Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols
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Publication Number
US-10576090-B2
Publication Date
2020-03-03
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 describes an oral formulation for modulating solubility, stability, absorption, metabolism, and pharmacokinetic profiles of lipophilic or poorly water-soluble therapeutic agents by using sterols or sterol esters, preferably phytosterols, and optionally one or more non-sterol solubilizers and/or enhancing agents. The formulation is directed to improving oral delivery performance, including increased plasma levels and improved bioavailability, while also addressing downstream metabolite levels such as dihydrotestosterone (DHT).
A particular emphasis is placed on improved oral androgen delivery by combining testosterone or testosterone esters, including testosterone undecanoate, with a defined mixture of phytosterols or phytosterol esters and a non-sterol solubilizing agent. The disclosure describes that the phytosterols or phytosterol esters provide increased plasma levels of testosterone following oral administration compared to a formulation free of phytosterols and phytosterol esters, including effects reflected in pharmacokinetic comparisons and ratios such as DHT/T.
The disclosure further discusses formulation concepts related to micelle and lymphatic transport in the gastrointestinal tract and includes discussion of formulation classes such as SEDDS and SMEDDS. It provides rationale and experimental support including modulation of dissolution profiles and improved dispersion, formulation stability considerations including oxidation minimization, and in vivo pharmacokinetic results in beagle dogs with predicted human pharmacokinetic outcomes showing increased testosterone exposure and altered DHT/T relationships.
Claims Coverage
The document provides one independent claim directed to a specific oral formulation composition and its comparative pharmacokinetic effect. The independent claim contains three principal inventive areas: the required testosterone undecanoate payload, a defined non-sterol solubilizing agent amount, and a defined phytosterol or phytosterol-ester mixture composition with a comparative statement that the phytosterols or phytosterol esters increase plasma testosterone levels versus a phytosterol-free formulation.
Testosterone undecanoate oral formulation
An oral formulation comprising testosterone undecanoate.
Non-sterol solubilizing agent effective for solubilization
An oral formulation comprising from about 10% to about 90% by weight of a non-sterol solubilizing agent effective for solubilization of the testosterone undecanoate.
Defined phytosterol or phytosterol ester mixture for plasma testosterone increase
An oral formulation comprising from about 2% to about 45% by weight of a mixture of phytosterols or phytosterol esters, wherein the mixture comprises from 40% to 58% by weight of beta-sitosterol or esters thereof; from 20% to 30% by weight of campesterol or esters thereof; from 14% to 22% by weight stigmasterol or esters thereof; from 0 to 6% by weight brassicasterol or esters thereof; from 0 to 5% by weight sitostanol or esters thereof; and from 0 mg/g to 15 mg/g tocopherols; and wherein the phytosterols or phytosterol esters provides increased plasma levels of testosterone following oral administration in comparison to the plasma levels of testosterone produced following oral administration of testosterone undecanoate in a formulation free of phytosterols and phytosterol esters.
Across the sole independent claim, the inventive concept is an oral formulation combining testosterone undecanoate with a defined amount of a non-sterol solubilizing agent and a defined phytosterol or phytosterol-ester mixture; the phytosterols or phytosterol esters are required to increase plasma testosterone levels after oral administration compared to a phytosterol-free formulation.
Stated Advantages
Increased plasma levels of testosterone following oral administration compared with testosterone undecanoate in a formulation free of phytosterols and phytosterol esters.
Improved oral androgen delivery performance, reflected by increased testosterone exposure and altered DHT/T relationships in pharmacokinetic comparisons.
Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profiles for lipophilic or poorly water-soluble therapeutic agents using sterols or sterol esters.
Documented Applications
Oral delivery of androgen therapy via testosterone or testosterone esters, including testosterone undecanoate, using a formulation containing phytosterols or phytosterol esters and a non-sterol solubilizing agent to increase plasma testosterone levels after oral administration.
Pharmacokinetic studies and performance evaluation including comparison of plasma testosterone levels and DHT/T relationships after oral administration, including beagle dog pharmacokinetic results and predicted human pharmacokinetics.
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