Oromucosal Liquid Estradiol Compositions

Abstract

The present invention relates to low dose estradiol solutions for oromucosal administration suitable in replacement therapy or suppletion of low estradiol levels and also for preventing, alleviating or treating symptoms associated with low endogenous levels of estradiol in female subjects.

1 - 20 . (canceled) 
     
     
         21 . A method of treating a human female patient having reduced estradiol levels, said method comprising administering oromucosally to a human female patient in need thereof one or more doses of a solution comprising 0.01-0.9% (w/v) of estradiol, or an equivalent amount of a pharmaceutically acceptable hydrate or ester thereof, 5-30% (v/v) of ethanol and 70-95% (v/v) of an ester of a C 2-6  alcohol and a C 8-22  fatty acid; wherein said dose comprises 0.01-0.3 mg of estradiol, or an equivalent amount of a pharmaceutically acceptable hydrate or ester thereof, wherein the solution is administered 1-6 times per day by spray, by drops or by a dosage pen, and wherein the solution does not contain water. 
     
     
         22 . The method according to  claim 21 , wherein a volume between about 10-500 μl of the estradiol solution is administered per dose. 
     
     
         23 . The method according to  claim 21 , wherein said dose is administered intermittently in a time period in the range 1 to 4 hours. 
     
     
         24 . The method according to  claim 21 , wherein the elevation and control of the estradiol levels in the female patient results in treating, preventing or relieving symptoms caused by insufficient endogenous production of estrogen, such as headaches, nausea, vasomotor symptoms (hot flushes), symptoms of urogenital atrophy, decrease in bone mineral density, osteoporosis and increased risk or incidence of bone fractures. 
     
     
         25 . The method according to  claim 21 , wherein the solution comprises 10-30% (v/v) of ethanol and 70-90% (v/v) of said ester. 
     
     
         26 . The method according to  claim 21 , wherein the C 2-6  alcohol is selected from ethanol, 1-propanol, isopropanol, butanol, pentanol, hexanol, propylene glycol, and glycerol; and the C 8-22  fatty acid is selected from myristic acid, palmitic acid, stearic acid, arachidic acid and oleic acid. 
     
     
         27 . The method according to  claim 21 , wherein the ester of the C 8-22  fatty acid and C 2-6  alcohol is isopropyl myristate, isopropyl palmitate or isopropyl stearate. 
     
     
         28 . The method according to  claim 21 , wherein the ester of the C 8-22  fatty acid and C 2-6  alcohol is a vegetable oil, such as sesame oil, corn oil, castor oil or olive oil. 
     
     
         29 . The method according to  claim 21 , comprising 0.01-0.9% of estradiol (w/v), 10 -30% (v/v) ethanol (v/v) and 70-90% (v/v) isopropyl myristate. 
     
     
         30 . The method according to  claim 21 , wherein the ratio of the volumes of said ethanol to said ester of a C 2-6  alcohol and a C 8-22  fatty acid is 30:70, 25:75, 20:80, 15:85, or 10-90 (v/v%).