Microarray for delivery of therapeutic agent and methods of use

Abstract

Microstructure arrays and methods for using and manufacturing the arrays are described.

What is claimed is: 
     
         1 . A microstructure apparatus, comprising:
 an approximately planar substrate having a first surface and a second surface opposed thereto; and   a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising at least one of: 
 (a) a water insoluble, biodegradable polymer, and at least one therapeutic agent; 
 (b) at least one low molecular weight polymer, at least one high molecular weight polymer, and at least one therapeutic agent; 
 (c) at least one biodegradable polymer, a hydrophilic component, and at least one therapeutic agent; or 
 (d) at least one polymer and at least one therapeutic agent, wherein a ratio of therapeutic agent to polymer in the matrix is low; and 
   wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours.   
     
     
         2 . The microstructure apparatus of  claim 1 , wherein the water insoluble polymer of (a) is selected from polylactide, polyglycolide, and co-polymers thereof. 
     
     
         3 . The microstructure apparatus of  claim 1 , wherein the polymer matrix of (a) comprises at least one of:
 i) about 1-50% therapeutic agent; and   ii) about 50-99% of the water insoluble, biodegradable polymer.   
     
     
         4 . The microstructure apparatus of  claim 1 , wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute. 
     
     
         5 . The microstructure apparatus of  claim 1 , wherein at least a portion of the microstructures are detachable from the substrate. 
     
     
         6 . The microstructure apparatus of  claim 1 , wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine. 
     
     
         7 . The microstructure apparatus of  claim 1 , wherein the low molecular weight polymer of (b) has a molecular weight of between about 1-10 K Da. 
     
     
         8 . The microstructure apparatus of  claim 1 , wherein the high molecular weight polymer of (b) has a molecular weight of between about 50-300 K Da. 
     
     
         9 . The microstructure apparatus of  claim 1 , wherein the low molecular weight polymer and high molecular weight polymers of (b) are present in a ratio of about 1 :1-1 :10. 
     
     
         10 . The microstructure apparatus of  claim 1 , wherein the polymer matrix of (c) comprises about 5%-40% of the hydrophilic component. 
     
     
         11 . The microstructure apparatus of  claim 1 , wherein the hydrophilic component of (c) is PEG-PLGA. 
     
     
         12 . The microstructure apparatus of  claim 1 , wherein the biodegradable polymer of (c) is a hydrophobic polymer selected from PLA, a-hydroxy acids, polycaprolactones, polyanhydrides, and co-polymers thereof. 
     
     
         13 . The microstructure apparatus of  claim 12 , wherein the a-hydroxy acid is PLGA. 
     
     
         14 . The microstructure apparatus of  claim 1 , wherein the ratio of therapeutic agent to polymer of (d) is between about 1 :2 to 1 :25. 
     
     
         15 . The microstructure apparatus of  claim 1 , further comprising:
 a backing layer positioned between a proximal portion of the plurality of microstructures and the substrate, the backing layer being formed of a second polymer matrix comprising (i) a biodegradable polymer, and (ii) the at least one therapeutic agent.   
     
     
         16 . The microstructure apparatus of  claim 1 , further comprising:
 an adhesive coating applied to at least one of i) at least a portion of at least some of the plurality of microstructures, ii) at least a portion of the substrate first surface between the microstructures, or iii) the apparatus further including a plurality of openings extending through the substrate and positioned between at least some of the plurality of microstructures, the adhesive coating being applied to at least a portion of the substrate second surface such that the adhesive is capable of contacting a subject’s skin through the openings when placed on the skin.   
     
     
         17 . The microstructure apparatus of  claim 16 , wherein the adhesive coating comprises an adhesive selected from a medical adhesive, a tissue adhesive, a surgical adhesive, a fibrin adhesive, a bioactive film, a pressure sensitive adhesive, or a rubber-based adhesive. 
     
     
         18 . The microstructure apparatus of  claim 17 , wherein the medical adhesive is selected from acrylic adhesives, silicone based adhesives, hydrogel adhesives, and synthetic elastomer adhesives. 
     
     
         19 . The microstructure apparatus of  claim 17 , wherein the tissue adhesive is a cyanoacrylate polymer. 
     
     
         20 . The microstructure apparatus of  claim 19 , wherein the cyanoacrylate polymer is selected from n-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate. 
     
     
         21 . The microstructure apparatus of  claim 16 , wherein the adhesive coating is noncontinuous. 
     
     
         22 . A method of making a sustained release microstructure apparatus, comprising:
 dissolving or suspending a therapeutic agent in a solvent to form a therapeutic agent solution or suspension;   dissolving at least one water insoluble, biodegradable polymer in a solvent to form a polymer solution;   mixing the therapeutic agent solution or suspension and the polymer solution or suspension to form a polymer matrix solution or suspension;   dispensing the polymer matrix solution or suspension on a mold having an array of microstructure cavities;   filling the microstructure cavities in the mold;   removing excess solution or suspension polymer matrix on the mold surface; and drying the matrix to form a plurality of microstructures;   dispensing a basement or backing layer on the mold surface;   drying the basement or backing layer.   
     
     
         23 . The method of  claim 22 , further comprising:
 affixing the basement or backing layer to a substrate.   
     
     
         24 . The method of  claim 22 , wherein at least one of the solvents is selected from DMSO and acetonitrile. 
     
     
         25 . The method of  claim 22 , wherein filling the microstructure cavities further comprises pressurizing the mold. 
     
     
         26 . The method of  claim 22 , wherein the therapeutic agent is crystalline, further comprising: heating the plurality of microstructures to about 110° C. for about 1 hour; and storing the microstructures in a dry cabinet for about 10 days. 
     
     
         27 . A method of modulating an initial release rate of a therapeutic agent from a microstructure apparatus comprising a plurality of microstructures formed of a polymer matrix comprising at least one polymer and at least one therapeutic agent, the method comprising at least one of:
 (a) wherein the at least one polymer comprises at least one high molecular weight polymer and at least one low molecular weight polymer, adjusting a ratio of the high molecular weight polymers to low molecular weight polymers in the polymer matrix to achieve a desired initial release rate of therapeutic agent from the polymer matrix;   (b) adjusting a ratio of therapeutic agent to the at least one polymer in the polymer matrix;   (c) adding at least one hydrophilic component to the polymer matrix; and/or   (d) selecting a solvent for preparing the polymer matrix that provides a desired initial release rate.   
     
     
         28 . The method of  claim 27 , wherein (a) comprises one of:
 i) increasing the ratio of high molecular weight polymer in the matrix to increase the initial release rate, or   ii) increasing the ratio of low molecular weight polymer in the matrix to decrease the initial release rate.   
     
     
         29 . The method of  claim 27 , wherein (b) comprises one of:
 i) increasing the ratio of therapeutic agent in the matrix to increase the initial release rate, or   ii) decreasing the ratio of low molecular weight polymer in the matrix to decrease the initial release rate.   
     
     
         30 . The method of  claim 27 , wherein (c) comprises adding the hydrophilic component as about 10-40% of the matrix to increase the initial release rate. 
     
     
         31 . The method of  claim 27 , wherein (d) comprises:
 i) selecting DMSO as the solvent to lower the initial release rate; or   ii) selecting acetonitrile as the solvent to increase the initial release rate.   
     
     
         32 . A method of delivering a therapeutic agent to a subject for an extended period of time, comprising:
 applying the microstructure apparatus of  claim 1  to a skin site of the subject; adhering the microstructure apparatus to the skin;   delivering the therapeutic agent from the microstructure array to the subject; and   removing the microstructure apparatus after at least about 10 minutes.   
     
     
         33 . The method of  claim 32 , wherein the microstructure apparatus is removed after at least about 15 minutes to 5 days. 
     
     
         34 . The method of  claim 32 , comprising delivering at least about 10-100% of a total dose of the therapeutic agent to the subject. 
     
     
         35 . The method of  claim 32 , further comprising:
 wherein applying the microstructure apparatus comprises:   positioning the microstructure apparatus on a plunger of an applicator;   actuating the applicator to release the plunger;   impacting the skin with the microstructure apparatus;   removing the applicator with the microstructure apparatus remaining on the skin site for an extended period of time.