Stable pharmaceutical form anticancer drug

 

The invention relates to the field of medicine and relates to a stable form of anti-cancer drug containing paclitaxel, and how it is received by dissolving crystalline paclitaxel in a neutral organic solvent selected from the group consisting of acetonitrile, dioxane, ethanol or mixtures thereof, provided that the contents of the individual solvents in the mixture is in the range from 5 to 95%, whereas the water content is in the range from 0 to 60%, optionally filtering the resulting solution, freezing and removal of the solvent by sublimation under reduced pressure at low temperature, and optional separation of dose in terms ensure sterility. The form has high stability and eliminates some used still harmful components. 2 ad and 3 C.p. f-crystals, 3 ill., 1 PL.

The technical field to which the invention relates

The present invention relates to stable pharmaceutical form anticancer drug and a method of producing a stable pharmaceutical form anticancer drug containing exclusively or together with other active substances nerest paclitaxel, presented on Fig.1, is a known chemical compound, which is extracted from the bark of the tree Taxus brevifolia or obtained by chemical synthesis. This connection is used in medicine in the treatment of malignant tumors that are resistant to other treatments (Slichenmyer WJ, Von Hoff DD. New natural products in cancer chemotherapy. J. Clin. Pharmacol. 1990, 30:770-88; Rowinnsky EK et al., Taxol: a novel investigational antimicrotubule agent. J. Natl. Cancer Inst. 1990, 82: 1247-59; Long HJ. Paclitaxel (Taxol): a novel anticancer chemotherapeutic drug. Mayo Clin. Proc. 1994, 69; Donehower RC. Paclitaxel (Taxol). N. Engl. J. Med. 1995, 332, and other publications).

In the treatment of cancer paclitaxel is injected intravenously, it is therefore necessary to prepare solutions of the respective concentrations in the biocompatible solvent system.

Very weak solubility of paclitaxel in water do not allow to enter it directly in the classical, conventional fluids for infusion. Thus, the only still used in commercial forms of pharmaceutical preparations containing paclitaxel are "basic" solutions of this substance in the mixture of polar solvent and surface active substance, which cannot enter the patient directly, but only after pre-dilution fluid for infusion.

Most izvestno mixture polyethoxyethanol castor oil, known under the trademark Cremophor EL and ethanol. A characteristic feature of these solutions is that after dilution with infusion fluid they may precipitate. Moreover, the chemical stability of paclitaxel in such solutions is low. After 2 months of storage at a temperature of 25With observed a reduction in the active ingredient content of 10%, and after 22 months the content of paclitaxel was only 67% of the original quantity. The decay rate strongly increases with temperature. The instability of paclitaxel in such solutions associated with the chemical properties of Cremophor EL and the presence of even minor amounts of water in ethanol. Obviously, these drugs are of very limited use and the introduction of their patients poses a real risk due to the introduction of a too low dose of a medicine due to its decomposition.

In patent No. 176826 was proposed method, partially removing the above mentioned disadvantages. It is a comprehensive commercial cleaning Cremophor EL in order to eliminate the chemical properties of paclitaxel that impair its stability, or the addition of acid to reduce the concentration in the solvent carb is, thus obtained, were much more stable and can be stored over a long time at room temperature without appreciable loss of activity. However, after dilution of these solutions infusion fluid there is a risk of sedimentation and therefore it is necessary to use a set for infusion, supplied with the appropriate filter.

However, the above procedure does not correct the serious flaws thus obtained pharmaceutical preparation is associated with the use of Cremophor EL, the presence of which in medicines, administered intravenously, in some cases, may be associated with the risk of anaphylactic shock (Rowinnsky EC et al. Taxol: a novel investigational antimicrotubule agent. J. Natl. Cancer Inst. 1990, 82: 1247-59).

In addition, the presence of ethyl alcohol in a medical drug, dose when the mode requires the introduction of large quantities of drugs can cause symptoms of intoxication.

In the description of the patent 169372 presents a method of obtaining solutions paclitaxel with higher concentrations of the active substance, which reduces the harmful effects of Cremophor EL. The method also allows to almost completely eliminate ethanol in obtaining and thus significantly reduce harmful in the form, obtained by the method according to the invention, solves all the aforementioned problems associated with the stability containing paclitaxel medication, and helps to eliminate some of the harmful components used so far.

The invention

According to the present invention, a stable pharmaceutical form anticancer drug containing paclitaxel shown in Fig.1, differs in that it is a solid, amorphous form of the active substance with a large surface, optionally with some crystalline additives.

According to the invention, a method of obtaining a stable pharmaceutical form anticancer drug is dissolved crystalline paclitaxel in a neutral organic solvent selected from the group consisting of acetonitrile, dioxane, ethanol or a mixture of these solvents, optionally with the addition of water, provided that the contents of the individual solvents in the mixture is in the range from 5 to 95%, whereas the water content is in the range from 0 to 60%; and the resulting solution is optionally filtered, freeze and remove the solvent by sublimation under reduced pressure, philnoll.

Preferably, in the method of the present invention the solution of paclitaxel possible after filtering is first poured into the containers according to the dose, and then freeze and remove the solvent by sublimation under reduced pressure and low temperature.

In the method according to the invention, removal of the solvent by sublimation, preferably, carried out at a temperature from -60C to +50C.

Pharmaceutical form of the anticancer drug according to the invention is chemically very stable and at the same time, easily soluble in various systems biocompatible solvents, which gives the opportunity to enter his patients.

Paclitaxel isolated from Taxus brevifolia, or obtained by chemical synthesis, is a crystalline substance, as shown in Fig.2, and its heat of dissolution in ethyl alcohol is 66,6 j/,

It was unexpectedly found that the substance obtained by the method of the present invention represented by the form in which the predominant amorphous structure shown in Fig.3, and its heat of dissolution in ethanol, equal to 32.4 j/g, was two times less compared to the crystalline form.

Because the drug is dissolved directly solutions while such complications were observed in the case of finished compositions in the form of "basic" solutions currently available.

Moreover, this stable form of paclitaxel does not limit the choice of therapeutically suitable solvents.

Medicinal product prepared in this way, a stable, and it can be dissolved just before the introduction of different solvent system containing components such as polyoxyethyleneglycol, Polysorbate, polyoxyethylene esters of fatty acids, ethanol, phospholipid fractions, lecithins, emulsion oil-in-water, propylene glycol, benzyl alcohol, dimethylacetamide, methylacetamide, esters of saccharides and fatty acid esters, copolymers of ethylene oxide, copolymers of propylene oxide, glycocholate sodium and others. The obtained solutions can be entered directly or after dilution with a suitable infusion fluid.

The implementation of the invention presents the following examples.

Example I

Dissolve 1500 mg paclitaxel in 100 ml of 1,4-dioxane. The resulting solution was sterilized under aseptic conditions by filtration through a Teflon filter of 0.2 μm. Then fill with a solution of sterile glass vials of 20 ml dose of 2 ml Vials provide steriljnije vials after the process of freeze drying. Solutions freeze at -40C. the drying Process is performed at a pressure of 0.1 mbar, with a gradual increase in the temperature of the plate to +30C. Upon completion of the drying process, the bottles are closed and the vacuum is reduced. After the vials are removed from lyophilizate, their closed lids and paste the appropriate labels. Each bottle contains 30 mg of paclitaxel. Thus obtained pharmaceutical preparation contains not more than 380 ppm dioxane and stable at least for 3 years.

Example II

Dissolve 1500 mg paclitaxel in 80 ml of 1,4-dioxane. Add 20 ml of water. The resulting solution was sterilized under aseptic conditions by filtration through a Teflon filter of 0.2 μm. Then fill with a solution of sterile glass vials of 20 ml dose of 2 ml Vials were supplied with sterile rubber stoppers for lyophilization. The vials are placed in lyophilizator, provided with a device for closing bottles after the process of freeze drying. Solutions freeze at -40C. the drying Process is performed at a pressure of 0.1 mbar, with a gradual increase in the temperature of the plate to +30C. At the end Plaut lids and paste the appropriate labels. Each bottle contains 30 mg of paclitaxel. Thus obtained pharmaceutical preparation contains not more than 380 ppm dioxane and stable at least for 3 years.

Example III

Dissolve 1500 mg paclitaxel in 50 ml of 1,4-dioxane. Add 50 ml of water. The resulting solution was sterilized under aseptic conditions by filtration through a Teflon filter of 0.2 μm. Then fill with a solution of sterile glass vials of 20 ml dose of 2 ml Vials were supplied with sterile rubber stoppers for lyophilization. The vials are placed in lyophilizator, provided with a device for closing bottles after the process of freeze drying. Solutions freeze at -40C. the Process of sublimation of the solvent is performed at a pressure of 0.1 mbar, with a gradual increase in the temperature of the plate to +30C. Upon completion of the drying process, the bottles are closed and the vacuum is reduced. After the vials are removed from lyophilizate, their closed lids and paste the appropriate labels. Each bottle contains 30 mg of paclitaxel. Thus obtained pharmaceutical preparation contains not more than 380 ppm dioxane and stable at least for 3 years.

Example IV

To the resulting solution was sterilized under aseptic conditions by filtration through a Teflon filter of 0.2 μm. Then fill with a solution of sterile glass vials of 20 ml dose of 2 ml Vials were supplied with sterile rubber stoppers for lyophilization. The vials are placed in lyophilizator, provided with a device for closing bottles after the process of freeze drying. The solution is frozen at a temperature of -50C. the drying Process is performed at a pressure of 0.1 mbar, with a gradual increase in the temperature of the plate to +40C. Upon completion of the drying process, the bottles are closed and the vacuum is reduced. After the vials are removed from lyophilizate, their closed lids and paste the appropriate labels. Each bottle contains 30 mg of paclitaxel. Thus obtained pharmaceutical preparation contains not more than 380 ppm dioxane and 0.5% ethanol and stable at least for 3 years.

Example V

In the same manner as in example I, dissolve 1500 mg paclitaxel, respectively, in 100 ml of different solvents, the composition of which is given in the table.

Drugs obtained by lyophilization of solutions a-e, was in amorphous form and were stable for 3 years.

Example VI

5 ml of sterile solvent, comprising Eventum, obtained according to examples I-V. Paclitaxel immediately were completely dissolved. The resulting solution is stable at least for 2 years at a temperature of +4C and at least 3 months at room temperature. This solution serves as a concentrate, is added to the appropriate infusion fluid, as shown in example VIII.

Example VII

5 ml of sterile solvent consisting of 300 mg of Polysorbate 80, 3400 mg Pharmacopoeia polyoxyethyleneglycol 300 and 1300 mg of anhydrous ethanol is added to liofilizovane the substances obtained according to examples I-V. Paclitaxel immediately were completely dissolved. The resulting solution was stable at room temperature for at least 8 hours. This solution serves as a concentrate, is added to the appropriate infusion fluid, as shown in example VIII.

Example VIII

The concentrate obtained in examples VI and VII, before intravenous patients diluted so that the final concentration of paclitaxel was 0.3-1.2 mg/ml For cultivation use the following: 0.9% NaCl, 5% glucose, and other infusion fluids such as ringer's solution, a mixture of 5% glucose and 0.9% NaCl solution, a mixture of 5% glucose solution is wow power. Such solutions are stable at room temperature of not less than b hours that allows you to safely enter their patients.

Example IX

150 mg of liofilizirovannogo substances obtained according to examples I-V, make 500 ml of a 30% emulsion of soybean oil for intravenous injection. The resulting liquid is thoroughly stirred until complete dissolution of paclitaxel. Formed the solution is stable at room temperature at least 8 hours and can be used for intravenous administration to patients.

Claims

1. Stable form of anti-cancer drug containing paclitaxel, characterized in that it is obtained by dissolving crystalline paclitaxel in a neutral organic solvent selected from the group consisting of acetonitrile, dioxane, ethanol or a mixture of these solvents, possibly with the addition of water, provided that the contents of the individual solvents in the mixture is in the range from 5 to 95%, whereas the water content is in the range from 0 to 60%, optionally filtering the resulting solution, its freezing, removal of the solvent by sublimation under reduced pressure, at low temperature and optional separation of the dose is tives such as those that crystalline paclitaxel dissolved in a neutral organic solvent selected from the group consisting of acetonitrile, dioxane, ethanol or a mixture of these solvents, possibly with the addition of water, provided that the contents of the individual solvents in the mixture is in the range from 5 to 95%, whereas the water content is in the range from 0 to 60%, and the resulting solution is optionally filtered, freeze and remove the solvent by sublimation under reduced pressure at low temperature, after which the drug is not necessarily divided into doses in conditions that ensure sterility.

3. The method according to p. 2, characterized in that the solution paclitaxel after sterilization by filtration is first poured into containers for doses under aseptic conditions, and then freeze and remove the solvent by sublimation under reduced pressure and low temperature.

4. The method according to p. 1 or 2, characterized in that the removal of the solvent by sublimation is carried out at a temperature in the range from - 60 to +50C.

5. The method according to p. 1 or 2, characterized in that the content of the individual solvents in the mixture is from 5 to 95%, and the water content is from 1 to 60%.

 

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