Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-08-22
2003-10-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S423000, C424S424000, C424S425000, C514S772100
Reexamination Certificate
active
06630155
ABSTRACT:
BACKGROUND OF THE INVENTION
A variety of approaches have been developed to permit controlled, sustained release of a biologically active agent into a subject. Examples of controlled release systems include the polymeric compositions described in U.S. Pat. Nos. 4,938,763; 5,278,201 and 5,278,202. The compositions described in these patents are administered to the body of a subject in a flowable state. Once in the body, the composition coagulates or cures to form a solid implant.
One polymeric composition includes a thermoplastic polymer or copolymer, an organic solvent and a biologically active agent. The thermoplastic polymer is biocompatible, biodegradable and substantially insoluble in aqueous body or tissue fluids. The organic solvent is also biocompatible and miscible to dispersible in aqueous body or tissue fluids. The polymeric composition is flowable and can be introduced into the body using a syringe, for example. When the polymeric composition comes into contact with an aqueous medium. such as body or tissue fluid, the solvent dissipates or diffuses into the aqueous medium. Concurrently, the substantially insoluble thermoplastic polymer precipitates or coagulates to form a solid implant. As the thermoplastic polymer precipitates or coagulates to form the solid matrix, the active agent is trapped or encapsulated throughout the polymeric matrix. The biologically active agent is then released by dissolution or diffusion through the polymeric matrix and/or the biologically active agent is released as the matrix biodegrades.
However, the formation of the solid matrix from the flowable delivery system is not instantaneous. Typically the process can occur over a period of minutes to several hours. During this period, the rate of diffusion of the biologically active agent from the coagulating polymeric composition may be much more rapid than the rate of release that occurs from the subsequently formed solid matrix. This initial “burst” of biologically active agent that is released during implant formation may result in the loss or release of a large amount of the active agent. If the active agent is particularly toxic, this initial release or burst is likely to lead to toxic side effects and may damage adjacent tissues.
Therefore, a flowable delivery system that allows for the in situ formation of an implant while reducing or eliminating the initial “burst effect” would represent a significant advancement. Such delivery systems would permit higher concentrations of an active agent to be safely incorporated into an implant. The efficacy of such systems would also be improved, since a much greater percentage of the active agent would remain in the implant for sustained release and not be lost during the initial burst.
SUMMARY OF THE INVENTION
The invention is directed to a polymer composition which includes a base polymer that is a pharmaceutically acceptable, biocompatible, biodegradable and/or bioerodible, thermoplastic polymer or copolymer which is substantially insoluble in an aqueous medium; a pharmaceutically-acceptable, organic solvent that is miscible to dispersible in an aqueous medium; a biologically active agent; and a polymeric controlled release additive. Preferably, the controlled release additive is a poly(lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block copolymer. When brought in contact with an aqueous enviroment, such as body or tissue fluids which typically surround tissues or organs in an organism, the organic solvent dissipates or disperses into the aqueous or body fluid. Concurrently, the substantially insoluble thermoplastic base polymer precipitates or coagulates to form a solid matrix or implant. The biologically active agent is trapped or encapsulated within the polymeric matrix as the implant solidifies. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it is solidifying to form the solid implant. Once the solid implant is formed, the biologically active agent is released from the solid matrix by diffusion or dissolution from within the polymeric matrix and/or by the degradation of the polymeric matrix.
The invention is also directed towards methods of using the controlled release composition.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the term “tissue site” includes any tissues in an organism. A tissue site is typically surrounded by an aqueous or body fluid such as interstitial fluid, blood, serum, cerebrospinal fluid or peritoneal fluid.
The term “tissue defect” is a subset of “tissue site” and includes tissues, such as abraded tissue, traumatized tissue, a surgical incision or surgically resected tissue. Examples of tissue defects include, but are not limited to, surgical incisions in an internal organ such as an ovary, heart, liver, intestine, stomach, etc.
The term “biodegradable” means that the polymer and/or polymer matrix of the film will degrade over time by the action of enzymes, by hydrolytic action and/or by other similar mechanisms in the human body. By “bioerodible,” it is meant that the film matrix will erode or degrade over time due, at least in part, to contact with substances found in the surrounding tissue fluids or cellular action. By “bioabsorbable,” it is meant that the polymer matrix will be broken down and absorbed within the human body, for example, by a cell or tissue. “Biocompatible” means that neither the polymer, the solvent nor the resulting implant cause substantial tissue irritation or necrosis at the tissue site.
“Flowable” means that the polymer formulation is easy to manipulate and may be shaped and molded within the tissue site as it coagulates. Flowable includes formulations with a low viscosity or water-like consistency to those with a high viscosity, such as a paste-like material. Advantageously, the flowability of the polymer formulation allows it to conform to irregularities, crevices, cracks, and/or holes in the tissue site.
“Substantially insoluble” in an aqueous medium means that the thermoplastic polymer does not dissolve in an aqueous medium.
“Soluble” in an organic solvent means that the thermoplastic polymer dissolves at a concentration of about 10% to about 70% by weight in an organic solvent.
“Initial burst” or “Burst effect” refers to the release of a biologically active agent from the polymeric composition during the first 24 hours after the polymeric composition is contacted with an aqueous fluid. The “Burst effect” is believed to be due to the increased release of biologically active agent from the polymeric composition while it is coagulating to form a solid implant and still in a flowable state.
The present invention relates to an in situ forming biodegradable implant useful as a delivery system for a biologically active agent to adjacent or distant tissues and organs in an animal. The polymer composition of the invention includes a base polymer that is a pharmaceutically acceptable, biocompatible, biodegradable and/or bioerodible, thermoplastic polymer or copolymer which is substantially insoluble in an aqueous medium; a pharmaceutically-acceptable, organic solvent that is miscible to dispersible in an aqueous medium; a polymeric controlled release additive; and a biologically active agent. Preferably, the controlled release additive is a poly(lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block copolymer.
When brought in contact with an aqueous environment, such as body or tissue fluids which typically surround tissues or organs in an organism, the organic solvent dissipates or disperses into the aqueous or body fluid. Concurrently, the substantially insoluble thermoplastic base polymer precipitates or coagulates to form a flexible matrix or film which traps or encapsulates the biologically active agent. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it coagulates to form a solid implant. Because the polymeric controlled release additive is also a thermoplastic polymer, it too
Chandrashekar Bhagya L.
Dunn Richard L.
Jarr Eileen M.
Zhou Mingxing
Atrix Laboratories, Inc.
Di Nola-Baron Liliana
Page Thurman K.
Schwegman Lundberg Woessner & Kluth P.A.
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