Bolaamphiphilic compounds, compositions and uses thereof
Inventors
Linder, Charles • Grinberg, Sarina • Heldman, Eliahu
Assignees
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Publication Number
US-11304964-B2
Publication Date
2022-04-19
Expiration Date
Abstract
Bolaamphiphilic compounds are provided according to formula I: HG2-L1-HG1 I where HG1, HG2 and L1 are as defined herein. Provided bolaamphiphilic compounds and the pharmaceutical compositions thereof are useful for delivering HIV active drugs into animal or human brain.
Core Innovation
The invention provides a formulation containing vesicles comprising one or more bolaamphiphilic compounds, cholesteryl hemisuccinate, cholesterol, and stearyl amine, together with an active agent which is tenofovir or fosamprenavir. The formulation is adjusted to a pH of 7.5 or 8 using a buffer to maximize tenofovir encapsulation, and the components are provided in defined per-1 mL amounts and ratios.
Bolaamphiphilic chitosan-conjugated amphiphile GLH-55b is described as a conjugated amphiphile used within the vesicle system. The disclosed core chemistry involves preparing GLH-55b through formation of chloroacetyl and carboxylic-acid (NHS) activated ester intermediates, attachment of an ACh head group, and conjugation to low molecular weight chitosan.
The disclosed compositions are directed to delivering HIV active agents to the brain across the blood-brain barrier, and the system is characterized by vesicle size and zeta potential. Tenofovir is quantified in brain and analyzed by pharmacokinetics, including comparison of brain delivery and persistence with V-Smart™ vesicles versus free tenofovir.
Claims Coverage
The independent claim covers a vesicle-containing drug formulation with specified bolaamphiphilic compounds and lipid-like excipients, an active agent tenofovir or fosamprenavir, and pH control to maximize tenofovir encapsulation. Dependent claims further restrict administration context, quantitative per-1 mL composition, and a specific pH value.
pH-adjusted vesicle formulation to maximize tenofovir encapsulation
A formulation containing vesicles comprising one or more bolaamphiphilic compounds, cholesteryl hemisuccinate, cholesterol, stearyl amine, and an active agent which is tenofovir or fosamprenavir, wherein the pH has been adjusted to a pH of 7.5 or 8 using a buffer to maximize tenofovir encapsulation.
Defined vesicle component composition and active-agent loading per 1 mL
For 1 mL of formulation the components are 10 mg GLH 19 and GLH 20 in a ratio of 2/1, 1 mg GLH-55b, 2.4 mg cholesteryl hemisuccinate, 1.6 mg cholesterol, 2.5 mg stearyl amine, and 5 mg tenofovir or fosamprenavir.
HEPES buffer and specified pH for the formulation
The buffer is a HEPES, and the formulation is adjusted so that its pH is 7.5.
Administration suitability with delivered active agent above a therapeutic threshold
A formulation suitable for IV, IP, oral, or transdermal administration that delivers an active agent at levels above a therapeutic threshold of 100 ng/mL.
Across the independent claim and its dependents, the inventive coverage centers on vesicle compositions using bolaamphiphilic compounds with cholesteryl hemisuccinate, cholesterol, and stearyl amine, containing tenofovir or fosamprenavir, with pH adjustment to maximize tenofovir encapsulation, and with delivery context including a therapeutic-threshold language.
Stated Advantages
Thin membranes.
Higher encapsulation.
Stability.
BBB penetration.
Maximize tenofovir encapsulation.
Deliver an active agent at levels above a therapeutic threshold of 100 ng/mL.
Documented Applications
Preventing/prophylaxis and treating using a therapeutically effective amount.
HIV drug delivery using tenofovir or fosamprenavir active agents in vesicle/bolavesicle formulations.
BBB penetration applications referenced for brain/Blood-brain barrier (BBB).
Administration in IV, IP, oral, or transdermal routes for delivering the active agent above a therapeutic threshold.
Bola vesicles/bolavesicles used for HIV drug delivery, including cellular and BBB-transport evaluations.
Quantification of tenofovir in brain homogenates and estimation of brain concentrations after IV administration of optimized tenofovir-loaded vesicles.
Delivering HIV active agents to the brain across the blood-brain barrier, including complexed/encapsulated tenofovir or fosamprenavir.
Tenofovir encapsulation into GLH 19/20 vesicles, with analysis of brain delivery and pharmacokinetics in mice, including comparison of V-Smart™ vesicles versus free tenofovir.
Use of the formulation for IV, IP, oral, or transdermal administration, with delivered active agent levels above a therapeutic threshold of 100 ng/mL.
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