Medicinal product on the basis of arbidol

 

(57) Abstract:

The invention relates to the pharmaceutical industry and relates to the connection of a number of oxyindole, namely ethyl ester of 6-bromo-4-dimethylaminomethyl-1-methyl-5-hydroxy-2-phenylthio-methylindolin-3-carboxylic acid hydrochloride, which is an active substance of the drug Arbidol, and the drug based on it in the form of gelatin capsules. The invention lies in the fact that it contains Arbidol and adjuvants, which are used potato starch, methylcellulose, polyvinylpyrrolidone molecular, aerosol, calcium stearinovokisly, tween-80 at a certain ratio of components, while gelatin capsule contains gelatin, glycerol and water at a specific ratio of ingredients. The invention provides for the creation of dosage forms with stability during storage with virpiniemi action against influenza A and B. table 1.

The invention relates to known compounds of a number of oxyindole, namely ethyl ester of 6-bromo-4-dimethylaminomethyl-1-methyl-5-hydroxy-2-phenylthio-methylindolin-3-carboxylic acid hydrochloride, which is an active substance of the drug Arbidol, and the drug in his day as an anti-influenza drugs are only two drug - amantadine and close its structural analog-remantadin. However, these drugs are inactive in the treatment of influenza type C. They are toxic. Their use in humans is accompanied by side effects, the drugs act on the Central nervous system (insomnia, headache, loss of concentration, vomiting). In addition, the widespread use of rimantadine and amantadine for the treatment of patients with influenza And led to the emergence of strains of influenza viruses that are resistant to these drugs.

Known drug Arbidol - domestic immunomodulator, is used for prophylaxis and treatment of influenza type a and/ Mashkovsky M. D. Handbook “Drugs” M, Medicine, 2001/.

It is known tool with interferon-inducing and immunomodulatory activity, containing 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate /Pat. Of the Russian Federation No. 2033157/.

It is known tool that has preventive and therapeutic effects against influenza virus type b, containing 1-methyl-2-phenylthiomethyl-3-carbethoxy-dimethylaminomethyl-5-hydroxy-6-bromido hydrochloride monohydrate /Pat. Of the Russian Federation No. 2008004/.

Known drug 1-methyl-2-Fe is nutrient supplements and possessing with interferon-inducing and immunomodulatory activity /Pat. Of the Russian Federation No. 2033157/.

All of these patents relate to the active substance of the drug Arbidol, which was held clinical studies and recommended for medical use. Arbidol is non-toxic, well tolerated and no side effects, insoluble in water, stable in storage only in the dark place.

The closest technical solution to the claimed composition is a drug in solid form on the basis of Arbidol - ethyl ester 6-bromo-5-hydroxy-4-dimethylaminomethyl-1-methyl-2-phenylthiomethyl-3-carboxylic acid hydrochloride monohydrate for prophylaxis and treatment of influenza and acute respiratory diseases /Pat. Of the Russian Federation No. 2033156/.

Lack of funds is unstable during storage, the low quality of the tablets (low strength), inconvenience in use.

The purpose of this invention is the creation of the dosage form of the drug on the basis of Arbidol in the form of capsules, from which the active substance is rapidly and completely released during the reception of its patients, the creation of dosage forms with stability during storage.

This goal is achieved through the use of the drug is performance communications additives, the tool consists of a gelatin capsule filled with a filler consisting of Arbidol and auxiliary additives, which are used potato starch, methylcellulose, polyvinylpyrrolidone molecular, aerosol, calcium stearinovokisly, tween-80 in the following ratio of ingredients, wt.%:

Arbidol 47-52

The Methylcellulose 1,0-1,5

The low-molecular polyvinylpyrrolidone 0,02-0,05

Aerosil 0,8-1,2

Tween-80 0,02-0,025

Calcium stearinovokisly 0,3-0,5

Potato starch Else

while gelatin capsule further comprises glycerin and water in the following ratio of ingredients, wt.%:

Gelatin 15-20

Glycerin 2-5

Water The Rest

The use of gelatin capsules for Arbidol unknown.

The claimed ratio of ingredients is best found experimentally and provides necessary as a means of compliance with the global Fund XI and shelf life of over 5 years.

As a suitable filler was selected starch. The use of starch with the ability to provide the required performance retract. In addition, the introduction of a starch composition having anti-friction properties, helps to reduce the content of other anti-friction additives, Aerosil and calcium stearinovokisly to values not exceeding the allowed Pharmacopoeia GF XI.

Comparison of the effect of different binding agents on the manufacturability of the process of granulation and drying, as well as on the quality of pharmaceutical forms revealed the inclusion of polyvinylpyrrolidone in the composition. For more uniform distribution of the polyvinylpyrrolidone used in the form of aqueous solution. Noncompliance found ratios of ingredients is not possible to achieve the required quality and stability of the composition during storage.

The proposed medication is in the form of powder filling, which are filled in gelatin capsules, which allows for maximum adaptability subsequent packaging.

The method of obtaining new funds includes mixing the sifted powders Arbidol, starch, methyl cellulose, Aerosil with an aqueous solution of the polyvinylpyrrolidone, the moist granulation by adding Tween-80, drying, dry granulation and dusting. To what lcium stearinovokisly or maybe its mixture with a small amount of starch.

Received the drug meets the requirements of the global Fund XI (in appearance, raspadaemosti, dissolution, uniformity of dosage and other requirements), with no bitter taste, stable in storage and has a shelf life of over 5 years.

The invention is illustrated by the following examples (see table).

Example 1. Mix the sifted powders Arbidol, potato starch and Aerosil, methylcellulose, vztah in estimated quantities, moisturize 3%-nm aqueous solution of polyvinylpyrrolidone is stirred until a uniform distribution of moisture, granularit adding Tween-80 and dried to a residual moisture content of 2%. Dry granules grind, optivault calcium stearinovokisly and possibly the rest of the starch. The obtained filler fill gelatin capsules on a machine for packaging (Capsulator Globex Mark-2, Nethelands) is usually adopted in pharmacy technology, which meets the requirements.

Technology of preparation of the proposed gelatin capsules is simple and is as follows: pour the gelatin with water and leave to swell for 1.5-2 h, then the mass when heated, liquefied and mix it with glycerin.

attachment, the absorption or bioavailability of a drug to obtain the desired therapeutic effect. In the world practice is widely used dosage forms based on natural polymers, in particular gelatin. Due to the physico-chemical properties of gelatin, his indifference to the body on the basis of the developed sufficient amount of dosage forms. A significant advantage of this framework is the easy absorption of drugs from her and easy digestibility of all components. Due to the slipperiness of the basis for the moisture in the oral cavity drug products based on it are easily ingested.

Improving the lubricating properties of gelatin capsules and bioavailability controlled using such physical factors as the melting temperature and the time of dissolution. The melting point was determined by method 3 GF XI edition. The time of dissolution was determined by valuation method raspadaemosti dosage forms. The base is a jelly-like homogeneous mass, without smell, taste changes depending on the number glycerine from sour-sweet to sweet and sour, the melting point varies 37,2-41,s in medical practice and are issued by enterprises in accordance with the requirements requirements of the relevant pharmacopoeial articles: gelatin - article 309 of the State Pharmacopoeia X edition, glycerin - FS 42-2202-84, purified water - FS 42-261989.

When the inventive composition of the filler comes in a capsule, on its walls when interacting with the gelatin forms the inner layer in the form of a gel film, resulting in improved performance during storage. Thus, the capsule is double-layered, i.e., consists of the upper gelatin layer and the internal in the form of a film.

Physical stability of gelatin capsules filled with tested while keeping thermostat (5°C To 40°C) temperature conditions change every 24 hours, and then tested the samples in a day, 1 week and 4 weeks. Samples which showed minimal or not observed any changes in the physical properties, were analyzed for their chemical stability properties.

Chemical stability of gelatin capsules filled with tested during storage of the sample at 70°C for 4 weeks.

The results of physico-chemical studies have attested to the fact that the relative humidity of the capsules remained almost without changes: 1 week - 0,84, 4 week - 0,81, the e effect of the proposed means of Arbidol in the form of gelatin capsules influenza virus type a and b confirmed in patients with clinical diagnosis of “flu”, located on outpatient treatment. The total number of patients treated by Arbidol in the form of gelatin capsules, amounted to 25 people, among them 5 people with the flu is caused by virus type, and 20 people with influenza A. the Diagnosis was confirmed by serological reactions. Patients received Arbidol 200 mg 3 times daily for 3 days.

Therapeutic efficacy was assessed (compared to placebo) duration of major symptoms of the flu-fever, intoxication and catarrhal syndrome, as well as the duration of the disease, the frequency and the form of arising complications. The results of the study of clinical effectiveness of Arbidol in gelatin capsules at outpatients indicate a therapeutic effect, expressed in significantly shortening the number of indicators in the duration of fever and such clinical symptoms as headache, chills, etc; the total duration of the disease; prevention of complications compared with patients who received symptomatic therapy.

A study of the effectiveness of Arbidol as a means of emergency prevention in family outbreaks of influenza a and B. Arbidol received 10 people who had contact sden within 5 days. The control group served 12 people exposed to the flu Century, These people received symptomatic treatment.

Analysis of the material on the application of Arbidol in gelatin capsules as a means of emergency prevention in family outbreaks of influenza indicate a high prophylactic efficacy of the drug.

Epidemiological data are confirmed by the results of immunological tests. The coefficient of effectiveness of Arbidol was 86.3% compared with the placebo group, and the rate of growth of antibodies to influenza virus In was equal to 4, while in control group it was 9.7.

Studies have shown that Arbidol the proposed structure in gelatin capsules are well tolerated and virtually harmless to the human body.

Thus, the positive effect of the invention is as follows: found part of Arbidol in the form of gelatin capsules, which has a strong virpiniemi effect against influenza virus a and b, treatment-and-prophylactic efficiency when influenza type a In humans, as well as having anti-influenza drugs amantadine and rimantadine of bctest in the treatment and prevention of influenza a and b, where these drugs are ineffective.

Drug, possess virpiniemi effect against influenza virus A and B, containing Arbidol and auxiliary additives, characterized in that it is made in the form of gelatin capsules containing Arbidol and adjuvants, which are used potato starch, methylcellulose, polyvinylpyrrolidone molecular, aerosol, calcium stearinovokisly, tween-80 in the following ratio, wt.%:

Arbidol 47-52

The Methylcellulose 1,0-1,5

The low-molecular polyvinylpyrrolidone 0,02-0,05

Aerosil 0,8-1,2

Tween-80 0,02-0,025

Calcium stearinovokisly 0,3-0,5

Potato starch Else

while gelatin capsule contains gelatin, glycerin and water in the following ratio of ingredients, wt.%:

Gelatin 15-20

Glycerin 2-5

Water The Rest



 

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