Oral (17-β)-3-oxoandrost-4-en-17-yl tridecanoate therapy
Inventors
Kim, Kilyoung • Patel, Mahesh V. • Chidambaram, Nachiappan
Assignees
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Publication Number
US-12318396-B1
Publication Date
2025-06-03
Expiration Date
Abstract
Disclosed are pharmaceutical compositions and oral dosage forms including capsules containing (17-β)-3-oxoandrost-4-en-17-yl tridecanoate, and related methods. The capsule fill can include an additive and about 14 wt % to about 42 wt % for androst-4-en-17β-ol-3-one esters that comprise (17-β)-3-oxoandrost-4-en-17-yl tridecanoate or a combination of (17-β)-3-oxoandrost-4-en-17-yl undecanoate, (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and (17-β)-3-oxoandrost-4-en-17-yl tridecanoate. A single oral administration to a male subject of one or more dosage forms with a total androst-4-en-17β-ol-3-one equivalent dose of about 150 mg to about 895 mg is provided. In another embodiment, a method for providing a serum concentration of androst-4-en-17β-ol-3-one within a target PK performance for a male subject is provided. In a further embodiment, the pharmaceutical compositions and methods comprising androst-4-en-17β-ol-3-one ester loading of 14 wt % to 42 wt % achieve androst-4-en-17β-ol-3-one PK performance targets and require titration(s) to show therapeutic effectiveness for treatment of hypogonadism.
Core Innovation
The patent describes pharmaceutical compositions and treating methods that administer to a subject at least one dose of a pharmaceutical composition comprising a plurality of testosterone esters having at least one non-undecanoate testosterone ester (NTU). The treatment targets conditions associated with fatigue, reduced muscle size, reduced muscle strength, reduced muscle mass, reduced muscle tone, reduced bone density, reduced body mass index (BMI), reduced energy, reduced motivation, reduced endurance, decreased libido, diminished memory, anemia, marrow failure, renal failure, chronic respiratory failure, cardiac failure, steroid-dependent autoimmune disease, muscle wasting, attacks of hereditary angioedema, attacks of hereditary urticaria, and hypogonadism and androgen deficiency.
The compositions and methods relate to oral hypogonadism therapy and testosterone ester formulations characterized by substantially crystalline versus substantially noncrystalline and/or solubilized androst-4-en-17β-ol-3-one ester forms. The document includes capsules comprising (17-β)-3-oxoandrost-4-en-17-yl tridecanoate, and optionally combinations including TT with undecanoate and/or dodecanoate, with ester loading about 14 wt% to about 42 wt%.
The patent further describes titration and maintenance-dose adjustment based on serum androst-4-en-17β-ol-3-one concentration relative to predetermined levels or ranges, including steady-state metrics such as Cavg and Cmax and, for a single-point approach, Ct measured at about 4 h to about 18 h after dosing. It also describes in vitro release testing in aqueous media containing Triton X-100 under USP-Type II dissolution apparatus conditions, with performance thresholds over time for the NTU release.
The formulation and product design rationale addresses poor oral bioavailability and first-pass metabolism, and specifically challenges for the tridecanoate ester. The document describes formulation design choices including substantially noncrystalline versus substantially crystalline forms, optionally solubilized forms, and formulation component selections for fatty acid/glycerides additives and surfactants, while also describing an optional absence of oils, triglycerides, and certain hydrophilic surfactants.
Claims Coverage
The independent claim material covers treatment using a plurality of testosterone esters with at least one non-undecanoate testosterone ester, together with titration or maintenance-dose adjustment based on serum androst-4-en-17β-ol-3-one. It also recites formulation and performance features including substantially non-crystalline and/or solubilized forms, specified in vitro release testing, and group-level eugonadal serum concentration performance criteria.
Treating by administering plural testosterone esters including NTU
A method of treating at least one listed condition by administering to a subject at least one dose of a pharmaceutical composition comprising a plurality of testosterone esters having at least one non-undecanoate testosterone ester (NTU).
Titration of maintenance dose based on androst-4-en-17β-ol-3-one level versus a predetermined range
Adjusting a maintenance dosage using serum concentration of androst-4-en-17β-ol-3-one relative to predetermined level or range, including using at least one of a decrease, an increase, or maintaining a substantially identical dose, using a steady-state serum concentration level and requiring improved Cavg responder rate versus an untitrated dosage regimen.
Single time-point measurement for serum concentration used in titration
Obtaining the subject’s serum concentration of androst-4-en-17β-ol-3-one by measuring it at a single time point between about 4 h and about 18 h after a previously administered dose.
In vitro release-rate testing of NTU in specified dissolution conditions
Exposing the pharmaceutical composition to 2% w/v Triton X-100 aqueous media at 37±1° C. in a USP-Type II dissolution apparatus at 100 rpm, wherein the in vitro release rate of said NTU meets specified minimum percentages at specified time periods.
Non-crystalline and/or solubilized form composition constraint
Defining the pharmaceutical composition as including at least one of a substantially non-crystalline form or a substantially solubilized form.
Group-level eugonadal serum concentration performance after steady state
For a group of at least 24 hypogonadal males, achieving a steady-state serum concentration level and after at least 7 days from a previously administered dose such that at least 75% of the group has a serum concentration Cavg in the eugonadal range.
The claims focus on treating conditions using oral testosterone-esters compositions that include at least one non-undecanoate testosterone ester, while further narrowing to serum-based titration, specified dissolution release-rate testing, composition inclusion of substantially non-crystalline and/or substantially solubilized forms, and defined group-level eugonadal performance criteria.
Stated Advantages
Improves Cavg responder rate versus an untitrated dosage regimen.
Reduced Cmax excursions versus no-titration.
Controls overexposure.
Achieves and maintains eugonadal serum concentration range for a substantial portion of a hypogonadal male group.
Provides higher bioavailability for substantially noncrystalline formulations versus crystalline formulations.
Documented Applications
Oral hypogonadism therapy targeted to achieve eugonadal serum concentrations of androst-4-en-17β-ol-3-one.
Treatment of conditions associated with fatigue, reduced muscle size, reduced muscle strength, reduced muscle mass, reduced muscle tone, reduced bone density, reduced body mass index (BMI), reduced body mass, reduced energy, reduced motivation, reduced endurance, decreased libido, diminished memory, anemia, marrow failure, renal failure, chronic respiratory failure, cardiac failure, steroid-dependent autoimmune disease, muscle wasting, attacks of hereditary angioedema, attacks of hereditary urticaria, hypogonadism, and androgen deficiency.
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