Particles containing an opioid receptor antagonist and methods of use

Abstract

Particles comprising an opioid receptor antagonist as well as methods of their use and methods of their preparation are provided herein. Such particles may be used for treating and preventing opioid-induced side effects in patients, and may be provided to chronic opioid users as well.

1 . A particle comprising an opioid receptor antagonist and at least one additive, wherein the diameter of the particle is between about 30-1000 nm. 
     
     
         2 . The particle of  claim 1 , wherein the at least one additive is a polymer. 
     
     
         3 . (canceled) 
     
     
         4 . The particle of  claim 1 , wherein the opioid receptor antagonist is a peripheral opioid antagonist. 
     
     
         5 . The particle of  claim 1 , wherein the opioid receptor antagonist is a quaternary or tertiary morphinan derivative, a piperidine-N-alkylcarboxylate, a carboxy-normorphinan derivative, or a quaternary benzomorphan. 
     
     
         6 . The particle of  claim 5 , wherein the quaternary morphinan is a quaternary salt of N-methylnaltrexone, N-methylnaloxone, N-methylnalorphine, N-diallylnormorphine, N-allyllevellorphan, or N-methylnalmefene. 
     
     
         7 . The particle of  claim 5 , wherein the peripheral opioid receptor antagonist is methylnaltrexone. 
     
     
         8 - 12 . (canceled) 
     
     
         13 . The particle of  claim 1 , wherein at least one additive is a hydrophilic additive. 
     
     
         14 . The particle of  claim 13 , wherein the particle comprises at least two hydrophilic additives. 
     
     
         15 . The particle of  claim 13 , wherein one hydrophilic additive is positively charged at acidic and neutral pH. 
     
     
         16 . The particle of  claim 15 , wherein the hydrophilic additive that is positively charged at acidic and neutral pH is further defined as chitosan. 
     
     
         17 . The particle of  claim 13 , wherein one hydrophilic additive is negatively charged at acidic and neutral pH. 
     
     
         18 . The particle of  claim 17 , wherein the hydrophilic additive that is negatively charged at acidic and neutral pH is further defined as pentasodium tripolyphosphate (TPP). 
     
     
         19 - 20 . (canceled) 
     
     
         21 . The particle of  claim 14 , wherein the two hydrophilic additives are further defined as chitosan and TPP. 
     
     
         22 - 26 . (canceled) 
     
     
         27 . The particle of  claim 1 , wherein the particle is comprised in an enteric coating to form an enterically coated particle, wherein the enterically coated particle has a diameter of about 30-1000 nm. 
     
     
         28 - 32 . (canceled) 
     
     
         33 . The particle of  claim 27 , wherein the enteric coating comprises both a Eudragit® polymer and a Myvacet™ distilled acetylated monoglyceride. 
     
     
         34 - 35 . (canceled) 
     
     
         36 . A pharmaceutical composition comprising the particle of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         37 - 40 . (canceled) 
     
     
         41 . The pharmaceutical composition of  claim 36 , further defined as a time release pharmaceutical composition, wherein the time release pharmaceutical composition is formulated to release the opioid receptor antagonist over time. 
     
     
         42 . A pharmaceutical composition comprising the enterically coated particle of  claim 27  and a pharmaceutically acceptable carrier. 
     
     
         43 - 52 . (canceled) 
     
     
         53 . A method of making a plurality of particles of  claim 1 , wherein each particle comprises an opioid receptor antagonist, the method comprising:
 (a) dissolving an opioid receptor antagonist in water to form a dissolved opioid receptor antagonist solution;   (b) adding the dissolved opioid receptor antagonist solution to a solution comprising a first additive to form an opioid receptor antagonist/first additive solution; and   (c) adding the opioid receptor antagonist/first additive solution to a solution comprising a second additive, such that the plurality of particles is made.   
     
     
         54 - 57 . (canceled) 
     
     
         58 . A heteroparticulate particle comprising:
 (a) an inner, larger particle comprising an opioid receptor antagonist; and   (b) an outer, smaller particle comprising at least one surfactant and at least one additive,   
       wherein the diameter of the outer particle is between about 100-500 nm. 
     
     
         59 . The heteroparticulate particle of  claim 58 , wherein the opioid receptor antagonist is a quaternary morphinan. 
     
     
         60 . The heteroparticulate particle of  claim 59 , wherein the quaternary morphinan is further defined as methylnaltrexone. 
     
     
         61 . The heteroparticulate particle of  claim 58 , wherein the inner, larger particle is further defined as a microparticle. 
     
     
         62 . The heteroparticulate particle of  claim 58 , wherein the inner, larger particle of part (a) further comprises a loading agent. 
     
     
         63 - 65 . (canceled) 
     
     
         66 . The heteroparticulate particle of  claim 58 , wherein the outer, smaller particle is formulated as an enteric coating. 
     
     
         67 - 73 . (canceled) 
     
     
         74 . A heteroparticulate particle comprising:
 (a) an inner phase comprising one larger particle, wherein the larger particle comprises an opioid receptor antagonist and a loading agent; and   (b) an outer phase comprising a plurality of smaller particles, wherein each smaller particle comprises Epikuron 170®, Tween® 80, a poly(caprolactone) polymer and a Eudragit® polymer.   
     
     
         75 . The heteroparticulate particle of  claim 74 , wherein the opioid receptor antagonist is further defined as methylnaltrexone. 
     
     
         76 - 127 . (canceled)