Patents by Inventor Pieter R. Cullis
Pieter R. Cullis has filed for patents to protect the following inventions. This listing includes patent applications that are pending as well as patents that have already been granted by the United States Patent and Trademark Office (USPTO).
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Patent number: 5922350Abstract: Dehydrated liposomes are prepared by drying liposome preparations under reduced pressure in the presence of one or more protective sugars, e.g., the disaccharides trehalose and sucrose. Preferably, the protective sugars are present at both the inside and outside surfaces of the liposome membranes. Freezing of the liposome preparation prior to dehydration is optional. Alternatively, the protective sugar can be omitted if: (1) the liposomes are of the type which have multiple lipid layers; (2) the dehydration is done without prior freezing; and (3) the dehydration is performed to an end point which results in sufficient water being left in the preparation (e.g., at least 12 moles water/mole lipid) so that the integrity of a substantial portion of the multiple lipid layers is retained upon rehydration.Type: GrantFiled: June 16, 1997Date of Patent: July 13, 1999Assignee: The Liposome Company, Inc.Inventors: Andrew S. Janoff, Pieter R. Cullis, Marcel B. Bally, Michael W. Fountain, Richard S. Ginsberg, Michael J. Hope, Thomas D. Madden, Hugh P. Schieren, Regina L. Jablonski
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Patent number: 5885613Abstract: The present invention provides a fusogenic liposome comprising a lipid capable of adopting a non-lamellar phase, yet capable of assuming a bilayer structure in the presence of a bilayer stabilizing component; and a bilayer stabilizing component reversibly associated with the lipid to stabilize the lipid in a bilayer structure. Such fusogenic liposomes are extremely advantageous because the rate at which they become fusogenic can be not only predetermined, but varied as required over a time scale ranging from minutes to days. Control of liposome fusion can be achieved by modulating the chemical stability and/or exchangeability of the bilayer stabilizing component(s). The fusogenic liposomes of the present invention can be used to deliver drugs, peptide, proteins, RNA, DNA or other bioactive molecules to the target cells of interest.Type: GrantFiled: June 7, 1995Date of Patent: March 23, 1999Assignee: The University of British ColumbiaInventors: John W. Holland, Thomas D. Madden, Pieter R. Cullis
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Patent number: 5837279Abstract: Dehydrated liposomes are prepared by drying liposome preparations under reduced pressure in the presence of one or more protective sugars, e.g., the disaccharides trehalose and sucrose. Preferably, the protective sugars are present at both the inside and outside surfaces of the liposome membranes. Freezing of the liposome preparation prior to dehydration is optional. Alternatively, the protective sugar can be omitted if: (1) the liposomes are of the type which have multiple lipid layers; (2) the dehydration is done without prior freezing; and (3) the dehydration is performed to an end point which results in sufficient water being left in the preparation (e.g., at least 12 moles water/mole lipid) so that the integrity of a substantial portion of the multiple lipid layers is retained upon rehydration.Type: GrantFiled: May 25, 1995Date of Patent: November 17, 1998Assignee: The Lipsome Company, Inc.Inventors: Andrew S. Janoff, Pieter R. Cullis, Marcel B. Bally, Michael W. Fountain, Richard S. Ginsberg, Michael J. Hope, Thomas D. Madden, Hugh P. Schieren, Regina L. Jablonski
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Patent number: 5837282Abstract: Novel methods are provided for loading a weakly basic drug into liposomes utilizing an electoneutral transport system. In these methods, ionophores are utilized with liposomes having a metal ion gradient to facilitate the exchange of metal ions for protons. The transported metal ion will, in some embodiments, be complexed with a chelating agent which is present in the external media.Type: GrantFiled: October 30, 1996Date of Patent: November 17, 1998Assignee: University of British ColumbiaInventors: David B. Fenske, Pieter R. Cullis, Kim Wong, Maurer Norbert, Johanna M. Leenhouts, Elisabeth Maurer, Nancy Boman
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Patent number: 5800833Abstract: Methods for the preparation of stable liposome formulations of protonatable therapeutic agents. The methods involve loading a therapeutic agent into preformed liposomes having a methylamine concentration gradient across the lipid bilayer of the liposomes. These methods provide liposome formulations which are more stable, more cost effective, and easier to prepare in a clinical environment than those previously available. The present invention also provides the pharmaceutical compositions prepared by the above methods, a kit for the preparation of liposome formulations of therapeutic agents, and methods for their use.Type: GrantFiled: February 27, 1995Date of Patent: September 1, 1998Assignee: University of British ColumbiaInventors: Michael Hope, Pieter R. Cullis, David Fenske, Kim Wong
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Patent number: 5795589Abstract: 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 tranamembrane pH gradient. Using this technique, trapping efficiencies approach 100%, and liposomes may be loaded with drug immediately prior to use, eliminating stability problem 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: February 5, 1997Date of Patent: August 18, 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: 5785987Abstract: Methods for the preparation of stable liposome formulations of protonatable therapeutic agents. The methods involve loading a therapeutic agent into preformed liposomes having a methylamine concentration gradient across the lipid bilayer of the liposomes. These methods provide liposome formulations which are more stable, more cost effective, and easier to prepare in a clinical environment than those previously available. The present invention also provides the pharmaceutical compositions prepared by the above methods, a kit for the preparation of liposome formulations of therapeutic agents, and methods for their use.Type: GrantFiled: February 27, 1996Date of Patent: July 28, 1998Assignee: The University of British ColumbiaInventors: Michael Hope, Pieter R. Cullis, David B. Fenske, Kim F. Wong
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Patent number: 5780054Abstract: Methods of increasing the circulation half-life of protein-based therapeutics in a host, the methods comprising: (a) administering to the host an amount of a first liposome formulation comprising liposomes and an antineoplastic agent; and (b) administering to the host a second formulation comprising the protein-based therapeutic, wherein the amount of the first liposome formulation is sufficient to suppress an immune response to the protein-based therapeutic of the second formulation, thereby increasing the circulation half-life of the protein-based therapeutic.Type: GrantFiled: January 17, 1996Date of Patent: July 14, 1998Assignee: University of British ColumbiaInventors: Paul G. Tardi, Erik Swartz, Marcel B. Bally, Pieter R. Cullis
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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: 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: 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: 5595756Abstract: Liposomal compositions encapsulating bioactive agents and having improved circulation longevity of the agents are disclosed. Such liposomes combine a low pH of the solution in which a bioactive agent is entrapped and a sugar-modified lipid or an amine-bearing lipid, the combination of which enhances the retention of the encapsulated bioactive agent and thereby promotes circulation longevity. The present invention also discloses methods of making and using such compositions.Type: GrantFiled: December 22, 1993Date of Patent: January 21, 1997Assignees: Inex Pharmaceuticals Corporation, University of British of ColumbiaInventors: Marcel B. Bally, Nancy L. Boman, Pieter R. Cullis, Lawrence D. Mayer
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Patent number: 5578320Abstract: Dehydrated liposomes are prepared by drying liposome preparations under reduced pressure in the presence of one or more protective sugars, e.g., the disaccharides trehalose and sucrose. Preferably, the protective sugars are present at both the inside and outside surfaces of the liposome membranes. Freezing of the liposome preparation prior to dehydration is optional. Alternatively, the protective sugar can be omitted if: (1) the liposomes are of the type which have multiple lipid layers; (2) the dehydration is done without prior freezing; and (3) the dehydration is performed to an end point which results in sufficient water being left in the preparation (e.g., at least 12 moles water/mole lipid) so that the integrity of a substantial portion of the multiple lipid layers is retained upon rehydration.Type: GrantFiled: February 24, 1993Date of Patent: November 26, 1996Assignee: The Liposome Company, Inc.Inventors: Andrew S. Janoff, Pieter R. Cullis, Marcel B. Bally, Michael W. Fountain, Richard S. Ginsberg, Michael J. Hope, Thomas D. Madden, Hugh P. Schieren, Regina L. Jablonski
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Patent number: 5552155Abstract: A liposome composition is provided which contains a liposome having: (i) an outermost lipid bilayer containing, in addition to a neutral, bilayer preferring lipid, a fusion-promoting effective amount of an ionizable lipid having a protonatable, cationic headgroup and an unsaturated acyl chain; and (ii) a compartment adjacent to the outermost lipid bilayer which contains an aqueous solution having a first pH. External to the liposome in the composition is an aqueous solution having a second pH. The first pH is less than the pK.sub.a of the ionizable lipid in the outermost lipid bilayer and the second pH is greater than the pK.sub.a of the ionizable lipid in the outermost lipid bilayer, such that there is a pH gradient across the outermost lipid bilayer and the ionizable lipid is accumulated in the inner monolayer of the outermost lipid bilayer in response to the gradient.Type: GrantFiled: August 15, 1994Date of Patent: September 3, 1996Assignee: The Liposome Company, Inc.Inventors: Austin L. Bailey, Pieter R. Cullis
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Patent number: 5525232Abstract: Methods are disclosed for entrapment of a cation in a vesicle having a membrane and an acidic aqueous compartment comprising contacting the vesicle with a buffer solution comprising the cation and a lipophilic, carboxylic ionophoretic antibiotic capable of complexing with the cation and increasing the cation's permeability across the vesicle membrane, wherein there is a pH gradient between the acidic aqueous compartment and the buffer solution. The cation can be for example iron or calcium and the ionophore A23187. The pH gradient can be established across the bilayer by a relatively acidic or basic intravesicular aqueous compartment of the unilamellar vesicle and the buffer solution and the cation loads via the pH gradient. The invention also contemplates a unilamellar vesicle comprising an aqueous compartment including a cationic species in a concentration between 100 mM and 500 mM.Type: GrantFiled: October 14, 1993Date of Patent: June 11, 1996Assignee: The Liposome Company, Inc.Inventors: Jeffrey A. Veiro, Ajoy C. Chakrabarti, Pieter R. Cullis
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Patent number: 5409704Abstract: Aminoglycosides, analogs and derivatives thereof, in the form of phosphate salts are described as well as the process for making and utilizing same. Aminoglycoside phosphate liposomes and nonguanadino aminoglycoside phosphate liposomes, their preparation and use, are particularly described.Type: GrantFiled: May 6, 1993Date of Patent: April 25, 1995Assignee: The Liposome Company, Inc.Inventors: Marcel B. Bally, Lois E. Bolcsak, Pieter R. Cullis, Andrew S. Janoff, Lawrence D. Mayer
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Patent number: 5399331Abstract: This invention relates to a method for synthesizing a substantially pure reactive lipid including, for example, N-[4-(p-maleimidophenyl)-butyryl]phosphatidylethanolamine (MPB-PE) and related compositions. The compositions of the present invention are useful as coupling agents and may be incorporated into liposomes and subsequently coupled to proteins, cofactors and a number of other molecules. A preferred coupling method is also disclosed as are protein conjugates.Type: GrantFiled: September 17, 1992Date of Patent: March 21, 1995Assignee: The Liposome Company, Inc.Inventors: Helen C. Loughrey, Pieter R. Cullis, Marcel B. Bally, Lewis S. Choi
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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: 5376452Abstract: 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: October 6, 1993Date of Patent: December 27, 1994Assignee: The Liposome Company, Inc.Inventors: Michael J. Hope, Pieter R. Cullis