Natural biodegradable matrices and uses thereof

Abstract

Matrices formed from a natural biodegradable material and that exhibit surface degradation in the presence of an enzyme are described. Matrices including a bioactive agent can be implanted or formed in a subject for release of the bioactive agent upon degradation of the matrix. The matrix can be provided in various forms, including coatings for implantable devices, implants, and in-situ formed matrices. The matrix can also be in the form of a medical device having a structure that is used to treat a medical condition.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present non-provisional application claims the benefit of commonly owned provisional Application having Ser. No. 60 / 719,466, filed on Sep. 21, 2005, and entitled ARTICLES AND COATINGS INCLUDING NATURAL BIODEGRADABLE POLYSACCHARIDES AND USES THEREOF.TECHNICAL FIELD[0002]The present invention relates to natural biodegradable matrices and medical uses thereof. Bioactive agents can be included in the matrices to provide a therapeutic effect to a patient.BACKGROUND[0003]Recently, the use of drug-eluting stents (DES) in percutaneous coronary interventions has received much attention. DES are medical devices that present or release bioactive agent into their surroundings (for example, luminal walls of coronary arteries). Generally speaking, a bioactive agent can be coupled to the surface of a medical device by surface modification, embedded, and released from within polymeric materials (matrix-type), or surrounded by and released through a c...

AI Technical Summary

Benefits of technology

[0033]Another advantage of the invention is that the natural biodegradable matrices (such as polysaccharide-based matrices) are more resistant to hydrolytic degradation than other biodegradable polymers, such as poly(lactides). As an example, degradation of the natural biodegradable polysaccharides of the invention are primarily enzyme-mediated, with minimal or no hydrolysis of the natural biodegradable polysaccharide occurring when a natural biodegradable polysaccharide-containing coating is prepared under ambient conditions. This allows natural biodegradable polysaccharide-based coatings to remain substantially stable (for example, resistant to degradation) prior to placing the coated-article in vivo. For example, a natural biodegradable polysaccharide coated article can be manipulated in a non-biological, aqueous-based-medium without risk that the coating will prematurely degrade due to non-enzyme-mediatated hydrolysis. Other coatings that are based on biodegradable polymers such as poly(lactide) or poly(lactide-co-glycolide) are subject to hydrolysis even at relatively neutral pH ranges (e.g., pH 6.5 to 7.5) and therefore do not offer this advantage.

[0034]Therefore, the invention includes natural biodegradable-material containing compositions, coatings, articles, and methods of preparing such that have the advantage of providing stability in the presence of an aqueous environment.

[0035]In one aspect, the invention provides a shelf-stable composition for preparing a biodegradable coating, the shelf stable composition comprising a natural biodegradable polysaccharide comprising coupling groups. These compositions could be obtained or prepared, according to the details provided herein, and then stored for a period of time before the composition is used to form a biodegradable coating or article, without significant degradation of the natural biodegradable polysaccharide occurring during storage. Accordingly, the invention also provides methods for preparing a biodegradable coating comprising preparing a biodegradable coating composition comprising a natural biodegradable polysaccharide comprising coupling group; storing the coating composition for an amount of time; and then using the coating composition to prepare a biodegradable coating or a biodegradable article. In some aspects, the biodegradable article is formed in situ, for example, by promoting the polymerization of the natural biodegradable polysaccharide within the body. Optionally, one or more bioactive agents and / or microparticles can be added before or after storage of the coating composition.

[0036]In a related aspect, the invention also provides the advantage of being able to perform methods wherein the natural biodegradable polysaccharide is subject to exposure to an aqueous solution without risking significant degradation of the natural biodegradable polysaccharide. For example, the natural biodegradable polysaccharide may be contacted with an aqueous solution in a synthetic or post-synthetic step, including addition synthesis reactions and purification steps, or a coating that includes the natural biodegradable polysaccharide can be contacted with an aqueous solution in, for example, a sterilization step or a step that involves incorporation of a bioactive agent into the biodegradable coating.

[0037]In yet another aspect, the invention relates to the stability of an article or a coating that is formed on an article. The invention provides a method comprising obtaining an article formed from, or having a coating comprising, a natural biodegradable polymer, and then contacting the article with an aqueous solution for a period of time wherein the article or coating remains predominantly stable in the solution. The aqueous solution can be, for example, a storage solution, a solution that is used to hydrate the surface of the coated device, or an aqueous sterilization solution.

[0038]Degradation of the coating or article formed of a natural biodegradable matrix may commence when placed in contact with a body fluid or tissue, which may include an enzyme capable of degrading the matrix at its surface. The enzyme can be a natural biodegradable polysaccharide-degrading enzyme, such as a carbohydrase.

Problems solved by technology

However, the molecular weight, porosity of the polymer, a greater percentage of coating exposed on the medical device, and the thickness of the polymer coating can contribute to adverse reactions to the medical device.

These types of biodegradable materials have the potential to degrade into products that cause unwanted side effects in the body by virtue of their presence or concentration in vivo.

These unwanted side effects can include immune reactions, toxic buildup of the degradation products in the liver, or the initiation or provocation of other adverse effects on cells or tissue in the body.

Another problem is that preparations of some biodegradable materials may not be obtained at consistent purity due to variations inherent in natural materials.

Inconsistencies in preparations of biodegradable materials can result in problematic coatings.

However, as the sealant materials degrade and are resorbed by the body, cells involved in tissue repair infiltrate the porous material and replace the sealant materials.

Despite their uses, there are drawbacks and concerns with using these types of sealant materials.

One particular problem is that it is difficult to produce consistent sealant compositions from these animal sources due to batch-to-batch variations inherent in their production.

In these cases there is the possibility that bovine collagen preparations may contain unwanted contaminants that are undesirable for introduction into a human subject.

Additional concerns are that preparations from animal sources may provide other unwanted contaminants, such as antigenic factors.

These antigenic factors may promote a localized immune response in the vicinity of the implanted article and foul its function.

These factors may also cause infection as well as local inflammation.

While synthetic materials can be used in the preparation of medical compositions, these synthetic materials have the potential of degrading into non-naturally occurring products.

These non-naturally occurring products have the potential to be at least partially toxic to the organism or immunogenic and cause inflammation, as well as infection, at or around the site of implantation.

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