Patent EA-004943-B1 (EA)
Title: Suspension of biodegradable microspheres and method for treating gliobastoma
Inventor: FAISANT NATHALIE
IPC: A61K9/16
Filed: 2000-05-17
Abstract: 1. A suspension consisting of a sterile solution containing 1 to 1.5% mass/volume of a viscosity modifier, 0.5 to 1.5% of a surfactant and 3.5 to 4.5% of an isotonicity agent, and of biodegradable microspheres which release an anticancer agent, which are coated with a polymer, the proportion of the microspheres representing 200 to 300 mg/ml of sterile solution. 2. The suspension as claimed in claim 1, characterized in that the microspheres consist of 15 to 35% by weight of anticancer agent and of 65% to 85% by weight of polymer. 3. The suspension as claimed in claim 1 or 2, characterized in that the polymer is poly(d,l-lactic acid-co-glycolic acid) preferably containing an equal amount of lactic acid and of glycolic acid. 4. The suspension as claimed in one of claims 1-3, characterized in that the sterile solution contains 1.25% weight/volume of sodium carboxy-methylcellulose, 1% of polysorbate 80 and 4% of mannitol. 5. A method for treating gliobastiloma comprising in simultaneously, separately or spread out over time use in a combination with radiotherapy said microspheres in a sterile solution as claimed in one of claims 1-4, wherein said microspheres being intended to be implanted into the operating locus after exeresis of the glial tumor to a depth of at least two centimeters, preferably between 2 and 3 centimeters, at least every cm, one injected dose is 100 mg, the microspheres containing the anticancer agent are coated with a polymer which delays the release of the anticancer agent and maintains, over time, a therapeutically effective concentration in the parenchymal space for at least 3 weeks, preferably for at least 4 weeks. 6. The method as claimed in claim 5, characterized in that the anticancer agent is hydrophilic and/or does not cross the blood-brain barrier. 7. The method as claimed in claim 5 or 6, characterized in that the anticancer agent does not show central neurotoxicity. 8. The method as claimed in one of claims 5-7, characterized in that the anticancer agent consists of a radiosensitizing anticancer compound or of a mixture of anticancer compounds containing at least one radiosensitizing anticancer compound, said anticancer compound(s) being, for example, chosen from 5-fluorouracil (5-FU), platins, such as carboplatin and cisplatin, taxanes, such as docetaxel and paclitaxel, gemcitabine, VP16, mitomycin, idoxuridine, topoisomerase 1 inhibitors, such as irinotecan, topotecan and camptothecins, nitrosoureas, such as BCNU, ACNU or MCNU, methotrexate, bleomycin, adriamycin, cytoxan and vincristine, immunomodulating cytokines, such as IL2, IL6, IL12 and IL13, and inteferons. 9. The method as claimed in claim 8, characterized in that the anticancer agent is 5-fluorouracil. 10. The method as claimed in claim 9, characterized in that the concentration of 5-FU in the cerebrospinal fluid, which mirrors the concentration in the parenchymal space, is between 3 and 20 ng/ml. 11. The method as claimed in one of claims 5-10, characterized in that a neuroprotective compound chosen from peptide growth factors, such as NGF or BDNF, is added to the anticancer agent. 12. The method as claimed in one of claims 5-11, characterized in that the polymer is chosen from ethylcellulose, polystyrene, poly([epsilon]-caprolactone), poly(d,l-lactic acid) and poly(d,l-lactic acid-co-glycolic acid). 13. The method as claimed in one of claims 5-12, characterized in that the polymer which coats the microspheres is a poly(d,l-lactic acid-co-glycolic acid). 14. The method as claimed in claim 13, characterized in that the polymer which coats the microspheres is a poly(d,l-lactic acid-co-glycolic acid) containing an equal amount of lactic acid and of glycolic acid. 15. The method as claimed in one of claims 5-14, characterized in that the microspheres have a mean diameter of 48+-20 mkm, preferably 46+-7 mkm. 16. The method as claimed in one of claims 5-15, characterized in that the microspheres contain 15 to 35% by weight of anticancer agent and 65 to 85% by weight of polymer. 17. The method as claimed in claims 9 and 16, characterized in that the microspheres contain 19 to 27% of 5-FU, preferably 20% of 5-FU. 18. The method as claimed in one of claims 5-17, characterized in that the microspheres are suspended in a sterile solution, the suspension obtained being intended to be injected into the walls of the operating locus after exeresis of the glial tumor, and in that said sterile solution contains from 1 to 1.5% mass/volume of a viscosity modifier, 0.5 to 1.5% of a surfactant and 3.5 to 4.5% of an isotonicity agent. 19. The method as claimed in claim 18, characterized in that the solution contains 1.25% weight/volume of sodium carboxymethylcellulose, 1% of polysorbate 80 and 4% of mannitol. 20. The method as claimed in claim 9, characterized in that the total dose of 5-FU injected is between 50 and 200 mg, preferably 130 mg. 21. The method as claimed in one of claims 5-20, characterized in that the radiotherapy is focused on the tumor volume, in that the volume irradiated encompasses the preoperative tumor with a margin of at least two centimeters in all directions and in that a total dose of between 50 Gy and 60 Gy is applied. 22. The method as claimed in one of claims 5-21, characterized in that the radiotherapy is preferably initiated between the second and seventh day after the operation. 23. The method as claimed in one of claims 5-22, characterized in that the radiotherapy is carried out with a total dose of 60 Gy for approximately six weeks. 24. The method as claimed in one of claims 18 and 19 or 21-23, characterized in that the suspension of microspheres is injected by stereotaxy on one or more occasions in the event of recurrence of the tumor. 25. The suspension as claimed in one of claims 1-4, characterized in that microspheres are prepared by a emulsification-extraction method consisting in dispersing the polymer and the anticancer agent in an organic solvent, in mixing the organic phase obtained with an aqueous phase so as to obtain an emulsion, in extracting the organic solvent by adding water, and then in filtering the suspension of microspheres obtained, characterized in that the anticancer agent is dispersed in the organic solvent, with vigorous stirring, before the polymer is added. 26. The suspension as claimed in claim 25, characterized in that the organic solvent is dichloromethane. 27. The suspension as claimed in claim 25 or 26, characterized in that the aqueous phase and the organic phase have an identical temperature, preferably equal to approximately 2 degree C, when they are mixed. 28. The suspension as claimed in one of claims 25 to 27, characterized in that the organic phase contains 11% of polymer. 29. The suspension as claimed in one of claims 25 to 28, characterized in that the aqueous phase/organic phase proportion is equal to 100/3. 30. The suspension as claimed in one of claims 25 to 29, characterized in that the emulsion consisting of the aqueous phase and of the organic phase is mixed for at least 3 minutes. 31. The suspension method as claimed in one of claims 25 to 30, characterized in that the water required to extract the organic solvent is added in a proportion such that the emulsion/water ratio by volume is equal to 1/3. 32. The suspension method as claimed in one of claims 25 to 31, characterized in that the temperature of the water required to extract the organic solvent is 4 degree C. 33. The suspension method as claimed in one of claims 25 to 32, characterized in that the anticancer agent is ground before being dispersed in the organic solvent, such that the size of the crystals of the anticancer agent is between 15 and 50 mkm. 34. The suspension method as claimed in one of claims 25 to 33, characterized in that after the extraction water has been added, the suspension obtained is filtered under an inert atmosphere. 35. The suspension method as claimed in one of claims 25 to 34, characterized in that the microspheres are lyophilized.