Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
The present invention refers to a new enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives starting from the corresponding 17α,21-diesters which comprises an enzymatic alcoholysis reaction. Furthermore, the present invention refers to new crystalline forms of cortexolone-17α-propionate and 9,11-dehydro-cortexolone 17α-butanoate.
1. Crystalline form I of cortexolone-17α-propionate characterized by:
a DRX as shown in FIG. 1 ; or
a DRX with at least peaks at about: 7.6, 8.4, 14.3, 14.8, 15.7, 17.0, and 20.1 degrees 2theta.
2. A pharmaceutical composition comprising at least one physiologically acceptable excipient and crystalline form I of cortexolone-17α-propionate, wherein crystalline form I of cortexolone-17α-propionate is characterized by:
a DRX as shown in FIG. 1 ; or
a DRX with at least peaks at about: 7.6, 8.4, 14.3, 14.8, 15.7, 17.0, and 20.1 degrees 2theta.
3. The composition of claim 2 , wherein the at least one physiologically acceptable excipient is propylene glycol, cetylic alcohol, glyceryl monostearate, liquid paraffin, or a combination of any of the foregoing.
4. The composition of claim 2 , further comprising mixed tocopherols, polysorbate 80, or a combination thereof.
5. The composition of claim 2 , wherein the composition is in the form of a tablet, capsule, powder, pellet, suspension, emulsion, cream, gel, ointment, lotion, or paste.
6. The composition of claim 2 , wherein the composition is in the form of a solid, semi-solid, or a paste.
7. The composition of claim 5 , wherein the composition is in the form of a cream.
8. The composition of claim 7 , wherein the composition further comprises solubilized cortexolone-17α-propionate.
9. The composition of claim 8 , wherein the solubilized cortexolone-17α-propionate is present in the composition in a concentration of from 0.1 to 2% by weight of the composition.
10. The composition of claim 2 , wherein the composition further comprises solubilized cortexolone-17α-propionate.
11. The composition of claim 10 , wherein the solubilized cortexolone-17α-propionate is present in the composition in a concentration of from 0.1 to 2% by weight of the composition.
12. The composition of claim 8 , wherein the solubilized cortexolone-17α-propionate and crystalline form I of cortexolone-17α-propionate together comprise 0.1 to 2% by weight of the composition or comprise 0.2 to 1% by weight of the composition.
13. The composition of claim 8 , wherein the composition further comprises any of crystalline forms II, III, or IV of cortexolone-17α-propionate, and wherein the solubilized cortexolone-17α-propionate and crystalline form I of cortexolone-17α-propionate together with any of crystalline forms II, III, or IV of cortexolone-17α-propionate, or any combination thereof, comprise 0.1 to 2% by weight of the composition or 0.2 to 1% by weight of the composition.
14. The composition of claim 8 , wherein the composition further comprises any of crystalline forms II, III, or IV of cortexolone-17α-propionate, and wherein the solubilized cortexolone-17α-propionate and crystalline form I of cortexolone-17α-propionate together with any of crystalline forms II, III, or IV of cortexolone-17α-propionate, or any combination thereof, comprise 1% by weight of the composition.
15. A process for preparing crystalline form I of cortexolone-17α-propionate, the process comprising crystallizing cortexolone-17α-propionate from tert-butylmethylether.
16. The process of claim 15 , wherein crystallizing cortexolone-17α-propionate takes place at a concentration of 0.9 to 1.1 g of cortexolone-17α-propionate in 9 to 11 ml tert-butylmethylether.
17. A method of treating a pathology affecting the skin and/or the cutaneous appendages, wherein the pathology affecting the skin and/or the cutaneous appendages is acne, androgenetic alopecia, hirsutism, or seborrheic dermatitis, the method comprising administering to a subject in need thereof an effective amount of crystalline form I of cortexolone-17α-propionate, wherein crystalline form I of cortexolone-17α-propionate is characterized by:
a DRX as shown in FIG. 1 ; or
a DRX with at least peaks at about: 7.6, 8.4, 14.3, 14.8, 15.7, 17.0, and 20.1 degrees 2theta.
18. The method of claim 17 , wherein crystalline form I of cortexolone-17α-propionate is applied topically.
19. The method of claim 18 , wherein the pathology affecting the skin and/or the cutaneous appendages is acne.
20. The method of claim 18 , wherein the pathology affecting the skin and/or the cutaneous appendages is androgenetic alopecia.
21. The method of claim 18 , wherein the pathology affecting the skin and/or the cutaneous appendages is hirsutism.
22. The method of claim 18 , wherein the pathology affecting the skin and/or the cutaneous appendages is seborrheic dermatitis.
23. The method of claim 18 , wherein the crystalline form I of cortexolone-17α-propionate is formulated in a composition comprising form I of cortexolone-17α-propionate and at least one physiologically acceptable excipient.
24. The method of claim 23 , wherein the pathology affecting the skin and/or the cutaneous appendages is acne.
25. The method of claim 23 , wherein the pathology affecting the skin and/or the cutaneous appendages is androgenetic alopecia.
26. The method of claim 23 , wherein the pathology affecting the skin and/or the cutaneous appendages is hirsutism.
27. The method of claim 23 , wherein the pathology affecting the skin and/or the cutaneous appendages is seborrheic dermatitis.
28. The method of claim 23 , wherein the at least one physiologically acceptable excipient is propylene glycol, cetylic alcohol, glyceryl monostearate, liquid paraffin, or a combination of any of the foregoing.
29. The method of claim 28 , wherein the pathology affecting the skin and/or the cutaneous appendages is acne.
30. The method of claim 28 , wherein the pathology affecting the skin and/or the cutaneous appendages is androgenetic alopecia.
31. The method of claim 28 , wherein the pathology affecting the skin and/or the cutaneous appendages is hirsutism.
32. The method of claim 28 , wherein the pathology affecting the skin and/or the cutaneous appendages is seborrheic dermatitis.
33. The method of claim 23 , wherein the composition is in the form of a tablet, capsule, powder, pellet, suspension, emulsion, cream, gel, ointment, lotion, or paste.
34. The method of claim 33 , wherein the composition is a cream.