RU2184533C1 - Method of preparing pharmaceutical composition solution based on substance of gene engineering (recombinant) human insulin - Google Patents

Abstract

FIELD: medicine, endocrinology, pharmacy. SUBSTANCE: invention relates to treatment of patients with diabetes mellitus with the preparation of rapid effect - the solution of domestic gene engineering (recombinant) human insulin prepared in cartridges and/or flasks. Preparation that is stable at storage is prepared by mixing solution containing a preserving agent m-cresol and sodium acetate with solution containing gene engineering human insulin, zinc chloride and glycerol. Sodium hydroxide solution is added to the prepared mixture to pH = 6.9-7.8, then sterilizing filtration is carried out, required volume is brought about and the preparation is placed into cartridges or flasks. Method provides safety of physical- chemical and biological properties of preparation at storage. EFFECT: improved method of preparing, expanded arsenal of antidiabetic agents. 3 cl, 2 tbl

Description

 The invention relates to the field of healthcare, namely to the preparation of fast-acting insulin preparations used in the treatment of diabetes mellitus. The invention can be used in the pharmaceutical industry for the manufacture of a solution of domestic genetically engineered (recombinant) human insulin 100 IU / ml for injection in vials or in cartridges (inserts) used, as a rule, for use in syringe pens.

 Various insulin solutions are known, containing 40 IU / ml, intended for dispensing drugs into vials (1-3).

 Known fast-acting preparations of human biosynthetic insulin with a hormone content of 40 and 100 PIECES / ml, intended for bottling, and preparations with a human insulin content of 100 PIECES / ml, which are poured into cartridges (4).

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

 The objective of the invention is to develop a method for preparing a pharmaceutical composition of a solution of domestic genetically engineered (recombinant) human insulin 100 IU / ml for pouring it into cartridges and / or bottles, which makes it possible to carry out the process more efficiently than the known method (5).

 The problem is solved by creating a method for preparing a solution of genetically engineered human insulin with the addition of zinc chloride, using m-cresol as a preservative instead of nipagin and eliminating pre-filtration before sterilizing filtration.

 The claimed method is as follows.

 Solutions of the following components are preliminarily prepared (per 1 ml of injection water): 3.86-4.71 mg of m-cresol and 1.94 mg of sodium triacetate (solution "A); 38.5 mg of the substance of domestic genetically engineered insulin human, 5.8-35.8 mg of zinc chloride and 160 mg of glycerol (insulin substance solution). Then, a solution of insulin substance and 0.15 M sodium hydroxide solution are added to solution "A" with stirring to a pH of 6.9-7, 8 (solution "B"). Then through the sterilizing filter, successively, in a sterile container, filter solution "B", and then at remeshivanii solution it is filtered injectable water to 1 liter. The solution was then poured into cartridges of 1.5 or 3 ml, or in bottles of 5 or 10 ml, which was sealed and run in them on caps.

 The developed method allows to prepare a solution of domestic genetically engineered human insulin for cartridges and / or vials, preserving its physico-chemical and biological properties during storage for a long time (see tables 1 and 2).

 A draft Pharmacopoeia article of the enterprise (FSP) was developed for the drug.

 The development of the claimed drug makes it possible to provide healthcare with a new effective and inexpensive domestic drug for the treatment of diabetes and significantly reduce the import of expensive foreign drugs.

 The claimed method is illustrated by the following examples.

 Example 1

 Preparation of solution "A". 2.7 g of m-cresol and 1.36 g of sodium acetic acid trihydrate are dissolved in 400 ml of injection water. After complete dissolution of the introduced components, the volume of the solution was adjusted with injection water to 700 ml.

Preparation of a solution of insulin substance. 3.85 g of genetically engineered human insulin with an activity of 26 PIECES / mg and a zinc content of 0.12% is poured into 25 ml of injection water cooled to a temperature of 4 ^° C and mixed, then a 0.2 M hydrochloric acid solution is added to the suspension with stirring to pH 3.0-3.4. The suspension is stirred until the insulin is completely dissolved, and then, 1.21 ml of a 1% solution of zinc chloride containing 4.8 mg of zinc in 1 ml is added to the solution without stopping mixing. Stirring is continued for 5 minutes, and then, without stopping stirring, 16.0 g of glycerol are added to the solution. After complete dissolution of glycerol, the volume of the solution is injected with injection water to 100 ml.

 Preparation of solution "B". In solution "A", with constant stirring, make 100 ml of a solution of the substance of insulin, after which a 0.15 M sodium hydroxide solution is adjusted to pH 6.9.

 Preparation of insulin solution. Through a sterilizing filter with a pore diameter of 0.22 μm, solution “B” and the missing amount (up to 1 L) of injection water are filtered into a sterile container.

 Filling a solution of insulin 100 IU / ml. The solution is poured into cartridges of 1.5 or 3 ml, or into bottles of 5 or 10 ml. Cartridges or vials are corked and caps are rolled on them.

 Example 2

 Preparation of solution "A". 3.3 g of m-cresol and 1.36 g of sodium acetic acid trihydrate are dissolved in 400 ml of injection water. After complete dissolution of the introduced components, the volume of the solution was adjusted with injection water to 700 ml.

Preparation of a solution of insulin substance. 3.85 g of genetically engineered human insulin with an activity of 26 PIECES / mg and a zinc content of 0.12% is poured into 25 ml of injection water cooled to a temperature of 10 ^° C and stirred, then a 0.2 M hydrochloric acid solution is added to the suspension with stirring to pH 3.0-3.4. The suspension is stirred until complete dissolution of the insulin, and then 7.46 ml of a 1% zinc chloride solution containing 4.8 mg of zinc in 1 ml is added to the solution without stopping mixing. Stirring is continued for 15 minutes, and then, without stopping stirring, 16.0 g of glycerol are added to the solution. After complete dissolution of glycerol, the volume of the solution is injected with injection water to 100 ml.

 Preparation of solution "B". In solution "A", with constant stirring, make 100 ml of a solution of the substance of insulin, after which a pH of 7.15 is adjusted with a 0.15 M sodium hydroxide solution.

 Preparation of insulin solution. Through a sterilizing filter with a pore diameter of 0.22 μm, solution “B” and the missing amount (up to 1 L) of injection water are filtered into a sterile container.

 Filling a solution of insulin 100 IU / ml. The solution is poured into cartridges of 1.5 or 3 ml, or into bottles of 5 or 10 ml. Cartridges or vials are corked and caps are rolled on them. The results of the stability control of the drug at different shelf life in cartridges and vials are shown in tables 1 and 2.

LITERATURE
1. Jakcson RL, Storvick WO 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, class A 61 K 37/26, 10/15/1994 (State Institute of Blood Substitutes and Medicines).

 4. Register of medicines of Russia (Encyclopedia of medicines). - M .: "Radar-2000", 199, p. 946.

 5. RF patent 2157238, class A 61 K 38/28, 10.10.2000 (State Institute of Blood Substitutes and Medicines).

Claims (3)

 1. A method of preparing a solution of a pharmaceutical composition based on insulin for cartridges and / or vials, comprising preparing an insulin preparation in the form of an aqueous solution with a concentration of 100 PIECES / ml and adding excipients, characterized in that the preparation of the preparation uses a substance of domestic genetic engineering ( recombinant) human insulin, zinc chloride is additionally added to the resulting solution, m-cresol is added as a preservative in a solution of sodium acetate, while at the beginning the solution is prepared containing 1.3-1.4 mg of sodium acetate and 2.5-3.5 mg of m-cresol per 100 IU of insulin, then the resulting solution is mixed with a solution containing insulin and 5-40 μg of zinc chloride and 14-18 mg of glycerol per 100 PIECES of insulin, establish a pH of 6.9-7.8 by adding an aqueous solution of sodium hydroxide and injection water to a final concentration of insulin in the preparation of 100 PIECES / ml.  2. The method according to p. 1, characterized in that the filling is carried out in cartridges having a volume of 1.5 or 3.0 ml.  3. The method according to p. 1, characterized in that the filling is carried out in bottles of 5.0 or 10.0 ml.

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