Solid dosage form of enalapril and its preparation

 

(57) Abstract:

The invention relates to medicine, in particular to pharmacology relates to solid dosage forms amlodipine and method of reception. Solid dosage form of enalapril includes granules of a mixture of enalapril maleate, milk sugar, starch and polyvinylpyrrolidone, the powdered magnesium stearate, and hydrogen at a certain ratio. A method of obtaining a dosage form comprises blending of enalapril maleate with potato starch and milk sugar, moisturizing mixture of an alcoholic solution of polyvinylpyrrolidone, wet granulating the mixture by spraying an alcoholic solution of polyvinylpyrrolidone above the fluidized mass, drying the granules, dusting granules and tableting. The composition provides obtaining tablets with raspadaemost to 1 min when their high strength. 2 S. and 1 C.p. f-crystals, 1 table.

The group of inventions relates to medicine, more precisely to the pharmacy, and can be used in the preparation of solid dosage forms, the active principle of which is enalapril maleate.

The enalapril maleate is an inhibitor of angiotensin converting enzyme. His primogenial of enalapril maleate is hydrolyzed to enalaprilat, which is an inhibitor of the enzyme. This tool is used in various forms of hypertension, including renovaskulyarnoy form, congestive heart failure. The ingestion of enalapril maleate is absorbed quickly, but it lasts a long time (see Mashkovsky M. D. Medicines, Kharkov, Torgsin", ed. 13, 1998, T. 1, page 426).

Cardiovascular diseases remain the leading cause of death worldwide. One of the most important risk factors for cardiovascular disease is hypertension. On the other hand, the effective control of high blood pressure leads to decrease cardiovascular morbidity and mortality. For the treatment of arterial hypertension are several groups of drugs, among them one of the leading positions are occupied by angiotensin-converting enzyme inhibitors (ACEI). This group presents different chemical structure and duration of action drugs. One of the most studied ACEI is enalapril.

Enalapril is a prodrug that is hydrolyzed with the formation of the active compound - enalaprilat, inhibition angiotensinii arterial hypertension use of enalapril leads to reduction of blood pressure mainly due to the decrease SVR and regardless of the level of plasma renin.

Known medicines on the basis of enalaprilat used as antihypertensive drugs, including solid dosage forms, for example, in U.S. patent N 5562921, A 61 K 9/20, 1996, U.S. patent N 5573780 described solid drug based on the Na-salts of amlodipine. In the patent of Russian Federation N 2140261 described solid dosage form on the basis of enalapril maleate, which contains the active principle, lactose, starch, polyvinylpyrrolidone, calcium stearate or magnesium. This technical solution chosen as a prototype. A method of obtaining a known composition includes a mixture of enalapril maleate with starch and milk sugar in two stages, then served hot polyvinylpyrrolidone and stirred, followed by wet granulation, drying of the granulate, powder granules, re-pass the mass through a granulator, re optivault. The resulting tablets have a high strength and raspadaemost within 2-3 minutes

A disadvantage of this known technical solution should include the complexity of making a tablet form due to repeated repetition of the same operation, and relatively high raspadaemost. Given neobhodimi strength raspadaemost no more than 1 min.

The technical result of the invention is to provide such a composition which would provide faster raspadaemost while simplifying manufacturing process. This is achieved by the fact that the solid dosage form of enalapril, comprising granules of a mixture of enalapril maleate, milk sugar, starch and polyvinylpyrrolidone (PVP), the powdered magnesium stearate, additionally consists of granules of sodium bicarbonate in the following ratio of ingredients, wt.%:

Enalapril maleate - 4,5-5,5

Sodium bicarbonate - 0,5-1,5

Milk sugar - 70,0-90,0

Potato starch - 7,0-15,0

Polyvinylpyrrolidone - 1,0-3,6

Magnesium stearate - 0,4-1,0

The technical result is also achieved by the fact that the method of obtaining the claimed dosage forms involves mixing of enalapril maleate with sodium bicarbonate, potato starch, milk sugar, the mixture is moistened 6,6-15,0% PVP solution in ethyl alcohol, damp granulation by spraying an alcoholic solution of polyvinylpyrrolidone above the fluidized mass, the granulate is dried, optivault of magnesium stearate and tabletirujut.

The new method involves obtaining tabletas weight in color excluded operation dry granulation, and interoperational moving tabletas mixture.

Example. 1.

Provide training materials by sieving of enalapril maleate, sodium bicarbonate, lactose, starch and magnesium stearate.

Prepare 10% solution of polyvinylpyrrolidone in 96,6% ethyl alcohol. Get a mixture of powdered ingredients: 5 wt.% enalapril maleate weight of the load, 80 wt.% milk sugar, 1 wt.% sodium bicarbonate, 11 wt.% potato starch. The mixture is prepared in a fluidized bed installation WSG - 60 when the temperature of the air inlet 45oC to obtain the mass temperature 24-26oC. Hydration of the mixture of an alcoholic solution of PVP hold there for 30 minutes siaosi air has a temperature at the inlet 38oC. the Dried granulate for 3 min, then optivault moving substances within 1-2 minutes

Received tabletow mass tabletirujut to press the Feta R 2001 with the punch diameter 8 mm, weight tablets 0,2 g Form tablets face with beveled edges and scored.

The strength of the tablets in the manufacture (40-50) N, raspadaemost to 1 min.

The resulting tablets have the following composition, wt.%: enalapril maleate ENES optimal parameters of the process of obtaining tabletas mass.

Thus, the claimed composition and method for producing tablets allow you to obtain a new effective means of enalapril maleate with optimum manufacturing technology.

The results of the use of the medicinal product

Enalapril maleate FSUE "moskhimpharmpreparati, Russia, the appointment within 8 weeks. at a dose of 5-20 mg per day in patients with mild and moderate arterial hypertension has a good antihypertensive effect with normalization of clinical dad in 60% of patients, satisfactory effect with a decrease in DBP of not less than 10 mm RT.article in 33.3% of patients. Ineffective antihypertensive effect observed in 6.7% of patients.

According to the daily monitoring of HELL this tool reduces the average systolic and diastolic blood pressure during periods of wakefulness, sleep and during the day as a whole, without affecting heart rate and variability of blood pressure. It is well tolerated. Side effects observed in 13.3% of patients in the form of sore throat and dry cough. These phenomena did not require withdrawal of the drug.

Conclusion: the drug enalapril is indicated in patients with mild and moderate arterial hypertension as an antihypertensive and can be recommended for meditsinskaia maleate, milk sugar, starch and polyvinylpyrrolidone, the powdered magnesium stearate, wherein the dosage form comprising granules further comprises sodium bicarbonate in the following ratio of ingredients, wt.%:

Enalapril maleate - 4,5 - 5,5

Sodium bicarbonate - 0,5 - 1,5

Milk sugar - 70,0 - 90,0

Potato starch - 7,0 - 15,0

Polyvinylpyrrolidone - 1,0 - 3,6

Magnesium stearate - 0,4 - 1,0

2. Method of producing solid dosage forms amlodipine by mixing enalapril maleate with potato starch and milk sugar, add polyvinylpyrrolidone, wet granulation, drying of the granulate, powder granules, tablets, characterized in that the addition of polyvinylpyrrolidone is carried out by wetting a mixture of an alcoholic solution of polyvinylpyrrolidone and wet granulation carried out by spraying an alcoholic solution of polyvinylpyrrolidone above the fluidized mass.

3. The method according to p. 2, characterized in that the wetting and dispersion using 6,6 - 15,0% solution of polyvinylpyrrolidone in ethanol.

 

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