RU2481827C2 - Pharmaceutical composition for injections, method of its obtaining and perfusion solution based on pharmaceutical composition - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with pharmaceutical composition of anti-tumor action, its obtaining and perfusion solution. Essence of invention lies in the following: solution contains taxane derivatives in surface-active layer. Said solutions are used for preparation of perfusion solutions. Method of solution obtaining lies in dissolution of active substance in ethanol and introduction of surface-active substance.

EFFECT: invention makes it possible to reduce dose of active substance, reduce ethanol concentration.

8 cl, 1 tbl, 10 ex

Description

The present invention relates to a new pharmaceutical composition having antitumor and anti-leukemic activity, in particular to a new composition for injection containing substances of the taxane class, especially such as taxol or one of its analogues or derivatives of the following general formula:

,

,

in which R represents hydrogen or acetyl, R _I represents a tert-butoxycarbonylamino or benzoylamino radical. Two derivatives are preferred for which R represents an acetyl group and R _I represents a benzoylamino group or for which R represents hydrogen and R _I represents a tert-butoxycarbonylamino radical.

The first of these two compounds is known as Taxol, and the second is known as Taxotere.

It is known that these substances have a significant effect on malignant tumors in a living organism, which made it possible to study them in the treatment of diseases resistant to all other anti-cancer therapies.

However, they have poor solubility in water, so there is a need for a composition that can be used for injection based on a surfactant and ethanol. Ethanol is the best solvent that allows you to dissolve the molecules corresponding to the formula (I).

It is known (Rowinsky, Larraine, Cazenave and Donehower, journal of the National Cancer Institute, Volume 82, No. 15, pp. 1247-1259, August 1990) to obtain the so-called "mother liquor" containing about 6 mg / ml taxol in a solvent mixture consisting of of:

- 50% by volume of ethanol;

- 50% by volume Cremophor EL.

During injection, this solution is mixed with a perfusion fluid containing sodium chloride or dextrose.

To obtain a stable mixture, the authors of this article believe that the concentration of the active principle in the perfusion solution should be limited to concentrations of approximately 0.03-0.6 mg / ml.

However, it is advisable to inject sufficient doses of the active principle, approximately 0.3-1 mg / ml in the perfusion fluid, above these doses there are signs of anaphylactic shocks, which are suppressed with difficulty, mainly caused by Cremophor.

To obtain the indicated concentrations (0.3-1 mg / ml), it is always necessary to inject solutions containing simultaneously the active principle, with concentrations of each of the following compounds, ethanol and especially Cremophor, about 8 g per 100 ml of the solution, treatment requiring frequent administration of elevated doses of the active principle and a relatively low concentration of the active principle in the solution during large volume injection leads, in addition to provoking, in addition to the anaphylactic symptoms, symptoms of chronic poisoning a with alcohol.

As a result of the use of the pharmaceutical compositions of the present invention, it has been found that it is possible either to significantly reduce the concentration of ethanol, or also completely eliminate Cremophor and ethanol in the perfusion compositions.

According to the first method, a stock solution is prepared prior to the invention, containing the active principle in a solvent mixture, including ethanol, which is the best biocompatible solvent of the active principles of the taxane class, and a surfactant selected from polysorbates sold under the name Tween, polyoxyethylene glycol esters sold for sale, for example, under the name Emulfor, or esters of polyethylene glycol and castor oils sold for sale, for example, under the name Cremophor.

The mother liquor is prepared by dissolving the active principle in ethanol with the gradual addition of a surfactant. Thus, it is possible to prepare solutions containing from 10 to 100 mg / ml of active principle in a mixture containing about 50% surfactant.

Moreover, according to the present invention, ethanol, the best solvent of the active principle, can be almost completely removed.

To prepare solutions with a low ethanol content, the active principle is dissolved in ethanol, as described above, then any surfactant selected among those mentioned above or among others is added, which allows dilution of the aqueous medium to ensure the formation of micelles containing the active principle encapsulated in the surface active substance. Then, the ethanol contained in this solution is removed at least partially by evaporation in vacuo or by any other appropriate method.

According to a second method for preparing the mother liquor, the active principle is dissolved directly in the surfactant. Preferably, a surfactant solution containing 1-2% ethanol is prepared, and the active principle is continuously added to this solution, mixing with, for example, a helicoidal crusher or a turbine with crushing. The presence of a small amount of ethanol gives some advantages, the medium has a lower viscosity, the wetting of the powder improves, and the final filtration of the solution.

The mother liquor with a low ethanol content contains predominantly less than 5% ethanol, preferably 2% ethanol. This solution is stable and may also contain up to 200 mg / ml, preferably up to 80 mg / ml of the active principle in the surfactant.

Taxol mother liquor preferably has a concentration of 6-20 mg / ml of active ingredient in the surfactant. This solution is mixed, depending on the concentration of 0.1-1 mg / ml, with a perfusion liquid, which is either saline or glucose solution. The perfusion composition obtained on the basis of the previous mother liquors, with a low ethanol content, mainly contains 0.3-0.5 mg / ml taxol and less than 1 ml / l ethanol.

A taxol-based perfusion composition containing an active principle without ethanol has a physical stability of 8-100 hours. By physical stability is meant the fact that the solution does not form a precipitate after 8-10 hours of storage at room temperature.

Taxotere mother liquor has a predominantly concentration of 20-80 mg / ml of active ingredient in the surfactant. This solution is mixed, depending on the concentration of 0.1-0.5 mg per milliliter, with a perfusion liquid, which is either physiological saline or glucose solution. The perfusion formulations obtained on the basis of the previous mother liquors, with a low ethanol content, also contain mainly 0.1-0.3 mg / ml Taxotere; they contain less than 15 ml / l of surfactant and less than 1 ml / l of ethanol.

The Taxotere-based perfusion composition containing the active principle without ethanol has physical stability, which can reach several months.

Then, the perfusion composition of Taxol or Taxotere is injected into a person at a rate previously determined depending on the amount of active principle that is necessary during the injection. No anaphylactic shock phenomena observed with prior art solutions are observed.

Thus, these latter perfusion formulations can reduce, by comparison with the prior art, the amount of surfactant administered by injection to humans by about 80% and the amount of ethanol by almost 100%.

The invention is illustrated by the following examples, which should not be construed as limiting the invention.

Comparative example

Dissolve 0.180 g of taxol in 15 ml of ethanol. Such an amount of Cremophor is added to obtain 30 ml of a solution containing 6 mg / ml taxol. This solution is diluted in 5% glucose perfusion solution at a rate of 1 mg / ml, the perfusion solution contains 87.7 ml / l Cremophor and 87.7 ml / l ethanol.

The perfusion solution is stable for more than 21 hours.

Examples according to the invention

32 g of Taxotere are dissolved in 340 ml of absolute ethanol, then 830 g of polysorbate 80 is added. Ethanol is evaporated on a rotary evaporator at 30 ° C and a pressure of 15 mmHg for 2 hours.

The resulting solution is stable, it contains 40 mg / ml taxotere.

After dilution in a perfusion solution with 5% glucose at concentrations of 0.1; 0.3 and 0.5 mg / ml observe the stability of the resulting solutions.

Reproduce the same method based on a solution containing 60 mg / ml Taxotere.

Reproduce the same experiment on the basis of solutions of taxol containing 12 and 20 mg / ml taxol.

The results are shown in table 1.

Table 1 Substance Solvent Stock solution concentration The active principle in the perfusion composition Perfusion surfactant Ethanol perfusion composition Stability Taxol Polysorbate 20 mg / ml 1 mg / ml 50 mg / ml <0.3 mg / ml > 8H Taxol Polysorbate 20 mg / ml 0.3 mg / ml 15 mg / ml <0.09 mg / ml > 24H Taxol Polysorbate 12 mg / ml 1 mg / ml 83.3 mg / ml <0.05 mg / ml > 48H Taxotere Polysorbate 40 mg / ml 0.5 mg / ml 11.6 mg / ml 0.009 mg / ml 8H-23H Taxotere Polysorbate 40 mg / ml 0.3 mg / ml 6.9 mg / ml 0.05 mg / ml 8H-23H Taxotere Polysorbate 40 mg / ml 0.1 mg / ml 2.3 mg / ml 0.02 mg / ml 29H-45H Taxotere Polysorbate 60 mg / ml 0.1 mg / ml 1.5 mg / ml <0.01 mg / ml 8H-23H

Example 8

258 g of Taxotere are introduced into a steel reactor, which is dissolved in 2425 g of ethanol with stirring for 45 minutes.

6156 g of polysorbate 80 are added and homogenized with mechanical stirring for 15 minutes.

The solution is transferred to the reactor and the alcohol is distilled off under reduced pressure from 10 to 50 mbar (1000-5000 Pa), the temperature is maintained between 18 and 28 ° C.

Alcohol is distilled off until its content is below 2%.

The resulting solution was filtered on a filter having a pore size of 0.2 μm. It contains:

- 1.3% ethanol,

- 39.6 mg / ml Taxotere.

After dilution to 1 mg / ml in a perfusion cup containing 5% glucose, the solution is stable without visible precipitation for more than 2 months.

Example 9

Dissolve 160 g of Taxotere or 160 mg of taxol in 10 ml of a mixture of absolute ethanol and Cremophor EL (218), ethanol is evaporated on a rotary evaporator at 30 ° C at a pressure of 25 mm Hg. within 3 hours.

The resulting solutions are resistant. They contain 20 mg / ml Taxotere or Taxol. After dilution in a perfusion solution with 5% glucose at concentrations of 0.1 and 0.5 mg / ml, precipitation is observed between 30 and 95 hours.

Example 10

Dissolve in an Erlenmeyer flask with a volume of 500 ml 275.5 g of polysorbate 80 in 5.4 g of absolute ethanol, then mix with a magnetic stirrer until the mixture is completely homogenized.

26.13 g of the solution obtained above are charged into a 50 ml flask. The flask was placed in a water bath heated earlier and maintained at 30 ° C throughout the experiment. Stirred at approximately 600 rpm using an artificial magnet.

Add 1,076 g of Taxotere in several portions to achieve the disappearance of lumps between the two additives (the duration of the operation is approximately one hour). After the last portion of Taxotere has been introduced, stirring is maintained until the solution is clear (approximately two hours).

Claims (8)

1. A pharmaceutical solution of antitumor action containing as active principle derivatives of taxanes and a pharmaceutically acceptable solvent, characterized in that as a solvent it contains a surface-active agent selected from polysorbates and polyethylene glycol esters. 2. The solution according to claim 1, characterized in that as compounds of the class of taxanes it contains compounds of the general formula I

in which R represents a hydrogen atom or acetyl;
R ₁ means tert. Butoxycarbonylamino or benzoylamino. 3. The solution according to claim 1, characterized in that it contains less than 5% ethanol, mainly less than 2% ethanol. 4. The solution according to claim 1 or 2, characterized in that it contains up to 200 mg / ml, preferably up to 80 mg / ml of the compound of formula I. 5. The solution according to claim 1, or 2, or 3, characterized in that it contains from 20 to 80 mg / ml of a compound of formula I, in which R is hydrogen and R ₁ is tert-butoxycarbonylamino. 6. The solution according to claims 1 to 3, characterized in that it contains from 6 to 20 mg / ml of the compound of formula I, in which R is acetyl, and R ₁ is benzoylamino. 7. A method of obtaining a pharmaceutical solution of an antitumor effect, comprising dissolving the active substances of taxane derivatives in a pharmaceutically acceptable solvent, characterized in that the active substance is dissolved in ethanol, then a surfactant is introduced and ethanol is evaporated, or the active substance is slowly introduced into the surface-active solution substances in ethanol contained in an amount of 1-2%. 8. A perfusion solution for injection of toxane derivatives based on a pharmaceutically acceptable solvent, characterized in that the concentration of taxane derivatives is 0.1-1 mg / ml, and ethanol is less than 1 ml / l.