RU2372912C2 - Gindarine composition - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to an oral gindarine tranquiliser. There is offered composition for capsule containing as an active substance, gindarine in the form of gindarine hydrochloride, and an adjuvant chemically inert to the active substance and physiologically acceptable or number of adjuvants enabling prolonged release of gindarine hydrochloride. The composition represents granules, or mixed powders, or mixed granules and powder, or liquid, or soft form. As adjuvants, the composition contains an excipient, alone or combined with a disintegrant, or an antifriction substance, or a binding substance, or mixture thereof. The composition representing the liquid form - suspension, or the soft form - gel, as adjuvant contains a liquid base, alone or mixed with a thickener or a preservative, or mixture thereof.

EFFECT: according to the invention the composition is characterised by prolonged release of gindarine from oral dosage capsular form.

10 cl, 18 ex

Description

The invention relates to the pharmaceutical industry and medicine, in particular to oral preparations based on indindarin with tranquilizing properties.

The known alkindoid gindarin (L-tetrahydropalmatin, 5,8,13,13a-tetrahydro-2,3,9,10-tetramethoxy-6H-dibenzo [a, g] quinolizine), which is available in the form of hindarin hydrochloride in the form of tablets coated a shell with an active substance content of 0.05 g and also containing auxiliary components (//lekmed.ru/lekarstva/ psiholepticheskie / gindarin.html).

Hindarina hydrochloride is a powder, sparingly soluble in water, chloroform and 95% alcohol (1 to 3%), practically insoluble in ether (FS 42-1036-76, p. 2).

This drug is effective in the treatment of functional disorders of the central nervous system (neurasthenia, compulsive neurosis), traumatic encephalopathy, schizophrenia, cerebrovascular diseases, epilepsy (convulsive seizures, epileptic psychosis), chronic alcoholism due to a pronounced calming effect. This drug also has a beneficial effect on children with neurotic conditions. The drug has a mild effect, is well tolerated by patients, does not cause a feeling of heaviness in the head and general depression when waking up (www.golkom.ru/price/group/4630.html?hn=0159).

The disadvantages of the oral drug gindarin in the form of tablets is the multistage and the duration of the preparation of the coated tablet dosage form, that is, the complexity of the process, and as a result, the cost of the drug gindarin in this dosage form is significantly higher. In addition, tablets can overheat when pressed, which can lead to marriage.

The objective of the invention is to provide a composition containing indindarin, for use as an oral drug in the form of capsules.

Technical results that can be obtained by using the present invention: simplification of the manufacturing process of the oral drug gindarin and, as a result, a decrease in the manufacturing cost of this drug, a decrease in the number of rejects during manufacture, an increase in the duration of action (prolongation) of the gindarin in the oral dosage form capsules.

To solve this problem, the present invention proposes a composition comprising, as an active substance, indarine in the form of a physiologically acceptable compound, for example, indarine hydrochloride, and chemically inert to the active substance and a physiologically acceptable excipient or several excipients, in the following ratio of components in the composition (wt. .%):

gindarin hydrochloride - 2.0 - 50.0 excipient - the rest

Moreover, the excipient or some of the excipients that make up the composition, provide a prolonged release of the active substance of indindrin hydrochloride from the proposed dosage form.

Moreover, the proposed composition is a granule, or a mixture of powders, or a mixture of powder and granules, or a liquid, or a soft form.

A composition is provided comprising hydindarin in the form of a physiologically acceptable compound, for example hydindarin hydrochloride, representing a mixture of powders or granules, or a mixture of powder and granules, which as an adjuvant contains a disintegrant (disintegrant), or an anti-friction substance, or a binder, or an excipient, or a mixture thereof, for example, with the following content of components in the composition (wt.%):

gindarin hydrochloride - 2.0-50.0 disintegrant - 0.5-10.0 anti-friction substance - 0.2-10.0 binder - 0.5-5.0 filler - the rest

Also provided is a composition comprising hydindarin in the form of a physiologically acceptable compound, for example hydindarin hydrochloride, which is a liquid, for example a suspension, or a mild form, for example a gel, which, as auxiliary substances, contains a liquid base or a liquid base mixed, for example, with a thickener, or a preservative, or a mixture thereof, in the following content of components in the composition (wt.%):

gindarin hydrochloride - 2.0-50.0 thickener - 0.1-20.0 preservative - 0.5-5.0 liquid base - the rest

Filler (diluent), including providing a prolonging action of the active substance --indarine, are, for example, collagen, or methyl cellulose (MC), or the sodium salt of carboxymethyl cellulose (Na-CMC), or microcrystalline cellulose (MCC), or polyvinylpyrrolidone (PVP) or calcium alginate, or polyacrylic acid, or an interpolymer complex of polymethacrylic acid and polyethylene glycol of the equimolar composition CPN-1, or a mixture of these components.

A disintegrant (baking powder) is, for example, agar-agar, or alginic acid, or starch (rice, wheat, corn, potato), or a mixture of these components.

An antifriction substance, including one providing a prolonging action of the active substance --indarine, is, for example, aerosil, or polyethylene oxide-4000, or a mixture thereof.

The binder, including the prolonging action of the active substance - indindarin, is, for example, hydroxyethyl cellulose, or polyvinyl alcohol, or sodium or potassium alginate, or a mixture of these components.

The thickening agent, including the prolonging effect of the active substance, ginzrin, is, for example, microcrystalline cellulose, or collagen, or methyl cellulose, or carboxymethyl cellulose, or its sodium salt, or polyvinyl pyrrolidone, or aerosil, or polyvinyl alcohol, or a mixture of these components .

Preservatives are, for example, parabens (nipagin, nipazole, or a 1: 3 mixture thereof), or sorbic acid.

In the case of a composition for the oral preparation of indindarin, which is a liquid, for example a suspension, or a soft form, for example a liquid gel, the base is, for example, glycerin or lactulose, or a mixture of the above components.

Gindarin in experimental conditions showed significant suppression of motor activity, caused central muscle relaxation, inhibition of conditioned-reflex activity, decreased animal aggressiveness, anticonvulsant and analgesic effects. Gindarin reduces serotonin and norepinephrine in the brain and small intestine, inhibits the subcortical formations of the central nervous system, eliminates the effect of adrenaline on blood pressure, and reduces the toxicity of phenamine (www.golkom.ru/price/group/4630.html?hn=0159) .

Excipients included in the proposed composition must satisfy the following requirements:

- correspond to the medical prescription of the drug, that is, to ensure the manifestation of the therapeutic effect of the drug substance, taking into account its pharmacokinetics;

- the quantities used must be biologically harmless and biocompatible with body tissues, and also not have an allergenic and toxic effect;

- to ensure compliance with the formative properties of the manufactured dosage form;

- must not chemically and physico-chemically interact with medicinal substances, packaging materials, as well as material of technological equipment during the preparation of medicines and during their storage;

- meet the requirements of permissible microbial contamination, provide the possibility of sterilization;

- be economically accessible.

For many medicinal substances, which includeindarine in the form of, for example, indarine hydrochloride, the selection of excipients for the composition that satisfy the above properties is individual, depending on the properties of the active substance.

In a number of cases of functional disorders of the central nervous system with phenomena of increased excitement, for example, obsessive motor neurosis and other states of obsession, chronic alcoholism and drug addiction in the stage of denarcotization, the prolonged action of the active substance ,indarine, is necessary. When prolonging the action of the drug, the concentration of the drug in plasma does not exceed an undesirable level, above which the side effect of the drug is possible.

For prolonged components, in addition to the requirements for excipients, this includes maintaining the optimal level of the drug substance in the body, and the absence of sharp fluctuations in its concentration. The maximum concentration of a drug substance in the blood is directly proportional to the dose administered, the rate of absorption, and inversely proportional to the rate of excretion of the substance from the body.

There are various technological methods for prolonging the action of drugs: increasing the viscosity of the dispersion medium (inclusion of the active substance in the gel); the conclusion of the drug substance in film coatings; suspension of insoluble medicinal substances, etc. The most preferred for liquid oral forms of prolonged action is the conclusion of the medicinal substance in a gel or the use of non-aqueous solvents as a dispersion medium. As a gel for prolonged drugs, solutions of high molecular weight compounds of various concentrations are more often used, which allows you to adjust the time of prolongation (S. Marchenko, “Lecture notes on the course technology of dosage forms and galenic drugs”, lecture No. 6 t, www.opu.odessa. ua / konsp / KI.229.doc).

There are a number of solutions for controlling the rate of release of an active substance from an oral dosage form, for example, in the form of capsules. Some of these solutions are listed below.

Modified-release capsules contain special excipients in the contents or shell (or both at the same time) to change the rate or place of release of the active substances. To give the capsules prolonged properties, technological methods of introducing special ingredients into the compositions of the fillers are used. Usually, combinations of substances that prevent the rapid release of active ingredients are used, among which acrylic polymers, cellulose derivatives and other substances are most often used (Industrial Technology of Medicines, edited by Prof. V. I. Chueshov, vol. 2, p. 394 and p. 398).

The bioavailability of encapsulated preparations is influenced by the active substance and excipients in the contents of the capsules, as well as the capsule filling method (Industrial Technology of Medicines, edited by Prof. V. I. Chueshov, vol. 2, p. 414). It is known that packaged powders in capsules disintegrate twice as long as freely filled ones, but the difference becomes insignificant when disintegrants are introduced (Industrial Technology of Medicines, edited by Prof. V. I. Chueshov, vol. 2, p. 407) . In addition, it is known that with an increase in the concentration of a binder, the release rate of a medicinal substance decreases (Marchenko SI, “Lecture notes on the course of technology of dosage forms and galenic preparations”, www.opu.odessa.ua/konsp/KI.229.doc )

Thus, by the density of the composition filling the capsules, the content of the disintegrant and the binder therein, the release time of the active substance from the oral capsule-like substance can be controlled.

In addition, the release rate of the contents of the capsule can be controlled either by changing the size of the capsule, or by changing the ratio of active substance to excipients in the capsule filling composition.

Another way to prolong the solid formed oral agents is to create an oral skeleton preparation with an insoluble skeleton. To obtain them, auxiliary substances are used that form a network structure (matrix), in which the drug substance is included. Depending on the nature of the matrix, it can swell and slowly dissolve or maintain its geometric shape throughout the entire stay in the body and is excreted unchanged in the form of a porous mass, the pores of which are filled with liquid. The drug substance from the matrix is released by leaching. At the same time, the rate of its release does not depend on the content of enzymes in the environment, nor on its pH value and remains fairly constant as the drug passes through the gastrointestinal tract.

The release rate of a drug substance is determined by such factors as the nature of the excipients and their properties, the solubility of drugs, the ratio of drugs in the composition of the drug and the matrix-forming substances, the porosity of the form of the solid oral preparation, and the method of its preparation. To create channels in an insoluble matrix, substances soluble in water and gastric juice are added to the pharmaceutical composition. Washing out of the drug framework, they create conditions for the gradual isolation of drug molecules (Marchenko SI, “Lecture notes on the course of technology of dosage forms and galenic preparations”, lecture No. 12 t, www.opu.odessa.ua/konsp/KI. 229.doc).

In the proposed composition for oral medicinal preparations, components inert to hindarin hydrochloride are used as auxiliary substances.

A promising filler and thickener for the proposed composition is collagen, which satisfies the above properties of excipients in combination with hydindarin hydrochloride. At the same time, the drug substance, falling into the “loops” of collagen molecules, forms a compound — inclusion of the type of clathrates, thereby providing a prolonged action (Marchenko SI, “Lecture notes on the course of technology of dosage forms and galenic preparations”, www.opu.odessa. ua / konsp / KI.229.doc).

A method of producing collagen in the form of a powder used in the manufacture of various dosage forms, including as a prolongator, is described in patent RU 2076718, A61K 35/36, 1997.04.10; It is supplied as an auxiliary substance in the form of dry pharmaceutical collagen (www.medgate.ru/drug/11/914).

A promising filler and thickener for the proposed composition is polyacrylic acid or polymethacrylic acid, which satisfy the above properties of excipients in combination with indarine hydrochloride.

Polyacrylic and polymethacrylic acids are polymers of acrylic acid, soluble in water, alcohols and other organic solvents, having a melting point + 13 ° C, boiling point + 141 ° C. Polyacrylic acid is a white powder, insoluble in monomer, but soluble in water, ethanol and formamide (www.ntcp.rn / work / library / p / 2916).

Polymethacrylic acid is a dull white solid, soluble in water, but insoluble in non-polar organic solvents. High molecular weight polymethacrylic acid does not dissolve in water, but only swells in it (www.ntcp.ru/work/library/p/2952). Composite polymer carrier KPN-1 for drugs of prolonged action is manufactured industrially from it, which represents an interpolymer complex of polymethacrylic acid and polyethylene glycol of equimolar composition.

This carrier provides protection of the active substance from inactivation by gastric juice and its uniform entry into the environment of the gastrointestinal tract for a long time (up to 24 hours) (www.advtech.ru/Nipolymer/kpn1ru.htm). Based on polyacrylic acid, polymer matrices are developed that are sensitive to the pH of the medium. These matrices dosed release the active substance in certain sections of the digestive tract, and also serve as a protective membrane. The swelling of the matrix at which the drug substance is released occurs at a certain pH, which in the stomach is pH 1.4 and in the intestine pH 6.7-7.4 (Filippova O.E. “Smart” polymer hydrogels, “ Nature ”No. 8, 2005, // vivovoco.ibmh.msk.su/VV/ JOURNAL / NATURE / 08_05 / GELS.HTM).

A promising filler and thickener for the proposed composition is microcrystalline cellulose (MCC), which satisfies the above properties of excipients in combination with indarine hydrochloride.

Cellulose is one of the most common biopolymers that make up the walls of plants and microorganisms. The developed capillary-porous structure of cellulose includes: intrafibrillar packing irregularities (size 1.5 nm); interfibrillar pores (1.5-10 nm); pores arising as a result of internal stresses (several tens of nm); channels and pores with a diameter of several microns. Hydrolysis of cotton cellulose produces microcrystalline cellulose (MCC), the degree of crystallinity of which is 70-85%, the average crystal length is 7-10 nm (www.xumuk.ru/encyklopedia/2/5126.html).

MCC is a fiber concentrate that represents the purest form of cellulose and is obtained by fine grinding and thorough cleaning of cotton pulp. MCC is used in the pharmaceutical and food industries, in medicine, both as a food additive and as an inert filler for drugs (www.biysk.ru/~bialt/mkc.htm).

Microcrystalline cellulose powder is insoluble in water, well dispersible in water and dilute acids (www.propartners.ru/eng/tables/mcc_info_and_qc.html). Microcrystalline cellulose has sorption properties that are used in medical practice to normalize the intestinal tract (www.herpes.ru/hudo/prep/mkts.htm). Microcrystalline cellulose forms an inert insoluble matrix in solid dosage form in which the active drug substance is uniformly distributed. This matrix is a barrier that limits the contact of a medicinal substance with gastrointestinal fluids and controls its release (Industrial Technology of Medicines, edited by Prof. V.I. Chueshov, vol. 2, pp. 693-694).

The filler, thickener and binder for the proposed composition is also the sodium salt of carboxymethyl cellulose, which satisfies the above properties of excipients in combination with hydindarin hydrochloride. It is soluble in water, aqueous solutions of alkalis. When dissolved in water (solubility up to 15%), it forms viscous transparent pseudoplastic solutions in the form of gels, which are used to obtain prolonged action drugs. Moreover, the selection of the concentration of sodium salt of CMC regulates the time of prolongation (Marchenko SI "Lecture notes on the course technology of dosage forms and galenic preparations", lecture No. 6 t, www.opu.odessa.ua/konsp/KI.229.doc).

Filler, thickener and disintegrant for the proposed composition is also methylcellulose, which satisfies the above properties of excipients in combination with hydarin hydrochloride. It is soluble in cold water, formic and acetic acids, lactic acid, hot glycol, glycerin, etc. In aqueous solutions, methyl cellulose is compatible with other water-soluble cellulose ethers, synthetic and natural polymers.

When dissolved in water, it forms pseudoplastic solutions with practically no thixotropic properties, with a pronounced dependence of viscosity on molecular weight and concentration, which are used for prolonged-release drugs. Moreover, the selection of the concentration of MC regulates the time of prolongation (Marchenko S.I. "Synopsis of lectures on the course technology of dosage forms and galenic preparations", lecture No. 6 t, www.opu.odessa.ua/konsp/KI.229.doc).

The filler, thickener and binder for the proposed composition is also polyvinylpyrrolidone, which satisfies the above properties of auxiliary substances in combination with hydindarin hydrochloride. It is soluble in water, alcohols, glycerin. It is used as a stabilizer of emulsions and suspensions, a prolonging component, a filler for oral forms of drugs (//protabletki.ru/eng/tehno/page6.html). Moreover, the selection of the concentration of PVP is regulated by the time of prolongation (Marchenko S.I. “Summary of lectures on the course technology of dosage forms and galenic preparations”, lecture No. 6 t, www.opu.odessa.ua/konsp/KI.229.doc).

The disintegrant for the proposed composition is agar-agar, which satisfies the above properties of excipients in combination with hydindarin hydrochloride. Agar agar is obtained from marine red algae (e.g., Cracilaria). It does not dissolve in cold water, but swells in it. When applied, air-dry agar binds water in a 4-10-fold amount to its mass. In hot water (completely soluble in the range from 95 to 100 ° C) it forms a colloidal solution, which when cooled to 35-40 ° C gives a gel with a glassy fracture. Supplied in powder form (www.neo-plan.ru/). Agar-agar refers to hydrophilic matrices used in the manufacture of sustained-release oral preparations (Industrial Technology of Medicines, edited by Prof. V.I. Chueshov, vol. 2, p. 693).

The disintegrant, as well as the filler, thickener and binder for the proposed composition is alginic acid and its salts, which satisfy the above properties of excipients in combination with hydindarin hydrochloride. Alginic acid is a high molecular weight compound derived from brown algae. It is poorly soluble in water and swells in it. When swelling, it can absorb 200-300 times the amount of water. It is soluble in hot water and alkali solutions. Acidification solutions form gels.

Sodium and potassium salts of alginic acid are readily soluble in water and give highly viscous solutions. With divalent cations, alginic acids form gels or insoluble alginates. Alginic acid and its salts are thickeners, stabilizers of suspensions and emulsions, gelling agents in the manufacture of pharmaceuticals (Alginic acids, www.chemport.ru/ chemical_encyclopedia_article_128.html). The formation of a gel structure in alginate solutions occurs as a result of the interaction of their molecules with each other with the participation of bivalent calcium ions.

Moreover, gel formation during the interaction of alginate with calcium ions is considered as an ion-exchange process of replacing a monovalent cation (e.g. sodium) in a molecule of a water-soluble salt of alginic acid with the formation of butt zones through a divalent metal cation. The use of alginates in pharmacy is based on the interaction of their water-soluble salt forms in the presence of calcium ions, which leads to the modification of rheological properties (increasing viscosity or the formation of helium structures (www.rusnauka.com/NPM_2006/Chimia/4_polischuk%20t.s.doc.htm) For the deposition of medicinal substances with their subsequent slow release, granules made on the basis of calcium alginate are also used.

Alginic acid molecules representing hydrophilic macroanions are used as matrices to create various pharmaceuticals with prolongation of their action in a living organism. For this purpose, a liposome gel based on alginic acid and its salts is used, into which hydrophilic or hydrophobic medicinal substances are introduced (up to 98%).

A known method of controlling the rate of release of drugs from matrices based on sodium alginate by creating a coating of calcium alginate on the surface of these matrices. A polymer film on the surface of the matrix was created by treating it with aqueous or alcoholic solutions of calcium chloride (A. Slivkin “Polyuronides, structure, properties, applications (review)”, VGU Bulletin, chemistry, biology series, 2000, pp. 32, 40, 41).

Alginic acid and its salts are a sorbent. Alginates bind and remove radionuclides, heavy metals and toxins from the body, without disturbing the macro- and microelement balance. Alginates are capable of sorbing not only stable metals, but also their radioisotopes. Alginic acid and its salts, in addition to sorption ability, stop bleeding, improve tissue regeneration, have an antacid effect, enhance the obligate intestinal microflora, inhibit the activity of pathogenic bacteria, exhibit antimicrobial activity, enhance weakened intestinal motility, have antisclerotic effect (Titov AM “Preventive and therapeutic effect of kelp ", BIONET Center for Biotechnology LLC, www.npacific.ru/np/gazeta/2004/?n=7&id=3114&nb-13114 S & cHZ & t-h).

Alginates, to varying degrees, have an immunostimulating effect, increasing macrophage phagocytic activity and anti-infection immunity. Known therapeutic efficacy of alginates in infections of the skin and soft tissues of various etiologies, as well as their hepatoprotective effect (Bogdanova T.Ya. et al. “Medical and biological studies of alginic acid salts” www.esus.ru/php/content.php?id= 5119).

Alginates sorb through the intestinal wall and thereby make the immune complexes circulating in the blood, consisting of an immunoglobulin antigen, inactive. With a high concentration of such complexes, the body does not have time to clear them. An excess of circulating immune complexes damages the vascular wall of small blood vessels in almost all organs and causes an inflammatory reaction, which occurs with many diseases (bronchial asthma, rheumatism, rheumatoid arthritis, glomerulonephritis, chronic hepatitis, myasthenia gravis, autoimmune anemias, thrombocytopenia).

Sodium alginate neutralizes hydrochloric acid of gastric juice, forming a viscous alginic acid gel during the neutralization reaction, enveloping the mucous membrane of the gastrointestinal tract, thereby helping to stop local bleeding with ulcerative lesions of the gastric and intestinal mucosa. Alginic acid itself swells during digestion, also exerting an enveloping effect on the walls of the gastrointestinal tract, contributing to a significant weakening of pathological reflexes, including pain ones. The enveloping effect of alginic acid helps to delay the absorption of water in the intestine, which gives normalization to stool ("Alginates", //co.tcw.ru/energolam/alginate).

The disintegrant, as well as the filler (diluent) for the proposed composition is starch (rice, corn, wheat, potato), which satisfies the above properties of excipients in combination with gindarin hydrochloride.

Starch consists of 2 fractions - amylase and amylopectin. Amylase dissolves in warm water, and amylopectin only swells. Starch is mainly used in the manufacture of solid dosage forms. It improves the mobility of the bulk composition and contributes as a disintegrant of disintegration of capsules and tablets. As a stabilizer for suspensions and emulsions, starch is used in the form of a 10% solution (SI Marchenko, “Lecture notes on the course of technology for dosage forms and galenic preparations”, lecture No. 5 t, www.opu.odessa.ua/konsp/KI.229 .doc). Starch paste is used as a binding substance (Industrial Technology of Medicines, edited by prof. V.I. Chueshov, vol. 2, p. 313).

Antifriction substance, as well as a thickener for the proposed composition is Aerosil, which satisfies the above properties of auxiliary substances in combination with hydindarin hydrochloride. Aerosil - silicon dioxide, micronized powder with pronounced adsorption properties. It is used to stabilize suspensions. The thickening ability of Aerosil is used in the preparation of gels. Its adsorption properties are used to stabilize dry extracts (their hygroscopicity decreases). Aerosil powder is used in the manufacture of hygroscopic mixtures and as a dispersant (Marchenko SI, “Lecture notes on the course of technology of dosage forms and galenic preparations”, lecture No. 5 t, www.opu.odessa.ua/konsp/KI.229.doc )

Aerosil is able to bind water in an amount up to 40% relative to its mass without loss of flowability. Water is bound by the chemisorption mechanism as a result of the presence on the surface and partially inside of particles of silanol groups (Si-OH) and their mutual binding using hydrogen bridges that do not allow moisture to penetrate to the particles of the active substance (Yarnykh T.G. et al. " Development of the composition and study of the encapsulated dosage form with the propolis preparation ”//capsulator.narod,ru/propolis.html). In the manufacture of compositions for capsules and tablets, Aerosil is used as an anti-friction substance in an amount of up to 10% of the total weight of the composition. It is also used as an inorganic matrix in sustained-release preparations (Industrial Technology of Medicines, edited by Prof. V. I. Chueshov, vol. 2, p. 313 and p. 633).

The antifriction substance for the proposed composition is polyethylene oxide-4000, which satisfies the above properties of excipients in combination with hydindarin hydrochloride. Polyethylene oxide-4000 is soluble in water and ethanol (S. Marchenko, “Lecture notes on the course of technology for dosage forms and galenic preparations”, lecture No. 5 t, www.opu.odessa.ua/konsp/KI.229.doc).

The binder and filler for the proposed composition is polyvinyl alcohol, which satisfies the above properties of excipients in combination with hydindarin hydrochloride.

Polyvinyl alcohol (PVA) is a solid crystalline polymer with a molecular weight of 10,000-1,000,000. Polyvinyl alcohol of different grades differs in solubility in water and viscosity (the lower the degree of hydrolysis, the lower the solubility, the higher the molecular weight - the higher the viscosity of the polymer solution). When the content of acetate groups is up to 5%, PVA swells in cold water and dissolves in heated to 90-100 ° C. When the content of acetate groups is up to 10%, PVA dissolves in water at temperatures above 65 ° C. When the content of acetate groups is 10-15%, the polymer dissolves in cold water, but precipitates from solution when heated above 40 ° C. When the content of acetate groups is higher than 30%, PVA in water only swells and dissolves in aqueous solutions of alcohols. With the addition of gelatin or other collagen glue, starch, dextrin, CMC, the solubility of PVA in water increases. PVA is soluble in aliphatic glycols, glycerin, urea aqueous solutions, dimethylformamide, dimethyl sulfaxide.

As a plasticizer, glycerin and water are used. PVA molecules are highly polarized, as a result of which polymer films have good adhesion to various types of substrates (Polyvinyl Alcohol, www.art-con.ru/node/575). In practice, water is the solvent for polyvinyl alcohol. It is not soluble in organic solvents, and is also resistant to diluted acids and alkalis. It is used, for example, as an emulsifier, thickener, glue. Low molecular weight polyvinyl alcohol is used in the food industry, as well as in medicine (in the manufacture of drugs, plasma substitutes for blood transfusion, etc.) ("Polyvinyl alcohol", www.slantsy.spb.ru/show _prod.php? Id = 2).

Polyvinyl alcohol-based macroporous hydrogels are known that are formed upon freezing and subsequent thawing of solutions of this polymer, which can be used as components of systems with controlled release of the active substance. They are a system consisting of a set of interconnected pores with porosity up to 90% and pore sizes from units to hundreds of micrometers, occupying the bulk of the volume, separated by sections of crosslinked polymer.

Such an open porous structure enables rapid sorption of liquid in the direction of the center of the dried matrix due to capillary forces, which makes possible rapid swelling of a macroporous hydrogel, regardless of the size of its particles. Moreover, most of the liquid absorbed by the hydrogel during swelling fills the free space of the pores that occupy the bulk of the matrix (up to 90%). The contribution of the polymer part of the material with a small degree of swelling is small (the equilibrium swelling of the polymer part of this hydrogel is about 4 ml of water per 1 g of dry material).

A macroporous hydrogel based on polyvinyl alcohol, due to its structure, slightly changes its equilibrium swelling when environmental conditions change, for example, when the ionic strength or pH changes. This hydrogel has high biocompatibility and the absence of toxic properties (A. Artyukhov, “Macroporous hydrogels based on crosslinked polyvinyl alcohol”, Abstract of dissertation for the degree of candidate of chemical sciences, Moscow-2006).

The binder for the proposed composition is hydroxyethyl cellulose, which satisfies the above properties of excipients in combination with indarine hydrochloride.

Oxyethyl cellulose is a solid amorphous substance, highly soluble in water, in ethanol-water mixtures (30:70), in all cellulose solvents, etc. It does not crystallize, it is biologically inactive (www.xumuk.ru/encvklopedia/2/3069.html) . It is used in the manufacture of oral medicines as a binder (Industrial Technology of Medicines, edited by prof. V.I. Chueshov, vol. 2, p. 313).

Preservatives used in this composition, for example, parabens (nipagin, nipazole, or a 1: 3 mixture thereof), or sorbic acid.

Nipagin is a methyl ester of parahydroxybenzoic acid. Nipazole is propyl ester of parahydroxybenzoic acid. A stronger effect is exerted by their combination in the form of one part of nipazole and three parts of nipagin. The low toxicity of parabens allows their use in drugs for internal use - syrups, tinctures, suspensions, gelatin capsules, etc.

Sorbic acid is used for preserving syrups, extracts, liniment, ointments, etc. (Marchenko S.I., “Lecture notes on the course of technology of dosage forms and galenic preparations”, lecture No. 6 t, www.opu.odessa.ua/konsp/KI .229.doc).

To determine the type and amount of excipients, the physicochemical and technological properties of the active substance were taken into account when developing the composition for the oral drug indindarin. The analysis of these properties showed the need for the use of auxiliary substances that would be chemically inert with respect to the active substance, reduce clumping of the substance, reduce moisture sorption activity and improve the flowability of the composition in the form of a mixture of powders.

In the manufacture of the composition in the form of a suspension or liquid gel, including for filling capsules, the rheological properties of the suspension were taken into account, which ensured the filling of capsules and the chemical inertness of the liquid filler with respect to the active substance, for example, to gindarin hydrochloride.

At the same time, excipients were introduced into the composition of the composition, providing a sustained release from the preparation of the active substance in the form of hydindarin hydrochloride.

The preparation of the composition for the oral preparation in the form of capsules, including the active substance of indindarin, in the form of a physiologically acceptable compound, for example, of the indian hydrochloride, is carried out by known methods in which the powders of the indian hydrochloride and excipients are sieved, weighed and mixed in appropriate proportions. After that, capsules are filled directly with the mass obtained in the form of a mixture of powders, or the obtained powder mixture is granulated by dry or wet granulation using binders, including those providing a prolonged action of the drug. Then, hard gelatin capsules are filled with granulate, including with compaction of the composition, which ensures an increase in the time of receipt of the hydindarin hydrochloride in the environment of the gastrointestinal tract.

The manufacture of a liquid composition for an oral preparation in the form of soft capsules, including gindarin as an active substance, in the form of a physiologically acceptable compound, for example, gindarin hydrochloride, is carried out by known methods in which gindarin hydrochloride powder and, if necessary, powders of auxiliary substances, including those providing prolonged action the drug is sieved, weighed in appropriate proportions and dispersed in a liquid base, making a suspension or liquid gel. After which, in a known manner, a soft or hard gelatin capsule is filled with a suspension or liquid gel.

The technological processes for the production of indindar capsules according to the invention are much simpler than the industrial processes for the manufacture of indindar tablets, due to the fact that the capsules can be filled with the drug unchanged without exposing it to heat and pressure, as in a complex pressing process in the manufacture of tablets. This reduces the cost of the hindarin preparation in capsule form compared to the cost of the hindarin drug in tablet form.

In addition, during encapsulation, the thermal effect on the preparation characteristic of tablet compression is eliminated, which can lead to marriage due to the thermal effect on the components of the tablet mixture.

The preparation of the preparation of gindarin in capsules without granulation, that is, by direct encapsulation of a mixture of powders, further reduces the manufacturing cost due to its economy, since additional equipment for granulation is not required, energy costs are reduced, and labor productivity is increased.

Gelatin capsules easily and quickly disintegrate even in severe disorders of the human gastrointestinal system. The advantage of the capsules is that they are easily swallowed. Gindarin capsules are the most promising for use in gerontology and child psychiatry.

The possibility of carrying out the invention is illustrated by the following examples, but not limited to.

Example 1

A method of obtaining a composition with indarine hydrochloride is carried out according to the following scheme:

1. Sift the ingredients (powders) through a sieve.

2. Weigh the ingredients (powders).

3. Mix the powder of the active substance - Hindarin hydrochloride with powders of auxiliary components with the mandatory control of the heterogeneity of the mixture.

After that, the prepared composition is encapsulated on a Zanazi machine in No. 3 hard gelatin capsules with compaction to a mass of 0.2 g ± 10% in each capsule, to obtain capsules of the oral preparation gindarin of the following composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 25.0 Collagen powder 0.134 67.0 Aerosil 0.002 1,0 Sodium Alginate 0.004 2.0 Corn starch 0.01 5,0 The mass of the contents of the capsule 0.2 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 2

The method of obtaining the composition with indarine hydrochloride is carried out according to the scheme described in example 1. After that, the prepared composition is encapsulated on a Zanazi machine in hard gelatin capsules No. 2 with a seal to a mass of 0.250 g ± 10% in each capsule, receiving capsules of the following oral drug indindarine composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 20,0 Microcrystalline cellulose 0.18 72.0 Potassium alginate 0.01 4.0 Polyethylene Oxide - 4000 0.005 2.0 Polyvinyl alcohol 0.005 2.0 The mass of the contents of the capsule 0.25 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 3

A method of obtaining a composition with indarine hydrochloride is implemented according to the following scheme:

The first three stages are carried out as described in Example 1.

4. Moisturize the resulting mixture of powders with a 1% aqueous solution of hydroxyethyl cellulose.

5. The wet mixture is sieved through a sieve with a hole diameter of 3 mm.

6. The granules are dried at a temperature not exceeding 50 ° C.

7. Dry granules are dusted with aerosil powder.

After that, the prepared composition in the form of a granulate is encapsulated on a Zanazi machine in No. 2 hard gelatin capsules with compaction to a weight of 0.25 g ± 10% in each capsule, to obtain capsules of the oral preparation gindarin of the following composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 20,0 Calcium alginate 0.17125 68.5 Polyvinylpyrrolidone 0,025 10.0 Aerosil 0.00125 0.5 Hydroxyethyl cellulose 0.0025 1,0 The mass of the contents of the capsule 0.25 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 4

The method of obtaining the composition with indarine hydrochloride is implemented as described in Example 3, while in the fourth stage, the resulting mixture is moistened with purified water.

The prepared composition in the form of a granulate is encapsulated on a Zanazi machine in No. 3 hard gelatin capsules with a seal to a mass of 0.2 g ± 10% in each capsule, to obtain capsules of the oral preparation gindarin of the following composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 25.0 Interpolymer complex of polymethacrylic acid and polyethylene glycol KPN-1 0.148 74.0 Aerosil 0.002 1,0 The mass of the contents of the capsule 0.2 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 5

A method of obtaining a composition with indarine hydrochloride is implemented according to the following scheme:

1. Sift the ingredients (powders) through a sieve.

2. Weigh the ingredients (powders).

3. Dry ingredients are introduced into a liquid base and dispersed at a temperature of 50-60 ° C until a homogeneous suspension is obtained.

4. The prepared liquid composition is sterilized at a temperature of 120 ° C for 30 minutes in an airtight volume.

After cooling to room temperature, the gelatin capsules No. 3 are filled with the syringe dispenser using the syringe dispenser and the capsules receive the oral preparation of the following composition, indindarine.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 25.0 Polyvinylpyrrolidone Nicomolecular (8000 ± 2000) 0.01 5,0 Carboxymethyl Cellulose Sodium 0.004 2.0 Nipagin 0.001 0.5 Glycerol 0.135 67.5 The mass of the contents of the capsule 0.20 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 6

A method of obtaining a composition with indarine hydrochloride is implemented according to the following scheme:

1. Sift the ingredients (powders) through a sieve.

2. Weigh the ingredients (powders).

3. Enter the dry ingredients in a liquid base and disperse at a temperature of 50-60 ° C until the concentration of the components in the suspension is uniform.

Then, the prepared composition using a syringe dispenser fill gelatin capsules No. 1, receiving capsules with the gel of the oral preparation Gindarin of the following composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 12.5 Microcrystalline cellulose 0.02 5,0 Cellulose 0.008 2.0 Nipazole 0.004 1,0 Lactulose Syrup 0.318 79.5 The mass of the contents of the capsule 0.4 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 7

A method of obtaining a composition with indarine hydrochloride is implemented as described in Example 6.

Then, the prepared composition using a syringe dispenser fill gelatin capsules No. 1, receiving capsules with the gel of the oral preparation Gindarin of the following composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 12.5 Collagen 0.016 4.0 Polyvinyl alcohol 0.008 2.0 Aerosil 0.004 1,0 Sorbic acid 0.002 0.5 Glycerol 0.32 80.0 The mass of the contents of the capsule 0.4 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 8

A method of obtaining a composition with indarine hydrochloride is implemented as described in Example 6.

After that, the prepared composition with the help of a syringe dispenser is filled into gelatin capsules No. 1, receiving capsules with a liquid gel of the oral preparation gindarin of the following composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 12.5 Cellulose 0.02 5,0 Polyvinylpyrrolidone 0.004 1,0 Nipagin 0.0012 0.3 Nipazole 0.0028 0.7 Glycerol 0.322 80.5 The mass of the contents of the capsule 0.4 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

Example 9

A method of obtaining a composition with indarine hydrochloride is implemented as described in Example 6.

After that, gelatin capsules No. 1 are filled with the syringe dispenser using the prepared liquid composition to obtain capsules with a suspension of the oral preparation of the indindarine of the following composition.

Composition of one capsule The components that make up the capsule Component weight g % Gindarin hydrochloride 0.05 12.5 Polyvinylpyrrolidone 0.004 1,0 Nipagin 0,0008 0.2 Nipazole 0.0024 0.6 Lactulose Syrup 0.2228 55.7 Glycerol 0.12 30,0 The mass of the contents of the capsule 0.4 one hundred

According to this technology, 1000 pieces of hindarine capsules have been accumulated.

The following are examples that confirm the reliability and objectivity of obtaining a technical result — prolonged release ofindarin from capsules compared to a control example.

Comparison of the composition of the control example with the compositions of the examples indicated in the application was carried out according to the dissolution profile of capsules with pharmaceutical compositions containing the active substance of indarine chloride.

The method of measuring solubility is given in the XI State Pharmacopoeia, pp. 159-160. Each dissolution measurement was carried out at a solvent volume of 1 l, a temperature of + 37 ° C, and a basket rotation speed of 100 rpm. The solvent is a solution of hydrochloric acid with a pH of 2 (simulating a gastric environment with a pH of 1 to 3) for 30 minutes, and then a phosphate buffer solution with a pH of 7.5 (simulating a medium of the small intestine with a pH of 7 to 8).

The tables show the data on the released gindarin hydrochloride - this is the amount of the gindarin hydrochloride of the composition transferred to the solution (as a percentage of its content in the capsule, which was taken as 100%). It was calculated as the average of 5 capsules of each composition.

In accordance with the XI State Pharmacopoeia, p. 160, in conventional preparations of prolonged action, the dissolution of 75% of the active substance occurs in an average of 45 minutes. Such drugs are called conditionally immediate-acting drugs.

Example 10

Control composition

The composition of the composition of one capsule No. 1 (capacity - 0.5 ml) The components that make up the capsule Component weight g % Gindarin hydrochloride 0,050 25.0 Potato starch 0,098 49.0 Stearic acid 0.002 1,0 Sugar 0,050 25.0 The mass of the contents of the capsule No. 1 0,200 one hundred

The dissolution profile of the control composition

Time h Released Hindarin hydrochloride,% 0.1 0.5 0.2 2.0 0.4 22.0 0.6 67.0 0.8 92.0 1,0 96.0 1,2 98.0 1.4 98.0 1,6 99.0 1.8 99.0 2.0 100.0

Capsule filling is free, without tamping (compaction) of the powder in the capsule.

The dissolution time of 75% of indindarine hydrochloride in the immediate-release control composition is about 40 minutes (less than 45 minutes).

That is, this composition is an immediate preparation.

Example 11. The solubility of the composition according to Example 1

In this composition, collagen is used as a filler, sodium alginate and starch as a binder, aerosil as an antifriction substance and gel thickener.

Filling of capsules No. 3 with the proposed composition was carried out with compaction of the powder mixture to a filling mass of 0.2 g in each capsule.

The dissolution profile of the composition

Time h Released Hindarin hydrochloride,% 0.1 0 0.5 0.5 1,0 33.0 1,5 62.0 2.0 87.0 2.5 91.0 3.0 97.0 3,5 98.0 4.0 99.0 4,5 one hundred

The dissolution time of 75% of indindrin hydrochloride in this example is about 1.7 hours.

When hydrochloric acid of gastric juice penetrates into a capsule filled with a pharmaceutical composition, indarine hydrochloride gradually dissolves in a liquid medium, penetrating the collagen structure.

At the same time, sodium alginate binds and neutralizes hydrochloric acid of gastric juice, forming a viscous gel of alginic acid during the neutralization reaction, not allowing liquids to penetrate to the particles of the active substance and collagen. Starch, absorbing moisture, forms a starch paste, which additionally binds together particles of the pharmaceutical composition. Aerosil thickens the resulting gel, making it difficult to disintegrate the formed capsule and exit from it of the hydindarin hydrochloride and gel. In addition, it binds the liquid, not allowing moisture to penetrate to the particles of the active substance, keeping it in the mixture, that is, it is used as an inorganic matrix for sustained release preparations.

Example 12. The solubility of the composition according to Example 2

In this composition, microcrystalline cellulose is used as a filler, potassium alginate is used as a binder and a gelling agent, polyvinyl alcohol is used as a binder and a polymer coating for the particles of hydindarine hydrochloride, and polyethylene oxide 4000 is used as an antifriction substance and gel thickener.

The dissolution profile of the composition

Time h Released Hindarin hydrochloride,% one 2 2 24 3 44 four 58 5 77 6 91 7 94 8 98 9 one hundred

Filling of capsules No. 2 with the proposed composition was carried out with compaction of the powder mixture to a filling mass of 0.25 g in each capsule.

The dissolution of 75% of indindarine hydrochloride in this example occurs in approximately 4.8 hours.

Microcrystalline cellulose is insoluble in water and has sorption properties. Moreover, in solid dosage form, microcrystalline cellulose particles, interconnected with particles of other components by binders, form an inert insoluble matrix in which the particles of hydindarine hydrochloride are evenly distributed. This matrix is a barrier that restricts the contact ofindarin hydrochloride with fluids of the gastrointestinal tract (GIT) and ensures its prolonged action.

To ensure the prolonged action of the pharmaceutical composition, the particles of hydrochloride gindrin, having sizes from about 10 to about 100 microns, are coated with a polyvinyl alcohol shell before mixing with other components in a fluidized bed installation, followed by drying. In addition, solid porous polyvinyl alcohol particles are added to the pharmaceutical composition that are resistant to diluted acids and alkalis and provide sorption of the liquid entering the capsule.

When hydrochloric acid of gastric juice penetrates into a capsule filled with the proposed pharmaceutical composition, indarine hydrochloride gradually dissolves in a liquid medium, penetrating into the structure of the matrix of microcrystalline cellulose and polyvinyl alcohol. In this case, potassium alginate binds and neutralizes hydrochloric acid of gastric juice, forming a viscous gel of alginic acid during the reaction, which impedes the penetration of gastrointestinal fluids to the particles of the hydrochloride hydrochloride and the particles of the microcrystalline cellulose matrix and polyvinyl alcohol, while bonding them to each other. Polyethylene oxide-4000 thickens the resulting gel, making it difficult to disintegrate the formed capsule and exit from it of hydindarin hydrochloride and gel in the digestive tract. In addition, it binds the liquid of the gastrointestinal tract, not allowing moisture to penetrate to the particles of the active substance, keeping it in the mixture.

Example 13. The solubility of the composition according to Example 3

The granules of the composition are made from a mixture of hydindarin hydrochloride, calcium alginate, polyvinylpyrrolidone and aerosil. To improve the binding in the granules of the particles of the particles of the components, the granules are made on the basis of an aqueous solution of hydroxyethyl cellulose.

In this case, calcium alginate in granules provides the deposition of the active substance and its prolonged release.

Additionally, the granules are coated in a "fluidized bed" installation, followed by drying with a polyvinylpyrrolidone shell and then dusted with aerosil powder.

The dissolution profile of the composition

Time h Released Hindarin hydrochloride,% one less than 1 2 6 3 12 four 21 5 34 6 51 7 66 8 74 9 87 10 95 eleven 98 12 one hundred

Filling of capsules No. 2 with the proposed composition was carried out with compaction of granules to a filling mass of 0.25 g in each capsule.

The dissolution time of 75% of indindarine hydrochloride in this example is a little more than 8 hours.

Example 14. The solubility of the composition according to Example 4

In this example, the interpolymer complex of polymethacrylic acid and polyethylene glycol (KPN-1) is used as a filler and a polymer shell of granules in their manufacture, and Aerosil is used as an antifriction substance and thickener.

In the manufacture of granules, they are additionally torn by a polymer shell of polymethacrylic acid in a "fluidized bed" installation, followed by drying.

Polymethacrylic acid with a high molecular weight, which is part of the composition of CPN-1, does not dissolve in water, but only swells in it. This carrier provides a uniform flow of hydarin hydrochloride into the gastrointestinal tract for a long time.

The dissolution profile of the composition

Time h Released Hindarin hydrochloride,% 2 one four eleven 6 23 8 39 10 55 12 64 fourteen 84 16 96 eighteen 97 twenty 98 22 99 24 one hundred

Filling of capsules No. 3 with the proposed composition was carried out with compaction of granules to a filling mass of 0.2 g in each capsule.

The dissolution time of 75% of indindrin hydrochloride in this example is about 13 hours.

Example 15. The solubility of the composition according to Example 5

In this composition, glycerin is used as a liquid base, polyvinylpyrrolidone as a thickener, carboxymethyl cellulose sodium salt as a thickener and gelling agent, and nipagin as a preservative.

The dissolution profile of the composition

Time h Released Hindarin hydrochloride,% 0.5 fourteen 1,0 51 1,5 87 2.0 94 2.5 96 3.0 97 3,5 99 4.0 one hundred

Filling of capsules No. 3 with the proposed composition was carried out to a filling mass of 0.2 g in each capsule.

The dissolution of 75% of indindarine hydrochloride in this example occurs in approximately 1.3 hours, that is, in a time longer than for a control composition with immediate release.

Example 16. The solubility of the composition according to Example 6

In this composition, lactulose syrup is used as a liquid base, microcrystalline cellulose is used as an insoluble matrix in which hydindarine hydrochloride is evenly distributed, methylcellulose is used as a thickener, and nipazole is used as a preservative.

The dissolution profile of the composition

Time h Released Hindarin hydrochloride,% 0.5 3 1,0 9 1,5 22 2.0 35 2.5 53 3.0 72 3,5 83 4.0 92 4,5 96 5,0 98 5.5 one hundred

Filling of capsules No. 1 with the proposed composition was carried out to a filling mass of 0.4 g in each capsule.

The dissolution time of 75% of indindarine hydrochloride in this example is about 3.2 hours.

Example 17. The solubility of the composition according to Example 7

In this composition, glycerin is used as a liquid base, collagen is used as a matrix in which hydindarine hydrochloride is evenly distributed, polyvinyl alcohol and aerosil are used as a thickener, and sorbic acid is used as a preservative.

The dissolution profile of the composition

Time h Released Hindarin hydrochloride,% 0.5 8 1,0 22 1,5 43 2.0 61 2.5 82 3.0 91 3,5 94 4.0 96 4,5 98 5,0 99 5.5 one hundred

Filling of capsules No. 1 with the proposed composition was carried out to a filling mass of 0.4 g in each capsule.

The dissolution time of 75% of indindrin hydrochloride in this example is about 2.3 hours.

Example 18

30 pcs capsules No. 0 were filled with granules from Example 5 of the description of the invention, granules from example 4 of the description of the invention and a mixture of powders from control example 1 in a percentage weight ratio of 40:30:30 with compaction to a weight of 0.5 g in each capsule. After that, the dissolution profile of these capsules was determined.

The dissolution profile of the composition

Time h Hindarin hydrochloride released (%) one 29th 2 33 four 41 6 55 8 68 10 81 12 86 fourteen 94 16 98 eighteen 99 twenty one hundred

The dissolution of 75% of indindarine hydrochloride in this example takes about 9 hours.

The above examples show that the proposed composition has a prolonged effect in comparison with the control composition of the immediate release of the active substance (the dissolution time of 75% of the hydroxychloride hydrochloride of various compositions is from 1, 3 hours to 13 hours, instead of 48 minutes for the control composition).

The therapeutic activity ofindarin in the form ofindarin hydrochloride in combination with the above excipients has not been known to date and does not follow from the prior art.

When developing the composition, the physical and technological properties of the active substance of Hindarin hydrochloride and the selected auxiliary substances were taken into account. When developing the composition, the chemical inertness of the active substance to the auxiliary substances that make up the composition and the material of the capsules was also taken into account. In this regard, the choice of excipients of the proposed composition and their percentage in it for the active substance --indarina hydrochloride, is an individual procedure that depends on the above properties of a particular active substance and excipients included in the proposed composition.

Thus, the proposed composition in the form of a capsular oral form simplifies the manufacturing process of the oral drug gindarin and, as a result, reduces the manufacturing cost of this drug, reduces the amount of marriage during manufacture, as well as the possibility of prolonging the action of the active substance.

The proposed composition based on indindarin can be used for serial production of oral preparations in the pharmaceutical industry.

Claims (10)

1. A composition comprising, as the active substance, indindarine in the form ofindarine hydrochloride, and chemically inert to the active substance and a physiologically acceptable excipient or several excipients, characterized in that at least one excipient included in the composition provides prolonged release ofindarine gyrochloride in the following ratio of components in the composition, wt.%:
gindarin hydrochloride 2.0-50.0 excipient rest,
wherein the composition is granules, or a mixture of powders, or a mixture of granules with a powder, or a liquid, or a soft form. 2. The composition according to claim 1, representing a mixture of powders, or granules, or a mixture of granules with a powder, which as excipients contains a filler, or a filler in combination with either a disintegrant, or an antifriction substance, or a binder, or a mixture thereof, characterized in that the content of components in the composition is as follows, wt.%:
gindarin hydrochloride 2.0-50.0 disintegrant 0.5-10.0 anti-friction substance 0.2-10.0 binder 0.5-5.0 filler rest 3. The composition according to claim 1, which is a liquid form - a suspension or a soft form - gel, characterized in that as an auxiliary substance it contains a liquid base or liquid base mixed with a thickener or preservative, or with a mixture thereof, in the following the content of components in the composition, wt.%:
gindarin hydrochloride 2.0-50.0 thickener 0.1-20.0 preservative 0.5-5.0 liquid base rest 4. The composition according to claim 2, characterized in that the filler, including providing a prolonging effect of the active substance --indarine, is selected from the following series of substances: collagen, methyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, calcium alginate, polyacrylic acid, interpolymer complex of polymethacrylic acid and polyethylene glycol KPN-1 or a mixture of these components. 5. The composition according to claim 2, characterized in that the disintegrant is selected from a number of the following substances: agar-agar, alginic acid, starch (rice, wheat, corn, potato) or a mixture of these components. 6. The composition according to claim 2, characterized in that the antifriction substance, including one providing the prolonged action of the active substance --indarine, is selected from the following substances: aerosil, polyethylene oxide-4000 or a mixture of these components. 7. The composition according to claim 2, characterized in that the binder, including providing a prolonging action of the active substance --indarina, is selected from the following substances: hydroxyethyl cellulose, polyvinyl alcohol, sodium or potassium alginate or a mixture of these components. 8. The composition according to claim 3, characterized in that the thickener, including one providing the prolonging action of the active substance - indarine, is selected from the following substances: microcrystalline cellulose, collagen, methyl cellulose, carboxymethyl cellulose or its sodium salt, polyvinylpyrrolidone, aerosil, polyvinyl alcohol or a mixture of these components. 9. The composition according to claim 3, characterized in that the preservative is selected from a number of the following substances: nipagin, nipazole, sorbic acid or a mixture of these components. 10. The composition according to claim 3, characterized in that the liquid base is glycerin or lactulose syrup or a mixture of these components.