Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11590146-B2
Publication Date
2023-02-28
Expiration Date
Abstract
A formulation for drug delivery, providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of a lipophilic therapeutic agent by formulation with sterols and/or sterol esters, resulting in higher bioavailability of a therapeutic agent administered to a subject in need of such therapeutic agent. The formulation contains a therapeutic agent and a sterol or sterol ester, and can, optionally, further contain a solubilizer and/or an enhancing agent. Also described are pharmaceutical compositions containing the formulations and methods of making and methods of using the formulations and pharmaceutical compositions. Formulations of the disclosure can be constituted to minimize the synthesis of dihydrotestosterone when the therapeutic agent includes testosterone or testosterone esters.
Core Innovation
The disclosure relates to drug-delivery formulations for lipophilic, poorly water-soluble therapeutics that include a sterol or sterol ester together with an optional non-sterol solubilizer and/or absorption and stability-enhancing agents. The stated intent is to improve solubility, stability, absorption, metabolism, and the pharmacokinetic profile.
A major focus is androgen therapy using testosterone and especially testosterone undecanoate, with an emphasis on maintaining a desired testosterone exposure while limiting dihydrotestosterone exposure. The disclosure describes formulation approaches intended to enhance solubility and uptake, including improved absorption, metabolism modulation, and pharmacokinetics.
The formulations incorporate phytosterol or phytosterol esters, including mixtures of phytosterol esters, together with solubilizing and/or absorption and stability enhancing components. The document also addresses oxidative stability and shelf-life improvements for lipid formulations through the inclusion of phytosterols, and it provides supportive findings in beagle dog PK and preliminary human prediction contexts.
In the reported supporting context, co-dosing phytosterol or phytosterol esters with testosterone undecanoate formulations increases TU exposure and can improve DHT/T ratios toward physiological values. The disclosure further describes the role of enhanced lymphatic transport in reducing first-pass metabolism and improving bioavailability.
Claims Coverage
The provided independent claim describes an oral formulation with three core inventive components: testosterone undecanoate; a non-sterol solubilizing agent; and a specified mixture of phytosterol esters comprising beta-sitosterol and stigmasterol. Dependent claims refine composition ranges, specify named solubilizing agents, narrow the formulation type to self-emulsifying/self-microemulsifying systems, and optionally add alpha-tocopherol or alpha-tocopherol acetate.
Oral formulation with testosterone undecanoate plus non-sterol solubilizing agent
An oral formulation comprising testosterone undecanoate and from about 10% to about 90% by weight of a non-sterol solubilizing agent effective for solubilization of the testosterone undecanoate.
Mixture of phytosterol esters comprising beta-sitosterol and stigmasterol
An oral formulation including from about 2% to about 45% by weight of a mixture of phytosterol esters, wherein the mixture comprises esters of beta-sitosterol and stigmasterol.
Non-sterol solubilizing agent as propylene glycol monolaurate
The non-sterol solubilizing agent comprises propylene glycol monolaurate.
Self-emulsifying or self-microemulsifying oral formulation
The oral formulation is self-emulsifying or self-microemulsifying.
Optional inclusion of alpha-tocopherol or alpha-tocopherol acetate
The oral formulation further comprises alpha-tocopherol or alpha-tocopherol acetate.
Across the independent claim and its refinements, the coverage centers on an oral testosterone undecanoate formulation that uses a non-sterol solubilizing agent together with a defined mixture of phytosterol esters (beta-sitosterol and stigmasterol), optionally implemented as a self-emulsifying/self-microemulsifying system and optionally supplemented with alpha-tocopherol or alpha-tocopherol acetate.
Stated Advantages
Improves solubility.
Improves stability.
Improves absorption.
Modulates metabolism.
Improves pharmacokinetic profile.
Increases bioavailability.
Reduces first-pass metabolism via enhanced lymphatic transport.
Can improve DHT/T ratios toward physiological values.
Improves lipid formulation oxidative stability (shelf-life).
Documented Applications
Androgen therapy using testosterone, especially testosterone undecanoate, in oral formulations intended to manage testosterone exposure and limit dihydrotestosterone (DHT) exposure.
Oral drug-delivery formulations for lipophilic, poorly water-soluble therapeutics using sterol/sterol ester and solubilizing/enhancing components to improve solubility, stability, absorption, metabolism, and pharmacokinetics.
Pharmacokinetic assessment and prediction contexts including beagle dog PK and preliminary human prediction contexts.
Interested in licensing this patent?