Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Patent
1995-04-28
1997-04-22
Nutter, Nathan M.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
525 542, 525 543, 536 3, A61K 4748
Patent
active
056227183
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
One of the significant drawbacks of antitumor or antineoplastic agents is their failure to discriminate between normal dividing cells and tumor cells. When acting on normal dividing cells, these agents cause undesireable side effects, including nausea, apolecia, and bone marrow toxicity. Their cardiotoxicty is a primary contributor to dosage limitation.
Kopecek et al., U.S. Pat. No. 5,037,883, describe a drug conjugate which includes inert synthetic N-(2 hydroxypropyl) methacrylamide polymeric carriers combined through peptide spacers with a bioactive molecule, with a targeting moiety, and with an optional cross-linkage. The peptide spacers contain between 2 and 6 naturally occurring amino acids.
Yang et al., Proc. Natl. Acad. Sci. USA vol. 85, pp. 1189-1193 (1988) describe doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan. The conjugate suppresses the growth of established tumor xenografts in nude mice.
Dillman et al., Cancer Research vol. 48, pp. 6097-6102 (1988) describe the superiority of an acid-labile daunorubicin-monoclonal antibody immunoconjugate compared to free acid.
Shen et al., Biochemical and Biophysical Research Communications vol. 102, no. 3, pp. 1048-1054 (1981) describe cis-aconityl spacer between daunomycin and macromolecular carriers.
SUMMARY OF THE INVENTION
The invention is an alginate-bioactive agent conjugate which comprises: biodegradable spacer linkage. Preferably, the linkage is an acid labile linkage.
The present invention also comprises pharmaceutical compositions which comprise at least one conjugate of the invention and an inert, physiologically acceptable carrier. The compositions can be administered orally or by injection, for example by intraperitoneal, intravenous or intramuscular injection.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows percent daunomycin in vitro release over time.
FIG. 2 shows .mu.g/ml daunomycin in vitro release over time.
FIG. 3 shows the effect of daunomycin release on tumor cell growth.
DETAILED DESCRIPTION OF THE INVENTION
The invention permits combination of controlled release of a bioactive material and the beneficial biological properties of alginates. Non-toxic alginates display inherent properties which provoke beneficial pharmacological activity and when covalently bound to a bioactive material (including drugs and prodrugs), alginates can be used to control the rate of release of the material.
Alginate, as used herein, refers to sodium alginate, alginic acid sodium salt of algin (see page 41, The Merck Index, 11.sup.th Edition (1989), Merck & Co., Inc.) Alginates are gelling polysaccharides extracted from giant brown seaweed (Macrocysris pyrifera) or horsetail kelp (Laminaria digitata) or from sugar kelp (Laminaria saccharina). In seaweed, polysaccharides are present as a mixed sodium and/or potassium, calcium and magnesium salt. Alginates are commercially available from Kelco, a Division of Merck & Co., Inc. (San Diego, Calif.).
Various alginates useful in this invention are described in detail by I. W. Cottrell and P. Kovacs in "Alginates", Chapter 2 of Davidson, ed., Handbook of Water-Soluble Gums and Resins (1980). Most preferred herein are naturally derived algal sodium alginates (also called "algin" or "alginic acid sodium salt"), such as those sold commercially under the trademarks KELTEX.RTM., KELGIN.RTM. and KELTONE.TM. by Kelco Division of Merck & Co., Inc.
Alginates also include "bioalgin", microbially produced polysaccharides produced by both Pseudomonas and Azotobacter strains as described, for example, in Jannan et al., U.S. Pat. No. 4,235,966. These alginates are polysaccharides consisting of a partially acetylated variable block copolymer of D-mannuronic and L-guluronic acid residues. Jarman et al. state that the polysaccharide produced is similar to that produced from seaweed except that the molecule is partially acetylated.
Alginates contain both mannuronic acid and guluronic acid. The presence of three kinds of polymer segments in al
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Al-Shamkhani Aymen
Duncan Ruth
Keele University
Nutter Nathan M.
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