Dosage forms of active ingredients containing hydroxystilbene for treating menopausal complaints

Abstract

The invention provides novel hydroxystilbene-containing dosage forms, processes for producing these dosage forms and the use thereof for the treatment of menopausal symptoms in women, juvenile oligomenorrhea and dysmenorrhea, primary and secondary amenorrhea or endometritis.

1 . A solid dosage form comprising an active-ingredient-containing solid core with a pharmaceutically acceptable carrier and an active ingredient content of about 1 to 20% by weight, based on the total weight of the core, wherein the active ingredient is a hydroxystilbene-containing active ingredient or a hydroxystilbene-containing active ingredient combination selected the group consisting of precursors of resveratrol and piceatannol, resveratrol, piceatannol, stereoisomeric forms thereof and functional derivatives thereof, in each case in the form of their salts or in the phenol form. 
     
     
         2 . The solid dosage form as claimed in  claim 1 , wherein the active ingredient or the active ingredient combination is obtainable from roots of  Rheum rhaponticum.    
     
     
         3 . The solid dosage form as claimed in  claim 1 , where the active ingredient combination substantially comprises rhaponticin and deoxyrhaponticin in a ratio of about 2:28 to 28:2 by weight. 
     
     
         4 . The solid dosage form as claimed in  claim 1 , wherein the active ingredient combination substantially consists of approximately 60-66% by weight rhaponticin, 30-35% by weight deoxyrhaponticin, 0-2% by weight rhapontigenin; and 0-2% by weight deoxyrhapontigenin. 
     
     
         5 . The solid dosage form as claimed in  claim 1 , wherein the total active ingredient content is about 2 to 20 mg per dose unit. 
     
     
         6 . The solid dosage form as claimed in  claim 1 , wherein the core is lactose-free core. 
     
     
         7 . The solid dosage form as claimed in  claim 1  in the form of a pill, of a tablet, of an extrudate or of granules. 
     
     
         8 . The solid dosage form as claimed in  claim 1 , which has a gastro-resistant coating. 
     
     
         9 . The solid dosage form as claimed in  claim 8 , wherein the coating comprises substantially no plasticizer. 
     
     
         10 . The solid dosage form as claimed in  claim 1 , having a total weight in the range of about 150 mg±20 mg, a core weight of 84 mg±10 mg and an active ingredient content of about 3 to 10 mg per dose unit. 
     
     
         11 . The solid dosage form as claimed in  claim 1 , having a uniformity of active ingredient content (averaged over 10 or 20 randomly selected individual dose units) not exceeding ±5% by weight based on the total weight of the dose unit. 
     
     
         12 . A process for producing a solid dosage unit as claimed in  claim 1 , comprising:
 a) mixing the active ingredient or the active ingredient combination with a pharmaceutically acceptable carrier; and   b) consolidating the mixture to give the active ingredient core.   
     
     
         13 . The process as claimed in  claim 12 , wherein the active ingredient or active ingredient combination is dissolved or dispersed in an inert liquid and mixed with the carrier, and the solvent is removed during or after the consolidating step. 
     
     
         14 . The process as claimed in  claim 12 , wherein the active ingredient or the active ingredient combination is prepared by:
 a) providing an active ingredient-containing part of a medicinal plant;   b) adding an aqueous extractant thereto;   c) after the extractant has acted, obtaining a liquid extract phase from the mixture; and   d) removing the extractant from the liquid extract phases, thereby preparing the active ingredient combination.   
     
     
         15 . The process as claimed in  claim 14 , wherein the active ingredient-containing part of a medicinal plant is provided in comminuted form. 
     
     
         16 . The process as claimed in  claim 14 , further comprising repeating the extraction several times. 
     
     
         17 . The process as claimed in  claim 14 , wherein the extraction with the aqueous extractant is carried out at a pH of the mixture in the alkaline range. 
     
     
         18 . The process as claimed in  claim 14 , the medicinal plant is selected from plants of the genus  Rheum  sp.,  Astragalus  sp.,  Cassia  sp. and  Picea  sp. 
     
     
         19 . The process as claimed in  claim 12 , wherein the total amount of the active ingredient or of the active ingredient combination is mixed in portions with the pharmaceutically acceptable carrier, and mixing is carried out after each addition of carrier. 
     
     
         20 . The process as claimed in  claim 19 , wherein mixing is carried out after each addition with a ball mill over a period of from 30 minutes to 3 hours. 
     
     
         21 . The process as claimed in  claim 12 , wherein the active ingredient core is provided with a gastro-resistant coating. 
     
     
         22 . The process as claimed in  claim 21 , where the coating comprises substantially no plasticizer. 
     
     
         23 . The process as claimed in  claim 12 , wherein the core is sugar-coated. 
     
     
         24 . A liquid dosage form comprising an active ingredient or an active ingredient combination as claimed in  claim 1  in a proportion of about 0.1 to 20 mg/ml in a solvent mixture comprising water and a pharmaceutically acceptable alcohol. 
     
     
         25 . The liquid dosage form as claimed in  claim 24 , wherein the solvent mixture is a water/ethanol mixture with an ethanol content of from 10 to 50% by volume. 
     
     
         26 . The liquid dosage form as claimed in  claim 24 , formulated as drops for oral administration. 
     
     
         27 . A semisolid dosage form comprising an active ingredient or an active ingredient combination as claimed in  claim 1  in a proportion of about 1 to 12% by weight in a conventional semisolid carrier. 
     
     
         28 . The semisolid dosage form as claimed in  claim 27 , formulated as vaginal gel or vaginal suppositories. 
     
     
         29 . A pharmaceutical composition comprising a solid dosage form as claimed in 1 and a pharmaceutically acceptable carrier. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the solid dosage form is produced as claimed in 39. 
     
     
         31 . A pharmaceutical composition comprising a liquid dosage form as claimed in  claim 24  and a pharmaceutically acceptable carrier. 
     
     
         32 . A pharmaceutical composition comprising a semisolid dosage form as claimed in  claim 27  and a pharmaceutically acceptable carrier. 
     
     
         33 . A method of treating menopausal symptoms, juvenile oligomenorrhea and dysmenorrhea, primary and secondary amenorrhea or endometritis in a subject comprising administering to the subject a solid dosage form, a liquid dosage form or a semisolid dosage form, wherein the solid dosage form, liquid dosage form or semisolid dosage form comprises the hydroxystilbene-containing active ingredient or a hydroxystilbene-containing active ingredient combination as claimed in  claim 1 . 
     
     
         34 . The method of  claim 33 , wherein the active ingredient or active ingredient combination brings about treatment by selective activation of ERβ. 
     
     
         35 . The method of  claim 33 , wherein the menopausal symptoms occur in perk or postmenopause. 
     
     
         36 . The method of  claim 35 , wherein the menopausal symptoms are selected from the group consisting of hot flushes, sweating episodes, sleep disorders, irritability, psychological and mental exhaustion, sexual problems and urinary tract symptoms. 
     
     
         37 . The method of  claim 33 , wherein the menopausal symptoms are the result of natural or therapeutically induced menopause. 
     
     
         38 . A method for selective activation of ERβ in vivo or in vitro comprising contacting a cell with the hydroxystilbene-containing active ingredient or a hydroxystilbene-containing active ingredient combination as claimed in  claim 1 .