Nasal spray steroid formulation and method

Abstract

The present invention relates to an improvement in a method of contraception, in treatment of benign gynecological disorders, and in hormone replacement. The improved method includes administering intranasally an estrogenic compound and an androgenic compound, and in some embodiments an optional progestin compound, in a once-daily bolus formulation comprised of the two or three steroids complexed with a cyclodextrin. An intranasal delivery system for administration of the formulation is also described.

1 . An intranasal drug-delivery system for use in contraception, in treatment of benign gynecological disorders, or in hormone replacement, by administration of an estrogenic compound and an androgenic compound, and an optional progestin compound, comprising: 
 (a) a nasal-spray nebulizer, and    (b) contained in the nebulizer, a formulation comprising an estrogenic compound and an androgenic compound, said compounds in a solubilized form complexed with a cyclodextrin, where the amount of the compounds administered intranasally is such as to produce a biological effect comparable to that produced when the estrogenic compound and the androgenic compound are administered transdermally.    
   
   
       2 . The system of  claim 1 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.  
   
   
       3 . The system of  claim 2 , wherein the 2-hydroxypropyl-β-cyclodextrin has a degree of substitution between 2 and 8.  
   
   
       4 . The system of  claim 2 , wherein the concentration of 2-hydroxypropyl-β-cyclodextrin in the formulation is between 50 to 300 mg/mL.  
   
   
       5 . The system of  claim 2 , wherein the estrogenic compound and the androgenic compound have a combined molar occupancy with respect to the cyclodextrin that is greater than the molar occupancy achievable with either steroid alone.  
   
   
       6 . The system of  claim 2 , wherein the estrogenic compound is 17β-estradiol at a daily dose between 0.15 mg and 0.6 mg and the androgenic compound is testosterone at a daily dose between 0.15 mg and 1.0 mg.  
   
   
       7 . The system of  claim 6 , wherein the mole ratio of 17-β estradiol to testosterone is between 1:1 and 1:5.  
   
   
       8 . The system of  claim 1 , wherein said formulation further comprises a progestin compound as a third steroid.  
   
   
       9 . The system of  claim 1 , wherein said nebulizer is effective to deliver a spray volume of between about 30 μL to 200 μL  
   
   
       10 . A method of formulating two or more different steroids in a water-soluble form suitable for uptake by a human subject through mucosal tissue, comprising 
 forming an aqueous solution of a cyclodextrin,    adding the steroids to the solution in amounts effective to achieve a combined molar occupancy of the two or more steroids which is greater than the molar occupancy achievable with any of the steroids alone.    
   
   
       11 . The method of  claim 10 , further comprising, prior to said adding, heating the aqueous solution of cyclodextrin to above about 70° C.  
   
   
       12 . The method of  claim 10 , wherein said adding includes adding the first steroid to the solution until a maximum or near-maximum molar occupancy is reached, then adding the second steroid until a combined maximum or near-maximum molar occupancy is reached.  
   
   
       13 . The method of  claim 10 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin and said two or more steroids are an estrogenic compound and an androgenic compound.  
   
   
       14 . The method of  claim 13 , wherein said estrogenic compound is 17β-estradiol and said androgenic compound is testosterone.  
   
   
       15 . The method of  claim 14 , wherein said two or more steroids further comprises a progestin compound as a third steroid.