Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1996-02-20
1998-04-14
Knode, Marian C.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424 7817, 424488, 514410, 5147721, 514785, A61K 932, A61K 4730, A01N 4338, A01N 2508
Patent
active
057388644
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/IB94/00259 filed Aug. 17, 1994.
FIELD OF THE INVENTION
The present invention relates to the field of pharmaceutical products for use in chemotherapy, especially cancer chemotherapy. More particularly, the invention is concerned with providing drug-delivery agents in the form of polymer/drug conjugates comprising aziridine ring containing mitomycin compounds, such as the anti-neoplastic drug mitomycin-C (abbreviated MMC), covalently coupled through linking spacer groups to macromolecules that can serve as relatively inert polymeric drug carriers in biological systems.
BACKGROUND
Mitomycin-C, which has the structure shown below, has been known for some time as a promising antitumour drug, being a cytotoxic agent that appears to be effective against a number of human cancers. There is currently particular interest in developing methods of using it for the treatment of colorectal and other cancers. Up to now, however, its clinical application has been severely limited due to unacceptable levels of general toxicity and side effects when administered as the free drug. In consequence, it has generally been used clinically only in low doses and in combination with other drugs. ##STR1##
In the hope of reducing these disadvantages of mitomycin-C for clinical use and of improving targeting of the drug to the particular tissues where its effect is required, some attempts have already been made by Japanese research groups to develop macromolecular drug carrier systems in which conjugate compounds are formed by attaching or coupling molecules of the mitomycin-C through covalent linkages to biologically compatible macromolecules or polymers so as to provide drug delivery agents that, after administration, may transport the drug to the tissues concerned, preferably in a selective manner. See, for example, Y. Takakura et al, Pharmaceutical Research, 7, No. (1990); C. F. Roos et al, International Journal of Pharmaceutics, 22 (1984); and Y. Kaneo et al, "Preparation and Properties of a Mitomycin-C albumin Conjugate" published 1990 by the Department of Pharmacy & Pharmaceutical Sciences, Fukuyama University, under the auspices of the Pharmaceutical Society of Japan.
Many proposals are already well documented in the literature for the general design and use of drug delivery systems in which macromolecules, in the form of natural, synthetic or semi-synthetic polymers, are used as carriers for bioactive drug molecules which may be coupled thereto to form a polymer/drug conjugate through spacer groups and biodegradable covalent linkages adapted to permit a controlled or sustained release of the drug within the body of the recipient, such release in some instances occurring actually within particular tissue cells that are able to take up and internalise The polymer/drug conjugate, usually by the process of pinocytosis. At least with soluble biologically inert macromolecular polymer carriers capable of becoming distributed or circulating within The body, apart from the fact that such carriers may naturally tend to accumulate selectively in certain tissues such as tumour tissues for example, there can also be a possibility of attaching or coupling, to the polymer carrier, residues or molecular entities, termed targeting moieties or determinants, that are capable of recognising and interacting with specific sites or cell surface receptors whereby the polymer drug carrier may be more specifically "targeted" to those tissues or cells where the drug is required to act. Thus, such targeting moieties or determinants, which can include molecular entities such as hormones, antibodies or antibody fragments, and other proteins, can permit site-specific drug delivery. Once at the target location, drug release may then take place by biodegradation or cleavage of The bonds linking or coupling the bioactive drug molecules to the polymer carriers, e.g. by hydrolytic cleavage promoted by intracellular enzyme systems, especially lysosomal enzyme systems, following pinocytic uptake of The carrier/drug conjugate.
REFERENCES:
DeMarre et al. Apr. 1, 1994 J controlled release 31 pp. 89-87.
DeMarre et al. Aug. 1, 1994 J controlled release 32 pp. 129-137.
Duncan Ruth
Ferruti Paolo
Schacht Etienne Honore
European Community
Knode Marian C.
Zeman Mary K.
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