Process for the preparation of liposomes without the use of an o

Details Process for the preparation of liposomes without the use of an o Process for the preparation of liposomes without the use of an o

1998-04-30

2000-08-15

Kishore, Gollamudi S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

424401, 4284022, 264 41, 264 43, A61K 9127, A61K 700

Patent

active

06103259&

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the preparation of liposomes without the use of an organic solvent.
Liposomes generally comprise a lipid surfactant as well as cholesterol and/or one/more encapsulated active product(s). The cholesterol (more generally a sterol) binds with the phospholipid to improve the elastic and impermeability properties of the lipid membrane. If the cholesterol or the active product to be encapsulated are mixed directly with the lipid and the aqueous solvent, the mixture remains non-homogeneous. For example, it can be observed that the cholesterol remains, after a number of days, in the form of small crystals which do not dissolve in the preparation, even with the addition of a large excess of water. In order to overcome this problem, a process known as "spraying" is used (see EP-A-87 993), which process comprises mixing the different constituents in an organic solvent (generally a chlorinated solvent, such as chloroform or dichloro-methane; methanol is also used) before their use in an aqueous medium. Evaporation of this solvent produces a powder which is then used directly in the process for the preparation of liposomes (see, for example, EP-A-0 107 559). The disadvantage of this process is that passing through the spraying stage can leave traces (small but impossible to remove) of solvent in the final preparation. In view of the harmful effects of such traces on the health, it is essential to succeed in preparing liposomes without the use of an organic solvent.
Similar processes are used for incorporating membrane proteins in liposomes, that is to say proteins which are soluble in the membranes but which are difficult to dissolve in water.
The present invention is aimed at providing a process for the preparation of liposomes which makes it possible to avoid the spraying stage. The novelty of the process is based on the use of a well-chosen cosurfactant which makes it possible to dissolve the cholesterol or the active product to be encapsulated without the use of an organic solvent.
The subject of the present invention is therefore a process for the preparation of liposomes comprising: hydrophilic head and a (C.sub.2 -C.sub.16) hydrocarbon chain, of a sterol and/or a membrane protein and/or of a product to be encapsulated, so as to obtain dissolution of the sterol and/or of the product to be encapsulated; as to form a homogeneous lamellar liquid crystal phase or a liquid crystal phase suspension in water, and phase suspension into liposomes.
It should be noted that, in certain cases, the conversion of the liquid crystal phase into liposomes takes place spontaneously.
The size of the spontaneous liposomes is typically from 100 to 500 nm, more generally from 50 to 5000 nm. The spontaneous liposomes obtained are multi-lamellar liposomes generally containing from 10 to 10,000 alternate layers of water and of surfactants (hydrophilic and lipophilic), including to the heart of the liposomes.
However, another subject of the invention is the liquid crystal phase or the liquid crystal phase suspension obtained in the second stage.
The present invention will now be described in more detail.
The surfactant used in the first stage comprises a branched or unbranched (C.sub.2 -C.sub.16) carbon chain and preferably a (C.sub.6 -C.sub.14) carbon chain.
The hydrophilic head is generally an alcohol or an ethoxylated alcohol but can also be a carboxylic acid or a salt of a fatty acid, a quaternary ammonium, a sulphonate or a sulphate or any other polar non-ionic or ionic group.
In the first stage, the aqueous solvent, the surfactant and the cholesterol and/or a membrane protein and/or the product to be encapsulated are mixed in suitable proportions. Generally, the surfactant is used in a proportion of 1 to 50% by weight, preferably of 5 to 25%, and the cholesterol in a proportion of 0% to 25% by weight. After stirring, the mixture is generally left standing for 1 to 2 hours. In certain cases, the cholesterol can be dissolved in this mixture with or without heating (40 to 100.degree. Celsiu

REFERENCES:
patent: 5182097 (1993-01-01), Byron et al.
D. Chapman, "Physicochemical Properties of Phospholipids and Lipid-Water Systems", Liposome Technology, vol. 1, pp. 1-19, 1984.

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