New Technologies For The Preparation Of Liposomes And Oil-Based Formulations Using Cosolvent Systems And Their Applications

Based on the study of phospholipids/TBA/water mixtures, three novel technologies are developed, which can be used to prepare liposomes and oil-based formulations of hydrophilic drugs.Our data show that the three-phase diagram of phospholipids/TBA/water can be divided into three main regions corresponding to a clear solution of lipid in aqueous TBA, suspensions of stacked hydrated lipid bilayers in excess aqueous TBA, and liposomes.Through the investigations of mono-phase solutions, a novel method is developed for the preparation of sterile and pyrogen-free submicron liposomes of narrow size distribution, which is named "freeze-drying of monophase solutions". The method is based on the formation of a homogenous dispersion of lipids in water-soluble carrier materials. In order to obtain the lipid-containing solid dispersion, liposome-forming lipids and water-soluble carrier materials are dissolved in TBA/water cosolvent systems to form an isotropic mono-phase solution, and then the resulting solution is lyophilized after sterilization by filtration through 0.2 μm pores. On addition of water, the lyophilized product spontaneously forms homogenous liposome preparation. After investigation of the various parameters associated with this process, it is found that the lipid/carrier ratio, the type of carriers and lipid compositions are the key factors affecting the size and the polydispersity of liposome preparations. Based on the data from DSC, X-ray diffraction and size measurements, a possible liposome formation mechanism is proposed. It seems that lipids are dispersed in the amorphous sugar matrix in the form of tiny phospholipid bilayer fragments and sucrose can effectively inhibit the fusion and aggregation of different lipid minidomains. On hydration, phospholipid bilayer fragments are forced to form submicron liposomes of narrow size distribution.This method can be used to load drugs by means of "passive loading" or "active loading". When the drugs are loaded in an active means, it is a good option to use our method in conjunction with pH gradient method. Our method may possess the following advantages: simplicity, easy handling in sterilization, no need of special equipments, long shelf time of final product, scalability.The studies on liposome region lead to another liposome preparation procedure, which includes the following steps: mixing the solution of lipids in TBA and sucrose...