Conjugate based systems for controlled drug delivery

Abstract

Conjugates which comprise a drug and a ligand which includes a first saccharide; wherein the conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a second saccharide. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.

1 - 387 . (canceled) 
     
     
         388 : A conjugate comprising an insulin molecule conjugated to one or more ligands that are independently selected from the group consisting of aminoethylglucose (AEG), aminoethylmannose (AEM), aminoethylbimannose (AEBM), aminoethyltrimannose (AETM), β-aminoethyl-N-acetylglucosamine (AEGA), and aminoethylfucose (AEF) wherein the one or more ligands are indirectly conjugated to the insulin molecule via a conjugate framework. 
     
     
         389 : The conjugate of  claim 388 , wherein the insulin molecule is conjugated via the A1 amino acid residue, via the B1 amino acid residue, via the epsilon-amino group of Lys B29  or-via the epsilon-amino group of Lys B3 . 
     
     
         390 - 392 . (canceled) 
     
     
         399 : conjugate of  claim 388 , wherein the insulin molecule is conjugated to two or more separate ligands. 
     
     
         400 - 402 . (canceled) 
     
     
         403 : The conjugate of  claim 399 , wherein the two or more separate ligands are conjugated to a single conjugate framework that is also conjugated to the insulin molecule. 
     
     
         404 : The conjugate of  claim 399 , wherein the two or more separate ligands and insulin molecule are each located on a separate branch of a single branched conjugate framework. 
     
     
         405 : The conjugate of  claim 404 , wherein the two or more separate ligands and insulin molecule are each located on termini of separate branches of a single branched conjugate framework. 
     
     
         406 : The conjugate of  claim 399 , wherein the two or more separate ligands are conjugated to the insulin molecule via two or more different conjugation points. 
     
     
         407 : The conjugate of  claim 406 , wherein the insulin molecule is conjugated via the A1 amino acid residue and the epsilon-amino group of Lys B29 . 
     
     
         408 : The conjugate of  claim 407 , wherein the insulin molecule is conjugated to two separate conjugate frameworks that are each conjugated to one or more separate ligands. 
     
     
         409 . (canceled) 
     
     
         410 : The conjugate of  claim 407 , wherein the insulin molecule is conjugated to two separate branched conjugate frameworks that are each conjugated to two ligands. 
     
     
         411 : The conjugate of  claim 410 , wherein the ligands are located on separate branches of the branched conjugate frameworks. 
     
     
         412 : The conjugate of  claim 411 , wherein the ligands are located on termini of separate branches of the branched conjugate frameworks. 
     
     
         413 : The conjugate of any one of  claims 399 - 412 , wherein the two or more separate ligands are aminoethylglucose (AEG). 
     
     
         414 : The conjugate of any one of  claims 399 - 412 , wherein the two or more separate ligands are aminoethylmannose (AEM). 
     
     
         415 : The conjugate of any one of  claims 399 - 412 , wherein the two or more separate ligands are aminoethylbimannose (AEBM). 
     
     
         416 : The conjugate of any one of  claims 399 - 412 , wherein the two or more separate ligands are aminoethyltrimannose (AETM). 
     
     
         417 : The conjugate of any one of  claims 399 - 412 , wherein the two or more separate ligands are β-aminoethyl-N-acetylglucosamine (AEGA). 
     
     
         418 : The conjugate of any one of  claims 399 - 412 , wherein the two or more separate ligands are aminoethylfucose (AEF). 
     
     
         430 : The conjugate of  claim 388 , wherein the insulin molecule is selected from the group consisting of human insulin, porcine insulin, and bovine insulin. 
     
     
         431 : The conjugate of  claim 388 , wherein the insulin molecule is selected from the group consisting of insulin lispro, insulin aspart, and insulin glulisine. 
     
     
         432 : The conjugate of  claim 388 , wherein the insulin molecule is insulin glargine or insulin detemir.