Short-acting benzodiazepine salts and their polymorphic forms
The invention relates to besylate salts of the compound of formula (I): Methods of preparing the salts, and their use as medicaments, in particular for sedative or hypnotic, anxiolytic, muscle relaxant, or anticonvulsant purposes is also described.
1. A method of producing sedation in a subject, comprising:
(a) reconstituting a lyophilized composition with an aqueous solution to afford an aqueous pharmaceutical composition; and
(b) administering to the subject an effective amount of the aqueous pharmaceutical composition;
wherein the lyophilized composition comprises a besylate salt of the compound of formula (I)
and at least one pharmaceutically acceptable carrier, excipient or diluent, and wherein the lyophilized composition maintains at least 96.7% of the original amount of the compound of formula (I) comprising the lyophilized composition following storage of the lyophilized composition at 40° C. and 75% relative humidity for a time period of from 1 week to 4 weeks, and wherein the amount of the compound of formula (I) in the lyophilized composition is measured by high-performance liquid chromatography.
2. The method according to claim 1 , wherein the aqueous solution comprises dextrose or saline.
3. The method according to claim 2 , wherein the aqueous solution comprises saline.
4. The method according to claim 2 , wherein the aqueous solution comprises dextrose.
5. The method according to claim 1 , wherein the aqueous pharmaceutical composition is administered to the subject by subcutaneous, intramuscular, intradermal or intravenous administration.
6. The method according to claim 5 , wherein the aqueous pharmaceutical composition is administered to the subject by intravenous administration.
7. The method according to claim 6 , wherein the intravenous administration comprises a bolus injection or a continuous infusion.
8. The method according to claim 7 , wherein the intravenous administration comprises a bolus injection.
9. The method according to claim 7 , wherein the intravenous administration comprises a continuous infusion.
10. The method according to claim 1 , wherein the aqueous pharmaceutical composition is administered to the subject during the time the subject is undergoing a diagnostic, operative or endoscopic procedure.
11. The method according to claim 10 , wherein the aqueous pharmaceutical composition is administered to the subject during the time the subject is undergoing a diagnostic procedure.
12. The method according to claim 10 , wherein the aqueous pharmaceutical composition is administered to the subject during the time the subject is undergoing an operative procedure.
13. The method according to claim 10 , wherein the aqueous pharmaceutical composition is administered to the subject during the time the subject is undergoing an endoscopic procedure.
14. The method according to claim 1 , wherein the aqueous pharmaceutical composition is administered to the subject by intravenous administration during the time the subject is undergoing a diagnostic, operative or endoscopic procedure.
15. The method according to claim 1 , wherein:
(a) the aqueous solution comprises dextrose or saline;
(b) the aqueous pharmaceutical composition is administered to the subject by subcutaneous, intramuscular, intradermal or intravenous administration; and
(c) the aqueous pharmaceutical composition is administered to the subject during the time the subject is undergoing a diagnostic, operative or endoscopic procedure.
16. The method according to claim 15 , wherein, the aqueous pharmaceutical composition is administered to the subject by intravenous administration.
17. The method according to claim 16 , wherein the intravenous administration comprises a bolus injection or a continuous infusion.
18. The method according to claim 15 , wherein:
(a) the aqueous solution comprises saline;
(b) the aqueous pharmaceutical composition is administered to the subject by intravenous administration; and
(c) the intravenous administration is a bolus injection or a continuous infusion.
19. The method according to claim 18 , wherein the intravenous administration is a bolus injection.
20. The method according to claim 18 , wherein the intravenous administration is a continuous infusion.
21. The method according to claim 1 , wherein the lyophilized composition maintains at least 96.7% of the original amount of the compound of formula (I) comprising the lyophilized composition following storage of the lyophilized composition at 40° C. and 75% relative humidity for 1 week, and wherein the amount of the compound of formula (I) in the lyophilized composition is measured by high-performance liquid chromatography.
22. The method according to claim 1 , wherein the lyophilized composition maintains at least 96.7% of the original amount of the compound of formula (I) comprising the lyophilized composition following storage of the lyophilized composition at 40° C. and 75% relative humidity for 2 weeks, and wherein the amount of the compound of formula (I) in the lyophilized composition is measured by high-performance liquid chromatography.
23. The method according to claim 1 , wherein the lyophilized composition maintains at least 96.7% of the original amount of the compound of formula (I) comprising the lyophilized composition following storage of the lyophilized composition at 40° C. and 75% relative humidity for 3 weeks, and wherein the amount of the compound of formula (I) in the lyophilized composition is measured by high-performance liquid chromatography.
24. The method according to claim 1 , wherein the lyophilized composition maintains at least 96.7% of the original amount of the compound of formula (I) comprising the lyophilized composition following storage of the lyophilized composition at 40° C. and 75% relative humidity for 4 weeks, and wherein the amount of the compound of formula (I) in the lyophilized composition is measured by high-performance liquid chromatography.