Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1996-11-27
1998-09-15
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
A61K 3700
Patent
active
058075739
DESCRIPTION:
BRIEF SUMMARY
This application is a 3717 PCT/SEQS /00593 filed May 24, 1995.
TECHNICAL FIELD
The present invention relates to the field of polar lipids and, more specifically, to a new biologically active composition, which is based on polar lipids and has been found to yield significant improvements as compared with previously known lipid-based compositions used as carriers for biologically active materials. More concretely, the invention relates to a new composition whose L2-phase and cubic liquid crystalline phase each confer advantages in the controlled release of biologically active material encapsulated therein, as compared with previously known, similar L2-phases and cubic phases, respectively, and are mutually positioned in a phase diagram so as to also confer valuable advantages for some specific applications in which special demands are placed on the release of biologically active materials.
BACKGROUND OF THE INVENTION
Polar lipids are amphiphilic molecules, i.e. they are both "hydrophilic" and "hydrophobic". When placed in an aqueous solution, they must thus unite in some way or another to form different kinds of aggregates. The most well-known of the aggregates formed in water is probably the spheric micelle, which typically contains 50-100 lipid molecules arranged in such a manner that their hydrocarbon tails (the hydrophobic part) form the interior of the micelle concerned and the polar main groups (the hydrophilic part) act as a shield against the surrounding water.
The micelle, however, is only- one of many different types of aggregate formed. It is also possible to find both bar-shaped micelles and reversed-type micelles (L2), which are also called microemulsions in which water forms the internal phase.
A number of liquid crystalline structures are also normally found in systems of polar lipid and water. These comprise hexagonal phases of the normal type (HI) and of the reversed type (HII), as well as the lamellar phase (L.alpha.). The lamellar structure provides, at an excess of water, liposomes, which are spheroidal shells of lipid bilayers. These have been studied to a very large extent and have been used in the release of pharmaceutical preparations, for example in chemotherapy of cancer. The first liposome product on the market contains amphoteracin and is intended for treatment of infections.
Many cubic crystalline phases are said to be both water- and oil-continuous, i.e. bicontinuous. These phases consist of lipid bilayers whose centre forms a minimum surface, separating two water channel systems. There are four main positions in the phase diagram, in which cubic phases can be found. Cubic phases of normal topology (oil-in-water) can be found either adjacent the micellar solution (in many cases between the normal micellar solution (L1) and the hexagonal HI-phases), or between the HI-phase and the lamellar L.alpha.-phase. In the first-mentioned case, the structures are considered to be anisotropic micellar aggregates. In the last-mentioned case, the structures seem to be permanently bicontinuous. Cubic phases may also be found between the L.alpha.- and the HII-phase. In this case, the structures are also bicontinuous. Cubic liquid crystalline phases occurring in the fourth possible position in the phase diagram, i.e. between the HII-phase and the reverse micellar solution (L2), have been studied by J. M. Seddon in Biochemistry, Vol. 29, No. 34, 1990, pp 7997-8002, and by V. Luzzati et al, in Biochemistry 1992, 31, pp 279-285, but these articles do not concern the properties which these phases have been found to possess in the release of biologically active materials.
Furthermore, certain compositions are per se known, whose L2-phase, hexagonal phase and/or cubic phase (formed when mixing water and amphiphilic lipids) have been used for the release of biologically active materials. As examples of publications illustrating this, mentioned can be made of U.S. Pat. No. 4,388,307, U.S. Pat. No. 5,143,934, U.S. Pat. No. 5,151,272, U.S. Pat. No. 5,196,201, U.S. Pat. No. 5,262,164, EP,B1, 314,689,
REFERENCES:
patent: 4388307 (1983-06-01), Cavanak
patent: 5143934 (1992-09-01), Lading et al.
patent: 5151272 (1992-09-01), Engstrom et al.
patent: 5164191 (1992-11-01), Tabibi
patent: 5196201 (1993-03-01), Larsson et al.
patent: 5262164 (1993-11-01), Damani
Biochemistry, vol. 29, 1990, John M. Seddon, "An Inverse Face-Centered Cubic Phase Formed by Diacylglycerol-Phosphatidylcholine Mixtures", p. 7997.
"Lipid Polymorphism: A Correction. The structure of the Cubic Phase of Extinction Symbol Fd--Consists of Two Types of Disjointed Reverse Micelles Embedded in a Three-Dimensional Hydrocarbon Matrix", Vittorio Luzzati et al., Biochemistry, 1992, 31, pp. 279-285.
"Formulation of a Drug Delivery System Based on a Mixture of Monoglycerides and Triglycerides for Use in Treatment of Periodontal Disease", Tomas Norling et al., J. Clin. Periodontal, 1992, 19, pp. 687-692.
Larsson K.ang.re
Ljusberg-Wahren Helena
GS Development AB
Kishore Gollamudi S.
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