Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1998-02-03
2001-10-02
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
06296870
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to liposomes containing active agents such as therapeutic drugs, where the liposome membrane is formulated to provide a liposome with increased carrying capacity for poorly water-soluble active agents. Alternatively or in addition, the active agent may be contained within, or adsorbed onto, the liposome bilayer. The active agent may be aggregated with a lipid surfactant and carried within the liposome's internal space; the liposome membrane is formulated to resist the disruptive effects of the active agent-surfactant aggregate.
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 vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 &mgr;m. Liposomes with several nonconcentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
Conventional liposomes are formulated to carry drugs or other active agents either contained within the aqueous interior space (water-soluble drugs) or partitioned into the lipid bilayer (water-insoluble drugs). As used herein, active agents “entrapped” within liposomes are those which are in the interior space of the liposome, compared to those which are partitioned into the lipid bilayer and contained in the vesicle membrane itself. Active agents which 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 severely limited by the rapid clearance of liposomes from the blood by cells of the reticuloendothelial system (RES).
The action of many drugs involves their direct interaction with hydrophobic sites within a cell, or their ability to pass through the cell membrane into cytoplasmic and nuclear compartments. These hydrophobic interactions are due to regions on the molecule that are poorly solvated by water, such that the overall aqueous solubility of the drug is compromised. One such drug is TAXOL®, which has a water solubility of about 1 micromolar. The solubility of TAXOL® can be somewhat increased by chemical modification, but it is not clear how such modifications affect the function of the drug.
The efficacy of many drugs is limited by their inability to reach the intended therapeutic site. In many cases only a small fraction of the administered dose of a drug (even if water soluble) reaches the therapeutic site; most of the drug is distributed throughout the body. This distribution into healthy organs and tissues often limits dosage. Drug formulations and drug delivery methods that suspend significant amounts of a therapeutic compound in an aqueous medium, that are stabilized against dissolution in the body, and that provide for site specific delivery are therefore desirable.
The formulation of drugs with poor water solubility has traditionally focused on the use of emulsions and other association colloids, such as micelles, that dissolve the drug and therefore increase its concentration in aqueous media. However, these emulsions (and particularly micellar suspensions) are not necessarily stable and targetable to specific anatomic sites. When placed in contact with plasma or whole blood, a repartitioning of drug from a micelle or emulsion into cells and macromolecular components occurs, and the drug solubilizing system no longer retains the drug.
A liposome consists of a lipid membrane surrounding an aqueous interior, and thus has the capacity to carry both water-soluble and water-insoluble drugs in its interior and its membrane, respectively. The liposome membrane, however, represents only a small part of the total volume of the total liposome construct; the capacity of a liposome to carry and release a poorly water-soluble drug in a dispersible form is limited by the small volume of the liposome membrane. The present invention optimizes the lipid composition of liposome bilayers, so that the lipid membrane can carry increased amounts of drug. The present invention also provides methods to optimize the ability of the aqueous interior to carry drug. The present invention, in particular, provides a liposome designed to carry large amounts of TAXOL®.
It is accordingly desirable to devise liposome formulations capable of delivering therapeutic amounts of active agent via parenteral administration, and resulting in an extended half-life of active agent in the blood stream.
SUMMARY OF THE INVENTION
It is therefore a general object of the present invention to provide a liposome composition and method for administering a therapeutically effective amount of a compound for an extended period in the bloodstream.
A first object of the present invention is a liposome containing an active agent, where the liposome bilayer membrane contains vesicle-forming lipid derivatized with hydrophilic polymer. The active agent is aggregated with a lipid surfactant and entrapped within the liposome. The liposome membrane contains polymer-derivatized lipid in an amount sufficient to inhibit fusion of the membrane with the active agent/surfactant aggregate entrapped therein.
A further object of the present invention is a liposome containing an active agent, where the liposome bilayer membrane contains vesicle-forming lipid derivatized with polyethylene glycol. the active agent is aggregated with a lipid surfactant and entrapped within the liposome. The liposome membrane contains polyethylene glycol in an amount sufficient to inhibit fusion of the membrane with the active agent/surfactant aggregate entrapped therein.
A further object of the present invention is a liposome containing a micellar preparation of paclitaxel, where the liposome bilayer membrane contains from 1 mole percent to 22 mole percent vesicle-forming lipid derivatized with polyethylene glycol of molecular weight 750 daltons.
A further object of the present invention is a method for preparing an active agent for intravenous administration, by entrapping an active agent aggregated with lipid surfactant in a liposome, where the lipid bilayer membrane of the liposome contains vesicle-forming lipids derivatized with a hydrophilic polymer. the polymer-derivatized lipid is contained in the liposome membrane in an amount sufficient to inhibit fusion of the membrane with the active agent-lipid aggregate contained therein.
A further object of the present invention is a liposome containing an active agent, where the liposome bilayer membrane contains cholesterol. The active agent is aggregated with a lipid surfactant and entrapped within the liposome. The liposome membrane contains cholesterol in an amount sufficient to inhibit fusion of the membrane with the active agent/surfactant aggregate entrapped therein.
A further object of the present invention is a liposome containing an active agent, where the liposome lipid bilayer membrane contains protective molecules extending from the surface of the lipid bilayer. The active agent is aggregated with a lipid surfactant and entrapped within the liposome, and the liposome membrane contains protective molecules in an amount sufficient to inhibit fusion of the liposome membrane with the active agent-lipid surfactant aggregate therein.
A further aspect of the present invention is a liposome containing an active agent, where the lipid bilayer of the liposome comprises phospholipid, an active agent that is poorly water soluble, and surfactant with a low Critical Micelle Concentration (CMC). The surfactant is contained in the lipid bilayer in an amount sufficient to increase the
Needham David
Sarpal Ranjit S.
Duke University
Kishore Gollamudi S.
Myers Bigel Sibley & Sajovec P.A.
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