ORODISPERSIBLE DOSAGE UNIT CONTAINING AN ESTETROL COMPONENT

Abstract

The invention provides an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit consisting of: 0.1-25 wt.% of estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and 75-99.9 wt.% of one or more pharmaceutically acceptable ingredients; the solid dosage unit comprising at least 100 µg of the estetrol component; and wherein the solid dosage unit can be obtained by a process comprising wet granulation of estetrol particles having a volume weighted average particle size of 2 µm to 50 µm. The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration.

Description

Claims

1-28. (canceled)

29. A solid pharmaceutical dosage unit having a weight of 30 to 1,000 mg, the dosage unit comprising: (a) 60-99.7 wt % dry of estetrol-containing granules, the dry estetrol-containing granules comprising: (i) 70-95 wt % of one or more granulation excipients; and(ii) 5-30 wt % of estetrol particles having a volume median diameter of 2 µm to 50 µm, the estetrol particles containing at least 90 wt % of an estetrol component selected from estetrol, estetrol esters, hydrates of estetrol, and combinations thereof; and(b) 0.3-40 wt % of one or more tableting excipients.

30. The solid pharmaceutical dosage unit according to claim 29, wherein the estetrol particles contain at least 90 wt % of the estetrol component.

31. The solid pharmaceutical dosage unit according to claim 29, wherein the solid pharmaceutical dosage unit comprises at least 1 wt % of the estetrol component.

32. The solid pharmaceutical dosage unit according to claim 29, wherein the solid pharmaceutical dosage unit comprises 1-20 mg of the estetrol component.

33. The solid pharmaceutical dosage unit according to claim 29, wherein the estetrol component is estetrol monohydrate.

34. The solid pharmaceutical dosage unit according to claim 29, wherein the estetrol particles have a volume median diameter of 3 µm to 35 µm.

35. The solid pharmaceutical dosage unit of claim 29, wherein the one or more granulation excipients comprise one or more selected from water-soluble carbohydrates, diluents/fillers, binders, disintegrating agents, glidants, and lubricants.

36. The solid pharmaceutical dosage unit of claim 29, wherein the one or more tableting excipients comprise one or more selected from lactose, mannitol, xylitol, microcrystalline cellulose, starch, croscarmellose sodium, and polyvinyl pyrrolidone.

37. The solid pharmaceutical dosage unit according to claim 29, wherein one or both of the granulation excipients and the tableting excipients comprise one or more disintegrants.

38. The solid pharmaceutical dosage unit of claim 37, wherein the one or more disintegrants comprise one or more selected from modified starches, crosslinked polyvinylpyrrolidone, and crosslinked carmellose.

39. The solid pharmaceutical dosage unit according to claim 37, wherein the one or more disintegrants comprise one or more sodium salts of carboxymethyl starch.

40. The solid pharmaceutical dosage unit of claim 29, wherein the one or more granulation excipients comprise at least 30 wt % water-soluble carbohydrate.

41. The solid pharmaceutical dosage unit of claim 29, wherein the one or more granulation excipients comprise at least 40 wt % water-soluble carbohydrate.

42. The solid pharmaceutical dosage unit of claim 29, wherein the granulation excipients comprise at least 50 wt % water-soluble carbohydrate.

43. The solid pharmaceutical dosage unit of claim 29, wherein the dry estetrol-containing granules comprise 0.2-20% wt binder.

44. The solid pharmaceutical dosage unit according to claim 29, wherein the dosage unit has a disintegration time of less than 5 minutes when subjected to a disintegration test according to one or both of Ph. Eur. 2.9.1 (“Disintegration of tablets and capsules”) and USP <701> (“Disintegration”).

45. The solid pharmaceutical dosage unit according to claim 29, wherein the dosage unit releases at least 70% of the estetrol component after 5 minutes when subjected to dissolution testing by placing one unit in 900 mL of an aqueous dissolution medium comprising KH2PO4 and NaOH at pH 6.8 and a temperature of 37 ± 0.5° C., in a paddle and basket dissolution tester at a stirring speed of 50 rpm.

46. The solid pharmaceutical dosage unit according to claim 29, wherein the dosage unit releases at least 80% of the estetrol component after 5 minutes when subjected to dissolution testing by placing one unit in 900 mL of an aqueous dissolution medium comprising KH2PO4 and NaOH at pH 6.8 and a temperature of 37 ± 0.5° C., in a paddle and basket dissolution tester at a stirring speed of 50 rpm.

47. The solid pharmaceutical dosage unit of claim 32, further comprising 0.1-5 mg drospirenone.

48. The solid pharmaceutical dosage unit of claim 29, wherein the dosage unit is a tablet.