WO2024005770A1 - COMPOSITIONS DE (17-β)-3-OXOANDROST-4-EN-17-YL DODÉCANOATE ET PROCÉDÉS DE PRÉPARATION ET D'UTILISATION - Google Patents

COMPOSITIONS DE (17-β)-3-OXOANDROST-4-EN-17-YL DODÉCANOATE ET PROCÉDÉS DE PRÉPARATION ET D'UTILISATION Download PDF

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WO2024005770A1
WO2024005770A1 PCT/US2022/034463 US2022034463W WO2024005770A1 WO 2024005770 A1 WO2024005770 A1 WO 2024005770A1 US 2022034463 W US2022034463 W US 2022034463W WO 2024005770 A1 WO2024005770 A1 WO 2024005770A1
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Prior art keywords
pharmaceutical composition
dodecanoate
oxoandrost
derivative
disease
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PCT/US2022/034463
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English (en)
Inventor
Kilyoung Kim
Mahesh V. Patel
Nachiappan Chidambaram
Joel Frank
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Lipocine, Inc.
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Priority to PCT/US2022/034463 priority Critical patent/WO2024005770A1/fr
Publication of WO2024005770A1 publication Critical patent/WO2024005770A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

Definitions

  • Different solid state forms of an ester of an active pharmaceutical ingredient (API) or esterified active pharmaceutical ingredient (EAPI) may possess different properties that can provide a formulation, in which the EAPI is included, with specific advantages, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different solid state forms may also translate to benefits to a final dosage form, for instance, by providing or contributing to improved bioavailability. Different solid state forms of an EAPI may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid EAPI.
  • EAPI An important characteristic of EAPI is that its dissolution or release rate does not change substantially over time period. Changes in dissolution or release rate of EAPI over time period can result from otherwise identical products except for the solid state form (e.g., having the same EAPI, formulations components and amounts thereof), but can result in different pharmacokinetic properties which can change or alter the efficacy or safety of a drug product.
  • the stability of EAPI in pharmaceutical preparations is also important. For example, if the EAPI changes physical form (e.g., crystal form or amount thereof) in a pharmaceutical composition or unit dosage form, this can also affect pharmacokinetic properties and therefore related safety and efficacy parameters.
  • EAPI ester derivative of an API
  • Solubility, release, dissolution and partitioning of EAPI in a particular solvent is a function of lipophilicity and is related to solid state characteristics e.g., the physical form of the drug substance such as crystal form, solvation, whether or not amorphous material is present, etc. Therefore, the solid state physical form is one of the key properties with respect to ease of manufacturing, storage, and performance of the EAPI for enabling safe and effective levels of API.
  • Esters of (17- ⁇ )-Hydroxy-4-Androsten-3-one which themselves are not thought to be biological active, are known to be transformed to the biologically active molecule ((17- ⁇ )-Hydroxy-4-Androsten-3-one in vivo and other related metabolites like (17- ⁇ )-hydroxy-5 ⁇ -androstan-3-one, and therefore can be used for treating patients in need of (17- ⁇ )-Hydroxy-4-Androsten-3-one treatment.
  • Steroids including steroid esters, such as testosterone and testosterone esters are known to exhibit different solid state forms that have different properties including dissolution, bioavailability and absorption (See e.g., Ballard BE, Biles J, Steroids, 1964; 4: 273; Bouche R, Draguet-Brughmans M, J Pharm Belg, 1977; 32: 347; Carless et al. Journal of Pharmacy and Pharmacology Volume 20, Issue 8, pages 630–638, August 1968; Borka & Haleblian (1990) Acta Pharm. Jugosl.40:71-94).
  • a composition for administration to a human subject in need of ((17- ⁇ )-Hydroxy-4-Androsten-3-one therapy is provided: e.g., the composition comprising or made from a) a solid state of (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate and b) a pharmaceutically acceptable carrier, wherein upon oral administration of the solid state of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate to the human subject, at least about 0.1% 0.5%, 1%, 2%, 3%, 5%,8% or 10% of the (17- ⁇ )-Hydroxy-4-Androsten-3-one (testosterone) equivalent dose is bioavailable to the human subject.
  • a solid state EAPI which is (17- ⁇ )-3-Oxoandrost- 4-en-17-yl dodecanoate.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is crystalline.
  • the crystalline solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate is a crystal form substantially free of other non-crystal forms.
  • the crystalline solid state (17- ⁇ )-3-Oxoandrost-4-en-17- yl dodecanoate described herein is substantially free of amorphous forms.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate provided herein has a characteristics of particle size distribution.
  • the particle sizes of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate are less than 200 nm (“nanometer”), from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m (“micrometer”), from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate has a d 50 of greater than 1000 ⁇ m, from 355 to 1000 ⁇ m, from 180 to 355 ⁇ m, from 125 to 180 ⁇ m, 90 to 125 ⁇ m, from 1 to 90 ⁇ m, or less than 1 ⁇ m.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate has a D10, D50, or D90 that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate having a characteristics of particle size distribution or size characteristics is crystalline.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate having a characteristics of particle size distribution or size characteristics is a crystal form substantially free of other non-crystalline forms.
  • Pharmaceutical compositions provided herein comprise or are prepared from a solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate as described in the paragraphs above.
  • the pharmaceutical composition is prepared from or comprises a solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and one or more pharmaceutically acceptable excipients, carriers, or additives.
  • the pharmaceutical composition described herein can comprise or be prepared from crystalline solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • the pharmaceutical composition comprises or is prepared from solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate, where is not-milled or is milled, micronized or nanosized.
  • the pharmaceutical composition comprises or is prepared from solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate wherein the particle size is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 ⁇ m to 250 ⁇ m, from 250 ⁇ m to 500 ⁇ m, from 500 ⁇ m to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the pharmaceutical composition comprises or is prepared from solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate having a d50 of greater than 1000 ⁇ m, from 355 to 1000 ⁇ m, from 180 to 355 ⁇ m, from 125 to 180 ⁇ m, from 90 to 125 ⁇ m, from 1 to 90 ⁇ m, or less than 1 ⁇ m.
  • the pharmaceutical composition comprises or is prepared from solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate having a D 10 , D 50 , or D90 that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the pharmaceutical composition of solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate is formulated for topical, enteral or parenteral administration.
  • the pharmaceutical composition of solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate is formulated for buccal, sublingual, or sublabial administration. In some specific aspects, the pharmaceutical composition of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is formulated for nasal, rectal or vaginal administration. In some specific aspects, the pharmaceutical composition of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is formulated for intravenous, subcutaneous, intramuscular, intradermal, intraspinal, intrathecal, or intra-arterial administration.
  • the pharmaceutical composition of solid state (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate is formulated as liquid, solution, suspension, dispersion (see: https://en.wikipedia.org/wiki/Dispersion_(chemistry)), solid, semi-solid, gel, lotion, paste, foam, spray, suspension, dispersion, syrup, or ointment.
  • the pharmaceutical composition of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is formulated as a tincture, patch, injectable, or oral dosage form.
  • the pharmaceutical composition of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate comprises solubilized or partially solubilized (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • the pharmaceutical composition or unit dosage form is suitable for oral administration (e.g., capsule or tablet). [0018] Provided herein are pharmaceutically compositions or unit dosage forms comprising or prepared from solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate as described in the paragraphs above.
  • FIG. 1 shows a first heat cycle heat enthalpy change plot for a solid state form of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate measured by differential scanning calorimetry as disclosed herein; [0021] FIG.
  • FIG. 2 shows a result of an XRD measure for a solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate as disclosed herein with 8 distinguishable peaks for a crystalline structure;
  • FIG. 3 shows general formulation processes for producing a variety of different forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in a pharmaceutical composition or dosage form to improve physical, chemical, pharmacokinetic, and pharmacodynamic properties for enhancing bioavailability as disclosed herein, and; [0023] FIG.
  • an excipient includes reference to one or more of such excipients
  • the carrier includes reference to one or more of such carriers.
  • the terms “treat,” “treatment,” or “treating” and the like refers to administration of a therapeutic agent to a pathogen-infected subject who is either asymptomatic or symptomatic. In other words, “treat,” “treatment,” or “treating” can refer to reducing, ameliorating or eliminating symptoms associated with a condition present in an infected subject.
  • “androgen receptor agonists” refers to compounds, molecules, or agents such as testosterone that bind and activate an androgen receptor.
  • Examples of androgen receptor agonists include, but are not limited to, dihydrotestosterone, mibolerone, testosterone, alkylated testosterone, derivatives of testosterone esters, methyltrienolone, oxandrolone, nandrolone and fluoxymesterone. Where appropriate, fatty acid esters of these androgen receptor agonists can be used herein accordingly.
  • testosterone ester refers to testosterone esterified with a fatty acid.
  • Exemplary testosterone esters include without limitation testosterone undecanoate, testosterone decanoate, testosterone dodecanoate, testosterone tridecanoate, testosterone decanoate, testosterone enanthate, testosterone palmitate, testosterone cypionate, and testosterone propionate.
  • testosterone agent refers to an active pharmaceutical agent that produces a physiologic action or effect of testosterone in-vivo.
  • testosterone agents are found throughout the present application.
  • One example of a testosterone agent is testosterone (T).
  • Another example is a testosterone ester, such as testosterone undecanoate or testosterone tridecanoate.
  • the terms “therapeutic agent,” “active agent,” and the like can be used interchangeably and refer to agent that can have a beneficial or positive effect on a subject when administered to the subject in an appropriate or effective amount.
  • the therapeutic or active agent can be an androgenic steroid.
  • additional active agent can be used interchangeably and refer to a compound, molecule, or material other than an androgenic steroid that has physiologic activity when administered to a subject in an effective amount.
  • formulation and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipients.
  • dosage form can include one or more formulation(s) or composition(s) provided in a format for administration to a subject.
  • an “oral dosage form” can be suitable for administration to a subject’s mouth.
  • a “topical dosage form” can be suitable for administration to a subject’s skin by rubbing, etc.
  • a “subject” refers to an animal. In one aspect the animal may be a mammal. In another aspect, the mammal may be a human.
  • in need of treatment refers to a subject that has a disease or is suspected of having the disease according to various diagnostic criteria typically used in practice, or desires treatment or is indicated for treatment. Thus, "in need of treatment” can include the step of identifying a subject in need of treatment.
  • identifying a subject in need of treatment can include the step of obtaining a biological sample from the subject and determining the level of one or more biomarkers as described herein (RT-PCR detection of a virus gene), assessing a biological sample obtained from said subject, performing an imaging analysis on the subject, assessing one or more clinical characteristics of said subject (e.g., assessing symptoms or overt symptoms), or a combination thereof.
  • an “acute” condition refers to a condition that can develop rapidly and have distinct symptoms needing urgent or semi-urgent care.
  • a “chronic” condition refers to a condition that is typically slower to develop and lingers or otherwise progresses over time.
  • Some examples of acute conditions can include without limitation, an asthma attack, bronchitis, a heart attack, pneumonia, and the like.
  • Some examples of chronic conditions can include without limitation, arthritis, diabetes, hypertension, high cholesterol, and the like.
  • serum testosterone or “serum (17- ⁇ )-Hydroxy-4-Androsten-3- one levels,” “serum T levels,” “serum testosterone concentration,” “plasma testosterone concentration,” “testosterone concentration in the blood,” and “serum testosterone concentration,” are used interchangeably and refer to the “total” serum testosterone concentration which is the sum of the bioavailable testosterone including free and bound testosterone fractions or concentrations.
  • the method employed to measure initial serum testosterone levels may be consistent with the method used to monitor and re-measure serum testosterone levels during clinical testing and testosterone therapy for a subject.
  • testosterone concentration refers to serum total testosterone concentration.
  • Average serum testosterone concentrations can be determined using methods and practices known in the art. For example, the average baseline plasma testosterone concentration of a human male is the arithmetic mean of the total plasma testosterone concentration determined on at least two consecutive time points that are reasonably spaced from each other, for example from about 1 hour to about 168 hours apart. In a particular case, the plasma testosterone concentration can be determined on at least two consecutive times that are about 12 hours to about 48 hours apart.
  • the plasma testosterone concentration of the human male can be determined at a time between about 5 o'clock and about 11 o'clock in the morning. Further, the plasma testosterone concentration can be the determined by standard analytical procedures and methods available in the art, such as for example, automated or manual immunoassay methods, liquid chromatography or liquid chromatography-tandem mass spectrometry (LC-MSMS) etc.
  • the term “baseline” refers to a level or concentration of the substance in a subject prior to administration of an active agent. For example, the baseline level of serum testosterone in a subject would the subject’s testosterone serum level prior (e.g. just prior) to the commencement of testosterone administration or therapy.
  • free testosterone serum concentration refers to the fraction of total testosterone that is not bound to a protein e.g., SHBG (see: https://en.wikipedia.org/wiki/Sex_hormone-binding_globulin) or albumin.
  • free testosterone serum concentrations are used instead of serum total testosterone concentrations.
  • a subject can appear to have total serum testosterone levels in the normal range, but can be still considered testosterone deficient based on free testosterone levels.
  • testosterone serum levels or concentrations can provide express support for free testosterone serum concentrations, unless the context or recitation clearly dictates otherwise.
  • oral administration represents any method of administration in which an active agent can be administered by swallowing, chewing, or sucking of the dosage form. Oral administration can be intended for enteral delivery of an active agent or transmucosal delivery of the active agent.
  • the composition of the current inventions can be admixed with food or drink prior to being orally consumed.
  • a “dosing regimen” or “regimen” such as an “initial dosing regimen” or “starting dose” or a “maintenance dosing regimen” refers to how, when, how much, and for how long a dose of the compositions of the present invention can be administered to a subject.
  • an initial or starting dose regimen for a subject may provide for a total daily dose of from about 15 mg to about 1500 mg administered in two divided doses at least 12 hours apart (e.g. once with breakfast and once with dinner) with meals repeated daily for 30 days.
  • “daily dose” refers to the amount of active agent (e.g. a testosterone ester) administered to a subject over a 24-hour period of time.
  • the daily dose can be administered one or more administrations during the 24-hour period.
  • the daily dose provides for two administrations in a 24-hour period.
  • an “initial dose” or initial daily dose” refers to a dose administered during the initial regimen or period of a dosing regimen.
  • an “effective amount” or a “therapeutically effective amount” of a drug refers to a non-toxic, but sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is known to be effective. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an “effective amount” or a “therapeutically effective amount” may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine.
  • single unit when used to describe dosing of a subject refers to the dosage form being a single dosage form, e.g. a single tablet, capsule, pump or squirt of gel or solution, etc.
  • multiple unit when used to describe dosing of a subject refers to the dosage including two or more dosage forms, e.g. 2 capsules, 3 tablets, 2-4 pumps or squirts, etc.
  • Consisting essentially of or “consists essentially of” have the meaning generally ascribed to them by U.S. Patent law. In particular, such terms are generally closed terms, with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the compositions nature or characteristics would be permissible if present under the “consisting essentially of” language, even though not expressly recited in a list of items following such terminology.
  • comparative terms such as “increased,” “decreased,” “better,” “worse,” “higher,” “lower,” “enhanced,” “improved,” “maximized,” “minimized,” and the like refer to a property of a device, component, composition, biologic response, biologic status, or activity that is measurably different from other devices, components, compositions, biologic responses, biologic status, or activities that are in a surrounding or adjacent area, that are similarly situated, that are in a single device or composition or in multiple comparable devices or compositions, that are in a group or class, that are in multiple groups or classes, or as compared to an original (e.g. untreated) or baseline state, or the known state of the art.
  • a composition that “increases” testosterone serum levels provides a testosterone serum level in a subject that is elevated as compared to a serum level at a previous point in time, such as a baseline level (e.g. prior to treatment), or as compared to an earlier treatment with a different (e.g. lower dose).
  • a baseline level e.g. prior to treatment
  • a different e.g. lower dose.
  • the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context.
  • the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. Unless otherwise stated, use of the term “about” in accordance with a specific number or numerical range should also be understood to provide support for such numerical terms or range without the term “about”. For example, for the sake of convenience and brevity, a numerical range of “about 50 angstroms to about 80 angstroms” should also be understood to provide support for the range of “50 angstroms to 80 angstroms.” Furthermore, it is to be understood that in this specification support for actual numerical values is provided even when the term “about” is used therewith.
  • (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate can be converted in vivo to (17- ⁇ )-hydroxy- 5 ⁇ -androstan-3-one (directly or via the corresponding ester) which is also biological activity as well as other metabolites.
  • the term “EAPI” means an ester of (17- ⁇ )-Hydroxy- 4-Androsten-3-one, a prodrug of the biologically active agent. It is understood that the EAPI can also have biological activity without cleavage of the ester, but for the purpose of this invention the API is considered the pharmacological agent, which is (17- ⁇ )-Hydroxy- 4-Androsten-3-one (testosterone).
  • the term AUC t1-t2 is the area under the curve of a plasma- versus-time graph determined for the analyte from the time “t1 to t2” wherein t1 and t2 are times (in hours) post dosing.
  • t1 could be 1 hour and t2 could be 2 hours post dose.
  • Cavg Cavg
  • Cave or “C-average” are used interchangeably and determined as the mean values obtained from AUC t1-t2 divided by the time period (
  • all Cavg values are considered to be Cavgt0-t24 and unless otherwise stated, all the time values are expressed in hours (h).
  • the term C avg t0-t24 denotes C avg from time zero (0) to 24 hours post dosing.
  • C t refers to the serum concentration of testosterone at time “t” after administration of the dosage of the current invention.
  • the time “t” is generally in hours post administration, unless otherwise specified.
  • a C t of “C (-2 to 0) refers to serum testosterone concentration measured in sample collected between the time of about 2 hours before and just immediately prior to dosage administration to the subject tested.
  • C t of “C (2 to 4) ” refers to serum testosterone concentration measured in sample collected between the time of about 2 hours and 4 hours after administration of a dosage to the subject tested.
  • (17- ⁇ )-Hydroxy-4-Androsten-3-one refers to a chemical having an IUPAC name of (8R,9S,10R,13S,14S,17S)-17-Hydroxy-10,13- dimethyl- 1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[a]phenanthren-3-one and a CAS number of 58-22-0.
  • (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate generically refers to compounds having the (17- ⁇ )-Hydroxy-4-Androsten-3-one structure but the hydroxyl group at the 17 th carbon site on the testosterone structure is esterified with lauric acid (e.g., 12-carbon chain saturated alkanoic acid).
  • lauric acid e.g., 12-carbon chain saturated alkanoic acid
  • (8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[a]phenanthren-17-yl dodecanoate is the IUPAC name for (17- ⁇ )- Hydroxy-4-Androsten-3-one esterified with a straight chain saturated 12 carbon long alkanoic acid called lauric acid.
  • Dodecanoic acid, alternatively named lauric acid as well, is the IUPAC name for the saturated alkanoic acid having CAS number 143-07-7.
  • (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate refers to those of (17- ⁇ )-3-Oxoandrost-4-en-17-yl laurate specifically disclosed herein.
  • it refers to the dodecanoic (17- ⁇ )-Hydroxy-4-Androsten-3-one ester (referred to herein as (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate, (17- ⁇ )-3-Oxoandrost-4-en-17-yl laurate, or the dodecanoic ester of (17- ⁇ )-Hydroxy-4-Androsten-3-one and the such (CAS No.59232- 78-9)).
  • (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate has the following chemical structure as shown in Exhibit 1: Exhibit 1 [0059] Solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate can exist in different crystalline forms as well as in non-crystalline forms. A non-crystalline solid form is referred to herein as an “amorphous form”, which is a disordered arrangement of (17- ⁇ )- 3-Oxoandrost-4-en-17-yl dodecanoate molecules.
  • Crystalline forms are identified or characterized by any suitable methods, e.g., x-ray diffraction (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa., p 173 (1990); The United States Pharmacopeia, 23rd ed., pp.1843-1844 (1995)).
  • polymorphic forms Such different crystalline forms are referred to herein as “polymorphic forms” or “non-solvated forms”, which mean that they are essentially free of residual solvents, e.g., organic solvents. If the substances incorporate stoichiometric or non-stoichiometric amounts of water (“hydrate” as used herein), or any other solvent (“solvate” as used herein), in the crystal structure, these are referred to herein as a “pseudopolymorphic form.” [0060]
  • amorphous form as used herein in connection with solid state refers to a non-crystalline solid form (i.e., not in a crystalline form), which is a disordered arrangements of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate molecules.
  • crystal refers to a solid structure, typically formed by a solidification or crystallization, that generally has an ordered molecular packing structure (characteristic shapes and cleavage planes formed by the arrangement of molecules in a pattern referred to as a “lattice”).
  • a number of crystallites agglomerate and then form any grains, which can be packed to form any particles. That is, particle size is greater than grain size, which is greater than any crystal size.
  • seeding refers to starting or promoting a crystallization event using a small amount of materials.
  • Triton X100 or Triton “X-100” is a non-ionic detergent and refers to a composition as known as polyethylene glycol p-(1,1,3,3- tetramethylbutyl)-phenyl ether, octyl phenol ethoxylate, polyoxyethylene octyl phenyl ether, 4-octylphenol polyethoxylate, Mono 30, TX-100, t-octylphenoxypolyethoxyethanol, or Octoxynol-9 and associated with CAS NO.9002-93-1.
  • a “pharmaceutical composition” or “formulation” as used herein refers to a composition comprising or prepared from a solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and one or more pharmaceutically acceptable carriers, excipients, or additives.
  • an exemplary composition may be any of the compositions taught in the Patents.
  • a “unit dosage form” as used herein refers to a medicament prepared from or comprising a pharmaceutical composition and includes tablets, capsules, caplets, gelcaps, ampoules, suspensions, solutions, gels, dispersions and other dosage units typically associated with parenteral, enteral, topical or other forms of administration of (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate to a subject in need thereof.
  • a “pharmaceutically acceptable carrier”, “pharmaceutically acceptable excipient”, “pharmaceutically acceptable additive”, or similar term refers to one or multiple components or ingredients that are acceptable (1) as being compatible with the other ingredients in compositions or formulations comprising (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and (2) are not deleterious nor overly deleterious to a subject to whom the composition or formulation is to be administered.
  • Excipients include any of the excipients disclosed in the Patents.
  • Carriers e.g., pharmaceutically acceptable excipients or additives
  • methods of preparing oral pharmaceutical compositions comprising (17- ⁇ )-3-Oxoandrost- 4-en-17-yl dodecanoate are available to the skilled artisan in view of this application which typically involve a specific solid state form of the (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • Solid state forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate have one or more advantageous properties compared to other forms such as chemical or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability (e.g., such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion), stability towards hydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility and bulk density.
  • advantageous properties compared to other forms such as chemical or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability (e.g., such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion),
  • (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate Specific solid state forms of (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate are provided herein. [0069] (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate can be prepared by a number of synthetic routes (as well as other corresponding esters in an analogous fashion).
  • (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is prepared under the corresponding alcohol via an esterification reaction with (17- ⁇ )-Hydroxy-4-Androsten-3- one and an activated fatty acid of n-dodecanoic acid (IUPAC name as lauric acid, CAS number 143-07-7): e.g., a lauroyl chloride or anhydride, in a suitable solvent under suitable conditions to produce the product (e.g., pyridine as a catalyst of esterification).
  • the (17- ⁇ )-Hydroxy-4-Androsten-3-one is prepared from a phytosterol or cholesterol or any other suitable starting material.
  • the product is worked up via any number of techniques.
  • the product is dissolved in a solvent (e.g., organic solvent such as heptanes or any other solvent); washed successively with e.g., cold water (2X), 0.05 N NaOH, saturated NaHCO 3 (2X), water, brine, then dried over anhydrous Na2S04 ( ⁇ 50 g), followed by drying process (e.g., rotavap/Tbath ⁇ 30 °C).
  • a solvent e.g., organic solvent such as heptanes or any other solvent
  • 2X cold water
  • 0.05 N NaOH saturated NaHCO 3
  • water brine
  • drying process e.g., rotavap/Tbath ⁇ 30 °C
  • an example of recrystallized or crystallized solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is provided here.
  • (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is dissolved in a solvent (e.g., heptane) and allowed to crystallize or recrystallize or after a first crystallization is transferred to another solvent and allowed to crystallize or recrystallize.
  • a solvent e.g., heptane
  • the crystalline mass can be isolated (e.g., filtered by suction), optionally washed (e.g., with water), optionally dried (e.g., over phosphorous pentoxide) and optionally re-crystallized from another solvent e.g., oleic acid, hexane, heptanes, etc.
  • another solvent e.g., oleic acid, hexane, heptanes, etc.
  • the solvent for crystallization or recrystallization
  • is an alcohol e.g., ethanol, methanol, or propanol
  • fatty acid e.g., oleic acid, linoleic acid, or linoeladic acid
  • alkane e.g., hexane, heptane, pentane, or halogenated alkane
  • oil e.g., vegetable oil, castor oil, or hydrogenated oil
  • any other suitable solvent e.g., pyridine, benzene, or toluene.
  • a solvent refers to a liquid in which (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is soluble.
  • Crystalline forms of a substance can be obtained by a number of techniques, as is known in the art.
  • Exemplary techniques for obtaining, producing, or manufacturing crystalline forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate include melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as in nanopores or capillaries, recrystallization on surfaces or templates such as on polymers, recrystallization in the presence of additives, such as co-crystal counter- molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
  • specific crystalline forms of active pharmaceutical ingredients can be distinguished from each other by one or more physical or chemical properties such as rate of dissolution, infrared or Raman spectroscopy, x-ray diffraction techniques (e.g., single crystal and powder diffraction techniques), solid state-NMR (SS-NMR) (see: https://en.wikipedia.org/wiki/Solid- state_nuclear_magnetic_resonance), thermal techniques such as melting point, differential thermal analysis (DTA) (see: https://en.wikipedia.org/wiki/Differential_thermal_analysis), differential scanning calorimetry (DSC) (see: https://en.wikipedia.org/wiki/Differential_scanning_calorimetry), thermal gravimetric analysis (TGA) (see: https://en.wikipedia.org/wiki/Thermogravimetric_analysis) and other methods as disclosed elsewhere in the specification or available to the skilled artisan.
  • DTA differential thermal analysis
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric
  • a solid state form of (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate wherein the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate has one or more advantageous properties compared to other forms, such as chemical properties, crystalline, or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability (e.g., such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion), stability towards hydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvent(s) and advantageous processing and handling characteristics such as compressibility and bulk density.
  • advantageous properties compared to other forms, such as chemical properties, crystalline, or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in this disclosure is a crystalline form.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is useful for administration to a human.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is a specific crystalline form characterized by an analytical techniques known in the ordinary skilled artisan (e.g., substantially similar to that characterized in the Examples and Figures by XRD and DSC).
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate found here has two endothermic transition peaks, that can represent change of a kind of crystalline form to a different form of solid state or phase changes (e.g., solid to liquid).
  • FIG. 1 displays a first cycle heat enthalpy change plot for the solid state form of (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate measured by differential scanning calorimetry as disclosed herein.
  • one small endothermic peak showing at 35 to 45 °C in FIG.1 can be a glass transition peak, which can be a stable solid form to a meta-state solid from (e.g., amorphous form).
  • one small endothermic peak showing at 35 to 45 °C in FIG.1 can be a lattice-form transition peak, which can be a crystalline form to a different crystalline from.
  • the other large endothermic peak showing at 45 to 70 °C represents the melting point (e.g., the phase change from solid state to liquid state) of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate disclosed herein as determined by differential scanning calorimetry.
  • the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate is a crystalline form having a melting point in the range of 45 to 70 °C, 50 to 70 °C, or 50 to 65 °C as determined by differential scanning calorimetry.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is a crystalline form having a melting point in the specific range of 51 to 63 °C as determined by differential scanning calorimetry as shown in See FIG.1.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is a crystalline form having at least 1, 2, 3, 4, 5, 6 or more distinguished peaks as determined by XRD corresponding to those in FIG. 2.
  • the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate is a crystalline form which is not milled or is milled, micronized, or nanosized.
  • the particle size of the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate has a d 50 of greater than 1000 ⁇ m, from 355 to 1000 ⁇ m, from 180 to 355 ⁇ m, from 125 to 180 ⁇ m, from 90 to 125 ⁇ m, from 1 to 90 ⁇ m, or less than 1 ⁇ m.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate has particle size distribution of less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 ⁇ m to 250 ⁇ m, from 250 ⁇ m to 500 ⁇ m, from 500 ⁇ m to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the particle size of the solid state (17- ⁇ )- 3-Oxoandrost-4-en-17-yl dodecanoate has a D 10 , D 50 , or D 90 that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 ⁇ m, from 50 to 250 ⁇ m, from 250 to 500 ⁇ m, from 500 to 1000 ⁇ m, or greater than 1000 ⁇ m.
  • the release profile of the (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate does not change substantially as a function of storage time.
  • a number of different forms including crystalline forms of (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate may exist.
  • 17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate can be transformed to at least one of a single crystalline form, amorphous form, polymorphic crystalline form, meta-stable solid form, or liquid form of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate by making a pharmaceutical composition comprising at least one of pharmaceutically acceptable excipients, carriers, or ingredients.
  • a variety of different forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in a pharmaceutical composition can be provided by methods available to the ordinary skilled artisan in view of this disclosure: see FIG.3.
  • FT-Raman Fourier Transform-Raman Spectroscopy
  • FT-Raman Fourier Transform-Raman Spectroscopy
  • different solid state forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate may be characterized using a Bruker RFS100 instrument, with Nd:YAG 1064 nm excitation, 300 mW laser power, Ge detector, using 64 scans over the range of 25-3500 cm ⁇ 1 , and with 2 cm ⁇ 1 resolution.
  • the parameters and instrumentation for FT-Raman may be modified depending on the instrument, the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate, and goal(s) of the analysis.
  • XRD XRD
  • XRD can be performed with a Bruker D8 Advance X-ray diffractometer with CuK ⁇ -radiation.
  • the standard measuring conditions are e.g., tube power 40 kV/40 mA; step size 0.010° (2 ⁇ ); step time 57.6 sec; scanning range 3°-40° (2 ⁇ ); divergence slit 0.600 mm; antiscatter slit 4.800 mm; slit mode fixed; sample rotation speed 15.000 °/min; detector LYNXEYE_XE (1D mode); goniometer radius 280.0 nm; wavelength for display 1.54060 ⁇ .
  • FIG.2 shows well defined peaks corresponding to the crystalline from of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate with little or no characteristics of amorphous forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate (as indicated by the absence of an “amorphous halo” in the spectra in the 5-30 degree 2 ⁇ range and peaks not broadened).
  • the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate described herein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more of the peaks that correspond to those in FIG.2 that have an intensity of above 25, 50, 100, 150, or 200 counts.
  • the intensity can be a random relative value compared to one measured from the control.
  • TG-FTIR Thermogravimetric-Fourier transform Infrared Spectroscopy
  • Characterization/Analysis of a solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate can also be performed using Differential Scanning Calorimetry (“DSC”).
  • DSC can be performed with a Perkin Elmer Differential Scanning Calorimeter, using closed Pan Al crucibles, a heating rate of 10 °C min ⁇ 1 over a range from 0 °C to 100 °C (or e.g., over a range from 5 °C to 150 °C): For example, see FIG.1.
  • the parameters and instrumentation for DSC may be modified depending on the instrument, the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and goal(s) of the analysis.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate provided herein has a melting point in the range of about 45 to 70 °C, as determined by DSC.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate provided herein has a melting point in the range of about 50 to 65 °C, as determined by DSC.
  • Dynamic Vapor Sorption (DVS) (see: https://en.wikipedia.org/wiki/Dynamic_vapor_sorption) analysis is another technique for characterizing and analyzing (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • DVS can be performed with a Surface Measurement Systems DVS-1 water vapor sorption analyzer. The experiments can be run by placing the sample on a quartz holder on top of a microbalance, and allowing the sample to equilibrate at 50% relative humidity (RH) before starting the pre-defined humidity program.
  • RH relative humidity
  • the program can proceed e.g., in the following steps: 1 hour at 50% RH; 50% to 0% RH at a rate of 5% RH change per hour; 5 hours at 0% RH; 0% RH to 96% RH at 5% RH change per hour; 5 hours at 95% RH; 95% RH to 50% RH at a rate of 5% RH change per hour, and followed by one hour at 50% RH
  • the parameters and instrumentation for DVS may be modified depending on the instrument, the solid state (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate and goal(s) of the analysis.
  • High performance liquid chromatography (HPLC) (see: https://en.wikipedia.org/wiki/High-performance_liquid_chromatography) is also useful for analyzing or characterizing (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • the purity of crystalline forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate as measured by HPLC is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% based on total area under the curve as observed at a suitable wavelength e.g., about 240 nm or about 250 nm.
  • a suitable wavelength e.g., about 240 nm or about 250 nm.
  • the crystalline form of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate disclosed herein is about 98.0% to 100.0% pure as measured by HPLC as area under the curve as observed at a suitable wavelength, e.g., at a wavelength of from about 200 nm to about 300 nm, e.g., about 240 nm or 250 nm.
  • the purity of different forms of (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate in a pharmaceutical composition as measured by HPLC is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% based on total area under the curve as observed at a suitable wavelength e.g., about 200 nm to about 300 nm, or about 240 nm to about 250 nm.
  • a suitable wavelength e.g., about 200 nm to about 300 nm, or about 240 nm to about 250 nm.
  • different forms of (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate in a pharmaceutical composition is about 98.0% to 100.0% pure as measured by HPLC based on area under the curve as observed at a suitable wavelength, e.g., at a wavelength of from about 200 nm to about 300 nm, e.g., about 240 nm or 250 nm.
  • a suitable wavelength e.g., at a wavelength of from about 200 nm to about 300 nm, e.g., about 240 nm or 250 nm.
  • compositions having different particles sizes or distributions of particles sizes can be produced by any suitable method. Micronization techniques can be based on friction to reduce particle size; such methods include milling, bashing and grinding.
  • Another technique of producing different sized (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate particles involves supercritical fluids where the (17- ⁇ )-3-Oxoandrost-4-en-17- yl dodecanoate is dissolved in a solvent at high temperature and pressure and the mixture is sprayed out of a nozzle, causing the formation of particles of particular sizes or within particular size ranges/distributions.
  • RESS process Rapid Expansion of Supercritical Solutions
  • RESS process Rapid Expansion of Supercritical Solutions
  • Particle Size Distribution and Morphology Analysis Particle size distribution of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate particles can be analyzed by a number of techniques. For example, particle size distribution can be analyzed by photon correlation spectroscopy (PCS) (see: https://www.sciencedirect.com/topics/chemical-engineering/photon-correlation- spectroscopy): e.g., Malvern ZetaSizer 2000 HS (Malvern Instruments, Malvern, UK). The measuring mode applied can be e.g., Contin-Auto mode.
  • PCS photon correlation spectroscopy
  • PCS yields the mean diameter of the bulk population (z-average) and a polydispersity index (PI) ranging from 0 (monodisperse) through 0.10–0.20 (relatively monodisperse) to > 0.5 for a broad size distribution.
  • the measuring range of PCS is approximately 3 nm – 3 ⁇ m.
  • the parameters and instrumentation for PCS may be modified depending on the instrument, the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and goal(s) of the analysis.
  • Particles of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate can also be visually analyzed by Scanning Electron Microscopy (SEM) (see: https://en.wikipedia.org/wiki/Scanning_electron_microscope). Solid particles are deposited on metallic stubs then placed in liquid nitrogen and dried under vacuum. The metal stubs are coated uniformly with gold or palladium. All samples are examined for morphology and surface properties using a scanning electron microscope (e.g., Joel, SEM, JSM-25 SII, Tokyo, Japan).
  • SEM Scanning Electron Microscopy
  • Particle size, polydispersity index and zeta potential can be initially measured by a laser particle size analyzer (Submicron Particle Size Analyser 90 plus, Brookhaven Instrument Co., Holtsville, NY, USA).
  • An aliquot of solid state (17- ⁇ )- 3-Oxoandrost-4-en-17-yl dodecanoate particles can be diluted with e.g., 3 ml of deionized water.
  • the diluted (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate samples are loaded into a 4 ml cuvette and the particle size and zeta potential measurement can be conducted at ambient temperature.
  • particles of the solid state (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate characterized as shown in FIG. 1 and 2 were measured by a scanning electron microscope.
  • FIG. 4 shows the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate particles exist as one or more crystallites, grains, and particles with a shape of flat thin panel. As shown in FIG.4, those size ranges over one or more of about less than 1 ⁇ m, about 1 – 5 ⁇ m and about 5 – 50 ⁇ m.
  • the parameters and instrumentation for electron microscopy may be modified depending on the instrument, the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and goal(s) of the analysis.
  • crystallite sizes of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate disclosed here which agglomerate to particles of the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate as seen in FIG.4, can also be estimated by XRD e.g., by applying the Sherrer equation (see: https://en.wikipedia.org/wiki/Scherrer_equation) where the size of crystallites agglomerated to build particles of the solid state (e.g., crystal particles or crystallites) can be calculated, in a solid to the broadening of a peak in a diffraction pattern.
  • Sherrer equation see: https://en.wikipedia.org/wiki/Scherrer_equation
  • particles are made from agglomeration of grains, which are agglomerated from many crystallites of the solid state.
  • the mean crystallite size of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17- yl dodecanoate disclosed here was measured about 50 nm with standard deviation of about 7 nm.
  • Table 1 summarizes the crystallite sizes measured from each peak (8 distinguishable peaks) as shown in FIG.2 using the Scherrer equation. Table 1.
  • the release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of the solid state (17- ⁇ )-3-oxoandrost-4-en-17-yl dodecanoate found here does not change substantially as a function of storage time.
  • the release amount of the solid state crystalline (17- ⁇ )-3-oxoandrost-4-en-17-yl dodecanoate is less than 10%, 9%, 8%, 7%, 6%, or 5% up to at least 60 min, 120 min, 180 min, 240 min, 360 min, 24 hours, or 48 hours in a USP type 2 apparatus at 100 rpm in about 1000 mL 8% Triton X-100 solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0 °C ( ⁇ 0.5).
  • the release profile of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In one aspect, the release profile of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months.
  • the release test is performed using a USP type 2 apparatus at 100 rpm in about 1000 mL 8% Triton X-100 solution in water at a specific temperature e.g., 20.0, 37.0 or 40.0 °C ( ⁇ 0.5).
  • a release profile that does not substantially change over a period of time refers to a release profile that changes by less than plus/minus 50%, 40%, 30%, 20%, or 10% or less of the amount of (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate released at one or more specific time point under specific conditions.
  • compositions Comprising or Prepared from the Solid State (17- ⁇ )- 3-Oxoandrost-4-en-17-yl dodecanoate
  • the pharmaceutical compositions and dosage forms e.g. capsule or tablet
  • the pharmaceutical compositions and dosage forms comprising or prepared from the solid state (17- ⁇ )-3-Oxoandrost-4-en-17- yl dodecanoate
  • Non-limiting examples of components that can be included as components of the pharmaceutical carrier include lipophilic surfactants, hydrophilic surfactants, triglycerides, fatty acid (C8 to C22), fatty acid glycerides (mono-, di-, tri-, or a combination thereof), additives or a combination thereof.
  • the pharmaceutical composition or dosage form comprising or prepared from the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is as described herein.
  • the pharmaceutical composition or dosage form is prepared from solid state crystalline (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • the pharmaceutical composition or dosage form is prepared from specific crystalline forms of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • the pharmaceutical composition or dosage form is prepared from the crystalline form of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate as characterized by DSC and XRD as shown in FIG.1, 2, and 4.
  • the crystalline form of the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate can be transformed to amorphous, substantially amorphous, partially amorphous, or amorphous-like forms in the pharmaceutical composition or dosage formulation post processes for making the compositions or dosage formulations with pharmaceutically acceptable carriers.
  • Amorphous-like refers to one of physical states of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in a dosage form or pharmaceutical composition in which a substantial amount of the (17- ⁇ )-3-Oxoandrost-4- en-17-yl dodecanoate is not in a structured crystalline form (e.g., dissolved or dispersed in a solvent).
  • the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate in the pharmaceutical composition or dosage form can be semi-solid forms or substantially free of crystalline forms.
  • the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in the pharmaceutical composition or dosage form can be partially maintained with the same crystalline forms as intact.
  • the pharmaceutical composition or dosage form is prepared from crystalline forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and the pharmaceutical composition comprises amorphous or amorphous-like solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • the pharmaceutical composition or dosage form is prepared from crystalline forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and the pharmaceutical composition comprises substantially free of amorphous solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate.
  • the pharmaceutical composition or dosage form is prepared from crystalline forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and the pharmaceutical composition comprises solubilized (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate.
  • the pharmaceutical composition or unit dosage form comprising or prepared from the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate has improved release properties as compared to the release from the crystalline forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate without any carriers or excipients.
  • a pharmaceutical composition or unit dosage form comprising or prepared from the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate releases more (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate than do crystalline forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate release at a specified time point (e.g., 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 15 min, 20 min, 25 min, 30 min, 35 min, 45 min, 60 min, 75 min, 90 min, 105 min, 120 min, 180 min, and 240 min.) in a USP Type 2 apparatus in about 1000 mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or 40.0 °C ( ⁇ 0.5)) at 100 rpm.
  • Releasing more (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate from the pharmaceutical composition or unit dosage form refers to releasing more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or more than the crystalline forms of solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in the dissolution aqueous media (e.g., 8% Triton X100 solution in water).
  • aqueous media e.g., 8% Triton X100 solution in water
  • the pharmaceutical composition or unit dosage form having (or made from) the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate has a release profile (e.g., single time point or multiple time points) of (17- ⁇ )-3-Oxoandrost-4- en-17-yl dodecanoate that does not change substantially as a function of storage time as measured using a USP type 2 apparatus in about 1000 mL 8% Triton X100 solution in water at specific temperature (e.g., 20.0, 37.0 or 40.0 °C ( ⁇ 0.5)) at 100 rpm.
  • release profile e.g., single time point or multiple time points
  • the release profile does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In one aspect, the release profile does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. In one aspect, a release profile that does not substantially change over a period of time refers to a release profile that changes by less than plus/minus 50%, 40%, 30%, 20%, or 10% or less of the amount of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate released at one or more specific time point under specific conditions.
  • the unit dosage form or pharmaceutical composition as described herein comprising, or prepared from the solid state (17- ⁇ )-3-Oxoandrost-4-en- 17-yl dodecanoate and a pharmaceutically acceptable carrier, wherein the dosage form or pharmaceutical composition releases 20% or more (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate as measured with a USP Type 2 apparatus having 1000 mL 8% Triton X100 solution in water at thirty minutes at a specific temperature at 100 RPM than an equivalent release amount of crystalline solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate without any excipient or carrier that does not release more than 1% of the (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate amount as measured with a USP Type 2 apparatus having 1000 mL 8% Triton X100 solution in water at thirty minutes, is provided.
  • the pharmaceutically acceptable carrier of the composition can include a lipophilic additive.
  • lipophilic additives can include lipophilic surfactants, mono, di, or triglycerides, tocopherol, tocopherol succinate, tocopherol acetate, tocopherol derivatives, a sterol, a phytosterol and combinations thereof.
  • the lipophilic additive can include a fatty acid or fatty acid glyceride.
  • the lipophilic additive can include the fatty acid glyceride which can be a monoglyceride, a diglyceride, a triglyceride or mixtures thereof.
  • Non-limiting examples of fatty acid glycerides that can be used in the oral pharmaceutical compositions and dosage forms of the present invention include monoglycerides and/or diglycerides derived from sources such as maize oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil, and mixtures thereof.
  • the pharmaceutical composition or dosage form thereof comprises one or more maize oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil, or combination thereof.
  • the composition includes one or more triglycerides.
  • the lipophilic additive is a C8-C22 saturated fatty acid (or has 1, 2, or 3 unsaturations on ester chain), a mono-, di-, or triglyceride thereof (including mixtures), or a combination thereof.
  • the C8-C22 fatty acid is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, or linoelaidic acid.
  • the mono-, di-, or triglyceride is a glyceride of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, or linoelaidic acid or a combination thereof.
  • the lipophilic additive can include a lipophilic surfactant.
  • a lipophilic surfactant is considered when it has a Hydrophilic-Lipophilic Balance (HLB) value of 10 or less.
  • Various lipophilic surfactants can be used including, but not limited to mono-, di- glycerides of fatty acids like glyceryl monolinoleate (e.g. MAISINE 35-1), mono- and di glycerides of caprylic-capric acid (e.g. CAPMUL MCM), glyceryl monooleate, mixtures of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils such as PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g. LABRAFIL M 2125 CS), PEG-6 almond oil (e.g.
  • LABRAFIL M 1966 CS PEG-6 apricot kernel oil (e.g. LABRAFIL M 1944 CS), PEG-6 olive oil (e.g. LABRAFIL M 1980 CS), PEG-6 peanut oil (e.g. LABRAFIL M 1969 CS), PEG-6 hydrogenated palm kernel oil (e.g. LABRAFIL M 2130 BS), PEG-6 palm kernel oil (e.g. LABRAFIL M 2130 CS), PEG-6 triolein (e.g. LABRAFIL M 2735 CS), PEG-8 corn oil (e.g. LABRAFIL WL 2609 BS), PEG-20 corn glycerides (e.g. CROVOL M40), PEG-20 almond glycerides (e.g.
  • lipophilic polyoxyethylene-polyoxypropylene block co-polymers e.g. PLURONIC L92, L101, L121 etc.
  • propylene glycol fatty acid esters such as propylene glycol monolaurate (e.g. Lauroglycol FCC), propylene glycol ricinoleate (e.g. Propymuls), propylene glycol monooleate (e.g. Myverol P-O6), propylene glycol dicaprylate/dicaprate (e.g. CAPTEX 200), and propylene glycol dioctanoate (e.g. CAPTEX 800), propylene glycol mono- caprylate (e.g.
  • propylene glycol oleate e.g. LUTROL OP2000
  • propylene glycol myristate propylene glycol mono stearate; propylene glycol hydroxy stearate; propylene glycol ricinoleate ; propylene glycol isostearate; propylene glycol mono-oleate; propylene glycol dicaprylate/dicaprate; propylene glycol dioctanoate; propylene glycol caprylate-caprate; propylene glycol dilaurate; propylene glycol distearate; propylene glycol dicaprylate; propylene glycol dicaprate; mixtures of propylene glycol esters and glycerol esters such as mixtures composed of the oleic acid esters of propylene glycol and glycerol (e.g.
  • ARLACEL 186 sterol and sterol derivatives such as cholesterol, sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soya sterol, PEG-10 soya sterol, PEG-20 soya sterol, and the like; glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl monostearate, or a combination thereof; sorbitan fatty acid esters such as sorbitan monolaurate (e.g. ARLACEL 20), sorbitan monopalmitate (e.g. Span-40), sorbitan monooleate (e.g.
  • Span-80 sorbitan monostearate, and sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate, and the like; fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidyl choline, bile salts, and the like, and mixtures thereof.
  • fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidyl choline, bile salts, and the like, and mixtures thereof.
  • the lipophilic surfactant can be selected from the group consisting of glyceryl monolinoleate (e.g. MAISINE 35-1), mono- and di glycerides of caprylic, capric acid (e.g.
  • glyceryl monooleate propylene glycol mono caprylate, propylene glycol oleate, propylene glycol monostearate, propylene glycol monolaurate, propylene glycol mono-oleate, propylene glycol dicaprylate/dicaprate, sorbitan monooleate, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG- 9 hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, sorbitan monolaurate (e.g.
  • the oral pharmaceutical compositions or dosage forms e.g., the oral pharmaceutical compositions or dosage forms (e.g., the oral pharmaceutical compositions or dosage forms).
  • hydrophilic additive is selected from the group consisting of hydrophilic surfactants, e.g., celluloses - such as hydroxypropyl celluloses with low molecular weight, low viscosity types (e.g. METHOCEL E5, E6, E10 E15, LV100 etc. grades) and hydroxypropyl celluloses having higher molecular weight, medium to high viscosity (e.g. METHOCEL K4M, K15M, K100M etc.); polyvinylpyrrolidones (e.g. KOLLIDON k17, K30 etc.); polyvinyl acetates and combinations thereof.
  • hydrophilic surfactants e.g., celluloses - such as hydroxypropyl celluloses with low molecular weight, low viscosity types (e.g. METHOCEL E5, E6, E10 E15, LV100 etc. grades) and hydroxypropyl celluloses having higher molecular weight, medium to high viscos
  • the hydrophilic additive can be a hydrophilic surfactant.
  • a hydrophilic surfactant is considered when it has an HLB value of greater than 10.
  • Non-limiting examples of hydrophilic surfactants include non-ionic surfactants, ionic surfactants and zwitterionic surfactants.
  • hydrophilic surfactants suitable for the current invention include, but not limited to, alcohol-oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulphate salts, dioctyl sulfosuccinate salts; polyethylene glycol fatty acids esters; polyethylene glycol fatty acids mono- and di- ester mixtures; polysorbates, polyethylene glycol derivatives of tocopherol and the like.
  • the hydrophilic additive can be a hydrophilic surfactant.
  • Non-limiting examples of hydrophilic surfactants can include PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polyethylene glycol fatty acids mono- and di- ester mixtures, polysorbate 80, polysorbate 20, polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterol fatty acid esters, and mixtures thereof.
  • surfactants utilized in the pharmaceutical compositions described herein include sterols and derivatives of sterols.
  • these surfactants are hydrophilic or lipophilic.
  • hydrophilic sterol surfactants are lanosterol PEG-24 cholesterol ether (e.g. SOLULAN C-24, Amerchol), PEG-30 soya sterol (e.g. Nikkol BPS-30, from Nikko), PEG-25 phyto sterol (e.g. Nikkol BPSH-25 from Nikko), PEG-30 cholestanol (e.g. Nikkol DHC, from Nikko).
  • lipophilic sterol surfactants are cholesterol, sitosterol, phytosterol (e.g. GENEROL series from Henkel), PEG-5 soya sterol (e.g.
  • the pharmaceutical composition or unit dosage form includes an additive as described in the following paragraphs.
  • Suitable additives utilized in various embodiments described herein include, by way of non-limiting example, adsorbing agents, anti-adherents, anticoagulants, antifoaming agents, antioxidants, anti-caking agents, anti-static agents, binders, bile acids, bufferants, bulking agents, chelating agents, coagulants, colorants, co-solvent, opaquants, congealing agents, coolants, cryoprotectants, diluents, dehumidifying agents, desiccants, desensitizers, disintegrants, dispersing agents, enzyme inhibitors, glidants, fillers, hydrating agent, super disintegrants, gums, mucilages, hydrogen bonding agents, enzymes, flavorants, humectants, humidifying agents, lubricant oils, ion-exchange resins, lubricants, plasticizers, pH modifying agents, preservatives, solidifying agent, solvents, solubilizers,
  • the unit dosage form is a hard gel or soft gel capsule or a tablet.
  • Methods of Use for Treatment of Disease [00109]
  • the pharmaceutical compositions or unit dosage forms comprising or prepared from the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate have a number of methods for use.
  • Subjects that can be treated by administration of pharmaceutical compositions and unit dosage forms of the present disclosure can be any mammal (e.g., a human male or female) in need thereof.
  • the human male may be at least 14 years of age.
  • the human male is an adult of at least age 16, 18, or 20. In another embodiment, the human male is an adult of at least age 21, 23, or 25. In another embodiment, the human male is an adult of at least age 30. In a further embodiment, the subject can be an adult male of at least age 50. In yet a further embodiment, the subject can be an adult male of at least age 60.
  • Subjects that can be treated by pharmaceutical compositions and unit dosage forms of the present disclosure e.g., comprising or prepared from the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate characterized as shown in FIG 1, 2, and 4) can be any human female in need thereof. In particular, in one embodiment, the human female may be at least 14 years of age.
  • the human female is an adult of at least age 30.
  • the subject can be an adult female of at least age 50.
  • the subject can be an adult female who has deficient endogenous serum testosterone levels.
  • the subject can be an adult female who has undergone unilateral or bilateral oophorectomy.
  • the subject can be an adult female who has undergone unilateral or bilateral oophorectomy.
  • the subject can be a post-menopausal woman.
  • the subjects having diseases related to lack of therapeutically effective testosterone levels can be treated with the pharmaceutical compositions or formulations prepared from or comprising the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in this disclosure.
  • hypogonadism e.g., testosterone deficiency or absence of testosterone
  • liver disease or lung disease related to steatosis inflammatory or fibrotic cytokines, chemokines, enzymes, or biomarkers
  • the present invention also provides for a method of treating a human subject in need of testosterone therapy is provided.
  • the method can include the steps of administering any of the pharmaceutical compositions or dosage forms (e.g., capsule or tablet) disclosed herein.
  • the pharmaceutical compositions and the dosage forms of the present invention can be used to treat any condition associated with testosterone deficiency, including complete absence, of endogenous testosterone in male or female subjects.
  • Examples of conditions associated with testosterone deficiency that can be treated using the dosage forms (e.g., capsule or tablet) and/or compositions of the present invention include, but are not limited to, congenital or acquired primary hypogonadism, hypogonadotropic hypogonadism, cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter's syndrome, post castration, eunuchoidism, hypopituitarism, endocrine impotence, infertility due to spermatogenic disorders, impotence, male sexual dysfunction (MSD) including conditions such as premature ejaculation, erectile dysfunction, decreased libido, and the like, micropenis and constitutional delay, penile enlargement, appetite stimulation, testosterone deficiency associated with chemotherapy, testosterone deficiency associated with toxic damage from alcohol, testosterone deficiency associated with toxic damage from heavy metal, osteoporosis associated with androgen deficiency, and combinations thereof.
  • compositions and dosage forms disclosed herein include idiopathic gonadotropin, LHRH (luteinizing hormone- releasing hormone) deficiency, or pituitary hypothalamic injury from tumors, trauma, or radiation. Typically, these subjects have low serum testosterone levels but have gonadotropins in the normal or low range.
  • the compositions or oral dosage forms may be used to stimulate puberty in carefully selected males with clearly delayed puberty not secondary to a pathological disorder.
  • compositions and oral dosage forms may be used in female-to-male transsexuals in order to maintain or restore male physical and sexual characteristics including body muscle mass, muscle tone, bone density, body mass index (BMI), enhanced energy, motivation and endurance, restoring psychosexual activity etc.
  • pharmaceutical compositions and unit dosage forms of the present disclosure e.g., prepared from or comprising the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate disclosed here
  • compositions and unit dosage forms of the present disclosure can be used to provide treatment of one or more symptoms associated with female sexual dysfunction, anorgasmia, osteoarthritis, hormonal male contraception.
  • pharmaceutical compositions and unit dosage forms of the present disclosure e.g., prepared from or comprising the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate in this finding
  • compositions and unit dosage forms of the present disclosure can be used to treat or improve the symptoms of subjects suffering from conditions such as carcinoma, sarcoma, melanoma, lymphoma, leukemia, an end-stage condition related to liver disease, an end-stage condition related to lung disease, an end-stage condition related to kidney disease, an end-stage condition related to musculoskeletal system disease, an end-stage condition related to cardiovascular disease, an end-stage condition related to blood disease, an end-stage condition related to endocrine gland disease, an end-stage condition related to gastrointestinal disease, an end-stage condition related to skin disease, an end- stage condition related to genital organ disease, an end-stage condition related to central nervous system disease, hepatic fibrosis, hepatic inflammation, hepatic steatosis, non- alcoholic stea
  • conditions such as carcinoma, sarcoma, melanoma, lymphoma, leukemia, an end-stage condition related to liver disease, an end-stage condition related to lung disease
  • EXAMPLE 1 Preparation of Solid State (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate
  • the (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate can be produced utilizing the generalized scheme set forth below: [00115] 1) (17- ⁇ )-Hydroxy-4-Androsten-3-one (0.1 mol) is weighed and placed into a 1000 mL 4N RB flask containing a stir bar. [00116] 2) Pyridine (160 mL) is added to the flask. [00117] 3) The flask is placed in an ice-water bath and fitted with a nitrogen inlet, addition funnel, thermocouple, and stopper. Stirring and nitrogen flow are started. [00118] 4) The funnel is charged with a solution of acid chloride (1.56 equiv.
  • the melting point of the specific crystalline forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is identified at 51 – 63 °C based on the DSC results.
  • EXAMPLE 4 XRD Crystallography of Solid State (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate [00125] The solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is crystalline or substantially crystalline as indicated by XRD as shown in an example of an XRD spectra in FIG.
  • FIG.2 displays well defined peaks corresponding to the crystalline forms of the solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate with little or no amorphous forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate (as indicated by the absence of an “amorphous halo” in the spectra in the 5-30 ° of 2 ⁇ range and no broadening of the peaks).
  • EXAMPLE 5 Pharmaceutical compositions or dosage forms having a variety of different forms of (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate prepared by typical formulation methods [00126] Pharmaceutical compositions or dosage forms described herein are formulated or prepared from a specific crystalline forms of the solid state (17- ⁇ )-3- Oxoandrost-4-en-17-yl dodecanoate characterized by DSC and XRD, as shown in FIG. 1 and 2.
  • compositions or dosage forms disclosed herein are prepared from the specific solid state (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate and at least one of pharmaceutical acceptable carriers by any suitable process including one or more steps of, by way of non-limiting example, agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, encapsulation, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, grinding, milling, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or the like, as shown in FIG.

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Abstract

Des compositions de (17-β)-3-oxoandrost-4-en-17-yl dodécanoate à l'état solide biodisponibles et des procédés d'utilisation à des fins d'administration à des mammifères en ayant besoin sont divulgués. Le (17-β)-3-oxoandrost-4-en-17-yl dodécanoate se présente préférentiellement sous la forme d'un cristal à l'état solide comprenant une pluralité de pics correspondant aux pics illustrés dans la FIG. 2, une pluralité de cristallites dont la taille est comprise entre environ 40 nm et environ 60 nm identifiées par des spectres de diffraction des rayons X sur poudre, et un point de fusion compris dans la plage d'environ 51 °C à environ 63 °C. Les compositions peuvent être administrées par voie orale ou injectable aux fins du traitement d'affections nécessitant une thérapie de testostérone. Une structure chimique donnée à titre d'exemple d'une composition de (17-β)-3-oxoandrost-4-en-17-yl dodécanoate divulguée dans la présente invention est la suivante : [FORMULE].
PCT/US2022/034463 2022-06-22 2022-06-22 COMPOSITIONS DE (17-β)-3-OXOANDROST-4-EN-17-YL DODÉCANOATE ET PROCÉDÉS DE PRÉPARATION ET D'UTILISATION WO2024005770A1 (fr)

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