WO2016122349A1 - Method of producing an injectable form of a chondroitin sulphate-based preparation - Google Patents

Abstract

The invention relates to the field of medicine, and more particularly to producing an injectable form of a chondroitin sulphate (CS) preparation for the treatment of arthritic and rheumatic diseases, based on an Xa salt of chondroitin sulphate, which is a mucopolysaccharide from animal tissues. The method consists in preparing the ingredients of the injectable form of the preparation separately during production. More particularly: a chondroitin sulphate substance is dissolved in warmed injectable water. Next, solutions of benzyl alcohol and sodium hydroxide are prepared. Then, the benzyl alcohol and sodium hydroxide solutions and water for injection are added, under agitation, to the cooled sterile solution of CS. The resultant mixture is analyzed, the solution is adjusted according to the requirements of the manufacturer's monograph, sterilization filtration is carried out and the mixture is poured into 1 or 2 ml vials, which are then sealed. The technical result consists in replacing repeated intermediate sterilization filtration operations with terminal sterilization filtration, thereby making it possible to produce a preparation of the requisite quality while eliminating unnecessary expenditure in the production of the preparation.

Description

 METHOD FOR PRODUCING INJECTION FORM

 SULFATE CHONDROITIN-BASED DRUG

The invention relates to the field of medicine, specifically to the production of an injectable form of the preparation of chondroitin sulfate (CS) for the treatment of arthrological and rheumatic diseases based on the Ha-salt of chondroitin sulfate - mucopolysaccharide from animal tissues. The drug affects metabolic processes in connective tissue, including cartilage, stimulating and normalizing the biosynthesis of glycosaminoglycans.

 The method of obtaining the drug, which the Ministry of Health of Russia has been given the name "Mukosat", can be used by pharmaceutical companies producing injection forms of drugs.

A known method of producing an injectable form of the preparation of chondroitin sulfate, which includes: preparing pre-solutions of the following components (per 1 ml of injection water): 100 mg of the substance of chondroitin sulfate (solution "A"); 9-1 1 mg of benzyl alcohol (solution "B"); 0.04-0.05 mg sodium hydroxide (solution "B"). Then, sterile solutions “B” are added to the cooled sterile solution “A” with stirring to a pH of 6.2–6.8 and “B” (solution T is obtained). Sterile injection water up to 1 liter is added to solution “D”. Then the drug is poured into ampoules of 1 or 2 ml, after which the ampoules are sealed (prototype).

 The disadvantages of this method include the fact that:

 a) in the industrial production of a drug containing cholesterol, according to the technology described in the prototype, it is necessary to prepare several units for sterile filtration of solutions (preparation of a sterile cholesterol solution, sterile filtration of a benzyl alcohol solution, sterile filtration of a MaOH solution,

 - bringing the volume of sterile injectable water), which leads to an increase in production costs;

 b) before bottling the drug, it is necessary to conduct an analysis on the content of basic substances and the pH of the solution with its subsequent adjustment. Since, after filling and capping the preparation, the technology for its preparation does not provide for thermal or other sterilization, due to the physicochemical characteristics of the components, there is a danger of microbial contamination of the finished dosage form and production defects. Re-sterilizing filtration of the solution after its adjustment leads to losses and cost of production of the drug.

c) the section "The claimed method is carried out as follows" is not described correctly: when combining solution "A" (100 mg / ml) and solution "B" (9-1 1 mg / ml) and further, the resulting solution will have a basic substance content of at least half that.

 d) in the description and example, there is an ambiguity in bringing the volume of the drug “to 1 liter” - is it the volume of injection water spent on the preparation of the solution or the volume of the prepared solution? The concentration of the active substance in the final product depends on the answer to this question.

 d) based on the claims, it is impossible to obtain a sterile solution of the dosage form since sterilizing filtration is indicated only for solution “A”, the remaining components are not subjected to sterilizing filtration.

 The objective of the invention is to develop such a method of preparation of the drug, which minimizes the possibility of microbial contamination of the solution and eliminates unreasonable costs in the production of the drug.

This problem is solved by the fact that upon receipt of the injectable form of the drug, its components are prepared separately. Namely: the substance of chondroitin sulfate is dissolved in heated injection water. Next, solutions of benzyl alcohol and sodium hydroxide are prepared. Then, solutions of benzyl alcohol, sodium hydroxide and water for injection are added to the cooled sterile cholesterol solution with stirring. The resulting mixture is analyzed, the solution is adjusted in s in accordance with the requirements of the FSP, sterilizing filtration is carried out and poured into ampoules of 1 or 2 ml, after which the ampoules are sealed.

 Received by the claimed method, the drug is minimized the possibility of microbial contamination of the finished product and excludes unnecessary costs in the industrial production of this dosage form.

 The claimed method is as follows.

 Dissolve the required (to obtain the cholesterol content in the final solution (100 mg / ml) the amount of chondroitin sulfate in injection water heated to a temperature of 40-50 C in a ratio of 1: 4 (not less) (solution “A”) Dissolve the required (to obtain the final solution of benzyl alcohol content is 8-11 mg / ml) the amount of benzyl alcohol in injection water in the ratio 1: 25 (not less) (solution "B"). Solution "B" is added to solution "A" with a temperature of not more than 35 ° C. , adjust the pH to 6.0-7.5 with a solution of 0.1 M MaOH and add injection water to the desired volume MA (solution "G"). After analysis and adjustment (if necessary), the solution is subjected to sterilizing filtration, poured into ampoules of 1 or 2 ml, the ampoules are sealed.

 The claimed method is illustrated by example.

Example 1 Preparation of solution "A". In 500 ml of injection water, heated to a temperature of 50 ° C, 100.0 g of cholesterol (in terms of the content of the basic substance) is dissolved. After complete dissolution of the cholesterol, the solution is cooled to a temperature of no higher than 35 C.

 Preparation of solution "B". To 9.0-1 1.0 g of benzyl alcohol add 350 ml of injection water and mix until the benzyl alcohol is completely dissolved.

 Preparation of solution "G". 350 ml of solution "B", a solution of 0.1 M HaON to a pH of 6-6.5 and injection water to a volume of 1 liter are poured into solution "A" with constant stirring.

 An analysis is carried out for the content of basic substances and the pH of the solution; if necessary, the solution is adjusted.

 Getting the drug. Solution T "is subjected to sterilizing filtration in a sterile container.

 Pouring a solution of the drug. The solution is poured into ampoules of 1, 0 or 2.0 ml. Ampoules are sealed.

In the preparation prepared by this method, the development of staining does not occur, the possibility of microbial contamination of the drug is minimized and unreasonable costs in the production of the drug are eliminated. Information sources:

1. Patent of the Russian Federation 2200018, cl. IPC A 61 K. Date of publication 10.03.2003. (State Institute of Blood Substitutes and Medicines).

 2. Industrial regulations for the production of the drug Mucosat PR 42-004821 11377-09 // Federal State Institution “State Institute of Blood Substitutes and Medicines. - M, 2009.

Claims

CLAIM 1. A method of manufacturing an injection form of a preparation of chondroitin sulfate (CS), comprising dissolving a cholesterol, benzyl alcohol in injection water, using heating to 50 ° C, sterilizing filtration, filling into ampoules and sealing machines, characterized in that the solutions of the components of the preparation are prepared separately, first, the cholesterol substance is dissolved in heated injection water with subsequent cooling (solution A), then a solution of benzyl alcohol (solution B) is prepared, then solution B is added to solution A with stirring, the pH is adjusted solution to 6.0-7.5 and diluted with injection water, the resulting mixture is subjected to sterilizing filtration, poured into ampoules and sealed.  2. The method according to claim 1, characterized in that to obtain a sterile injectable form of the drug, use the final sterilizing filtering.