Solvent-cast microprotrusion arrays containing active ingredient

Abstract

In an aspect of the invention, an array of microprotrusions is formed by providing a mold with cavities corresponding to the negative of the microprotrusions, casting atop the mold a first solution comprising a biocompatible material and a solvent, removing the solvent, casting a second solution atop the first cast solution, removing the solvent from the second solution, and demolding the resulting array from the mold. The first solution preferably contains an active ingredient.

It is claimed: 
     
         1 . A microprotrusion array comprising:
 an approximately planar base; and   a plurality of microprotrusions, wherein each of the microprotrusions comprises at least a first and a second layer arranged roughly parallel to the plane of the base,   the first layer is contained in a distal end of the microprotrusions and comprised of a first biodegradable polymer and an active ingredient;   the second layer is positioned at a proximal end of the microprotrusions, the second layer comprised of a second polymer that is non-biodegradable.   
     
     
         2 . The array of  claim 1 , wherein the biodegradable polymer is selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(caprolactone), polyanhydrides, polyamines, polyorthoesters, polydioxanones, polyacetals, polyketals, polyphosphoesters, polyorthocarbonates, polyphosphazenes, polyvinyl alcohols, poly(malic acid), poly(amino acids), hydroxycellulose, polyphosphoesters, polysaccharides, hyalouronidase, and chitin. 
     
     
         3 . The array of  claim 2 , wherein the polysaccharide is selected from dextran and tetrastarch. 
     
     
         4 . The array of  claim 1 , wherein the non-biodegradable polymer is selected from poly(lactic acid-co-glycolic acid), polyesteramides, polycarbonates, polyacrylates and polymethacrylates. 
     
     
         5 . The array of  claim 1 , wherein the first layer further comprises a component to facilitate degradation. 
     
     
         6 . The array of  claim 5 , wherein the component to facilitate degradation is selected from sugars, sugar alcohols, cyclodextrins, and water-swellable polymers. 
     
     
         7 . The array of  claim 6 , wherein the sugar is selected from dextrose, fructose, galactose, maltose, maltulose, iso-maltulose, mannose, lactose, lactulose, sucrose, and trehalose. 
     
     
         8 . The array of  claim 6 , wherein the sugar alcohol is selected from sorbitol, lactitol, malitol or mannitol. 
     
     
         9 . The array of  claim 5 , wherein the biodegradable polymer is dextran, the component to facilitate biodegradation is sorbitol, and the active ingredient is parathyroid hormone. 
     
     
         10 . The array of  claim 1 , wherein at least some of the microprotrusions detach from the base following insertion into skin. 
     
     
         11 . The array of  claim 1 , wherein the array achieves a skin penetration efficiency of at least about 80%, at least about 90%, or at least about 95%. 
     
     
         12 . The array of  claim 1 , wherein the second layer does not penetrate the skin when the microprotrusion is in use. 
     
     
         13 . The array of  claim 1 , wherein the second layer contains the entire base and a portion of the microprotrusions. 
     
     
         14 . The array of  claim 1 , wherein the number of microprotrusions in the array is at least about 100 or at least about 50 per cm 2  of base area. 
     
     
         15 . A method for forming an array of microprotrusions, comprising the steps of:
 (a) dispensing onto a mold having an array of microprotrusion cavities corresponding to the negative of the microprotrusions,   (b) casting a solution atop the mold, the casting solution comprising:
 (i) a first solvent, 
 (ii) a biodegradable polymer, and 
 (iii) an active ingredient; 
   (c) removing the first solvent,   (d) casting a second solution atop the mold, the second solution comprising:
 (i′) a second solvent, and 
 (ii′) a non-biodegradable polymer; and 
   (e) removing the second solvent; and   (f) demolding the resulting array from the mold.   
     
     
         16 . The method of  claim 15 , wherein step (b) is carried out at least in part at a pressure lower than atmospheric pressure. 
     
     
         17 . The method of  claim 15 , wherein a pressure higher than atmospheric pressure is applied after step (b) and before step (c). 
     
     
         18 . The method of  claim 15 , further comprising a step (a) of placing the mold under compression. 
     
     
         19 . The method of  claim 15 , wherein step (c) is carried out at least in part under an atmosphere comprising a gaseous substance which passes readily through the solvent or through the mold. 
     
     
         20 . The method of  claim 15 , wherein the mold is comprised of a material selected from a ceramic material, a silicone rubber, a polyurethane, or a wax. 
     
     
         21 . The method of  claim 15 , further comprising a step of sonicating the mold following casting. 
     
     
         22 . The method of  claim 15 , further comprising applying a pressure above atmospheric pressure after the casting of step (b).