Crosslinked hydrogel copolymers

Details Crosslinked hydrogel copolymers Crosslinked hydrogel copolymers

2002-10-18

2004-10-05

Sellers, Robert (Department: 1712)

Colloid systems and wetting agents; subcombinations thereof; pro

Continuous or semicontinuous solid phase

The solid phase contains organic material

C424S436000, C424S501000, C514S772100, C514S772200, C516S102000, C524S604000, C525S059000, C525S404000, C525S445000, C525S450000

Reexamination Certificate

active

06800663

ABSTRACT:

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 polymers decomposed after a period of time after implantation in the human body, and those decomposition products were absorbed by the human body without any adverse or toxic effects.
In addition to use as suture material, degradable polymers have been used in other biomedical applications, such as polymer-based drug delivery systems. In such a system, degradable polymers are used as a matrix for the controlled or sustained delivery or release of biologically active agents, such as protein drugs, to the human body. In addition, the development of endoscopic surgical techniques has resulted in the need for developing such degradable drug delivery systems wherein the placement of the drug delivery device is targeted for specific anatomical locations. Examples of such polymer-based drug delivery systems are described in the following U.S. patents: U.S. Pat. No. 6,183,781, entitled “Method for Fabricating Polymer-based Controlled-release Devices”; U.S. Pat. No. 6,110,503, entitled “Preparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agent”; U.S. Pat. No. 5,989,463, entitled “Methods for Fabricating Polymer-based Controlled-release Devices”; U.S. Pat. No. 5,916,598, entitled “Preparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agent”; U.S. Pat. No. 5,817,343, entitled “Method for Fabricating Polymer-based Controlled-release Devices”; U.S. Pat. No. 5,650,173, entitled “Preparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agent.” Other examples of polymer-based drug delivery systems are described in U.S. Pat. No. 5,922,253, entitled “Production Scale Method of Forming Microparticles” and U.S. Pat. No. 5,019,400, entitled “Very Low Temperature Casting of Controlled Release Microspheres,” the technology described therein also known as Prolease®. All of the above-identified patents are assigned to Alkermes Controlled Therapeutics, Inc. of Cambridge, Mass., and are incorporated herein by reference.
Degradable polymers have also been used in other biomedical applications, including use as polymer scaffolds for tissue engineering, and are described in U.S. Pat. No. 6,103,255, for example, incorporated herein by reference. Additional biomedical applications for synthetic biodegradable polymers include use with fracture fixation, for example, as absorbable orthopedic fixation devices, and are described in U.S. Pat. Nos. 5,902,599 and 5,837,752, both of which are incorporated herein by reference. Synthetic biodegradable polymers are also used in dental applications, and are described, for example, in U.S. Pat. No. 5,902,599.
The wide variety of biomedical applications just described for synthetic biodegradable polymers demonstrates the need for the development of different types of polymers with varying physical properties for use in various biomedical applications.
Synthetic degradable absorbable polymers already developed to date for use in biomedical applications include, for example, poly(p-dioxanone), which is an alternating ether-ester polymer, and its copolymers; polycaprolactone; polyhydroxyalkanoates; poly(propylene fumarate); poly(ortho esters); other polyesters including poly(block-ether esters), poly(ester amides), poly(ester urethanes), polyphosphonate esters, and polyphosphoesters; polyanhydrides; polyphosphazenes; poly(alkylcyanoacrylates); and polyacrylic acids, polyacrylamides, and their hydrogels. These synthetic absorbable polymers are discussed in detail in
Handbook of Biodegradable Polymers
, edited by Domb, Kost, and Wiseman (Harwood Academic Pub. 1997), incorporated herein by reference.
In addition, synthetic polymers based on the polymerization of caprolactone, lactic acid, and glycolic acid have become mainstays in the field of degradable polymers, in particular the field of degradable polyesters, and are available commercially. Caprolactone is the cyclic ester derivative of hydroxy caproic acid, HO(CH
2
)
5
CO
2
H, and can be ring-opened to form the polyester poly(caprolactone), —[O(CH
2
)
5
CO
2
]—. It should be noted that caprolactone has two structural isomers, designated &egr;- and &dgr;-caprolactone. Any discussion of caprolactone generally applies to both forms, unless specifically noted.
Polylactide, polyglycolide, and the copolymers of lactide with glycolide are known for their applications as biodegradable polymers because of their proven biocompatibility and versatile degradation properties. 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. Rather, lactic acid- and glycolic acid-based polymers are typically obtained by ring-opening polymerization of the corresponding diester dimers, lactide and glycolide, respectively, themselves. Alternatively, the reaction can be carried out as a condensation of lactic and glycolic acid. The resulting polymers of these polymerization reactions are poly(lactic acid), also referred to as poly(lactide), abbreviated PLA and poly(glycolic acid), also referred to as poly(glycolide), abbreviated PGA. Copolymers incorporating both monomers are also available and are termed poly(lactide-co-glycolides) abbreviated PLGA and poly(glycolide-co-lactides) abbreviated PGLA, or collectively PLGs. U.S. Pat. No. 5,650,173, incorporated herein by reference, describes examples of these commercially available polymers and copolymers based on lactic acid and glycolic acid. It should be noted that lactide has two structural isomers, denoted D and L. Any discussion of lactide generally is referring to a racemic mixture of both isomers, i.e., D,L-lactide, abbreviated DLLA, unless specifically noted.
All of these polymers and copolymers derived from caprolactone, lactic and glycolic acid contain ester linkages in the backbone of the polymer chain. The presence of this ester linkage provides the necessary functionality to permit degradability, particularly biodegradability in the human body. As opposed to other linkages, such as amides, which require severe conditions in order to decompose, the ester linkage undergoes hydrolysis under even mildly basic conditions such as those found in vivo. In contrast, the amide linkage requires more stringent conditions and is not easily hydrolyzed even under strongly acidic or basic conditions. In vivo, the only available route for cleavage of an amide bond is enzymatic, and that cleavage is often specific to the amino acid sequence. The highly crystalline nature of polyamides, e.g., nylon, further slows degradation by preventing or blocking access to the amide bond by water molecules and enzymes.
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. For example, polylactide has a very low water uptake

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