Oral Transmucosal Compositions including Aromatase Inhibitors for Low Testosterone Levels in Men

Abstract

Formulations for oral transmucosal compositions that include aromatase inhibitors (AIs) in combination with transmucosal absorption enhancers are disclosed. Disclosed oral transmucosal compositions may be for immediate release or slow release, and may be administered to increase bloodstream testosterone levels and thereby reduce symptoms of testosterone deficiency. Disclosed oral transmucosal compositions may include liquid dosage forms, solid dosage forms, and chewing gums. Further dosage forms may include mucoadhesive thin strips, thin films, tablets, patches, and tapes, among others. Other dosage forms may be: mucoadhesive liquids such as gel-forming liquid; gel-forming; semisolids; and gel-forming powders, among other dosage forms that exhibit mucoadhesive properties, and provide oral transmucosal delivery of AIs. Disclosed oral transmucosal compositions may allow the delivery of AIs directly into the patient's bloodstream, thus providing high bioavailability of AIs; therefore, required dose may be lower. Additionally, adjustments of AIs dosages may be achieved when using disclosed oral transmucosal compositions.

1 . A method of oral transmucosal delivery of aromatase inhibitors into a patient's bloodstream comprising administering a composition comprising at least one aromatase inhibitor and a transmucosal absorption enhancer,
 wherein the aromatase inhibitor bypasses hepatic metabolism, and   wherein in the patient is a male with low testosterone levels.   
     
     
         2 . The method of  claim 1 , wherein the aromatase inhibitor is a selective aromatase inhibitor. 
     
     
         3 . The method of  claim 2 , wherein the selective aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, and combinations thereof. 
     
     
         4 . The method of  claim 1 , wherein the aromatase inhibitor is a non-selective aromatase inhibitor. 
     
     
         5 . The method of  claim 4 , wherein the non-selective aromatase inhibitor is selected from the group consisting of aminoglutehimide, testolactone, and combinations thereof. 
     
     
         6 . The method of  claim 1 , wherein the transmucosal absorption enhancer is selected from the group consisting of an enzyme inhibitor; a chitosan or derivative thereof; a cylcodextrin; a bile salt; a chelating agent; a fatty acid or derivatives thereof; a lecithin; a phospholipid; a sulfoxide; urea or derivative thereof; and a surfactant. 
     
     
         7 . The method of  claim 1 , wherein the composition further comprises a mucoadhesive polymer. 
     
     
         8 . The method of  claim 1 , wherein the composition is administered to a sublingual, buccal, gingival, or palatal site. 
     
     
         9 . The method of  claim 8 , wherein the composition is administered to a sublingual site in a dosage form selected from the group consisting of a solution, emulsion, suspension, liquid spray and tablet. 
     
     
         10 . The method of  claim 8 , wherein the composition is administered to a buccal site in a dosage form selected from the group consisting of a buccal troche. 
     
     
         11 . The method of  claim 1 , wherein the composition is formulated as a chewing gum. 
     
     
         12 . The method of  claim 3 , wherein the composition administered is (a) about 0.05 mg/day to about 1.0 mg/day of anastrozole; (b) about 10 mg/day to about 50 mg/day of exemestane; or (c) about 0.025 mg/day to about 5.0 mg/day of letrozole. 
     
     
         13 . The method of  claim 1 , wherein the composition further comprises an additive selected from the group consisting of diluents, binders, disintegrants, glidants, lubricants, thickening agents, pH adjusters, preservatives, sweetners, flavors, colors, effervescent agents, stabilizing agents, antioxidants, surfactants, and combinations thereof. 
     
     
         14 . A composition consisting of (a) at least one aromatase inhibitor; (b) a transmucosal absorption enhancer; (c) a vehicle; and (d) optionally, one or more additives. 
     
     
         15 . The composition of  claim 14 , wherein the aromatase inhibitor is a selective aromatase inhibitor. 
     
     
         16 . The composition of  claim 15 , wherein the selective aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, and combinations thereof. 
     
     
         17 . The composition of  claim 14 , wherein the aromatase inhibitor is a non-selective aromatase inhibitor. 
     
     
         18 . The composition of  claim 17 , wherein the non-selective aromatase inhibitor is selected from the group consisting of aminoglutehimide, testolactone, and combinations thereof. 
     
     
         19 . The composition of  claim 14  further consisting of a mucoadhesive polymer. 
     
     
         20 . A composition comprising:
 (a) about 0.25 to about 2.5 mg letrozole;   (b) about 1-5% gelatin;   (c) about 1-5% pectin;   (d) about 1-10% sodium carboxymethylcellulose;   (e) about 0.1-5% xanthan gum;   (f) 1-10% polyethyleneglycol;   (g) a penetration enhancer; and   (h) a plasticized base.