Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use
View Patent ↗The present invention provides compositions containing clopidogrel, present as a free base or a pharmaceutically acceptable salt thereof, and sulfoalkyl ether cyclodextrin (SAE-CD). The compositions can be liquid, suspension or solid compositions. They can be adapted for oral, peroral or parenteral administration. The SAE-CD serves to aid in dissolution and stabilization of the clopidogrel in aqueous media. The stability of clopidogrel against hydrolytic degradation, thermal degradation, and photolytic degradation are improved. SAE-CD provides improved results over other cyclodextrin derivatives. The SAE-CD-containing composition of clopidogrel can be provided in liquid form, solid form or as a reconstitutable powder. Both ready-to-use and concentrated liquid compositions can be prepared. The liquid composition is optionally available as a clear solution. The compositions herein can be administered perorally or parenterally and provide substantial pharmacokinetic, pharmacodynamic and/or therapeutic advantages over a tablet composition administered perorally and excluding SAE-CD.
1. A method of treating sickle cell crisis, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a SAE-CD of Formula 1:
wherein: n is 4, 5, or 6; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each, independently, —O— or a —O—(C 2 -C 6 alkylene)—SO 3 − group, wherein at least one of R 1 to R 9 is independently a —O—(C 2 -C 6 alkylene)—SO 3 − group; and S 1 , S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8 and S 9 are each, independently, a pharmaceutically acceptable cation, to the composition, and clopidogrel, in combination with a second therapeutic agent is selected from the group consisting of: folic acid, hydroxyurea, NSAIDs, antibiotics, iron chelators, bronchodilators, diuretics, anxiolytics, α-agonists, hydralazine, pentoxifylline, diltiazem, gonatropin-releasing hormone analogs, diethylstilbestrol, and combinations of the foregoing.
2. The method of claim 1 , wherein the second therapeutic agent is formulated in the pharmaceutical composition.
3. The method of claim 1 , wherein the second therapeutic agent is administered separately from the pharmaceutical composition.
4. The method of claim 1 wherein the pharmaceutical composition and the second therapeutic agent are independently administered perorally or parenterally.
5. The method of claim 4 , wherein the pharmaceutical composition and the second therapeutic agent are both administered perorally.
6. The method of claim 4 , wherein the pharmaceutical composition and the second therapeutic agent are both administered parenterally.
7. The method of claim 4 , wherein the second therapeutic agent is selected from the group consisting of: folic acid, hydroxyurea, NSAIDs, antibiotics, iron chelators, bronchodilators, diuretics, anxiolytics, α-agonists, hydralazine, pentoxifylline, diltiazem, gonatropin-releasing hormone analogs, and combinations of the foregoing.
8. The method of claim 7 , wherein the second therapeutic agent is selected from the group consisting of: folic acid, hydroxyurea, NSAIDs, antibiotics, iron chelators, bronchodilators, diuretics, anxiolytics, and combinations of the foregoing.
9. The method of claim 7 , wherein the second therapeutic agent is selected from the group consisting of: folic acid, hydroxyurea, NSAIDs, antibiotics, iron chelators, bronchodilators, and combinations of the foregoing.
10. The method of claim 7 , wherein the second therapeutic agent is selected from the group consisting of: folic acid, hydroxyurea, NSAIDs, antibiotics, iron chelators, and combinations of the foregoing.
11. The method of claim 7 , wherein the second therapeutic agent is selected from the group consisting of: folic acid, hydroxyurea, NSAIDs, antibiotics, and combinations of the foregoing.
12. The method of claim 7 , wherein the second therapeutic agent is selected from the group consisting of: folic acid, hydroxyurea, NSAIDs, and combinations of the foregoing.
13. The method of claim 7 , wherein the second therapeutic agent is folic acid.
14. The method of claim 7 , wherein the second therapeutic agent is an NSAID.
15. The method of claim 7 , wherein the second therapeutic agent is hydroxyurea.
16. The method of claim 7 , wherein the second therapeutic agent is an antibiotic.