Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1994-04-25
1999-11-23
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
4284022, 554 79, 554 80, 554213, A61K 9127, C07C 5900
Patent
active
059895870
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel polyether lipids, to liposomes comprising polyether lipids, and to methods for producing such liposomes.
DESCRIPTION OF THE PRIOR ART
Artificial lipid vesicles (liposomes) have become an important tool in numerous basic and applied research areas. They have been used extensively as biological membrane systems for the study of such processes as transmembrane transport, lipid bilayer permeability, membrane fusion and lipid-protein interaction. They may also serve as immunological adjuvants or as carriers of drugs and skin care compounds, insecticides, genetic material and enzymes.
Currently, liposomes are made from ester-lipids, such as egg phosphatidylcholine (EPC). The inherent physico-chemical instability of such liposomes is one of the major impediments to their commercial application. Accordingly, cholesterol is often included in the liposome composition to increase stability, decrease porosity, and prevent their fusion or aggregation. Moreover, the ester bonds of these liposomes are susceptible to enzymatic and chemical hydrolysis, which causes disruption of the liposome structure. Ester lipid fatty acyl chains are often unsaturated and therefore subject to oxidation in air and loss of the structural integrity of liposomes. A practically desirable shelf life of two years is normally not achieved and special storage conditions may be required, such as the removal of oxygen and/or lowered temperatures.
Archaeobacteria contain very different membrane lipid structures than their procaryotic and eucaryotic counterparts. Instead of fatty acyl chains, which are often unsaturated and are esterified to glycerol at carbons sn-1,2, archaeobacterial membrane lipids are composed of saturated phytanyl chains in ether linkage to glycerol carbons with sn-2,3 configuration. In addition to having the ubiquitous diether C20,20-lipid various methanogens can also have phytanyl chains modified to give rise to tetraether, hydroxydiether and macrocyclic diether lipids. Variations in the polar head groups are numerous and may provide a molecular taxonomic fingerprint for identification of each methanogen genus.
There are few reports of liposome formation from archaeobacterial lipids. Of these, one group reported on the formation of large liposomes, i.e. Ring, K. et al (1986) In Liposomes as Drug Carriers (Schmidt, K. H., ed), p. 101-123, Georg Thieme, Verlag, Stuttgart and New York. Specifically, Ring et al produced large vesicles (approximated as 600 nm) by controlled detergent dialysis of a single tetraether lipid component purified from the total lipid contents from the archaeobacterium Thermoplasma acidophilum. However, there is no teaching or suggestion of the application of this process to the production of liposomes from the total polar lipids of archaeobacteria. Also, these liposome structures were not defined by electron microscopy. Using the methods employed here with total polar and/or the total lipid extracts, we avoid the costly and difficult process of preparing purified lipid molecular species.
In another report by MacDonald, R. C. et al (1991) Biochim. Biophys. Acta 1061: 297-303, ester lipid liposomes are formed by pressure extrusion. However, there is no teaching of making unilamellar liposomes from the total polar lipid extracts of archaeobacteria. Because of the stability inherent in the archaeobacterial lipid structures it is possible to make liposomes over a wide range of conditions, including gas phase, temperature, and pH. These factors are central to their usefulness in industrial applications as is the stability of these liposomes to a variety of conditions. Moreover, the formation of liposomes within a broad range of conditions, is not the case for ester lipids.
Liposomes have been made by sonication from a subfraction of the ether lipids of Sulfolobus acidocalcarius [Elferinck et al. (1992) J. Biol. Chem. 267: 1375-1381].
SUMMARY OF THE INVENTION
It is an object of the invention to provide novel polyether lipids.
It is another object of t
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Choquet Christian G.
Ekiel Irena
Patel Girishchandra B.
Sprott G. Dennis
Anderson J. Wayne
Kishore Gollamudi S.
National Research Council of Canada
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