Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Patent
1997-10-09
2000-07-04
Levy, Neil S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
424486, 424487, 424488, 424405, 424406, 424417, 424422, 424423, 424 851, 424 854, 424 856, 4241581, 530351, 514 12, 514803, 514825, 514885, 514889, 514903, 514921, 514974, A61K 916
Patent
active
060835346
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
The present application is the national stage under 35 U.S. C. .sctn.371 of international application PCT/US96/03121, filed Mar. 1, 1996, and claims priority from Israeli application 112,834, filed Mar. 1, 1995.
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions for controlled delivery of soluble forms of receptors from a polymeric matrix.
BACKGROUND OF THE INVENTION
Controlled release systems deliver a drug at a predetermined rate for a definite time period, that may range from days to years. These systems provide advantages over conventional drug therapies. For example, after ingestion or injection of standard dosage forms, the blood level of the drug rises, peaks, and then declines. Since each drug has a therapeutic range above which it is toxic and below which it is ineffective, oscillating drug levels may cause alternating periods of ineffectiveness and toxicity. In contrast, a controlled release preparation maintains the drug in the desired therapeutic range by a single administration. Other potential advantages of controlled release system include: (i) localized delivery of the drug to a particular body compartment, thereby lowering the systemic drug level; (ii) preservation of medications that are rapidly destroyed by the body (this is particularly important for biologically sensitive molecules such as proteins); (iii) reduced need for follow up care; (iv) increased comfort; and (v) improved compliance.
Optimal control of drug release may be achieved by placing the drug in a polymeric material. Polymeric materials generally release drugs by diffusion, chemical reaction, or solvent activation.
The most common release mechanism is diffusion, whereby the drug migrates from its initial position in the polymeric system to the polymer's outer surface and then to the body. Diffusion may occur through a reservoir, in which a drug core is surrounded by a polymer film, or in a matrix, where the drug is uniformly distributed through the polymeric system. Drugs can also be released by chemical reaction such as degradation of the polymer or cleavage of the drug from a polymer backbone.
Combinations of the above mechanisms are possible. Release rates from polymeric systems can be controlled by the nature of the polymeric material (for example, crystallinity or pore structure for diffusion controlled systems; the hydrolytic lability of the bonds or the hydrophobicity of the monomers for chemically controlled systems) and the design of the system (for example, thickness and shape). The advantage of having systems with different release mechanisms is that each can accomplish different goals.
For many years, controlled release systems were only capable of slowly releasing drugs of low molecular weight (<600). Large molecules, such as proteins, were not considered feasible candidates, because polypeptides were considered too large to slowly diffuse through most polymeric materials, even after swelling of the polymer. The discovery that matrices of solid hydrophobic polymers containing powdered macromolecules enabled molecules of nearly any size to be released for over 100 days permitted controlled delivery of a variety of proteins, polysaccharides, and polynucleotides. See Langer, 1990.
The proteins and polypeptides incorporated up to this date in polymeric materials for controlled release are mainly effector molecules, such as insulin, as opposed compositions for controlled release of molecules that will bind and neutralize effector molecules produced in the human body.
Tumor necrosis factor-.alpha. (TNF.alpha.) is a potent cytokine which elicits a broad spectrum of biological responses. TNF.alpha. is cytotoxic to many tumor cells and may be used in the treatment of cancer. TNF.alpha. enhances fibroblast growth and acts as a tissue remodeling agent, being thus suitable in wound healing. It further induces hemorrhagic necrosis of transplanted tumors in mice, enhances phagocytosis and cytotoxicity of polymorphonuclear neutrophils, and m
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Eliaz Rom
Kost Josef
Wallach David
Ben-Gurion University of the Negev
Levy Neil S.
Yeda Research and Development Co. Ltd.
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