Patent EA-004587-B1 (EA)
Title: Parenteral cisplatin emulsion
Inventor: PAI SRIKANTH ANNAPPA
IPC: A61K33/243
Filed: 2000-07-26
Abstract: 1. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration comprising: a) oily phase selected from group of vegetable oils, esters of medium or long chain fatty acids, fractionated or modified oil; b) cisplatin incorporated in oily phase; c) emulsifiers such as natural phosphatides, modified phosphatides, synthetic non-ionic surfactants; d) tonicity modifying agents selected from a group of compounds such as glycerin, mannitol, dextrose; e) chelating agents selected from a group of compounds such as edetates, desferrioxamine mesylate; and f) water. 2. A sterile pharmaceutical cisplatin composition as claimed in claim 1 wherein the content of Cisplatin is from 0.005% to 0.5% by weight of the composition. 3. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1 or 2 wherein the content of Cisplatin is from 0.05% to 0.1% by weight of the composition. 4. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1-3 wherein the content of Cisplatin is about 0.05% by weight of the composition. 5. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1-3 wherein the content of Cisplatin is about 0.1% by weight of the composition. 6. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1-5 wherein the oily phase is up to 30% by weight of the composition. 7. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1-6 wherein the oily phase is from about 10% to 20% by weight of the composition. 8. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1-7 wherein the oily phase is vegetable oil or fractionated vegetable oil or modified vegetable oil or ester of a fatty acid or a mixture thereof. 9. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1-8 wherein the vegetable oil is soybean oil. 10. A sterile pharmaceutical cisplatin composition as claimed in any of claims 1-9 wherein the chelating agent used is disodium edetate. 11. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 1-10 wherein content of disodium edetate is up to about 0.1% by weight of the composition. 12. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 1-11 wherein content of disodium edetate is from about 0.005% to 0.05% by weight of the composition. 13. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 1-12 wherein the emulsifier used is a natural phosphatide. 14. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 1-13 wherein the natural phosphatide is egg phosphatide or soya phosphatide or a mixture thereof. 15. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 1-14 wherein tonicity modifier used is in a quantity sufficient to make the product isotonic with blood. 16. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims1-15 wherein tonicity modifier used is glycerin. 17. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims1-16 wherein the content of glycerin is about 2.25% by weight of the composition. 18. A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims1-17 wherein aqueous sodium hydroxide is used to get the required pH. 19. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 1-18 comprising dispersing Cisplatin in oily phase, preparing aqueous phase with tonicity modifying agent, chelating agent; adjusting pH to 8-11 and emulsifying the two phases after addition of emulsifying agent either to the aqueous phase or to the oily phase or to both phases; homogenising the emulsion to a particle size below 2 microns, keeping temperature of homogenised product below about 25 degree C; filtering, filling in glass containers under nitrogen, sealing the filled containers and sterilising the sealed containers by autoclaving. 20. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in claim 19 wherein the content of Cisplatin is from 0.005% to 0.5% by weight of the composition. 21. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19 or 20 wherein the content of Cisplatin is from 0.05% to 0.1% by weight of the composition. 22. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-21 wherein the content of Cisplatin is about 0.05% by weight of the composition. 23. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-21 wherein the content of Cisplatin is about 0.1% by weight of the composition. 24. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-23 wherein the oily phase is up to 30% by weight of the composition. 25. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-24 wherein the oily phase is from about 10% to 20% by weight of the composition. 26. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-25 wherein the oily phase is vegetable oil or fractionated vegetable oil or modified vegetable oil or ester of a fatty acid or a mixture thereof. 27. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-26 wherein the vegetable oil is soybean oil. 28. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-27 wherein the chelating agent used is disodium edetate. 29. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-28 wherein content of disodium edetate is up to about 0.1% by weight of the composition. 30. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-29 wherein content of disodium edetate is from about 0.005% to 0.05% by weight of the composition. 31. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-30 wherein the emulsifier used is a natural phosphatide. 32. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-31 wherein the natural phosphatide is egg phosphatide or soya phosphatide or a mixture thereof. 33. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-32 wherein tonicity modifier used is in a quantity sufficient to make the product isotonic with blood. 34. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-33 wherein tonicity modifier used is glycerin. 35. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-34 wherein the content of glycerin is about 2.25% by weight of the composition. 36. A process for the preparation of a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration as claimed in any of claims 19-35 wherein aqueous sodium hydroxide is used to get the required pH.