Two-stage microparticle-based therapeutic delivery system and method

Abstract

A system for delivery of a therapeutic agent to a site in mucosal tissue is provided. The system includes a porous, mucoadhesive polymeric matrix having a first and a second opposed surfaces. The matrix is formed by a composition including chitosan. The composition may also include any or all of a hydration promotor, a microparticle adhesion inhibitor, and a microparticle aggregation inhibitor. A plurality of microparticles having an average diameter between 500 nm and 2000 nm are embedded within the matrix. The microparticles contain a therapeutic agent and have a coating around the therapeutic agent. The first surface of the matrix is configured to be attached to the site in the mucosal tissue and the matrix is configured to provide controlled release of the microparticles through the first surface. The coating of the microparticles includes chitosan so as to provide controlled release of the agent from the microparticles.

1 - 20 . (canceled) 
     
     
         21 . A composition for oral administration and delivery of a therapeutic agent to gastrointestinal mucosal tissue, the composition comprising a plurality of nanoparticles comprising chitosan and the therapeutic agent,
 wherein the plurality of nanoparticles is stable to stomach pH of 1.5 to 2.5; and   wherein the therapeutic agent is encapsulated within the nanoparticles.   
     
     
         22 . The composition of  claim 21 , wherein the plurality of nanoparticles is programmed to degrade at about pH 5 for targeted release of the therapeutic agent to the jejunum. 
     
     
         23 . The composition of  claim 21 , wherein the plurality of nanoparticles is programmed to degrade at about pH 6 for targeted release of the therapeutic agent to the small intestine. 
     
     
         24 . The composition of  claim 21 , wherein the plurality of nanoparticles is programmed to degrade at about pH 7 for targeted release of the therapeutic agent to the ileum or colon. 
     
     
         25 . The composition of  claim 21 , wherein the plurality of nanoparticles comprises:
 a first population of nanoparticles programmed to degrade at about pH 5 for targeted release of the therapeutic agent to the jejunum; and   a second population of nanoparticles programmed to degrade at about pH 6 for targeted release of the therapeutic agent to the small intestine.   
     
     
         26 . The composition of  claim 21 , wherein the plurality of nanoparticles comprises:
 a first population of nanoparticles programmed to degrade at about pH 5 for targeted release of the therapeutic agent to the jejunum; and   a third population of nanoparticles programmed to degrade at about pH 7 for targeted release of the therapeutic agent to the ileum or colon.   
     
     
         27 . The composition of  claim 21 , wherein the plurality of nanoparticles comprises:
 a first population of nanoparticles programmed to degrade at about pH 5 for targeted release of the therapeutic agent to the jejunum;   a second population of nanoparticles programmed to degrade at about pH 6 for targeted release of the therapeutic agent to the small intestine; and   a third population of nanoparticles programmed to degrade at about pH 7 for targeted release of the therapeutic agent to the ileum or colon.   
     
     
         28 . The composition of  claim 21 , wherein the plurality of nanoparticles comprises:
 a second population of nanoparticles programmed to degrade at about pH 6 for targeted release of the therapeutic agent to the small intestine; and   a third population of nanoparticles programmed to degrade at about pH 7 for targeted release of the therapeutic agent to the ileum or colon.   
     
     
         29 . The composition of  claim 21 , wherein the chitosan in the nanoparticles is pure chitosan. 
     
     
         30 . The composition of  claim 21 , wherein the nanoparticle further comprises a cross-linking agent which is sodium tripolyphosphate. 
     
     
         31 . The composition of  claim 21 , wherein the therapeutic agent is a chemotherapeutic pharmaceutical. 
     
     
         32 . The composition of  claim 21 , wherein the therapeutic agent is a nucleic acid therapeutic. 
     
     
         33 . The composition of  claim 32 , wherein the therapeutic agent is nicotinic acid adenine dinucleotide phosphate. 
     
     
         34 . The composition of  claim 21 , which is provided as a freeze-dried powder. 
     
     
         35 . A formulation for oral administration and delivery of a therapeutic agent to gastrointestinal mucosal tissue, comprising the composition of  claim 21 . 
     
     
         36 . The formulation of  claim 35 , wherein the formulation further comprises a liquid delivery medium. 
     
     
         37 . The formulation of  claim 36 , wherein the liquid delivery medium comprises fruit juice. 
     
     
         38 . A method of preparing a nanoparticle comprising chitosan and a therapeutic agent, wherein the nanoparticle is stable to stomach pH of 1.5 to 2.5, and the therapeutic agent is encapsulated within the nanoparticle, the method comprising:
 (1) obtaining a first solution comprising chitosan and acetic acid;   (2) adjusting the first solution to a pH of between about 2.0 and about 5.0;   (3) obtaining a second solution comprising the therapeutic agent and tripolyphosphate; and   (4) introducing the second solution to the first solution at a constant flow rate to form the nanoparticle comprising chitosan and a therapeutic agent.   
     
     
         39 . The method of  claim 38 , wherein step (2) comprises adjusting the first solution to a pH of between about 2.0 and about 5.0. 
     
     
         40 . The method of  claim 38 , wherein the constant flow rate is 1.5 mL/min. 
     
     
         41 . The method of  claim 38 , further comprising the step of freeze-drying the nanoparticle comprising chitosan and a therapeutic agent. 
     
     
         42 . A nanoparticle prepared by the method of  claim 38 , wherein the nanoparticle is stable to pH of up to about 4.0. 
     
     
         43 . A nanoparticle comprising chitosan and a therapeutic agent,
 wherein the nanoparticle is stable to stomach pH of 1.5 to 2.5, and   wherein the therapeutic agent is encapsulated within the nanoparticle.   
     
     
         44 . The nanoparticle of  claim 43 , wherein the nanoparticle further comprises a cross-linking agent which is sodium tripolyphosphate. 
     
     
         45 . The nanoparticle of  claim 43 , wherein the therapeutic agent is a chemotherapeutic pharmaceutical. 
     
     
         46 . The nanoparticle of  claim 43 , wherein the therapeutic agent is a nucleic acid therapeutic. 
     
     
         47 . The nanoparticle of  claim 43 , wherein the therapeutic agent is nicotinic acid adenine dinucleotide phosphate.