Control of drug release by transient modification of local microenvironments

Abstract

Methods, formulations, and devices are provided for enhancing drug delivery from a medical device. The method is provided for increasing the rate or quantity of a drug formulation released from an implantable drug delivery device, which method comprises the step of providing a release-modifying agent within or proximate to the implantable drug delivery device, in a manner effective to inhibit gelation, aggregation, or precipitation of the drug formulation being released from the device. The drug formulation and the release-modifying agent may be stored together in at least one reservoir in the implantable drug deliver device. Alternatively, the release-modifying agent may be stored in one or more reservoirs separate from the drug formulation.

1 . A method for inhibiting the gelation, aggregation, or precipitation of a drug released from a reservoir in an implanted drug delivery device comprising:
 providing a drug which has limited solubility or tends to undergo gelation, aggregation, or precipitation at a physiological pH at a site at which said drug delivery device is to be implanted; and   formulating the drug in a dry solid form with a release-modifying agent within said reservoir;   opening said reservoir to permit the physiological fluid to solubilize the drug, wherein the release modifying agent is present in an amount effective to changes the pH of a microenvironment in or about the reservoir in an amount effective to inhibit gelation, aggregation, or precipitation of the drug, whereby the solubilized drug can be released from the implanted drug delivery device.   
   
   
       2 . The method of  claim 1 , wherein the drug comprises an amino acid, a peptide, or a protein. 
   
   
       3 . The method of  claim 1 , wherein the drug comprises human parathyroid hormone or an analog thereof. 
   
   
       4 . The method of  claim 1 , wherein the drug comprises a leutenizing hormone-releasing hormone, a gonadotropin-releasing hormone, a natriuretic peptide, exenatide, pramlintide, a tumor necrosis factor (TNF) inhibitor, an analog thereof, or a combination thereof. 
   
   
       5 . The method of  claim 1 , wherein the release-modifying agent comprises at least one non-volatile, monoprotic or polyprotic organic acid. 
   
   
       6 . The method of  claim 1 , wherein the release-modifying agent comprises citric acid, tartaric acid, or a combination thereof. 
   
   
       7 . The method of  claim 1 , wherein the reservoir is a microreservoirs. 
   
   
       8 . The method of  claim 1 , wherein the volume of said reservoir is between 1 nL and 500 μL. 
   
   
       9 . The method of  claim 1 , wherein the drug comprises human parathyroid hormone or an analog thereof and the release-modifying agent comprises citric acid. 
   
   
       10 . The method of  claim 1 , wherein the dry solid form is a lyophilized cake. 
   
   
       11 . The method of  claim 1 , wherein the step of opening said reservoir comprises disintegrating at least one reservoir cap which closed off at least one opening in said reservoir. 
   
   
       12 . An implantable medical device for the storage and controlled release of a drug formulation comprising:
 a body portion having at least one reservoir which has one or more release openings;   a drug formulation, which comprises a drug and a release-modifying agent, disposed in a dry solid form within the at least one reservoir;   one or more reservoir caps closing off the one or more release openings; and   electrical circuitry, a power source, and a controller for disintegrating said reservoir caps to release the drug formulation,   wherein the release modifying agent comprises a non-volatile, monoprotic or polyprotic organic acid or a non-volatile, mono- or poly-functional base.   
   
   
       13 . The device of  claim 12 , wherein the drug formulation comprises an amino acid, a peptide, or a protein. 
   
   
       14 . The device of  claim 13 , wherein the release-modifying agent comprises citric acid. 
   
   
       15 . The device of  claim 14 , wherein the drug formulation comprises human parathyroid hormone, a leutenizing hormone-releasing hormone, a gonadotropin-releasing hormone, a natriuretic peptide, exenatide, pramlintide, a tumor necrosis factor (TNF) inhibitor, an analog thereof, or a combination thereof. 
   
   
       16 . The device of  claim 13 , wherein the dry solid form is a lyophilized cake.