Controlled-Released Peptide Formulations

Abstract

Described herein are methods and compositions for modulating the release and/or drug loading characteristics of encapsulated bioactive agents in polymer-based delivery systems via direct modification of the isoelectric point and/or net charge of the bioactive agent.

We claim: 
     
         1 . A controlled-release pharmaceutical formulation comprising a modified bioactive agent encapsulated by a polymer, wherein the isoelectric point of said modified bioactive agent has been increased relative to a parent molecule to increase drug loading efficiency. 
     
     
         2 . The controlled-release pharmaceutical formulation according to  claim 1 , wherein the modified bioactive agent comprises additional positive charge relative to a parent molecule. 
     
     
         3 . The controlled-release pharmaceutical formulation according to  claim 2 , wherein said modified bioactive agent is conjugated to a positively-charged accessory molecule. 
     
     
         4 . The controlled-release pharmaceutical formulation according to  claim 2 , wherein said modified bioactive agent comprises positively-charged amino acid substitutions. 
     
     
         5 . The controlled-release pharmaceutical formulation according to  claim 3 , wherein said modified bioactive agent is a peptide having the amino acid sequence set forth as SEQ ID NO:2. 
     
     
         6 . The controlled-release pharmaceutical formulation according to  claim 4 , wherein said modified bioactive agent is a peptide having the amino acid sequence set forth as SEQ ID NO:9. 
     
     
         7 . A controlled-release pharmaceutical formulation comprising a modified bioactive agent encapsulated by a biodegradable polymer, wherein the isoelectric point of said modified bioactive agent has been increased or decreased relative to a parent molecule to increase the erosional release rate. 
     
     
         8 . The controlled-release pharmaceutical formulation according to  claim 7 , wherein the modified bioactive agent comprises additional positive charge relative to a parent molecule. 
     
     
         9 . The controlled-release pharmaceutical formulation according to  claim 8  wherein said modified bioactive agent is conjugated to a positively-charged accessory molecule. 
     
     
         10 . The controlled-release pharmaceutical formulation according to  claim 8 , wherein said modified bioactive agent comprises positively-charged amino acid substitutions. 
     
     
         11 . The controlled-release pharmaceutical formulation according to any one of  claims 7  to  10 , wherein said polymer is an acid-terminated polymer. 
     
     
         12 . A controlled-release pharmaceutical formulation comprising a modified bioactive agent encapsulated by a polymer, wherein the isoelectric point of said modified bioactive agent has been decreased relative to a parent molecule to reduce the initial diffusion rate of the agent from the polymer. 
     
     
         13 . The controlled-release pharmaceutical formulation according to  claim 12 , wherein the modified bioactive agent comprises additional negative charge relative to a parent molecule. 
     
     
         14 . The controlled-release pharmaceutical formulation according to  claim 13 , wherein said modified bioactive agent is conjugated to a negatively-charged accessory molecule. 
     
     
         15 . The controlled-release pharmaceutical formulation according to  claim 13 , wherein said modified bioactive agent comprises negatively-charged amino acid substitutions. 
     
     
         16 . The controlled-release pharmaceutical formulation according to any one of  claims 12  to  15 , wherein said polymer is an ester-terminated polymer. 
     
     
         17 . A controlled-release pharmaceutical formulation comprising a modified bioactive agent encapsulated by a polymer, wherein the isoelectric point of said modified bioactive agent has been increased relative to a parent molecule to increase the initial diffusion rate of the agent from the polymer. 
     
     
         18 . The controlled-release pharmaceutical formulation according to  claim 17 , wherein the modified bioactive agent comprises additional positive charge relative to a parent molecule. 
     
     
         19 . The controlled-release pharmaceutical formulation according to  claim 18 , wherein said modified bioactive agent comprises a positively-charged accessory molecule. 
     
     
         20 . The controlled-release pharmaceutical formulation according to  claim 18 , wherein said modified bioactive agent comprises positively-charged amino acid substitutions. 
     
     
         21 . The controlled-release pharmaceutical formulation according to  claim 18 , wherein said modified bioactive agent further comprises an acetate counter ion. 
     
     
         22 . The controlled-release pharmaceutical formulation according to any one of  claims 17  to  21 , wherein said polymer is an ester-terminated polymer. 
     
     
         23 . The controlled-release pharmaceutical formulation according to any one of  claims 1  to  6 , and  12  to  22 , wherein said polymer is a non-biodegradable polymer. 
     
     
         24 . The controlled-release pharmaceutical formulation according to any one of  claims 1  to  6 , and  12  to  22 , wherein said polymer is a biodegradable polymer. 
     
     
         25 . The controlled-release pharmaceutical formulation according to any one of  claims 2  to  4 ,  8  to  11 , and  18  to  22 , wherein said additional positive charge is distributed uniformly across the bioactive agent. 
     
     
         26 . The controlled-release pharmaceutical formulation according to any one of  claims 2  to  4 ,  8  to  11 , and  18  to  22 , wherein said additional positive charge is distributed non-uniformly across the bioactive agent. 
     
     
         27 . The controlled-release pharmaceutical formulation according to any one of  claims 13 - 16 , wherein said additional negative charge is distributed uniformly across the bioactive agent. 
     
     
         28 . The controlled-release pharmaceutical formulation according to any one of  claims 13 - 16 , wherein said additional negative charge is distributed non-uniformly across the bioactive agent. 
     
     
         29 . The controlled-release pharmaceutical formulation according to any one of  claims 1  to  28 , wherein said bioactive agent is a peptide molecule. 
     
     
         30 . The controlled-release pharmaceutical formulation according to any one of  claims 1  to  29 , wherein said controlled-release pharmaceutical formulation is a microparticle. 
     
     
         31 . A method for increasing bioactive agent loading efficiency in a polymer-based delivery system, comprising modifying the isoelectric point of the bioactive agent prior to encapsulation in the polymer-based delivery system. 
     
     
         32 . The method according to  claim 31 , wherein the isoeletric point of the bioactive agent is increased such that it carries a more positive charge in the environment of the polymer-based delivery system. 
     
     
         33 . A method for modulating the erosional release rate of a bioactive agent from a polymer-based delivery system, comprising modifying the isoelectric point of the agent prior to encapsulation in the polymer-based delivery system. 
     
     
         34 . The method according to  claim 33 , wherein the erosional release rate is increased by quantitatively increasing or decreasing the isoelectric point of the bioactive agent such that it carries a greater net positive or negative charge, respectively, compared to the parent molecule in the environment of the polymer-based delivery system. 
     
     
         35 . The method according to  claim 34 , wherein the isoelectric point of the bioactive agent is increased or decreased by adding additional positive or negative charge to a parent molecule to produce a stoichiometric increase or decrease in net charge relative to the parent molecule. 
     
     
         36 . The method according to  claim 35 , wherein additional positive charge is added to a neutral or cationic parent molecule to increase the erosional release rate. 
     
     
         37 . The method according to  claim 35 , wherein additional negative charge is added to a neutral or anionic parent molecule to increase the erosional release rate. 
     
     
         38 . A method for modulating the initial diffusional release of a bioactive agent from a polymer-based delivery system, comprising modifying the isoelectric point of the agent prior to encapsulation in the polymer-based delivery system. 
     
     
         39 . The method according to  claim 38 , wherein the isoelectric point of the bioactive agent is increased or decreased such that it carries a greater net positive or negative charge, respectively, relative to the parent molecule in the environment of the desired polymer-based delivery system. 
     
     
         40 . The method according to  claim 39 , wherein the initial diffusional release rate is increased by adding additional positive charge to the parent molecule to produce a stoichiometric increase in net charge relative to the parent molecule.