A method of obtaining a bronchodilator drug composition of the prolonged action on the basis of theophylline

 

(57) Abstract:

The invention relates to medicine, in particular to the pharmacy. The purpose of the invention is the increase in the duration of maintaining an effective concentration of a drug in the blood. This objective is achieved in that the original mix theophylline with interpolymer complexes (IPC) polymethacrylic acid and polyethylene glycol, the mixture is then moistened with a solution of FDI in phosphate buffer, alcohol or in an aqueous-alkaline solution of pH 4.5 and 7.5, the resulting mass is subjected to wet granulation, then dried and conduct follow-on operations for the manufacture of finished dosage forms. Alternatively, the tablets can be obtained by the method of briquetting. Tablet cover film-forming solution based on the same IPC. The product obtained by the proposed method, is effective in a dose of 450 - 600 mg/day, maintains therapeutic concentrations of theophylline in plasma with 2 - fold admission, the mean absorption time 12 noon, 2 C.p. f-crystals, 3 tables.

The invention relates to medicine, more specifically to a method for producing tablets of theophylline prolonged action, which are used in medicine as a bronchodilator in all FEMA and others.

Currently, a large variety of bronchodilator drug compositions prolonged action on the basis of theophylline containing various polymeric carriers of natural and synthetic origin, obtained by different technological methods: microencapsulation, microgranuloma, pressed into pellets and others. It is known drugs manufactured by the leading companies of different countries, such as Quibron", "Slophillin", "Teostat", "Bronchoretard". "Teo-24". "Teo-Dur".

A method of obtaining a bronchodilator drug composition with a prolonged action, containing encapsulated theophylline, polyvinylpyrrolidone, sugar, ethylcellulose. Medication in pill form is obtained by applying the solution of theophylline with polyvinylpyrrolidone on sugar granules with a diameter of 0.71-0.84 mm, with subsequent evaporation of the solvent. Received theophileescargot granules coated with ethyl cellulose solution in ethyl alcohol. The granules are mixed with the lactose and tabletirujut, as a lipid coating applied gidrirovannoe vegetable oil. By changing the ratio of polyvinylpyrrolidone and cellulose, achieve different dissolution rate. Patients the past 12 o'clock The specified drug is characterized by a large mass used auxiliary substances and complexity of the technological process of its receipt.

Also known is a method of obtaining pharmaceutical compositions on the basis of theophylline following composition (tablets), mg: Theophylline monohydrate 330

Oxypropylated - allysa (100 SP) 92

Oxypropylated - cellulose (15000 SP) 25 Lactose 80 magnesium Stearate 5 the silicon Dioxide 3

This method consists in mixing the source of the ingredients, followed by pelletizing, and the composition is characterized by complexity and the large number of auxiliary substances.

A method of obtaining pharmaceutical compositions on the basis of theophylline, of the following composition (tablets), mg: Theophylline 300

Disubstituted calcium phosphate 300

Acetylphenyl - cellulose 30 Ethylcellulose 30 Stearate 4,6

This method consists in mixing theophylline disubstituted with calcium phosphate. The resulting mixture is moistened with a solution of acetylcellulose and ethyl cellulose in a mixture of organic solvents (50 ml of isopropyl alcohol and 150 ml of methylene chloride) and get a granulate which is dried, optivault (stearate) and the table is cherished the complexity and high content of auxiliary substances (55% by weight of the tablet). In addition, the method of obtaining this song toxic, flammable and explosive organic solvents complicates the process requires additional equipment.

Closest to the proposed to the technical essence and the achieved effect are the tablets of theophylline prolonged action on the basis of polyvinyl chloride and the way they are received. Tablets consist of a polymer matrix, allowing a controlled release of single therapeutic doses of theophylline for about 8 hours Tablets contain a therapeutically effective amount, about 100-1000 mg of anhydrous theophylline, 5-15 wt. polyvinyl chloride (PVC), counting on a lot of tablets, and 0-2 wt. hydrophobic moving.

The method consists in the wet granulation of theophylline with a solvent containing ethanol, drying the granules at 110aboutC for 20-30 min, Blagoi granulation PVC with solvent containing ethyl alcohol and methylene chloride in an equal volume ratio, drying the granules PVC at temperatures below 90aboutWith the mixing of theophylline granules and PVC, optional addition of moving, such as stearate, again requiring protect personnel from harmful fumes, and equipment fire and explosion measures.

The aim of the invention is to remedy these disadvantages.

This goal is achieved by using a method of receiving bronchodilators composition of prolonged action, including a mixture of theophylline with the polymer matrix, the introduction of a moisturizing agent, granulation, drying the mixture and then get the dosage form, characterized in that the polymer matrix used interpolymer complex polymethacrylic acid and polyethylene glycol, wetting agent is water or 5-15 wt. the solution of interpolymer complex pH 4.5 and 7.5 in aqueous-alkaline solution, phosphate buffer or ethanol.

It was found that if the wetting agent to use a solution of interpolymer complex in phosphate buffer, in aqueous-alkaline medium or in ethanol, improving such technological parameters of granules as bulk density and flowability, and also improves the quality of the finished tablets. This goal, as it turns out, can be accomplished by using another variant of the method, which is that mixed in a dry state theophylline out grinding, optivault obtained granules with magnesium stearate or calcium and tabletirujut.

In both cases, to mask the bitter taste of the dosage form in the form of tablets and increase the duration of action of the drug in the body can be applied to these forms of protective polymeric membranes from solutions 5-15 wt. the same interpolymer complex, 0-4,5 wt. caustic soda or sodium bicarbonate, 1-5 wt. Tween-80 with the addition of 0-2 wt. diocese titanium in distilled water or ethyl alcohol.

In table. 1 shows the technological characteristics of the granules obtained in the first embodiment of the proposed method, which prove the efficiency of the solutions of the CPN as a moisturizing agent. Indicators release of theophylline are shown in table. 2.

The inventive method allows for simplified technology to obtain the target product of high quality. The method is simple to implement, does not require special equipment. Get a bronchodilator drug composition has pharmacological properties typical of theophylline. Bronchodilatory effect of the proposed drug develops slowly over 3-6 h after administration. Theophylline desire in the blood within 12-24 hours Persistent clinical effect is achieved after a few days of treatment.

Studies of chronic toxicity of the composition prepared by the proposed method, carried out in experiments on dogs have shown that the drug with the introduction of an oral dose of 100 mg/kg for 6 months. does not cause any changes on the part of animal behavior, weight gain, peripheral blood, as well as indicators of the morbid morphological studies of organs and tissues in experimental dogs.

In the clinic, the drug is tested in comparison with a known drug Teodor. Special attention was paid to pharmacokinetic studies. Using strictly selected according to age, weight, severity of the disease group of patients, determined the concentration of theophylline in blood by high performance liquid chromatography after 1, 2, 6, 9, 12, and 24 h after administration of a dose of 300 mg of the compound prepared by the present method, and also collected urine at intervals 0-6, 6-12 and 12-24 hours

The results of calculations of pharmacokinetic parameters are presented in table. 3.

Slow absorption of theophylline from prolonged forms is clearly seen when comparing independent of the parameter "average time of suction". For drugs the niche 8,2 h, for conventional tablets of theophylline this parameter is only 1.4 hours, a Similar ratio is obtained by comparing the time of the suction 75% dose. The result is full, but slow suction, there is a significant increase in the duration of circulation of theophylline when receiving prolonged forms. Integral parameter that characterizes the "average lifetime" medicinal substance in the body for compositions prepared by the present method, is equal to an average of 21 hours for tablets Teodora 16,8 PM

At clinical examination in 95% of patients already on day 4-5 reception compositions noted improvement in overall health, decreased quantity and intensity of asthma attacks during the day, there was an increase of physical activity, lower intensity, and loss of nocturnal asthma attacks.

In the long-term clinical study of the composition revealed that the drug has a high efficiency at a dose of 450-600 mg/day, is capable of maintaining therapeutic concentrations of theophylline in plasma with 2-fold receiving long-term control of bronchial patency and reduce the need for in other groups of drugs used in T with improvement of the clinical status of patients that is reflected in increased physical activity, reduction in the frequency and intensity of asthma attacks, the disappearance of night attacks of dyspnea, and decrease the needs of patients in inhalation sympathomimetics and systemic corticosteroids.

P R I m e R 1. In the mixer load 3.0 kg of theophylline and 1.0 kg of interpolymer complex mix. To the mixture was added 500 ml of 10% aqueous solution of interpolymer complex in phosphate buffer pH 7.5, with stirring. This is followed by wet granulation and drying the granulated mixture at a temperature of 50-60aboutC to a residual moisture content of the granules 1-2% Yield is 97 wt. Dried granulated mixture optivault the calcium stearate and tabletirujut.

P R I m m e R 2. The process is carried out analogously to example 1, using as a moisturizing agent 5% solution of interpolymer complex 1.5% aqueous solution of sodium bicarbonate, the pH of the resulting solution of the complex is equal to 4.5. Dried granulated mixture optivault the calcium stearate and tabletirujut.

P R I m e R 3. The process is carried out analogously to example 1, using as a moisturizing agent 15% solution of interpolymer complexness polymethacrylic acid and polyethylene glycol, mix. The resulting mixture bitteroot followed by granulation grinding, receiving granules in the size range of 0.05-1.5 mm Granulated mixture optivault the calcium stearate and tabletirujut. Get tablets containing of 0.1; 0.2; 0.3 g each of theophylline.

P R I m e R 5. In the mixer load 3.0 kg of granulate of theophylline and 0.98 kg interpolymer complex polymethacrylic acid and polyethylene glycol, mix. The resulting mixture bitteroot followed by granulation grinding, receiving granules in the size range of 0.05-1.5 mm Granulated mixture optivault the calcium stearate and tabletirujut. Get tablets containing of 0.1; 0.2; 0.3 g each of theophylline.

P R I m e R 6. In the mixer load 3.0 kg of theophylline and 1.0 kg of interpolymer complex mix. To the mixture was added 500 ml of 10% aqueous solution of interpolymer complex pH 7.5 in the sodium hydroxide solution with stirring. This is followed by wet granulation and drying the granulated mixture at a temperature of 50-60aboutC to a residual moisture content of the granules 1-2% Yield is 97 wt. Dried granulated mixture optivault the calcium stearate and tabletirujut. The obtained tablet cover film-forming solution, after which To 1 liter

500 g of tablets are loaded into the hopper installation for coating in the fluidized bed. The coating is carried out at a temperature of the air flow at the entrance 40-50aboutWith, the exhaust temperature 20-30aboutWith the flow of the film-forming coating 10-20 ml/min or coated tablets is performed with the use of film-forming solution of the following composition, g/l:

Specified interpoly - dimensional complex 100 tween-80 20 Ethyl alcohol To 1 l

1. A method of OBTAINING a BRONCHODILATOR DRUG COMPOSITION of the PROLONGED ACTION ON the BASIS of THEOPHYLLINE, including the mixing of theophylline with polymer matrix, moisturizing, granulation, drying, pelleting, characterized in that the polymer matrix used interpolymer complex (IPC) polymethacrylic acid and polyethylene glycol, and hydration are 5 to 15% solution of the same IPC with a pH of 4.5 to 7.5 in phosphate buffer or in an aqueous-alkaline solution, or in ethanol.

2. A method of obtaining a bronchodilator drug composition of the prolonged action on the basis of theophylline, including the mixing of theophylline with polymer matrix, granulation and tableting, characterized in that the polymer matrix ptx2">

3. The method according to PP. 1 and 2, characterized in that the tablets are covered with film forming solution on the basis of the specified IPC.

 

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