Cyclodextrin-based polymers for delivering the therapeutic agents covalently bound thereto

Abstract

The present invention relates to novel compositions of therapeutic cyclodextrin containing polymeric compounds designed as a carrier for small molecule therapeutics delivery and pharmaceutical compositions thereof. These cyclodextrin-containing polymers improve drug stability and solubility, and reduce toxicity of the small molecule therapeutic when used in vivo. Furthermore, by selecting from a variety of linker groups and targeting ligands the polymers present methods for controlled delivery of the therapeutic agents. The invention also relates to methods of treating subjects with the therapeutic compositions described herein. The invention further relates to methods for conducting pharmaceutical business comprising manufacturing, licensing, or distributing kits containing or relating to the polymeric compounds described herein.

1 . A compound represented by Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         P represents a linear or branched polymer chain; 
         CD represents a cyclodextrin moiety; 
         L 1 , L 2  and L 3 , independently for each occurrence, may be absent or represent a linker group; 
         D, independently for each occurrence, represents a therapeutic agent or a prodrug thereof; 
         T, independently for each occurrence, represents a targeting ligand or precursor thereof; 
         a, m and v, independently for each occurrence, represent integers in the range of 1 to 10; 
         n and w, independently for each occurrence, represent an integer in the range of 0 to about 30,000; and 
         b represents an integer in the range of 1 to about 30,000; and 
         wherein either P comprises cyclodextrin moieties or n is at least 1. 
       
     
     
         2 . The compound of  claim 1 , wherein the polymer chain comprises n′ units of U, wherein n′ represents an integer in the range of 1 to about 30,000; and U is represented by the general formula: 
       
         
           
           
               
               
           
         
         wherein 
         CD represents a cyclodextrin molecule, or derivative thereof; 
         L 4 , L 5 , L 6 , and L 7 , independently for each occurrence, may be absent or represent a linker group; 
         D and D′, independently for each occurrence, represent the same or different therapeutic agent or prodrugs thereof; 
         T and T′, independently for each occurrence, represents the same or different targeting ligand or precursor thereof; 
         f and y, independently for each occurrence, represent an integer in the range of 1 and 10; and 
         g and z, independently for each occurrence, represent an integer in the range of 0 and 10. 
       
     
     
         3 . A compound represented by Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 P represents a monomer unit of a polymer; 
 T, independently for each occurrence, represents a targeting ligand or a precursor thereof; 
 L 6 , L 7 , L 8 , L 9 , and L 10 , independently for each occurrence, may be absent or represent a linker group; 
 CD, independently for each occurrence, represents a cyclodextrin moiety or a derivative thereof; 
 D, independently for each occurrence, represents a therapeutic agent or a prodrug form thereof; 
 m, independently for each occurrence, represents an integer in the range of 1 to 10; 
 o represents an integer in the range of 1 to about 30,000; and 
 p, n, and q, independently for each occurrence, represent an integer in the range of 0 to 10, 
 wherein CD and D are each present at least once in the compound. 
 
     
     
         4 . A compound represented by Formula III: 
       
         
           
           
               
               
           
         
       
       wherein
 CD represents a cyclodextrin molecule, or derivative thereof; 
 L 4 , L 5 , L 6 , and L 7 , independently for each occurrence, may be absent or represent a linker group; 
 D and D′, independently for each occurrence, represent the same or different therapeutic agent or prodrugs thereof; 
 T and T′, independently for each occurrence, represent the same or different targeting ligand or precursor thereof; 
 f and y, independently for each occurrence, represent an integer in the range of 1 and 10; 
 h represents an integer in the range of 1 to about 30,000; and 
 g and z, independently for each occurrence, represent an integer in the range of 0 and 10, 
 wherein at least one occurrence of g represents an integer greater than 0. 
 
     
     
         5 . The compound of  claim 1 , wherein the linker group represents a hydrocarbylene group wherein one or more methylene groups is optionally replaced by a group Y (provided that none of the Y groups are adjacent to each other), wherein each Y, independently for each occurrence, is selected from, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or —O—, C(═X) (wherein X is NR 1 , O or S), —OC(O)—, —C(═O)O, —NR 1 CO—, —C(O)NR 1 —, —S(O) n — (wherein n is 0, 1, or 2), —OC(O)—NR 1 , —NR 1 —C(O)—NR 1 —, —NR 1 —C(NR 1 )—NR 1 —, and —B(OR 1 )—; and R 1 , independently for each occurrence, represents H or a lower alkyl. 
     
     
         6 . The compound of  claim 1 , wherein the linker group represents an amino acid or peptide, or derivative thereof. 
     
     
         7 . The compound of  claim 1 , wherein said therapeutic agent is a small molecule, a peptide, a protein or a polymer that has therapeutic activity. 
     
     
         8 . The compound of  claim 1 , wherein the therapeutic agent is hydrophobic (log P>0.4, 0.6, 0.8, 1). 
     
     
         9 . The compound of  claim 1 , wherein the therapeutic agent has low aqueous solubility. 
     
     
         10 . The compound of  claim 1 , wherein therapeutic agent or targeting ligand is covalently-bonded to the linker group via biohydrolyzable bond. 
     
     
         11 . The compound of  claim 10 , wherein the biohydrolyzable bond is selected from an ester, amide, carbonate, or a carbamate. 
     
     
         12 . The compound of  claim 1 , wherein therapeutic agent is selected from an anti-cancer, anti-fungal, anti-bacterial, anti-mycotic, or anti-viral therapeutic. 
     
     
         13 . The compound of  claim 1 , wherein the therapeutic agent is a receptor agonist. 
     
     
         14 . The compound of  claim 1 , wherein the therapeutic agent is a receptor antagonist. 
     
     
         15 . The compound of  claim 1 , wherein the compound is biodegradable or bioerodable. 
     
     
         16 . The compound of  claim 1 , wherein the compound has a number average (M n ) molecular weight between 1,000 to 500,000 amu. 
     
     
         17 . The compound of  claim 1 , wherein the polymer has a number average (M n ) molecular weight between 5,000 to 200,000 amu. 
     
     
         18 . The compound of  claim 1 , wherein the polymer has a number average (M n ) molecular weight between 10,000 to 100,000 amu. 
     
     
         19 . A pharmaceutical preparation comprising a pharmaceutical excipient and a compound of  claim 1 , or a pharmaceutically acceptable ester, salt, or hydrate thereof. 
     
     
         20 . A pharmaceutical dosage form comprising of a therapeutically effective amount of the compound of  claim 1 . 
     
     
         21 - 35 . (canceled)