HU188202B - Process for production of stabilized, injectable medical preparates consisting of - as reagents - 2-(4-)3-/2- chlorine-phentiazine-10-il/-propil)-1-piperazinil/-ethil /3,4,5-trimetoxi/benzoate-diethansulphonate - Google Patents

Abstract

Stabilised injectable tranquiliser prepns. based on 2-4-(3-(2-chloophenthiazin-lo-yl) propyl)-1-piperazinyl ethyl-(3,4,5-trimethoxy) -benzoate-diethane-sulphonate (known as methophenazate-diethane-sulphonate) by adding to 0.1-1.0 pts. by wt. of the drug 0.08-0.13 pts. by wt. 3,4,5-trimethoxy-benzoic-acid, 60-80 pts. by vol. propane-1,2-diol, 1-10 pts. by vol. ethanol, 10-40 pts. by vol. water and 0.07-0.35 pts. by wt. additives, adjusting the pH of the mixt. to 3.0-4.5, and making from this soln. an injectable pharmaceutical prepn. by known methods.

Description

ONE PHARMACEUTICAL CHEMICALS FACTORY, Budapest (54) PROCEDURE AS ACTIVE SUBSTANCE FOR THE MANUFACTURE OF A MEDICINAL PRODUCT (57) EXTRACT

This invention relates to 2- {4- [3- (2-chloropentiazin-10-yl) propyl] -1-piperazinyl} ethyl (3,4,5-trimethoxy) benzoate diethanesulfonate (methofenazate diethanesulfate) as an active ingredient. ) containing a stabilized injectable pharmaceutical composition.

According to the invention, 0.11.0 parts by weight of methofenazate-diethanesulfonate, 0.08-0.13 parts by weight of 3,4,5-trimethoxybenzoic acid, 60-80 volumes of propane-1,2-diol, 1- 10 volumes of ethanol,

10-40 volumes of water and 0.07-0.35 parts by weight of additive (s) are mixed, the pH of the mixture is adjusted to 3-4.5 and the solution is made into an injectable preparation.

The stabilized, injectable pharmaceutical composition can be used as major tranquillizers and can be stored for up to 1-2 years without significant degradation.

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The present invention relates to a process for the preparation of a stabilized injectable pharmaceutical preparation containing 2- [4- [3- (2-chloropentiazin-10-yl) propyl] -1-piperazinyl] ethyl (3,4,5-trimethoxy) as an active ingredient. Contains benzo-diethanesulfonate (metofenazate-diethanesulfonate). Metophenazate diethanesulfonate is widely used as a major tranquilizer in human medicine.

Metophenazate diethanesulfonate is highly soluble in water and therefore its aqueous solution may in principle be used for the preparation of an injectable pharmaceutical preparation.

Metophenazate diethanesulfonate is known to be readily hydrolyzed in alkaline media and during hydrolysis is 2-chloro-10- {3- [4- (2-hydroxyethyl) -piperazin-1-yl] -propyl-1-phenythiazine and 3,4, 5-Trimethoxybenzoic acid is formed [Acta Pharm. Hung., 94, 114; C. A., 61: 5458 g (1964)].

In our studies, it has been found that the hydrolysis of the ester group of methofenazate also occurs in an acidic medium, and when stored at room temperature for a few months, 40-60% of the active ingredient is decomposed in aqueous solution containing methofenazate diethanesulfonate. Naturally, at higher storage temperatures, the rate of decomposition increases.

In order to be placed on the market, the injectable medicinal product must be stable for at least one year without significant decomposition exceeding 4-5%.

An attempt was made to use anhydrous organic solvents and a mixture of water and one or more organic solvents to suppress the hydrolysis of methofenazate diethanesulfonate. Among the anhydrous solvents commonly used for injection, N-oxyethyl lactamide, N-methylpyrrolidone, glycerol and polyethylene glycols could not be used because of the significant increase in photosensitivity, and significant degradation was also achieved by poor light. However, other anhydrous solvents did not dissolve the active ingredient to the desired extent.

Attempts were made to use a mixture of 60-80 volumes of propane-1,2-diol, 1-10 volumes of ethanol, and 10-40 volumes of water to dissolve the methofenazate-diethanesulfonate. A suitable solution containing 1-10 mg / ml of active ingredient could be prepared, however, even in this reduced water medium, the hydrolysis proved to be too high.

After a few weeks of storage at room temperature, about 5% of the active ingredient is degraded, and after 6 months it is 11-12%.

It has been found that the hydrolysis of methofenazate diethanesulfonate in the presence of water can be practically completely suppressed and a shelf-life of more than 1 year can be achieved with the active ingredient methofenazate diethanesulfonate and 60-80 volumes of propane-1,2-diol as solvent. A solution of a mixture of 1 to 10 volumes of ethanol and 10 to 40 volumes of water, if, by adding 3,4,5-trimethoxybenzoic acid in the solution, a concentration of 0,8 to 1,3 mg / ml 3,4,5-trimethoxybenzoic acid and The pH is adjusted to 4.5.

According to the invention, 0.08-0.135% of 3,4,5-trimethoxybenzoic acid added to the injectable composition effectively inhibits the decomposition of the methofenazate diethylsulfonate. This was confirmed by the comparative study below.

The solution prepared in Examples 3 and 4, described below, was stored under standard storage conditions for 2 years at 20-30 ° C in summer and 15-22 ° C in winter, during which time the decomposition of methofenazate-diethanesulfonate was repeatedly determined. Storage and assays were also performed with solutions without the addition of 3,4,5-trimethoxybenzoic acid, otherwise having the composition of Examples 3 and 4, respectively.

The degree of degradation of methofenazate diethanesulfonate was determined from the amount of 3,4,5-trimethoxybenzoic acid formed during storage. This was done by adding an excess of potassium bicarbonate to the test solution and extracting with ether. In the decomposition, methofenazate diethanesulfonate and 2-chloro-10- {3- [4- (2-hydroxyethyl) piperazin-1-yl] propyl} phentazine formed by decomposition passed into the ether phase, while 3,4, The potassium salt of 5-trimethoxybenzoic acid and ethanesulfonic acid remained in the aqueous phase. In the aqueous phase, the amount of 3,4,5-trimethoxybenzoic acid was selectively determined based on its extinction at 258 nm. The potassium ethanesulfonate present here has no significant absorbance and thus practically does not affect the accuracy of the determination.

The results obtained are shown in the following table, which gives the percent degradation of the active ingredient of each sample immediately after preparation of the sterile solution and after 3, 6, 9, 12, 18 and 24 months.

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Spreadsheet

Tested sample 0 % Decomposition of the active ingredient after preparation of the sterile solution 24 3 6 9 months later 12 18 Example 3 solution 0 0.57 1.02 2.04 2.61 4.20 6.81 Example 3 solution 3,4,5-tri- methoxy-benzoic acid acid addition without 2.43 7.78 12.07 17.40 23.70 32.42 38.18 Example 4 solution 0 0.91 1.30 . 2.21 3.29 4.76 6.63 Example 4 solution 3,4,5-tri- methoxy-benzoic acid acid addition without 2.03 8.43 12.68 17.65 23.60 30,98 36.20

From the data in the table it can be seen that in the presence of 0.08-0.13% by weight of 3,4,5-limethoxybenzoic acid, the decomposition of methofenazate-diethanesulfonate is minimal, after only one year only 2-3%. However, without added 3,4,5-trimethoxybenzoic acid, after 3 months of storage the decomposition is 7-8% and after 1 year it is 23-24%, which means that the solution can no longer be used as a pharmaceutical.

According to the invention, 3,4,5-trimethoxybenzoic acid added in an amount of 0.08-0.13% by weight to the solution containing the methofenazate diethanesulfonate is considered to be biologically inert at the concentration used. In addition, the compound is slightly toxic and has an LD ₅₀ value of 1000 mg / kg in mice when administered intravenously. Given that the maximum recommended daily dose of methofenazate diethylsulfonate is 30 mg, this would result in a total daily dose of 3,4,5-trimethoxybenzoic acid, when used in Example 6, which is a negligible amount per kilogram body weight.

Thus, in accordance with the present invention, a stabilized injectable pharmaceutical formulation containing methofenazate diethanesulfonate as the active ingredient is prepared from 0.1 to 1.0 parts by weight of methofenazate diethanesulfonate, 0.08 to 0.13 parts by weight of 3,4,5-trimethoxybenzoic acid, 60 to 80 parts by weight. propane-1,2-diol, 1-10 volumes of ethanol, 10-40 volumes of water and 0.07-0.35 parts by weight of additive / substance are mixed, the pH of the mixture is adjusted to 3-4.5, and the solution is into an injectable pharmaceutical composition.

Additives include, for example, antioxidants such as sodium pyrosulfite, ascorbic acid and the like. It can be used. Several additives may be used at the same time.

In preparing the stabilized injectable solution, the ingredients may be added together in any order. Conveniently, the active ingredient is dissolved in water and a solution of the additive (s) in water-propylene glycol is added to this aqueous solution. Finally, a solution of 3,4,5-trimethoxybenzoic acid in ethyl alcohol is added to the obtained side, the acidity of the solution is adjusted to a pH of 3 to 4.5, and the final volume is adjusted with propane-1,2-diol.

The pH of the solution is adjusted to a pH of 3 to 4.5 with a base such as aqueous sodium hydroxide.

The resulting solution is formulated into an injectable pharmaceutical preparation in a known manner. This usually involves filtering the solution and filling into ampoules of the desired size and sealing the ampoules. In the case where the solution is filtered through a filter having a pore size greater than 0.22 µm, the soldered ampoules will generally also be subjected to heat sterilization. This can be done, for example, at 100 ° C for 25-40 minutes.

The process of the present invention is simple to carry out and provides ₄₀ pounds of injectable pharmaceutical formulation without significant degradation for 1-2 years

The invention is illustrated by the following examples.

Example I

Dissolve 0.68 g of methofenazate-diethanesulfonate in 18 ml of distilled water.

Dissolve 0.15 g of sodium pyrosulfite in 4 ml of distilled water, add 22 ml of propane-1,2-diol, and add the resultant solution to an aqueous solution of methofenazate-diethanesulfonate.

0.1275 g of 3,4,5-trimethoxybenzoic acid is dissolved in 10 ml of 96% ethanol with gentle heating and the alcoholic solution is added to the above solution. The pH is adjusted to 3.0 with 10% aqueous sodium hydroxide solution and the solution is made up to 100 ml with about 46 ml of propane-1,2-diol.

⁶⁰ Each dissolution and mixing is carried out under a nitrogen átbuborékeltatása.

The solution is filtered and filled into 1 ml ampoules under nitrogen and sealed. If filtration is greater than 0.22 pm

i

Using a 188,202 pore filter, the sealed ampoules were sterilized for 30 minutes at 100 ° C.

Example 2

Injectable solutions of the following composition were prepared in the same manner as in Example 1 in a volume of 1 ml. Azascorbic acid is sodium pyrosulph2

metofenazát diethanesulfonate 1.0 mg nátriumpiroszulfit 0.75 mg ascorbic acid 0.75 mg 3,4,5-trimethoxy benzoic acid 0.80 mg ethanol 0.200 mL distilled water 0.120 ml propane-1,2-diol (ad 1 ml) pH 4.5 0.680 ml

fill it together.

methofenazate diethanesulfonate 6.8 mg sodium pyrosulfite 0.7 mg ascorbic acid 1.5 mg

3,4,5-Trimethoxybenzoic acid 1.275 mg ethanol 96% 0.010 ml distilled water 0.200 ml propane-1,2-diol (ad 1 ml) 0.790 ml pH 3.5

Example 6

In the same manner as in Example 1, 5 ml of the following formulations were prepared:

Example 3

Prepared in the same manner as in Example 1, the following composition, injectable volume of 15 ml of methofenazate-diethanesulfonate, 50.0 mg of sodium pyrosulfite, 7.0 mg,

3,4,5-Trimethoxybenzoic acid 6.375 mg of ethanol in 0.100 ml of distilled water 1.500 ml of propane-1,2-diol (ad 5 ml) 3.400 ml of pH 3.9 solutions:

methofenazate diethanesulfonate 6.8 mg sodium pyrosulfite 1.5 mg

3,4,5-Trimethoxybenzoic acid 1.275 mg ethanol 0.020 ml distilled water 0.300 ml propane-1,2-diol (ad 1 ml) 0.680 ml pH 3.2

Example 7

An injectable volume of 1 ml4 was prepared as described in Example I. example

An injectable solution of the following composition was prepared in the same manner as in Example 2:

Metophenazate Diethanesulfonate 10.0 mg Sodium Pyrosulfite 2.0 mg

3,4,5-Trimethoxybenzoic acid 1.3 mg ethanol 0.38 ml distilled water 0.015 ml propane-1,2-diol (add 1 ml) 0.605 ml pH 3.0-3.5 solutions:

methofenazate diethanesulfonate 6.8 mg sodium pyrosulfite 1.0 mg ascorbic acid 1.0 mg

3,4,5-Trimethoxybenzoic acid 0.85 mg ethanol 0.100 ml distilled water 0.200 ml propane-1,2-diol (ad 1 ml) 0.700 ml pH 3.2

Example 5

An injectable solution of the following composition was prepared in the same manner as in Example 2:

A patent claim

Claims (1)

40 Process as Stabilized Containing 2-N- [3- (2-k) -Hydrothiazin-10-yl) -propyl] -1-piperazinyl; Ethyl (3,4,5-trimethoxy) benzoate Diethanesulfonate (Metophenazate Dielanesulfonate) for the preparation of an injectable pharmaceutical composition, characterized in that 0.1 to 1.0 parts by weight of methofenazate-diethanesulfonate, 0.08 to 0.13 parts by weight of 3,4,5-trimethoxybenzoic acid, 60 to 80 volumes of propane-1,2-diol, 1 to 10 parts by volume of ethanol, 10 to 40 parts by volume of water and from 0.07 to 0.35 parts by weight of additives / ingredients adjusted to ₅₀ were mixed, the pH is between 3 to 4.5, and the solution was converted to an injectable pharmaceutical composition.