Delivery agents for enhancing mucosal absorption of therapeutic agents

Abstract

A delivery agent for delivering a biologically active agent to a warm-blooded animal includes a hydrophobic moiety covalently bonded to a hydrophilic moiety. The hydrophobic moiety can include bile acids, sterols, or hydrophobic small molecules. The hydrophilic moiety can include α-amino acids, dipeptides or tripeptides, or hydrophilic small molecules. An illustrative delivery agent is N α -deoxycholyl-L-lysine-methylester. The delivery agent and the biologically active agent are mixed together to form a complex, which is then administered to the animal. These complexes are particularly useful for oral administration of biologically active agents, but other routes of administration may be used.

1 . A delivery agent for delivery of a biologically active agent to a warm-blooded animal, the delivery agent comprising (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having molecular weights of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydrophobic moiety, wherein the hydrophilic moiety is positively charged, negatively charged, or a salt. 
     
     
         2 . The delivery agent of  claim 1  wherein the hydrophobic moiety is a bile acid selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, and mixtures thereof. 
     
     
         3 . The delivery agent of  claim 1  wherein the hydrophobic moiety is a sterol selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof. 
     
     
         4 . The delivery agent of  claim 1  wherein the hydrophilic moiety comprises a charged α-amino acid. 
     
     
         5 . The delivery agent of  claim 1  wherein the hydrophilic moiety comprises a polyamine. 
     
     
         6 . The delivery agent of  claim 1  wherein the hydrophilic agent comprises a chelating agent. 
     
     
         7 . The delivery agent of  claim 1  wherein the hydrophilic agent comprises a charged alkyl derivative. 
     
     
         8 . The delivery agent of  claim 1  wherein the hydrophilic moiety comprises a hydrophilic small molecule having a molecular weight of about 100 to about 3000. 
     
     
         9 . The delivery agent of  claim 1  wherein the hydrophilic moiety comprises a positively charged group selected from the group consisting of primary amines, secondary amines, tertiary amines, quaternary amines, and mixtures thereof. 
     
     
         10 . A composition comprising a mixture of a biologically active agent and a delivery agent, wherein the delivery agent comprises (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having a molecular weight of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydrophobic moiety, wherein the hydrophilic moiety is positively charged, negatively charged, or a salt thereof. 
     
     
         11 . The composition of  claim 10  wherein the composition comprises a reversible complex that is decomplexed in the blood stream after delivery to a warm-blooded animal. 
     
     
         12 . The composition of  claim 10  wherein the biologically active agent is a member selected from the group consisting of human growth hormone, recombinant human growth hormone, bovine growth hormone, porcine growth hormone, growth hormone-releasing hormone, alpha-interferon, beta-interferon, gamma-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), insulin-like growth factor-1 (IGF-1), glucagon-like peptide-1 (GLP-1), heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, pentasaccharide, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin, atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thromboprotein, fugrastim, prostaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, parathyroid hormone, fragments of parathyroid hormone, desferrioxamine, antimicrobial agents, antifungal agents, and vitamins; analogs, fragments, mimetics, and polyethylene glycol-modified derivatives thereof; and mixtures thereof. 
     
     
         13 . The composition of  claim 10  wherein the hydrophobic moiety is a bile acid selected from the group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, and mixtures thereof. 
     
     
         14 . The composition of  claim 10  wherein the hydrophobic moiety is a sterol selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof. 
     
     
         15 . The composition of  claim 10  wherein the hydrophilic moiety comprises a charged α-amino acid. 
     
     
         16 . The composition of  claim 10  wherein the hydrophilic moiety comprises a polyamine. 
     
     
         17 . The composition of  claim 10  wherein the hydrophilic agent comprises a chelating agent. 
     
     
         18 . The composition of  claim 10  wherein the hydrophilic agent comprises a charged alkyl derivative. 
     
     
         19 . The composition of  claim 10  wherein the hydrophilic moiety comprises a positively charged group selected from the group consisting of primary amines, secondary amines, tertiary amines, quaternary amines, and mixtures thereof. 
     
     
         20 . A method for administering a biologically active agent to a warm-blooded animal, the method comprising administering a composition comprising a mixture of the biologically active agent and a delivery agent, wherein the delivery agent comprises (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having a molecular weight of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydrophobic moiety, wherein the hydrophilic moiety is positively charged, negatively charged, or a salt thereof. 
     
     
         21 . The method of  claim 20  wherein the administering of the composition is by oral or intra-jeju-ileum administration. 
     
     
         22 . The method of  claim 20  wherein the delivery agent comprises N α -deoxycholyl-L-lysine-methylester.