RU2188017C1 - Method for obtaining tablets of combined trimetoprime preparation and sulfametoxasole - Google Patents

Abstract

FIELD: pharmaceutics. SUBSTANCE: it is conducted a step-by-step mixing of trimetoprime with additional substances - pre-prepared mixture of starch and milk sugar, and then - with sulfametoxasole. The mixture obtained is impregnated with granulating liquid as 10% polyvinylpyrrolidone aqueous solution at 25000-40000 molecular weight. Then comes damp granulation, drying, dry granulation, powdering due to successive mixing of dry granulate with reduced substandard tablets and calcium stearate, and tabletting. The method enables to utilize substandard production, introduce a substance which softens the taste of a tablet due to decreased number of additional substances along with keeping both integrity and decomposition capacity of a tablet. The tablets are very useful in treating infections of respiratory, urinary and gastrointestinal tracts, surgical infection and other infectious diseases. EFFECT: higher efficiency.

Description

 The invention relates to the production of solid forms of antibacterial combined preparations containing a derivative of diaminopyrimidine - trimethoprim and sulfonamide - sulfamethoxazole, used as a chemotherapeutic agent for infections of the respiratory tract, urinary tract, gastrointestinal tract, surgical infection and other infectious diseases.

 In 1961, the antimicrobial effect of trimethoprim was shown, and in 1965-1967. the combined preparation of trimethoprim with sulfamethoxazole - bactrim was released. The principle of the drug’s action is based on its inhibition by the components of the synthesis of the vitamin necessary for microorganisms - folic acid. Resistance to this drug develops rather slowly and weakly, due to the combined composition. Bactrim (biseptol, cotrimazole, etc.) is produced in tablets for children and adults, containing 20 or 80 mg of trimethoprim and 100 or 400 mg of sulfamethoxazole, respectively (A. Chernomordik. Use of antibiotics and other chemotherapeutic drugs. Reference book, Kiev, Vysha school 1988, p. 161-162).

 A known method of producing tablets of the combined preparation of trimethoprim with sulfamethoxazole by mixing the active substances - trimethoprim and sulfamethoxazole with excipients and moistening the mixture with an aqueous or alcoholic solution of tylose - granulating liquid (FR 2321893 A, 1976). The amount of excipients is about 40%, which increases the solubility time of the tablet and the release time of the active substances.

 Closest to the invention are a known method for producing tablets of the combined preparation of trimethoprim and sulfamethoxazole and tablets obtained by this method, which consists in mixing the active substances - trimethoprim and sulfamethoxazole with excipients, granulation, drying, dusting and tabletting, and dusting is carried out with a mixture of starch with stearate calcium or magnesium (RU 2141823 C1, 1997). The patent does not indicate what is a granulating liquid, the molecular weight of polyvinylpyrrolidone (PVP) used in the composition of excipients is also not indicated. The amount of auxiliary substances is 18.82-19.93 wt.%. It is shown that the auxiliary substances with which the active substances are mixed are starch and PVP; pellets to be tabletted also contain a “substrate” of starch hydrolyzate. The tablets do not contain substances that soften their taste. In addition, the production is inevitable is the formation of a certain number of substandard tablets, the disposal of which in a known manner is not provided.

 An object of the invention is to reduce the total amount of the listed auxiliary substances and to introduce due to this substance softening the unpleasant taste of the tablets, as well as the disposal of substandard products while maintaining the strength and disintegration of the tablets.

 The specified technical result is achieved by the fact that in the method for producing tablets of the combined preparation of trimethoprim with sulfamethoxazole by mixing the active substances — trimethoprim and sulfamethoxazole with excipients, mixing the resulting mixture with granulating liquid, wet granulation, drying, dusting and tabletting, the trimethoprim is mixed with excipients sequentially - a pre-cooked mixture of starch and milk sugar, and then with sulfameth ksazolom, as the granulating liquid is a 10% aqueous solution of PVP having a molecular weight of 25000-40000, after drying, is carried out further dry granulation and powdering is carried out by mixing the dry granulate consistent with the broke substandard tablets and calcium stearate.

 The experiments showed that PVP molecular weight beyond these limits (less than 25,000 and more than 40,000) can not only dramatically reduce the strength of the tablets, but also adversely affect the rate of release of the active substance.

 The total amount of excipients, including milk sugar, in the method according to the invention is about 25 wt.% Per tablet, but more than 13 wt. % of them are milk sugar, which is necessary to soften the taste of the tablet. In addition, part of the excipients used for dusting was replaced with ground substandard tablets (about 0.48 wt.% Per tablet), which avoided the presence of production waste.

 Such a change in the composition of the pharmaceutical composition was made possible only thanks to a new technology for the preparation of tablets.

 Any permitted HF XI starch, preferably potato, may be used in the process.

 The color of the tablets is determined by the color of the components of the pharmaceutical composition. So, sulfamethoxazole from Virkh Laboratories LTD, India and Siris LTD, India is characterized as a white or almost white crystalline powder, and trimethoprim from Dong Ha Pharm. Ind. Co. LTD, Korea - white or yellowish-white powder. Therefore, the finished tablets according to the invention ("Dvaseptol") are characterized as "white or white with a creamy tint" color. In appearance, the tablets meet the requirements of the Global Fund XI, issue 2, p. 154.

 The average weight of tablets with a dose of 0.12 g (0.1 sulfamethoxazole and 0.02 g of trimethoprim) intended for children under 12 years is from 0.154 to 0.166 g, and with a dose of 0.48 g (0.4 g of sulfamethoxazole and 0.08 g of trimethoprim) - from 0.62 to 0.68 g.

 The drug withstands the requirements for microbiological purity (GF XI, issue 2, p. 193, change 1, category 3 g).

 The invention is illustrated by the following example.

 EXAMPLE 1

In the tray dryer, potato starch with a moisture content of 18% is loaded, dried at 50 ^{° C.} for 4.5 hours to a moisture content of 5% and sieved. PVP with a molecular weight of 35,000 was dissolved in water at 65 ^° C and stirring for 15 minutes to obtain a uniform, clear, 10% solution.

 Sifted sulfamethoxazole in the amount of 17.62 kg is loaded into the mixer. 2.19 kg of dried and sifted potato starch and 3.71 kg of sifted milk sugar are mixed in a separate container. Sifted trimethoprim (3.56 kg) is triturated with the resulting mixture of starch and milk sugar. Then the trituration mixture is added to the mixer, stirred for 10 minutes and then moistened with a solution of PVP with stirring. After stirring for 5 min, a uniformly moistened mass is obtained, which is passed through a granulator with a diameter of the drum holes of 1.2 mm, laid out on trays and sent for drying.

The wet granulate is dried in a tray dryer for 14 hours at 45 ^o C, periodically mixing, to a residual moisture content of 2.0%. Then the dried mass is passed through a granulator with a hole diameter of 1.0 mm 27.24 kg of dry granulate is loaded into the boiler to obtain a tablet mass, then 0.13 kg of ground substandard tablets are added. The contents are mixed for 12 minutes, 0.255 kg of sieved calcium stearate are added, mixed for another 2 minutes and discharged.

 Tableting is carried out on a rotary press, for Dvaiseptol tablets 0.12 g - punches with a diameter of 8 mm, flat punches with a bevel without risks; for tablets "Dvaseptol" 0.48 g - punches 13 mm, flat punches with a risk and a facet. 3 kg of the mixture are poured into the press hopper and tabletting is started. Filling is carried out as the hopper is released. The resulting tablets are screened under draft in a fume hood through a metal sieve from dust, substandard tablets are rejected. Conditioned tablets have a flat-cylindrical shape, solid edges, a smooth uniform surface and sufficient strength under mechanical stress. Substandard tablets are collected in a separate container and sent for grinding into a granulator. The resulting tablets correspond to FSP 42-0055-0364-00, GF XI, issue 2, p. 154. The output at the stage of obtaining tablets is 98.74%. Disintegration of the tablet in an aqueous medium 11 min. Dissolution tests are stable.

Claims (1)

 A method of producing tablets of a combined preparation of trimethoprim with sulfamethoxazole by mixing the active substances - trimethoprim and sulfamethoxazole with excipients, mixing the resulting mixture with granulating liquid, wet granulation, drying, dusting and tabletting, characterized in that trimethoprim is mixed with excipients in succession - a pre-prepared mixture starch and milk sugar, and then with sulfamethoxazole, as granulating fat bone using a 10% aqueous solution of polyvinylpyrrolidone having a molecular weight of 25000-40000, after drying, is carried out further dry granulation and powdering is carried out by mixing the dry granulate consistent with the broke substandard tablets and calcium stearate.