Glucose-responsive insulin delivery microneedle system

Abstract

A closed-loop insulin delivery system is described. More particularly, the presently disclosed insulin delivery system can comprise glucose-responsive vesicles that release insulin in response to hypoxia triggered by enzymatic reduction of glucose. In addition or as an alternative to insulin, the delivery system can release other diabetes treatment agents, such as non-insulin-based diabetes treatment agents. The vesicles can be prepared from a hypoxia sensitive polymer, such as a hypoxia-sensitive hyaluronic acid (HS-HA). The HS-HA can comprise hydrophobic groups that can be reduced in hypoxic environments to form hydrophilic groups. The vesicles can be loaded into microneedles and microneedle array patches for use in the treatment of diabetes or to otherwise regulate blood glucose levels in subjects in need of such treatment.

1 - 33 . (canceled) 
     
     
         34 . A microneedle array comprising a matrix comprising a diabetes treatment agent and a glucose-sensing moiety, wherein the matrix is designed to undergo a structural transformation in response to a glucose concentration change leading to glucose-stimulated release of the diabetes treatment agent. 
     
     
         35 . The microneedle array of  claim 34 , wherein said microneedle array comprises a plurality of microneedles wherein each of said plurality of microneedles has a length of between about 20 and about 1000 microns. 
     
     
         36 . The microneedle array of  claim 35 , wherein each of the plurality of microneedles has a length of about 600 microns. 
     
     
         37 . The microneedle array of  claim 34 , wherein the glucose-sensing moiety is selected from the group consisting of a phenylboronic acid or a derivative thereof, a glucose binding protein, and glucose oxidase or a biologically active variant thereof. 
     
     
         38 . The microneedle array of  claim 34 , wherein the diabetes treatment agent is an insulin or a bioactive derivative thereof. 
     
     
         39 . The microneedle array of  claim 38 , wherein the insulin or bioactive derivative thereof is selected from a human insulin, a recombinant human insulin, insulin from a non-human animal, a fast-acting insulin, a rapid-acting insulin analog, an intermediate-acting insulin, and/or a long-acting insulin. 
     
     
         40 . The microneedle array of  claim 34 , wherein the microneedle array is provided as part of a skin patch. 
     
     
         41 . The microneedle array of  claim 40 , wherein said patch comprises one or more backing layers and/or skin-compatible adhesives. 
     
     
         42 . A dosed-loop insulin delivery system comprising a microneedle array of  claim 34 . 
     
     
         43 . A method of delivering a diabetes treatment agent to a subject in need thereof, the method comprising:
 providing a microneedle array, wherein said microneedle array comprises a matrix comprising a diabetes treatment agent and a glucose-sensing moiety, wherein the matrix is designed to undergo a structural transformation in response to a glucose concentration change leading to glucose-stimulated release of the diabetes treatment agent; and   applying said array to a skin surface of said subject.   
     
     
         44 . The method of  claim 43 , wherein the delivery of the diabetes treatment agent is at a rate corresponding to the glucose concentration coming into contact with the microneedle array. 
     
     
         45 . The method of  claim 43 , wherein the diabetes treatment agent is insulin or a bioactive derivative thereof. 
     
     
         46 . The method of  claim 43 , wherein the subject is a mammal. 
     
     
         47 . The method of  claim 43 , wherein the subject is diabetic.