Drug delivery system containing phospholipid and cholesterol
Inventors
Shih, Sheue-Fang • Chang, Po-Chun • TSENG, Yun-Long • Guo, Luke S. S. • Hong, Keelung
Assignees
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Publication Number
US-11771766-B2
Publication Date
2023-10-03
Expiration Date
Abstract
An ophthalmic drug delivery system that contains phospholipid and cholesterol for prolonging drug lifetime in the eyes.
Core Innovation
A drug delivery system includes a delivery vehicle comprising cholesterol and a phospholipid mixture, where the phospholipid mixture comprises a first phospholipid and a second phospholipid. The first phospholipid is phosphatidylcholine (PC) and the second phospholipid is phosphatidylethanolamine (PE) or phosphatidylglycerol (PG). The cholesterol is present in an amount of 5-40 mole percent relative to the delivery vehicle.
The delivery system further comprises dexamethasone sodium phosphate, with the delivery vehicle being free of fatty acid, cationic lipid and mucoadhesive polymer. The system requires that 50-90% of the dexamethasone sodium phosphate is in non-associated form, and that the weight ratio of the combination of the phospholipid mixture and cholesterol to the dexamethasone sodium phosphate is 5-80 to 1. In related embodiments, the phospholipid mixture is defined to include DOPC and DOPG with specified mole percent ranges.
In an ophthalmic drug delivery system context, the lipid delivery vehicle formulation is used to carry dexamethasone sodium phosphate with cholesterol/phospholipid composition constraints and non-associated dexamethasone sodium phosphate content. Documented results in rabbits include increased vitreous concentrations and pharmacokinetic extension for therapeutic agents including a VEGF antibody and dexamethasone sodium phosphate, with sustained detection at later timepoints. The lipid composition is described as affecting the outcome, including the role of cholesterol and the impact of DOPG on the effect.
Claims Coverage
The claim coverage includes three independent claims, each centered on an ophthalmic or drug delivery system combining a cholesterol/phospholipid delivery vehicle with dexamethasone sodium phosphate. Each independent claim includes multiple inventive features defined by component selection, exclusion of specific excipients, non-associated drug fraction, and a specific weight-ratio relationship.
Cholesterol/phospholipid delivery vehicle with defined phospholipid types
A delivery vehicle comprising cholesterol and a phospholipid mixture, where the phospholipid mixture comprises PC and either PE or PG, and cholesterol is present in an amount of 5-40 mole percent relative to the delivery vehicle.
Dexamethasone sodium phosphate carried in a restricted lipid composition
A drug delivery system comprising dexamethasone sodium phosphate, where the delivery vehicle is free of fatty acid, cationic lipid and mucoadhesive polymer.
Non-associated dexamethasone sodium phosphate fraction
50-90% of the dexamethasone sodium phosphate is in non-associated form.
Weight ratio of (phospholipid mixture + cholesterol) to dexamethasone sodium phosphate
The weight ratio of the combination of the phospholipid mixture and cholesterol to the dexamethasone sodium phosphate is 5-80 to 1.
Defined DOPC/DOPG/phospholipid composition with constrained cholesterol
A delivery vehicle in which the phospholipid mixture comprises DOPC and DOPG, with DOPC at 56.25-72.5% and DOPG at 7.5-18.75 mole percent relative to the delivery vehicle, and cholesterol at 10-33 mole percent relative to the delivery vehicle.
Ophthalmic application with the same lipid, exclusion, and ratio constraints
An ophthalmic drug delivery system comprising a delivery vehicle with DOPC and DOPG at 56.25-72.5% (DOPC) and 7.5-18.75% (DOPG) mole percent relative to the delivery vehicle, cholesterol at 10-33 mole percent relative to the delivery vehicle, dexamethasone sodium phosphate, and where the delivery vehicle is free of fatty acid, cationic lipid and mucoadhesive polymer, with 50-90% non-associated dexamethasone sodium phosphate and a weight ratio of 5-80 to 1.
Across the independent claims, the key inventive theme is a cholesterol and phospholipid-mixture delivery vehicle with specific phospholipid identities or DOPC/DOPG composition and cholesterol mole-percent constraints, excluding fatty acid, cationic lipid, and mucoadhesive polymer, while requiring a defined fraction of non-associated dexamethasone sodium phosphate and a defined weight ratio of lipid combination to dexamethasone sodium phosphate.
Stated Advantages
Increased vitreous concentrations for therapeutic agents including dexamethasone sodium phosphate and a VEGF antibody.
Prolonged pharmacokinetic exposure, including extended half-life/AUC and sustained detection at later timepoints.
The lipid composition (including cholesterol and DOPG) is described as affecting pharmacokinetic outcomes.
Documented Applications
Ophthalmic drug delivery system using the described cholesterol/phospholipid delivery vehicle to carry dexamethasone sodium phosphate.
Pharmacokinetic and vitreous concentration evaluation in rabbits for therapeutic agents including a VEGF antibody and dexamethasone sodium phosphate.
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