Patent EA-003908-B1 (EA)
Title: Pharmaceutical complex of eletriptan and a cyclodextrin derivative
Inventor: BILLOTTE ANNE
IPC: A61K47/48
Filed: 2000-06-02
Abstract: 1. A complex of eletriptan and a cyclodextrin derivative of formula (I): wherein <R1A-G>, R<2A-G> and R<3A-G> each independently represent -OH or -O(CH2)4SO3H; provided that at least one of R<1A-G> represents -O(CH2)4SO3H; or a pharmaceutically acceptable salt thereof; 2. A formulation as claimed in claim 1, wherein the average number of -O(CH2)4SO3H groups per molecule of the derivative of the formula (I) is in the range from 6.1 to 6.9. 3. A formulation as claimed in claim 1 or 2, wherein each -O(CH2)4SO3H group present in the derivative of the formula (I) is in the form of an alkali metal salt. 4. A formulation as claimed in any of claims 1-3, wherein the molar ratio of eletriptan: cyclodextrin derivative of the formula (I) is in the range from 1:1 to 15:1. 5. A formulation as claimed in claim 4, wherein the molar ratio of eletriptan: cyclodextrin derivative of the formula (I) is in the range from 1:1 to 10:1. 6. A formulation as claimed in any of claims 1-5, wherein eletriptan is presented in the form of the hemisulphate salt. 7. A pharmaceutical formulation, comprising a complex as claimed in any of claims 1-6 and pharmaceutically acceptable excipient, diluent or carrier. 8. A formulation as claimed in claim 7, wherein from 50 to 120mg/g of eletriptan hemisulphate is present. 9. A formulation as claimed in any of claims 7 or 8, wherein from 15 to 25% weight/weight of the sulphobutylether-beta-cyclodextrin is present. 10. A formulation as claimed in any of claims 7, 8 or 9 including one or more of an anti-oxidant, a co-solvent and an organic polymer. 11. A formulation as claimed in claim 10, wherein antioxidant is an ascorbic acid. 12. A formulation as claimed in claim 11, wherein from 0.25 to 0.80% weight/weight of ascorbic acid is present. 13. A formulation as claimed in any of claims 10-12, wherein the cosolvent is glycerol. 14. A formulation as claimed in claim 13, wherein from 10.0 to 25.0% weight/weight of glycerol is present. 15. A formulation as claimed in any of claims 10-14, wherein the organic polymer is carboxymethylcellulose or polyvinylpyrrolidone. 16. A formulation as claimed in claim 15, wherein from 0.05 to 0.20% weight/weight of carboxymethylcellulose or polyvinylpyrrolidone is present. 17. A formulation as claimed in any of claims 7-16 that is in the form of an aqueous solution. 18. An aqueous formulation as claimed in claim 17 that has a pH of from 4.0 to 5.0. 19. A formulation as claimed in any of claims 7-18, which is adapted for parenteral administration. 20. A formulation as claimed in any of claims 7-18, which is adapted for intranasal administration. 21. A formulation as claimed in any of claims 7-18, which is adapted for administration by inhalation. 22. A formulation as claimed in claim 7 that is an aqueous solution comprising: 80mg/g of eletriptan hemisulphate; 20% weight/weight of the sulphobutylether-beta-cyclodextrin as defined in claim 1 having an average sulphobutylether substitution of 6.5 per cyclodextrin molecule with each sulphobutylether unit present as its sodium salt; 20% weight/weight of glycerol; and 0.7% weight/weight of ascorbic acid; with the formulation having been adjusted to from pH 4.0 to 5.0, preferably about pH 4.5, using aqueous sodium hydroxide solution. 23. A formulation as claimed in claim 7 that is an aqueous solution comprising: 80mg/g of eletriptan hemisulphate; 20% weight/weight of the sulphobutylether-beta-cyclodextrin as defined in claim 1 having an average sulphobutylether substitution of 6.5 per cyclodextrin molecule with each sulphobutylether unit present as its sodium salt; 0.10% weight/weight of polyvinylpyrrolidone; and 0.7% weight /weight ascorbic acid: with the composition having been adjusted to from pH 4.0 to 5.0, preferably about pH 4.5, using aqueous sodium hydroxide solution. 24. Use of a complex as claimed in any of claims 1-6 as a medicine. 25. Use of a complex as claimed in any of claims 1-6 as a medicine for treatment of a disease, for which a 5HT1B/1D receptor agonist is indicated. 26. Use of a complex as claimed in any of claims 1-6 as a medicine to treat migraine or to prevent migraine recurrence. 27. A method of treatment of a mammal to treat a disease, for which a 5HT1B/1D receptor agonist is indicated including treating said mammal with an effective amount of a complex as claimed in any of the claims 1-6 or with a pharmaceutically acceptable formulation as claimed in any of claims 7-23. 28. A method of treatment of a mammal to treat migraine or to prevent migraine recurrence including treating said mammal with an effective amount of a complex as claimed in any of claims 1-6 or with pharmaceutically acceptable formulation as claimed in any of claims 7-23. 29. A process for the preparation of a formulation as claimed in claim 1, which comprises combining eletriptan, or a pharmaceutically acceptable salt thereof with the cyclodextrin derivative or pharmaceutically acceptable salt thereof. 30. A process for the preparation of a formulation as claimed in claim 7, which comprises combining either (i) a complex as defined in claim 1, or (ii) eletriptan, or a pharmaceutically acceptable salt thereof, and the cyclodextrin derivative, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable excipient, diluent or carrier.