Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,... – Conjugated via claimed linking group – bond – chelating agent,...
Patent
1983-03-01
1984-12-18
Love, Ethel G.
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
Conjugated via claimed linking group, bond, chelating agent,...
536 64, 536 54, 536118, 536 172, 536 173, A61K 3170, C08B 3708
Patent
active
044890656
DESCRIPTION:
BRIEF SUMMARY
Many clinical situations exist in which it is advisable, sometimes necessary, to administer a drug in a controlled manner such that the concentration in the tissues of the patient is high enough to be effective but not so high as to cause toxic or other undesirable side effects. The rate of drug release can be controlled in a variety of ways, such as by encapsulation in a material which dissolves slowly in the body fluids, by entrapment in a bolus or matrix from which the drug diffuses slowly, or by conversion into a so-called "prodrug," in which the drug is bound with another substance into a substantially inactive compound or complex and is gradually released by physiological action when injected into the tissues of the patient.
The present invention relates to a novel class of prodrugs in which the drug substance is bonded ionically or covalently to a glycosaminoglycan of the class of the chondroitins, and to the use of such prodrugs in the treatment of animal and human patients.
Danishefsky and Siskovic, Carbohydrate Research, 16, 199 (1971), while studying the structure-function implication of the glycosaminoglycans, found that the amino function of certain amino acids can be covalently linked to the carboxyl group of a glycosaminoglycan. This is, of course, a conventional amidation; and while a similar reaction is employed in making some of the substances of the present invention, Danishefsky and Siskovic did not make, or suggest the possibility of making, a prodrug.
Mill et al U.S. Pat. No. 4,003,792 teaches that proteins may be bound to acid polysaccharides of plant origin, specifically alginic acid, pectic acid, celluronic acid, and carageenan. Such polysaccharides are food carbohydrates, alien to the blood and tissues of animals, and are clearly distinct both chemically and physiologically from the chondroitins used in the present invention. While Mill et al indicate that their complexes may be used for preparing antisera and for slow release of antisera, they do not describe how slow release of antisera can be achieved. In contrast, the chondroitin complexes of the present invention are compatible with animal blood and tissue and are normally cleaved by body metabolism to release the active drug.
Yannas and Burke U.S. Pat. Nos. 4,060,081 and 4,059,572 use the ionic properties of mucopolysaccharides (an older term essentially coextensive with the glycosaminoglycans) to flocculate or complex ionically with proteins. For example, an artificial skin formulation was prepared from chondroitin sulfate and collagen.
Heparin (a glycosaminoglycan) is very effective in slowing the clotting of blood, but is relatively short-acting when administered. A variety of derivatives have therefore been made to delay its absorption and prolong its pharmacological action. Thus, Mardiguian and Fournier U.S. Pat. No. 3,835,112 esterifies the hydroxyl groups of heparin with long chain fatty acids to give insoluble complexes which slowly regenerate the active soluble heparin upon cleavage of the ester bond. Bernasconi et al (G. Ital. Chemioter., 3, 79 (1956)) react heparin with tetracycline to produce a slowly soluble salt complex with a prolonged payout of heparin.
Laland Norwegian Patent No. 97,467 (1961) prepares a long-acting salt of adrenocorticotropic hormone (ACTH) and hyaluronic acid. The latter, a mammalian polyuronide, is a non-sulfated glycosaminoglycan, and perhaps for this reason the complex shows no autocatalytic effect and no significant amount of fast hydrolysis.
The advantages of using the chondroitins in the preparation of prodrugs lie in the fact that such molecules are found throughout the body, are biocompatible, are not species-dependent, and are metabolically cleaved from the drug substance in prolonged periods ranging from days to months.
In accordance with the present invention, a chondroitin is reacted in a known manner with a drug substance as hereinafter defined to produce a derivative which, upon injection into the body in the form of a solution or finely divided suspension, is metabolically d
REFERENCES:
patent: 4105760 (1978-08-01), Szejtli et al.
Thesis Entitled "The Synthesis and Characterization of Crosslinked Chondroitin-4-Sulfate Hydrogels: Potential Biomaterials", by Randall V. Sparer, Publicly Available Apr. 4, 1980.
Moersdorf, Chemical Abstracts, 80, 141061 (1974).
Ekwuribe Nnochiro
Sparer Randall V.
Walton Alan G.
Love Ethel G.
Valcor Scientific Ltd.
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