferably processed into a flat sheet material, for which purpose it is preferable to use an extruder with a flat head or pour solution on a flat, smooth substrate or base.

After drying method described above from flat sheet material by cutting or calendering to obtain a finished dosage forms. In addition, the solution can also by the method described above peerabad is to rods, to separate them, preferably after drying on a separate part and mould of them finished dosage forms.

In another embodiment, the solution can also be divided into individual portions, after drying, of which the mass of each of them corresponds to the weight of one of the finished dosage form, for which the solution is preferable to distribute the forms, the configuration of the cavity which corresponds to the geometric shape of one dosage form.

When splitting the solution into any number of portions of their after drying if necessary, you can re-unite and prepare from them, dosage form, for example, packaged in capsules or pressed into tablets.

Solvent mixture of the components of the dosage form preferably be processed at temperatures in the range from 20 to 40°C, without using elevated temperatures except for the required drying temperature to remove solvent and may present dispersant. The temperature for drying is necessary to choose below the temperature of decomposition of the components of the dosage form. If necessary, after forming the dosage form additionally can be subjected to drying in accordance with the above recommendations.

For preparation of the proposed invention the dosage form can also use the combination of each individual stage of the above methods.

The above-described methods 2 and 4 involve the extrusion of the composition containing the component (A), component (C)may be used, the component (B) and optionally component (D). As the extruder while it is preferable to use dvuhjarusnye extruders or planetary roller extruders, particularly preferably dvuhjarusnye extruders.

With the invention it has been unexpectedly found that the planetary-roller and dvuhjarusnye extruders allow to obtain extrudates with a preferred morphology. Thus, in particular, it was found that under appropriate conditions it is possible to obtain an extrudate, which side surface is formed by covering it around the entire circumference of a kind extruded surface layer. It is about having a form of a tubular shell structure, which circumferentially encompasses the extrudate along the longitudinal axis of extrusion and the outer surface which thereby forms a continuous lateral surface of the extrudate. This extrudate extruded surface layer is not usually covered only his ends.

In his morphology of the extruded surface layer differs from the inner part (core) of the extrudate, which it covers the type of shell and with which it is connected mostly seamless. Usually castrogiovanni surface layer can be seen in the cross section of the extrudate to the naked eye, and in some cases under a microscope, because the core and extruded surface layer due to differences in the morphology of the forming of these materials differ in their optical properties. Probably as a result of the extrusion process forming the extruded surface layer material is subjected to other mechanical, accordingly, thermal stress, rather than forming the core of the extrudate material than is due to receive the extrudate with heterogeneous, radially symmetric when using the extrusion head with a channel of circular cross-section morphology. In addition, the material forming the extruded surface layer, and the material forming the core and differ mainly by their morphology, but preferably not in its composition, primarily neoclassically content of the component (A), component (C)may be used of the component (B) and optionally the component (D).

Usually extruded surface layer covers the entire side surface of the extrudate in the form of solid, tubular shell, regardless of the cross-sectional shape of the channel of the extrusion head. Thus, in particular, the extrudate may have a cross-section of the circular, elliptical or other shape.

Extruded surface layer preferably should in order to have a uniform thickness. The thickness of the extruded surface layer should preferably be from 0.1 to 4.0 mm, more preferably from 0.15 to 3.5 mm, especially preferably from 0.2 to 3.0 mm, most preferably from 0.2 to 2.5 mm, especially 0.2 to 2.0 mm. In one of the preferred options extruded surface layer has a thickness, which is total on both opposite sides of the extrudate falls from 0.5 to 50%, more preferably from 1.0 to 40%, particularly preferably from 1.5 to 35%, most preferably from 2.0 to 30%, especially from 2.5 to 25%, of the total diameter of the extrudate.

Figure 4 schematically shows the extrudate 71 having a form of shell extruded surface layer 72, which completely covers the core 73 of the extrudate along the longitudinal axis 74 of its extrusion. The outer surface of the extruded surface layer 72 forms a side surface 75 of the die 71.

With the invention it has been unexpectedly found that extrudates with such extruded surface layer have preferred mechanical properties. Such extrudates optimal for further processing, first of all by their division into separate parts and/or molding, and therefore, the most suitable as intermediates in the preparation of proposed izaberete the AI application forms.

When preparing proposed in the invention forms application by extrusion, in which as an intermediate product is obtained as described above, characterized by the presence of extruded surface layer extrudate, obtained from the dosage form in the preferred embodiment is also characterized by special morphology.

In a preferred embodiment, those parts which in the extruded intermediate product was formed extruded surface layer, are also visible in the cross-section of the dosage form to the naked eye, and in some cases under a microscope. This is due to the fact that the further processing of the extrudate, primarily through its division into separate parts and/or molding, differences in the structure of the core material and the material of the extruded surface layer, and thus differences in their optical properties are usually saved. In the following description, the portion of the dosage form, which in the course of further processing of the extrudate (intermediate product) in the dosage form formed from extruded surface layer, referred to as "shell".

In a preferred embodiment of the proposed invention in dosage form has a shell portion and located inside the core. When this shell is part mostly seamless connected with the core. Shell portion and the core should preferably have basically the same chemical composition, i.e. mainly the same relative content of the component (A), component (C)may be used of the component (B) and optionally the component (D). Forming a shell part material has a morphology that is different from the morphology of forming the core material. Usually such differences in morphology are evident in the differences in optical properties, and therefore shell portion and the core in most cases can be distinguished in the cross-section of the dosage form already with the naked eye.

The proposed invention the dosage form coated with, for example, film coating, the shell portion is located between it and the core.

Because the extrudate (intermediate product) with extruded surface layer can be further processed in the proposed invention the dosage form in a variety of ways, the location and the length of the shell part in the proposed invention in the form of application can also be different. However, regardless of the location of the shell part, it partially covers the surface of the core, but usually not the whole of its surface. Shell part mostly not covered, or at least not totally the Yu-covered surface of the core with its two opposite (face) of the parties. In other words, the shell part primarily there are two located against each other holes/cut-outs.

Shell portion may have a uniform thickness. However, when processing the extrudate in a dosage form different parts of the extruded surface layer due to deformation or deformation of the extrudate (e.g., pressing) can also be compressed or stretched in different size, and therefore the thickness of the shell part may vary within a single dosage form.

Shell portion preferably should have a thickness in the range from 0.1 to 4.0 mm, more preferably from 0.15 to 3.5 mm, especially preferably from 0.2 to 3.0 mm, most preferably from 0.2 to 2.5 mm, especially 0.2 to 2.0 mm

On figa and 5B schematically show two proposed invention the dosage form with the preferred location they shell part. Both dosage forms 81 are shell portion 82, which partially enclosed the core 83. Core surface 83 on both of its opposite sides a and 84b, however, not covered shell part 82.

Cooking method proposed in the invention the dosage form is preferably carried out in continuous mode. In the preferred embodiment, this method is extrusion Homo the military a mixture of component (A), component (C)may be used of the component (B) and optionally the component (D). Resulting intermediate product, such as extrudate, in the preferred embodiment, must have uniform properties in its longitudinal and transverse directions.

Most desirable for obtaining an intermediate product with a uniform density, uniform distribution of physiologically active substances, with homogeneous mechanical properties, with uniform porosity, with uniform surface properties, etc. Only under these conditions can also provide all forms of application uniformity of pharmacological properties, such as the constancy of the release characteristics of physiologically active substances, and thus to maintain the percentage of defects at a low level.

In the implementation proposed in the invention method, the share of marriage should preferably be less than 25%, more preferably less than 20%, most preferably less than 15%, especially less than 10%of the total number of received application forms, criteria otbrakovyvanie which are thus determined by the Management standards on quality control of food, drugs and cosmetics (USA), defining requirements for the variability of the content of the project component (A), the profile of its release and/or density of the dosage form when comparing between the two forms of application, which should preferably be selected from the same batch.

With the invention it has been unexpectedly found that the above properties can be obtained by processing the mixture components of the dosage form on dvuhserijnyj extruders and planetary roller extruders, most preferably dvuhserijnyj extruders.

Proposed in the invention method in a preferred embodiment provides for the extrusion of a mixture of component (A), component (C)may be used of the component (B) and optionally the component (D), preferably using a planetary roller extruder or dvuhseriynogo extruder. The resulting extrusion, the extrudate is preferably further divided into separate parts, mould and, if necessary, to provide the coating with obtaining in this way the finished dosage form.

In one of the preferred options proposed in the invention method, the mixture of component (A), component (C)may be used of the component (B) and optionally the component (D) is formed in plastinirovannogo condition. With the invention it has been unexpectedly found that during extrusion of certain polymer is (In), primarily of oxides with high molecular weight, get intermediate products, manifesting a certain memory effect, i.e. a certain effect of restoring the original shape, namely, in forming, for example, for pressing, divided into separate parts of the extrudates at ambient temperature get dosage forms, which when stored in extreme conditions exhibit a tendency to take its original external form, i.e. to return to the form they had before molding.

The instability of the external shape of the finished dosage form when stored in extreme conditions, for example at a temperature of 40°C and 75%relative humidity, may be due to other reasons.

The memory effect significantly affects the stability of the dosage form during storage, because when restoring dosage form its original external shape is changing many of its properties. This refers to any change in dosage form its external shape otherwise.

In the claimed invention, it was found that, for example, depending on the extrusion conditions is significant swelling (increase in cross-sectional dimension) of the extrudate, which is accompanied by an increase in its volume, i.e. the reduction of its tightly the tee. Such a die swell can be compensated by subsequent pressing divided into separate parts of the extrudate at a sufficiently high pressure, since under these conditions, the remaining material can be returned to the original size.

However, during the pressing process at ambient temperature memory effect results when storing compressed or compacted extrudate to its swelling and expansion, which dosage form is greatly increased in volume.

With the invention it has been unexpectedly found that such a memory effect can be suppressed when forming divided into separate parts of the extrudate at elevated temperatures, i.e. in plastinirovannogo state mixture component (A), component (C)may be used of the component (B) and optionally the component (D). The molding thus preferably when the force or pressure molding at least 1 kN, more preferably when the force or pressure in the range of 2 to 50 kN, for example, on a tablet press. It is preferable to carry out the molding at the temperature of about 40°C., more preferably about 30°C., especially about 25°C below the melting temperature of the mixture of the component (A), component (C)may be used of the component (B) and the possible used of the component (G). The melting point of the mixture of a given composition can be determined by traditional methods, preferably by differential scanning calorimetry (DSC) (for example, using a calorimeter DSC model 2920, TA Instruments, new castle), using ultra-pure nitrogen as a purge gas during its flow rate 150 ml/min, using a sample mass of approximately 10-20 g, placed in a sealed, non-hermetic aluminum pans, and using a temperature gradient (heating rate) 10°C/min).

In one of the preferred options of the dosage form in the main do not change their external shape during storage, preferably in open vessels, for at least 12 hours, preferably for at least 24 h at 40°C and 75%relative humidity.

In another preferred embodiment, the volume of applications during storage for at least 12 hours, preferably for at least 24 h at a temperature of 20°C below the melting temperature of the mixture of the component (A), component (C)may be used of the component (B) and optionally the component (D), and in some cases at a temperature of 40°C and 75%relative humidity increases by not more than 20% or 17.5%, more preferably not more than 15% or 12,5%, especially predpochtitel is but not more than 10% or 7.5%, most preferably not more than 6.0%, 5,0% or 4.0%, especially not more than 3.0%, and 2.0% or 1.0%.

Proposed in the invention of the dosage form is a dosage form with controlled release of her active substance. In the preferred embodiment, it is suitable for twice a day patient.

In addition, the proposed invention in dosage form may be a dosage form with at least partially retarded (retardirovannah) release from it one or more physiologically active substances (A), the retardation of the release which may be achieved using conventional, well-known materials and methods, for example, by introducing a physiologically active substance in delaying its release matrix or by applying one or more delaying its release coatings. However, when the regulated release of physiologically active substances must comply with the condition, according to which the addition of slow release of physiologically active substances materials shall not reduce the required hardness of the dosage form.

Controlled release of physiologically active substances of the invention the dosage form of predpochtitel is about to provide, through the introduction of a physiologically active substance in the matrix. Serve as the matrix excipients to control the release of physiologically active substances. Forming the matrix material may represent, for example, hydrophilic gel-forming materials, the release of which physiologically active substances occurs mainly by diffusion or hydrophobic materials, the release of which physiologically active substances occurs mainly by diffusion from the pores in the matrix.

As forming matrix materials can be used known physiologically compatible hydrophilic materials. As forming a hydrophilic matrix materials, preferably polymers, most preferably ethers, cellulose, esters of cellulose and/or acrylic resin. In a particularly preferred form the matrix materials include ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or its derivatives such as its salts, amides or esters.

Equally as forming the matrix material, it is preferable to use hydrophobic materials such as hydrophobic polymers, waxes, fats, fatty acids long chain fatty alcohols or corresponding complex or simple esters of l is Bo mixture of these materials. Particularly preferred for use as the hydrophobic matrix materials include mono - or diglycerides of fatty acids with C12-C30and/or fatty alcohols with C12-C30and/or waxes or mixtures of these materials.

As forming matrix materials can also be used mixtures of the above hydrophilic and hydrophobic materials.

In addition, and components (C), as well as components used (G), which according to the invention are used to give shape to apply the required resistance to the destruction of at least 400 N, can serve as an additional forming matrix materials.

Proposed in the invention of the dosage form, when it is intended for ingestion in a preferred embodiment, may also be resistant to gastric juices coating that dissolves depending on the pH of the environment in which there is a release of physiologically active substance from the dosage form. If such coverage offered in the invention, the dosage form passes through the stomach without dissolving in it and begins to dissolve and release the active ingredient only in the intestine. In a preferred embodiment, resistant to gastric juice the coating process is taken when the pH value in the range from 5 to 7.5.

Appropriate materials and methods used for the retardation of release of active substances, and also for coating resistant to gastric juice coatings are known, for example from "Coated Pharmaceutical Dosage Forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials"by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st ed., published by Medpharm Scientific Publishers, 1998. In accordance with this this publication is included in the present description by reference and is part of it.

The object of the invention is also the use of the above-described physiologically active substance (a) and/or the above-described synthetic or natural polymer (C) for the preparation of the proposed invention in dosage forms intended for the prevention and/or treatment of disease with overdose prevention physiologically active substance (A), primarily as a result of crushing the dosage form by mechanical action on it.

The invention relates further to the use of the above-described physiologically active substance (a) and/or the above-described synthetic or natural polymer (C) to prepare proposed in the invention the dosage form to the prevention of unintentional violations, first of all eliminate, the effect of slow release of her physiologically act the main substance (A) as a result of crushing the dosage form by mechanical action on it.

The invention relates also to the use of the proposed invention the dosage form for the preparation of medicaments intended for the prevention and/or treatment of disease with overdose prevention physiologically active substance (A), primarily as a result of the grinding of the drug by mechanical impact on him.

In addition, the invention relates to the use of the proposed invention the dosage form for the preparation of medicaments intended for the prevention and/or treatment of diseases, prevention of unintentional violations, first of all eliminate, the effect of slow release from it physiologically active substance (A) due to crushing medicine by mechanical impact on him.

Under mechanical influence in the preferred embodiment, means the effect selected from the group including chewing, rubbing in a mortar, strikes with a hammer and use a special device for grinding into powder traditional forms application.

Resistance prepared according to the invention forms applications destruction define the following method of measurement, which can be experienced not only tablets but also different dosage forms.

For definition wide-angle the resistance offered to the invention the dosage form to the destruction of the prepared dosage forms, preferably the tablets with a diameter of 10 mm and a thickness (height) 5 mm

Further in accordance with the method of determining the resistance of tablets to destruction, published in the European Pharmacopoeia 1997 year of publication, S. 143, 144, method No. 2.9.8, using the following equipment determine the resistance produced by such application forms, preferably tablets, destruction. As the measuring equipment used machine for testing materials type Zwick Z 2.5" firm Zwick to develop maximum force Fmax equal to 2.5 kN, with the progress of the cross, equal to a maximum of 1150 mm and exhibited with the help of an adjusting mechanism consisting of columns and the lead screw, with the free working space at the rear of 100 mm, with speed tests, adjustable in the range from 0.1 to 800 mm/min, and software "testControl". For measurements using the plug with screw inserts and cylinder (diameter 10 mm) and Mendoza with the maximum measured force Fmax 1 kN, with a diameter of 8 mm, with an accuracy of measurement according to ISO 7500-1, corresponding to class 0.5, starting with 10 N, and class 1, starting with 2 N, and issued by the manufacturer test certificate M according to DIN 55350-18 (calculated by the method of the company Zwick maximum total force Fmax of 1.45 kN) (all equipment manufactured by Zwick GmbH & Co. KG, Ul is, Germany, with the following order codes: BTC-FR 2.5 TONS. D09 to the testing machine, BTC-LC 0050N. P01 for Mendoza and 70000 S06 for centering device).

Figure 6 schematically shows a device for measuring the resistance of tablets to destruction and, in particular, is used for this purpose, the adjusting device 6 for alignment position 4 tablets before and during measurement. For measurements of the tablet 4 is placed between the upper pressure plate 1 and the lower pressure plate 3 is not shown in the drawing, the device for loading and fixed by means of two two-part clamps 2, each of which after setting required for fixing and centering the analyzed tablets distances 5 is firmly connected to the upper, respectively the lower pressure plate (not shown). For adjusting distance 5 the two parts of each clamp can be pushed or to push in the horizontal direction by movement of the respective push plate on which they are installed. These positions relate solely to 6.

In the case of the dispersed form of drug resistance of its individual particles destruction in another embodiment, can also be defined using two pressure plates, as shown, for example, 7.

7 shows the upper cover layer is 10 and the bottom cover plate 11, between which is placed the sample 12, such as spherical granules (pellets). After placing the sample between the two pressure plates of their shift, applying thus the compressive force to the sample. Otherwise, the measurement results are analyzed similar to the method discussed above with reference to Fig.6.

It is resistant to degradation caused by certain mechanical loads also include tablets which, when the application specified efforts are not destroyed, but in some cases plastically deformed.

Below the invention is illustrated by examples. Everything discussed in these examples, explanations are purely illustrative and do not limit the scope of the invention.

In the first series of examples as active substances (physiologically active substances (A)) used diltiazem hydrochloride, verapamil hydrochloride and carbamazepine.

Example 1

td align="center"> 1233,6 mg
ComponentsQty per pillTotal Qty
Diltiazem hydrochloride90,0 mg720 mg
The polyethylene oxide, NF, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)to 154.2 mg
The total mass244,2 mg1,9536 g

All components were mixed together in the gravitational mixer. Tablet form, consisting of an upper punch, lower punch and die and intended for the manufacture of tablets with a diameter of 10 mm and a radius of curvature of convex surfaces 8 mm, was heated in a drying oven at 80°C. Then heated in tablet form was pressed powder mixture, clamping tablet form in a vise with the necessary pressing force of at least 15 C.

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed with a hammer. Grind the pill failed and with the help of mortar and pestle.

Features of release of the active substance from the prepared dosage forms in vitro was determined using apparatus with postoloprty stirrer in accordance with the method described in European Pharmacopoeia (stirrer and weighting (device, preventing the ascent of the analyzed dosage forms)). The temperature of the medium, which was released active substance (environment is svobodne), was 37°C, and the rotation speed of the stirrer was equal to 50 min-1. In the beginning of the experiment each tablet was placed in 900 ml of simulating gastric juice artificial environment with a pH of 1.2. After 30 min by the addition of alkali, the pH value was increased to 2.3, then after 90 min was increased to 6.5 and then after another 60 min increased to 7.2. The number released in the solvent environment of the active substance was determined in the given below points in time by spectral photometry at 236 nm in 2 mm cuvettes.

TimeThe released amount of the active substance
30 min12%
240 min43%
480 min63%
600 rpm71%
720 min77%

Example 2

Analogously to example 1 from the following table components made oblong tablets with a width of 9 mm and a length of 20 mm.

ComponentsNumber of calc is the one pill Total Qty
Verapamil hydrochloride240,0 mg1920 mg
The polyethylene oxide, NF, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)411,4 mg3291,2 mg
The total mass651,4 mg4,2112 g

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets force of 500 N was not any of their destruction.

The release of the active substance from the tablets in vitro was determined analogously to example 1 (UV detection at 279 nm) and got the following results:

TimeThe released amount of the active substance
30 min6%
240 min20%
480 min30%
600 rpm35%
720 min39%

PR is measures 3

Analogously to example 1 from the following table components produced round tablets with a diameter of 20 mm

ComponentsQty per pillTotal Qty
Carbamazepine600 mg4800 mg
The polyethylene oxide, NF, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)1028,5 mg8228,0 mg
The total mass1628,5 mg13,028 g

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets force of 500 N was not any of their destruction.

The release of the active substance from the tablets in vitro was determined analogously to example 1 (UV detection at 285 nm) and got the following results:

TimeThe released amount of the active substance
30 min1%
240 min 5%
480 min9%
600 rpm11%
720 min13%

In the next series of examples as active ingredient (physiologically active substance (A)used nifedipine.

Example 4

Of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Nifedipine20 mg2 g10%
The polyethylene oxide, mol. weight 900000 (Polyox WSR 1105, the company Dow Chemicals)180 mg18 g90%

Nifedipine was mixed with polyethylene oxide in the gravitational mixer. The resulting mixture on an eccentric tablet press (model EC 0 firm Korsch) extruded tablets weighing 200 mg. way got round tablets with a diameter of 8 mm and a radius of curvature of a convex n the surfaces 8 mm Tablet form, consisting of a matrix, the upper punch and the lower punch and intended for the manufacture of tablets with a diameter of 10 mm and a radius of curvature of convex surfaces 8 mm, was heated in an oven to 100°C. and Then heated in tablet form was again pressed previously manufactured tablets, while maintaining the necessary pressing force for at least 15 C.

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

Example 5

Analogously to example 4 of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Nifedipine20 mg2 g10%
The polyethylene oxide, mol. weight of 600,000 (Polyox WSR 205, the company Dow Chemicals)180 mg18g 90%

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

Example 6

Analogously to example 4 of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Nifedipine20 mg2 g10%
The polyethylene oxide, mol. weight 5000000 (Polyox WSR Coagulant, the company Dow Chemicals)180 mg18 g90%

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

Example 7

p> Analogously to example 4 of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Nifedipine20 mg2 g10%
The polyethylene oxide, mol. weight 100000 (Polyox WSR N-10, Dow Chemicals)20 mg2 g10%
The polyethylene oxide, mol. weight 5000000 (Polyox WSR Coagulant, the company Dow Chemicals)160 mg160 g80%

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

In the next series of examples produced tablets of tramadol hydrochloride as a physiologically active substance (A).

Example 8

ComponentsQty per pillTotal Qty
Tramadol hydrochloride100 mg100 g
The polyethylene oxide, NF, IL (190°C. under a 21.6 kg/10 min)<0.5 g, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)200 mg200 g
The total mass300 mg300 g

Tramadol hydrochloride was mixed with polyethylene oxide powder in a gravity mixer. Tablet form, consisting of an upper punch, lower punch and die and intended for the manufacture of tablets with a diameter of 10 mm and a radius of curvature of convex surfaces 8 mm, was heated in a drying oven at 80°C. Then heated tablets were compressed on 300 mg of the powder mixture, the clamping tablet form in a vise with the necessary pressing force of at least 15 C.

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed with a hammer. Blend the ü tablets failed and with the help of mortar and pestle.

Features of release of the active substance from the prepared dosage forms in vitro was determined using apparatus with postoloprty stirrer in accordance with the method described in the European Pharmacopoeia. The temperature of the medium, which was released active substance, was 37°C, and the rotation speed of the stirrer was equal to 75 min-1. In the beginning of the experiment each tablet was placed in a 600 ml simulating gastric juice artificial environment with a pH of 1.2. After 30 min by the addition of alkali, the pH value was increased to 2.3, then after 90 min was increased to 6.5 and then after another 60 min increased to 7.2. The number released in the solvent environment of the active substance was determined in the given below points in time by spectral photometry.

TimeThe released amount of the active substance
30 min15%
240 min52%
480 min80%
720 min99%

Example 9

The powder mixture of example 8 portions 300 mg were heated is up to 80°C and placed in a matrix tablet form. After that, the mixture was pressed. The resulting tablets had the same properties as the tablets of example 8.

Example 10

Raw materialsQty per pillTotal Qty
Tramadol hydrochloride50 mg100 g
The polyethylene oxide, NF, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)100 mg200 g
The total mass150 mg300 g

Tramadol hydrochloride was mixed with the above component in the gravity mixer. Tablet form, consisting of an upper punch, lower punch and die and intended for the manufacture of tablets with a diameter of 7 mm, was heated in a drying oven at 80°C. Then heated in tablet form was pressed on 150 mg of powder mixture, clamping tablet form in a vise with the necessary pressing force of at least 15 C.

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N't is rockodile any of their destruction.

The release of the active substance from the tablets in vitro was determined as in example 8 and got the following results:

TimeThe released amount of the active substance
30 min15%
240 min62%
480 min88%
720 min99%

Example 11

Raw materialsQty per pillTotal Qty
Tramadol hydrochloride100 mg100 g
The polyethylene oxide, NF, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)180 mg180 g
Xanthan gum, NF20 mg20 g
The total mass300 mg300 g

Tramadol hydrochloride was mixed with Xante the om and polyethylene oxide in a gravity mixer. Tablet form, consisting of an upper punch, lower punch and die and intended for the manufacture of tablets with a diameter of 10 mm and a radius of curvature of convex surfaces 8 mm, was heated in a drying oven at 80°C. Then heated tablets were compressed on 300 mg of the powder mixture, the clamping tablet form in a vise with the necessary pressing force of at least 15 C.

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Under the effect of this effort tablets several plastically deformed.

The release of the active substance from the tablets in vitro was determined as in example 8 and got the following results:

TimeThe released amount of the active substance
30 min14%
240 min54%
480 min81%
720 min99%

Example 12

Raw materialsQty per pillTotal Qty
Tramadol hydrochloride50 mg100 g
The polyethylene oxide, NF, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)90 mg180 g
Xanthan gum, NF10 mg20 g
The total mass300 mg300 g

Tramadol hydrochloride was mixed with xanthan gum and polyethylene oxide in a gravity mixer. Tablet form, consisting of an upper punch, lower punch and die and intended for the manufacture of oblong tablets with a length of 10 mm and a width of 5 mm, was heated in a drying oven at 90°C. Then heated in tablet form was pressed on 150 mg of powder mixture, clamping tablet form in a vise with the necessary pressing force of at least 15 C.

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 And there was no damage. In what Sodeistvie specified efforts tablets several plastically deformed.

The release of the active substance from the tablets in vitro was determined as in example 8 and got the following results:

TimeThe released amount of the active substance
30 min22%
120 min50%
240 min80%
360 min90%
480 min99%

15

Example 13

As described in example 8 method of the following in the table of components produced tablets.

ComponentsQty per pillQty per party
Of oxycodone hydrochloride20.0 mg0,240 g
Xanthan gum, NF20.0 mg0,240 g
The polyethylene oxide, NF, IL (190°C. under a 21.6 kg/10 min)<0.5 g, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals) 110,0 mg1,320 g
The total mass150,0 mg1,800 g

20

Features of release of the active substance from the tablets was determined in the following way. Features of release of the active substance from the tablets in vitro was determined using apparatus with postoloprty stirrer in accordance with the method described in the European Pharmacopoeia. The temperature of the medium, which was released active substance, was 37°C, and the rotation speed of the stirrer was equal to 75 rpm as the environment in which the released active substance used is described in USP phosphate buffer with pH 6.8. The number released in the solvent environment and its active substance was determined in the given below points in time by spectral photometry.

TimeAverage
0 min0%
30 min17%
240 min61%
480 min90%
720 min101,1%

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets force of 500 N was not any of their destruction.

Example 14

Of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Tramadol hydrochloride100 mg10 g20%
The polyethylene oxide 7000000 (Polyox WSR 303, Dow Chemicals)375 mg37,5 g75%
Carnauba wax25 mg2.5 g5,0%

Tramadol hydrochloride was mixed with polyethylene oxide, and Carnauba wax in a gravity mixer. The resulting mixture on an eccentric tablet press (model EC 0 firm Korsch) extruded tablets weighing 500 mg. In this way they got round tablets with a diameter of 10 mm and a radius of curvature of convex surfaces 8 mm. Tablet form, consisting of a matrix, the upper punch and the lower punch and intended for the manufacture of tablets with a diameter of 10 mm and a radius of curvature of convex surfaces 8 mm, was heated in a drying oven at 130°C. Then heated in tablet form was again pressed previously manufactured tablets, while maintaining the necessary pressing force for at least 15 C.

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

Example 15

Analogously to example 14 of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Tramadol hydrochloride100 mg10 g20%
The polyethylene oxide, mol. weight 5000000 (Polyox WSR Coagulant, the company Dow Chemicals)375 mg37,5 g75%
Carnauba wax25 mg2.5 g5,0%

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

Example 16

Of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Tramadol hydrochloride100.0 mg1490 g29,8%
The polyethylene oxide, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)151,0 mg2250 g45,0%
Hypromellose (Metholose 0 SH, 100000 JV, the company ShinEtsu)33.6 mg500 g10,0%
Product Eudragit E, granulate (the company Röhm)16,8 mg250 g5,0%
PEG 600033.6 mg500 g10,0%
α-tocopherol0.1 mg5 g0,1%
Aerosil (highly dispersed silicon dioxide)0.1 mg5 g0,1%

50 g of polyethylene oxide together with 5 g of α-tocopherol and Aerosil were processed in a mortar to obtain a homogeneous mixture. This mixture was mixed with other components in the gravity mixer for 15 minutes then the mixture was extrudible on planetary roller extruder type BCG 10 firms LBB Bohle (Ennigerloh). In the extruder used 4 planetary worm. The extruder was equipped with an extrusion head with a diameter of 8 mm, an Extrudable mixture was gravimetrically dosed out in an extruder with a flow rate of 10 kg/h Extrusion was performed with the following parameters:

rotation speed: 50 rpm, the temperature to which Cusa: 100°C, the temperature of the Central worm: 100°C, the temperature of the heated extrusion head: 120°C. After production of extrudates were cooled to room temperature. Then the extrudates were cut into separate parts discoid shape, the mass of each of which was equal to the weight of one tablet. Then such individual parts discoid shape was molded tablets on an eccentric tablet press type EC 0 firm Korsch. As tablet form used a round punch (diameter 10 mm) with a radius of curvature of the concave working surfaces 8 mm

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

Features of release of the active substance of the manufactured tablets in vitro was determined in the apparatus with postoloprty stirrer and weighting (device, preventing the ascent of the analyzed drug form) in accordance with the method described in the European Pharmacopoeia. The temperature of the medium, which was released active substance, was 37°C, and the rotation speed of the stirrer was equal to 75 min-1. As a medium, which was released to the action of the General substance used intestinal juice with a pH of 6.8 in the amount of 600 ml of the Number released in the solvent environment of the active substance was determined in the given below points in time by spectral photometry.

TimeThe released amount of the active substance
30 min17%
240 min65%
480 min93%
720 min99%

Example 17

Analogously to example 16 of the following in the table of components produced tablets.

Raw materialsQty per pillQty per partyThe relative quantity
Tramadol hydrochloride100.0 mg1490 g29,8%
The polyethylene oxide, mol. weight 7000000 (Polyox WSR 303, Dow Chemicals)151,0 mg 2250 g45,0%
Hypromellose (Metholose 90 SH, 100000 JV, the company ShinEtsu)33.6 mg500 g10,0%
Product Stamylan 1965 (low-density polyethylene SABIC®LDPE 1965T)16,8 mg250 g5,0%
PEG 600033.6 mg500 g10,0%
α-tocopherol0.1 mg5 g0.1%
Aerosil (highly dispersed silicon dioxide)0.1 mg5 g0,1%

The resistance of tablets to destruction was determined by the method described above using the above equipment. When exposed to tablets with force 500 N there was no damage. Tablets cannot be crushed either with a hammer or using a mortar and pestle.

Features of release of the active substance of the manufactured tablets in vitro was determined in the apparatus with postoloprty stirrer and weighting (device, preventing the ascent Ana is isirimah dosage forms) in accordance with the method, described in the European Pharmacopoeia. The temperature of the medium, which was released active substance, was 37°C, and the rotation speed of the stirrer was equal to 75 min-1. As the environment in which the released active substance, used intestinal juice with a pH of 6.8 in the amount of 600 ml of the Number released in the solvent environment of the active substance was determined in the given below points in time by spectral photometry.

TimeThe released amount of the active substance
30 min17%
240 min62%
480 min85%
720 min94%

1. Dosage form that contains a physiologically active substance (A), including oxycodone hydrochloride, optionally one or more physiologically compatible auxiliary substances (B), synthetic or natural polymer (C) and do not necessarily natural, semi-synthetic or synthetic wax (D) and has resistance to destruction of at least 400 N to 500 N and in which Phi is biologicheskikh conditions after 5 h releases a maximum of 99% of oxycodone hydrochloride.

2. Dosage form according to claim 1, characterized in that it presents in the form of tablets.

3. Dosage form according to claim 1, characterized in that it presents in dispersed form of the resistance of individual particles to the destruction of at least 400 N.

4. Dosage form according to claim 3, characterized in that the particles are compressed into tablets, or packaged in capsules.

5. Dosage form according to claim 1, characterized in that the polymer (C) selected from the group comprising polyalkylene, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers and mixtures thereof.

6. Dosage form according to claim 1, characterized in that the polymer (C) is polyalkylene selected from the group comprising polyethylenoxide, polyethylene oxide, polypropyleneoxide, their copolymers and their copolymers and mixtures thereof.

7. Dosage form according to claim 5, characterized in that the polymer (C) has srednevozrastnoe molecular weight of at least 0,5·106g/mol.

8. Dosage form according to claim 1, characterized in that it has a shell part (82) and located inside the core (83), with which the shell part (82) is connected, seamless, thus forming a shell part (82) material and forming a core (83), we have basically the same chemical composition but different morphology.

9. Drug is the first form of claim 8, wherein the forming the shell part (82) material and forming a core (83) material have different optical properties.

10. Dosage form of claim 8, wherein the thickness of the shell part (82) is from 0.1 to 4 mm

11. Dosage form according to claim 1, characterized in that its volume when stored for at least 12 hours at a temperature of 20°C below the melting temperature of the mixture of the component (A), component (C)may be used of the component (B) and optionally the component (D) is increased by not more than 20%.

12. Dosage form according to claim 1, characterized in that it contains at least one wax (D) with a softening temperature at least 50°C.

13. Dosage form according to item 12, wherein the wax (D) is a Carnauba wax or beeswax.

14. Dosage form according to claim 1, characterized in that the physiologically active substance is present in a slow release matrix.



 

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SUBSTANCE: invention refers to N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide, and/or their mixture, as well as to applying it in a pharmaceutical composition, a method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease. Also, the invention refers to methods for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide and its intermediate compounds. .

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaadamantane derivatives of formula (I), to their pharmaceutically acceptable salts possessing the properties of nAChR ligands, their application, a method of treating and based pharmaceutical compositions, and also to intermediate compounds of formula (VI) and (VII) and to application of the compound of formula (V) for preparing the compound (I). In general formulas

L1 represents -O- or -NRa-; A represents -Ar1 or -Ar2-L2- Ar3; Ar1 represents 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxyalkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2, (NH2)carbonyl and oxido; Ar2 represents 5-6-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxy alkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2 and (NH2) carbonyl; Ar3 represents aryl, optionally substituted alkoxy, alkoxyhalogenalkyl, alkyl, aryl, halogenalkoxy, halogen, hydroxy and -NH2; or Ar3 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, carboxy, carboxyalkyl, halogenalkyl, heterocyclyl and tritylaryl; L2 represents a bond, -O- or -C(O)NRa-; and Ra represents hydrogen.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of nAChR ligands.

41 cl, 11 dwg, 162 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form for pain management and controlled release of 3-(2-dimethylaminomethylcyclohexyl)phenol or one of its pharmaceutically acceptable salts contains said active substance and a polymer matrix of cellulose ether, which has a viscosity ranging within 3000 to 150000 mPa·s in the concentration of 2.0 wt % in a water solution at 20°C. Cellulose ether is selected from a group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. The dosage form ensures in vivo a maximum plasma level of the active substance in 2-10 h.

EFFECT: dosage form under the invention provides maintaining the plasma concentration of the active substance 3-(2-dimethylaminomethylcyclohexyl)phenol at a pharmacologically effective level for at least 12 h and shows minimum spectrum of side effects including nausea and/or vomiting.

35 cl, 1 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a sublingual tablet and a method for preparing it. The sublingual tablet contains an opioid 20 mg/tablet applicable for sublingual application, a directly compressible diluent in the form of an inert core presenting considerably spherical granules containing sucrose and starch. The inert core is covered with at least one active layer containing at least 5 wt % of the inert core of said opioid. A method for preparing the sublingual low-dose opioid tablet involves a stage of producing microgranules by spraying a solution, a suspension or a colloidal dispersion containing said opioid on a surface of the inert core, and compressing the prepared microgranules. The sublingual tablets under the invention have disintegration time making less than 15 min., and fragility making less than 1%.

EFFECT: fast opioid release promotes immediate absorption of the latter in a buccal cavity and fast pain management.

22 cl, 1 dwg, 5 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. A method involves application of IL-31 antagonist for IL-31 induced signal transduction inhibition in dorsal root ganglion cells. The IL-31 antagonist inhibits IL-31 polypeptide binding containing amino acid residues 27-164 SEQ ID NO:2 with its heterodimeric receptor containing IL-31RA and OSMR-beta. The antagonist represents a humanized monoclonal antibody or a chimeric antibody.

EFFECT: use of the method effectively relieves inflammation, pain and itching.

8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol maleate of formula in form of enantiomer with absolute configuration (1R, 2R), which possesses pain-killing action.

EFFECT: invention relates to methods of obtaining said maleate, including crystalline forms A and B, pharmaceutical composition and application of maleate of formula (i) for preparation of pharmaceutical composition, intended for treatment of pain states.

33 cl, 4 dwg, 4 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and deals with medical form and method for delivery of medical substances, in particular, dependence habit-forming medical substances, which are characterised by stability to solvent extraction, compression, crushing and milling.

EFFECT: ensuring initial fast release of medicinal substance with following continuous period of controlled release of medicinal substance.

42 cl, 9 ex, 34 tbl, 22 dwg

Organic compounds // 2430921

FIELD: chemistry.

SUBSTANCE: invention relates to an azathiabenzo-azulene derivative of formula I

,

where R3 denotes C1-C6alkyl, R4 denotes OH, R5 denotes halogen and R6 denotes H or halogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having anti-inflammatory or analgesic action.

EFFECT: obtained compounds and pharmaceutical composition can be used to treat arthritis and arthritis-related conditions, and for relieving inflammation and pain associated with acute inflammation of body parts, primarily joints, as a result of injury or as a result of arthritic conditions or other diseased conditions.

17 cl, 8 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: declared invention refers to medicine. What is declared is a delayed release complex pharmaceutical composition containing a delayed release part and an immediate release part. The delayed release part contains AII-receptor blocker as an 'active ingredient'. The immediate release part contains HMG-CoA reductase inhibitor as an active ingredient.

EFFECT: declared composition is effective for treating hypertension and preventing complications in the patients suffering metabolic syndromes, such as diabetes, obesity, hyperlipidemia, coronary vessel disease, etc.

10 dwg, 13 bl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical preparation for controlled release of a contained active ingredient, differing by the fact that said pharmaceutical preparation contains medically acceptable yeast able for alcoholic fermentation.

EFFECT: invention provides release of the active ingredient from the pharmaceutical preparation regardless of the environmental conditions.

13 cl, 4 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and may be used for treating patients with hypertension and lipid storage disease. There is applied a combined drug containing dihydropyridine, calcium canal blockers, and statin, a hypolipidemic agent. The drug is prepared in such a manner that release rate of said ingredients can be controlled with respect to each other.

EFFECT: method allows higher clinical effectiveness and compliance, prevented antagonist and side effects of the combined therapy.

27 cl, 12 tbl, 10 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: there are offered an oral pharmaceutical composition containing a) a testosterone ester and a fatty acid ester of a medium chain size; and b) two or more lipid ingredients, at least first of which contains a hydrophilic surfactant and at least second of which contains a lipophilic surfactant; said lipid ingredients together provide solubilisation of said testosterone ester in amount 10-20 % of weight of a pharmaceutical composition; a method for prevention or release of testosterone deficiency symptoms in mammal subjects and a method for maintenance of prolonged oral testosterone release.

EFFECT: invention provides medium-size testosterone and fatty acid ester delivery of intensified and prolonged adsorption, desired testosterone levels which are detected in people who do not suffer testosterone deficiency.

30 cl, 15 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to chemical-pharmaceutical industry, in particular to drug form, such as capsule, ordinary or orally disintegrating tablet, able to deliver nitrogen-(N)-containing therapeutic medications, which have pKa in range from approximately 5 to 14 in organism in form with delayed release in order to be suitable for two-time or one-time day regimen of dosage, includes, at least, one organic acid, which solubilises medication before its release into unfavourable intestine environment, in which said medication is practically insoluble.

EFFECT: single drug form, composed of multitude of multi-layered particles, is manufactured in such a way, that said weak-base medication and said organic acid do not come into close contact with formation in situ of acidic adducts, guaranteeing that acid will not run out before release of medication finishes.

39 cl, 1 tbl, 10 ex, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutical and food industry, in particular to production of vitamin-mineral complexes (VMC) and food additives, used for prevention and treatment of vitamin-mineral deficiency. Simultaneously, taken into account are all antagonistic and synergic interactions between active VMC components, arising in production, storage and application of medication. Delivery of micronutrients by time and place of their digestion is realised within one preparative form, which is made in form of tablet or capsule, containing several independent elements - pellets. Pellets have their time of dissolution, depending on acidity of surrounding medium. During movement of ready form along GIT time of beginning of substances release from one pellet follows time of end of substances release from other pellet in such a way that simultaneously in solution there were no active substances that have antagonistic interaction.

EFFECT: invention is aimed at increase of VMC efficiency and improvement of user's comfort during its application.

23 cl, 10 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and deals with method of obtaining microspheres from biodegradable polymer, including: addition of organic solvent to polymer, obtaining polymer solution (stage 1); dispersion of glucose level-regulating peptide in stage 1 polymer solution, obtaining medication dispersion and mixing alcohol or mixture of alcohol and organic acid with medication dispersion, obtaining solution with dispersed in it medication (stage 2); and obtaining microsphere from solution with dispersed in it stage 2 medication (stage 3), where glucose level-regulating peptide represents exedin-4 and where biodegradable polymer is selected from group, consisting of poly-L-lactic acid, D-lactic acid and glycolic acid copolymer, L-lactic acid and glycolic acid copolymer and D,L-lactic acid and glycolic acid copolymer.

EFFECT: invention ensures obtaining microsheres which demonstrate neither initial burst effect nor incomplete release, ensure release of medications of zero order and high efficiency of incapsulation and high stability.

13 cl, 15 ex, 7 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition of microparticles or nanoparticles for local delivery and delivery to a mucous surface of an active ingredient containing 0.1-99.5 wt % of an inorganic element chosen from alkaline, earth or transition metal, lanthanide or silicon dioxide, alkoxide, oxide, oxalate, ureate, nitrate or acetate, 0.01-95 wt % of a pharmaceutical or cosmetically active ingredient, and 0.001-75 wt % of a release control agent chosen from natural, synthetic or semisynthetic polymers, polysaccharides, monosaccharides, salts, fibres or peptides. Also, the invention covers methods for making said composition which involve dissolving each ingredient in a solvent, mixing the prepared solutions, adding a solution of alkaline hydroxide and producing a dry powder composition or gel colloidal solution of nanoparticles. Besides, the invention refers to a kit comprising said composition, a delivery device and an application data sheet.

EFFECT: invention provides better fixation in an effective area, effective absorption and controlled release.

34 cl, 9 tbl, 2 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: vitamin dosage form contains a combination of biologically active substances chosen, first of all, from a group of vitamins, mineral substances and microelements, and also their mixtures and at least partially included or introduced in a swellable matrix providing controlled or time shift release of biologically active substances after intake of such composition.

EFFECT: higher bioavailability of the biologically active substances, optimised absorbtion in a gastrointestinal tract, preferentially with avoided time overdose of the relevant biologically active substances and prevented excessive load on involved absorption systems.

22 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: pellet-form pharmaceutical composition for treating vertigo containing cinnarizine and dimenhydrinate wherein the release of active ingredients is slowed down, and the composition also contains a binding agent, a slow-release agent, an excipient and a pharmaceutical aid taken in a certain ratio. The application of the pharmaceutical composition for treating vertigo of any genesis.

EFFECT: slow-release composition is effective in treating vertigo.

6 cl, 4 dwg, 3 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is a dosage form containing a drug substance for treating insomnia, containing a layer or a matrix-surrounding coating wherein a drug substance is dissolved or dispersed with said drug substance released after a time of delay (at least 1 hour after the introduction) which is not substantially accompanied by the drug substance release, and the coating material contains less than 5 % of substances which possess an ability to swell or gelate, and the matrix contains an release control agent.

EFFECT: invention provides exactly establishing and observing the time of delay before the active substance release that enables the patient to work before sleeping, being in the non-sleepy state.

20 cl, 3 dwg, 8 tbl, 6 ex

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