Biodegradable bioactive agent releasing matrices with particulates

Abstract

The present invention is directed to biodegradable polymeric matrices for the controlled release of a hydrophilic bioactive agent. Generally, the biodegradable matrices include an aliphatic polyester copolymer and microparticulates that include the hydrophilic bioactive agent. In some embodiments, the matrix includes a second biodegradable polymer comprising hydrophilic and hydrophobic portions. Exemplary matrix forms are device coatings and medical implants. Matrices of the invention demonstrated high bioactive agent loading, were able to modulate release of the bioactive agent in a therapeutic manner, and also maintained high levels of activity for therapeutically useful large molecule bioactive agents, such as proteins.

Description

PRIORITY CLAIM[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61 / 217,615 filed Jun. 2, 2009, entitled BIODEGRADABLE BIOACTIVE AGENT RELEASING MATRICES WITH PARTICULATES, the disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to biodegradable polymeric matrices for hydrophilic drug delivery and related methods. More specifically, the present invention relates to biodegradable polymeric matrices containing particulates and related methods.BACKGROUND OF THE INVENTION[0003]In recent years, much attention has been given to site-specific delivery of drugs within a patient. Site-specific drug delivery focuses on delivering the drugs locally, i.e., to the area of the body requiring treatment. One benefit of the local release of bioactive agents is the avoidance of toxic concentrations of drugs that are at times necessary, when given systemically, to achieve therapeutic concentrations at ...

AI Technical Summary

Benefits of technology

[0009]The hydrophilic bioactive agent, being in the form of microparticulates, can be dispersed throughout the biodegradable matrix in discrete microdomains. The use of microparticulates is advantageous over other matrix-forming processes that may result in the hydrophilic bioactive agent becoming aggregated or grossly non-dispersed in the matrix. Further, using microparticulates, the elution control matrix can have high bioactive agent loading. Finally, the use of bioactive agent in microparticulate form, along with the processing steps described herein, allows the bioactive agent that is incorporated into the matrix to retain most or all of its activity.

[0010]The matrices of the invention provide desirable properties for use in association with, or in the form of, an implantable or injectable medical article. For example, when used in the form of coating on the surface of an implantable medical device, the matrices demonstrate good adhesion to the device surface, compliance, and durability.

[0011]In addition, it has been found that the matrices of the invention can include a high load of hydrophilic bioactive. Even at high loads, the hydrophilic bioactive agent was capable of being released from the matrix in a controlled manner. Therefore, following implantation, an initial release burst, which can deplete a substantial amount of bioactive agent from the biodegradable polymeric matrix, can be avoided. In addition, the matrix can be completely degraded, making all of the bioactive agent contained in the matrix available to the subject after a period of implantation. This allows the implants to be useful for the prolonged release of therapeutically effective amounts of bioactive agents to treat medical conditions. For example, the matrices can be used to deliver a hydrophilic bioactive agent requiring a course of treatment for a period of time of greater than a month. Given the prolonged release of bioactive agent, the need for periodic administration of the bioactive agent is not required. This is beneficial as it eliminates or significantly reduces need for patient compliance.

[0013]In one aspect, the invention provides a biodegradable bioactive agent-releasing matrix that includes a biodegradable polymer comprising an aliphatic polyester copolymer, the aliphatic polyester comprising monomeric units of the following formulawherein R1 is a divalent saturated or unsaturated hydrocarbon group that includes two carbon atoms (such as a monomeric unit derived from lactide), and wherein the monomeric unit is present in the aliphatic polyester copolymer in an amount of greater than 17% by weight. The biodegradable bioactive agent-releasing matrix also includes microparticulates that comprise a hydrophilic bioactive agent. In an implantable or injectable form, the biodegradable bioactive agent-releasing matrix comprises a surface that is in direct contact with body fluid and / or body tissue. It was found that using this arrangement, polymeric matrices formed using the aliphatic polyester with amounts of lactide greater than 17% by were able to suppress the burst of the hydrophilic bioactive agent, even at high loading levels.

[0015]In this embodiment of the invention, it was found that the use of aliphatic polyesters with amounts of a monomeric unit of formula II greater than 15% rendered the matrix very sensitive to the inclusion of second biodegradable polymer and its effect on elution of the hydrophilic bioactive agent. In other words, the aliphatic polyesters comprising the higher caprolactone content, when combined with the second polymer, provided biodegradable matrices that not only showed the ability to suppress the burst of the hydrophilic bioactive agent (even when the bioactive agent was used at high loads), but also revealed remarkable tunability for providing a desired bioactive agent release rate. It was found that the release rate could be readily tuned by adjusting the ratio between the first and second biodegradable polymers in the matrix.

Problems solved by technology

Further, using microparticulates, the elution control matrix can have high bioactive agent loading.

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