Liposomes with a negative excess charge

Details Liposomes with a negative excess charge Liposomes with a negative excess charge

1995-02-15

1997-05-06

Mullis, Jeff

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

264 41, 264 43, A61K 914, A61K 9127

Patent

active

056268670

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The invention concerns liposomes with a negative excess charge, in particular for administering cytostatic agents and cytokines.
Liposomes are spherical structures comprising one or several lipid double layers with an aqueous inner space (lipid vesicle). Such vesicles can be produced by the mechanical very fine dispersion of phospholipids (e.g. lecithin) in aqueous media.
Bangham et al., J. Mol. Biol. 13 (1965), 238-252 observed that phospholipids form superstructures in the presence of water. Depending on physical parameters such as pressure, temperature and ionic concentration, micelles, unilamellar or multilamellar liposomes or even simple lipid double layers form (cf. Liposomes: From physical structure to therapeutic application (1981), Knight, C. G. (ed.), Elsevier, North Holland Biomedical Press, chapter 2: H. Eibl, Phospholipid synthesis, 19-50; chapter 3: F. Szoka and D. Papahadjopoulos, Liposomes: Preparation and Characterization, 51-104). Small unilamellar liposomes are spherical structures with a diameter of 20 to 200 nm (cf. Barenholtz et al., FEBS Let. 99 (1979) 210-214). Their inner volume is comprised of an aqueous medium which is bordered on the outside by the lipid double layer. Depending on their lipophilicity or hydrophilicity, active substances can either be entrapped in the lipid double layer or in the aqueous inner volume of the liposomes and transported and distributed in the organism via the body fluids.
Due to their structure, liposomes serve as a model for membranes in biochemistry and molecular biology. In past years numerous papers on the properties of liposomes and their use as carriers of medicinal agents have also been published (cf. e.g. H. Schreiner and M. Raeder-Schikorr, "Pharmazie in unserer Zeit" 11 (1982), 97-108). Previously published experiments on animals generally show that the liver and spleen dominate over other organs with respect to the uptake of liposomes. About 8% of the liposomes are found in the liver after 1 hour and about 15% after 24 hours.
The possible use of liposomes in medicine is mainly aimed at the selective treatment of diseases. The desired effects of the active substance entrapped in the liposomes should be promoted whereas the undesired effects should be reduced. In this manner it is intended to achieve an improvement in the therapeutic index.
Liposomes are known from DE-OS 40 13 632.9 which contain at least 1 mol % of a compound having a positive excess charge.
However, a disadvantage of administering known liposomes is that their uptake in the liver is relatively limited and that the liposomes can circulate for a long period in the blood. This applies particularly to liposomes which are composed of phospholipids such as lecithin and cholesterol. In this manner the active substance contained in the liposomes is distributed throughout the body which in turn can lead to an increase in the occurrence of undesired side effects of the active substance.
An object of the present invention was therefore to provide new liposomes which exhibit an increased liver uptake compared to liposomes of the state of the art.
This object is achieved by the provision of liposomes which are characterized in that they contain cholesterol, phospholipids and 1 to 14 mol % relative to the total lipid components of the liposomes of one or several compounds of the general formula I ##STR2## or their salts, in which R.sup.1 and R.sup.2 can be the same or different and represent hydrogen, C.sub.1 -C.sub.4 alkyl groups or saturated or unsaturated C.sub.8 -C.sub.24 acyl groups which can if desired, be branched or/and substituted provided that at least one of the residues R.sup.1 and R.sup.2 is an acyl group as defined above.
Under physiological conditions the above compounds (I) are generally in the form of partially protonated anions so that the liposomes according to the invention have a negative excess charge. The amount of negatively charged carrier substances according to formula (I) is generally 1 to 14 mol %, preferably 3 to 10 mol % relative to the total

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