Oligosaccharide formulations of kappa opioid receptor agonists

Abstract

The invention provides formulations for oral delivery of a therapeutic wherein the formulation comprises a kappa opioid receptor agonist, an oligosaccharide stabilizing agent and an optional absorption enhancer. The kappa opioid receptor agonist may be coated with, embedded in or mixed with an oligosaccharide, such as trehalose. Also provided are capsules containing the oral formulations of the kappa opioid receptor agonists, the oligosaccharide and the absorption enhancer of the invention. The invention further provides methods of manufacture of the formulations and methods of their use for the prophylaxis, inhibition and treatment of variety of kappa opioid receptor-associated diseases and conditions such as pain, pruritus and inflammation. The methods of use include administering to the mammal the formulation of the kappa opioid receptor agonist, oligosaccharide and optional absorption enhancers.

1 . A formulation for oral delivery of a kappa opioid receptor agonist, the formulation comprising,
 a particle including a kappa opioid receptor agonist and an oligosaccharide, wherein kappa opioid receptor agonist is selected from the group consisting of:
 (1) CR845 having the formula: 
   
       
         
           
           
               
               
           
         
         D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH or a hydrate, salt, acid salt or acid salt hydrate thereof;
 (ii) 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); 
 
         and wherein the oligosaccharide is selected from the group consisting of trehalose, sucrose, maltose, mannose, lactose and inulin. 
       
     
     
         2 . The formulation for oral delivery of a kappa opioid receptor agonist according to  claim 1 , wherein the kappa opioid receptor agonist is embedded in the oligosaccharide included in the particle. 3 The formulation for oral delivery of a kappa opioid receptor agonist according to  claim 2 , wherein the kappa opioid receptor agonist embedded in the oligosaccharide included in the particle is formed on a bead or microbead. 
     
     
         4 . The formulation according to  claim 1 , wherein the kappa opioid receptor agonist is CR845 and the oligosaccharide is trehalose. 
     
     
         5 . The formulation according to  claim 4 , further comprising one or more absorption enhancers selected from the group consisting of sodium caprate, lauroyl L-carnitine, Tween® 80. Tween® 60, Labrasol® ALF, Kolliphor® EL, Kolliphor® HS 15, Gelucare® 44/14, and a quaternary ammonium salt. 
     
     
         6 . The formulation according to  claim 4 , wherein the formulation further comprises a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
         7 . The formulation according to  claim 4 , 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. 
     
     
         8 . The formulation according to  claim 7 , wherein the salt of the carboxylic acid comprises a citrate salt, the absorption enhancer comprises lauroyl L-carnitine, and the chelating agent comprises EDTA. 
     
     
         9 . A pharmaceutically acceptable tablet, caplet, capsule, powder, slurry, liquid suspension or gel comprising the formulation according to  claim 4 . 
     
     
         10 . The pharmaceutically acceptable tablet, caplet, capsule, or powder according to  claim 9 , wherein the tablet, caplet, capsule, or powder is:
 an enteric coated tablet, caplet, capsule, or powder; or   a tablet, caplet, capsule, or powder with a coating having intrinsic enteric properties.   
     
     
         11 . A method of manufacture of a formulation for oral delivery of a kappa opioid receptor agonist comprising:
 (i) spray drying a mixture comprising a kappa opioid receptor agonist and an oligosaccharide to form particles of kappa opioid receptor agonist embedded in the oligosaccharide; or   (ii) coating a mixture comprising a kappa opioid receptor agonist and an oligosaccharide onto one or more beads or microbeads forming one or more beads or microbeads coated with the kappa opioid receptor agonist embedded in the oligosaccharide;   
       wherein the oligosaccharide is selected from the group consisting of trehalose, sucrose, maltose, mannose, lactose and inulin. 
     
     
         12 . The method according to  claim 11 , wherein the oligosaccharide is trehalose. 
     
     
         13 . The method according to  claim 12 , further comprising:
 encapsulating the one or more beads or microbeads coated with the kappa opioid receptor agonist embedded in the oligosaccharide in a capsule and coating the capsule with an enteric coating; or   encapsulating the one or more beads or microbeads coated with the kappa opioid receptor agonist embedded in the oligosaccharide in a capsule having intrinsic enteric properties.   
     
     
         14 . The method according to  claim 12 , further comprising coating the one or more beads or microbeads coated with the kappa opioid receptor agonist embedded in the oligosaccharide with an enteric coating, forming one or more enteric coated beads or microbeads coated with the kappa opioid receptor agonist embedded in the oligosaccharide. 
     
     
         15 . The method according to  claim 14 , further comprising encasing the one or more enteric coated beads or microbeads coated with the kappa opioid receptor agonist embedded in the oligosaccharide in a capsule.