Stable liposome aqueous suspension

Details Stable liposome aqueous suspension Stable liposome aqueous suspension

1994-10-21

1996-10-15

Kishore, Gollamudi S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

4284022, A61K 9127

Patent

active

055652131

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to an aqueous suspension of liposomes which can be preserved stably.


BACKGROUND ART

Liposomes are closed vesicles comprising a lipid bilayer. Taking advantage of bioaffinity of liposomes, a number of proposals have been made to incorporate various drugs into the inner aqueous phase or the lipid bilayer of liposomes for use as a drug carrier. In many cases, however, liposomes as suspended in water are colloid-chemically instable, tending to undergo agglomeration or fusion among themselves, precipitation due to crystallization of the membrane component, an increase in particle size, or hydrolysis to form lyso-phospholipids that are considered to be hemolytic. These changes in effect and appearance result in impairment of commercial values.
Unexamined Published Japanese Patent Application No. 42733/87 furnishes a solution for the problem, which comprises stabilizing liposomes using an amino acid. What is achieved by this technique is stabilization in preservation at room temperature or lower temperatures, and stabilization in high temperature preservation was still insufficient. The technique was also insufficient for inhibition of lyso-phospholipid formation.
An object of the present invention is to provide a stable liposome aqueous suspension which does not undergo precipitation, agglomeration or change in particle size even when preserved at 40.degree. C. for 6 months and in which lyso-phospholipid formation is suppressed.


DISCLOSURE OF THE INVENTION

The present invention provides a liposome aqueous suspension containing taurine and benzalkonium chloride.
Taurine is added in an amount of from 0.5 to 5.0% by weight, preferably from 1.0 to 3.0% by weight, based on the total amount of the liposome preparation, which amount corresponds to a molar ratio of from 1:13 to 1:133, preferably from 1:27 to 1:80, to the membrane component of the liposomes. Benzalkonium chloride is added in an amount of from 0.05 to 20 mol %, preferably from 2 to 8 mol %, based on the membrane component of the liposomes.
While not limiting, the liposome aqueous suspension of the present invention can be prepared as follows. A membrane component hereinafter described is dissolved in an organic solvent, and the organic solvent is evaporated. The residual lipid membrane is then subjected to (A) hydration with an aqueous solution containing taurine and benzalkonium chloride or (B) hydration with a taurine aqueous solution followed by addition of benzalkonium chloride.
The membrane component which can be used in the present invention includes hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine. A membrane stabilizer, such as cholesterol, may be added to the system, while not essential. The amount of the membrane component to be used ranges usually from 0.0005 to 0.025 part by weight, and preferably from 0.001 to 0.008 part by weight, per part by weight of water.
The organic solvent to be used includes chloroform and dichloromethane.
It is preferable to adjust the liposome aqueous suspension to a pH around neutrality (i.e., pH 6.0 to 7.0) with sodium hydroxide, potassium hydroxide, etc.
If desired, the size of liposome may be controlled by means of a polycarbonate-made membrane filter or a high-pressure jet type homogenizer.
If desired, the liposome aqueous suspension of the present invention may further contain additives as long as the effects of the present invention are not impaired. Useful additives include antiseptics (e.g., methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, and propyl p-hydroxybenzoate), antihistaminics (e.g., diphenhydramine hydrochloride, isothipendyl hydrochloride, and chloropheniramine maleate), vitamins (e.g., vitamin A or esters thereof, activated vitamin B.sub.2, vitamin B.sub.6, vitamin B.sub.12, and vitamin E and esters thereof), topical anesthetics (e.g., lidocaine, lidocaine hydrochloride, procaine hydrochloride, and dibucaine hydrochloride), refreshers (e.

REFERENCES:
patent: 4818537 (1989-04-01), Guo
patent: 5228446 (1993-07-01), Unger

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