Oral formulations of kappa opioid receptor agonists

Abstract

The invention provides formulations for oral delivery of a therapeutic agent wherein the formulation comprises a kappa opioid receptor agonist and an absorption enhancer, the absorption enhancer includes a medium chain fatty acid or a salt of a medium chain fatty acid; and a medium chain fatty acid glyceride. The kappa opioid receptor agonist may be embedded in an oligosaccharide, such as trehalose. Also provided are capsules containing the oral formulations of the kappa opioid receptor agonists and the absorption enhancer of the invention and methods use of these formulations for the prophylaxis and treatment of variety of kappa opioid receptor-associated diseases and conditions such as pain, pruritus and inflammation; the method comprising administering to the mammal the formulation comprising the kappa opioid receptor agonist and an absorption enhancer.

What is claimed is: 
     
         1 . A formulation for oral delivery of a kappa opioid receptor agonist, the formulation comprising:
 the kappa opioid receptor agonist and an absorption enhancer, wherein the absorption enhancer comprises:
 (a) a medium chain fatty acid or a salt of a medium chain fatty acid; 
 (b) a medium chain fatty acid glyceride; or 
 (c) (i) a medium chain fatty acid or a salt of a medium chain fatty acid and (ii) a medium chain fatty acid glyceride. 
   
     
     
         2 . The formulation according to  claim 1 , wherein kappa opioid receptor agonist is selected from the group consisting of:
 (i) CR845 having the formula:
                     
 D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH; 
   (ii) to asimadoline (N-[(1S)-2-[(3S)-3-hydroxy-pyrrolidin-1-yl]-1-phenylethyl]-N-methyl-2,2-diphenylacetamide), and   (iii) nalfurafine ((2E)-N-[(5α,6β)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxymorphinan- 6-yl]-3-(3-furyl)-N-methylacrylamide).   
     
     
         3 . The formulation according to  claim 1 , wherein the medium chain fatty acid comprises capric acid and/or a capric acid salt. 
     
     
         4 . The formulation according to  claim 1 , wherein the medium chain fatty acid glyceride comprises a medium chain fatty acid triglyceride. 
     
     
         5 . The formulation according to  claim 4 , wherein the medium chain triglyceride is selected from the group consisting of Miglyol® 810, Miglyol® 812, Capmul® MCM, Captex® 100, Captex® 200, Captex® 300, Captex® 355, Neobee® 1053, Neobee® M5, Capmul® PGMC, Tween® 60, Tween® 80, Lubrisol® ALF, Kolliphor® EL, Kolliphor® HS 15, and Gelucare® 44/14. 
     
     
         6 . The formulation according to  claim 2 , wherein the formulation further comprises a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
         7 . A capsule containing a formulation for oral delivery of a therapeutic agent, wherein the formulation comprises a kappa opioid receptor agonist and an absorption enhancer, wherein the absorption enhancer comprises: a medium chain fatty acid or a salt of a medium chain fatty acid; and a medium chain fatty acid glyceride, wherein the capsule is an enteric coated capsule or a capsule having intrinsic enteric properties. 
     
     
         8 . A bioactive composition comprising a kappa opioid receptor agonist embedded in an oligomeric saccharide comprising one or more glucose monomers forming a particle comprising a stabilized kappa opioid receptor agonist. 
     
     
         9 . The bioactive composition according to  claim 8 , wherein the kappa opioid receptor agonist comprises CR845 and the oligomeric saccharide comprises trehalose. 
     
     
         10 . The bioactive composition according to  claim 9 , further comprising one or more of a salt of a carboxylic acid, an absorption enhancer, a binding agent, a chelating agent and a pharmaceutically acceptable carrier or excipient. 
     
     
         11 . The bioactive composition according to  claim 10 , wherein the salt of the carboxylic acid comprises sodium citrate, the chelating agent comprises EDTA and the absorption enhancer comprises lauroyl L-carnitine. 
     
     
         12 . The bioactive composition according to  claim 9 , further comprising one or more medium chain fatty acid or one or more salt of a medium chain fatty acids, and a medium chain fatty acid glyceride. 
     
     
         13 . A pharmaceutically acceptable tablet, caplet, capsule, powder, or liquid suspension comprising the bioactive composition according to  claim 9 . 
     
     
         14 . The bioactive composition according to  claim 13 , wherein the liquid suspension further comprises one or more of an absorption enhancer, and a pharmaceutically acceptable (C 8 -C 12 ) short chain fatty acid triglyceride. 
     
     
         15 . The bioactive composition according to  claim 14 , further comprising one or more of an emulsifying agent, a salt of a carboxylic acid, an absorption enhancer, a binding agent and a pharmaceutically acceptable carrier or excipient.