Pharmaceutically Active Agent Complexes, Polymer Complexes, and Compositions and Methods Involving the Same

Abstract

The present disclosure generally provides complexes including a pharmaceutically active agent and a functionalized polymer, wherein the functionalized polymer includes repeat units, the repeat units including ionizable repeat units having at least one ionizable side group and/or ionizable end group, a plurality of the at least one ionizable groups forming non-covalent bonds with the pharmaceutically active agent. Polymers which may be used to form such complexes as well as methods of making and using the complexes and related compositions are also provided.

What is claimed is: 
     
         1 . A complex comprising:
 a pharmaceutically active agent, and   a functionalized polymer, the functionalized polymer comprising repeat units, the repeat units comprising ionizable repeat units comprising at least one ionizable side group, a plurality of the at least one ionizable side groups forming a plurality of non-covalent bonds with the pharmaceutically active agent,   wherein at least 10% of the repeat units comprise at least one ionizable side group.   
     
     
         2 . The complex of  claim 1 , wherein the percentage of the repeat units comprising at least one ionizable side group ranges from 20% to 80%. 
     
     
         3 . The complex of  claim 1  or  2 , wherein the functionalized polymer is synthetic. 
     
     
         4 . The complex of any one of  claims 1  to  3 , wherein the functionalized polymer is a polyester. 
     
     
         5 . The complex of any one of  claims 1  to  4 , wherein the at least one ionizable side group comprises at least one member selected from ammonium, carboxylate, hydrazinium, guanidinium, sulfate, sulfonate, phosphonate, and phosphate. 
     
     
         6 . The complex of any one of  claims 1  to  5 , wherein the at least one ionizable side group is covalently bound to the polymer through click chemistry. 
     
     
         7 . The complex of any one of  claims 1  to  6 , wherein the non-covalent bonds comprise electrostatic interactions. 
     
     
         8 . The complex of any one of  claims 1  to  7 , wherein the pharmaceutically active agent comprises at least one member selected from a peptide, protein, and small molecule, the small molecule having a molecular weight less than 500 Daltons. 
     
     
         9 . The complex of any one of  claims 1  to  8 , wherein the at least one ionizable side group comprises a positively ionizable side group. 
     
     
         10 . The complex of any one of  claims 1  to  9 , wherein the at least one ionizable side group comprises a negatively ionizable side group. 
     
     
         11 . The complex of any one of  claims 1  to  10 , wherein the functionalized polymer has a weight average molecular weight ranging from 1000 Daltons to 200,000 Daltons, as measured by gel permeation chromatography. 
     
     
         12 . The complex of any one of  claims 1  to  11 , wherein the functionalized polymer has a solubility in water of at least 0.01 mg/ml and less than or equal to 10 mg/ml at 25° C. and pH 7.4. 
     
     
         13 . The complex of any one of  claims 1  to  12 , wherein the complex has a solubility of less than 0.01 mg/mL in water at 25° C. at pH 7.4. 
     
     
         14 . The complex of any one of  claims 1  to  13 , wherein the ratio of the amount of the pharmaceutically active agent to the amount of the functionalized polymer in the complex is from 1:1 to 1:10 by weight. 
     
     
         15 . The complex of any one of  claims 1  to  14 , wherein the ionizable repeat units comprise one or more ionizable side groups that comprise an optionally substituted heteroarylene ring. 
     
     
         16 . The complex of  claim 13 , wherein the optionally substituted heteroarylene ring is a 1,2,3-triazole ring. 
     
     
         17 . The complex of any one of  claims 1  to  16 , wherein the functionalized polymer is not a polyamino acid. 
     
     
         18 . A complex as defined in any one of  claims 1  to  17  for use as a medicament. 
     
     
         19 . A method comprising:
 providing a precursor polymer comprising repeat units, the repeat units comprising functionalizable repeat units comprising at least one functionalizable side group;   obtaining a functionalized polymer by transforming, using click chemistry, said functionalizable repeat units into ionizable repeat units comprising at least one ionizable side group; and   combining the functionalized polymer with a pharmaceutically active agent to form a complex in which a plurality of the at least one ionizable side groups form a plurality of non-covalent bonds with the pharmaceutically active agent.   
     
     
         20 . The method of  claim 19 , wherein said transforming, using click chemistry, comprises effecting a cycloaddition reaction. 
     
     
         21 . The method of  claim 20 , wherein said cycloaddition reaction is a Diels-Alder cycloaddition reaction. 
     
     
         22 . The method of  claim 20 , wherein said cycloaddition reaction is a Huisgen 1,3-dipolar cycloaddition reaction. 
     
     
         23 . The method of  claim 20 , wherein said cycloaddition reaction is a cycloaddition reaction between an azide and an alkyne to form a linkage comprising a 1,2,3-triazole. 
     
     
         24 . The method of any one of  claims 19  to  23 , wherein the functionalizable side group is an azido group and wherein the transforming, using click chemistry, comprises reacting the precursor polymer with an alkyne to form the functionalized polymer, the functionalized polymer comprising at least one 1,2,3-triazole ring. 
     
     
         25 . The method of any one of  claims 19  to  23 , wherein the functionalizable side group is a leaving group and wherein the transforming, using click chemistry, comprises: (a) transforming the leaving group into an azido group and thereby providing a polymer intermediate; and (b) reacting the polymer intermediate with an alkyne to form the functionalized polymer, the functionalized polymer comprising at least one 1,2,3-triazole ring. 
     
     
         26 . The method of any one of  claims 19  to  23 , wherein the functionalizable side group is an alkynyl group and wherein the transforming, using click chemistry, comprises reacting the precursor polymer with an azide to form the functionalized polymer, the functionalized polymer comprising at least one 1,2,3-triazole ring. 
     
     
         27 . The method of any one of  claims 19  to  26 , wherein the transforming, using click chemistry, comprises a monovalent copper catalyzed reaction or a ruthenium catalyzed reaction. 
     
     
         28 . The method of any one of  claims 19  to  27 , wherein the transforming, using click chemistry, comprises a copper catalyzed azide-alkyne cycloaddition reaction.