RU2428175C2 - Method of obtaining parenteral pharmaceutical solution - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with method of obtaining parenteral pharmaceutical solution of anti-tumour action based on derivatives of taxanes, which includes dissolution of taxane derivative in ethanol, introduction of surface-active substance and further removal of ethanol, characterised by the fact that ethanol removal is performed by method of inert gas barbotage through obtained ethanol solution at room temperature.

EFFECT: method ensures obtaining of parenteral pharmaceutical solution with reduced content of additives.

5 cl, 2 dwg, 3 ex

Description

The present invention relates to the field of medicine and pharmaceuticals and relates to a method for producing a parenteral pharmaceutical composition of an antitumor effect based on taxane derivatives in the form of a solution.

Every year, hundreds of new promising biologically active compounds are detected in the world. However, only a few reach the production of medicines on their basis and widespread use in clinical practice.

The reason for this may be the side effects of the use of the compound identified in the initial clinical and preclinical studies, or difficulties in creating a suitable dosage form due to the low solubility of the compound in pharmaceutically acceptable solvents. Many of the antitumor drugs developed over the past few decades are cytostatics - compounds that can inhibit, inhibit, or block cell proliferation.

Parenteral intravenous administration of anticancer drugs, in particular cytostatics, is a difficult task. The mechanism of action of many cytostatic drugs is to suppress DNA synthesis and / or cell cycle disruption, leading to cell death. In this case, it is preferable to maintain the concentration of the drug in the blood and / or infected tissue for such a time that the largest number of tumor cells passes through the phase of the cell cycle to which the drug acts.

In this regard, standard treatment combinations for many malignant tumors (for example, non-small cell lung cancer, breast cancer) involve chemotherapy regimens with prolonged infusions of anticancer drugs [1]. For this, the dosage form of the drug must be suitable for intravenous administration and remain stable when diluted with infusion solutions (pharmacy glucose, Reopoliglyukin, sodium chloride solution, Ringer's solution, etc.) for at least several hours (infusion time).

In the case of biologically active compounds that are poorly soluble in water, the solution to the water solubility problem is to create a dosage form based on biocompatible alcohols (in particular ethanol), which, in order to increase the solubility of the active substance and the stability of its solution when diluted with infusion solutions, are additionally mixed with various surfactants substances.

Examples of such solutions are widely used in clinical practice and approved in the USA and Europe for the treatment of various tumors, dosage forms of taxanes, more specifically, paclitaxel and docetaxel [2, 3].

One of the problems in obtaining a liquid pharmaceutical composition based on ethanol and a surfactant is the tendency of taxanes to hydrolyze and other degradation methods when heated, which is fraught with a partial loss of activity of the pharmaceutical composition. In this regard, even slight heating at the stage of ethanol evaporation is undesirable [4].

Another problem is the sterilization of the pharmaceutical composition. In the prior art, it is carried out either by autoclaving, which in the case of pharmaceutical compositions with taxanes will lead to partial hydrolysis and other types of taxane degradation, or by membrane filtration. A problem for the implementation of membrane filtration after evaporation of ethanol may be the increased viscosity of the solution, which can lead to losses during filling of the resulting composition into bottles.

A known method of obtaining a pharmaceutical composition for injection based on taxanes by dissolving taxane derivatives in ethanol, followed by the introduction of surfactants and evaporation of ethanol under reduced pressure [5]. The solution remains stable for 2-3 hours. Information on the presence of impurities in the liquid pharmaceutical composition obtained according to [5] is not given. In addition, the presence of even 1.3% ethanol in the injection solution and the need to inject large volumes can lead to symptoms of alcohol poisoning during treatment.

In the process of creating this invention, it was found that the removal of ethanol by sparging an inert gas reduces the amount of undesirable impurities resulting from hydrolysis and other types of taxane degradation (the nature of undesirable impurities resulting from the synthesis of docetaxel and its degradation is given, for example, in the application of the United States US 2003032820 [6]), reduce the amount of remaining ethanol and increase the stability of the resulting solutions.

In accordance with the invention, a method is described for preparing a parenteral pharmaceutical solution of an antitumor action based on taxane derivatives, comprising dissolving a taxane derivative in ethanol, introducing a surfactant and then removing ethanol by bubbling an inert gas through the resulting ethanol solution at room temperature. If necessary, sterile filtration of the solution is carried out before or after ethanol blowing.

The technical result of the invention is to improve the technology of obtaining pharmaceutical compositions based on taxanes by upgrading one of the stages, namely the stage of removal of ethanol. As a result of this modernization, the amount of impurities in the pharmaceutical composition resulting from hydrolysis and other taxon degradation pathways is reduced, and the solution stability is improved.

In accordance with the method according to the invention, a solution of the active substance, a derivative of taxanes, in ethanol is prepared with a concentration of from 1 to 100 mg / ml. Not in all cases it is possible to obtain a homogeneous transparent solution, the dissolution takes, depending on the amount of taxane, from 10 minutes to 2 hours. Then, a surfactant is added to the ethanol solution.

According to a preferred embodiment of the invention, the surfactant is selected from the group consisting of polysorbates, in particular Tween 80 and Cremophor.

Ethanol removal is carried out by bubbling an inert gas (for example, nitrogen or at room temperature argon) in a container with a solution at room temperature, while it is desirable to ensure maximum immersion of the gas pipe. The duration of this stage depends on the downloads and can range from 1 hour to 6 hours. Sparging can be carried out both in glass flasks, by introducing a glass or plastic tube sealed in a thin section, and in semi-industrial and industrial steel reactors of various designs. In order to accelerate the removal of ethanol in the case of large loads, it is possible to make a tight connection of the system with a water-jet pump.

An additional advantage of inert gas sparging is the elimination of the additional influence of atmospheric air on hydrolysis and other taxon degradation pathways.

After reaching the required concentration of ethanol, the mixture is poured into vials under sterile conditions.

Depending on the ratio of the active principle of the class of taxanes, ethanol and surfactant, as a result of ethanol removal, a solution with a higher viscosity value can be obtained, which makes it difficult to transfer the resulting solution to vials and filtration.

If necessary, sterile filtration of the resulting mixture is carried out by passing 0.22 μm through a membrane filter. If the solution obtained after ethanol removal cannot be filtered due to high viscosity, the solution is filtered until ethanol is removed, and all subsequent steps are carried out under sterile conditions.

In another embodiment, overpressure is applied with an inert gas and sterile filtration of the viscous solution is carried out.

As a result of applying the method according to the invention, pharmaceutical compositions based on taxanes with a reduced content of impurities are obtained, which have increased stability upon dilution with infusion solutions.

The invention is further illustrated by drawings and examples, not limiting the scope of the invention.

Figure 1 - HPLC of the solution of example 1, the main peak corresponds to docetaxel.

Figure 2 - HPLC of the solution of example 2, the main peak corresponds to docetaxel.

Examples

Example 1

2 g of docetaxel is dissolved in 50 ml of ethyl alcohol, on a stirrer, without heating for one hour. Add 30 ml of ethanol and 50 ml of tween 80. The working solution is subjected to sterile filtration on a membrane filter with a pore size of 0.22 μm.

Evaporation of alcohol is carried out in a two-necked flask, into which a sterile tube is lowered, connected through a hose to a nitrogen cylinder. At the end of the work, the volume was ~ 42-44 ml. In laminar conditions, 0.6 ml of the drug is poured into sterile vials with a sterile syringe. The bottles are corked, run in and left for storage at a temperature of + 5 ° C.

The alcohol content, according to HPLC, is less than 0.5%, the docetaxel content is 40.3 mg / ml.

Undiluted solution is stable during storage for more than 2 months.

Example 2 (comparative)

30 g of docetaxel is dissolved under stirring with a magnetic stirrer in 350 ml of anhydrous ethanol, and 300 ml of polysorbate 80 (tween 80) (OOO AS Angra, Belgium) (L. Chrosolv Ethanol, Merck) are added and the mixture is evaporated under vacuum using a rotary evaporator in for 2 hours at 15 mm Hg

The residual ethanol content according to HPLC was 0.93%, the docetaxel content was 41.0 mg / ml.

The HPLC data of the resulting solution are shown in FIG. 2. The solution is stable during storage for more than 2 months.

Example 3

In a steel reactor equipped with an inert gas supply system for sparging and a mechanical stirrer, 100 g of paclitaxel, 2000 ml of ethanol, 2000 ml of polysorbate 80 (tween 80) are charged and inert gas is bubbled. The mixture resulting from the removal of ethanol is fed through a branch in the lower part of the reactor to a 0.22 mm filter; if necessary, a slight overpressure is created by supplying an inert gas.

The reactor is washed with a minimum amount of a mixture of ethanol and tween 80 1: 3. After filtration, the mixture is dispensed into vials.

The residual ethanol content according to HPLC was 1.03%.

Information sources

1. Instructions for use of the drug Taxotere. http://ru.sanofi-aventis.com/products/Taxotere.pdf

2. Taxol: A Novel Investigational Antimicrotubule Agent. E.K. Rowinsky, L.A. Cazenave, R.C. Donhower, Journal of the National Cancer Institute, 82 (15), 1247-1259 (1990).

3. Vidal Handbook, AstraPharm Service Publishing House, 8th edition, p. B-597.

4. Degradation of paclitaxel and related compounds in aqueous solutions I: Epimerization. J. Tian, V. J. Stella, Journal of Pharmaceutical Sciences, Volume 97, Issue 3, Pages 1224-1235.

5. RU 2134123 C1, A61K 47/10, 08/10/99.

6. US2003032820 A1, C07BD 35/14, 02/13/2003.

Claims (5)

1. A method of obtaining a parenteral pharmaceutical solution of an antitumor effect based on taxane derivatives, comprising dissolving a taxane derivative in ethanol, introducing a surfactant and then removing ethanol, characterized in that the ethanol is removed by bubbling an inert gas through the obtained ethanol solution at room temperature. 2. The method according to claim 1, in which sterile filtration is carried out. 3. The method according to claim 2, in which sterile filtration is carried out until the removal of ethanol. 4. The method according to claim 1, wherein the taxane derivative is docetaxel or paclitaxel. 5. The method according to claim 1, in which the surfactant is selected from the group comprising polysorbates and Cremophor.

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