Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1993-06-03
1998-07-07
Preselev, Elli
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 65, A61K 3170
Patent
active
057769044
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a dispersion preparation containing amphotericin B.
BACKGROUND ART
Even today, about 30 years after its development, amphotericin B is widely used as an important antifungal agent which may be administered to the entire body and which exhibits reliable effects. However, this substance has a drawback in that it causes serious side effects due to its hemolytic toxicity and nephrotoxicity.
In order to alleviate these side effects, amphotericin B has been administered in the form of a liposome preparation containing phospholipids, a lipid complex preparation, or a fatty emulsion preparation prepared by emulsifying soybean oil with a small amount of a phospholipid (Szoka, P. C. Jr, et al., Antimicrobial Agents and Chemotherapy, 31, 421-429, 1987, hereunder referred to as "Document 1"; Kirsh, R., et al., Journal of Infectious Diseases, 158, 1065-1070, 1988, hereunder referred to as "Document 2"; and Japanese Patent Application Disclosure SHO 63-66123, hereunder referred to as "Document 3", etc.).
Nevertheless, although these various types of liposome preparations, lipid composite preparations and fatty emulsion preparations reduce the hemolytic toxicity of amphotericin B and are successful in reducing acute toxicity, practically no effects have been observed towards reduction of nephrotoxicity, which is the greatest problem in the clinic. In addition, these various types of liposome preparations, lipid composite preparations and fatty emulsion preparations have serious drawbacks both economically, as they use large amounts of high-cost lipids, and in that during their prolonged administration, they add to the influence of other additives to produce hypercholesteremia, fatty liver, etc.
In contrast, dispersion preparations do not require the lipids which cause the above mentioned disadvantages.
Known amphotericin B dispersion preparations include amphotericin B syrups, etc. intended for only oral administration, but the use of large amounts of glycerin, carboxymethyl cellulose, etc. therein as aids, whose crystals easily precipitate upon dilution, leads to many disadvantages including the possibility of toxic effects of those aids in the body. No amphotericin B dispersion preparation for parenteral administration has heretofore existed.
In order to administer amphotericin B at a high concentration, it is more preferable to use amphotericin B dispersed in a dispersion preparation, rather than combined with another ingredient such as a carrier, etc. It is necessary to alleviate the hemolytic toxicity and nephrotoxicity without influencing the pharmacological mechanism (antifungal action) of amphotericin B itself on the molecular level. It is the object of the present invention to provide a solution to these problems,
DISCLOSURE OF THE INVENTION
The present invention is largely characterized by providing an amphotericin B preparation which may be administered intravenously without the use of adjuvants of any kind.
It has been heretofore commonly known in making preparations that preparations for intravenous administration must not contain insolubles (this is specified in Japanese Pharmacopoeia), and in order to administer an effective amount of the hardly soluble amphotericin B as a drug, there has been no method other than using an adjuvant such as a synthetic surfactant, etc. or administering it as an inclusion in a carrier. The method described in Document 1 for its administration as a liposome type or lipid complex also follows this line of thought.
However, it became clear that, in contrast to what has been common knowledge, amphotericin B itself will exist in a permanently stable manner when uniformly dispersed as minute particles in a generally used injectable solvent such as physiological saline, etc., even without the use of any type of adjuvant, and without causing precipitation or aggregation.
We the inventors of the present invention came across this fact in a coincidental manner, and the present invention was completed based thereupon.
The gist of
REFERENCES:
patent: 3928570 (1975-12-01), Metzger
patent: 4002741 (1977-01-01), Kulbakh et al.
patent: 4035567 (1977-07-01), Sipos
patent: 4844900 (1989-07-01), de Albornoz et al.
patent: 5043107 (1991-08-01), Adler-Moore et al.
Szoka et al, Antimicrobial Agents And Chemother., 31: 421-429 (1987).
Kirsh et al, J. Infec. Dis., 158: 1065-1070 (1988).
Seki Junzo
Yamamoto Hirofumi
Nippon Shinyaku Co. Ltd.
Preselev Elli
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