STABLE, INJECTABLE SOLUTIONS OF VINCRISTINE SALTS

Abstract: A stable, injectable pharmaceutical composi­ tion of vinca dimer salts. The compositions are in the form of an aqueous solution comprising per 1 ml of solution: from about 0.2 to about 2 mg of one or more pharmaceutically acceptable vinca dimer salts; from aobut 0.1 to about 1.0 mg of a pharma­ ceutically acceptable ethylenediamine-tetra­ acetic acid (EDTA) salt; acetate buffer in an amount necessary to maintain said aqueous solution at a pH of from about 3.0 to about 5.5; and from about 1.5 to about 2.5 mg of a preserva­ tive selected from methyl paraben, propyl paraben and mixtures thereof.

Description: This invention provides a stable, injectable aqueous solution of vincristine salts, suitable for intravenuous injection for the treatment of neoplastic diseases, particularly leukemias, in humans. Certain vinca alkaloids, being dimeric indole-dihydroindole compounds, have been used for some time in chemotherapy as oncolytic drugs, particularly for the treatment of leukemias. Among those so-called vinca dimers, there might be mentioned especially vincristine, vinblastine and vindesine (an amide derivative of vinblastine). The treatment consists of intravenous administration of pharmaceutically acceptable salts of the vinca dimers, in most cases the sulfate salt, to patients suffering from neoplastic diseases. Owing to the toxic properties of the vinca dimer salts, these must be administered in carefully accurate dosages. In recent years, vinca dimer salts for chemotheraphy, and particularly vincristine sulfate, were marketed in sealed vials containing a desired dosage of lyophilized vinca dimer salt, from which an aqueous solution for injection had to be reconsituted in situ. Such a procedure involves many drawbacks as compared to the use of ready-made injectable solutions, the main drawbacks being: errors in concentration of the vinca dimer salt owing to improper reconsitution of the lyophilized product; risk of contact with the toxic drug to the medical personnel preparing the injectable solutions; and waste of these very expensive drugs resulting from the need to discard the excesses of such reconstituted injectable solutions, which can be stored for comparatively short periods only (the recommended life of a reconsituted vincristine sulfate solution is 14 days at refrigerator temperatures, whereafter the solution becomes hazy and a precipitate forms). GB-A-2 020 180 (Nelson R & D) discloses vinblastine compositions containing EDTA as a stabilizer, a preservative mixture of methyl and propyl parabens, and a pH 7 acetate buffer, for ophthalmic use. Stable, ready-to-use aqueous solutions of vinca dimer salts were disclosed in Israel Patent Specification No. 69203 to Eli Lilly & Company and in the corresponding U.S. Patent 4,619,935. In accordance with said Israel Patent the formulation comprises, in addition to a pharmaceutically acceptable vinca dimer salt, a polyol, an acetate buffer to maintain the pH of the solution between 3.0 and 5.0 and a preservative. In contrast, U.S. Patent 4,619,935 is restricted to formulations comprising an aqueous solution of about 1-2 mg/ml of a vincristine salt, about 10-100 mg/ml of a polyol selected from mannitol, sorbitol and sucrose, an acetate buffer as in the corresponding Israel Patent and about 1-2 mg/ml of a preservative selected from methyl paraben and propyl paraben, singly or in combination. The formulations of this U.S. patent thus roughly correspond to the preferred embodiments described and claimed in Israel Patent 69203. Both said Israel and U.S. patents state (in Example 4 therein) that the vincristine sulfate formulations disclosed therein "have remained physically and chemically acceptable for pharmaceutical use for periods up to 1 year at 5°C". However, the stability test results given in the same Example 4 of these patents merely showed that said formulations "maintained 94-99% of their initial concentration after storage at 5°C for about 9 months". It is the object of the present invention to provide injectable aqueous solutions of vincristine salts having a significantly increased storage stability, as compared to the aforementioned known solutions. The above object is achieved by the present invention as a consequence of the totally unexpected and surprising finding, that when 0.1-1.0 mg/ml of a salt of ethylenediamine-tetraacetic acid (also referred to as "Edetate salt" and hereinafter as "EDTA-salt") is added to aqueous solutions of vincristine salts, comprising the conventional acetate buffer system and conventional preservatives (but no polyol as required in Israel Patent 69203 and U.S. Patent 4,619,935), the solutions remain stable for about 20 months, and even up to 30 months, at temperatures of 2-8°C, according to the accepted stability specifications (i.e. 90-110% of the labelled amount of the vinca dimer salt component). Furthermore, aqueous vincristine sulfate solutions in accordance with the present invention were found to be stable for up to 9 months, even at room temperature. The invention thus provides a stable, injectable pharmaceutical composition consisting of an aqueous solution comprising per 1 ml of solution: from 0.2 to 2 mg of a vincristine salt; from 0.1 to 1.0 mg of a pharmaceutically acceptable ethylenediamine-tetraacetic acid (EDTA) salt; acetate buffer in an amount necessary to maintain said aqueous solution at a pH of from 3.0 to 5.5; and from 1.5 to 2.5 mg of a preservative selected from methyl paraben, propyl paraben and mixtures thereof. The above formulation is applicable to any of the conventional salts of vincristine and the present invention is not restricted to vincristine sulfate solutions which are described in detail in the Examples herein, by way of non-limiting example only. The vincristine salts are present in the injectable aqueous solutions according to the invention at concentrations of from 0.2 to 2 mg/ml as stated above, preferably from 0.5 to 1 mg/ml. For commercial reasons concentrations of 0.5 and 1.0 mg/ml of these salts are the most preferred ones. The EDTA salts which may be used in accordance with the present invention are illustrated in the following non-limiting examples by the ethylenediamine-tetraacetic acid disodium salt (EDTA-Na₂) but the invention is in no way restricted thereto and any other pharmaceutically acceptable EDTA salt, such as the dipotassium salt, can be used. As stated above the injectable solutions according to the present invention are maintained at a pH of 3.0-5.5, preferably 4.0-5.0, by means of an acetate buffer system. A suitable such buffer system consists of 1.0 mg/ml of sodium acetate (trihydrate) in combination with 0.005 ml/ml of a 10% v/v aqueous acetic acid solution. For vincristine sulfate solutions, a pH of 4.5 is most preferred. The preservatives included in the injectable solutions of the vincristine salts in accordance with the present invention, namely methyl paraben and propyl paraben (i.e. methyl and propyl hydroxybenzoates, respectively) and combinations thereof, have been found to be most suitable for preserving such solutions. The total concentration of the methyl and/or propyl paraben in the solutions according to the invention will generally be between 1.5 to 2.5 mg/ml, preferably 2.0 mg/ml. A particularly preferred combination is 1.8 mg/ml of methyl paraben and 0.2 mg/ml of propyl paraben. It has been found in accordance with the present invention that solutions of vincristine salts including 1.8 mg/ml of methyl paraben and 0.2 mg/ml of propyl paraben generally retained more than 90% of the total initial concentration of parabens after 20 months of storage at 2-8°C and even after storage at room temperatures for the same length of time. The invention will now be described in more detail, by way of illustration only, in the following non-limiting examples: EXAMPLE 1: A stable injectable aqueous solution containing 0.5 mg/ml of vincristine sulfate is prepared as follows: Materials: Vincristine sulfate BP/USP - Plantex, Israel Methyl hydroxybenzoate BP/NF (methyl paraben) - Machteshim, Israel Propyl hydroxybenzoate BP/NF (propyl paraben) - Machteshim, Israel Edetate disodium BP/USP - Merck, Germany Sodium Acetate · 3H₂O BP/USP - Merck, Germany Acetic acid BP/NF - Merck, Germany Procedure: The work was carried out in a sterile laboratory and an inert atmosphere (nitrogen) was kept throughout the manufacturing procedure. 0.5 g of EDTA-Na₂, 1.8 g of methyl paraben and 0.2 g of propyl paraben were dissolved in boiling, deaerated water. The solution was cooled to room temperature and 1.0 g of sodium acetate trihydrate and 0.005 ml of an aqueous 10% v/v acetic acid solution were added. The resulting solution was cooled to 2-8°C and 0.5 g of vincristine sulfate were dissolved therein. The solution was then brought to a final volume of 1 liter with deaerated water and filtered through a 0.2 µm filter. 1 ml portions of the solution were filled into glass vials (Amber BP/USP Type I) which were sealed under an inert nitrogen atmosphere. EXAMPLE 2: A stable aqueous vincristine sulfate solution containing 1 mg/ml of vincristine sulfate was prepared by the procedure of Example 1, except that 1.0 g of vincristine sulfate was used instead of 0.5 g. EXAMPLE 3: Stability Test: Amber glass vials containing 2, 4 or 10 ml of a 0.5 mg/ml vincristine sulfate solution prepared in accordance with Example 1 and similar vials containing 1, 2 or 5 ml of a 1 mg/ml solution of vincristine sulfate prepared in accordance with Example 2, were stored in the dark for periods up to 20 months at a temperature of 2-8°C and up to 9 months at room temperatures. The results are summarized in the following Tables I and II as % of the initial vincristine sulfate concentration. Each of the values in Tables I and II is the mean of the values obtained from duplicate samples analyzed in accordance with the SI-10115 assay method (by HPLC; for validation of this method cf. SI-24506).

Claims: Claims for the following Contracting States: AT, BE CH DE FR GB IT LI NL SE A stable, injectable pharmaceutical composition consisting of an aqueous solution comprising per 1 ml of solution: from 0.2 to 2 mg of a vincristine salt; from 0.1 to 1.0 mg of a pharmaceutically acceptable ethylenediamine-tetra-acetic acid (EDTA) salt; acetate buffer in an amount necessary to maintain said aqueous solution at a pH of from 3.0 to 5.5; and from 1.5 to 2.5 mg of a preservative selected from methyl paraben, propyl paraben and mixtures thereof. A pharmaceutical composition according to Claim 1, wherein said vincristine salt is vincristine sulphate. A pharmaceutical composition according to Claim 2, wherein said aqueous solution comprises per 1 ml: from 0.5 to 1 mg of vincristine sulphate; from 0.25 to 0.75 mg of EDTA-disodium salt (EDTA-Na₂); acetate buffer in an amount sufficient to maintain a pH of from 4.0 to 5.0 in the solution; and 2.0 mg of a preservative selected from methyl paraben, propyl paraben and mixtures thereof. A pharmaceutical composition according to Claim 3, wherein the pH is 4.5. A pharmaceutical composition according to Claim 3, wherein said aqueous solution comprises per 1 ml: 1.0 mg of vincristine sulphate; 1.8 mg of methyl paraben; 0.2 mg of propyl paraben; 0.5 mg of EDTA-Na₂; 1.0 mg of sodium acetate (trihydrate); and 0.005 ml of a 10% v/v aqueous acetic acid solution. A pharmaceutical composition according to Claim 3, wherein said aqueous solution comprises per 1 ml: 0.5 mg of vincristine sulphate; 1.8 mg of methyl paraben; 0.2 mg of propyl paraben; 0.5 mg of EDTA-Na₂; 1.0 mg of sodium acetate (trihydrate); and 0.005 ml of a 10% v/v aqueous acetic solution. Claims for the following Contracting State: ES A process for preparing a stable, injectable pharmaceutical composition consisting of an aqueous solution comprising per 1 ml of solution: from 0.2 to 2 mg of a vincristine salt; from 0.1 to 1.0 mg of a pharmaceutically acceptable ethylenediamine-tetra-acetic acid (EDTA) salt; acetate buffer in an amount necessary to maintain said aqueous solution at a pH of from 3.0 to 5.5; and from 1.5 to 2.5 mg of a preservative selected from methyl paraben, propyl paraben and mixtures thereof, by mixing the components in a manner known per se. A process according to Claim 1, wherein said vincristine salt is vincristine sulphate. A process according to Claim 2, wherein said aqueous solution comprises per 1 ml: from 0.5 to 1 mg of vincristine sulphate; from 0.25 to 0.75 mg of EDTA-disodium salt (EDTA-Na₂); acetate buffer in an amount sufficient to maintain a pH of from 4.0 to 5.0 in the solution; and 2.0 mg of a preservative selected from methyl paraben, propyl paraben and mixtures thereof. A process according to Claim 3, wherein the pH is 4.5. A process according to Claim 3, wherein said aqueous solution comprises per 1 ml: 1.0 mg of vincristine sulphate; 1.8 mg of methyl paraben; 0.2 mg of propyl paraben: 0.5 mg of EDTA-Na₂: 1.0 mg of sodium acetate (trihydrate); and 0.005 ml of a 10% v/v aqueous acetic acid solution. A process according to Claim 3, wherein said aqueous solution comprises per 1 ml: 0.5 mg of vincristine sulphate; 1.8 mg of methyl paraben; 0.2 mg of propyl paraben; 0.5 mg of EDTA-Na₂; 1.0 mg of sodium acetate (trihydrate); and 0.005 ml of a 10% v/v aqueous acetic solution.

Inventors: KASAN, RODNEY, SEIFFE, MICHAEL, YELLIN, HAIM
Applicants: TEVA PHARMACEUTICAL INDUSTRIES LIMITED
Application year: 1988
Main classification: A61K31
IPC codes: A61K31, A61K47, A61K9