Anti-infective and osteogenic compositions and methods of use
Cationic steroidal antimicrobials (“CSAs” or “ceragenins”) and methods of making and using the same. Particularly advantageous uses include treating infections in patient and sub-patient populations, especially those having a bone disease, a broken bone, a bone infection, or a bone implant.
1. A method of reducing the likelihood of a bone infection in a subject having a broken bone, a bone implant, osteoporosis, or osteoarthritis while concurrently promoting osteogenesis in a subject in need thereof, the method comprising:
administering to the subject in need thereof a CSA compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein Z 1 and Z 2 are independently selected from the group consisting of optionally substituted alkyl; optionally substituted alkenyl; and optionally substituted alkynyl, or H, with the proviso that Z 1 and Z 2 are not both H,
wherein R 2 , R 3 , and R 4 , are independently selected from the group consisting of optionally substituted protected or unprotected amino-C a -alkyl; optionally substituted protected or unprotected amino-C a -alkylcarbonyl; and optionally substituted protected or unprotected amino-C a -alkylthiocarbonyl, and
wherein a is 2-5; and
co-administering a bone growth factor to the subject,
wherein co-administering the bone growth factor and the CSA compound potentiates a synergistic effect in promoting osteogenesis and reduces the likelihood of a bone infection associated with the broken bone, the bone implant, osteoporosis, or osteoarthritis in the subject.
2. The method of claim 1 , wherein the subject is a mammal.
3. The method of claim 1 , wherein the subject is a human.
4. The method of claim 1 , wherein Z 1 and Z 2 are optionally substituted alkyl.
5. The method of claim 1 , wherein Z 1 and Z 2 are independently selected from the group consisting of optionally substituted C 1 -C 20 -alkyl; optionally substituted C 3 -C 20 -alkenyl; and optionally substituted C 3 -C 20 -alkynyl.
6. The method of claim 1 , wherein Z 1 and Z 2 are independently selected from the group consisting of optionally substituted C 3 -C 10 -alkyl; optionally substituted C 3 -C 10 -alkenyl; and optionally substituted C 3 -C 10 -alkynyl.
7. The method of claim 1 , wherein Z 1 and Z 2 are independently selected from the group consisting of optionally substituted C 5 -C 8 -alkyl; optionally substituted C 3 -C 10 -alkenyl; and optionally substituted C 5 -C 8 -alkynyl.
8. The method of claim 1 , wherein Z 1 and Z 2 are optionally substituted C 5 -C 8 -alkyl.
9. The method of claim 1 , wherein Z 1 and Z 2 are unsubstituted C 5 -C 8 -alkyl.
10. The method of claim 1 , wherein R 2 , R 3 , and R 4 , are amino-C a -alkyl or amino-C a -alkylcarbonyl.
11. The method of claim 1 , wherein R 2 , R 3 , and R 4 , are amino-C a -alkyl.
12. The method of claim 1 , wherein R 2 , R 3 , and R 4 , are amino-C a -alkylcarbonyl.
13. The method of claim 10 , wherein a is selected from 2, 3, 4, or 5.
14. The method of claim 1 , wherein the protected amino-C a -alkyl and the protected amino-C a -alkylcarbonyl are protected with a group independently selected from Fmoc, Boc, allyl, acetyl, benzyl, or CBz.
15. The method of claim 1 , wherein R 2 , R 3 , and R 4 , are independently selected from the group consisting of carbamate protected or unprotected amino-C a -alkyl and carbamate protected or unprotected amino-C a -alkylcarbonyl.
16. The method of claim 1 , wherein R 2 , R 3 , and R 4 , are independently selected from the group consisting of Fmoc protected or unprotected amino-C a -alkyl and Fmoc protected or unprotected amino-C a -alkylcarbonyl.
17. The method of claim 1 , wherein R 2 , R 3 , and R 4 , are independently selected from the group consisting of Boc protected or unprotected amino-C a -alkyl and Boc protected or unprotected amino-C a -alkylcarbonyl.
18. The method of claim 1 , wherein the compound of Formula (I) is:
19. The method of claim 1 , wherein the compound is not substituted.
20. The method of claim 1 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.
21. The method of claim 1 , wherein the growth factor comprises a bone morphogenetic protein.
22. A method of treating osteoarthritis in a subject in need thereof, comprising:
administering to the subject in need thereof a CSA compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein Z 1 and Z 2 are independently selected from the group consisting of optionally substituted alkyl; optionally substituted alkenyl; and optionally substituted alkynyl, or H, with the proviso that Z 1 and Z 2 are not both H,
wherein R 2 , R 3 , and R 4 , are independently selected from the group consisting of optionally substituted protected or unprotected amino-Ca-alkyl; optionally substituted protected or unprotected amino-Ca-alkylcarbonyl; and optionally substituted protected or unprotected amino-Ca-alkylthiocarbonyl, and wherein a is 2-5.
23. A method of treating a degenerative bone condition or a bone condition caused by a microbial infection while concurrently promoting osteogenesisin a subject in need thereof, comprising:
providing a CSA-90 compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a recombinant bone morphogenetic protein on a drug delivery vehicle:
wherein Z 1 and Z 2 are independently selected from the group consisting of optionally substituted alkyl; optionally substituted alkenyl; and optionally substituted alkynyl, or H, with the proviso that Z 1 and Z 2 are not both H,
wherein R 2 , R 3 , and R 4 , are independently selected from the group consisting of optionally substituted protected or unprotected amino-C a -alkyl; optionally substituted protected or unprotected amino-C a -alkylcarbonyl; and optionally substituted protected or unprotected amino-C a -alkylthiocarbonyl, and
wherein a is 2-5; and
administering the drug delivery vehicle to a site of the degenerative bone condition or to a site of the bone condition caused by the microbial infection to synergistically promote osteogenesis and to prevent or treat the microbial infection.
24. The method of claim 22 , further comprising co-administering a bone growth factor to the subject, wherein co-administering the bone growth factor and the CSA compound potentiates a synergistic effect in promoting osteogenesis in the subject.
25. The method of claim 23 , wherein between about 25 μg to about 250 μg of the CSA compound is provided on the drug delivery vehicle.
26. The method of claim 23 , wherein at least about 10 μg of the recombinant bone morphogenetic protein is provided on the drug delivery vehicle.
27. The method of claim 25 , wherein the recombinant bone morphogenetic protein comprises one or more of BMP-2, BMP-3, BMP-4, BMP-5, BMP-5, or BMP-7.
28. The method of claim 26 , wherein the recombinant bone morphogenetic protein comprises BMP-2.