Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1995-10-10
1998-01-06
Low, Christopher S. F.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
424461, 514 44, 560224, A61K 9127
Patent
active
057051887
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 U.S.C. 371 application of PCT/JPG4/00238 filed 17 Feb. 1994 published as WO94/18987 Sep. 1, 1994.
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition characterized by comprising a lipid device and a single-stranded nucleic acid copolymer.
The term lipid device as used herein means a device comprising a natural or artificial lipid as a component thereof and having the function of promoting the intracellular uptake of a physiologically active substance.
BACKGROUND ART
Unlike a nucleic acid polymer-nucleic acid polymer complex such as polyinosinic acid-polycytidylic acid, a single-stranded nucleic acid copolymer such as poly (adenylic acid-uridylic acid) does not display interferon-inducing activity and hence, has no antitumor effect when administered alone.
Meanwhile, it is known that certain kinds of positively charged lipid devices (e.g. cationic liposomes) are instrumental to the delivery of genes into cells (e.g. JP-A-4108391, WO91/17424). It is also known that when a certain kind of nucleic acid such as a double-stranded RNA is administered together with a lipid device such as cationic liposomes, a potentiated interferon inducer action is realized (U.S. Pat. No. 5,049,386). It is generally conjectured that since the nucleic acids of, for example, genes are negatively charged, they form complexes with cationic liposomes and the complexes become fused to the cell membrane and the nucleic acids of genes or the like find their way into the cell.
However, it remains to be known whether application of a lipid device to a single-stranded nucleic acid copolymer gives rise to interferon inducer activity or an antitumor action.
DISCLOSURE OF INVENTION
The object of the present invention is to implement an effective utilization of a single-stranded nucleic acid copolymer and provide a pharmaceutical composition having antitumor activity.
In the course of intensive research, the inventors of the present invention discovered that applying a lipid device to a single-stranded nucleic acid copolymer such as poly(adenylic acid-uridylic acid) results in high interferon inducer activity and have accordingly developed the instant invention.
The lipid device that can be used includes Lipofectin (trademark, manufactured by Bethesda Research Laboratories Life Technologies Inc.) and Genetransfer (trademark, manufactured by Wako Pure Chemical Industries), which are known, and a mixture of a compound of the following general ##STR1## wherein R.sup.1 and R.sup.2 are not the same and each represents OY or --A--(CH.sub.2)n-E. n represents a whole number of 0-4. E represents pyrrolidino, piperidino, substituted or unsubstituted piperazino, morpholino, substituted or unsubstituted guanidino, or ##STR2## (R.sup.3 and R.sup.4 are the same or different and each represents hydrogen, lower(C.sub.1-4) alkyl, hydroxy-lower(C.sub.1 -.sub.4) alkyl, or mono- or di-(lower) alkylaminoalkyl(C.sub.2 -.sub.6)). A represents the followings 1, 2, 3, 4, 5 6 or 7. ##STR3##
R and Y are the same or different and each represents a saturated or unsaturated aliphatic hydrocarbon group of 10-30 carbon atoms or a saturated or unsaturated fatty acid residue of 10-30 carbon atoms.
The substituted piperazino for E includes 4-methylpiperazino, 4-ethylpiperazino, 4-n-propylpiperazino, 4-isopropylpiperazino, 4-n-butylpiperazino, 4-isobutylpiperazino, 4-(2-hydroxyethyl)piperazino, 4-(2-hydroxypropyl)piperazino, and 4-(3-hydroxypropyl)piperazino, among others.
The substituted guanidino for E includes methylguanidino, ethylguanidino, n-propylguanidino, N,N-dimethylguanidino, N,N-diethylguanidino, N,N-di-n-propylguanidino, N,N'-dimethylguanidino, N,N'-diethylguanidino, N,N'-di-n-propylguanidino, N,N,N'-trimethylguanidino, N,N,N'-triethylguanidino, N,N,N'-tri-n-propylguanidino, N,N,N',N'-tetramethylguanidino, N,N,N',N'-tetraethylguanidino, and N,N,N',N'-tetra-n-propylguanidino, among others.
The lower alkyl for R.sup.3 and R.sup.4 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and te
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Alberts, B et al. Molecular Biology of the Cell, second edition. p. 98. Garland Publishing, New York, 1989.
Yu, ACH et al. Inhibition of GFAP synthesis by antisense RNA in astrocytes. J. Neuroscience Res. 30:72-79, 1991.
Magee, WE, et al. A comparison of negatively and positively charged liposomes containing entrapped polyinosinic-polycytidylic acid for interferon induction in mice. Biochim. Biophys. Acta 451:610-618, 1976.
Solodin, I. et al. A novel series of amphiphilic imidazolinium compounds for in vitro and in vivo gene delivery. Biochemistry 34:13537-13544, 1995.
Felgner, PL et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc. Natl. Acad. Sci. USA 84:7413-7417, Nov. 1987.
Hovanesssian, AG et al. Enhancement of natural killer cell activity and 2-5a synthetase in operable breast cancer patients treated with polyadenylic;polyuridylic acid. Cancer 55:357-362, 1985.
Derwent WPI Abstract of JP-A-3-240,795, JP-A-61-103,824 and JP-A-59-033,222 .
Junichi Yano
Ohgi Tadaaki
Low Christopher S. F.
Nguyen Dave T.
Nippon Shinyaku Company Ltd.
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