CZ300795B6 - Pharmaceutical composition and process for its preparation - Google Patents

Abstract

The present invention relates to a pharmaceutical composition prepared by ice vacuum sublimation and comprising oxaliplatin as an active substance and pharmaceutically acceptable carrier, wherein the invented pharmaceutical composition is characterized in that as a carrier it contains at least one alcoholic sugar of non-animal origin, whereas weight ratio of oxaliplatin to alcoholic sugar of the non-animal origin or alcoholic sugars of non-animal origin ranges within 1:3 to 1:7. The solution also relates to a process for preparing such pharmaceutical composition.

Description

Pharmaceutical composition and process for its preparation

Technical field

The present invention relates to a pharmaceutical composition prepared by frost sublimation and comprising oxaliplatin as an active ingredient and a pharmaceutically acceptable carrier, wherein the administration of the composition comprises a reduction in the risk of viral contamination, in particular agents of animal spongiform encephalopathy.

BACKGROUND OF THE INVENTION

Oxaliplatin, referred to in the nomenclature ΓΝΝ as oxaliplatin, was first prepared 15 in optically pure form in 1978 by isolation from a mixture of isomers [J.Clin.Hematol.Oncol 1977, 7 (1),

197-210], Chemically it is {trans (-) 1,2-cyclohexanediamine} (oxalato) platinum (II) complex

Oxaliplatin is a cytostatic that is used in the treatment of testicular, ovarian, malignant melanoma, bronchogenic carcinoma, and in particular in the treatment of metastatic colon cancer in combination with fluoropyrimidines. Compared to the cisplatin used hitherto, oxaliplatin has lower nephrotoxicity and a broader spectrum of antitumor activity. Oxaliplatin is usually administered at a dose of 100 to 135 mg / m ² , as an infusion lasting 2 to 6 hours. The infusion solution is prepared by diluting the final dosage form with a 5% aqueous glucose solution.

Numerous liquid dosage forms of oxaliplatin based on its aqueous solutions have been described in the prior art but have not yet found use in therapeutic practice due to their lack of stability. The cause of this instability is the known fact that oxaliplatin decomposes by hydrolysis to form toxic platinum aquacomplexes. The only stable form of oxaliplatin so far is the oxaliplatin powder composition obtained by freeze-drying under freeze-drying. This dry powder composition contains, in addition to oxaliplatin, a lactose carrier which ensures the consistency of the dry oxaliplatin matrix formed by freeze-drying under vacuum and prevents it from cracking which would otherwise lead to leakage of a portion of the oxaliplatin from vials in which freeze-freeze-drying is performed. A significant disadvantage of the lactose carrier used so far, which is an animal product, is the risk of viral contamination of the pharmaceutical composition with viruses that may be contained in the lactose. Reducing the risk of such viral contamination, in particular reducing the risk of transmission of animal spongiform encephalopathy, is currently a topical problem in most dosage forms containing excipients, animal substances, especially bovine origin. Lactose, which has been used in oxaliplatin pharmaceutical compositions to date, has very good cryoprotective effects and its replacement with another suitable carrier while maintaining the properties of oxaliplatin lyophilisate and the economics of vacuum freeze-sublimation have not been satisfactorily solved yet.

SUMMARY OF THE INVENTION

The above-mentioned desirable replacement of the lactose carrier with another carrier substantially eliminating the above risk of viral contamination is solved by the pharmaceutical composition of the present invention prepared by vacuum frost sublimation under vacuum and containing oxaliplatin as an active ingredient and a pharmaceutically acceptable carrier. it contains at least one alcoholic sugar of non-animal origin, the ratio by weight of oxaliplatin to alcoholic sugar of non-animal origin or to alcoholic sugars of non-animal origin is 1: 3 to 1: 7.

The pharmaceutical composition of the invention preferably comprises oxaliplatin and a non-animal alcoholic sugar or non-animal alcoholic sugars in a weight ratio of 1: 5.

The pharmaceutical composition of the invention preferably comprises mannitol as a non-animal alcohol sugar.

The invention also relates to a process for the production of the aforementioned pharmaceutical composition, characterized in that a sterile aqueous solution of oxaliplatin and at least one alcohol of non-animal origin containing oxaliplatin and alcohol of non-animal origin or alcoholic sugars of non-animal origin 1: 7 and having a total weight concentration of said substances of 2.8 to 3.2%, are filled into the vial in a volume of not more than 60% of the usable volume of the vial, after which the vial is cooled to 2 to 8 ° C a linear temperature drop of 0.1 to 0.5 ° C / min to a final temperature of -35 to -45 ° C, held at this temperature for 1 to 6 hours, and then subjected to freeze-drying under vacuum.

The pharmaceutical composition of the invention, when dissolved in a suitable pharmaceutically acceptable solvent, provides a clear solution which contains no undissolved matter or haze and is thus particularly suitable for parenteral applications. The composition of the invention is also easy to manufacture, has high stability and does not present a risk of viral contamination when administered.

The method of the invention solves the problems that would arise in the case of merely replacing lactose with mannitol, while maintaining the existing regime applicable to the use of lactose. Indeed, in the treatment of solutions in which lactose is simply replaced by mannitol, the lyophilisate leaks frequently from the vials and the glass vials crack due to increased mechanical stress caused by the volume changes of the frozen solution, which is manifested in particular by the dropping of the vial bottom during frost sublimation. Within the scope of the invention, it has been found that the temperature regime of the process of the invention significantly eliminates said cracking of the vials during freeze-drying under vacuum. It has thus been found that a total weight concentration of oxaliplatin and at least one alcohol sugar in the aqueous solution prior to freezing sublimation in the range of 2.8 to 3.2% is necessary to achieve an optimal freeze-sublimation rate. Furthermore, it has been found that a sterile solution of oxaliplatin and mannitol in the stated weight ratio can be filled into the vials at a volume of up to 60% of the usable vial volume without altering the lyophilisate quality or leaking the lyophilisate from the vials or rupturing the vials. represents a very advantageous solution in terms of utilizing the capacity of the frost sublimation device.

Due to its properties, the pharmaceutical composition of the invention is particularly suitable for use in the treatment of oxaliplatin-sensitive tumors.

In the following, the invention will be explained in more detail by way of examples of specific embodiments thereof, these examples being illustrative only and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Under GMP conditions, 0.50 kg of pharmacopoeial oxaliplatin and 2.50 kg of pharmacopoeial mannitol were gradually dissolved in 70 kg of water at 20-25 ° C. The obtained solution was sterilized by filtration through a 0.22 µm filter and filled into colorless clear vials of type 20H first hydrolytic class marketed by Saint Gobain Desjonqueres, i.e. the amount of solution in the vial corresponded to 50 mg of the dissolved active ingredient. The filled vials were fitted with freezing sublimation stoppers and placed in the chamber of the freezing sublimation apparatus cooled to 5 ° C. After equalizing the temperature of the vial solution to the ambient temperature, the vial solution was slowly frozen while maintaining a linear temperature drop

0.2 ° C / min to a final temperature of -40 ° C and the frozen solution was left at this temperature for a period of time

It was subjected to freeze-drying under vacuum for 4 hours.

The lyophilisate obtained had a white compact form and a water content of 0.8% by weight. Upon dissolution of the lyophilisate, a clear Ph solution was obtained. Eur. Art.2.2.1.

Example 2

Under GMP conditions, 0.50 kg of pharmacopoeial oxaliplatin and 2.50 kg of pharmacopoeial mannitol were gradually dissolved in 70 kg of water at 20-25 ° C. The obtained solution was sterilized by filtration through a 0.22 µm filter and filled into colorless clear vials of type 20H first hydrolytic class marketed by Saint Gobain Desjonqueres, with the amount of solution in the vial corresponding to 100 mg of the dissolved active ingredient. The filled vials were fitted with freezing sublimation stoppers and placed in the chamber of the freezing sublimation apparatus cooled to 5 ° C. After equilibrating the solution temperature in the vial to ambient temperature, the solution in the vial was slowly frozen while maintaining a linear temperature drop of 0.2 ° C / min to a final temperature of -40 ° C and the frozen solution was kept at this temperature for 4 hours before being subjected to frost sublimation under vacuum.

The lyophilisate obtained had a white compact form and a water content of 1.0% by weight. Upon dissolution of the 35 to lyophilisate, a clear Ph solution was obtained. Eur. Article 2.2.1,

Example 3

In this example, the stability of the pharmaceutical composition prepared in Example 1 was tested when stored at 40 ° C and 75% relative humidity. The results obtained are shown in Table 1 below.

Table 1

Evaluated parameter In the begining storage After 6 months storage Appearance of lyophilisate white compact white compact Chromatographic purity of the lyophilisate: - oxalic acid (%) -a summary of all non-pollutants- 0.10 0.08 tot (%) 0.11 0.16 -L-isomer (%) <0.1 <0.1 Water content of lyophilisate (%) 0.8 1.0 Appearance of solution after reconstitution of the lyophilisate (3% aqueous solution) clear by Clear by Ph.Eur.čl.2.2.1 Ph.Eur.čl.2.2.1 Contamination of solution lyophilisate without visible without visible of particles Particles

The percentages given in Table 1 are percentages by weight.

Example 4

In this example, the stability of the pharmaceutical composition prepared in Example 2 was tested at storage at 40 ° C and 75% relative humidity. The results obtained are shown in Table 2 below.

Cl 300795 B6

Table 2

Evaluated parameter In the begining storage After 6 months storage Appearance of lyophilisate white contact white compact Chromatographic purity of lyophilisate: - oxalic acid (%) -a summary of all non-pollutants- 0.10 <0.1 tot {%) 0.11 0.12 -L-isomer (%) <0.1 <0.1 Water content in lyophilized stopper (%) 1.0 1.1 Appearance of solution after reconstitution of the lyophilisate (3% aqueous solution) clear by clear by Contamination of solution Ph.Eur.čl.2.2.1 Ph.Eur.čl.2.2.1 lyophilisate without visible without visible Particles of particles

The percentages given in Table 2 are percentages by weight.

Claims (5)

PATENT CLAIMS 1. A pharmaceutical composition prepared by freeze-drying under vacuum and containing oxaliplatin as active ingredient and a pharmaceutically acceptable carrier, characterized in that it comprises at least one alcoholic sugar of non-animal origin, wherein the weight ratio of oxaliplatin to alcoholic sugar of non-animal origin or alcoholic sugars of non-animal origin is equal to 1: 3 to 1: 7. Pharmaceutical composition according to claim 1, characterized in that it contains oxaliplatin and alcoholic sugar of non-animal origin or alcoholic sugars of non-animal origin in a weight ratio of 1: 5. 25 Pharmaceutical composition according to claim 1 or 2, characterized in that it contains mannitol as the non-animal alcohol sugar. A process for the manufacture of a pharmaceutical composition according to claim 1, characterized in that a sterile aqueous solution of oxaliplatin and at least one non-animal alcoholic sugar comprising oxaliplatin and non-animal alcoholic sugar or non-animal alcoholic sugars in a weight ratio of 1: 3 to 1: 7; having a total weight concentration 5 to 2.8% to 3.2% by volume of the vial, making up not more than 60% of the usable volume of the vial, after which the contents of the vial are cooled to 2 to 8 ° C, then frozen while maintaining a linear temperature drop of 0.1 to 0.5 ° C / min to a final temperature of -35 to -45 ° C, held at this temperature for 1 to 6 hours, and then subjected to freeze-drying under vacuum.