Photocleavable drug conjugates

Abstract

Novel photocleavable drug conjugates for forming drug depots comprise drugs attached to photocleavable groups. The drug is crosslinked via photocleavable group(s) to themselves to form a photocleavable drug conjugate that generally forms the depot.

What is claimed and desired to be secured by Letters Patent is as follows: 
     
         1 . A depot suitable for implantation into a patient comprising a photocleavable drug conjugate,
 said photocleavable drug conjugate comprising a plurality of drug molecules crosslinked to other drug molecules with a plurality of crosslinkers;   wherein the crosslinkers comprise crosslinkers having 2 to 5 photocleavable groups linked to a central bridging molecule;   wherein the conjugate does not comprise a polymer chain that functions as a backbone; and   wherein the ratio of the drug to the crosslinkers is at least 80:20 based on molecular weight.   
     
     
         2 . The depot of  claim 1  wherein said photocleavable group is cleaved upon exposure to visible light. 
     
     
         3 . The depot of  claim 1  wherein said photocleavable group is cleaved upon exposure to ultraviolet light. 
     
     
         4 . The depot of  claim 1  wherein said photocleavable group is cleaved upon exposure to infrared light. 
     
     
         5 . The depot of  claim 1  wherein said photocleavable group has an ortho-nitro aromatic core scaffold. 
     
     
         6 . The depot of  claim 1  wherein said photocleavable group is selected from the group consisting of coumarins, acridines, nitroaromatics, and arylsulfonamides 
     
     
         7 . The depot of  claim 1  wherein said drug molecules comprise therapeutic peptides. 
     
     
         8 . The depot of  claim 7  wherein said therapeutic peptide is selected from the group consisting of glucagon, its analogs, its derivatives and combinations thereof. 
     
     
         9 . The depot of  claim 1  wherein said drug molecules comprise drug molecules having a plurality of amine functionalities and the photocleavable group has a plurality of n-hydroxy succinamide ester functionalities, and wherein said crosslinking comprises forming a carbamate from said amine functionalities and said n-hydroxy succinamide ester functionalities. 
     
     
         10 . The depot of  claim 1  wherein the drug molecules comprise drug molecules selected from the group consisting of insulin, glucagon, their analogs, their derivatives and combinations thereof and the photocleavable group is derived from a compound having the structure of: 
       
         
           
           
               
               
           
         
         wherein the photocleavable group can react with the drug molecule displacing X to form at least one photocleavable bond; 
         wherein R 1  is H or alkyl; 
         wherein R 2  is H or alkyl; 
         wherein X is a leaving group; 
         wherein Y is a linker chain; and 
         wherein M is an integer from 2 to 5. 
       
     
     
         11 . The depot of  claim 1  wherein said drug molecules comprise drug molecules having a plurality of carboxyl functionalities and said photocleavable group has a plurality of diazo functionalities, and wherein said crosslinking comprises forming an ester from said carboxyl functionalities and said diazo functionalities. 
     
     
         12 . The depot of  claim 1  wherein the drug molecules comprise drug molecules selected from the group consisting of insulin, glucagon, their analogs, their derivatives and combinations thereof and the photocleavable group is derived from a compound having the structure of: 
       
         
           
           
               
               
           
         
         wherein the photocleavable group can react with the drug at the diazo functional group to form at least one photocleavable bond; 
         wherein RI is H or alkyl; 
         wherein R2 is H or alkyl; 
         wherein Y is a linker chain; and 
         wherein M is an integer from 2 to 5. 
       
     
     
         13 . The depot of  claim 1  wherein said crosslinking occurs via triazole bridging between said drug molecules and said crosslinkers. 
     
     
         14 . The depot of  claim 13  wherein said photocleavable group has an azide functionality, and wherein said crosslinking occurs via an alkyne platform having two or more alkynes. 
     
     
         15 . The depot of  claim 14  wherein said drug molecule is selected from the group consisting of glucagon, its analogs, its derivatives and combinations thereof; and said glucagon molecules are selected from the group consisting of a glucagon monoazide, a glucagon diazide, a glucagon, and combinations thereof. 
     
     
         16 . The depot of  claim 14  wherein said alkyne platform comprises two or more dibenzylcyclooctyne groups. 
     
     
         17 . The depot of  claim 14  wherein said alkyne platform is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The depot of  claim 15  wherein said alkyne platform defined according to: 
       
         
           
           
               
               
           
         
       
       or mixtures thereof. 
       wherein R4 is alkyl, ether. 
     
     
         19 . The depot of  claim 8 , wherein said photocleavable group has an alkyne functionality, and wherein said crosslinking occurs via an azide crosslinker. 
     
     
         20 . The depot of  claim 1 , wherein the photocleavable group is also acid labile, esterase labile, peptidase labile, or is a combination thereof. 
     
     
         21 . The depot of  claim 1 , wherein the crosslinkers comprise crosslinkers having 3 or more photocleavable groups linked to a central bridging molecule. 
     
     
         22 . The depot of  claim 21 , wherein the central bridging molecule is an alkyne platform having three or more alkynes. 
     
     
         23 . The depot of  claim 1 , wherein the drug molecules comprise drug molecules wherein a single reactive group of the drug molecule is crosslinked. 
     
     
         24 . The depot of  claim 1 , wherein the drug molecules comprise drug molecules having at least three reactive functional groups. 
     
     
         25 . A system for administering a drug to a patient comprising:
 a depot comprising a photocleavable drug conjugate of  claim 1 ; and   a light emitting device.   
     
     
         26 . The system of  claim 25 , wherein said light emitting device is programmed to provide light in response to a biological variable in a patient and wherein said system further comprises a sensor for measuring said biological variable to provide feedback to said light emitting device