Hyperbranched polymeric micelles for encapsulation and delivery of hydrophobic molecules

Abstract

Polymeric micelles for encapsulation of hydrophobic molecules are provided. Methods and formulations for delivering hydrophobic molecules to a host via these micelles are also provided. Methods of stabilizing liposomes or lipid based formulations by addition of polymeric micelles are also provided.

What is claimed is:  
     
         1 . A polymer having a structure selected from the group consisting of:  
       R(—O—R 1 ), and R(—NH—R 1 ) x    wherein R(—O—) x  is a polyol moiety and R(—NH) x  is a polyamine moiety, with x being between 2 and 10, inclusive, and each R 1  independently has the structure:                          wherein                           is a divalent amino acid moiety with R 2  being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0;    wherein                           is a divalent dicarboxylic acid moiety in which R 3  is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about 10 hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with from 3 to about 24 carbon atom carboxylic acids; and    wherein R 4  is a poly(alkylene oxide) having the structure:    R 5 —(R 6 —O—) a —R 6 -Q-    with R 5  being selected from the group consisting of 1 to 40 carbon atom alkyl groups, —OH, —OR 7 , —NH 2 , —NHR 7 , —NHR 7 R 8 , —C—OH, —C—OR 7 , —C—O—C—R 7 , —C—NH 2 , —C—NHR 7  and —C—NR 7 R 8 ;    R 6 , R 7  and R 8  being independently selected from the group consisting of 2 to 40 carbon atom, straight-chain or branched alkylene groups;    Q being a divalent linkage moiety; and    a being between 2 and 110, inclusive;    with the proviso that when y is 0 and R is a 1,1,1-tris(hydroxyphenyl)ethane moiety, the divalent dicarboxylic acid moiety is not an acylated mucic acid moiety.    
     
     
         2 . The polymer of  claim 1 , wherein x is 3 or 4.  
     
     
         3 . The polymer of  claim 2 , having the structure R(—NH—R 1 ) x , wherein R(—NH—) x  a polyamine moiety.  
     
     
         4 . The polymer of  claim 2 , having the structure R(—O—R 1 ) x , wherein R(—O—) x  is a polyol moiety.  
     
     
         5 . The polymer of  claim 4 , wherein said polyol moiety is an aromatic polyol moiety.  
     
     
         6 . The polymer of  claim 5 , wherein said polyol moiety is a 1,1,1-tris(hydroxyphenyl)ethane moiety.  
     
     
         7 . The polymer of  claim 1 , wherein every hydroxyl group of said divalent dicarboxylic acid moiety is acylated with a 6 to 24 carbon atom carboxylic acid group.  
     
     
         8 . The polymer of  claim 7 , wherein y is 0.  
     
     
         9 . The polymer of  claim 7 , wherein said divalent dicarboxylic acid mucic acid moiety is a mucic acid moiety.  
     
     
         10 . The polymer of  claim 4 , wherein said polyol moiety is an aliphatic or cycloaliphatic polyol moiety.  
     
     
         11 . The polymer of  claim 4 , wherein said polyol moiety is a cyclic crown ether or cyclodextrin moiety.  
     
     
         12 . The polymer of  claim 1 , wherein said poly(alkylene oxide) is a methoxy-terminated poly(ethylene glycol) and Q is —NH—.  
     
     
         13 . The polymer of  claim 1 , wherein Q is —O—, or forms an anhydride linkage.  
     
     
         14 . A hydrophobic molecule encapsulated in a polymer, said polymer having a structure selected from the group consisting of:  
       R(—O—R 1 ) x  and R(—NH—R 1 ) x    wherein R(—O—) x  is a polyol moiety and R(—NH—) x  is a polyamine moiety, with x being between 2 and 10, inclusive, and each R 1  independently has the structure:                          wherein                           is a divalent amino acid moiety with R 2  being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0;    wherein                           is a divalent dicarboxylic acid moiety in which R 3  is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms, substituted with a total of from 1 to about hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with from 3 to about 24 carbon atom carboxylic acids; and    wherein R 4  is a poly(alkylene oxide) having the structure:    R 5 —(—R 6 —O—) a —R 6 -Q    with R 5  being selected from the group consisting of 1 to 40 carbon atom alkyl groups, —OH, —OR 7 , —NH 2 , —NHR 7 , —NHR 7 R 8 , —C—OH, —C—OR 7 , —C—O—C—R 7 , —C—NH 2 , —C—NHR 7 , and —C—NR 7 R 8 ;    R 6 , R 7  and R 8  being independently selected from the group consisting of 2 to 40 carbon atom, straight-chain or branched alkylene groups;    Q being a divalent linkage moiety; and    a being between 2 and 110, inclusive;    with the proviso that when y is 0 and R is a 1,1,1-tris (hydroxyphenyl)ethane moiety, the divalent dicarboxylic acid moiety is not a mucic acid moiety acylated with carboxylic acids having less than 6 carbon atoms.    
     
     
         15 . The encapsulate of  claim 14 , wherein said hydrophobic molecule has biological or pharmaceutical activity.  
     
     
         16 . The encapsulate of  claim 14 , wherein said hydrophobic molecule is a fragrance, dye, protein or vitamin.  
     
     
         17 . The encapsulate of  claim 14 , having the structure R(—O—R 1 ) x , wherein R(—O—) x , is a polyol moiety.  
     
     
         18 . The encapsulate of  claim 17 , wherein said polyol moiety is a 1,1,1-tris(hydroxyphenyl)ethane moiety.  
     
     
         19 . The encapsulate of  claim 17 , wherein all of said hydroxyl groups of said dicarboxylic acid moiety are acylated with carboxylic acids having from 6 to 24 carbon atoms.  
     
     
         20 . The encapsulate of  claim 19 , wherein y is 0.  
     
     
         21 . The encapsulate of  claim 19 , wherein said divalent dicarboxylic acid moiety is a mucic acid moiety.  
     
     
         22 . The encapsulate of  claim 14 , wherein said poly(alkylene oxide) is a methoxy-terminated poly(ethylene glycol) and Q is —NH—.  
     
     
         23 . A formulation comprising the encapsulate of  claim 14  and an acceptable vehicle.  
     
     
         24 . The formulation of  claim 23  wherein the accetable vehicle comprises an aqueous solution, suspension, dispersion, emollient, lotion, cream, salve, balm or ointment.  
     
     
         25 . The formulation of  claim 23 , wherein the concentration of said encapsulate in said formulation is between about 10 −10  M and 10 6  M.  
     
     
         26 . The formulation of  claim 25 , wherein said encapsulate concentration is between about 10 −8  M and about 10 6  M.  
     
     
         27 . The formulation of  claim 23 , wherein the hydrophobic molecule of the encapsulate has biological or pharmaceutical activity.  
     
     
         28 . The formulation of  claim 23 , wherein the hydrophobic molecule of the encapsulate is a dye, fragrance, protein, or vitamin.  
     
     
         29 . A method of delivering a hydrophobic molecule to a host comprising administering to the host an encapsulate of  claim 14 .  
     
     
         30 . The method of  claim 29  wherein the host is an animal and the encapsulate is administered orally, subcutaneously, intramuscularly, intraperitoneally or intravenously.  
     
     
         31 . The method of  claim 29 , wherein the encapsulate is administered topically to the host.  
     
     
         32 . The method of  claim 29  wherein the hydrophobic molecule of the encapsulate is biologically or pharmaceutically active.  
     
     
         33 . The method of  claim 29  wherein the hydrophobic molecule of the encapsulate is a dye, fragrance, protein or vitamin and the encapsulate is administered topically.  
     
     
         34 . A transdermal device for the controlled release of a biologically or pharmaceutically active agent to the skin or mucosa of an animal, said device comprising a laminate of: 
 (a) a reservoir layer having a first surface and a second surface, and having the encapsulate of  claim 15  incorporated therein;    (b) a backing layer having an inner surface and an outer surface, wherein said second surface of said reservoir layer and said inner surface of said backing layer are laminated together so that said encapsulate cannot permeate from said second surface of said reservoir layer through said outer surface of said backing layer; and    (c) a pressure sensitive adhesive layer coated on said first surface of said reservoir layer or said inner surface of said backing layer for affixing said laminate to said skin or mucosa of said host, so that said encapsulate is capable of being continuously released from said first surface of said reservoir layer thereto.    
     
     
         35 . The device of  claim 34 , wherein said backing layer comprises one or more layers of an occlusive material.  
     
     
         36 . A method of stabilizing a liposome or lipid-based formulation comprising adding to the liposome or lipid-based formulation a polymer of  claim 1.