Patents Represented by Attorney Allen Bloom
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Patent number: 5380531Abstract: The present invention relates to liposomal compositions having a concentration gradient which load amino acids and peptides exhibiting weak acid or base characteristics into liposomes. Specifically loaded into liposomes by the methods of the present invention are C-terminal substituted amino acids or peptides. The liposomes are preferably large unilamellar vesicles. The concentration gradient is formed by encapsulating a first medium in the liposomes, said medium having a first concentration of the one or more charged species, and suspending the liposomes in a second medium having a second concentration of the one or more charged species, such as for example a pH gradient. Also disclosed are pharmaceutical preparations comprising such C-terminal substituted amino acids or peptides which have been loaded into the liposomes by the method of the invention.Type: GrantFiled: June 2, 1992Date of Patent: January 10, 1995Assignee: The Liposome Company, Inc.Inventors: Ajoy Chakrabarti, Ian Clark-Lewis, Pieter R. Cullis
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Patent number: 5366958Abstract: This invention encompasses new and substantially improved methods and compositions for delivery of therapeutic agents to specifically chosen body sites. Conjugation of fibronectin to bioactive agents or to lipids or to liposomes which entrap the bioactive agents permits immobilization of the bioactive agent when administered at collagen-, heparin-, hyaluronic acid-, fibrin/fibrinogen-, or ganglioside-rich sites. Covalent conjugation is achieved by two methods: (1) the enzymatically catalyzed cross-linkage of fibronectin to an amine containing compound, and (2) by a modified NHS method which permits formation of peptide bonds between fibronectin and lipid compounds.Type: GrantFiled: August 20, 1993Date of Patent: November 22, 1994Assignee: The Liposome Company, Inc.Inventors: Alan L. Weiner, Robert P. Lenk, Sharon S. Carpenter-Green, Michael W. Fountain
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Patent number: 5330689Abstract: Methods and compositions are described for the preparation of alpha-tocopherol vesicles, the bilayers of which comprise a salt form of an organic acid derivative of alpha-tocopherol such as the Tris salt form of alpha-tocopherol hemisuccinate. The method is rapid and efficient and does not require the use of organic solvents. The alpha-tocopherol vesicles may be used to entrap compounds which are insoluble in aqueous solutions. Such preparations are especially useful for entrapping bioactive agents of limited solubility, thus enabling administration in vivo.Type: GrantFiled: March 29, 1993Date of Patent: July 19, 1994Assignee: The Liposome Company, Inc.Inventors: Andrew S. Janoff, Lois E. Bolcsak, Alan L. Weiner, Paul A. Tremblay, Michael V. W. Bergamini, Robert L. Suddith
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Patent number: 5288499Abstract: Methods and compositions are described for the preparation of bioactive agents entrapped in lipid vesicles the bilayers of which comprise a salt form of an organic acid derivative of a sterol, such as the tris-salt form of a sterol hemisuccinate, and to compositions comprising a mixture of tris(hydroxymethyl)aminomethane salt of cholesteryl hemisuccinate with either an antifungal compound or a peptide. These compositions have various applications in vivo.Type: GrantFiled: September 12, 1991Date of Patent: February 22, 1994Assignee: The Liposome Company, Inc.Inventors: Andrew S. Janoff, Mircea C. Popescu, Alan L. Weiner, Lois E. Bolcsak, Paul A. Tremblay, Christine E. Swenson
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Patent number: 5262168Abstract: A liposome composition and methods for making same are disclosed, such compositions comprise an arachidonic acid metabolite such as a prostaglandin, preferably prostaglandin E.sub.1, a lipid, and a drying protectant such as a saccharide. The liposomes may be loaded with prostaglandin passively, or using a transmembrane concentration gradient, preferably using a transmembrane pH gradient. Using this transmembrane loading technique, trapping efficiencies of 50% to 100% are achieved, and the release rate of the prostaglandin from the liposomes is reduced. The liposome size is maintained after lyophilization and reconstitution.Type: GrantFiled: January 16, 1992Date of Patent: November 16, 1993Assignee: The Liposome Company, Inc.Inventors: Robert P. Lenk, Michelle L. Tomsho, Robert L. Suddith, Robert J. Klimchak
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Patent number: 5252263Abstract: Methods are described for controlling the transbilayer distribution of ionizable lipids and proteins in vesicles. Control of the ion gradient of the exterior bathing medium in relation to that of the interior entrapped aqueous compartment of the vesicles induces migration of ionizable lipids or proteins to one or the other of the monolayers comprising the bilayer. This can result in an asymmetric distribution of the ionizable lipid or ionizable protein. The basic ionizable lipids, such as stearylamine and sphingosine, are sequestered into the inner monolayer when the liposome interior is acidic relative to the liposome exterior. Conversely, acidic ionizable lipids such as oleic acid and stearic acid are sequestered into the inner monolayer when the liposome interior is basic relative to the liposome exterior bathing solution.Type: GrantFiled: March 17, 1992Date of Patent: October 12, 1993Assignee: The Liposome Company, Inc.Inventors: Michael J. Hope, Pieter R. Cullis
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Patent number: 5234634Abstract: Methods and compositions are described for the preparation of alpha-tocopherol vesicles, the bilayers of which comprise a salt form of an organic acid derivative of alpha-tocopherol such as the Tris salt form of alpha-tocopherol hemisuccinate. The method is rapid and efficient and does not require the use of organic solvents. The alpha-tocopherol vesicles may be used to entrap compounds which are insoluble in aqueous solutions. Such preparations are especially useful for entrapping bioactive agents of limited solubility, thus enabling administration in vivo.Type: GrantFiled: October 17, 1990Date of Patent: August 10, 1993Assignee: The Liposome Company, Inc.Inventors: Andrew S. Janoff, Lois E. Bolcsak, Alan L. Weiner, Paul A. Tremblay, Michael V. W. Bergamini
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Patent number: 5231112Abstract: Methods and compositions are described for the preparation of bioactive agents entrapped in lipid vesicles the bilayers of which comprise a salt form of an organic acid derivative of a sterol, such as the tris-salt form of a sterol hemisuccinate, and to bompositions comprising a mixture of tris(hydroxymethyl)aminomethane salt of cholesteryl hemisuccinate with either an antifungal compound or a peptide. These compositions have various applications in vivo.Type: GrantFiled: October 23, 1989Date of Patent: July 27, 1993Assignee: The Liposome Company, Inc.Inventors: Andrew S. Janoff, Mircea C. Popescu, Alan L. Weiner, Lois E. Bolcsak, Paul A. Tremblay, Christine E. Swenson
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Patent number: 5204112Abstract: Methods are described for controlling the transbilayer distribution of ionizable lipids and proteins in vesicles. Control of the ion gradient of the exterior bathing medium in relation to that of the interior entrapped aqueous compartment of the vesicles induces migration of ionizable lipids or proteins to one or the other of the monolayers comprising the bilayer. This can result in an asymmetric distribution of the ionizable lipid or ionizable protein. The basic ionizable lipids, such as stearylamine and sphingosine, are sequestered into the inner monolayer when the liposome interior is acidic relative to the liposome exterior. Conversely, acidic ionizable lipids such as oleic acid and stearic acid are sequestered into the inner monolayer when the liposome interior is basic relative to the liposome exterior bathing solution.Type: GrantFiled: June 12, 1987Date of Patent: April 20, 1993Assignee: The Liposome Company, Inc.Inventors: Michael J. Hope, Pieter R. Cullis
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Patent number: 5200393Abstract: Methods and compositions are described for liquid or gel forms of a lipid excipient to be used in pharmaceutical or cosmetic preparations. The lipid excipient comprises a phospholipid such as a lysophospholipid, for example, mono-oleoyl-phosphatidylethanolamine ("MOPE"). Relatively low concentrations of the lipid can be employed in forming the gel, e.g., about 1-2%. The invention discloses the use of a lipid delivery system at a relatively low lipid concentration as a non-toxic, non-irritating carrier or excipient alone or in combination with other agents, for both drugs and cosmetics. For example, the lipid excipient in sprayable or droppable form has special utility in the non-irritating delivery of peptides (e.g., calcitonin and insulin) to the nasal mucosa, due to the ability of the excipient to enhance absorption across nasal membranes. As a cosmetic, it can be used alone or in combination with biologically active agents.Type: GrantFiled: August 27, 1991Date of Patent: April 6, 1993Assignee: The Liposome Company, Inc.Inventor: Alan L. Weiner
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Patent number: 5188951Abstract: A method of preparing a soluble monovalent salt of a phosphatidyl ester which comprises reacting a phospholipid with a primary alcohol in the presence of an enzyme catalyst in a divalent cationic buffered solution and a water immiscible non-ether solvent that does not inactivate the enzyme, to form a divalent cationic salt of the phosphatidyl ester, and suspending the product in the presence of a stoichiometric amount of a monovalent cationic salt whose anion forms an insoluble salt with the divalent cation. The use of Centrifugal Partition Chromatography facilitates the enzyme reaction. The monovalent salt is preferably an ammonium/sodium mixed salt.Type: GrantFiled: May 1, 1991Date of Patent: February 23, 1993Assignee: The Liposome Company, Inc.Inventors: Paul-Alain Tremblay, Frank Marziani, John A. F. Tino, Frank G. Pilkiewicz
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Patent number: 5171737Abstract: 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 phosphatidylethanolamine in which case 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: March 3, 1989Date of Patent: December 15, 1992Assignee: The Liposome Company, Inc.Inventors: Alan L. Weiner, Sharon Carpenter-Green
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Patent number: 5171578Abstract: The present invention describes a composition consisting of liposomes covalently or non-covalently coupled to the glycoprotein streptavidin. The streptavidin may additionally be coupled to biotinated proteins such as Immunoglobulin G or monoclonal antibodies.The liposomes of the invention may have a transmembrane potential across their membranes, and may be dehydrated. In addition, the composition may contain ionizable bioactive agents such as antineoplastic agents, and may be used in diagnostic assays.Type: GrantFiled: June 6, 1991Date of Patent: December 15, 1992Assignee: The Liposome Company, Inc.Inventors: Marcel B. Bally, Helen Loughrey, Pieter R. Cullis
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Patent number: 5169637Abstract: A new and substantially improved type of lipid vesicle, called stable plurilamellar vesicles (SPLVs), are described, as well as the process for making the same and X-ray diffraction methods for identifying the same. SPLVs are characterized by lipid bilayers enclosing aqueous compartments containing one or more entrapped solutes, the concentration of such solutes in each aqueous compartment being substantially equal to the emunization of solutes used to prepare the SPLVs. The bilayers of SPLVs are substantially non-compressed. SPLVs are stable during storage and can be used in vivo for the sustained release of compounds and in the treatment of disease.Type: GrantFiled: April 2, 1991Date of Patent: December 8, 1992Assignee: The Liposome Company, Inc.Inventors: Robert P. Lenk, Michael W. Fountain, Andrew S. Janoff, Mircea C. Popescu, Steven J. Weiss, Richard S. Ginsberg, Marc J. Ostro, Sol M. Gruner
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Patent number: 5154930Abstract: A pharmacological agent-lipid solution preparation comprising a lipophilic pharmacological agent, a desalted charged lipid and an aqueous-miscible lipid solvent such that upon introduction into an aqueous medium a suspension of lipid aggregates associated with the pharmacological agent are formed, and methods of manufacture and use.Type: GrantFiled: February 25, 1988Date of Patent: October 13, 1992Assignee: The Liposome Company, Inc.Inventors: Mircea C. Popescu, Paul A. Tremblay, Andrew S. Janoff, Marc J. Ostro, Elaine Chan, Alan Weiner
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Patent number: 5100662Abstract: The present invention relates to novel liposomes and liposome-like structures (vesicles) comprising an amount of a derivatized sterol either alone or in combination with additional liposome-forming lipids.Sterols such as cholesterol or other lipids, to which numerous charged or neutral groups are attached, may be used to prepare liposomes and liposome-like structures such as micelles, reverse micelles and hexagonal phases, suspensions of multilamellar vesicles or small unilamellar vesicles. The novel liposomes of the present invention may be prepared with or without the use of organic solvents. These vesicles may entrap compounds varying in polarity and solubility in water and other solvents.Type: GrantFiled: October 16, 1989Date of Patent: March 31, 1992Assignee: The Liposome Company, Inc.Inventors: Lois E. Bolcsak, Lawrence Boni, Mircea C. Popescu, Paul A. Tremblay
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Patent number: 5084215Abstract: A process for the separation and purification of individual phospholipids, especially phosphatidylcholine or lecithin and phosphatidylethanolaine, from mixtures containing members of the sub-class of phosphatides, incorporating methods of solvent extraction appropriate to the scale of the sample and utilizing an acetonitrile, acetonitrile-hydrocarbon, or acetonitrile-fluorocarbon solvent, which exhibit differential solubility properties towards the individual phospholipids.Type: GrantFiled: October 20, 1988Date of Patent: January 28, 1992Assignee: The Liposome Company, Inc.Inventors: John J. Kearns, Paul A. Tremblay
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Patent number: 5082664Abstract: A liposome composition and methods for making same are disclosed, such compositions comprise an arachidonic acid metabolite such as a prostaglandin, preferably prostaglandin E.sub.1, a lipid, and a drying protectant such as a saccharide. The liposomes may be loaded with prostaglandin passively, or using a transmembrane concentration gradient, preferably using a transmembrane pH gradient. Using this transmembrane loading technique, trapping efficiencies of 50% to 100% are achieved, and the release rate of the prostaglandin from the liposomes is reduced. The liposome size is maintained after lyophilization and reconstitution.Type: GrantFiled: May 18, 1988Date of Patent: January 21, 1992Assignee: The Liposome Company, Inc.Inventors: Robert P. Lenk, Michelle L. Tomsho, Robert L. Suddith, Robert J. Klimchak
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Patent number: 5077056Abstract: 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: December 12, 1988Date of Patent: December 31, 1991Assignee: 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: D381809Type: GrantFiled: August 3, 1995Date of Patent: August 5, 1997Assignee: Fortune Dragon PTE Ltd.Inventors: Richard Weoi Meng Chee, Sharon Ah Hoon Low