LU84910A1 - IMPROVEMENTS ON VINCA ALKALOID COMPOSITIONS - Google Patents

Description

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Vinca alkaloids are, in general, dimeric indole-dihydroindole compounds. Two of the alkaloids obtained from the leaves of the Vinca rosea plant, vincristine (VCR) and Vinblastine (VLB}, are marketed for the treatment of leukemia and similar neoplasms in humans. Vindesine (VDS), an amide derivative of Vinblastine, is marketed for the treatment of neoplastic diseases in humans in several European countries and is undergoing clinical trials in the United States. These three drugs are described in the patents of EUA No. 3,205,220 (vincristine) '3,097,137 (Vinblastine) and 4,203,898 (vindesine) The drugs are administered intravenously to patients with sensitive neoplasms. The usual pharmaceutical composition used has been a lyophilized flask of a sulfuric acid salt which is reconstituted in use. The sulfuric acid salts are prepared by adding the theoretical amount of sulfuric acid to a solution of the free base. e alkaloid. In the case of rindesine, however, the sulphate prepared by the ordinary method is not stable and a salt of sulfuric acid - - special described in the patent of the USA. No. 4,259,242 is used in the lyophilized pharmaceutical composition.

25 Researchers and medical personnel have long believed that it would be desirable to have ready-made solutions of vincristine sulfate or other vinca alkaloids. First, improper reconstitution of a lyophilized product sometimes results in the formation of airborne droplets which can be a hazard to hospital staff preparing the solution for an intravenous injection. Vincristine is an extremely potent oncolytic drug and it is desirable to avoid contact with this drug as much as possible. In addition, it is desirable to avoid everything! -2- contact with any cytostatic drug and especially vincristine. In addition, there is still a potential problem during the reconstitution of a lyophilized composition because an inappropriate amount of diluent may be used or an incorrect amount of drug may be used due to a different vial capacity. The margin between toxic effects and the therapeutic dose is very small with vinca alkaloids. Errors in the concentration for intravenous injection resulting in accidental overdoses with vincristine have been recorded in the published technical literature. See, for example, the Journal of Pediatrics, 89, 671 (19763, Cancer Chemotherapy Reports, 55, 525 (1972), and Journal of Pediatrics, 90, 15 1042 (1977.).

Another drawback of lyophilized vincristine sulfate results from the method of calculating dosage levels for each individual. Vincristine sulfate is supplied in round amounts in milligrams (for example, 1 mg and 5 mg vials). As the dose is usually calculated at the rate of 2 mg per square meter of body surface for children and 1.4 mg per square meter of body surface for adults, the doses actually administered are usually decimal amounts in milli- 25 grams, so only part of the contents of a vial can be used. In addition, it should be repeated that there is a narrow margin between the toxic dose and the effective dose of vincristine. Thus, as the dose is usually calculated for the treatment of humans, there will usually be some excess of reconstituted vincristine left after a given treatment. This problem is not particularly serious in an important cancer clinic in that there is daily use of vincristine and that what is left by one patient can be used for the next. However, the recommended duration of use if -3- ί for reconstituted vincristine is 14 days at refrigerator temperature. Thus, in most cases, it may be necessary to dispose of excess reconstituted lyophilized vincristine which has exceeded its 14 day period of use. Vincristine is an extremely expensive drug and any amount of it that must be discarded will increase the total cost of operating a cancer clinic.

10 By abandonment, the physical changes noted for the reconstituted lyophilized vincristine (reconstituted using 0.9% aqueous sodium chloride solution containing benzyl alcohol as a preservative) are a general solution disorder followed by the appearance of a precipitate.

Another problem associated with reconstituted vincristine compositions is the need to incorporate a preservative in order to prevent the development of microorganisms. In general, vincristine solutions cannot be sterilized by heat, but can be sterilized by filtration. However, even if the latter method is used, a preservative must be present in the diluent used to reconstitute the lyophilized material or in a previously opened vial of sterilized liquid due to the possibility of air contamination. Otherwise, excess material should be scrapped immediately and could not be stored even for the maximum recommended period of 14 days.

The reconstituted solutions of Vinblas tine sulfate and vindesine sulfate are the source of similar problems and difficulties, but as these two compounds contain one. N ~ methyl group instead of the more labile N-formyl functionality present in vincristine, the stability issues are less severe, as indicated by the recommended stability listing in i · / "\ ί -4- state reconstituted thirty days.

According to the present invention there is provided a stable, ready-to-use solution of oncolytic vinca alkaloids for intravenous injection, the use of these compositions minimizes contact between hospital staff and the drug and provides a single concentration of solution for all sizes of vials and syringes used, thereby avoiding error in reconstitution, In particular, according to the invention, an aqueous pharmaceutical composition which comprises a pharmaceutically acceptable vinca dimer salt, a polyol, an acetate buffer, which keeps the pH of the solution between 3.0 and 5.0 and a preservative is useful as a stable oncolytic preparation.

The present invention is particularly useful for the preparation of stable, ready-to-use solutions of vinüa dimers, comprising vincristine sulfate, Vinblastine sulfate and vindesine sulfate.

The invention is also useful for the preparation of stable, ready-to-use solutions of certain vinca dimers which are currently in clinical trials or will soon be in clinical trials as oncolytic agents. In this second class of compounds are included 4'-deoxy-1-formylleurosidine sulfate and leuroformin. The present invention can also provide stable, ready-to-use solutions of other vinca dimers whose clinical use has not yet been determined, but which may be marketed as clinically useful oncolytic agents in the future.

The stabilized compositions according to the present invention are more applicable, and useful, with vinca dimers containing an N-formyl group such as vincristine or 4'-deoxy-1-formylleurosidine because these compounds decompose by an additional mechanism, ή / -5- f namely the loss of the N-formyl group, which is not present with Vinblastine or vindesine.

Pharmaceutically acceptable salts other than sulfate, such as phosphate, can be used in the stable solutions of the present invention, although sulfates are preferred. The pharmaceutically acceptable salts are the. salts useful in the chemotherapy of warm-blooded animals. The alkaloids are usually present in the composition at a concentration of about 0.01 to 2.0 mg / ml, preferably at a concentration of 0.1 to 1.0 mg / ml.

The polyols useful in these stable, ready-to-use solutions of oncolytic vinca dimers are generally those derived from sugars, such as mannitol and sorbitol, or are themselves sugars such as lactose and sucrose. Other useful polyols will be recognized by those skilled in the art. Lactose and especially mannitol are the preferred polyols used in the present invention. The polyol is usually present in the composition at about 10-100 mg / ml.

The acetate buffer system used in these stable solutions should maintain the pH in the range 3.0-5.0. Preferred pH ranges vary with the individual vinca alkaloid. In the case of vincristine sulfate, a pH range of 4.4-4.8 is preferred.

For Vinblastine sulfate, the preferred range is 3.8-4.2, and for Vindesine sulfate, a pH range of 3.0-3.6 is preferred, especially the range of 3.2- 3.4. A buffer system with a molarity in the range of about 0.0005-0.02 M, preferably 0.002-0.01 M, is used. The molar ratio of acetate to vinca dimer is preferably about 20 to 1 or less. In the case of vindesin sulfate, those skilled in the art will understand that, for pHs below 3.6, the "buffer" consists only of acetic acid and one! does not use acetic acid salt. Although at pH 3.0 the concentration of acetic acid approaches 0.06 M, at the preferred pH range of 3.2-3.4, the concentration of acetic acid is approximately 0.02-0.01 M.

5 The stabilizing effect of the acetate buffer may be due in part to the fact that it prevents a change in pH of the solution due to leaching of an alkali from the glass or the stopper of the flask, or degradation due to the change in pH caused by the decomposition of the alkaloid.

In general, the preservatives tested in solutions of vinca dimers had an adverse effect on activity, clarity and pharmaceutical presentation - but, among them, parabens, methyl- and »propyl-paraben, appear to have little effect on these parameters and 15 are therefore preferred. Parabens can be used singly or in combination, usually at a total amount of 1-2 mg / ml. Other potential preservatives include benzyl alcohol, phenol or; m-cresol. The liquid compositions produced in the present invention are sterilized by filtration.

In addition to the ingredients that are present in these sterile, stable alkaloid solutions, the concentration of chloride ions should be minimized because the chloride ion has a detrimental effect on the various oncolytic vinca dimers.

The following nonlimiting examples are presented to further illustrate the invention.

Example 1

A stable, ready-to-use solution of vincristine sulfate is prepared as follows: a 1 mg vial contains vincristine sulfate, 1 mg; methyl paraben, 1.3 mg; propyl paraben, 0.2 mg ’? mannitol, 100 mg; acetic acid, 0.0255 ml of a 0.2 M solution; sodium acetate, 0.0245 ml of 0.2 M solution; water, sufficient for 1 ml. Vials / λ i / f f f -7- containing 2 mg or 5 mg of drug are prepared in a similar manner with proportionally larger amounts of material. The solution thus prepared is sterilized by filtration and introduced into compatible glass vials in the appropriate volume. The vials can be purged using an inert gas, such as nitrogen, before the vials are closed with a compatible cap.

Alternatively, hypodermic syringes of predetermined volume may be filled with the sterile filtered solution to give a ready-to-use solution which is also ready for injection. Using the pre-filled syringe further reduces the risk of exposure to patients or hospital or pharmacist staff by eliminating the need to transfer the contents of a vial to an empty syringe. Ideally, the syringe should be graduated and disposable.

Example 2

An example of a stable, ready-to-use solution of Vinblastine sulfate contains the following ingredients: a 10 mg vial contains Vinblastine sulfate, 10 mg; methyl paraben, 13 mg; propyl paraben, 2 mg; mannitol, 1000 mg; acetic acid, 0.41 ml of a 0.02 M solution; sodium acetate, 0.09 ml of a 0.2 M solution; water, sufficient for 10 ml.

* The vials are treated in the same manner as described above in Example 1. Hypodermic syringes as described above can be filled with the Vinblastine solution.

30 Example 3

An example of a stable, ready-to-use solution of vindesin sulfate contains the following ingredients: for a 5 mg vial or syringe, vindesin sulfate, 5 mg; methyl paraben, 6.5 mg; propyl paraben, 1 mg; Mannitol, 500 mg; acetic acid,. 0.25 ml of a solution / -8-

F

0.2 Μ; water, sufficient quantity for 5 ml. The solution can be used to fill vials or syringes as described above.

Example 4 Ready-to-use compositions of this type should be stable for periods of time allowing dispensing to the pharmacy and a reasonable shelf life. Vincristine sulfate compositions prepared according to the present invention have remained physically and chemically acceptable for pharmaceutical use for periods of up to one year at 5 ° C.

The compositions of the present invention were evaluated for their stability using high pressure analytical liquid chromatography and thin layer chromatography to determine the content; vincristine and quality. For example, three batches of vincristine sulfate composition retained

94-99% of their initial concentration after storage at 5 ° C

{for about nine months. (all three lots; had the following composition: vincristine sulfate, '; 1 mg / ml solution; methyl paraben, 1.3 mg / ml solution; propyl paraben, 0.2 mg / ml solution; mannitol, 100 mg / ml. of solution? acetic acid, 0.0255 ml of a 0.2 M solution per ml of solution; sodium acetate, 0.0245 ml of a * l 0.2 solution M per ml of solution; water, make-up to the desired volume The solutions were sterilized by filtration and placed in type 1 amber flasks treated with acid, stoppered with gray butyl rubber plugs coated with Teflon or with corks. Stelmi 632. (Teflon is the registered trademark of EI duPont de Nemours and Co., Inc., for polytetrafluoroethylene resins and products made of these resins.) The final pH of the solution was approximately 4.6.

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Claims (13)

1. An aqueous pharmaceutical composition which comprises 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. 2. A composition according to claim 1, charac terized in that the vinca dimer is vincristine, Vinblastine, vindesine, 4’-deoxy-l-formylleurosidine or leuroformine. 3. A pharmaceutical composition according to claim 1, characterized in that the vinca dimer salt is a vincristine salt. ', 4. A pharmaceutical composition according to claim 3, characterized in that the polyol is a sugar or is derived from a sugar. 5. A composition according to one of claims 1 to 4, characterized in that the preservative is methyl paraben and / or propyl paraben. 6. A composition according to one of claims 1 to 5, characterized in that the concentration of the acetate buffer is 0.0005-0.02 M.: ~ 7. A composition according to one of claims 1 to 6, characterized in that the polyol is mannitol or lactose. 8. A composition according to one of claims 1 25 to 7, characterized in that it contains per ml of final solution 1 mg of vincristine sulfate, 10-100 mg of mannitol or lactose, 1-2 mg of a container chosen from methyl paraben and propyl paraben, individually or in combination, and water in sufficient quantity for 30 1 ml, with a pH of this solution of between approximately 4.4 and 4.8 maintained by a acetate buffer 0f002 ^ 0.01 M. 9. A composition according to claim 8, characterized in that it contains, per ml of final solution,; Λ / -10- [approximately 1 mg of vincristine sulfate, 100 mg of mannitol, 1.3 mg of methyl paraben and - 0.2 mg of propyl paraben. 10. A composition according to one of claims 1, 2 or 5 to 7, characterized in that it contains, per ml 5 of final solution, approximately 1 mg of Vinblastine sulfate, 10-100 mg of mannitol or lactose , 1-2 mg of a preservative chosen from methyl paraben and propyl paraben, individually or in combination., And water in an amount sufficient for 1 ml, the pH of the solution being between approximately 10 3.8 and 4.2, maintained by an acetate buffer 0.01-0.002 M. 11. A composition according to claim 10 / characterized in that it contains, per ml of final solution, approximately 1 mg of Vinblastine sulfate, 100 mg of mannitol, 1.3 mg of methyl paraben and 0.2 mg of propyl paraben. 12. A composition according to one of claims 1, 2 or 5 to 7, characterized in that it contains, per ml of final solution, approximately 1 mg of vindesin sulfate, 10-100 mg of mannitol or lactose, 1-2 mg of a preservative chosen from methyl paraben and propyl paraben, individually or in combination, and water in sufficient quantity for 1 ml, the pH of this solution being between approximately 3.0 and 3.6. 13. A composition according to claim 12, 2.5 characterized in that it contains, per ml of final solution, approximately 1 mg of vindesin sulfate, 100 mg of mannitol, 1.3 mg of methyl paraben and 0.2 mg of propyl paraben, with a pH of this solution between approximately 3.2 and 3.4. -Vaaaxw,