Responsive microgel and methods related thereto

Abstract

A responsive microgel is provided which responds volumetrically and reversibly to a change in one or more aqueous conditions selected from the group consisting of (temperature, pH, and ionic conditions) comprised of an ionizable network of covalently cross-linked homopolymeric ionizable monomers wherein the ionizable network is covalently attached to an amphiphilic copolymer to form a plurality of ‘dangling chains’ and wherein the ‘dangling chains’ of amphiphilic copolymer form immobile micelle-like aggregates in aqueous solution. A responsive microgel is further provided that comprises at least one therapeutic entity and delivers a substantially linear and sustained release of the therapeutic entity under physiological conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a divisional of U.S. patent application Ser. No. 10 / 298,808 filed Nov. 18, 2002 which claims the benefit of U.S. Provisional Application Ser. No. 60 / 352,200 filed on Jan. 29, 2002 all of which are hereby incorporated in their entirety by reference to this application.FIELD OF THE INVENTION [0002] The present invention relates to microgels comprised of an ionizable network covalently attached to an amphiphilic copolymer, which forms aggregates capable of solubilizing drugs in aqueous solution. The responsive microgel reversibly responds volumetrically to factors such as temperature, pH, and ionic conditions. Particularly, the responsive microgel is able to imbibe or solubilize a large amount of therapeutic agent and deliver a substantially linear and sustained release of therapeutic agent under physiological conditions. BACKGROUND OF THE INVENTION [0003] Volumetric changes (shrinking or swelling) of temperature-sensiti...

AI Technical Summary

Problems solved by technology

However, poly(alkylacrylamides) are perceived to be toxic, especially in biomedical applications.

Furthermore, nonionic nature of poly(alkylacrylamides) prevents creating ion-sensitive microgels.

However, chemical moieties (amide or other) required to accomplish linkage between an amphiphilic copolymer such as polyether and the polyelectrolyte (i.e. a chemical group absent in parent polyether and polyelectrolyte) are generally toxic and unacceptable for use in pharmaceutical and other applications.

However, these prior art graft-comb copolymers are not permanently cross-linked and therefore cannot respond volumetrically to changes in their environment.

However, physical blends are colloidally unstable and either phase separate or dissociate at physiological pH.

Therefore, these blends fail to provide a linear, sustained release of a hydrophobic or amphiphilic compound such as imbibed or loaded drug, for example, in drug delivery applications.

However, by definition, previous gels are unstable upon dilution due to dissociation of the physical aggregates below a certain concentration.

Accordingly, due to dissociation under physiological conditions, previous gels were not able to provide a linear, sustained release of a hydrophobic or amphiphilic compound such as imbibed or loaded drug, for example, in drug delivery applications.

However, due to the steric constrains imposed by chemical linking on both termini, the hydrophobic parts of the amphiphilic copolymer are unable to aggregate at well-defined temperatures and concentrations.

As a result, such previous gels also were not able to provide a linear, sustained release of a hydrophobic or amphiphilic compound such as imbibed or loaded drug, for example, in drug delivery applications.

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