Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols
Inventors
Assignees
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Publication Number
US-12295961-B2
Publication Date
2025-05-13
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 provides lipophilic, poorly water-soluble drug formulations that combine a sterol or sterol ester, preferably phytosterols, with an optional non-sterol solubilizer and optionally an absorption/metabolic-enhancing agent. The formulation approach is directed to modulating solubility, stability, GI absorption/lymphatic uptake, metabolism, and pharmacokinetics, thereby increasing bioavailability.
The disclosure emphasizes delivering testosterone, including testosterone undecanoate (TU), using oral formulation concepts including SEDDS and SMEDDS, and also sustained or modified-release concepts. Phytosterol components are described as enhancing lymphatic absorption and as reducing DHT formation risk, which is linked to modulation of metabolism.
The disclosure further describes incorporating specific enhancing agents such as 5α-reductase inhibitors and/or P450 inhibitors and/or P-gp inhibitors to enhance absorption and metabolic outcomes and to support improved pharmacokinetic performance. The disclosure includes supporting dissolution/dispersion, in vivo canine PK results, stability data indicating that phytosterols reduce oxidation and extend shelf life, and human PK predictions for selected capsule embodiments.
Claims Coverage
The independent claim covers a method of treating male hypogonadism using an oral formulation with three principal inventive composition elements: testosterone undecanoate, a non-sterol solubilizing agent, and a defined mixture of phytosterol esters (beta-sitosterol and stigmasterol). Dependent claims refine these elements by adding quantitative composition/dosage ranges, specifying non-sterol solubilizing agent selections, adding vitamin E-related components, and restricting dosing frequency to once daily or twice daily.
Oral formulation for treating male hypogonadism with testosterone undecanoate, non-sterol solubilizing agent, and phytosterol esters mixture
A method of treating male hypogonadism comprising administering an oral formulation comprising testosterone undecanoate, from about 10% to about 90% by weight of a non-sterol solubilizing agent effective for solubilization of the testosterone undecanoate, and from about 2% to about 45% by weight of a mixture of phytosterol esters, wherein the mixture comprises esters of beta-sitosterol and stigmasterol.
Overall, the claim coverage centers on oral delivery of testosterone undecanoate through a defined combination with a non-sterol solubilizing agent and a specific phytosterol ester mixture (beta-sitosterol and stigmasterol), with dependent claims further defining component amounts/agents, optional vitamin E components, and dosing frequency.
Stated Advantages
Improves solubility, stability, GI absorption/lymphatic uptake, metabolism, and pharmacokinetics, thereby increasing bioavailability.
Enhances lymphatic absorption.
Reduces DHT formation risk.
Improves pharmacokinetic exposure (bioavailability increases up to about 2–3x for TU as described).
Phytosterols reduce oxidation and extend shelf life (stability).
Documented Applications
Treating male hypogonadism in a subject in need thereof by administering an oral formulation containing testosterone undecanoate with a non-sterol solubilizing agent and a defined mixture of phytosterol esters.
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