Sustained-release pharmaceutical compositions comprising an immunomodulating agent and uses thereof
Inventors
Hong, Keelung • GWATHNEY, Walter • FANG, JONATHAN • Kao, Hao-Wen • Lin, Yi-Yu
Assignees
Lc Biopharmaceuticals Inc • Taiwan Liposome Co Ltd • TLC Biopharmaceuticals Inc
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Publication Number
US-12274785-B2
Publication Date
2025-04-15
Expiration Date
Abstract
The present invention relates to a pharmaceutical composition comprising at least one liposome and a therapeutic agent for treating an auto-immune disease with a high therapeutic agent 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 an auto-immune disease using the pharmaceutical composition disclosed herein.
Core Innovation
The invention relates to a sustained-release liposomal pharmaceutical composition that includes at least one liposome having a bilayer membrane, a trapping agent, and an S1P receptor agonist selected from fingolimod or ozanimod. The bilayer membrane comprises specified mole percent amounts of a first lipid selected from HSPC, DPPC, DMPC, or combinations thereof, cholesterol, and a second lipid selected from PEG-DSPE, DPPG, or combinations thereof. The composition further requires that the molar ratio of the S1P receptor agonist to the lipid is higher than about 0.87 and that the S1P receptor agonist is encapsulated with an encapsulation efficiency higher than about 90%.
The trapping agent is selected from triethylammonium sucrose octasulfate, ammonium sulfate, and ammonium phosphate, with the trapping agent selection specified as triethylammonium sucrose octasulfate, ammonium sulfate, or ammonium phosphate when the S1P receptor agonist is fingolimod, and ammonium sulfate when the S1P receptor agonist is ozanimod. This design is directed to achieving sustained release/extended half-life behavior of the encapsulated S1P receptor agonist from the liposome.
The document also describes a fingolimod liposome embodiment in which less than 10% of fingolimod is released into a dialysis bag over 24 hours. Together, the specified lipid mixture, trapping agent, high drug-to-lipid molar ratio, and high encapsulation efficiency are presented as enabling sustained release properties for an S1P receptor agonist encapsulated in liposomes.
Claims Coverage
The document provides two independent claims directed to liposomal pharmaceutical compositions comprising a specified liposome bilayer composition, a selected trapping agent, and an S1P receptor agonist with high encapsulation efficiency and a drug-to-lipid molar ratio above about 0.87, and a fingolimod liposome composition with ammonium sulfate as the trapping agent and a release limit of less than 10% over 24 hours in a dialysis bag. Across the independent claims, the core inventive features involve lipid-bilayer composition ranges, trapping-agent selection, high encapsulation efficiency, drug-to-lipid molar ratio requirements, and a sustained-release criterion measured by dialysis-bag release.
Specified liposome bilayer for S1P receptor agonists
The bilayer membrane comprises about 45 to about 80 mole percent of a first lipid selected from HSPC, DPPC, DMPC and any combination thereof; about 20 to about 55 mole percent of cholesterol; and 0.1-10 mole percent of a second lipid selected from PEG-DSPE, DPPG and any combination thereof.
Trapping agent selection for encapsulation
A trapping agent selected from triethylammonium sucrose octasulfate, ammonium sulfate, ammonium phosphate, and any combination thereof is used, where the trapping agent selection depends on whether the S1P receptor agonist is fingolimod or ozanimod.
High drug-to-lipid molar ratio and high encapsulation efficiency
The molar ratio of the sphingosine-1-phosphate (S1P) receptor agonist to the lipid is higher than about 0.87 and the S1P receptor agonist is encapsulated in the liposome with an encapsulation efficiency higher than about 90%.
Dialysis-bag sustained release limit for fingolimod
For fingolimod encapsulated using ammonium sulfate, less than 10% of fingolimod is released into a dialysis bag over 24 hours.
Overall, independent claim coverage focuses on liposome bilayer lipid composition ranges combined with trapping-agent selection and S1P receptor agonist encapsulation constraints, and on a dialysis-bag release criterion for a fingolimod embodiment using ammonium sulfate.
Stated Advantages
Sustained-release/extended half-life behavior of the S1P receptor agonist from the liposome.
Reduced dosing frequency and improved tolerability.
Documented Applications
Treatment context is associated with autoimmune disease via use of an S1P receptor agonist (fingolimod or ozanimod) in a sustained-release liposomal pharmaceutical composition.
In vitro release profiling using a dialysis bag over 24 hours to assess the release of fingolimod from liposomes.
Pharmacokinetics evaluation in Sprague-Dawley rats with intravenous or subcutaneous administration for liposomal fingolimod and comparisons to oral fingolimod.
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