Acryloyloxyethylphosphorylcholine Containing Polymer Conjugates and Their Preparation

a polymer and phosphorylcholine technology, applied in the field of polymer reagents and conjugates, can solve the problems of short biological half-life, unsatisfactory forms, painful and/or inconvenient, etc., and achieve the effect of reducing steric hindrance, preventing or reducing the efficiency of bonding

Inactive Publication Date: 2010-07-01
KODIAK SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0120]In one embodiment, the phosphorylcholine polymer is covalently bonded to a spacer and the biologically active agent is covalently bonded to the spacer. That is, in certain instances it may be useful to attach a biologically active agent to the phosphorylcholoine containing polymers of the invention using a spacer such as (Steve, may want to mention a few linker types here). For example, covalently bonding a phosphorylcholoine containing polymer to a biologically active agent by use of a spacer may reduce steric hindrance which prevents or reduces the efficiency of the bonding (i.e., the chemical bonding reaction) that provides for the coupling of the phosphorylcholoine containing polymer to the biologically active agent.

Problems solved by technology

However, even where direct administration, such as by injection, of biologically active agents is possible, formulations may be unsatisfactory for a variety of reasons including the generation of an immune response to the administered agent and responses to any excipients including burning and stinging.
Even if the active agent is not immunogenic and satisfactory excipients can be employed, biologically active agents can have a limited solubility and short biological half-life that can require repeated administration or continuous infusion, which can be painful and / or inconvenient.
Less frequent dosing reduces the overall number of injections, which can be painful and which require inconvenient visits to healthcare professionals.
Although some success has been achieved with PEG conjugation, “PEGylation” of biologically active agents, remains a challenge as PEG conjugation may result in the loss of biological activity.
While branched polymer may overcome some of the problems associated with conjugates formed with long linear PEG polymers, neither branched nor linear PEG polymer conjugates completely resolve the issues associated with the use of conjugated bioactive agents.
Both linear and branched PEG conjugates can, for example, suffer from rates of degradation that are either too long or too short.
A rapid rate of degradation can result in a conjugate having too short of an in vivo half-life, whereas, too slow of a rate of degradation can result in an unacceptable long conjugate half-life in vivo.

Method used

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  • Acryloyloxyethylphosphorylcholine Containing Polymer Conjugates and Their Preparation
  • Acryloyloxyethylphosphorylcholine Containing Polymer Conjugates and Their Preparation
  • Acryloyloxyethylphosphorylcholine Containing Polymer Conjugates and Their Preparation

Examples

Experimental program
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Effect test

example 1

Preparation of 2-Ethylacrylic Acid From Diethyl Malonate

[0381]Ethylacrylic acid was prepared from diethyl malonate by preparation of 2-carbethoxybutyric acid that was subsequently converted into 2-ethylacrylic acid (EAA).

2-Carboethoxybutyric Acid

[0382]Diethyl ethylmalonate was stirred overnight with 95% ethanol in the presence of 1M KOH. The white precipitate that forms was filtered out of solution, and the filtrate was concentrated under reduced pressure (e.g., on a rotary evaporator). The yellowish oil obtained upon concentration of the filtrate was added to the precipitate and the mixture was dissolved in a minimum amount of water. After acidification with dilute aqueous HCl to a pH of 2, an oil separates from the solution. The oil was taken up into diethyl ether and the aqueous layer was extracted three times with further with diethyl ether. The ether extracts 0.92 were combined, dried over magnesium sulfate and filtered. A quantitative yield of 2-carboethoxybutyric acid was obt...

example 2

Preparation of 2-methacryloyloxyethyl phosphorylcholine (HEMA-PC or MPC)

[0384]

[0385]To a solution of 2-hydroxyethyl methacrylate (HEMA) (4.4 g; 40 mmol) in dry THF (40 mL) was added dry triethylamine (3.4 g, 40 mmol). This mixture was stirred at room temperature for 3 minutes, then cooled to −20° C. To the cooled solution was added COP (4.5 g, 40 mmol) as a solution in THF (20 mL) over a period of 1 hour. The temperature of the reaction mixture was maintained around −20° C. The white precipitate was filtered, and the remaining solution concentrated under reduced pressure to yield 6.7 g (71%) of 2-(2-oxo-1, 3, 2, dioxaphospholoyloxy)ethylmethacrylate (OPEMA) as pale yellow liquid. OPEMA (4.0 g, 16 mmol) was stirred in dry acetonitrile (30 mL) in a reaction bottle. The bottle was cooled to −20° C., and anhydrous trimethylamine (4 mL) was added rapidly to the solution. The bottle was closed quickly, and the mixture heated to 60° C. for 24 hours, then kept at −10° C. for 12 hours. MPC w...

example 3

Preparation of 2-Bromo-2-methyl-propionic acid pyrrolidin-1-yl ester

[0386]

[0387]A solution of N-hydroxysuccinimide (NHS) (3.0 g, 26 mmol) in dry methylene chloride (300 mL) was stirred under an inert (argon or nitrogen) atmosphere. Triethylamine (7.3 mL, 52 mmol) was added, the mixture was cooled to 0° C., and 2-bromo-2-methylpropionyl bromide (3.9 mL, 31 mmol) was added dropwise over a period of 15 minutes. The mixture was stirred for 1 hour at 0° C., then warmed to room temperature and stirred overnight. Most of the solvent was removed by evaporation, and the remaining mixture was diluted with cold water (400 mL), and extracted with diethyl ether (3×30 mL), then washed with aqueous potassium carbonate (3×30 mL) and 1M HCl(aq) (3×30 mL). The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated to give a brown solid. Crystallization from ethyl acetate gave the desired product as a white powder (2.62 g, 39%). 1H NMR (CDCl3) 5 (ppm) 2.09 (s, 6H, CH3...

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Abstract

The present invention relates to polymeric reagents and conjugates thereof, methods for synthesizing the polymeric reagents and conjugates, pharmaceutical compositions comprising the conjugates and methods of using the polymer conjugates including therapeutic methods where conjugates are administered to patients.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional patent application No. 60 / 776,916 filed Feb. 28, 2006, the disclosure of which is incorporated in its entirety herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to polymeric reagents and conjugates thereof, methods for synthesizing the polymeric reagents and conjugates, pharmaceutical compositions comprising the conjugates and methods of using the polymer conjugates including therapeutic methods where conjugates are administered to patients.BACKGROUND OF THE INVENTION[0003]Efforts to formulate biologically active agents for delivery must deal with a variety of variables including the route of administration, the biological stability of the active agent and the solubility of the active agents in physiologically compatible media. Choices made in formulating biologically active agents and the selected routes of administration can affect the bioavailability o...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/16C07K14/435C07K14/755C07K14/745C12N9/96C07K14/62C07K14/555C07K17/00C07K14/575C07K14/765A61K38/28A61K38/43A61K38/21A61K38/20A61K39/44A61K38/38A61P1/00
CPCC08F293/005A61K47/48176A61K47/58A61P1/00A61P25/00A61P35/00A61P5/06A61P7/06
Inventor CHARLES, STEPHEN A.
Owner KODIAK SCI
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