The method of preparation of the drug insulin ss suspension insulin cartridge for

 

(57) Abstract:

The invention relates to medicine, namely to the preparation used in the treatment of diabetes mellitus suspension pork Protamine-insulin cartridges - product of prolonged action. Suitable for long term storage preparation is prepared by mixing in a sequence of four fluids in the injection water containing the following components: phenol, m-cresol, preteenslut and glycerin, a substance porcine monocomponent insulin and glycerol, phenol, m-cresol, dihedral sodium phosphate disubstituted and 1M hydrochloric acid (to pH 7.5 to 7.7). Then filtering the mixture of the solutions, add water injection to a final concentration of insulin 100 IU/ml, crystallization at 20 - 25oC and the filling of the drug cartridge. The method ensures the safety of drugs, their physico-chemical and biological properties. 2 S. p. f-crystals, 1 table.

The invention relates to medicine, in particular the production used in the treatment of diabetes insulin preparations with prolonged action. The invention can be used in the medical industry for the manufacture of suspension pork Protamine-inclinationem insulin 100iu/ml in vials (1). The disadvantages of this method include the need for freeze drying of a solution containing insulin and phenol in acidified water, then to the lyophilisate add a mixture of preteenslut, glycerol and phenol in water. In addition, this method of receiving the suspension Protamine-insulin guarantees the stability and preservation of biological activity of the drug only for 3 months. In modern Pharmacopoeia requirements shelf-life of insulin should not be less than 24 months.

Known drugs biosynthetic human Protamine-insulin at concentrations of 40 and 100 IU/ml in vials and cartridges (2).

As for the suspension pork Protamine-insulin with insulin 100 IU/ml, then known only to this drug is intended for filling vials, but not in the cartridge (2).

The objective of the invention is to develop a method of preparation of the suspension pork Protamine-insulin 100 IU/ml, which is used for filling the cartridges.

The problem is solved by creating a method of preparation of the suspension of the insulin cartridge by using a substance porcine insulin. In cartridges pour the mixture su injecting water, namely, the solution of preservatives phenol and m-cresol solution, Protamine sulfate and glycerol solution of porcine insulin and glycerol and phosphate buffer solution followed by crystallization at 20-25oC and bottling suspension Protamine-insulin cartridges.

The inventive method is as follows.

Prepare preliminary solutions of the following components (per 1 ml of injectable water): 1,00-of 1.16 mg of phenol and 2,50-and 2.83 mg m-cresol (solution A); 4-8 mg preteenlolita and 80-140 mg of glycerol (solution B); 34,62-42,31 mg of the substance porcine monocomponent insulin and 95-105 mg of glycerol (solution); of 0.64 to 0.74 mg phenol, 1,60-1,82 mg m-cresol, 5,11 mg dihydrate sodium phosphate disubstituted and 1 M hydrochloric acid (to pH 7.5 to 7.7) (solution D). Then, the solution And mixed with solution B and solution when the stirring speed is about 90-130/min with subsequent sterilizing filtration. The resulting mixture at a speed of mixing 180-260 rpm combined with a sterile solution of G contribute injecting water to the final concentration of insulin 100 U/ml) and continue stirring for 1 hour. Then hold crystallization at 20-25oC for 72 hours and filling the resulting suspension pork Protamine-insulin in the second method allows you to prepare a suspension pork Protamine-insulin cartridge (s), (which are commonly used in conjunction with a syringe-pens) that maintain their physico-chemical and biological properties when stored in cartridges for a long period of time (see table). For drug developed a draft interim monograph (VFS), providing for the shelf life of 2.5 years (30 months).

Developed the drug has successfully passed preclinical study.

The state pharmacological Committee (PGA) of the Ministry of health of Russia allowed the clinical trials of the drug (minutes No. 7 dated 25 June 1998).

Commission on the instructions and the item PGA developed the drug recommended the name "INSULIN SS" ("PENSULIN SS) (minutes No. 7 dated September 28, 1998).

The claimed drug INSULIN SS allows you to provide health care new effective and inexpensive anti-diabetic agent and to reduce the penetration of the domestic market of expensive imported drugs insulin.

The claimed method is illustrated by the following examples.

Example 1.

Preparation of a solution of phenol and m-cresol. 3.0 g of phenol and 7.5 g of m-cresol are dissolved in 2 l of water injection and then the volume of the solution was adjusted injection what s for injection, heated to a temperature of 50oC, the solution was added 100 ml of injectable water, cooled to a temperature of 5-10oC, and 40.0 g of glycerin. The volume of solution preteenlolita bring injectable water up to 300 ml.

Preparation of substance insulin. 34,62 g substance insulin biological activity of 26 U/mg, with zinc content of not more than 0.04 mg per 100 U fill in 340 ml of chilled to a temperature of 5-10oC injection of water, stirred for 1-2 minutes. Then, under stirring, the suspension is added hydrochloric acid to pH 3.0 and 3.4. Stirring is carried out until complete dissolution of crystals of insulin, and then the solution was added 100.0 g of glycerin and bring the volume of solution injected with water to 1000 ml.

To a solution of phenol and m-cresol under stirring at a speed of 100 rpm was added a solution of preteenslut, stir the solution for 10 minutes, then make a solution of the substance insulin. Stirring is continued for 10 minutes, then hold sterilizing filtration using filters "Millipore" with a pore diameter of 0.22 μm and prefilters 0.45 µm.

Preparation of buffer solution with pH 7.5. 3.5 l injection of water dissolve 24 g of sodium phosphate (disubstituted), 3.0 g of phenol and 7.7 g m-the e spend sterilizing filtration using filters "Millipore" with a pore diameter of 0.22 μm and prefilters 0.45 µm.

In sterile buffer solution under stirring at 200 rpm make a mixture of sterile solutions of insulin, preteenlolita and phenol m-cresol. Stirring is continued for 15 minutes and then the suspension type of injection water to obtain the concentration of insulin 100 U/ml) and continue stirring for 1 hour.

After a specified time, stop stirring and leave the product for crystallization for 72 hours at a temperature of 20-25oC. Next, carry out the filling of the drug in the cartridge at 1.5 ml with subsequent capping and running.

The test results of the drug given in the table.

Example 2.

Preparation of a solution of phenol and m-cresol. 3.5 g of phenol and 8.5 g of m-cresol are dissolved in 2 l of water injection and then the volume of the solution was adjusted injectable water up to 3.0 liters

Preparation of the substance of preteenlolita. 4 g of preteenlolita dissolved in 100 ml of water for injection, pre-heated to a temperature of 50oC. After dissolution of preteenlolita in solution add 100 ml of injectable water, cooled to a temperature of 5-10oC, and 70.0 g of glycerin.

The volume of solution preteenlolita bring Nyiregyhaza activity 26 IU/mg, with zinc content of not more than 0.04 mg per 100 U fill in 340 ml of chilled to a temperature of 5-10oC injection water and mix for 1-2 minutes. Then, under stirring, the suspension is added hydrochloric acid to pH 3.0 and 3.4. Stirring is carried out until complete dissolution of insulin, and then the solution was added 100.0 g of glycerin and bring the volume of solution injected with water to 1000 ml.

To a solution of phenol and m-cresol under stirring at a speed of 120 rpm was added a solution of preteenslut, the resulting mixture is stirred for 15 minutes, then make a solution of the substance insulin. Stirring is continued for 15 minutes, followed by sterilizing filtration using filters "Millipore" with a pore diameter of 0.22 μm and prefilters 0.45 µm.

Preparation of buffer solution with a pH of 7.7. 3.5 l injection of water dissolve 24 g of sodium phosphate (disubstituted), 3.5 g of phenol and 8.5 g m-cresol. After complete dissolution of the included components to the solution was added 1 M hydrochloric acid (to pH of 7.7). Then hold sterilizing filtration using filters "Millipore" with a pore diameter of 0.22 μm and prefilters 0.45 µm.

In sterile buffer solution under stirring at a speed of 250 rpm make a mixture of minutes, and then to the suspension type of injection water to obtain the concentration of insulin 100 U/ml) and continue stirring for 1 hour.

After a specified time, stop stirring and leave the product for crystallization for 72 hours at a temperature of 20-25oC. Next, carry out the filling of the drug in the cartridge at 1.5 ml with subsequent capping and running.

The test results of the drug given in the table.

1. The method of preparation of the suspension of the insulin cartridge, including the preparation of the drug insulin in suspension at a concentration of 100 IU/ml with subsequent entry into the cartridge, characterized in that 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, followed by crystallization at 20 - 25oC.

2. The method according to p. 1, characterized in that the preparation is prepared by mixing a solution containing 1,00 - of 1.16 mg phenol, 2,50 - and 2.83 mg m-cresol in 1 ml of injectable water, with a solution of preteenlolita with a stirring speed of 90 - 130 rpm, containing 4 to 8 mg of preteenlolita and 80 - 140 mg of glycerin in 1 ml injection mg of insulin and 95 - 105 mg of glycerol 1 ml of acidified water, with the subsequent sterilizing filtration of the resulting solution and combining it with the stirring speed of 180 - 260 rpm with sterile buffer solution with a pH of 7.5 to 7.7, adding to the resulting solution was injected water to the final concentration of insulin 100 IU/ml, prepared by stirring the mixture with subsequent crystallization and filling of the drug received in the cartridge for subsequent capping and running.

3. The method according to PP.1 and 2, characterized in that the filling of the drug suspension pork Protamine-insulin is carried out in the cartridges at 1.5 and 3 ml.

 

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4 ex, 1 tbl

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12 ex

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6 ex

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