Soluble Hydrophobic Core Carrier Compositions for Delivery of Therapeutic Agents, Methods of Making and Using the Same

Abstract

The present invention relates to a soluble hydrophobic-core carrier composition comprising (i) a linear polymeric backbone; (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone and (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone. In certain embodiments, the weight ratio of hydrophilic protective chains to hydrophobic moieties in the carrier is at least 15:1. In other embodiments, at least 90% of the residues of the polymeric backbone are coupled to a hydrophilic polymeric protective chain or a hydrophobic moiety. In other embodiments, the composition further comprises (iv) a hydrophobic load molecule dissociably linked to the hydrophobic moiety of the carrier.

What is claimed is: 
     
         1 . A soluble hydrophobic-core carrier composition comprising:
 (i) a linear polymeric backbone;   (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons; and   (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone;   wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water.   
     
     
         2 . The composition of  claim 1  wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is at least 15:1, at least 17:1, at least 20:1, at least 50:1 or at least 100:1. 
     
     
         3 . The composition of  claim 1  wherein at least 90% of the residues of the polymeric backbone are derivatized with either hydrophilic protective chains or hydrophobic moieties. 
     
     
         4 . The composition of  claim 1 , wherein the protective side chains comprise polyethylene glycol, polypropylene glycol, a co-polymer of polyethylene glycol, a co-polymer of polypropylene glycol, polysaccharide, or alkoxy derivatives thereof. 
     
     
         5 . The composition in  claim 4 , wherein the alkoxy derivative is methoxypolyethylene glycol, methoxypolypropylene glycol, a methoxylated co-polymer polyethylene glycol and polypropyleneglycol, or ethoxylated polysaccharide. 
     
     
         6 . The composition of  claim 1 , wherein the linear polymeric backbone is selected from a group consisting of polylysine, polyaspartic acid, polyglutamic acid, polyserine, polythreonine, polycysteine, polyglycerol, natural saccharides, aminated polysaccharides, aminated oligosaccharides, polyamidoamine, polyacrylic acids, polyalcohols, sulfonated polysaccharides, sulfonated oligosaccharides, carboxylated polysaccharides, carboxylated oligosaccharides, aminocarboxylated polysaccharides, aminocarboxylated oligosaccharides, carboxymethylated polysaccharides, and carboxymethylated oligosaccharides. 
     
     
         7 . The composition of  claim 1  further comprising:
 (iv) a load molecule dissociably linked to the hydrophobic moiety of the backbone. 
 
     
     
         8 . The composition of  claim 7 , wherein the hydrophilic protective side chains comprise methoxypolyethylene glycol. 
     
     
         9 . The composition of  claim 8 , wherein the polymeric backbone comprises polylysine. 
     
     
         10 . The composition of  claim 9 , wherein the hydrophobic moieties comprise a fatty acid. 
     
     
         11 . The composition of  claim 10 , wherein the load molecule is a therapeutic agent. 
     
     
         12 . The composition of  claim 11 , wherein the therapeutic agent is a hydrophobic peptide, hydrophobic protein, or a hydrophobic drug. 
     
     
         13 . The composition of  claim 11 , wherein the therapeutic agent is GLP-1. 
     
     
         14 . The composition of  claim 11 , wherein the therapeutic agent is selected from GLP-2, leptin, islet amyloid polypeptide and vasoactive intestinal peptide. 
     
     
         15 . The composition of  claim 7 , wherein the linear polymeric backbone is polylysine. 
     
     
         16 . The composition of  claim 7 , wherein the hydrophobic moiety(ies) comprises a fatty acid selected from the range of  6 -carbon fatty acids to  36 -carbon fatty acids. 
     
     
         17 . The composition of  claim 7 , wherein the hydrophobic moiety(ies) comprise a fatty acid with at least one double bond. 
     
     
         18 . The composition of  claim 7 , wherein the hydrophobic moiety(ies) comprises a multi-fatty acid-containing moiety. 
     
     
         19 . The composition of  claim 7 , wherein the hydrophobic moiety(ies) comprises an aromatic ring containing moiety. 
     
     
         20 . The composition of  claim 7 , wherein the therapeutic agent is hydrophobic peptide, hydrophobic protein, and hydrophobic drugs. 
     
     
         21 . The composition of  claim 7 , wherein the therapeutic agent is selected from GLP-1, GLP-2, leptin, islet amyloid polypeptide and vasoactive intestinal peptide. 
     
     
         22 . The composition of  claim 7 , further comprising a targeting molecule covalently linked to the protective side chains. 
     
     
         23 . The composition of  claim 22 , wherein the targeting molecule is selected from a group consisting of an antibody, fragment of an antibody, chimeric antibody, lectins, receptor ligands, proteins, enzymes, peptides, saccharides, quasi substrates of enzymes, cell-surface-binding compounds, and extracellular-matrix-binding compounds. 
     
     
         24 . The composition of  claim 7 , further comprising a second set of protective chain covalently linked to the hydrophobic moiety. 
     
     
         25 . A pharmaceutical composition comprising a composition selected from compositions in  claims 7 - 24 , wherein the load molecule is a therapeutic agent. 
     
     
         26 . A method of making a composition comprising:
 (a) dissolving a polymeric backbone containing residues comprising free amino groups in an aqueous buffer of pH 7-8 to obtain solution A;   (b) activating a carboxyl group or alkyl carboxyl group of a protective chain by mixing it with a carbodiimide reagent in acidic buffer between pH 3-7 to obtain solution B; and   (c) adding solution B to solution A resulting in a solution C containing the polymeric backbone with covalently linked protective chains, wherein the pH of solution C is 7 or above.   
     
     
         27 . A method of making a composition, comprising:
 (a) dissolving in non-aqueous solvent with a tertiary amine, a component comprising a polymeric backbone covalently linked to protective chains, wherein the polymeric backbone comprises residues comprising free amino groups, thereby obtaining solution E;   (b) dissolving in a non-aqueous solvent hydrophobic molecules containing free carboxyl groups and activating the carboxyl groups by adding carbodiimide reagent to obtain solution F; and   (c) adding solution F to solution E to obtain solution G to form covalent linkage between the activated carboxyl groups and the free amine groups; wherein solution E is added to solution G until at least 90% of the residues are linked to protective chains or hydrophobic groups.   
     
     
         28 . A method of making a composition, comprising:
 (a) dissolving in partially-aqueous solvent at pH of 7 to 9 a component comprising a polymeric backbone covalently linked to protective chains, wherein the polymeric backbone comprises residues comprising free amino groups, thereby obtaining solution E,   (b) dissolving in partially-aqueous solvent with pH of 3 to 7, hydrophobic molecules containing free carboxyl groups and activating the carboxyl groups by adding carbodiimide reagent resulting in solution F,   (c) adding solution F to solution E while maintaining the pH of the mixture between 7-8 to obtain solution G, to form covalent linkage between the activated carboxyl groups and the free amine groups; wherein solution E is added to solution G until at least 90% of the residues are linked to protective chains or hydrophobic groups.   
     
     
         29 . A method of loading a composition, comprising:
 (a) dissolving in aqueous or partially-aqueous solvent A soluble hydrophobic-core carrier composition comprising: (i) a linear polymeric backbone; (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons; and (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone; wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water, thereby obtaining solution A.   (b) dissolving the load molecule in aqueous or partially-aqueous solvent to obtain solution B,   (c) mixing solution A with solution B to obtain solution C, incubating solution C for 30 minutes or longer followed by lyophilization or solvent evaporation to obtain a loaded carrier ready to be dissolved into appropriate solvent.   
     
     
         30 . A method of administering a therapeutic molecule to a subject comprising:
 administering to the subject a composition comprising:
 (i) a linear polymeric backbone; 
 (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons; 
 (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone; 
 (iv) a therapeutic molecule dissociably linked to the hydrophobic moiety of the backbone; 
 wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water. 
   
     
     
         31 . The method of  claim 30  wherein the composition is administered subcutaneously or intramuscularly. 
     
     
         32 . A pharmaceutical composition comprising:
 (a) a composition comprising:
 (i) a linear polymeric backbone; 
 (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons; 
 (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone; 
 (iv) a therapeutic molecule dissociably linked to the hydrophobic moiety of the backbone; 
   wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water; and   (b) a pharmaceutically acceptable carrier;   wherein the composition is in unit dose form.