Hydrolytically degradable alkylene oxide based polymers

Inactive Publication Date: 2006-10-26
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0029] Also provided is (i) a polymer activated for conjugation to a biologically active agent such as a protein or peptide, and (ii) the resulting polymer conjugate. The polymer can impart desirable characteristics to a given bioactive agent such as improved water solubility, reduced immunogenicity, and longer circulating half-life, although the reverse thermal gelation characteristics of the polymer itself may be lost.
[0032] Thus, this invention provides a versatile polymer that is especially suited for forming a thermally reversible hydrogel for sustained delivery of biologically active agents. The polymer is easy to prepare and can be synthesized in large quantities. The polymer can be formed in a single reaction with multiple degradable carbonate linkages in the backbone. The hydrogel of this invention can be degraded under physiological conditions to generate oligomers of predetermined molecular weight that can be easily cleared from the body.

Problems solved by technology

Methods such as these result in gels containing non-PEG contaminants.
As a result, degradation and dissolution of the matrix can result in undesirable or toxic components being released into the bloodstream.
Further, the harsh gelling conditions employed in such methods can often inactivate or degrade drug substances incorporated in such hydrogel compositions.
Organic solvents are often toxic and irritating to tissue.
However, Poloxamer-based gels are not biodegradable, making drug release from such systems highly unpredicable.
Moreover, certain poloxamer based gels have been unsuccessful in clinical trials, due not only to performance limitations, but also due to the adverse side effects attributed to the high concentrations of polymer that must be delivered in order to achieve gelation at body temperature.
In general, the development of hydrogel formulations for drug delivery has progressed rather slowly, partially due to the problems described above and additionally due to problems associated with parenteral administration of hydrogels.

Method used

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  • Hydrolytically degradable alkylene oxide based polymers
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  • Hydrolytically degradable alkylene oxide based polymers

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of a Hydrolytically Degradable Oligomer Composed of Copolymer Subunits of Ethylene Oxide-Propylene Oxide-Ethylene Oxide Covalently Linked by Carbonate Bonds, (I)

[0117] An illustrative polymer of the invention was synthesized as follows by coupling to one another block copolymers each composed of a propylene oxide block (i.e., a series of propylene oxide monomers) sandwiched between two ethylene oxide blocks, where the block copolymers are covalently attached to one another by intervening carbonate bonds to form the resulting oligomer.

[0118] Poloxamer 407 (10.0 g, 0.78 mmole) was dissolved in 30 ml of CH3CN in a 50 ml round-bottom flask fitted with a Dean-Stark trap and a reflux condenser. The solution was heated to reflux and 20 ml of solvent was collected. After the Dean-Stark trap was removed, di-(N-succinimidyl) carbonate, DSC (1.1 equivalents, 0.22 g, 0.86 mmole), available from Fluka, and 4-dimethylaminopyridine, DMAP (2 equivalents, 0.19 g, 1.56 mmole) available fr...

example 2

Sol-Gel Characteristics of a Hydrolytically Degradable Oligomer Composed Of Triblock Copolymer Subunits of Ethylene Oxide-Propylene Oxide-Ethylene Oxide Covalently Linked by Carbonate Bonds, (I)

[0124] The oligomeric product, (I), from Example 1 above was dissolved in phosphate buffer (0.1 M, pH 7.0) at 4° C. at a number of different concentrations. The aqueous polymer-containing solutions were placed in a temperature-controlled water-bath. The temperature of the water bath was slowly increased, and the temperature at which each of the solutions became a solid gel (based upon visual inspection) was recorded. The sol-gel phase transition was then further refined by monitoring gel formation within two minutes after solutions of (I) at 4° C. were placed in a water bath at preset temperatures. The data was then used to generate a phase diagram demonstrating the sol-gel behavior of (I) at different concentrations and temperatures and is shown as FIG. 1.

[0125] In looking at FIG. 1, it ca...

example 3

Gel Formation and Degradation of (I)

[0128] The following illustrates another advantage of the polymers of the invention, i.e., their biodegradability.

[0129] Polymer (I) was dissolved in phosphate buffer (0.1 M, pH 7.0) at 4° C. to final concentrations of 5%, 8%, 10%, 12% 15% and 18 wt %, respectively. The aqueous solutions (1 ml) were then each placed in an incubator at a temperature of 37° C. to form a gel. To the gel, 2 ml of phosphate buffer was added and the mixtures were then held at 37° C. until a solution formed. The dissolution of each of the gels at 37° C. was mainly due, not to a physical phase change, but due to their hydrolytic degradation over time (i.e., hydrolysis of the carbonate bonds). The dissolution of these representative gels over time is shown graphically as FIG. 2.

[0130] As can be seen from the dissolution data, dissolution times for each of the gel compositions increased with increasing polymer concentration of the gel. For example, the 5 wt % gel dissolv...

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Abstract

The present invention provides a water soluble, nonpeptidic polymer comprising two or more alkylene oxide-based oligomers linked together by hydrolytically degradable linkages such as carbonates. Typically, the oligomer portion of the polymer is an amphiphilic triblock copolymer having a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks. The polymer can be hydrolytically degraded into oligomers under physiological conditions. In aqueous media, the polymer preferably forms thermally reversible, hydrolytically degradable hydrogels that can be used, for example, for drug delivery and related biomedical applications.

Description

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application Ser. No. 60 / 357,350, the content of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention generally relates to water soluble, hydrolytically degradable, and nonpeptidic polymers. More specifically, the invention is directed to hydrolytically degradable polymers comprising oligomers of particular alkylene oxide triblock copolymers, and to compositions and uses thereof. The polymers are suitable for drug enhancement, in vivo delivery of biologically active agents, and use in medical devices. BACKGROUND OF THE INVENTION [0003] The hydrophilic polymer poly(ethylene glycol), abbreviated “PEG”, is of considerable utility in biological applications and in medicine. PEG is a polymer that is soluble in water and in many organic solvents, is non-toxic, and non-immunogenic. In recent years, the use of PEG has expanded into the biomedical, biotech...

Claims

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Application Information

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IPC IPC(8): A61K31/785C08G8/28A61K47/34C08G64/18C08G65/329C08G65/333
CPCA61K9/06A61K47/34C08G64/183C08G65/04C08G65/329A61K9/00C08G65/33337C08G65/33344C08G65/33396C08L2203/02C08G65/333
Inventor BENTLEY, MICHAEL D.HARRIS, J. MILTONZHAO, XUANBATTLE, WILLIAM DUDLEY IIISHEN, SIAOMING
Owner NEKTAR THERAPEUTICS INC
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