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 relates to metastable liposomes sized at greater than or equal to about 1 micron and up to about 100 microns, where one or more hydrophobic agents are entrapped within lipids that form the metastable liposomes. The formulations are positioned for local delivery of hydrophobic therapeutic, prophylactic, or diagnostic agents, including in bladder-related contexts. The disclosed metastable liposomes are described as enabling transfer via membrane fusion with target cell membranes rather than endocytosis.

The invention further defines metastability by a size-response metric: the ratio of the mean diameter at 25°C relative to the mean diameter following heating to a temperature that surpasses the gel-fluid phase transition of the one or more lipids is greater than 1.0. The metastable liposomes are described as large liposomes that become more reactive with target cell membranes, and the background discussion relates metastability to conformational degeneracy and relative diameter behavior across the gel-fluid phase transition.

The invention describes methods of making a dosage formulation and a pre-liposomal lyophilisate. Lipids capable of forming metastable liposomes are dispersed in a co-solvent system to form an isotropic monophasic solution, then lyophilized to produce a preliposomal lyophilisate, and then rehydrated to produce metastable liposomes. The partial content explicitly contemplates lipid and liposome components, optional excipients, hydrophobic agent classes, and manufacturing approaches including dehydration, rehydration, and lyophilization; it also describes instillation and topical application approaches such as intravesical instillation.

Claims Coverage

Two independent claims are identified. Both claims define methods for producing metastable liposome-containing formulations in which hydrophobic agents are entrapped, and both impose the metastability requirement based on a mean-diameter ratio after heating across the gel-fluid phase transition, together with a specified mean diameter range of 1 to 100 microns inclusive.

Across the two independent claims, the core inventive coverage centers on producing metastable liposomes via dispersion to an isotropic monophasic solution, lyophilization to a preliposomal lyophilisate, and rehydration, and on defining metastability by an increase in mean diameter upon heating across the gel-fluid phase transition for liposomes with mean diameter 1 to 100 microns inclusive, with entrapped hydrophobic therapeutic, prophylactic, or diagnostic agents.

Stated Advantages

Documented Applications