Title:  Degradable heterobifunctional poly(ethylene glycol) acrylates and gels and conjugates derived therefrom

United States Patent:  6,362,276

Assignee:  Debio Recherche Pharmaceutique S.A. (CH)

Filed:  January 6, 1999

A heterobifunctional poly(ethylene glycol) is provided having a hydrolytically degradable linkage, a first terminus comprising an acrylate group, and a second terminus comprising a target such as a protein or pharmaceutical agent or a reactive moiety capable of coupling to a target. Hydrogels can be prepared. The hydrogels can be used as a carrier for a protein or a pharmaceutical agent that can be readily released in a controlled fashion.

SUMMARY OF THE INVENTION

This invention provides heterobifunctional acrylates of poly(alkylene oxides), especially poly(ethylene glycol) (PEG) acrylates having linkages that are hydrolytically degradable and conjugates prepared from these acrylates having target materials such as proteins covalently linked thereto. Hydrogels can also be prepared from these acrylates. The target materials can be released from the hydrogels through controllable hydrolytic degradation of the hydrogels.

In one embodiment of the invention, heterobifunctional PEG is provided which is represented by the formula:

CH₂=CZ--CO₂ --PEG--W--Q

where Z is an alkyl group or hydrogen atom, W is a hydrolytically unstable linkage comprising a hydrolyzable covalent bond, and Q is a reactive moiety capable of reacting with a target to form a covalent linkage thus linking the PEG polymer to the target.

In another embodiment, this invention also provides a heterobifunctional PEG with a hydrolyzable linkage W in the PEG backbone and having an acrylate group at one terminus and a reactive moiety Q at the other terminus. The heterobifunctional PEG is represented by the formula of:

CH₂=CZ--CO₂ --PEG--W--PEG--Q

where Z is an alkyl group or hydrogen atom, W is a hydrolytically unstable linkage comprising a hydrolyzable bond, and Q is a reactive moiety capable of reacting with a moiety on a target such as protein or a drug.

The present invention also encompasses a conjugate having a formula of:

(CH₂=CZ--CO₂ --PEG--W--L)_x --T

where Z and W are as described above, T is a target, e.g., a protein or a drug, L is a covalent linkage formed in the reaction between Q and a reactive moiety of T, and x is a number from 1 to 10.

In yet another embodiment of the invention, a conjugate of heterobifunctional PEG and a target is provided having the formula

(CH₂=CZ--CO₂ --PEG--W--PEG--L)_x --T

where Z and W are as described above, T is a target, e.g., a protein or a drug, which is linked to the PEG polymer as a result of the reaction between the reactive moiety Q and a moiety on T, L is a covalent linkage formed in the reaction between Q and a reactive group of T, and x is a number of from 1 to 10.

This invention further provides polymers formed by vinyl polymerization of the aforementioned heterobifunctional PEG or conjugates thereof, represented by the formula: CH₂=CZ--CO₂ --PEG--W--Q, (CH₂=CZ--CO₂ --PEG--W--L)_x --T, CH₂=CZ--CO₂ --PEG--W--PEG--Q, and (CH₂=CZ--CO₂ --PEG--W--PEG--L)_x --T. The weak chemical linkages in the thus formed polymers provide for hydrolytic breakdown and concomitant release of bound target molecules. For example, polymerization of the above-mentioned conjugate:

(CH₂=CZ--CO₂ --PEG--W--PEG--L)_x --T

yields a water-soluble acrylate polymer which upon hydrolytic degradation liberates a smaller PEG fragment bearing a target such as a protein or a drug.

In another embodiment of the invention, hydrogels are formed by copolymerizing a heterobifunctional PEG conjugate of this invention with a PEG molecule having two or more acrylate groups ("PEG multiacrylate"). Exemplary examples of such PEG multiacrylate can be:

CH₂=CHCO₂ --PEG--O₂ CCH=CH₂

or

CH₂=CHCO₂ --PEG--O--CH₂ CO₂ CH(CH₃)CH₂ CONH--PEGO₂ CCH=CH₂

The hydrogel of the present invention is a cross-linked network in which protein or other target molecules are covalently bound to a degradable matrix. Because of the hydrolytically unstable linkages W in the hydrogels, the target molecules such as drug or protein molecules can be released as a result of the breakdown of the unstable linkages.

In the heterobifunctional PEG, polymers, and hydrogels of the present invention, the hydrolytic breakdown of the hydrolytically unstable linkages W can be controlled in part by varying W, in particular the number of methylene group proximate to the hydrolyzable bond in W. Specifically, as the number of methylene group increases, the hydrolysis rate of the hydrolyzable bond of W decreases.

Further, in the hydrogel of the present invention, the release rate of the target from the hydrogel can also be controlled by varying the number x in the above formula of the PEG conjugate, i.e., the number of the PEG acrylate linked to the target. The release rate of the target from the hydrogel is decreased when the number of PEG acrylate linked to the target is increased, and vice versa.

Thus, the present invention provides heterobifunctional PEG and hydrogels formed therefrom having target molecules covalently linked to the hyrogels. In contrast to the PEG hydrogels known heretofore in the art, the target molecules can be released in a controlled fashion from the PEG hydrogels of the present invention. Further, since the release rate of the target can be determined by both the number of the attached PEG and the structure of the hydrolytically unstable linkage in the attached PEG, more precise control of the release kinetics is made possible. Therefore, suitable drug carriers for drug delivery which meet different drug release requirements can be made in accordance with the present invention.

Claim 1 of 4 Claims

That which is claimed is:

1. A hydrogel comprising a co-polymerization product of a multiacrylate and at least one compound selected from the group consisting of compounds represented by the formula:

CH₂=CZ--CO₂ --POLY--W--POLY'--Q₁,

(CH₂=CZ--CO₂ --POLY--W--POLY'--L)_x --T,

CH₂=CZCO₂ --POLY--W--Q,

and

(CH₂=CZCO₂ --POLY--W--L)_x --T,

where

Z is H or an alkyl group;

POLY and POLY' are poly(alkylene oxides) that may be the same or different and are represented by the formula --(CH₂ CHRO)_n --CH₂ CHR-- in which R is H or alkyl, and n ranges from about 10 to about 4000;

W represents a hydrolytically unstable linkage;

Q represents a moiety reactive with a target molecule T;

L is hydrolytically stable linkage;

x is an integer of 1-10; and

T is a target molecule.

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