Sustained-release compositions comprising a therapeutic agent for treating depression or anxiety and uses thereof
Inventors
Hong, Keelung • Lin, Yi-Yu • Kao, Hao-Wen
Assignees
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Publication Number
US-12005142-B2
Publication Date
2024-06-11
Expiration Date
Abstract
The present invention relates to a pharmaceutical composition comprising at least one liposome and a therapeutic agent for treating depression or anxiety, with a therapeutic agent to lipid ratio equal to or higher than about 0.15. The pharmaceutical composition improves the pharmacokinetic profile and sustains the release of the therapeutic agent. Also provided is the method for treating depression or anxiety using the pharmaceutical composition disclosed herein.
Core Innovation
The invention relates to sustained-release liposomal pharmaceutical compositions for depression or anxiety, in which a therapeutic agent is encapsulated in liposomes having a bilayer membrane and a defined trapping agent for remote loading. The liposomes include a bilayer membrane with a first lipid that is HSPC, DMPC, or any combination thereof, cholesterol, and a PEG-DSPE second lipid. A trapping agent is used to provide encapsulation of the therapeutic agent using remote-loading with a polyatomic trapping agent and an encapsulation efficiency above a stated threshold.
The composition further requires a therapeutic agent-to-lipid molar ratio equal to or higher than about 0.2 for ketamine and equal to or higher than about 0.15 for scopolamine, while maintaining a mean particle size from about 50 nm to about 20 μm. For the ketamine compositions, the trapping agent is triethylammonium sucrose octasulfate, ammonium sulfate, or any combination thereof, with ketamine encapsulated and an encapsulation efficiency higher than about 60%. For the scopolamine compositions, the trapping agent includes specified concentration ranges of triethylammonium sucrose octasulfate, ammonium sulfate, and/or ammonium phosphate.
The background problem addressed is achieving sustained-release and improved pharmacokinetics for depression and anxiety therapeutics delivered as liposomes. The claimed compositions are directed to high encapsulation efficiency with sustained plasma exposure, including reported extended half-lives relative to free therapeutic agent, and reduced or absent burst release for at least a scopolamine example. The remote-loading and trapping-agent selection are used to improve in vivo pharmacokinetic performance while using therapeutic agents such as ketamine, including (R,S)-ketamine, (R)-ketamine, or (S)-ketamine, and scopolamine.
Claims Coverage
The document provides two independent pharmaceutical composition claims, one directed to ketamine and one directed to scopolamine. Across these independent claims, the inventive features focus on specific liposome bilayer lipid components with remote-loading trapping agents, together with defined therapeutic agent-to-lipid molar ratio, encapsulation efficiency, and mean particle size constraints.
Ketamine liposomal composition with remote-loading trapping agent and PEG-DSPE bilayer
A pharmaceutical composition comprising at least one liposome comprising a bilayer membrane with a first lipid of HSPC, DMPC or any combination thereof, cholesterol and a second lipid that is PEG-DSPE; a trapping agent that is triethylammonium sucrose octasulfate or ammonium sulfate or any combination thereof; and a therapeutic agent that is ketamine, wherein the molar ratio of the therapeutic agent to the lipid is equal to or higher than about 0.2, the therapeutic agent is encapsulated in the liposomes with an encapsulation efficiency higher than about 60% and the mean particle size of the liposome is from about 50 nm to about 20 μm.
Scopolamine liposomal composition with remote-loading trapping agent and optional PEG-DSPE/DPPG bilayer
A pharmaceutical composition comprising at least one liposome comprising a bilayer membrane with a first lipid that is HSPC, DPPC or any combination thereof, cholesterol and optionally a second lipid that is PEG-DSPE or DPPG or any combination thereof; a trapping agent that is 10 to 200 mM triethylammonium sucrose octasulfate, 300 to 600 mM ammonium sulfate, 100 to 600 mM ammonium phosphate or any combination thereof; and a therapeutic agent that is scopolamine, wherein the molar ratio of the therapeutic agent to the lipid is equal to or higher than about 0.15, the therapeutic agent is encapsulated in the liposomes with an encapsulation efficiency higher than about 60% and the mean particle size of the liposome is from about 50 nm to about 20 μm.
Overall, the claims cover sustained-release liposomal compositions that use remote-loading trapping agents to encapsulate either ketamine or scopolamine in a bilayer having specified lipid components, including cholesterol and PEG-DSPE for ketamine, and optionally PEG-DSPE and/or DPPG for scopolamine. Both independent claims require high encapsulation efficiency, a minimum therapeutic-agent-to-lipid molar ratio, and liposome mean particle size within a stated range.
Stated Advantages
Improved pharmacokinetics with sustained plasma exposure.
Extended half-life versus free therapeutic agent (at least 2-fold, as stated in dependent claims).
High encapsulation efficiency (greater than stated thresholds).
Reduced or absent burst release for scopolamine (as supported by the disclosed example/performance description).
Documented Applications
Treating depression by administering a pharmaceutical composition comprising scopolamine liposomes as recited.
Treating anxiety by administering a pharmaceutical composition comprising scopolamine liposomes as recited.
Sustained-release liposomal pharmaceutical use for depression/anxiety with remote-loading encapsulation performance described in the disclosed compositions and examples.
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