Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1992-06-22
1995-02-28
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
264 43, A61K 5722
Patent
active
053935306
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns liposomes with improved trans-membrane loading capacity. It also concerns a method for making such liposomes and the loading thereof with substances of interest.
As is well known, liposomes consist of small vesicles bounded by a membrane wall of lameliar lipids surrounding a core filled with an entrapped aqueous liquid phase. Liposome vesicles can be loaded with foreign substances like drugs and may thereafter be used to selectively deliver such encapsulated drugs to selected organs in the body. Liposomes, when in suspension in aqueous carriers, are particularly suitable to deliver drugs to patients by parenteral, peroral, topical and inhalation routes. Liposome drug formulations may improve treatment efficiency, provide prolonged drug release and therapeutic activity, increase the therapeutic ratio and may reduce the overall amount of drugs needed for treating a given kind of ailment or disorder. For a review, see Liposomes as Drug Carriers by G. Gregoriadis, Wiley & Sons, New-York (1988).
Many methods exist for preparing liposomes and loading them with foreign substances of interest, most of which methods involve forming the liposome vesicles within an aqueous carrier liquid containing said substances distributed therein. During liposome formation, a portion of said carrier liquid becomes entrapped within the vesicles, together of course, with a small amount of the desired substances to be encapsulated. This technique is called "passive entrappment". The efficiency of loading liposomes with passively entrapped aqueous phases is often quite low because it strongly depends on the nature of the carrier phase and, particularly, the concentration of the substances dissolved therein which may affect the yield of liposome formation, However, for drug delivery purposes, the loading efficiency (which is generally defined as the weight of material entrapped over the total weight of material involved in entrappment) is usually not critical because the non-entrapped material can generally be recovered and reused afterwards; hence, the important factor is rather the ratio of useful entrapped material versus the weight of the lipids used for entrappment, i.e., the lipids involved in forming the liposomes membrane. Clearly, minimizing lipid dead-weight upon injection or otherwise, i.e. keeping the weight of vector drug carriers administered to patients to the lowest possible level for a given amount of therapeutically active species is a strong asset in the development of new pharmaceuticals or diagnostic reagents. Now, obviously, the ratio of the weight of encapsulated material over the weight of encapsulating lipids is in direct relation with the so-called captured volume, i.e. the volume of the aqueous phase entrapped in the liposomes core per weight of liposome lipids (.mu.l/mg).
In a classical passive entrappment method described by BANGHAM et al., (J. Mol. Biol. 12, (1965), 238), the aqueous phase containing the compound of interest is put into contact with a film of dried phospholipids deposited on the walls of a reaction vessel. Upon agitation by mechanical means, swelling of the lipids will occur and multilamellar vesicles (MLV) will form. The captured volume of MLV's is low, typically near 2 to 4 .mu.l/mg of lipids. By sonication, the MLV's can be converted to small unilamellar vesicles (SUV) whose captured volume is even smaller, e.g., near 0.5-1 .mu.l/mg. Other methods of preparation giving liposomes with larger captured volume have been described, particularly large unilamellar vesicles (LUV). For instance, DEAMER & BANGHAM (Biochim. Biophys. Acta 443, (1976), 629) have described a method in which membrane forming lipids are dissolved in ether and, instead of first evaporating the ether to form a thin film on a surface, this film being thereafter put into contact with an aqueous phase to be encapsulated, the ether solution is directly injected into said aqueous phase and the ether is evaporated afterwards, whereby liposomes with captured volumes of 14 .mu.l/mg were obtained.
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Guillot Christian
Hyacinthe Roland
Lamy Bernard
Schneider Michel
Tournier Herve
Bracco International B.V.
Page Thurman K.
Venkat Jyothsnh
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