Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1998-06-18
2001-03-13
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S001210, C424S009321, C424S009510, C424S094300
Reexamination Certificate
active
06200598
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to thermosensitive liposomes, and more specifically to liposomes comprising phospholipids and a surface active agent, wherein the liposomes release their contents at mild hyperthermic temperatures.
BACKGROUND OF THE INVENTION
Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.05 &mgr;m in diameter; large unilamellar vesicles (LUVs) are typically larger than 0.05 &mgr;m. Oligolamellar large vesicles and multilamellar large vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 &mgr;m. Liposomes with several nonconcentric membranes, i.e., several small vesicles contained within a larger vesicle, are termed multivesicular vesicles.
Conventional liposomes are formulated to carry therapeutic agents, drugs or other active agents either contained within the aqueous interior space (water soluble active agents) or partitioned into the lipid bilayer (water-insoluble active agents). Copending U.S. patent application Ser. No. 08/795,100 discloses liposomes containing cholesterol in the lipid bilayer membrane, where an active agent is aggregated with a lipid surfactant to form micelles and the micelles are entrapped in the interior space of the liposome.
Active agents that have short half-lives in the bloodstream are particularly suited to delivery via liposomes. Many anti-neoplastic agents, for example, are known to have a short half-life in the bloodstream such that their parenteral use is not feasible. However, the use of liposomes for site-specific delivery of active agents via the bloodstream is limited by the rapid clearance of liposomes from the blood by cells of the reticuloendothelial system (RES).
Liposomes are normally not leaky but will become so if a hole occurs in the liposome membrane, if the membrane degrades or dissolves, or if the membrane temperature is increased to the phase transition temperature. The elevation of temperature (hyperthermia) at a target site in a subject to raise liposome temperature above the phase transition temperature, and thereby cause the release of the liposome contents, has been used for the selective delivery of therapeutic agents. Yatvin et al.,
Science
204:188 (1979). This technique is limited, however, where the phase transition temperature of the liposome is significantly higher than the normal tissue temperature.
It is accordingly desirable to devise liposome formulations capable of delivering therapeutic amounts of active agents in response to mild hyperthermic conditions.
SUMMARY OF THE INVENTION
In view of the foregoing, a first aspect of the present invention is a liposome containing an active agent. The liposome's lipid bilayer membrane contains phospholipids as the primary lipid source; lysolipids are contained in the bilayer membrane in an amount that increases the percentage of active agent released at the phase transition temperature, compared to that which would occur in the absence of lysolipid.
A further aspect of the present invention is a liposome having a lipid bilayer membrane comprising phospholipids as the primary lipid source, and from 2 mole percent to 30 mole percent lysolipid.
A further aspect of the present invention is a method for preparing an active agent for hyperthermic administration. The active agent is entrapped in a liposome having a lipid bilayer membrane comprising phospholipids as the primary lipid source, and from 1 to 30% lysolipid.
A further aspect of the present invention is a liposomal preparation comprising a plurality of liposomes as described above.
A further aspect of the present invention is a method of making liposomes containing an active agent in the liposome interior space. A phospholipid film containing lysolipid is first prepared, and then hydrated with an aqueous preparation containing the active agent and an equilibrating amount of lysolipid monomer. Lysolipid is contained in the liposome membrane in an amount sufficient to increase the percentage of active agent released at the phase transition temperature of the liposome membrane, compared to that which would occur in the absence of the lysolipid.
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Duke University
Kishore Gollamudi S.
Myers Bigel Sibley & Sajovec P.A.
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