The method of preparation of a solution of the pharmaceutical composition on the basis of the substance of genetically engineered (recombinant) human insulin

 

(57) Abstract:

The invention relates to medicine, in particular for the treatment of diabetes drug fast action - mortar domestic genetically engineered (recombinant) human insulin, prepared in the cartridges and/or vials. Stable during prolonged storage the product is prepared by mixing the solution containing the preservative is m-cresol and sodium acetic acid, with a solution containing a genetically engineered human insulin, zinc chloride and glycerine. To the mixture is added a solution of sodium hydroxide to a pH of 6.9-7,8, followed by sterilizing filtration, set the required volume and carry out the filling of the drug in the cartridges or vials. Effect: method provides the safety of a drug physico-chemical and biological properties during storage, expands the Arsenal of antidiabetic agents. 2 C.p. f-crystals, 2 tab.

The invention relates to the field of health, namely to obtain used in the treatment of diabetes medications rapid-acting insulin. The invention can be used in the pharmaceutical industry for the manufacture of a solution of domestic genetically-ingen anaemic, typically, for use in a syringe-pens.

There are various solutions of insulin containing 40 U/ml, designed to dispense drugs in vials (1-3).

Well-known fast-acting drugs biosynthetic human insulin with hormone, 40 and 100 U/ml intended for filling vials, and the preparations containing the human insulin 100 IU/ml, which is poured into the cartridge (4).

A known method of preparation of the drug solution porcine monocomponent insulin intended for filling cartridges (5). According to this method in the preparation of the preparation use of the substance porcine insulin, sterilized using prefilter with pore diameter of 0.45 μm and a filter with a pore diameter of 0.22 μm, and the preservative used nipagin. The disadvantages of this method are: a) use as preservative nipagina for dissolution which you want the heated mixture with water to a temperature of 85-90oC, followed by cooling with careful temperature control for possible reverse deposition of preservative; C) the need for pre-filtering before sterilizing filtration.

The task is about genetically engineered (recombinant) human insulin 100 IU/ml for filling it in to the cartridge and/or bottles which gives the opportunity to process more efficiently than the known method (5).

The problem is solved by the creation of a method of solution preparation of genetically engineered human insulin with the additional introduction of zinc chloride, used as a preservative is m-cresol instead of nipagin and with the exception of pre-filtering before performing a sterilizing filter.

The claimed method is as follows.

Prepare preliminary solutions of the following components (per 1 ml of injectable water): 3,86-4,71 mg m-cresol and of 1.94 mg of sodium acetate trihydrate (solution A); to 38.5 mg of the substance domestic genetically engineered human insulin, 5,8-to 35.8 mg of zinc chloride and 160 mg of glycerin (liquid substance insulin). Later in the solution "A" was added with stirring a solution of the substance insulin and 0.15 M solution of sodium hydroxide to a pH of 6.9-7,8 (solution B). Further through a sterilizing filter, sequentially, in a sterile container is filtered solution "B", then, while stirring the solution it is filtered injectable water up to 1 L. Then, the solution is poured into the cartridge at 1.5 or 3 ml, or in vials of 5 or 10 ml, which is sealed and the NGO-engineered human insulin cartridge and/or vials, keep their physico-chemical and biological properties when stored for a long time (see tables 1 and 2).

For drug developed project monograph enterprises (FSE).

The development of the claimed preparation makes it possible to provide health care new efficient and cost-effective domestic remedy for the treatment of diabetes and significantly reduce the import expensive foreign drugs.

The claimed method is illustrated by the following examples.

Example 1.

Preparation of the solution "And". In 400 ml of injectable water dissolve 2.7 g of m-cresol and 1.36 g of sodium acetate trihydrate. After complete dissolution of the listed components of the solution volume was adjusted injectable water up to 700 ml.

Preparation of a solution of the substance insulin. of 3.85 g of genetically engineered human insulin activity 26 U/mg and zinc content of 0.12% pour 25 ml of chilled to a temperature of 4oWith injection of water and stirred, then, under stirring, the suspension is added 0.2 M solution of hydrochloric acid to a pH of 3.0-3.4. The suspension is stirred until complete dissolution of insulin, and then in the solution without stirring, bring the and then, without stopping the stirring, the solution was added 16.0 g of glycerin. After complete dissolution of the glycerol solution volume of injection water is brought to 100 ml.

Preparation of the solution "B". In solution A, with constant stirring, bring to 100 ml of a solution of a substance insulin, then 0.15 M solution of sodium hydroxide was adjusted pH to 6.9.

Preparation of a solution of insulin. Through a sterilizing filter with a pore diameter of 0.22 μm, in a sterile container is filtered solution "B" and the missing number (up to 1 l) water injection.

The filling solution of insulin 100 IU/ml Solution is poured into the cartridge at 1.5 or 3 ml, or in vials of 5 or 10 ml. Cartridges or vials are sealed and practicing on them caps.

Example 2.

Preparation of the solution "And". In 400 ml of injectable water dissolve 3.3 g of m-cresol and 1.36 g of sodium acetate trihydrate. After complete dissolution of the listed components of the solution volume was adjusted injectable water up to 700 ml.

Preparation of a solution of the substance insulin. of 3.85 g of genetically engineered human insulin activity 26 U/mg and zinc content of 0.12% pour 25 ml of chilled to a temperature of 10oWith injection of water and stirred, sternula dissolution of insulin, and then in the solution without stirring, bring 7,46 ml of 1% solution of zinc chloride containing 4.8 mg of zinc in 1 ml. Stirring is continued for 15 minutes and then stopping stirring, the solution was added 16.0 g of glycerin. After complete dissolution of the glycerol solution volume of injection water is brought to 100 ml.

Preparation of the solution "B". In solution A, with constant stirring, bring to 100 ml of a solution of a substance insulin, then 0.15 M solution of sodium hydroxide was adjusted pH to 7.8.

Preparation of a solution of insulin. Through a sterilizing filter with a pore diameter of 0.22 μm, in a sterile container is filtered solution "B" and the missing number (up to 1 l) water injection.

The filling solution of insulin 100 IU/ml Solution is poured into the cartridge at 1.5 or 3 ml, or in vials of 5 or 10 ml. Cartridges or vials are sealed and practicing on their caps. The results of monitoring the stability of the drug at different periods of storage cartridges and vials are shown in tables 1 and 2.

LITERATURE

1. Jakcson R. L., Storvick W. O. et al. Neutral normal insulin.//Diabets. - 1972. - v.21. - p. 235-245.

2. Subcutantous insulin therapy. Berlin Heidelberg, New York, Tokyo: Springer - Verlag. - 1982.

3. Patent 2020954, CL A 61 K 37/26, 15.10.1994 (G is the funds of Russia (encyclopedia of medicine). - M.: "Radar-2000", 199, S. 946.

5. RF patent 2157238, CL And 61 To 38/28, 10.10.2000 (State Institute of blood and medicines).

1. The method of preparation of a solution of the pharmaceutical composition on the basis of the insulin cartridge and/or vials, including the preparation of a preparation of insulin in aqueous solution with a concentration of 100 U/ml and introduction of auxiliary substances, characterized in that in the preparation of the drug substance use domestic genetically engineered (recombinant) human insulin, the resulting solution additionally make zinc chloride as a preservative make a m-cresol solution of sodium acetate will first prepare a solution, containing 1.3 to 1.4 mg of sodium acetate and 2.5-3.5 mg m-cresol per 100 UNITS of insulin, then mix the resulting solution with a solution containing insulin and 5-40 µg of zinc chloride and 14-18 mg glycerin per 100 UNITS of insulin, set pH 6.9-7.8 for by adding an aqueous solution of sodium hydroxide and water injection to a final concentration of insulin in the preparation of 100 U/ml

2. The method according to p. 1, characterized in that the filling is carried out in the cartridges, having a volume of 1.5 or 3.0 mil

3. The method according to p. 1, characterized in that

 

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