Methods for enhanced epithelial permeation of y2 receptor-binding peptides for treating and preventing obesity

Abstract

A method for treating obesity, inducing weight-loss, or inducing satiety in a mammal comprising administering intranasally to the mammal a therapeutically effective amount of a pharmaceutical composition comprising PYY(3-36), a phosphatidylcholine or diglyceride, and a cyclodextrin, wherein the phosphatidylcholine or diglyceride and the cyclodextrin are present in an amount sufficient to enhance epithelial permeation.

1 . A method for treating obesity, inducing weight-loss, or inducing satiety in a mammal comprising administering intranasally to the mammal a therapeutically effective amount of a pharmaceutical composition comprising PYY(3-36), a phosphatidylcholine or diglyceride, and a cyclodextrin, wherein the phosphatidylcholine or diglyceride and the cyclodextrin are present in an amount sufficient to enhance epithelial permeation.  
     
     
         2 . The method of  claim 1 , wherein the phosphatidylcholine is L-α-phosphatidylcholine didecanoyl (DDPC).  
     
     
         3 . The method of  claim 1 , wherein the cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and methyl-β-cyclodextrin.  
     
     
         4 . The method of  claim 3 , wherein the cyclodextrin is methyl-β-cyclodextrin.  
     
     
         5 . The method of  claim 1 , wherein the composition is an aqueous composition having a pH of from about 3 to about 6.  
     
     
         6 . The method of  claim 5 , wherein the pH is 5.0±0.5.  
     
     
         7 . The method of  claim 1 , the composition further comprising a polyol.  
     
     
         8 . The method of  claim 7 , wherein the polyol is selected from the group consisting of sucrose, mannitol, sorbitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, trehalose, D-galactose, lactulose, cellobiose, gentibiose, glycerin and polyethylene glycol.  
     
     
         9 . The method of  claim 7 , wherein the polyol is sorbitol.  
     
     
         10 . The method of  claim 7 , further comprising a chelating agent.  
     
     
         11 . The method of  claim 10 , wherein the chelating agent is ethylene diamine tetraacetic acid (EDTA) or ethylene glycol tetraacetic acid (EGTA).  
     
     
         12 . The method of  claim 10 , wherein the chelating agent is ethylene diamine tetraacetic acid (EDTA).  
     
     
         13 . The method of  claim 1  wherein the mammal is a human.  
     
     
         14 . The method of  claim 1 , wherein the administration results in an increase in concentration of PYY(3-36) in the blood of the mammal by at least 5 pmol per liter of plasma to about 60 pmol per liter of plasma.  
     
     
         15 . The method of  claim 1 , wherein the administration is from 30 to 90 minutes before a feeding of the mammal.  
     
     
         16 . The method of  claim 1 , wherein the amount of PYY(3-36) is from 30 μg to 250 μg.  
     
     
         17 . The method of  claim 1 , wherein the amount of PYY(3-36) is from about 0.1 pmol to about 5.0 pmol per kilogram body weight of the mammal.  
     
     
         18 . The method of  claim 1 , wherein the composition is formulated for nasal mucosal delivery to a mammal.  
     
     
         19 . The method of  claim 1 , wherein the composition is formulated as an intranasal spray or powder.  
     
     
         20 . The method of  claim 1 , wherein the composition following mucosal administration to the mammal yields a peak concentration (C max ) of PYY(3-36) in a central nervous system (CNS) tissue or fluid or in a blood plasma of the mammal that is 25% or greater as compared to a peak concentration of PYY(3-36) in a CNS tissue or fluid or in a blood plasma following subcutaneous injection of an equivalent concentration or dose of PYY(3-36).  
     
     
         21 . The method of  claim 1 , wherein the composition following mucosal administration to the mammal yields an area under concentration curve (AUC) of PYY(3-36) in a CNS tissue or fluid or in a blood plasma of the mammal that is 25% or greater compared to an AUC of PYY(3-36) in a CNS tissue or fluid or in a blood plasma following subcutaneous injection of an equivalent concentration or dose of PYY(3-36).  
     
     
         22 . The method of  claim 1 , wherein the composition following mucosal administration to the mammal yields a time to maximal concentration (t max ) of PYY(3-36) in a CNS tissue or fluid or in a blood plasma of the mammal between about 0.1 to 1.0 hours.  
     
     
         23 . The method of  claim 1 , further comprising one or more sustained release-enhancing agent(s).  
     
     
         24 . The method of  claim 23 , wherein the sustained release-enhancing agent is polyethylene glycol (PEG).