RU2451511C1 - Method for production of injection form of alpha-lipoic acid based preparation - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the technology for production of the injection form of an alpha-lipoic acid based preparation that is applied for prevention and treatment of coronary atherosclerosis, liver diseases, diabetic polyneuropathy and intoxication. According to the new method, one first mixes N-methyl glucamine with water for injections with alpha-lipoic acid added to the produced solution; then Polyethylenglycol 300 solution is added to the mixture at the following ratio of initial components, wt %: alpha-lipoic acid 1,14-1,26, N-methyl glucamine - 1.121 -1.239, Polyethylenglycol 300 - 7.505-8.295, water for injections - balance up to 100 ml.

EFFECT: invention enables one to prepare a batch of the preparation during 2 hours with the preparation quality preserved and the energy and raw materials expenditure - reduced.

4 cl, 1 ex

Description

The invention relates to pharmacy, and in particular to a technology for the preparation of injectable forms of drugs that are used to prevent or treat coronary atherosclerosis, liver diseases, diabetic polyneuropathy, intoxication, and can be used in the pharmaceutical industry to obtain such drugs.

A known method for producing an injectable form of a preparation based on α-lipoic acid by mixing 250 g of solid α-lipoic acid with auxiliary substances: 352.3 g [2-amino-2- (hydromethyl) -1,3-propanediol] per 9.0 liters of water for injection, which contains 200 g of 1,2-propylene glycol. The resulting solution was filtered, poured into ampoules and sterilized. The preparation obtained contains 250 mg of a salt of α-lipoic acid and [2-amino-2- (hydromethyl) -1,3-propanediol]. [Pat. DE 4447599, IPC 6 A61K 31/385].

α-lipoic acid is poorly soluble in water - a universal pharmaceutical solvent. The known technology because of the poor selection of excipients does not provide sufficient solubility of the active substance, which does not exceed 2.5%, which, if necessary, a single administration of significant doses of the drug is 600 mg (Journal "Diabetes und Stoffwechsel", 5th issue, 1996, ext. Edition 3,1996, 3) leads to the introduction of significant volumes of fluid during injection.

The closest in technical essence is a method for producing an injection form of a preparation based on alpha-lipoic acid according to Ukrainian patent No. 73341 dated 07/15/2005, according to which PEG is first mixed with alpha-lipoic acid, after which N-methylglucamine and water are added in the following ratio components:

alpha lipoic acid 2.85 N-methylglucamine 2.98 polyethylene glycol 7.25-19.15 water for injections the rest is up to 100

The disadvantages of the prototype include low productivity and high duration of the process (more than 6 hours), additional energy costs for heating water to 80-90 ° C, double the cost of polyethylene glycol compared to the technology claimed in the invention.

The technical task of the invention is to develop a method for producing an injectable form of a preparation based on α-lipoic acid by using a different sequence of introducing and mixing the components, which increases the solubility of the active component and thereby reduces the volume of fluid during injection, which will significantly increase labor productivity, reduce preparation time of the preparation, reduce energy and raw material costs.

The solution to the problem lies in a method for producing an injection form of a drug based on α-lipoic acid by mixing it with N-methylglucamine, polyethylene glycol and water for injection, and in accordance with the invention, N-methylglucamine is first mixed in water with α-lipoic acid, after which it is added a solution of polyethylene glycol 300 (Macrogol 300) in water at a ratio of the starting components, wt.%:

ά-lipoic acid 1.14-1.26 N-methylglucamine 1,121-1,239 polyethylene glycol 7,505-8,295 water for injections the rest is up to 100 ml

The chemical scheme of the process of preparing a solution of meglumine salt of alpha-lipoic acid:

Meglumine salt of alpha lipoic acid and M _r = 401.54

C ₈ H ₁₄ O ₂ S ₂ + C ₇ H ₁₇ NO ₅ = C ₁₅ H _3l NO ₇ S ₂

According to the reaction equation, 206.33 g of alpha lipoic acid are reacted with 195.21 g of N-methylglucamine. In the preparation, when loading 12.0 g (0.0582 mol) of alpha-lipoic acid and 11.8 g / l (0.0604 mol) of N-methylglucamine, an excess of N-methylglucamine is created in an amount of 0.0023 mol (0.45 g / l).

A slight excess of N-methylglucamine shifts the reaction equilibrium towards the formation of meglumine salt, which helps to dissolve weak alpha-lipoic acid (pK = 4.76) and further stabilizes its aqueous solution. Without salt formation, alpha lipoic acid is insoluble in water.

To improve the dissolution process of α-lipoic acid and the stability of its solution during preparation, 2/5 of the total amount of water (VDI - water for injection) is loaded into the reactor, N-methylglucamine is added in portions with stirring, then α-lipoic acid and separately PEG 300 (Macrogol 300) is dissolved in water, mixed until completely dissolved, then combined with a solution of α-lipoic acid with N-methylglucamine, the prepared solution is mixed, filtered and sent to packaging in bottles.

Since α-lipoic acid and its solution are sensitive to light, the preparation of the injection form of the drug is carried out in a reactor that is protected from light, and the spill is carried out in dark glass bottles.

Due to the fact that the resulting solution is easily oxidized with atmospheric oxygen, the process of preparing the solution and pouring it into bottles is carried out under a layer of nitrogen.

N-methylglucamine is added to the reaction mass in excess relative to the amount of α-lipoic acid. The range of the amount of introduced PEG 300 ranges from 725 to 8.295 percent and is limited by its minimum amount, which ensures the stability of the injection solution during storage. As a result of changing the sequence of dissolution of the components, the preparation time of the drug decreased from 6 hours to 2 hours, labor productivity increased 3 times without changing the quality indicators.

An example of the preparation of a solution of 1.2% α-lipoic acid.

In a 2.0-liter reactor equipped with a stirrer and a dark shutter, 250 ml of water for injection was loaded and 11.8 g of N-methylglucamine (calculated as 100% substance) and 12.0 g of α-lipoic acid were added in portions. in terms of 100% substance). The mass was stirred until complete dissolution of α-lipoic acid. 79.0 g of Polyethylene glycol 300 (macrogol 300) was dissolved in 400 ml of water. The solution of PEG 300 using compressed nitrogen was transferred into a container with a solution of alpha-lipoic acid with N-methylglucamine, the volume of the solution was adjusted to 750 ml with water. The resulting solution was analyzed for quantitative indicators of the content of α-lipoic acid and N-methylglucamine, which were respectively 1.2% and 1.19%. The solution was filtered through a filter with a diameter of 0.22 μm and poured into dark glass bottles with a capacity of 50 ml under nitrogen pressure.

The bottles were corked with rubber stoppers, wrapped in aluminum caps and sterilized.

Technical result

As a result of changing the sequence of preparation of the solution of alpha-lipoic acid, which made it possible under the same conditions to prepare a batch of the drug within 2 hours (in the prototype - 6 hours), the cost of energy, raw materials decreased, and this did not affect the quality of the drug, but vice versa increased the stability of the solution.

Industrial applicability

The inventors on the basis of Farmak OJSC developed technical documentation, carried out preparatory work and produced an industrial batch of solution for infusion of 1.2% alpha-lipoic acid in 50 ml bottles.

Claims (4)

1. A method of producing an injection form of a preparation based on alpha-lipoic acid by mixing it with N-methylglucamine, polyethylene glycol and water for injection, characterized in that N-methylglucamine is first mixed with water for injection, alpha-lipoic acid is added to the resulting solution, after which a solution of Polyethylene glycol 300 is added to the mixture at a ratio of the starting components, wt.%:
alpha lipoic acid 1.14-1.26 N-methylglucamine 1,121-1,239 Polyethylene glycol 300 7,505-8,295 Water for injections The rest is up to 100 ml 2. The method according to claim 1, characterized in that at first 2/5 of the total amount of water is loaded, N-methylglucamine is added in portions with stirring, then alpha-lipoic acid is added and mixed until completely dissolved. 3. The method according to any one of claims 1 and 2, characterized in that the preparation of the injection form of the drug is carried out in a reactor that is protected from light, and the spill is carried out in dark glass bottles. 4. The method according to any one of claims 1 and 3, characterized in that the dissolution of alpha-lipoic acid, mixing the solutions and pouring into bottles is carried out under a layer of nitrogen.