Title:  Liposome encapsulated amphiphilic drug compositions

United States Patent:  6,149,937

Assignee:  Vrije Universiteit Brussel (Brussels, BE)

Filed:  November 19, 1998

PCT NO:  PCT/EP97/01384

102(e) Date:  November 19, 1998

PCT PUB. Date:  September 25, 1997

Foreign Application Priority Data:  Mar 21, 1996[GB] (9605915)

A process for the entrapment of amphiphilic compounds as uncharged or ionic with different mole ratios of phospholipid to the amphiphilic compound. Preparations of ionic species of amphiphilic compounds in the absence of crystals can be prepared, while preparations of uncharged amphiphilic compounds can be prepared with the compound exclusively entrapped inside the liposomes, or partly entrapped inside the liposomes with extraliposomal crystals.

SUMMARY OF THE INVENTION

Accordingly, in one aspect the present invention provides a process for preparing multilamellar liposomes and incorporating within the phospholipid bilayers ionic species of amphiphilic compounds comprising a hydrophilic and a hydrophobic portion, which method comprises the steps of:

i) extracting the hydrophilic ionic species from an aqueous medium by an organic solvent in which the phospholipid is dissolved;

ii) preparing a lipid film comprising the phospholipid and the amphiphilic compound by the evaporation to dryness of this solution; and

iii) preparing a suspension of multilamellar liposomes by hydration of the lipid film at an acidic pH in the range of from 4 and to 6.5, in such a way that the amphiphilic compound is at least partly inserted into the phospholipid layer beneath the fatty acid C₂ -C₃ hydrophilic interface.

In a second aspect the present invention provides a process for preparing multilamellar liposomes and incorporating within the phospholipid bilayers uncharged amphiphilic compounds comprising a hydrophilic and a hydrophobic portion, which method comprises the steps of

a) dissolving the apolar hydrophobic species of the amphiphilic compound in the phospholipid bilayers using predetermined phospholipid/compound mole ratios to obtain preparations of liposomes with the compound exclusively entrapped inside the liposomes without crystals of the compound, or is partly entrapped inside the liposomes with extraliposomal crystals;

b) preparing a lipid film comprising the phospholipid and the amphiphilic compound by the evaporation to dryness of this solution; and

c) preparing a suspension of multilamellar liposomes by hydration of the lipid film at a pH at which the amphiphilic compound remains in the uncharged form, in such a way that the amphiphilic compound is at least partly inserted into the phospholipid layer beneath the fatty acid C₂ -C₃ hydrophilic interface.

Claim 1 of 27 Claims

What is claimed is:

1. A process for preparing multilamellar liposomes and incorporating within the phospholipid bilayers thereof ionic species of amphiphilic compounds comprising a hydrophilic and a hydrophobic portion, which method comprises the steps of:

i) selecting an amphiphilic compound the ionic species of which will at least partly insert into the liposomal phospholipid bilayers by numeric molecular modelling or conformational analysis;

ii) extracting the hydrophilic ionic species of the said amphiphilic compound from an aqueous medium by means of an organic solvent in which the phospholipid is dissolved;

iii) preparing a lipid film comprising the phospholipid and the amphiphilic compound by the evaporation to dryness of this solution; and

iv) preparing a suspension of multilamellar liposomes by hydration of the lipid film at an acidic pH in the range of from 4 and to 6.5, whereby the ionic species of the amphiphilic compound is at least partly inserted into the phospholipid layer beneath the fatty acid C₂ -C₃ hydrophilic interface.

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