Drug delivery from rapid gelling polymer composition

Abstract

Compositions are disclosed that afford drug delivery from two-part polymer compositions that rapidly form covalent linkages when mixed together. Such compositions are particularly well suited for use in a variety of tissue related applications when rapid adhesion to the tissue and gel formation is desired along with drug delivery. For example, the compositions are useful as tissue sealants, in promoting hemostasis, in effecting tissue adhesion, in providing tissue augmentation, and in the prevention of surgical adhesions.

1 - 126 . (canceled) 
   
   
       127 . A drug-delivery system comprising:
 a first component comprising a sulfhydryl group-containing compound of formula: Compound 1  —(SH) m  wherein m≧2; and   a second component comprising a sulfhydryl reactive group-containing compound of formula: Compound 2  —Y n , wherein Y is a sulfhydryl reactive group and wherein n≧2; and   a hydrophobic drug,   wherein, when the first component contacts the second component in a liquid medium, Compound 1  —(SH) m  and Compound 2  —Y n , form covalent bonds between the sulfhydryl groups and Y to form a biocompatible gel in less than one minute, and wherein the hydrophobic drug is admixed in the biocompatible gel.   
   
   
       128 . The drug-delivery system of  claim 127 , wherein m and n are each 4 or 12. 
   
   
       129 . The drug-delivery system of  claim 127 , wherein Compound 1  and Compound 2  are each a polyalkylene oxide. 
   
   
       130 . The drug-delivery system of  claim 129 , wherein the polyalkylene oxide is polyethylene glycol. 
   
   
       131 . The drug-delivery system of  claim 127 , wherein Y is succinimidyl ester or maleimidyl. 
   
   
       132 . The drug-delivery system of  claim 127  wherein the first component is in a first container and the second component is in a second container. 
   
   
       133 . The drug-delivery system of  claim 132  wherein the first component is in a in a liquid medium having an alkaline pH and the second component is in either a liquid medium having a neutral or acidic pH or in powder form. 
   
   
       134 . The drug-delivery system of  claim 127  wherein the first component and the second component are a mixture of powders in a first container, and the drug-delivery system further comprises an acidic buffer solution in a second container. 
   
   
       135 . The drug-delivery system of  claim 134  further comprises an alkaline buffer solution. 
   
   
       136 . The drug-delivery system of  claim 127  wherein the hydrophobic drug is a cell cycle inhibitor or an analogue or derivative thereof. 
   
   
       137 . The drug-delivery system of  claim 136  wherein the cell cycle inhibitor is a microtubule stabilizing agent. 
   
   
       138 . The drug-delivery system of  claim 137 , wherein the microtubule stabilizing agent is paclitaxel, docetaxel, or Peloruside A. 
   
   
       139 . The drug-delivery system of  claim 138 , wherein the cell cycle inhibitor is a taxane. 
   
   
       140 . The drug-delivery system of  claim 139 , wherein the taxane is paclitaxel or an analogue or derivative thereof. 
   
   
       141 . A method for forming a drug-loaded biocompatible gel in situ, comprising:
 providing a first component comprising a sulfhydryl group-containing compound   of formula: Compound 1  —(SH) m  in a liquid medium having an alkaline pH, wherein m≧2;   providing a second component comprising a sulfhydryl reactive group-containing compound of formula: Compound 2  —Y n  in either a liquid medium having a neutral or acidic pH or in powder form, wherein Y is a sulfhydryl reactive group and wherein n≧2;   combining a hydrophobic drug with either the first component or the second component; and   combining the first component and the second component to form a gel incorporating the hydrophobic drug, wherein the sulfhydryl groups and the sulfhydryl reactive groups react with one another to form covalent bonds therebetween.   
   
   
       142 . The method of  claim 141 , wherein m and n are each 4 or 12. 
   
   
       143 . The method of  claim 141 , wherein Compound 1  and Compound 2  are each a polyalkylene oxide. 
   
   
       144 . The method of  claim 141 , wherein Y is succinimidyl ester or maleimidyl. 
   
   
       145 . The method of  claim 141  wherein the hydrophobic drug is a cell cycle inhibitor or an analogue or derivative thereof. 
   
   
       146 . A method for forming a drug-loaded biocompatible gel in situ, comprising:
 providing a powdered mixture of a sulfhydryl group-containing compound of formula: Compound 1  —(SH) m , wherein m≧2, a sulfhydryl reactive group-containing compound of formula: Compound 2  —Y n , wherein Y is a sulfhydryl reactive group and wherein n≧2, and a hydrophobic drug;   providing a first buffer having an acidic pH;   providing a second buffer having an alkaline pH;   combining the powdered mixture with the first buffer to obtain a solution;   combining the solution of the powdered mixture with the second buffer form a gel incorporating the hydrophobic drug, wherein the sulfhydryl groups and the sulfhydryl reactive groups react with one another to form covalent bonds therebetween.   
   
   
       147 . The method of  claim 146 , wherein m and n are each 4 or 12. 
   
   
       148 . The method of  claim 146 , wherein Compound 1  and Compound 2  are each a polyalkylene oxide. 
   
   
       149 . The method of  claim 146 , wherein Y is succinimidyl ester or maleimidyl. 
   
   
       150 . The method of  claim 146  wherein the hydrophobic drug is a cell cycle inhibitor or an analogue or derivative thereof.