Process, salts, composition and use
The present invention provides a novel process for preparing pleuromutilin derivatives, novel salts of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate or solvates thereof, novel pharmaceutical compositions or formulations for topical administration comprising mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate or a pharmaceutically acceptable salt or solvate thereof and their use in medical therapy, particularly antibacterial therapy.
1. A method of treating a microbial infection in a mammal, comprising administering topically to said mammal, in need thereof an effective amount of a crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterized by at least one of:
(i) an infra-red spectrum measured by attenuated total reflectance having peaks at 3234, 1735 and 1725 cm −1 ,
(ii) a differential scanning calorimetry profile having an endotherm with an onset temperature of 125-127° C., and
(iii) an X-ray powder diffraction pattern having peaks at about 9.6, about 12.8, about 13.9 and about 19.6.
2. The method according to claim 1 wherein the microbial infection is a skin or soft tissue infection.
3. The method according to claim 2 wherein the topical administration of the mutilin is twice daily.
4. The method according to claim 1 wherein the topical administration of the mutilin over a period of 5 to 7 days.
5. A method of treating a microbial infection in a mammal, comprising administering topically to said mammal in need thereof, an effective amount of a crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterized by at least one of:
(i) an infra-red spectrum measured by attenuated total reflectance having peaks at 3470, 1731 and 1711 cm −1 ,
(ii) a differential scanning calorimetry profile having an endotherm with an onset temperature of 168-170° C., and
(iii) an X-ray powder diffraction pattern having peaks at about 13.4, about 14.4 and about 20.7.
6. The method according to claim 5 wherein the microbial infection is a skin or soft tissue infection.
7. The method according to claim 6 wherein the topical administration of the mutilin is twice daily.
8. The method according to claim 5 wherein the topical administration of the mutilin over a period of 5 to 7 days.
9. A method of treating a microbial infection in a mammal in need thereof, comprising administering topically to said mammal an effective amount of a crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate which is characterized by the following properties:
(i) an infra-red spectrum measured by ATR (attenuated total reflectance) having peaks at 3234, 1735 and 1725 cm −1 , and
(ii) an XRPD (X-ray powder diffraction) pattern having peaks at about 9.6, about 12.8, about 13.9 and about 19.6.
10. The method according to claim 9 wherein the microbial infection is a skin or soft tissue infection.
11. The method according to claim 10 wherein the topical administration of the mutilin is twice daily.
12. The method according to claim 9 wherein the topical administration of the mutilin over a period of 5 to 7 days.
13. A method of treating a microbial infection in a mammal in need thereof, comprising administering topically to said mammal an effective amount of a crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate-which is characterized by one or more of the following properties:
(i) an infra-red spectrum measured by ATR (attenuated total reflectance) substantially in accordance with FIG. 1 ;
(ii) a DSC (differential scanning calorimetry) substantially in accordance with FIG. 2 ; and
(iii) an XRPD (X-ray powder diffraction pattern) substantially in accordance with FIG. 3 .
14. The method according to claim 13 wherein the microbial infection is a skin or soft tissue infection.
15. The method according to claim 11 wherein the topical administration of the mutilin is twice daily.
16. The method according to claim 13 wherein the topical administration of the mutilin over a period of 5 to 7 days.
17. A method of treating acne in a human, comprising administering topically to said human in need thereof, an effective amount of a crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterized by at least one of:
(i) an infra-red spectrum measured by attenuated total reflectance having peaks at 3234, 1735 and 1725 cm −1 ,
(ii) a differential scanning calorimetry profile having an endotherm with an onset temperature of 125-127° C., and
(iii) an X-ray powder diffraction pattern having peaks at about 9.6, about 12.8, about 13.9 and about 19.6.
18. A method of treating a microbial infection in a mammal, comprising administering topically to said mammal, in need thereof an effective amount of a crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterized by at least one or more of the following properties:
(i) an infra-red spectrum measured by ATR (attenuated total reflectance) having peaks at 3470, 1731 and 1711 cm -1 ,
(ii) a DSC (differential scanning calorimetry) profile having an endotherm with an onset temperature of 168-170° C,
(iii) an XRPD (X-ray powder diffraction) pattern having peaks at about 13.4, about 14.4 and about 20.7 2-theta.
19. The method according to claim 18 wherein the crystalline hydrosuccinate salt of the mutilin are particles incorporated into an ointment.
20. The method according to claim 19 wherein the ointment is petrolatum.
21. The method according to claim 19 wherein the D 90 of the particles in the composition is 15 μm to 25 μm.
22. The method according to claim 1 wherein the crystalline mutilin particles are incorporated into an ointment.
23. The method according to claim 22 wherein the ointment is petrolatum.
24. The method according to claim 22 wherein the D 90 of the particles in the composition is 15 μm to 25 μm.