Nasal spray formulation and method

Abstract

A nasal spray formulation for use in female contraception or in the treatment of benign gynecological disorders is described. The nasal preparation is comprised of a GnRH compound and an estrogenic compound in the form of a water-soluble complex with a water-soluble cyclodextrin. The preparation effectively suppresses ovarian estrogen and progesterone production, and prevents signs and symptoms of estrogen deficiency, without a significant increase in the risk of endometrial hyperplasia.

1 . An intranasal drug-delivery system for use in female contraception or in the treatment of benign gynecological disorders, comprising 
 a nebulizer operable to deliver a selected volume, and    contained in the nebulizer, a liquid formulation composed of (i) a liquid carrier, (ii) a GnRH compound capable of suppressing ovarian estrogen and progesterone production, and (iii) an estrogenic compound capable of preventing signs and symptoms of estrogen deficiency when co-administered with the GnRH compound,    where the concentration of GnRH compound and estrogenic compound in the formulation are effective, when administered intranasally, to suppress ovarian function and to prevent signs and symptoms of estrogen deficiency, without a significant increase in the risk of endometrial hyperplasia.    
     
     
         2 . The intranasal drug-delivery system of  claim 1 , wherein said nebulizer is operable to deliver a selected volume between 30 and 200 μL of an aqueous formulation in the form of a liquid-droplet aerosol.  
     
     
         3 . The intranasal drug-delivery system of  claim 1 , wherein said liquid formulation further comprises a water-soluble cyclodextrin present in the form of a water-soluble complex with the estrogenic compound.  
     
     
         4 . The intranasal drug-delivery system of  claim 3 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin, at a concentration between 50 and 300 mg/mL.  
     
     
         5 . The intranasal drug-delivery system of  claim 4 , wherein the 2-hydroxypropyl-β-cyclodextrin has a degree of substitution between 2 and 8.  
     
     
         6 . The intranasal drug-delivery system of  claim 1 , wherein the GnRH compound is deslorelin, at a dose between 0.025 and 1.5 mg.  
     
     
         7 . The intranasal drug-delivery system of  claim 1 , wherein the estrogenic compound is 17β-estradiol, at a dose between 0.15 and 0.6 mg.  
     
     
         8 . The intranasal drug-delivery system of  claim 3 , which further includes testosterone as a second or third steroid in the form of a water-soluble complex with the cyclodextrin, and at a dose of between 0.15 and 1 mg.  
     
     
         9 . The intranasal drug-delivery system of  claim 3 , which further includes a progestin as a second or third steroid in the form of a water-soluble complex with the cyclodextrin.  
     
     
         10 . The intranasal drug-delivery system of  claim 8 , wherein the estrogenic compound and the second or third steroid have a combined molar occupancy with respect to the cyclodextrin that is greater than the molar occupancy achievable with either steroid alone.  
     
     
         11 . The intranasal drug-delivery system of  claim 9 , wherein the estrogenic compound and the second or third steroid have a combined molar occupancy with respect to the cyclodextrin that is greater than the molar occupancy achievable with either steroid alone.  
     
     
         12 . The intranasal drug-delivery system of  claim 3 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin having a degree of substitution between 2 and 8, and a concentration between 50 and 300 mg/mL.  
     
     
         13 . The intranasal drug-delivery system of  claim 1 , wherein the GnRH compound is a GnRH peptide agonist.  
     
     
         14 . The intranasal drug-delivery system of  claim 1 , wherein the GnRH compound is selected from the group consisting of deslorelin, leuprolide, nafarelin, goserelin, decapeptyl, buserelin, histrelin, gonadorelin, abarelix, cetrorelix, azaline B, and degarelix, and analogs thereof.