Delivery of agents using metastable liposomes
Inventors
Kaufman, Jonathan H. • Chancellor, Michael B.
Assignees
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Publication Number
US-10639278-B2
Publication Date
2020-05-05
Expiration Date
Abstract
Metastable liposomal formulations for hydrophobic drug delivery to a tissue or tissue lumen such the bladder have been developed. These are at least one micron in diameter and formed of one or more lipids having entrapped in the lipid a hydrophobic therapeutic, prophylactic or diagnostic agent. The greater stability of these liposomes, as well as the enhanced transfer of entrapped agent into the adjacent tissue, provides for better delivery, especially of hydrophobic agents such as tacrolimus which does not penetrate tissue well. The metastable liposomal formulations can be administered locally, preferably by instillation, or topically, for example, by spraying or painting, to a tissue or tissue lumen such as the bladder in need of treatment.
Core Innovation
The invention provides a dosage formulation of multilamellar metastable liposomes having a mean diameter of between one and 100 microns, inclusive. The liposomes exhibit a metastable behavior defined by a ratio of the volume enclosed by the liposomes at 25°C relative to the volume enclosed following heating to a temperature that surpasses the gel-fluid phase transition of one or more lipids forming the liposomes, wherein the ratio is greater than 1.0. The formulation includes one or more hydrophobic therapeutic, prophylactic or diagnostic agents entrapped within the lipid forming the liposomes.
The invention also provides a preparation approach in which lipid forming liposomes are dispersed in a co-solvent system to create an isotropic monophasic solution, and the isotropic monophasic solution is mixed with the hydrophobic agent to form a pre-liposomal solution. The pre-liposomal solution is lyophilized to produce a pre-liposomal lyophilized formulation and then rehydrated to produce the liposomes.
In additional embodiments, the invention covers a method for making a pre-liposomal lyophilized formulation of metastable liposomes with entrapped hydrophobic therapeutic, prophylactic or diagnostic agent(s). The method comprises dispersing lipid forming the liposomes in a co-solvent system to create an isotropic monophasic solution, mixing with the hydrophobic agent to form a pre-liposomal solution, and lyophilizing to produce the pre-liposomal lyophilized formulation.
After rehydration, the pre-liposomal lyophilized formulation produces multilamellar metastable liposomes with a mean diameter of between one and 100 microns, inclusive, and with a volume-retention ratio greater than 1.0, with the hydrophobic agent entrapped within the liposome.
Claims Coverage
The document contains four independent claims. Across these claims, the same core inventive requirements recur: multilamellar metastable liposomes with a defined mean diameter range and a volume-retention ratio greater than 1.0, one or more hydrophobic therapeutic, prophylactic, or diagnostic agents entrapped within the liposomes, and formation via dispersion in a co-solvent to form an isotropic monophasic solution followed by lyophilization and rehydration where applicable.
Metastable multilamellar liposome dosage formulation with volume-retention ratio
A dosage formulation of multilamellar metastable liposomes having a mean diameter of between one and 100 microns, inclusive, wherein the ratio of the volume enclosed by the liposomes at 25°C relative to the volume enclosed by the liposomes following heating to a temperature that surpasses the gel-fluid phase transition of one or more lipids forming the liposomes is greater than 1.0.
Entrapment of hydrophobic therapeutic, prophylactic or diagnostic agent
One or more hydrophobic therapeutic, prophylactic or diagnostic agent(s), wherein the one or more hydrophobic agent(s) is entrapped within the lipid forming the liposomes.
Co-solvent isotropic monophasic solution followed by lyophilization and rehydration
Metastable liposomes are prepared by dispersing the lipid forming the liposomes in a co-solvent system to create an isotropic monophasic solution, mixing the isotropic monophasic solution with the hydrophobic agent to form a pre-liposomal solution, lyophilizing the pre-liposomal solution to produce a pre-liposomal lyophilized formulation, and rehydrating the pre-liposomal lyophilized formulation to produce the liposomes.
Treating an individual by administering metastable liposome dosage to tissue or tissue lumen
A method for treating an individual in need thereof comprising administering to a tissue or tissue lumen a dosage formulation of metastable liposomes comprising multilamellar metastable liposomes having a mean diameter of between one and 100 microns, inclusive, and wherein the ratio of the volume enclosed by the liposomes at 25°C relative to the volume enclosed by the liposomes following heating to a temperature that surpasses the gel-fluid phase transition of one or more lipids forming the liposomes is greater than 1.0.
Making a pre-liposomal lyophilized formulation for metastable liposomes
A method of making a pre-liposomal lyophilized formulation of metastable liposomes having entrapped within the lipid forming the liposomes one or more hydrophobic therapeutic, prophylactic or diagnostic agent(s), comprising dispersing the lipid forming the liposomes in a co-solvent system to create an isotropic monophasic solution, mixing the isotropic monophasic solution with the hydrophobic agent to form a pre-liposomal solution, and lyophilizing the pre-liposomal solution to produce the pre-liposomal lyophilized formulation.
Pre-liposomal lyophilized formulation producing entrapped metastable liposomes after rehydration
A pre-liposomal lyophilized formulation comprising one or more lipids and at least one hydrophobic therapeutic, prophylactic, or diagnostic agent which is prepared by dispersing lipid(s) in a co-solvent system to create an isotropic monophasic solution, mixing the isotropic monophasic solution with the at least one hydrophobic agent to form a pre-liposomal solution, and lyophilizing the pre-liposomal solution to produce a pre-liposomal lyophilized formulation.
Restored metastable liposomes with specified mean diameter and volume-retention ratio after rehydration
After rehydration, produces multilamellar metastable liposomes having a mean diameter of between one and 100 microns, inclusive, wherein the ratio of the volume enclosed by the liposomes at 25°C relative to the volume enclosed by the liposomes following heating to a temperature that surpasses the gel-fluid phase transition of the one or more lipids forming the liposome is greater than 1.0.
Entrapment of the hydrophobic agent within the liposome
The at least one hydrophobic agent is entrapped within the liposome.
Across all independent claims, the coverage is centered on metastable multilamellar liposomes defined by a specific mean diameter range and a volume-retention ratio greater than 1.0 after heating beyond the gel-fluid phase transition, together with entrapped hydrophobic therapeutic, prophylactic, or diagnostic agents and preparation via isotropic monophasic co-solvent dispersion, mixing to form a pre-liposomal solution, lyophilization, and rehydration where applicable.
Stated Advantages
Documented Applications
Treating an individual in need thereof by administering a dosage formulation of metastable liposomes to a tissue or tissue lumen.
Intravesical instillation into the individual’s bladder is described as an administration option.
Delivery through a cystoscope using an applicator chosen from a spray device, gauze, roller, or sponge is described as an administration option.
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