Microstructure array, methods of making, and methods of use

Abstract

A microprojection array comprising an approximately planar base and a plurality of microprojections, wherein the array comprises a therapeutic agent that is poorly soluble in water or an aqueous solvent.

What is claimed is: 
     
         1 . A method for making a microstructure array comprising:
 (a) providing a polymer solution or suspension comprising:
 (i) at least one therapeutic agent that is poorly soluble in an aqueous solvent, 
 (ii) one or more polymers, and 
 (iii) a solvent selected from an organic solvent and an organic solvent/aqueous solution mixture; 
   (b) dispensing the polymer solution or suspension on a mold having an array of microstructure cavities, thereby filling the microstructure cavities in the mold;   (c) removing excess solution or suspension on the mold surface; and   (d) drying the solution or suspension at about 5° C. to 50° C. to form a microstructure array.   
     
     
         2 . The method of  claim 1 , wherein drying the solution comprises drying the solution or suspension in a chamber having at least one of:
 (i) a partial pressure of about 30 psi to about 60 psi at a temperature of about 5° C. to about 50° C.; or   (ii) an atmosphere filled with solvent of the liquid casting formulation at a temperature of about 5° C. to 50° C.   
     
     
         3 . The method of  claim 2  further comprising:
 (e) drying the microstructure under vacuum at about 5° C. to 50° C. 
 
     
     
         4 . The method of  claim 2 , wherein the chamber uses at least one of convection, conduction or radiation for drying. 
     
     
         5 . The method of  claim 1 , further including a solubility enhancer in step (a). 
     
     
         6 . The method of  claim 3 , further comprising:
 (f) dissolving a polymer in a second organic solvent to form a backing polymer solution or suspension, wherein neither of the therapeutic agent nor the one or more polymers of step (a) are appreciably soluble in the second organic solvent;   (g) dispensing a basement or backing layer on the mold surface; and   (h) drying the basement or backing layer.   
     
     
         7 . The method of  claim 3 , further comprising:
 (f) dissolving a polymer in a second organic solvent to form a backing polymer solution or suspension, wherein the polymer solution or suspension and the backing polymer solution or suspension do not appreciably mix;   (g) dispensing a basement or backing layer on the mold surface; and   (h) drying the basement or backing layer.   
     
     
         8 . The method of  claim 7 , wherein the active agent is present in the backing polymer solution or suspension selected from less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10% or less than about 5%. 
     
     
         9 . The method of  claim 6 , wherein drying the basement or backing layer comprises drying in an oven at about 5° C. to 50° C. 
     
     
         10 . The method of  claim 7 , wherein drying the basement or backing layer comprises drying in an oven at about 5° C. to 50° C. 
     
     
         11 . The method of  claim 1 , wherein the aqueous solution/organic solvent mixture is selected from ethanol:H 2 O, DMSO:H 2 O, NMP:H 2 O, and isopropyl alcohol:H 2 O. 
     
     
         12 . The method of  claim 1 , wherein the mixture of aqueous solution/organic solvent comprises the organic solvent and aqueous solution in a ratio of about 10:90 to about 90:10. 
     
     
         13 . A method for transdermal delivery of a therapeutic agent to a subject, the method comprising:
 (a) providing a microstructure apparatus comprising:
 a backing having a first surface and a second surface opposed thereto; 
 a microstructure array comprising a plurality of microstructures extending outwardly from the first surface of the backing; 
 each of the plurality of microstructures comprising a biodegradable and/or a bioerodible, water soluble distal layer having a distal tip, wherein the distal layer comprises:
 (i) at least one therapeutic agent that is poorly soluble in aqueous media, and 
 (ii) one or more water soluble polymers selected from:
 (a) a polymer that is soluble in an aqueous media and soluble in an organic solvent, or 
 (b) a polymer that is soluble in an aqueous media/organic solvent mixture; and 
 
 
 wherein each distal layer in the plurality of microstructures comprises the distal tip formed as a piercing element adapted to penetrate at least a portion of the stratum corneum or a biological membrane; and 
   (b) applying said microstructure apparatus to the skin or a biological membrane of a subject.   
     
     
         14 . The method of  claim 13 , wherein the therapeutic agent has a solubility of less than 10 mg/mL in water at 25° C. 
     
     
         15 . The method of  claim 13 , wherein the at least one therapeutic agent is uniformly dispersed in the distal layer of the microstructures. 
     
     
         16 . The method of  claim 13 , wherein the distal layer further comprises at least one solubility enhancer. 
     
     
         17 . The method of  claim 13 , wherein the transdermal delivery is local transdermal delivery. 
     
     
         18 . The method of  claim 13 , wherein the transdermal delivery is systemic transdermal delivery. 
     
     
         19 . The method of  claim 13 , wherein the biological membrane is associated with a body tissue or organ which is exposed or accessible during surgery or during a surgical procedure. 
     
     
         20 . The method of  claim 13 , wherein the plurality of microstructures has mechanical strength sufficient to pierce through the stratum corneum. 
     
     
         21 . The method of  claim 13 , wherein the dissolution of the distal ends upon the at least partial penetration of the stratum corneum or biological membrane results in delivery of the therapeutic agent to the subject.