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-10576089-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 invention relates to an oral formulation and a method of treating male hypogonadism by administering testosterone undecanoate together with a phytosterol or phytosterol ester mixture and a non-sterol solubilizing agent. The formulation is characterized by defined weight ranges for the non-sterol solubilizing agent and for the phytosterol/phytosterol ester mixture, including specified proportions of beta-sitosterol, campesterol, stigmasterol, brassicasterol, and sitostanol, and a tocopherol content range.
A central aspect of the invention is that the phytosterols or phytosterol esters provide increased plasma levels of testosterone following oral administration when compared with testosterone produced after oral administration of testosterone undecanoate in a formulation free of phytosterols and phytosterol esters. The document further frames a reduction in undesired dihydrotestosterone (DHT) formation as part of the overall pharmacokinetic and exposure benefits.
The disclosed formulation concept is directed to testosterone-based therapy, with the sterol component optionally existing as phytosterols or phytosterol esters and with additional formulation components such as solubilizers and absorption or metabolic enhancing agents described in the partial content. The partial content also describes supportive evidence conceptually indicating improved testosterone exposure, a reduced DHT/T ratio, and favorable stability and dissolution profile behavior.
Claims Coverage
Independent claim clm-00001 covers a method of treating male hypogonadism using an oral formulation with four inventive features: testosterone undecanoate, a non-sterol solubilizing agent, a defined mixture of phytosterols or phytosterol esters, and increased plasma testosterone versus a phytosterol-free formulation. The claim also anchors the composition by weight percentage constraints.
Treatment of male hypogonadism with an oral testosterone undecanoate phytosterol formulation
A method of treating male hypogonadism in a subject in need thereof by administering to the subject an oral formulation comprising testosterone undecanoate.
Non-sterol solubilizing agent for solubilization of testosterone undecanoate
An oral formulation further comprising from about 10% to about 90% by weight of a non-sterol solubilizing agent effective for solubilization of the testosterone undecanoate.
Phytosterol/phytosterol ester mixture with defined subtype proportions and tocopherols
The 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 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.
Increased plasma testosterone levels versus phytosterol-free testosterone undecanoate formulation
The phytosterols or phytosterol esters provide 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.
Overall, the independent claim is centered on a constrained oral composition that combines testosterone undecanoate with a non-sterol solubilizing agent and a specifically proportioned phytosterol/phytosterol ester mixture, and on the claimed effect that this phytosterol-containing formulation increases plasma testosterone compared to a phytosterol-free formulation.
Stated Advantages
Increased plasma levels of testosterone following oral administration compared to a formulation free of phytosterols and phytosterol esters.
Documented Applications
Treating male hypogonadism in a subject in need thereof by administering an oral formulation comprising testosterone undecanoate, a non-sterol solubilizing agent, and a mixture of phytosterols or phytosterol esters.
Interested in licensing this patent?