Synthetic progestogens and pharmaceutical compositions comprising the same
Described herein are synthetic progestogens, such as 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone, as well as pharmaceutical compositions comprising the same. Also described are methods of use.
1. A pharmaceutical composition comprising:
granules comprising 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone; and
one or more pharmaceutically acceptable excipients,
wherein the pharmaceutical composition does not comprise estrogen, and the pharmaceutical composition is formulated such that:
(1) when orally administered to a patient under fasting conditions, the pharmaceutical composition provides a pharmacokinetic profile for the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone comprising:
(i) a mean T max ranging from 2.2 hours to 6 hours; and
(ii) a mean C max of less than 30 ng/ml; and
(2) no more than 50% of the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone initially present in the pharmaceutical composition is dissolved within 30 minutes if subjected to an in vitro dissolution test according to the USP XXIII Paddle Method.
2. The pharmaceutical composition of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a filler.
3. The pharmaceutical composition of claim 2 , wherein the filler comprises lactose anhydrous, microcrystalline cellulose, starch, pregelatinized starch, modified starch, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, lactose, dextrose, sucrose, mannitol, sorbitol, or a combination thereof.
4. The pharmaceutical composition of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a lubricant.
5. The pharmaceutical composition of claim 4 , wherein the lubricant comprises magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG, stearic acid, vegetable oil, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, mineral oil polyoxyethylene monostearate, or a combination thereof.
6. The pharmaceutical composition of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a binder.
7. The pharmaceutical composition of claim 6 , wherein the binder comprises a starch, a gum, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, or a combination thereof.
8. The pharmaceutical composition of claim 7 , wherein the starch comprises potato starch, wheat starch, corn starch, or a combination thereof.
9. The pharmaceutical composition of claim 7 , wherein the gum comprises gum tragacanth, acacia gum, gelatin, or a combination thereof.
10. The pharmaceutical composition of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a glidant.
11. The pharmaceutical composition of claim 10 , wherein the glidant comprises silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, or a combination thereof.
12. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition further comprises a coating, and the coating comprises hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, or a combination thereof.
13. The pharmaceutical composition of claim 1 ,
wherein the pharmaceutical composition is formulated such that at least 50% of the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone initially present in the pharmaceutical composition is dissolved within 4 hours if subjected to the in vitro dissolution test according to the USP XXIII Paddle Method.
14. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises from 2 milligrams (mg) to 6 mg of the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone.
15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition comprises from 3.0 mg to 4.5 mg of the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone.
16. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition comprises 4.0 mg of the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone.
17. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated such that at least 55% of the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone initially present in the pharmaceutical composition is dissolved within 4 hours if subjected to the in vitro dissolution test according to the USP XXIII Paddle Method.
18. The pharmaceutical composition of claim 1 , wherein the pharmacokinetic profile further comprises an AUC 0h-tlast of at least 300 ng*h/ml.
19. The pharmaceutical composition of claim 1 , wherein the pharmacokinetic profile further comprises an AUC 0h-tlast of at least 350 ng*h/ml.
20. The pharmaceutical composition of claim 1 , wherein the mean C max ranges from 15 ng/ml to less than 30 ng/ml.
21. The pharmaceutical composition of claim 1 , wherein the granules comprise particles comprising the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone.
22. The pharmaceutical composition of claim 21 , wherein the particles have a diameter of less than 200 micrometers (μm).
23. The pharmaceutical composition of claim 21 , wherein the particles have a d50 of less than 70 μm.
24. The pharmaceutical composition of claim 21 , wherein the particles have a d50 ranging from 10 μm to 60 μm.
25. The pharmaceutical composition of claim 21 , wherein the particles have a surface area ranging from 2000 cm 2 /g to 8000 cm 2 /g.
26. The pharmaceutical composition of claim 18 , wherein the granules comprise particles comprising the 6β,7β:15β,16β-Dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone.
27. The pharmaceutical composition of claim 26 , wherein the particles have a diameter less than 200 μm.
28. The pharmaceutical composition of claim 26 , wherein the particles have a d50 of less than 70 μm.
29. The pharmaceutical composition of claim 26 , wherein the particles have a d50 ranging from 10 μm to 60 μm.
30. The pharmaceutical composition of claim 26 , wherein the particles have a surface area ranging from 2000 cm 2 /g to 8000 cm 2 /g.