title: Enzymatically controlled drug delivery.
abstract: An approach for providing feedback control for polypeptide drugs in a polymeric controlled-release system uses a trigger molecule and a polymer-bound enzyme that, in the presence of that trigger molecule, will cause an acid or a base to form. When the pH inside the polymer system changes, the solubility of the drug shifts dramatically, which changes the diffusion or dissolution driving force, and hence the release rate changes correspondingly. This concept was tested using a controlled-release system of ethylene/vinyl acetate copolymer containing insulin and immobilized glucose oxidase. The enzymatic reaction of glucose to gluconic acid reduces the pH in the polymer microenvironment. Since insulin solubility increases with decreasing pH (at physiologic pH, this is true for an insulin with an isoelectric point of 7.4 or higher), the release of insulin increases in response to glucose concentration. The feasibility of this concept has been shown using trilysyl insulin with an isoelectric point of 7.4. Multiple exposures to buffered glucose solutions over several weeks caused insulin release to reversibly increase during each exposure. Polymer-implanted diabetic rats infused with glucose solutions showed a significant increase in insulin concentration in 30 min-an effect not observed in three different sets of control rats.
authors.affiliation: Massachusetts Institute of Technology, Department of Applied Biological Sciences, Cambridge, 02139.
authors.forename: F
authors.initials: F
authors.lastname: Fischel-Ghodsian
authors.forename: L
authors.initials: L
authors.lastname: Brown
authors.forename: E
authors.initials: E
authors.lastname: Mathiowitz
authors.forename: D
authors.initials: D
authors.lastname: Brandenburg
authors.forename: R
authors.initials: R
authors.lastname: Langer
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005246:Feedback; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005949:Glucose Oxidase / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007332:Insulin Infusion Systems; D007526:Isoelectric Point; D011145:Polyvinyls / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility
chemical_list: D007328:Insulin; D011145:Polyvinyls; C009565:insulin, tri-Lys-; C016438:ethylenevinylacetate copolymer; D005949:Glucose Oxidase; D005947:Glucose