Claims for Patent: 4,138,565

Summary for Patent: 4,138,565

Title:	Stable solutions and processes for their preparation
Abstract:	Solutions of certain hydrogenated ergopeptide alkaloids in mixtures of pharmacologically acceptable alcohols and water have improved stability. Preferred solvents are mixtures of ethanol, propylene glycol and glycerol containing from 15-40% wt. of water and having dielectric constants between 34 and 46. With these solutions it is not essential to carry out the filing operation under an inert atmosphere.
Inventor(s):	Ehrhardt; Lothar (Nuremberg, DE), Patt; Ludwig (Nuremberg, DE), Hartmann; Volker (Nuremberg, DE)
Assignee:	Sandoz Ltd. (Basel, CH)
Application Number:	05/833,784
Patent Claims:	1. A hydrogenated ergopeptide alkaloid solution which is stable against decomposition on storage consisting essentially of (a) a hydrogenated ergopeptide alkaloid or a pharmacologically acceptable acid addition salt thereof, or a mixture thereof (b) a pharmacologically acceptable alcohol or mixture thereof, and (c) up to 40% by weight of the solution of water, and having a dielectric constant of 50 or less. 2. A stable solution according to claim 1 consisting essentially of (a) a hydrogenated ergopeptide alkaloid of formula I, ##STR2## in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, other than t-butyl, R.sub.1 is methyl, ethyl or isopropyl, R.sub.2 is isopropyl, sec.-butyl, isobutyl or benzyl, and X is hydrogen or methoxy or a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof, (b) a pharmacologically acceptable alcohol or mixture thereof and (c) up to 40% by weight of the solution of water, said solution having a dielectric constant of 50 or less. 3. A solution according to claim 2 having a dielectric constant between 30 and 46. 4. A solution according to claim 3 having a dielectric constant between 34 and 46. 5. A solution according to claim 2 in which component (a) is a compound of formula I, stated in claim 2, in which R is methyl X is hydrogen and R.sub.1 is isopropyl or methyl, provided that R.sub.1 is methyl only when R.sub.2 is benzyl. 6. A solution according to claim 2 in which component (b) is propylene glycol. 7. A solution according to claim 2 in which the proportion of component (c) is from 15 to 40% by weight. 8. A solution according to claim 2 in which component (b) is a mixture of (b.sub.1) a pharmacologically acceptable monofunctional alcohol having up to 18 carbon atoms, or mixtures thereof, and (b.sub.2) a polyfunctional alcohol having up to 6 carbon atoms and 6 hydroxy groups or a polymeric polyfunctional alcohol having a molecular weight of from 200 to 20,000, or mixtures thereof, the weight ratio of component (b.sub.1) to component (b.sub.2) being 1:0.1 to 1:100. 9. A solution according to claim 8 in which the concentration of component (a) is from 0.01 to 1% by weight, component (b.sub.1) has up to 10 carbon atoms, the ratio of component (b.sub.1) to component (b.sub.2) is 1:1 to 1:10, and the proportion of component (c) is from 15 to 40% by weight. 10. A solution according to claim 9 in which component (b.sub.1) has up to 3 carbon atoms and component (b.sub.2) is a polyfunctional alcohol of 2 or 3 carbon atoms and 2 or 3 hydroxy groups or a polymeric polyfunctional alcohol having a molecular weight of 200 to 600. 11. A solution according to claim 10 in which the ratio of component (b.sub.1) to component (b.sub.2) is 1:1 to 1:2. 12. A solution according to claim 10 in which component (b.sub.1) is ethanol and component (b.sub.2) is propylene glycol or glycerol or mixtures thereof. 13. A solution according to claim 10 in which component (a) is dihydroergotamine. 14. A solution according to claim 10 in which component (a) is dihydroergotoxin. 15. A method of preparing a hydrogenated ergopeptide alkaloid solution which is stable to decomposition on storage according to claim 2, consisting essentially of dissolving a compound of formula I, stated in claim 2, or a pharmaceutically acceptable acid addition salt thereof or a mixture thereof in a solvent consisting essentially of: (a) a pharmacologically acceptable alcohol or a mixture thereof (b) up to 40% by weight of the solution of water, said solvent having a dielectric constant of 50 or less, at a temperature of 15 to 25.degree. C.