Efficient aqueous encapsulation and controlled release of bioactive agents

Abstract

A drug delivery system comprises a porous, self-healing biodegradable polymer matrix having a ionic, charged, biopolymer and a pH modifying species disposed within the pores. An ionic macromolecule having the opposite charge binds the biopolymer and forms a nonsoluble polyelectrolyte complex. The molecular weight of the biopolymer, the self healing polymer matrix, the concentration of pore forming agent and the concentration of the pH modifying species are selected for optimal binding and release of the macromolecule.

1 .- 20 . (canceled) 
     
     
         21 . A porous self-healing biodegradable polymer matrix suitable for encapsulation of an active macromolecule, wherein the matrix comprises a biodegradable polymer and has pores and wherein:
 a biopolymer is disposed within the pores; and   a pH modifying species is disposed within the pores;   wherein the biopolymer is present at a level of greater than 0.5% and below 10% by weight based on the weight of the biodegradable polymer, and   wherein the pH modifying species is selected from the group consisting of MgCO 3 , Mg(OH) 2 , and ZnCO 3 .   
     
     
         22 . The porous self-healing biodegradable polymer matrix of  claim 21  wherein the biodegradable polymer is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic-acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(hydroxymethyl glycolide-co-lactide), polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p-dioxanone), poly(alkylene oxalate)s, biodegradable polyurethanes, homopolymers, copolymers, and blended polymers. 
     
     
         23 . The porous self-healing biodegradable polymer matrix of  claim 22  wherein the self-healing biodegradable polymer comprises poly(lactic-co-glycolic acid). 
     
     
         24 . The porous self-healing biodegradable polymer matrix of  claim 21  wherein the biopolymer is selected from the group consisting of dextran sulfate, chondroitin sulfate, keratan sulfate, heparin, heparin sulfate, hyaluronic acid, and a combination thereof. 
     
     
         25 . The porous self-healing biodegradable polymer matrix of  claim 21  wherein the biopolymer comprises chondroitin sulfate and the pH modifying species comprises MgCO 3 . 
     
     
         26 . The porous self-healing biodegradable polymer matrix of  claim 21  wherein the biopolymer comprises chondroitin sulfate and the pH modifying species comprises ZnCO 3 . 
     
     
         27 . The porous self-healing biodegradable polymer matrix of  claim 21  wherein the biopolymer comprises heparan or heparan sulfate and the pH modifying species comprises MgCO 3 . 
     
     
         28 . The porous self-healing biodegradable polymer matrix of  claim 21 , wherein the biopolymer comprises heparan or heparan sulfate and the pH modifying species comprises ZnCO 3 . 
     
     
         29 . The porous self-healing biodegradable polymer matrix of  claim 21  wherein the biopolymer comprises hyaluronic acid and the pH modifying species comprises MgCO 3 . 
     
     
         30 . The porous self-healing biodegradable polymer matrix of  claim 21  wherein the biopolymer comprises hyaluronic acid and the pH modifying species comprises ZnCO 3 . 
     
     
         31 . The porous self-healing biodegradable polymer matrix of  claim 21 , wherein the active macromolecule is selected from net positively charged peptides and net positively charged proteins. 
     
     
         32 . The porous self-healing polymer matrix of  claim 21 , further comprising the active macromolecule encapsulated within the self-healing polymer matrix. 
     
     
         33 . A method for using a porous self-healing polymer matrix for making a drug delivery system for an active macromolecule, the method comprising:
 loading the active macromolecule into the porous self-healing polymer matrix according to  claim 21  by incubating the self-healing polymer matrix in an aqueous solution of the active macromolecule, wherein the matrix has pores connected to an outer surface of the matrix; and   closing the pores and encapsulating the active macromolecule.   
     
     
         34 . The method of  claim 33  wherein the active macromolecule is a positively charged peptide or a positively charged protein. 
     
     
         35 . The method of  claim 33  wherein the biopolymer is selected from the group consisting of dextran sulfate, chondroitin sulfate, keratan sulfate, heparin, heparin sulfate, hyaluronic acid, and a combination thereof. 
     
     
         36 . The method of  claim 33  wherein the biopolymer forms a nonsoluble polyelectrolyte complex with the active macromolecule to be delivered. 
     
     
         37 . The method of  claim 33  wherein the nonsoluble polyelectrolyte complex stabilizes the structure of the active macromolecule agent during the encapsulation process, and prevents the active macromolecule from leaching out of the porous polymer matrix. 
     
     
         38 . The method of  claim 33  wherein the loading of active macromolecule is at least 3.0% w/w of the delivery system. 
     
     
         39 . The method of  claim 33  wherein the encapsulation efficiency of the active macromolecule is at least 60%.