Controlled-Released Peptide Formulations
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.
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.