Title:  Non-polymeric sustained release delivery system

United States Patent:  6,120,789

Inventors:  Dunn; Richard L. (Fort Collins, CO)

Appl. No.:  282036

The invention relates to a method and composition for forming an implant in-situ within a body using non-polymeric materials, and the use of such implants as medical devices and drug delivery systems. The composition can be applied to an animal to treat periodontal disease or other tissue defect, enhance compatibility and performance of an implantable article, and deliver a biologically active agent.

SUMMARY OF THE INVENTION

The invention is directed to a non-polymeric composition for in situ formation of a solid matrix in an animal, and use of the composition as a medical device or as a sustained release delivery system for a biologically-active agent, among other uses.

The composition is composed of a biocompatible, non-polymeric material and a pharmaceutically-acceptable, organic solvent. The non-polymeric composition is biodegradable and/or bioerodible, and substantially insoluble in aqueous or body fluids. The organic solvent solubilizes the non-polymeric material, and has a solubility in water or other aqueous media ranging from miscible to dispersible. When placed into an implant site in an animal, the non-polymeric composition eventually transforms into a solid structure. The implant can be used for treating a tissue defect by enhancing cell growth and tissue regeneration, wound and organ repair, nerve regeneration, soft and hard tissue regeneration, and the like.

The composition can include a biologically-active agent (bioactive agent), as for example, an anti-inflammatory agent, an antiviral agent, antibacterial or antifungal agent useful for treating and preventing infections in the implant site, a growth factor, a hormone, and the like. The resulting implant provides a system for delivering the biologically-active agent to the animal.

The composition can also include optional ingredients such as a separate pore-forming agent for generating pores within the matrix, and/or a release rate modification agent for controlling the rate of breakdown of the implant matrix and/or the rate of release of a bioactive agent in vivo from the implant matrix. Examples of pore-forming agents include sucrose, sodium chloride, sodium carbonate, a cellulose-based polymer, and the like. Examples of release rate modification agents include dimethyl citrate, triethyl citrate, ethyl heptanoate, glycerin, hexanediol, and the like. The composition can also include a controlled release component associated with the active agent to control its release from the composition during formation of the implant and/or from the formed implant. Examples of controlled release components include a microcapsule, microsphere, liposome, nanoparticle or other microstructure; a fiber, bead or other macrostructure; a low water-solubility salt of the agent; a complex or covalently-bonded conjugate of the agent and a carrier molecule; and the like.

To form a solid implant in situ, the composition can be placed in a syringe and injected into the body of an animal using a standard needle. The injection may be subcutaneous, intramuscular, intraperitoneal, intralesional, and the like. The composition can also be dispensed by brushing or squirting it onto the surface of a tissue. The material can also be administered as a spray from an aerosol dispensing device under pressure, from a pump dispenser, or other pressure applicator.

The composition can be applied to an implant site such as a void, a tissue defect, surgical incision, the surface of the skin to cover a burn area or surface wound, and the like. The composition is flowable with a consistency that ranges from watery to slightly viscous to a putty or paste. The non-polymeric material will eventually coagulate to a microporous, solid matrix upon the dissipation of the organic solvent into adjacent tissue fluids. Unlike a solid implant, the non-polymeric composition can be manipulated and shaped within the defect site as it solidifies. Advantageously, the moldability of the composition as it hardens allows it to conform to irregularities, crevices, cracks, holes, and the like, in the implant site. The resulting solid matrix is biodegradable, bioabsorbable, and/or bioerodible, and will be gradually absorbed into the surrounding tissue fluids, and become disintegrated through enzymatic, chemical and/or cellular hydrolytic action.

Advantageously, the present non-polymeric composition has a lower flow viscosity than polymeric compositions. Because of this property, compositions can be formulated with a high solid content and low amount of solvent to provide a fluid form that can be administered using a pressure applicator such as injection into tissue through a syringe and needle. The non-polymeric materials can also be used where a high rate of degradation is desired because they are single molecules and require only one hydrolysis reaction before becoming solubilized and metabolized by the body. The non-polymeric compositions can also be enzymatically degraded by mechanisms other than hydrolysis. As such, matrices formed from these materials are degraded from the surface resulting in a bioerodible implant.

Claim 1 of 12 Claims

1. A flowable composition for forming a solid biodegradable implant in situ within a body, comprising:

(a) a non-polymeric, water-insoluble material that is biodegradable,

(b) a minor amount of biodegradable, bioabsorbable thermoplastic polymer; and

(c) a biocompatible, organic solvent that is miscible to dispersible in water or body fluids, and capable of dissipating, diffusing or leaching from the composition into body fluid upon placement within a body, whereupon the non-polymeric material coagulates or precipitates to form the implant.

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