Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-04-12
1997-04-29
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 58, 536 168, 536103, 5361231, A61K 31715, C07G 1100, C08B 3716
Patent
active
056249144
DESCRIPTION:
BRIEF SUMMARY
The present application is the U.S. national application corresponding to International Application No, PCT/US 92/08565, filed Oct. 14, 1992 and designating the U.S., which PCT application is in turn a continuation-in-part of U.S. application Ser. No. 07/777,864, filed Oct. 16, 1991, now abandoned.
BACKGROUND OF THE INVENTION
This invention relates to novel compositions of matter comprising a lipophilic oligosaccharide antibiotic, and to pharmaceutical formulations containing such compositions of matter and to methods of making and using such pharmaceutical compositions to treat and/or prevent microbial infections in animals especially mammals such as human beings.
Lipophilic oligosaccharide antibiotics including, for example, everninomicins, curamycins, avilamycins and flambamycins are members of the orthosomycin family of antibiotics which contain at least one acidic phenolic hydrogen, and two orthester linkages associated with carbohydrate residues. See for example. A. K. Ganguly in "Kirk-Othmer, Encyclopedia of Chemical Technology", (1978), Volume 2, pp. 205-209, Third Edition, John Wiley and Sons and W. D. Oillis, et al., Tetrahedron (1979), Volume 35, pp. 105-127. These lipophilic oligosaccharide antibiotics exhibit broad spectrum biological activity against gram positive and some gram negative bacteria in various in vitro-assays, and in-vivo activity in animal models such as mice, but to date no pharmaceutically acceptable formulation of such antibiotics useful for vivo administration has been available. Thus, we have observed that injection of these lipophilic oligosaccharide antibiotics cause an adverse reaction syndrome. The term "adverse reaction syndrome" as used herein means symptoms of the following type observed in animals such as mice upon parenteral administration of lipophilic oligosaccharide antibiotics: incoordination, ataxia, lateral recumbency, urination, hind leg rigidity, labored breathing, and arrest. Thus, in summary, there are no known pharmaceutically acceptable compositions of these lipophilic oligosaccharide antibiotics for the safe and effective use of these potent antibiotics in animals including mammals such as human beings.
Cyclodextrins are modified starches made from glucopyranose units and include .alpha.-cyclodextrin consisting of six glucopyranose units, .beta.-cyclodextrin consisting of seven glucopyranose units, and .gamma.-cyclodextrin consisting of eight glucopyranose units. The .alpha.-, .beta.- and .gamma.-cyclodextrins and derivatives thereof have an inside surface or cavity which is lipophilic and an outer surface which is hydrophilic. This combination of a hydrophobic cavity and a hydrophilic outer surface has led to the use of cyclodextrins and derivatives thereof for the molecular complexation or encapsulation of many hydrophobic and/or unstable drugs of suitable dimensions, thereby improving solubility, stability and bioavailability of such drugs. Derivatives of .alpha.-, .beta.- and .gamma.-cyclodextrins for example hydroxypropyl-.beta.-cyclodextdrins are disclosed by Jozsef Szejtli in Pharmaceutical Technology, Jun. 1991, 36-40.
Complexes of .alpha.-, .beta.- and .gamma.-cyclodextrins, mixtures and derivatives thereof are disclosed in, for example, N. Bodor U.S. Pat. No. 4,983,586. The Bodor U.S. Pat. No. 4,983,586 discloses a method of decreasing the incidence of precipitation of a lipophilic or water labile drug occurring at/or near the injection site and/or in the lungs following parenteral administration, by parenterally administering said drug in an aqueous solution containing a large quantity, i.e., 20 to about 50 weight percent of hydroxypropyl-.beta.-cyclodextrin.
Josef Pitha in U.S. Pat. No. 4,727,064 and The International J. of Pharmaceutics, (1986) 29, 73-82 disclose the use of a concentrated, i.e., 40-60 weight percent, aqueous solution of hydroxypropyl-.beta.-cyclodextrin to solubilize various drugs such as acetaminophen, sex steroids, cardiac glycosides such as digoxin, as well as retinoic acid and acid salts thereof. See also the Pitha
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Gullo Vincent P.
Hare Roberta
Kwon Heewon Y.
Loebenberg David
Miller George H.
Hoffman Thomas D.
Kight John
Schering Corporation
White Everett
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