The Liposome Company, Inc.

Elan Pharmaceuticalstechnologies, Inc.

J Craig Franklin

Andrew S Janoff

Eric G Mayhew

Shaukat Ali

Paul A Harmon

Suresh K Bhatia

Donna J Cabral-Lilly

Imran Ahmad

Paul R Meers

Charles Pak

Gil Koehane

Soumendu Bhattacharya

Walter R Perkins

Ravi K Erukulla

Patrick L Ahl

Ravi Erukulla

Robert A Reed

Provided herein is a taxane having a hydrocarbon attached at the 2&prime; and/or 7 positions, the hydrocarbon's alpha position being occupied by a &ldquo;hydrolysis-promoting group&rdquo; (&ldquo;HPG&rdquo;). In one embodiment, the hydrolysis promoting group is stereospecifically attached to the &agr;-carbon of the hydrophobic taxane. The Substitution of an HPG for the methylene unit ordinarily occupying the alpha position allows for enhanced in vivo hydrolysis of the hydrocarbon-taxane bond, and hence, for enhanced taxane therapeutic activity. Also provided herein are taxane-containing compositions, and methods of administering taxanes to animals, including those afflicted with cancers or inflammatory diseases.

Hydrolysis-promoting hydrophobic taxane derivatives

Provided herein is a taxane having a hydrocarbon attached at the 2&prime; and/or 7 positions, the hydrocarbon's alpha position being occupied by a &ldquo;hydrolysis-promoting group&rdquo; (&ldquo;HPG&rdquo;). In one embodiment, the hydrolysis promoting group is stereospecifically attached to the a-carbon of the hydrophobic taxane. The Substitution of an HPG for the methylene unit ordinarily occupying the alpha position allows for enhanced in vivo hydrolysis of the hydrocarbon-taxane bond, and hence, for enhanced taxane therapeutic activity. Also provided herein are taxane-containing compositions, and methods of administering taxanes to animals, including those afflicted with cancers or inflammatory diseases.

Peptide-lipid conjugates are incorporated into liposomes so as to selectively destabilize the liposomes in the vicinity of target peptidase-secreting cells, and hence, to deliver the liposomes to the vicinity of the target cells, or directly into the cells. The liposomes can thus be used to treat mammals for diseases, disorders or conditions, e.g., tumors, microbial infection and inflammations, characterized by the occurrence of peptidase-secreting cells.

Peptide-lipid conjugates, liposomes and lipsomal drug delivery

This invention provides a taxane derivative of the formula:

Hydrophobic taxane derivatives

Liposomal peptide-lipid conjugates and delivery using same

This invention provides a taxane derivative of the formula: ##STR1## wherein a hydrophobic organic moiety is attached to a taxane. R and R.sup.1 is each indepently H or a hydrophobic organic moiety, as long as at least one of R and R.sup.1 is not H. Attachment of a hydrophobic organic moiety to the taxane so as to obtain a taxane derivative generally stabilizes the association of the derivative with a lipid, including a liposomal lipid, carrier in the plasma of animals to which the derivative-carrier association is administered. Also provided herein is a composition containing the taxane derivative and a pharmaceutically acceptable medium; desirably, the medium also contains a lipid carrier, and the derivative is associated with the carrier. Further provided herein is a method of administering taxane derivatives to animals, for example, animals afflicted with cancers.

Preparation of liposomal taxanes

Provided herein is a taxane having a hydrocarbon attached at the 2' and/or 7 positions, the hydrocarbon's alpha position being occupied by a 'hydrolysis-promoting group' ('HPG'). In one embodiment, the hydrolysis promoting group is stereospecifically attached to the .alpha.-carbon of the hydrophobic taxane. The Substitution of an HPG for the methylene unit ordinarily occupying the alpha position allows for enhanced in vivo hydrolysis of the hydrocarbon-taxane bond, and hence, for enhanced taxane therapeutic activity. Also provided herein are taxane-containing compositions, and methods of administering taxanes to animals, including those afflicted with cancers or inflammatory diseases.

Peptide-lipid conjugates

Lipid-based carriers are provided herein that have a lamellar lipid component composed of an etherlipid and a complementarily shaped lipid. This novel combination of lipids allows for the incorporation of etherlipids in the carriers at higher concentrations than would otherwise be possible. Pharmaceutical compositions containing the carriers can be used therapeutically, for example, in the treatment of cancers.

Carriers containing an etherlipid/complementarily shape lipid

Endotoxin incorporated into liposomes, lipid bilayers or lipid complexes can be detected by combining an aqueous suspension of the liposomes, lipid complexes or lipid bilayers with a suitable detergent. Preferable detergents, e.g., Lubrol-PX.TM. or a polyoxyethylene ether, solubilize the lipid bilayers, liposomes or lipid complexes at acceptable lipid concentrations, forming micelles therefrom which contain lipid bilayer, liposome or lipid complex lipid, detergent and endotoxin, should it be present. The micelles are then assayed for the presence of endotoxin.

Detection of endotoxin levels in liposomes, lipid bilayers and lipid

Synthesis of hydrophobic taxane derivatives

Pharmaceutical compositions are provided herein that contain, in addition to a pharmaceutically acceptable carrier, a lamellar lipid. The lipid is composed of an ether lipid and a lipid having a molecular shape that is complementary to the molecular shape of the glycerolipid. These compositions can be used therapeutically, for example, in the treatment of cancers and inflammatory conditions.

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Skillman, NJ, United States of America

J Craig Franklin