United States Patent:  5,945,115

Assignee:  Atrix Laboratories, Inc. (Fort Collins, CO)

Filed:  August 8, 1997

The invention is directed to an improved system for controlled release of biologically active materials and to a liquid composition for its formation. The liquid composition is composed of a thermoplastic polymer, rate modifying agent, bioactive material and organic solvent. The liquid composition is capable of forming a biodegradable and/or bioerodible microporous, solid polymer matrix. The matrix is useful as an implant in patients (humans and animals) for delivery of biologically active substances to tissues or organs.

Summary of the Invention

The present invention is directed to a polymer system, a method for therapeutic treatment using the polymer system, and a precursor of the polymer system, a liquid composition.

The polymer system is a microporous, solid matrix of a biocompatible, biodegradable thermoplastic polymer, a rate modifying agent and a bioactive material. The system displays control of the rate and extent of release of the bioactive agent from the matrix. As used herein, the term "biologically active material" or "bioactive material" means a drug, medicament, or some other substance capable of producing an effect on a body, e.g., a mammal.

The liquid composition is a combination of an organic solvent, the biocompatible, biodegradable thermoplastic polymer, the rate modifying agent and the bioactive material.

The polymer system is formed by applying the liquid composition to an aqueous medium that is internal (body fluids) or external to the body. After application, the liquid composition coagulates to form the polymer system. Administration of the liquid composition directly into the body forms in situ the polymer system. External addition of the liquid composition to an aqueous liquid forms the polymer system outside the body. The solid implantable polymer system can then be surgically placed into the body. In all embodiments and applications, the polymer system is substantially insoluble in aqueous media.

The process by which the polymer system is formed in part is responsible for development of the rate and release control. Interaction of the liquid composition with an aqueous medium either in situ in the body or external to the body to coagulate the composition into the polymer system at least in part causes the desired controlled release profile as a function of the variation of the below-mentioned parameters and components. Simple combination of these components without passage through the liquid composition will not develop the controlled release profile of this invention.

When the liquid composition is added to the aqueous medium, the organic solvent diffuses into the surrounding medium (body fluids or an external water medium) and the polymer coagulates to form the solid matrix (polymer system). The more or less simultaneous diffusion and coagulation produce the microporous structure of the matrix that in part is believed to be a factor in the establishment of the desired control of rate and extent of release. Under certain conditions of the invention, the structure exhibits a core with large pores of diameters from about 10 to 500 microns and a relatively nonporous skin. The skin in this preferred embodiment actually has extremely fine pores of 0.01 to 0.1 microns in diameter.

Although it is not important for some uses, when the composition is placed in the body, the resulting polymer system adopts the shape of the cavity, pocket or intercellular space into which the composition is placed. When the polymer system is formed outside the body it can be molded or adapted into substantially the appropriate shape of the cavity or other space of the body into which it is being fitted.

Pursuant to the parameters and conditions of the invention, the polymer system can control the sustained release of biologically active materials in vivo. In particular, the rate and extent of release of the biologically active material from the polymer system of the invention are controlled over a range of speeds and amounts. This control is accomplished by variation of: (a) the polymer type and molecular weight, (b) the rate modifying agent, (c) the concentration of the polymer, (d) concentration of the biologically active material, (e) the form of the biologically active material, and (f) the concentration and kinds of other additives present, if any, within the polymer system. Preferably, the rate and extent of release of bioactive material from the polymer system according to the invention can be controlled by varying: (1) the type and molecular weight of the polymer or polymers, (2) the concentration of a suitable rate modifying agent, or a mixture of rate modifying agents and/or (3) the concentration of the polymer. More preferably, the control is accomplished by varying the molecular weight of the polymer and/or the concentration of the rate modifying agent present. Most preferably, the control is accomplished by varying both the molecular weight of the polymer and the concentration of the rate modifying agent. In preferred embodiments, the rate of release increases as polymer molecular weight increases, and independent of the polymer molecular weight, the rate of release increases as the concentration of the plasticizer decreases.

The method of the invention is based upon the therapeutic effect of the in situ controlled release of the bioactive material from the polymer system. The implantation of the liquid composition or implantation of the polymer system preformed as described above can generally occur anywhere within the body of a patient in need of therapeutic treatment. Examples include soft tissue such as muscle or fat; hard tissue such as bone; or a cavity or pocket such as the periodontal, oral, vaginal, rectal, nasal, or the cul-de-sac of the eye. The composition can be administered to the implant site by any suitable method for applying a liquid, as for example, by means of a syringe, needle, cannula or catheter. The polymer system preformed as an implant can be inserted by known surgical techniques.

Claim 1 of 4 Claims

1. A composition suitable for in situ formation of an implant in an animal, comprising:

(a) a pharmaceutically acceptable, biodegradable thermoplastic polymer that is insoluble in aqueous or body fluids;

(b) a biocompatible organic solvent which solubilizes the thermoplastic polymer, is miscible to dispersible in aqueous or body fluids, and is capable of dissipating from the polymer system into surrounding tissue fluid whereupon the thermoplastic polymer forms the implant; and

(c) a biologically active agent capable of enhancing bone growth.

____________________________________________
If you want to learn more about this patent, please go directly to the US Patent and Trademark Office web site to access the full patent.