Cyclodextrin polymer compositions for use as drug carriers

Abstract

This invention discloses compositions of cyclodextrin polymers for carrying drugs and other active agents. Compositions are also disclosed of cyclodextrin polymer carriers that release drugs under controlled conditions. The invention also discloses compositions of cyclodextrin polymer carriers that are coupled to biorecognition molecules for targeting the delivery of drugs to their site of action. The advantages of the water-soluble cyclodextrin polymer carrier are: (1) Drugs can be used based on efficacy without solubility or conjugation requirements. (2) Drugs can be delivered as macromolecules and released within the cell. (3) Drugs can be targeted by coupling the carrier to biorecognition molecules. (4) Synthesis methods are independent of the drug to facilitate multiple drug therapies.

What is claimed is:  
     
         1 . A controlled release pharmaceutical composition comprising; 
 a) cyclodextrin molecules selected from the group consisting of cyclodextrin derivatives, oxidized cyclodextrins, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers complexed with;    b) an active agent selected from the group consisting of prodrugs, anticancer drugs, antineoplastic drugs, antifungal drugs, antibacterial drugs, antiviral drugs, cardiac drugs, neurological drugs, alkaloids, antibiotics, bioactive peptides, steroids, steroid hormones, polypeptide hormones, interferons, interleukins, narcotics, prostaglandins, purines, pyrimidines, anti-protozoan drugs and anti-parasitic drugs wherein;    c) said cyclodextrin molecules are covalently cross-linked through a biocleavable linkage to form a polymer that has entrapped the active agent and wherein the cross-linking provides the function of controlled release.    
     
     
         2 . The composition of    claim 1    wherein the biocleavable linkage is selected from the group consisting of disulfide linkages, protected disulfide linkages, ester bonds, aldehyde bonds, amide bonds, polypeptide linkages and hydrazone linkages.  
     
     
         3 . The composition of    claim 1    further comprising a biorecognition molecule coupled to the pharmaceutical composition.  
     
     
         4 . The composition of    claim 1    wherein said cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers have been derivatized to provide groups selected from the group consisting of dialdehydes, sulfobutylethers, sulfopropylethers, hydroxyethyls, hydroxypropyls, dihydroxy propyls, carboxylates and phosphates.  
     
     
         5 . The composition of    claim 1    wherein the active agent is selected from the group consisting of ganciclovir, furosemide, indomethacin, camptothecins, cyclosporins, chlorpromazine, methotrexate, penicillin derivatives, anthracyclines, teramycins, tetracyclines, chlorotetracyclines, clomocyclines, butoconazole, ellipticines, guamecyclines, macrolides, filipins, fungichromins, nystatins, 5′-fluorouracil, 5′-fluoro-2′-deoxyuridine, allopurinol and paclitaxe.  
     
     
         6 . The composition of    claim 1    wherein said cyclodextrin molecules are coupled to an intermediate coupling substance selected from the group consisting of serum albumins, glycoproteins, lipoproteins, polysaccharides, lipopolysaccharides, amino polysaccharides, polyacrylamides, lipids, glycolipids, N-(2-hydroxypropyl) methacrylamides, poly cyanoacrylates, polyethylene glycols, poly (D,L-lactic-coglycolic adds), dendrimers, poly (D,L-lactide)-block-methoxypolyethylene glycols and magnetic particles.  
     
     
         7 . A controlled release pharmaceutical composition comprising; 
 a) cyclodextrin molecules selected from the group consisting of cyclodextrin derivatives, oxidized cyclodextrins, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers complexed with;    b) nucleic acid, wherein;    c) said cyclodextrin molecules are covalently cross-linked through a biocleavable linkage to form a polymer that has entrapped the active agent and wherein the cross-linking provides the function of controlled release.    
     
     
         8 . The composition of    claim 7    wherein the biocleavable linkage is selected from the group consisting of disulfide linkages, protected disulfide linkages, ester bonds, aldehyde bonds, amide bonds, polypeptide linkages and hydrazone linkages.  
     
     
         9 . The composition of    claim 7    further comprising a biorecognition molecule coupled to the pharmaceutical composition.  
     
     
         10 . The composition of    claim 7    wherein said cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers have been derivatized to provide groups selected from the group consisting of dialdehydes, sulfobutylethers, sulfopropylethers, hydroxyethyls, hydroxypropyls, dihydroxy propyls, carboxylates and phosphates.  
     
     
         11 . The composition of    claim 7    wherein the nucleic add is selected from the group consisting of DNA, RNA, sense and antisense oligonucleotides; sense and antisense oligodeoxynucleotides; sense and antisense oligonucleotides and oligodeoxynucleotides containing phosphodiesters, phosphorothioates, phosphorodithioates, phosphoroamidates, alkyl phosphotriesters, methylphosphonates, sulfamates, 3′-thioformacetals, methylene(methylimino)s, 3′-N-carbamates, and morpholino carbamates; synthetic nucleic add polymers, phosphoric acid ester nucleic acids and peptide nucleic acids.  
     
     
         12 . The composition of    claim 7    wherein said cyclodextrin molecules are coupled to an intermediate coupling substance selected from the group consisting of serum albumins, glycoproteins, lipoproteins, polysaccharides, lipopolysaccharides, amino polysaccharides, polyacrylamides, lipids, glycolipids, N-(2-hydroxypropyl) methacrylamides, poly cyanoacrylates, polyethylene glycols, poly (D,L-lactic-coglycolic acids), dendrimers, poly (D,L-lactide)-block-methoxypolyethylene glycols and magnetic particles.  
     
     
         13 . A controlled release pharmaceutical composition comprising; 
 a) cyclodextrin molecules selected from the group consisting of cyclodextrin derivatives, oxidized cyclodextrins, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers complexed with;    b) toxin, wherein;    c) said cyclodextrin molecules are covalently cross-linked through a biocleavable linkage to form a polymer that has entrapped the active agent and wherein the cross-linking provides the function of controlled release.    
     
     
         14 . The composition of    claim 13    wherein the biocleavable linkage is selected from the group consisting of disulfide linkages, protected disulfide linkages, ester bonds, aldehyde bonds, amide bonds, polypeptide linkages and hydrazone linkages.  
     
     
         15 . The composition of    claim 13    further comprising a biorecognition molecule coupled to the pharmaceutical composition.  
     
     
         16 . The composition of    claim 13    wherein said cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers have been derivatized to provide groups selected from the group consisting of dialdehydes, sulfobutylethers, sulfopropylethers, hydroxyethyls, hydroxypropyls, dihydroxy propyls, carboxylates and phosphates.  
     
     
         17 . The composition of    claim 13    wherein the active agent is selected from the group consisting of aflatoxins, ricins, bungarotoxins, irinotecan, pesticides, cevadines, desatrines, veratridine and cevine derivatives.  
     
     
         18 . The composition of    claim 13    wherein said cyclodextrin molecules are coupled to an intermediate coupling substance selected from the group consisting of serum albumins glycoproteins, lipoproteins, polysaccharides, lipopolysaccharides, amino polysaccharides, polyacrylamides, lipids, glycolipids, N-(2-hydroxypropyl) methacrylamides, poly cyanoacrylates, polyethylene glycols, poly (D,L-lactic-coglycolic acids), dendrimers, poly (D,L-lactide)-block-methoxypolyethylene glycols and magnetic particles.  
     
     
         19 . A pharmaceutical amylose composition comprising; 
 a) amylose selected from the group consisting of amylose segments, amylose derivatives, oxidized amylose and amylose polymers complexed with;    b) an active agent, wherein;    c) said amylose is covalently cross-inked to form a polymer that has entrapped the active agent.    
     
     
         20 . A biocleavable crosslinking agent comprising; 
 a) a compound containing a biocleavable linkage selected from the group consisting of polypeptide linkages and hydrazone linkages wherein;    b) said compound has terminal reactive coupling groups selected from the group consisting of N-succinimidyls, N-maleimidyls, p-nitrophenyl esters, iodoacetals, bromoacetals, oxiranes and imidoesters.    
     
     
         21 . A method for producing a cyclodextrin pharmaceutical composition comprising combining cyclodextrin molecules selected from the group consisting of cyclodextrin derivatives, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers with; 
 a) guest molecules coupled to a surface to form an inclusion complex between the cyclodextrin molecules and the guest molecules on the surface, and;    b) covalently cross-linking the cyclodextrin molecules to form a polymer.    
     
     
         22 . A method for producing a cyclodextrin pharmaceutical composition using a solid support comprising coupling a first cyclodextrin molecule selected from the group consisting of cyclodextrin derivatives, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers to a solid support through a cleavable coupling agent and; 
 a) coupling in succession, additional cyclodextrin molecules to the first cyclodextrin molecule that is coupled to the solid support to form a polymer and;    b) cleaving the first cyclodextrin molecule from the solid support.    
     
     
         23 . A pharmaceutical catalytic agent composition comprising; 
 a) cyclodextrin molecules selected from the group consisting of oxidized cyclodextrins, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers coupled with;    b) a catalytic group selected from the group consisting of carboxylates, imidazoles, histamines, hydroxyls, amines, amides, aldehydes, ketones, phosphates, sulfhydryls, halogens, amino acids, nucleic acids, chelators, and metals.