Patents Represented by Attorney, Agent or Law Firm Kenneth B. Rubin
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Patent number: 5783210Abstract: A composition having equal to or greater than about 97 percent by weight phosphatidylcholine and about equal to or less than about 3 percent by weight to about 0.5% sphingomylin and equal to or less than about 0.5% lysophosphatidylcholine (undetectable by UV at 205 nm) has been found to result in liposomes having improved stability. Methods for preparing the composition are disclosed whereby the phospholipids are extracted and then purified using silica chromatography.Type: GrantFiled: May 24, 1995Date of Patent: July 21, 1998Assignee: The Liposome Company, Inc.Inventors: Paul A. Tremblay, Robert L. Suddith, John J. Kearns
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Patent number: 5766624Abstract: Defensins are microbicidal, tumoricidal cytotoxic protein components of animal host defense systems. They can be entrapped in liposomes containing release-inhibiting lipid such that the defensins are neutralized, and their release from the liposomes is inhibited; however, the defensins remain effective when exposed to endocytosed material in endocytic vesicles. Liposomal defensin formulations are administered to animals for the treatment or prevention of microbial infections, for the treatment of cancers and for the treatment of disorders characterized by a deficiency of protein-mediated cytotoxic activity in cytoplasmic granules.Type: GrantFiled: May 24, 1995Date of Patent: June 16, 1998Assignee: The Liposme Company, Inc.Inventors: Andrew S. Janoff, Walter Perkins, Imran Ahmad
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Patent number: 5762958Abstract: Liposomes are provided which contain ether lipids having the formula: ##STR1## as well as an underivatized phosphatidylethanolamine, a sterol, and a phosphatidylethanolamine-dicarboxylic acid headgroup-derivatized lipid. These liposomes are useful in a variety of therapeutic regimens, including the treatment of cancers and inflammatory disorders.Type: GrantFiled: February 16, 1996Date of Patent: June 9, 1998Assignee: The Liposome Company, Inc.Inventors: Eric Mayhew, Andrew S. Janoff, Imran Ahmad, Suresh K. Bhatia
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Patent number: 5756774Abstract: Provided herein are novel syntheses of the phosphate-based inositol derivatives 1-O-?(+)-menthoxycarbonyl!-6-O-benzyl-2,3:4,5-di-O-isopropylidene-myo-inos itol (D4P), D-myo-inositol 1,4,5-trisphosphate (D-IP.sub.3), 6-O-benzyl-2,3:4,5-di-O-isopropylidene-myo-inositol H-phosphonate ((-)-3-HP) and L-myo-inositol 1,4,5-trisphosphate (L-IP.sub.3). These syntheses employ fewer column chromatography steps for the isolation of intermediates than do prior art syntheses, and hence, are more convenient, economical and efficient than are the previously known synthetic methods.Type: GrantFiled: February 4, 1997Date of Patent: May 26, 1998Inventors: Robert Bittman, Lawrence Leung
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Patent number: 5744158Abstract: A method for encapsulation of antineoplastic agents in liposomes is provided, having preferably a high drug:lipid ratio. Liposomes may be made by a process that loads the drug by an active mechanism using a transmembrane ion gradient, preferably a transmembrane pH gradient. Using this technique, trapping efficiencies approach 100%, and liposomes may be loaded with drug immediately prior to use, eliminating stability problems related to drug retention in the liposomes. Drug:lipid ratios employed are about 3-80 fold higher than for traditional liposome preparations, and the release rate of the drug from the liposomes is reduced. An assay method to determine free antineoplastic agents in a liposome preparation is also disclosed.Type: GrantFiled: May 25, 1995Date of Patent: April 28, 1998Assignee: The Liposome Company, Inc.Inventors: Lawrence D. Mayer, Marcel B. Bally, Pieter R. Cullis, Richard S. Ginsberg, George N. Mitilenes
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Patent number: 5736155Abstract: Methods for encapsulating ionizable antineoplastic agents in liposomes using transmembrane potentials are provided. Trapping efficiencies approaching 100% and rapid loading are readily achieved. Dehydration protocols which allow liposomes to be conveniently used in the administration of antineoplastic agents in a clinical setting are also provided. In accordance with other aspects of the invention, transmembrane potentials are used to reduce the rate of release of ionizable drugs from liposomes.Type: GrantFiled: June 5, 1995Date of Patent: April 7, 1998Assignee: The Liposome Company, Inc.Inventors: Marcel B. Bally, Pieter R. Cullis, Michael J. Hope, Thomas D. Madden, Lawrence D. Mayer
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Patent number: 5716526Abstract: The invention provides a method of separating liposomes or lipid complexes from a fluidic medium. The method involves passage of a fluidic medium containing liposomes or lipid complexes through a composite filter which retains the liposomes or lipid complexes while allowing the fluidic medium to pass through. The filter is composed of a ceramic membrane and a ceramic substrate that is thicker than the ceramic membrane. Moreover, the average pore size of the ceramic membrane, from about 0.1 to about 0.2 microns, is less than the average pore size of the substrate.Type: GrantFiled: February 12, 1996Date of Patent: February 10, 1998Assignee: The Liposome Company, Inc.Inventors: Robyne J. Kelemen, Anthony G. Durning
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Patent number: 5703117Abstract: 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"). 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.Type: GrantFiled: September 12, 1996Date of Patent: December 30, 1997Assignee: The Liposome Company, Inc.Inventors: Eric Mayhew, Shaukat Ali, Andrew S. Janoff
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Patent number: 5683715Abstract: Provided herein are liposomal taxane formulations where the liposomal lipid is a phosphatidylcholine; these formulations are useful for treating animals afflicted with cancers.Type: GrantFiled: June 7, 1995Date of Patent: November 4, 1997Assignee: The Liposome Company, Inc.Inventors: Lawrence Boni, Joel Portnoff
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Patent number: 5681589Abstract: This invention provides a compound having the formula R.sup.1 -Y.sup.1 --CHZ.sup.1 -CH(NY.sup.2 Y.sup.3)--CH.sub.2 -Z.sup.2, wherein: R.sup.1 is a straight-chained alkyl, alkenyl or alkynyl group having from 8 to 19 carbon atoms in the aliphatic chain; Y.sup.1 is --CH.dbd.CH--, --C.tbd.C-- or --CH(OH)CH(OH)--; Z.sup.1 is OH or a conversion-inhibiting group; Z.sup.2 is a conversion-inhibiting group; Y.sup.2 is H, a phenyl group, an alkyl-substituted phenyl group having from 1 to about 6 carbons in the alkyl chain, or an alkyl chain having from 1 to 6 carbons; Y.sup.3 is H or a group having the formula --C(O)R.sup.2 or --S(O).sub.2 R.sup.2 ; R.sup.2 is a straight-chained alkyl, alkenyl or alkynyl group having from 1 to 23 carbon atoms in the chain; and when Z.sup.2 is an amino, R.sup.2 is an aliphatic chain having from 1 to 9 or from 19 to 23 carbon atoms in the aliphatic chain.Type: GrantFiled: October 19, 1995Date of Patent: October 28, 1997Assignee: The Lipsome Company, Inc.Inventors: Yong Wei, Eric Mayhew, Imran Ahmad, Andrew S. Janoff
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Patent number: 5677337Abstract: This invention provides a compound having the formula R.sup.1 --Y.sup.1 --CHZ.sup.1 --CH(NY.sup.2 Y.sup.3)--CH.sub.2 --Z.sup.2, wherein: R.sup.1 is a straight-chained alkyl, alkenyl or alkynyl group having from 8 to 19 carbon atoms in the aliphatic chain; Y.sup.1 is --CH.dbd.CH--, --C.tbd.C-- or --CH(OH)CH(OH)--; Z.sup.1 is OH or a conversion-inhibiting group; Z.sup.2 is a conversion-inhibiting group; Y.sup.2 is H, a phenyl group, an alkyl-substituted phenyl group having from 1 to about 6 carbons in the alkyl chain, or an alkyl chain having from 1 to 6 carbons; Y.sup.3 is H or a group having the formula --C(O)R.sup.2 or --S(O).sub.2 R.sup.2 ; R.sup.2 is a straight-chained alkyl, alkenyl or alkynyl group having from 1 to 23 carbon atoms in the chain; and when Z.sup.2 is an amino, R.sup.2 is an aliphatic chain having from 1 to 9 or from 19 to 23 carbon atoms in the aliphatic chain.Type: GrantFiled: October 19, 1995Date of Patent: October 14, 1997Assignee: The Liposome Company, Inc.Inventors: Yong Wei, Eric Mayhew, Imran Ahmad, Andrew S. Janoff
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Patent number: 5662930Abstract: Provided herein is a method of administering a liposome composition to an animal, the method involving adminstering to the animal a liposome composition containing an adverse physiological reaction-reducing effective amount of a liposome which has, in addition to a bioactive agent, a lipid bilayer containing a lipid and a surface agent-modified molecule. An adverse physiological reaction which may be experienced by the animal upon administration of a liposome composition is reduced by way of the presence of the surface agent-modified molecule in the liposome's lipid bilayer.Type: GrantFiled: May 4, 1995Date of Patent: September 2, 1997Assignee: The Liposome Company, Inc.Inventors: Patrick L. Ahl, Suresh K. Bhatia, Sharma R. Minchey, Andrew S. Janoff
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Patent number: 5631394Abstract: This invention provides a compound having the formula R.sup.1 --Y.sup.1 --CHZ.sup.1 --CH(NY.sup.2 Y.sup.3)--CH.sub.2 --Z.sup.2, wherein: R.sup.1 is a straight-chained alkyl, alkenyl or alkynyl group having from 8 to 19 carbon atoms in the aliphatic chain; Y.sup.1 is --CH.dbd.CH--, --C.tbd.C-- or --CH(OH)CH(OH)--; Z.sup.1 is OH or a conversion-inhibiting group; Z.sup.2 is a conversion-inhibiting group; Y.sup.2 is H, a phenyl group, an alkyl-substituted phenyl group having from 1 to about 6 carbons in the alkyl chain, or an alkyl chain having from 1 to 6 carbons; Y.sup.3 is H or a group having the formula --C(O)R.sup.2 or --S(O).sub.2 R.sup.2 ; R.sup.2 is a straight-chained alkyl, alkenyl or alkynyl group having from 1 to 23 carbon atoms in the chain; and when Z.sup.2 is an amino, R.sup.2 is an aliphatic chain having from 1 to 9 or from 19 to 23 carbon atoms in the aliphatic chain.Type: GrantFiled: February 2, 1995Date of Patent: May 20, 1997Assignee: The Liposome Company, Inc.Inventors: Yong Wei, Eric Mayhew, Imran Ahmad, Andrew S. Janoff
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Patent number: 5626873Abstract: A novel oil and water emulsion useful for delivery of a bioactive agent is disclosed. The emulsion comprises a first HLB requirement amount of surfactant dioleoyl phosphatidylethanolamine. In particular embodiments the emulsion includes a secondary surfactant other than dioleoyl phosphatidylethanolamine except in the limiting case wherein the HLB requirement is the HLB value of dioleoyl phosphatidylethanolemine in which case the the HLB requirement amount of a secondary surfactant is 0. By appropriate selection of dioleoyl phosphatidylethanolamine to secondary surfactant ratios, it is possible to prepare emulsions for pharmaceutical delivery of a bioactive agent using an oil phase having a required HLB value up to about 17.4. Above a required HLB value of about 17.4. dioleoyl phosphatidylethanolamine may be used to reduce the amount of secondary surfactant required to form an emulsion.Type: GrantFiled: May 16, 1995Date of Patent: May 6, 1997Assignee: The Liposome Company, Inc.Inventors: Alan L. Weiner, Sharon Carpenter-Green
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Patent number: 5616334Abstract: Methods and compositions are described for nonliposomal lipid complexes in association with toxic hydrophobic drugs such as the polyene antibiotic amphotericin B. Lipid compositions are preferably a combination of the phospholipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) in about a 7:3 mole ratio. The lipid complexes contain a bioactive agent, and may be made by a number of procedures, at high drug:lipid ratios. These compositions of high drug:lipid complexes (HDLCs) may be administered to mammals such as humans for the treatment of infections, with substantially equivalent or greater efficacy and reduced drug toxicities as compared to the drugs in their free form. Also disclosed is a novel liposome-loading procedure, which may also be used in the formation of the HDLCs.Type: GrantFiled: April 28, 1995Date of Patent: April 1, 1997Assignee: The Liposome Company, Inc.Inventors: Andrew S. Janoff, Lawrence Boni, Thomas D. Madden, Pieter R. Cullis, Robert P. Lenk, John J. Kearns, Anthony G. Durning, Robert Klimchak, Joel Portnoff
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Patent number: 5616341Abstract: A method for encapsulation of antineoplastic agents in liposomes is provided, having preferably a high drug:lipid ratio. Liposomes may be made by a process that loads the drug by an active mechanism using a transmembrane ion gradient, preferably a transmembrane pH gradient. Using this technique, trapping efficiencies approach 100%, and liposomes may be loaded with drug immediately prior to use, eliminating stability problems related to drug retention in the liposomes. Drug:lipid ratios employed are about 3-80 fold higher than for traditional liposome preparations, and the release rate of the drug from the liposomes is reduced. An assay method to determine free antineoplastic agents in a liposome preparation is also disclosed.Type: GrantFiled: August 26, 1993Date of Patent: April 1, 1997Assignee: The Liposome Company, Inc.Inventors: Lawrence D. Mayer, Marcel B. Bally, Pieter R. Cullis, Richard S. Ginsberg, George N. Mitilenes
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Patent number: 5614216Abstract: A synthetic lung surfactant composition and process for depositing a monolayer of a phosphatidylcholine lung surfactant to the alveoli of a mammal. The composition comprises a phosphatidylcholine lung surfactant, a phosphatidylethanolamine, and cholesterol in proportions such that the composition is in lamellar form at or below a first temperature and in non-lamellar form at a second temperature which is higher than the first temperature. A preferred phosphatidylcholine lung surfactant for use in this invention is dipalmitoyl phosphatidylcholine (DPPC), which is known to be the major lipid constituent of natural mammalian lung surfactant, and a preferred phosphatidylethanolamine is dioleoyl phosphatidylethanolamine (DOPE). In particular embodiments, the composition is in lamellar form at about room temperature (25.degree. C.), and in non-lamellar form at a temperature in the range of about 30.degree. to 37.degree. C., which is at or below normal human body temperature (37.degree. C.).Type: GrantFiled: May 16, 1995Date of Patent: March 25, 1997Assignee: The Liposome Company, Inc.Inventor: Andrew S. Janoff
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Patent number: 5614214Abstract: Provided herein is a method of administering a liposome composition to an animal, the method involving adminstering to the animal a liposome composition containing an adverse physiological reaction-reducing effective amount of a liposome which has, in addition to a bioactive agent, a lipid bilayer containing a lipid and a surface agent-modified molecule. An adverse physiological reaction which may be experienced by the animal upon administration of a liposome composition is reduced by way of the presence of the surface agent-modified molecule in the liposome's lipid bilayer.Type: GrantFiled: May 20, 1994Date of Patent: March 25, 1997Assignee: The Liposome Company, Inc.Inventors: Patrick L. Ahl, Suresh K. Bhatia, Sharma R. Minchey, Andrew S. Janoff
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Patent number: 5583052Abstract: A formulation preparation device is provided herein which contains a valve assembly, transfer spikes, syringe port and tube, these components being interconnected so as to provide for controlled fluid flow between the spikes and port, through the assembly, in specific directions only. The device has an enclosed, sterilizable, gripable housing and can be used to mix combine fluids in reproducible and predetermined proportions. Combination is accomplished aseptically, avoiding contact between the device's operator and the fluids and the substances combined. Biologically active compounds can be combined with one or more fluids, including such aqueous liposome suspensions, using the device. A formulation preparation kit containing, in addition to the device, the fluids and compounds to be formulated is thus also provided herein; methods of using the device to prepare such formulations are further provided herein.Type: GrantFiled: May 23, 1995Date of Patent: December 10, 1996Assignees: The Liposome Company, Inc., B. Braun Medical, Inc.Inventors: Joel B. Portnoff, Royden M. Coe, John Grimm, Kenneth Raines, Joel Bartholomew
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Patent number: 5580899Abstract: 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.Type: GrantFiled: June 7, 1995Date of Patent: December 3, 1996Assignee: The Liposome Company, Inc.Inventors: Eric Mayhew, J. Craig Franklin, Suresh Bhatia, Paul A. Harmon, Andrew S. Janoff