Crosslinked hydrogel copolymers

Inactive Publication Date: 2005-01-27
ALKERMES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention advantageously can be used for the synthesis of biodegradable crosslinked hydrogel polymers heretofore unavailable. The synthetic methods of the present invention are easily adaptable to existing polymer synthesis protocols.
The present invention avoids the hydrophobicity of previous lactide- and/or glycolide-based polymers, while at the same time provides for the biodegradability of the resulting crosslinked hydrogel three-dimensional networks, which networks previously lacked acceptable degradation characteristics.
The present invention also provides for the random incorporation of unsaturated functionality into the polyester backbone of linear polymer chains, rather than merely at the ends of the polymer chains. As the amount of unsaturated functionality directly relates to the amount of subsequent crosslinking, controlling the incorporation of this unsaturation permits greater control over the physical properties of the resulting hydrogel, in particular, the consistency of the gel itself as well as the amount of ge

Problems solved by technology

Lactic acid- and glycolic acid-based polymers with high molecular weights are not obtained through direct condensation of the corresponding carboxylic acid due to reversibility of the condensation reaction, backbiting reactions, and the high degree of conversion required.
In contrast, the amide linkage requires more stringent conditions and is not easily hydrolyzed even under strongly acidic or basic conditions.
While these polymers based on lactide, glycolide, and/or caprolactone offer advantages in degradability as just discussed, they also suffer from the disadvantage that they are hydrophobic, i.e., they do not readily absorb or take up water molecules.
As a result, their applicability for use as drug delivery systems and compatibility with living systems can be limited.
However, hydrogel networks are generally insoluble due to the presence of chemical crosslinks (i.e., nodes or junctions) or of physical crosslinks (i.e., entanglements).
As a result, most hydrogels are not biodegradable, which limits their clinical use in the human body.
Nevertheless, the nonbiodegradability of hydrogel networks remains an obstacle i

Method used

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  • Crosslinked hydrogel copolymers
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  • Crosslinked hydrogel copolymers

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Poly(D,L-lactide-co-glycidyl methacrylate)-block-Poly(Ethylene Glycol)-block-Poly(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers via Ring-Opening Copolymerization of D,L-Lactide and Glycidyl Methacrylate Initiated from Poly(Ethylene Glycol) (Mn=4600).

D,L-Lactide (2 g), glycidyl methacrylate (2 mL) and poly(ethylene glycol) (PEG) (8.1 g, Mn=4600) were combined in a necked tube. After melting the reaction mixture at 150° C., 0.2 mL of 1 wt. % solution of 1,4-benzoquinone in dibutyl phthalate as a radical inhibitor and 0.5 mL of a 50 mg / mL solution of stannous octoate in dibutyl phthalate as a catalyst were added to the tube under nitrogen flow. The tube was degassed and sealed under vacuum. The reaction mixture was immersed in an oil bath and held at 175° C. for one hour. After opening the tube following the one hour reaction time, the reaction mixture was dissolved in THF and precipitated in ether. The copolymer that was obtained (Sample 1) was isolated by fil...

example 2

Synthesis of Poly(D,L-Lactide-co-Glycidyl Methacrylate)-block-Poly(Ethylene Glycol)-block-Poly(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers Containing Different Weight Ratios of D,L-Lactide and PEG (Mn=4600).

Poly(D,L-lactide-co-glycidyl methacrylate)-block-poly(ethylene glycol)-block-poly(D,L-lactide-co-glycidyl methacrylate) block copolymers with various D,L-lactide to poly(ethylene glycol) ratios were prepared according to the synthesis procedure described in Example 1, where PEG=poly(ethylene glycol) (Mn=4600); DLLA=D,L-lactide; and GMA=glycyidyl methacrylate. The results are summarized in Table 1.

TABLE 1PEG:DLLA:GMAPEG:DLLA:GMAPEG:DLLA:GMASample(wt. %:wt. %:wt. %)(mol:mol:mol)(mol:mol:mol)MwIVNo.FeedFeed1H NMR(g / mol)Mw / Mn(dL / g)166.5:16.4:17.11.0:8.2:9.1 1.0:1.3:1.8 10,3001.090.182A66.7:24.7:8.6 1.0:12.7:4.51.0:8.1:1.3 10,7001.090.17 2B*44.3:44.3:11.41.0:34.5:9.11.0:22.4:2.111,7001.080.202C66.5:33.5:0.0 1.0:16.1:0.01.0:14.0:0.010,1001.110.17

*Reaction time of 2 hour...

example 3

Synthesis of Poly(D,L-Lactide-co-Glycidyl Methacrylate)-block-Poly(Ethylene Glycol)-block-Poly(D,L-Lactide-co-Glycidyl Methacrylate) Block Copolymers Containing PEG with Different Molecular Weights.

Poly(D,L-lactide-co-glycidyl methacrylate)-block-poly(ethylene glycol)-block-poly(D,L-lactide-co-glycidyl methacrylate) block copolymers with various PEGs of different molecular weights were prepared according to the synthesis procedure described in Example 1, where PEG=poly(ethylene glycol) of the molecular weight indicated; DLLA=D,L-lactide; and GMA=glycyidyl methacrylate. All reaction times were 2 hours at 175° C. The results are summarized in Table 2.

TABLE 2PEG:DLLA:GMAPEG:DLLA:GMAPEG:DLLA:GMASolubility inSamplePEG(wt. %:wt. %:wt. %)(mol:mol:mol)(mol:mol:mol)Water atNo.(Mn)FeedFeed1H NMR20 wt. %3A10,00044.3:44.3:11.41.0:69.4:18.11.0:26.7:2.3Soluble2B4,60044.3:44.3:11.41.0:34.5:9.1 1.0:22.4:2.1Soluble3C3,35044.3:44.3:11.41.0:23.3:6.1 1.0:13.5:1.0Soluble3D1,50044.3:44.3:11.41.0:10....

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Abstract

The present invention relates to crosslinked polymers, synthesized through ring-opening polymerization of ethylenically unsaturated epoxides, in combination with α-hydroxy acids using a hydrophilic macroinitiator, such as poly(ethylene glycol), to form substituted copolymers having ethylenically unsaturated functionality randomly distributed along the polyester polymer backbone. That copolymer is subsequently crosslinked to form a hydrogel network. More particularly, the present invention relates to the synthesis of biodegradable poly(α-hydroxy acid-co-glycidyl methacrylate)-block-poly(ethylene glycol)-block-poly(α-hydroxy acid-co-glycidyl methacrylate) copolymers, which are subsequently crosslinked to form hydrogel networks. The invention also relates to the use of these hydrogel networks in various applications, in particular, for the controlled release of drugs and proteins.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the synthesis of crosslinked polymers. More particularly, the present invention relates to biodegradable crosslinked hydrogel copolymers. 2. Related Art Interest in the synthesis of new degradable polymers has expanded in recent years. The increased interest in the synthesis of new degradable polymers stems in part from the use of synthetic polymers in medical applications. In many medical applications, it is advantageous that the polymer be able to degrade and that the degradation products also must be compatible with the human body, i.e., be nontoxic. In this situation, the polymers are termed biodegradable, indicating their ability to degrade due to biological processes occurring inside the human body. As early as the 1960s, synthetic polymers were used in the field of surgical medicine as suture material. The polymeric suture material was both biodegradable and absorbable, that is, the pol...

Claims

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Application Information

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IPC IPC(8): C08G63/664C08G65/14C08G65/332C08J3/16C08L67/00C08L71/02
CPCC08G63/664C08G65/14C08G65/3324C08G2650/34C08G2650/58C08L71/02C08J3/16C08L67/00C08L2666/18
Inventor ASGARZADEH, FIROUZCOSTANTINO, HENRY R.
Owner ALKERMES INC
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