Delivery of agents using metastable liposomes

Inventors

Kaufman, Jonathan H. • Chancellor, Michael B.

Assignees

Lipella Pharmaceuticals Inc

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 describes metastable liposomes comprising tacrolimus for local delivery to tissue or a tissue lumen, including multilamellar metastable liposomes having a mean diameter of between one and 100 microns, inclusive. The metastable liposomes entrapped tacrolimus within the lipid forming the liposomes, and the liposome metastability is characterized 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, where the ratio is greater than 1.0.

The invention further describes a preparation pathway in which lipid forming materials are dispersed in a co-solvent system to create an isotropic monophasic solution. The isotropic monophasic solution is mixed with tacrolimus to form a pre-liposomal solution, which is then lyophilized to produce a pre-liposomal lyophilized formulation and subsequently rehydrated to produce the liposomes.

The metastable liposome dosage formulation includes tacrolimus present in an amount ranging from between 20 to 50 mg, and the pre-liposomal form is provided as a dry powder capable of being rehydrated to form the multilamellar metastable liposomes. Local administration is described in the context of delivering to a tissue lumen, including bladder-related delivery routes such as instillation and topical delivery, with embodiments emphasizing enhanced transfer to adjacent tissue via membrane fusion.

Claims Coverage

The document provides three independent claims: one directed to a metastable liposome dosage formulation, one directed to a pre-liposomal lyophilized dry powder formulation, and one directed to a method of administering the metastable liposome dosage formulation to a tissue or tissue lumen. Across the independent claims, the inventive features focus on multilamellar metastable liposomes with a defined mean diameter range, entrapment of tacrolimus, a specified enclosed-volume metastability ratio after heating above the gel-fluid phase transition, and defined preparation and reconstitution via isotropic monophasic co-solvent dispersion, mixing with tacrolimus, lyophilization, and rehydration.

Across the independent claims, the coverage centers on metastable multilamellar liposomes with a defined mean diameter range, entrapment of tacrolimus, and a volume-enclosed metastability ratio greater than 1.0 after heating above the gel-fluid phase transition. The claims further define dosage composition (tacrolimus amount 20–50 mg), provide a pre-liposomal lyophilized dry powder form capable of rehydration to the metastable liposomes, and include administration to a tissue or tissue lumen using liposomes produced via isotropic monophasic co-solvent dispersion, tacrolimus mixing, lyophilization, and rehydration.

Stated Advantages

Documented Applications