Sustained-release pharmaceutical compositions comprising a therapeutic agent for treating dementia and uses thereof
Inventors
Hong, Keelung • Kao, Hao-Wen • Lin, Yi-Yu • GWATHNEY, Walter
Assignees
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Publication Number
US-12268781-B2
Publication Date
2025-04-08
Expiration Date
Abstract
The present invention relates to pharmaceutical compositions comprising at least one liposome and a therapeutic agent for treating dementia with a high drug to lipid ratio and a high encapsulation efficiency. The pharmaceutical composition improves the pharmacokinetic profile and sustains the release of the therapeutic agent. Also provided is the method for treating dementia using the pharmaceutical composition disclosed herein.
Core Innovation
The patent describes sustained-release liposomal dementia therapeutics in which a therapeutic agent is encapsulated in a liposome with improved encapsulation efficiency and drug-to-lipid molar ratio. The liposome includes a bilayer membrane with about 40 to about 80 mole % of a first lipid selected from phosphatidylcholine (PC), HSPC, DSPC, DPPC, DMPC, PSPC, and any combination thereof, and about 20 to about 40 mole % cholesterol. The bilayer membrane optionally further comprises about 0.1 to 30 mole % of a second lipid selected from phosphatidylethanolamine, phosphatidylglycerol, PEG-DSPE, DPPG, and any combination thereof.
The composition further includes a trapping agent selected from about 10 to 200 mM triethylammonium sucrose octasulfate, about 100 to 600 mM ammonium sulfate, about 0.1 to 10 mM dextran sulfate, and any combination thereof. The therapeutic agent is an acetylcholinesterase inhibitor or memantine, and the molar ratio of the therapeutic agent to the lipid is equal to or higher about than 0.2. The therapeutic agent is encapsulated in the liposome with an encapsulation efficiency higher than about 50%.
The disclosed system is described as providing sustained release and improved pharmacokinetics by remote loading with trapping agents. In vitro release is reported to show markedly slower release of rivastigmine from liposomes versus free drug. Pharmacokinetics are reported in rats, including subcutaneous liposomal rivastigmine and liposomal donepezil with substantially prolonged half-lives and extended plasma detectability relative to free formulations.
Claims Coverage
The patent includes one independent claim that defines a pharmaceutical composition with a specified liposome bilayer composition, a specified trapping agent, and a specified therapeutic-agent encapsulation performance target, yielding at least one inventive feature set. Dependent claims further refine performance/ratio constraints and introduce additional treatment and administration parameters.
Liposome bilayer composition with cholesterol and optional second lipid
A liposome comprising a bilayer membrane, the bilayer membrane comprising about 40 to about 80 mole % of a first lipid selected from PC, HSPC, DSPC, DPPC, DMPC, PSPC, and any combination thereof, about 20 to about 40% mole % cholesterol, and optionally 0.1-30% mole % of a second lipid selected from phosphatidylethanolamine, phosphatidylglycerol, PEG-DSPE, DPPG, and any combination thereof.
Trapping agent selection for encapsulation
A trapping agent selected from about 10 to 200 mM triethylammonium sucrose octasulfate, about 100 to 600 mM ammonium sulfate, about 0.1 to 10 mM dextran sulfate, and any combination thereof.
Acetylcholinesterase inhibitor or memantine encapsulated at high efficiency and agent-to-lipid ratio
A therapeutic agent that is an acetylcholinesterase inhibitor or memantine, wherein the molar ratio of the therapeutic agent to the lipid is equal to or higher about than 0.2 and the therapeutic agent is encapsulated in the liposome with an encapsulation efficiency higher than about 50%.
Overall, the independent claim defines the combination of a specified cholesterol-containing liposome bilayer (with optional second lipid), a selected trapping agent class, and an acetylcholinesterase inhibitor or memantine encapsulated with both a therapeutic-agent-to-lipid molar ratio of at least about 0.2 and an encapsulation efficiency higher than about 50%. Dependent claims further cover related refinements such as half-life extension constraints and administration frequency and route.
Stated Advantages
Sustained release is described through markedly slower in vitro release of encapsulated drug from liposomes versus free drug.
Improved pharmacokinetics are described, including substantially prolonged half-lives and extended plasma detectability relative to free formulations.
Reduced dosing frequency and improved compliance are described as a rationale linked to improved sustained release and pharmacokinetics.
Documented Applications
Therapeutic use as dementia therapeutics is described in the context of acetylcholinesterase inhibitors and memantine.
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