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 comprising: 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 excipients; 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 that comprises compressing a dry blend of estetrol particles and one or more pharmaceutically acceptable excipients into a solid dosage unit. The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration.

1 . An orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, the dosage unit comprising:
 (a) 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   (b) 75-99.9 wt. % of one or more pharmaceutically acceptable excipients;   wherein the solid dosage unit contains at least 100 μg of the estetrol component; and   wherein the solid dosage unit can be obtained by a process comprising:   (i) providing estetrol particles having a volume median diameter between 2 μm to 50 μm and comprising at least 80 wt. % of an estetrol component selected from estetrol, estetrol esters and combinations thereof;   (ii) mixing the estetrol particles with one or more pharmaceutically acceptable excipients to obtain a dry blend; and   (iii) compressing the dry blend into a solid dosage unit.   
     
     
         2 . The dosage unit according to  claim 1 , wherein the dosage unit has a weight between 40 and 500 mg. 
     
     
         3 . The dosage unit according to  claim 1 , wherein the dosage unit contains 0.5-25 wt. % of the estetrol component. 
     
     
         4 . The dosage unit according to  claim 1 , wherein the dosage unit contains 0.3-100 mg of the estetrol component. 
     
     
         5 . The dosage unit according to  claim 1 , wherein the estetrol component is estetrol. 
     
     
         6 . The dosage unit according to  claim 1 , wherein the estetrol particles have a volume median diameter of 3-35 μm. 
     
     
         7 . The dosage unit according to  claim 1 , wherein the dosage unit contains 50-99.5 wt. % of filler selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt, microcrystalline cellulose, calcium salts and combinations thereof. 
     
     
         8 . The dosage unit according to  claim 7 , wherein the filler is selected from lactose, xylitol, sorbitol, erythritol, mannitol, microcrystalline cellulose and combinations thereof. 
     
     
         9 . The dosage unit according to  claim 7 , wherein the dosage unit contains at least 20 wt. % of sugar alcohol selected from mannitol, xylitol and combinations thereof. 
     
     
         10 . The dosage unit according to  claim 1 , wherein the dosage unit contains 0.1-20 wt. % of a disintegrating agent selected from modified starches, crosslinked polyvinyl pyrrolidone, crosslinked carmellose and combinations thereof. 
     
     
         11 . The dosage unit according to  claim 1 , wherein the dosage unit contains 0-60 wt. % of microcrystalline cellulose. 
     
     
         12 . The dosage unit according to  claim 1 , wherein the dosage unit contains 0.1-2 wt. % of lubricant selected from sodium stearyl fumarate, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, polyethylene glycol, calcium stearate and mixtures thereof. 
     
     
         13 . A method for female hormone replacement therapy, comprising sublingually, buccally or sublabially administering to a subject in need thereof the dosage unit according to  claim 1 . 
     
     
         14 . The method according to  claim 13 , wherein the administration is once daily for a period of at least 1 week. 
     
     
         15 . A method of female contraception, comprising sublingually, buccally or sublabially administering to a subject in need thereof a dosage unit according to  claim 1 . 
     
     
         16 . The method according to  claim 15 , wherein the administration is once daily for a period of at least 1 week. 
     
     
         17 . A process of preparing an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, the dosage unit comprising:
 (a) 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   (b) 75-99.9 wt. % of one or more pharmaceutically acceptable excipients;   wherein the solid dosage unit contains at least 100 μg of the estetrol component, the process comprising:   (i) providing estetrol particles having a volume median diameter between 2 μm to 50 μm and containing at least 80 wt. % of an estetrol component selected from estetrol, estetrol esters and combinations thereof, said estetrol particles;   (ii) mixing 1 part by weight of the estetrol particles with 2-1,000 parts by weight of one or more pharmaceutically acceptable excipients to obtain a dry blend; and   (iii) compressing the dry blend into a solid dosage unit.   
     
     
         18 . The process according to  claim 17 , wherein the process does not comprise addition of liquid solvent during or after the combining of the estetrol particles and the one or more pharmaceutically acceptable excipients. 
     
     
         19 . The process according to  claim 17 , wherein the solid dosage unit is formed by direct compression.