Particle-based multi-layer therapeutic delivery device and method

Abstract

A device for delivery of a first therapeutic agent and a second therapeutic agent to a site in epithelial tissue includes a first layer having a first, freeze-dried polymeric matrix having first and second opposed surfaces, formed by a composition including chitosan, a hydration promoter, a particle adhesion inhibitor, and a particle aggregation inhibitor, and a plurality of first particles embedded within the first matrix so as to be directly surrounded by, and in contact with, the first matrix, the first particles containing the first therapeutic agent and having a coating around the first therapeutic agent, the coating including chitosan. The device further includes a second layer, adjacent to the first layer, having a second, freeze-dried polymeric matrix containing the second therapeutic agent, the first layer and/or the second layer is configured to be attached to the site in the epithelial tissue.

What is claimed is: 
     
         1 . A device for delivery of a first therapeutic agent and a second therapeutic agent to a site in epithelial tissue, the device comprising:
 a first layer comprising:
 a first porous, mucoadhesive, freeze-dried polymeric matrix having first and second opposed surfaces, the first matrix formed by a composition comprising chitosan, a hydration promoter, a particle adhesion inhibitor, and a particle aggregation inhibitor, and 
 a plurality of first particles embedded within the first matrix so as to be directly surrounded by, and in contact with, the first matrix, the first particles containing the first therapeutic agent and having a coating around the first therapeutic agent, the coating comprising chitosan so as to provide controlled release of the first therapeutic agent from the first particles through one of the opposed surfaces of the first matrix; and 
   a second layer, adjacent to the first layer, the second layer comprising:
 a second, freeze-dried polymeric matrix having third and fourth opposed surfaces, the second matrix containing the second therapeutic agent, 
   wherein the first layer or the second layer, or each the first layer and the second layer, is configured to be attached to the site in the epithelial tissue.   
     
     
         2 . A device according to  claim 1 , wherein the second matrix is formed by a composition comprising chitosan. 
     
     
         3 . A device according to  claim 1 , wherein the second matrix further comprises a plurality of second particles embedded within the second matrix, the second particles containing the second therapeutic agent. 
     
     
         4 . A device according to  claim 3 , wherein the second particles have a coating around the second therapeutic agent, the coating comprising chitosan. 
     
     
         5 . A device according to  claim 1 , wherein the hydration promoter is selected from the group consisting of ethylene glycol, propylene glycol, beta-propylene glycol, glycerol and combinations thereof. 
     
     
         6 . A device according to  claim 1 , wherein the particle adhesion inhibitor is a non-ionic polymer. 
     
     
         7 . A device according to  claim 6 , wherein the non-ionic polymer is hydroxypropylmethylcellulose (HPMC). 
     
     
         8 . A device according to  claim 1 , wherein the particle aggregation inhibitor is selected from the group consisting of monosaccharides, disaccharides, sugar alcohols, chlorinated monosaccharides, chlorinated disaccharides, and combinations thereof. 
     
     
         9 . A device according to  claim 1 , wherein the first particles further comprise sodium tripolyphosphate. 
     
     
         10 . A device according to  claim 1 , wherein one or both of the opposed surfaces of the first matrix is permeable to water. 
     
     
         11 . A device according to  claim 1 , wherein one or both of the opposed surfaces of the second matrix is permeable to water. 
     
     
         12 . A device according to  claim 1 , wherein the average diameter of the first particles is from about 55 nm to about 395 nm. 
     
     
         13 . A device according to  claim 1 , wherein the first therapeutic agent and the second therapeutic agent are the same therapeutic agent. 
     
     
         14 . A method for manufacturing a multi-layer device for delivery of a first therapeutic agent and a second therapeutic agent to a site in epithelial tissue, the method comprising:
 forming a first precursor mixture comprising a first polymeric matrix precursor and the first therapeutic agent, the first polymeric matrix precursor comprising a plurality of particles, chitosan, a hydration promoter, a particle adhesion inhibitor, and a particle aggregation inhibitor, the plurality of particles containing the first therapeutic agent and have a coating around the first therapeutic agent, the coating comprising chitosan;   forming a second precursor mixture comprising a second polymeric matrix precursor and the second therapeutic agent;   freezing the first precursor mixture and the second precursor mixture in a bath containing an aqueous alcoholic solution at a temperature above the freezing temperature of the aqueous alcoholic solution and at most −40° C., to form a combined solid comprising a frozen first layer precursor adjacent to a frozen second layer precursor;   drying the combined solid to form the multi-layer device, the multi-layer device comprising a first layer comprising a first polymeric matrix with the plurality of particles embedded within the first polymeric matrix and a second layer comprising a second polymeric matrix, the first layer or the second layer configured to be attached to the site in the epithelial tissue.   
     
     
         15 . A method according to  claim 14 , wherein the freezing of the first precursor mixture precedes the freezing of the second precursor mixture. 
     
     
         16 . A method according to  claim 14 , wherein the bath further contains dry ice. 
     
     
         17 . A method according to  claim 14 , wherein the aqueous alcoholic solution comprises about 90 wt % ethanol to about 99 wt % ethanol. 
     
     
         18 . A method according to  claim 14 , wherein the second polymeric matrix precursor is chitosan. 
     
     
         19 . A method according to  claim 14 , wherein the drying is under vacuum. 
     
     
         20 . A method for manufacturing a multi-layer device for delivery of a first therapeutic agent and a second therapeutic agent to a site in epithelial tissue, the method comprising:
 forming a first precursor mixture comprising a first polymeric matrix precursor and the first therapeutic agent, the first polymeric matrix precursor comprising a plurality of particles, chitosan, a hydration promoter, a particle adhesion inhibitor, and a particle aggregation inhibitor, the plurality of particles containing the first therapeutic agent and having a coating around the first therapeutic agent, the coating comprising chitosan;   forming a second precursor mixture comprising a second polymeric matrix precursor and the second therapeutic agent;   freezing the first precursor mixture in a first mold containing a first aqueous alcoholic solution at a temperature above the freezing temperature of the first aqueous alcoholic solution and at most −40° C., to form a frozen first layer precursor;   freezing the second precursor mixture in a second mold containing a second aqueous alcoholic solution at a temperature above the freezing temperature of the second aqueous alcoholic solution and at most −40° C., to form a frozen second layer precursor;   applying a salt solution to a portion of the frozen first layer precursor, the frozen second layer precursor, or both, to form a coating on the portion;   combining the frozen second layer precursor with the frozen first layer precursor, to form a combined solid; and   drying the combined solid to form the multi-layer delivery device, the multi-layer device comprising a first layer comprising a first polymeric matrix with the plurality of particles embedded within the first polymeric matrix and a second layer comprising a second polymeric matrix, the first layer or the second layer configured to be attached to the site in the epithelial tissue.   
     
     
         21 . A method according to  claim 20 , further comprising combining a third layer precursor with the combined solid, to form a solid comprising the first layer, the second layer, and a third layer. 
     
     
         22 . A method according to  claim 20 , wherein the salt solution is saline. 
     
     
         23 . A method according to  claim 20 , wherein the second polymeric matrix precursor is chitosan. 
     
     
         24 . A method according to  claim 20 , wherein the first aqueous alcoholic solution and the second aqueous alcoholic solution are the same solution.