Pharmaceutical compositions of selective factor Xa inhibitors for oral administration
View Patent ↗The present invention provides pharmaceutical compositions for oral administration comprising a therapeutically effective amount of a selective factor Xa inhibitor or a pharmaceutically acceptable salt thereof and an enhancer, wherein the enhancer is a medium chain fatty acid or a salt, ester, ether, or derivative of a medium chain fatty acid and has a carbon chain length of from about 4 to about 20 carbon atoms. The present invention also provides a method for obtaining a reproducible bioavailability of selective factor Xa inhibitor in an object after oral administration comprising orally administering a pharmaceutical composition as described above.
1. A method for obtaining a reproducible bioavailability of fondaparinux or a pharmaceutically acceptable salt thereof in a subject after oral administration, comprising orally administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of fondaparinux or a pharmaceutically acceptable salt thereof and an enhancer, wherein the enhancer is a medium chain fatty acid salt and has a carbon chain length of from about 8 to about 14 carbon atoms, and wherein the bioavailability of fondaparinux or a pharmaceutically acceptable salt thereof has a coefficient of variation of no more than about 60%.
2. The method of claim 1 , wherein the enhancer is solid at room temperature.
3. The method of claim 1 , wherein the enhancer is a sodium salt of a medium chain fatty acid.
4. The method of claim 1 , wherein the enhancer is selected from the group consisting of sodium caprylate, sodium caprate, and sodium laurate.
5. The method of claim 1 , wherein the pharmaceutical composition is in a solid oral dosage form.
6. The method of claim 5 , wherein the dosage form is a tablet, a capsule or a multiparticulate dosage form.
7. The method of claim 5 , wherein the dosage form is a controlled release dosage form.
8. The method of claim 6 , wherein the tablet further comprises a rate controlling polymer material.
9. The method of claim 8 , wherein the rate-controlling polymer is hydroxypropyl methylcellulose.
10. The method of claim 8 , wherein the rate-controlling polymer is a polymer of acrylic or methacrylic acid or their respective esters or copolymers of acrylic or methacrylic acid or their respective esters.
11. The method of claim 5 , wherein the fondaparinux or a pharmaceutically acceptable salt thereof and enhancer and at least one auxiliary excipient are compressed into tablet form prior to coating with a rate controlling polymer or delayed release polymer.
12. The method of claim 8 , wherein the fondaparinux or a pharmaceutically acceptable salt thereof, the enhancer, the rate controlling polymer and at least one auxiliary excipient are compressed to form a controlled release matrix tablet.
13. The method of claim 12 , wherein the controlled release matrix tablet is coated with a rate-controlling polymer or delayed release polymer.
14. The method of claim 5 , wherein the fondaparinux or a pharmaceutically acceptable salt thereof, the enhancer and at least one auxiliary excipient are compressed into the form of a multilayer tablet prior to coating with a rate controlling-polymer or delayed release polymer.
15. The method of claim 8 , wherein the fondaparinux or a pharmaceutically acceptable salt thereof and enhancer are dispersed in the rate-controlling polymer material and compressed into the form of a multilayer tablet.
16. The method of claim 15 , wherein the multilayer tablet is coated with a rate-controlling polymer or delayed release polymer.
17. The method of claim 8 , wherein the fondaparinux or a pharmaceutically acceptable salt thereof, the enhancer, at least one auxiliary excipient, and the rate-controlling polymer material are combined into a multiparticulate form.
18. The method of claim 17 , wherein the multiparticulate form comprises discrete particles, pellets, minitablets, or combinations thereof.
19. The method of claim 17 , wherein the multiparticulate is encapsulated in hard or soft gelatin capsules.
20. The method of claim 19 , wherein the capsule is coated with a rate-controlling polymer or delayed release polymer.
21. The method of claim 18 , wherein the discrete particles or pellets are compressed into tablet form.
22. The method of claim 21 , wherein the tablet form is coated with a rate controlling polymer material or delayed release polymer.
23. The method of claim 18 , wherein the discrete particles or pellets are compressed into a multilayer tablet.
24. The method of claim 23 , wherein the multilayer tablet is coated with a rate controlling material or delayed release polymer.
25. The method of claim 1 , wherein the pharmaceutical composition provides a bioavailability of the fondaparinux or a pharmaceutically acceptable salt thereof of at least about 10% when orally administered to a human subject.
26. The method of claim 1 , wherein the pharmaceutical composition provides a bioavailability of the fondaparinux or a pharmaceutically acceptable salt thereof of at least about 15% when orally administered to a human subject.
27. The method of claim 1 , wherein the bioavailability of the fondaparinux or a pharmaceutically acceptable salt thereof has a coefficient of variation of no more than about 30%.