Dodecanoic acid (17-beta)-3-oxoandrostane-4-ene-17-ester compositions and methods of making and using

Abstract

The present application discloses a bioavailable solid state dodecanoic acid (17-beta)-3-oxoandrostane-4-ene-17-ester composition and a method for administration to a mammal in need thereof. The solid state dodecanoic acid (17-beta)-3-oxoandrostane-4-ene-17-ester composition is provided. The dodecanoic acid (17-beta)-3-oxoandrostane-4-ene-17-ester is preferably provided in a solid crystal form having a plurality of peaks corresponding to the peak shown in Figure 2, a plurality of microcrystals having a size in the range of about 40 nm to about 60 nm as identified by powder X-ray diffraction spectroscopy, and a melting point in the range of about 51 DEG C to about 63 DEG C. The dodecanoic acid (17-beta)-3-oxoandrostane-4-ene-17-ester has a plurality of peaks corresponding to the peak shown in Figure 2. The compositions may be provided in oral or injectable administration for use in the treatment of conditions in need of testosterone treatment. The exemplary chemical structure of the dodecanoic acid (17-beta)-3-oxoandrostane-4-ene-17-ester composition disclosed by the invention is shown as the following (I). # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This PCT patent application claims the benefit of co-pending U.S. patent application No. 16 / 953,607, filed on November 20, 2020 (expected to issue as U.S. Patent No. 11,370,811 on June 28, 2022), under PCT Section 4.10, which is expressly incorporated herein by reference in its entirety. Technical Field

[0003] Disclosed herein is a solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester (see: https: / / pubchem.ncbi.nlm.nih.gov / compound / Dodecanoate ), a novel ester of dodecanoic acid fatty acid, and a pharmaceutical composition thereof suitable for pharmaceutical use and methods of administering to a mammal (e.g., a human) in need of (17-β)-hydroxy-4-androsten-3-one. Background Art

[0004] Various bioavailable solid esters suitable for pharmaceutical use and administration to a mammal in need thereof are disclosed in the following U.S. patents and applications, which are expressly incorporated herein by reference in their entirety: 8,865,695 filed on February 26, 2014 and published on October 21, 2014, 9,034,858 filed on May 31, 2012 and published on May 19, 2015, 9,498,485 filed on August 28, 2015 and published on November 22, 2016, 9,757 filed on September 26, 2016 and published on September 12, 2017, 389, 2016 / 0184320 filed on August 28, 2015 and published on June 30, 2016, 2017 / 0035781 filed on June 22, 2016 and published on February 9, 2017, 2018 / 0125858 filed on August 8, 2017 and published on May 10, 2018, 2019,0275060 filed on August 6, 2018 and published on September 12, 2019, 2020 / 0046731 filed on February 12, 2019 and published on February 13, 2020 (patents).

[0005] Different solid-state forms of esters of active pharmaceutical ingredients (APIs) or esterified active pharmaceutical ingredients (EAPIs) can have different properties that can provide specific benefits to formulations containing the EAPIs, such as by promoting better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorphs and chemical stability) and shelf life. The changes in properties of different solid-state forms can also translate into benefits for the final dosage form, such as by providing or promoting improved bioavailability. Different solid-state forms of EAPIs can also produce various polymorphs or crystalline forms, which can in turn provide additional opportunities to evaluate changes in the properties and characteristics of solid EAPIs.

[0006] An important characteristic of an EAPI is that its dissolution or release rate does not substantially change over time. Changes in the dissolution or release rate of an EAPI over time can result in a product that is otherwise identical except for the solid form (e.g., having the same EAPI, formulation components and amounts thereof), but can result in different pharmacokinetic properties, which can alter or affect the efficacy or safety of the drug product.

[0007] The stability of the EAPI in pharmaceutical formulations (e.g., compositions and unit dosage forms) is also important. For example, if the EAPI changes physical form (e.g., its crystal form or amount) in a pharmaceutical composition or unit dosage form, this can also affect the pharmacokinetic properties and, therefore, the relevant safety and efficacy parameters.

[0008] Solid state must be stable to work. Multiple examples of bulk drug substances and pharmaceutical compositions / dosage forms with altered physical forms are known in the literature and have caused substantial problems for patients receiving these drugs. A well-known example is ritonavir, whose crystalline form has changed, causing the product to fail the dissolution test and be withdrawn from the market for a period of time (see Morissette et al., Proc Natl Acad Sci U SA. March 4, 2003: 100 (5): 2180-4). Other high-profile cases include the recall of multiple batches of Neupro (rotigotine) in 2008 due to the emergence of a new polymorph; the recall of 1.5 million warfarin tablets in 2010 due to 2-propanol level issues (which could potentially affect API crystallinity); and the recall of 60 million atorvastatin (Avalide) tablets in 2010 due to variability in the amount of a poorly soluble polymorph of irbesartan. See Lee et al., Annu. Rev. Chem. Biomol. Eng. 2011, 2, 259-280.

[0009] The absorption of any prodrug such as an ester derivative of an API (EAPI) needs to be managed to provide sufficient and sustained levels of API derived from the EAPI in vivo without increasing any safety issues associated with the ester or its metabolites. The solubility, release, dissolution and distribution of the EAPI in a specific solvent are functions of lipophilicity, which is related to solid state properties such as the physical form of the drug substance, such as crystalline form, solvation, presence of amorphous material, etc. Therefore, the solid state physical form is one of the key properties regarding the ease of manufacturing, storage and performance of the EAPI for achieving safe and effective API levels.

[0010] Esters of (17-β)-hydroxy-4-androsten-3-one, which are not themselves believed to be biologically active, are known to be converted in vivo to the bioactive molecule ((17-β)-hydroxy-4-androsten-3-one) and other related metabolites, such as (17-β)-hydroxy-5α-androstane-3-one, and are therefore useful in treating patients in need of (17-β)-hydroxy-4-androsten-3-one therapy. However, inadequate solubility, release, dissolution, partitioning and / or physical stability of solid EAPIs may result in poor bioavailability of (17-β)-hydroxy-4-androsten-3-one, which is a useful hormone for treating disease states associated with a need for (17-β)-hydroxy-4-androsten-3-one, such as, for example, male or female hypogonadism, lung disease or liver disease.

[0011] Several prodrug esters of (17-β)-hydroxy-4-androsten-3-one have been reported in the literature (Gooren LJ, Front Horm Res. 2009; 37: 32-5). However, in addition to overcoming the solubility challenges of esters of (17-β)-hydroxy-4-androsten-3-one, adequate absorption and parent drug conversion remain important design factors for the preparation and identification of solid esters of (17-β)-hydroxy-4-androsten-3-one. Methods to date have failed to disclose or fully characterize a specific solid-state dodecanoic acid (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, which is used to simplify the development of pharmaceutical compositions.

[0012] It is known that steroids, including steroid esters such as testosterone and testosterone esters, exhibit different solid forms with different properties, including solubility, bioavailability and absorption (see 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, Vol. 20, No. 8, pp. 630-638, August 1968; Borka & Haleblian (1990) Acta Pharm. Jugosl. 40:71-94).

[0013] Testosterone esterified with dodecanoic acid (lauric acid) is more suitable and preferred for treatment because lauric acid is a saturated medium chain fatty acid (MCFA) with 12 carbon atoms, which is associated with certain health benefits. There is a need for a stable and bioavailable solid form of dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester - a candidate new drug product for male or female hypogonadism, lung disease, sarcopenia (see: https: / / society-scwd.org / sarcopenia / ), cachexia (see: https: / / society-scwd.org / cachexia / ), muscle wasting (see: https: / / society-scwd.org / muscle-wasting / ) or liver disease, suitable for treating subjects in need of (17-β)-hydroxy-4-androstene-3-one. Summary of the invention

[0014] It was found that solid forms of dodecanoic acid ester derivatives of (17-β)-hydroxy-4-androsten-3-one are not all similar and suitable for treating mammals in need of (17-β)-hydroxy-4-androsten-3-one. It was found that specific solid dodecanoic acid ester derivatives of (17-β)-hydroxy-4-androsten-3-one, wherein at least 0.001% (e.g., at least 0.01, 0.1, 1.0 or 10%) of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester dissolved in 1000 mL of 8% Triton X100-containing aqueous solution in a USP Type 2 apparatus at 37° C., 100 rpm within 30 minutes, are more suitable for administration to humans (e.g., to treat or prevent a disease, condition or disorder).

[0015] In addition, it was found that the selected solid forms of the compositions described herein have sufficient bioavailability. In one embodiment, a composition for administration to a human subject in need of ((17-β)-hydroxy-4-androsten-3-one therapy is provided: for example, the composition comprises or is made of: a) solid-state (17-β)-3-oxoandrost-4-ene-17-ester of dodecanoic acid and b) a pharmaceutically acceptable carrier, wherein after oral administration of solid-state (17-β)-3-oxoandrost-4-ene-17-ester of dodecanoic acid to a human subject, at least about 0.1%, 0.5%, 1%, 2%, 3%, 5%, 8% or 10% of the (17-β)-hydroxy-4-androstene-3-one (testosterone) equivalent dose is bioavailable to the human subject.

[0016] Thus, in one embodiment, a solid EAPI, i.e., (17-β)-3-oxoandrost-4-ene-17-ester, is provided. The solid (17-β)-3-oxoandrost-4-ene-17-ester is crystalline. In a specific aspect, the crystalline solid (17-β)-3-oxoandrost-4-ene-17-ester is a crystalline form that is substantially free of other non-crystalline forms. In another specific aspect, the crystalline solid (17-β)-3-oxoandrost-4-ene-17-ester described herein is substantially free of amorphous forms.

[0017] Solid dodecanoic acid (17-β)-3-oxo androst-4-ene-17-ester provided herein has a particle size (particle size, particle size) distribution feature. In a specific aspect, the particle size of solid dodecanoic acid (17-β)-3-oxo androst-4-ene-17-ester is less than 200nm ("nanometer"), 200 to 500nm, 500 to 1000nm, 1 to 50μm ("micrometer"), 50 to 250μm, 250 to 500μm, 500 to 1000μm, or greater than 1000μm. In another ...μm, or greater than 1000μm. 50 is greater than 1000 μm, 355 to 1000 μm, 180 to 355 μm, 125 to 180 μm, 90 to 125 μm, 1 to 90 μm, or less than 1 μm. In another related aspect, the D of the solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate 10 , D 50 or D 90The solid-state (17-β)-3-oxoandrost-4-ene-17-olate having a particle size distribution characteristic or a size characteristic is crystalline. In another specific aspect, the solid-state (17-β)-3-oxoandrost-4-ene-17-olate having a particle size distribution characteristic or a size characteristic is a crystalline form that is substantially free of other non-crystalline forms.

[0018] The pharmaceutical composition provided herein comprises the solid-state dodecanoic acid (17-β)-3-oxo-androst-4-ene-17-ester described in the above paragraph or is prepared therefrom. For example, the pharmaceutical composition is prepared by solid-state dodecanoic acid (17-β)-3-oxo-androst-4-ene-17-ester and one or more pharmaceutically acceptable excipients, carriers or additives, or comprises solid-state dodecanoic acid (17-β)-3-oxo-androst-4-ene-17-ester and one or more pharmaceutically acceptable excipients, carriers or additives. The pharmaceutical composition described herein may comprise crystalline solid-state dodecanoic acid (17-β)-3-oxo-androst-4-ene-17-ester or be prepared therefrom. In some aspects, the pharmaceutical composition comprises solid-state dodecanoic acid (17-β)-3-oxo-androst-4-ene-17-ester (which is not ground or ground, micronized or nanosized) or is prepared therefrom. In a specific aspect, the pharmaceutical composition comprises or is prepared from solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate: wherein the particle size is less than 200 nm, 200 to 500 nm, 500 to 1000 nm, 1 to 50 μm, 50 μm to 250 μm, 250 μm to 500 μm, 500 μm to 1000 μm, or greater than 1000 μm. In another aspect, the pharmaceutical composition comprises d 50 In another related aspect, the pharmaceutical composition comprises D 10 , D 50 or D 90Solid-state (17-β)-3-oxoandrost-4-ene-17-ester of less than 200 nm, 200 to 500 nm, 500 to 1000 nm, 1 to 50 μm, 50 to 250 μm, 250 to 500 μm, 500 to 1000 μm, or greater than 1000 μm, or prepared therefrom. In some specific aspects, the pharmaceutical composition of solid-state (17-β)-3-oxoandrost-4-ene-17-ester of dodecanoic acid is formulated for topical, enteral or parenteral administration. In some aspects, the pharmaceutical composition of solid-state (17-β)-3-oxoandrost-4-ene-17-ester of dodecanoic acid is formulated for buccal, sublingual or sublabial administration. In some specific aspects, the pharmaceutical composition of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester is formulated for nasal, rectal or vaginal administration. In some specific aspects, the pharmaceutical composition of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester is formulated for intravenous, subcutaneous, intramuscular, intradermal, intraspinal, intrathecal or intraarterial administration. In some specific aspects, the pharmaceutical composition of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester is formulated as a liquid, solution, suspension, dispersion (see: https: / / en.wikipedia.org / wiki / Dispersion_(chemistry)), solid, semisolid, gel, lotion, paste, foam, spray, suspension, dispersion, syrup or ointment. In some specific aspects, the pharmaceutical composition of solid-state (17-β)-3-oxoandrost-4-ene-17-ester is formulated as a tincture, a patch, an injectable or an oral dosage form. In some aspects, the pharmaceutical composition of solid-state (17-β)-3-oxoandrost-4-ene-17-ester comprises solubilized or partially solubilized (17-β)-3-oxoandrost-4-ene-17-ester. In one aspect, the pharmaceutical composition or unit dosage form is suitable for oral administration (e.g., capsules or tablets).

[0019] Provided herein is a pharmaceutical composition or unit dosage form comprising or prepared from the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate described in the above paragraphs.

[0020] Additionally, described herein are methods of using solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate in pharmaceutical compositions whereby a male or female in need of (17-β)-hydroxy-4-androstene-3-one (testosterone) can be treated. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1A plot showing the first thermal cycle enthalpy change of (17-β)-3-oxoandrost-4-ene-17-dodecanoate in solid form as measured by differential scanning calorimetry is shown;

[0022] Figure 2 shows an XRD measurement of solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate disclosed herein, wherein the crystalline structure has 8 distinctive peaks;

[0023] Figure 3 The overall formulation process as disclosed herein is shown for preparing various different forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate in pharmaceutical compositions or dosage forms to improve physical, chemical, pharmacokinetic and pharmacodynamic properties to enhance bioavailability, and;

[0024] Figure 4 Two microscope images are shown, in which 20 μm and 5 μm scale solid-state (17-β)-3-oxoandrost-4-ene-17-ester particles are used in the pharmaceutical composition or dosage form described herein, wherein the solid-state (17-β)-3-oxoandrost-4-ene-17-ester particles have a specific shape, such as a flat thin plate shape. DETAILED DESCRIPTION

[0025] Before describing the embodiments of the invention, it should be understood that the present disclosure is not limited to the specific structures, process steps or materials disclosed herein, but extends to equivalent forms thereof that will be recognized by ordinary technicians in the relevant field. It should also be understood that the terms used herein are used only for the purpose of describing specific examples or embodiments, and are not intended to be limiting.

[0026] In addition, the features, structures or characteristics may be combined in one or more embodiments in any suitable manner. In the following description, many specific details are provided, such as examples of compositions, dosage forms, treatments, etc., to provide a thorough understanding of various invention embodiments. However, those skilled in the relevant art will recognize that such detailed descriptions of embodiments do not limit the overall inventive concept set forth herein, but are merely representative thereof.

[0027] It should be noted that the singular forms "a / an" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "an excipient" includes reference to one or more such excipients, and reference to "the carrier" includes vehicles for one or more such carriers.

[0028] As used herein, the terms "treat", "treatment" or "treating" and the like refer to administering a therapeutic agent to an asymptomatic or symptomatic pathogen-infected subject. In other words, "treat", "treatment" or "treating" may refer to reducing, alleviating or eliminating symptoms associated with a condition present in an infected subject.

[0029] As used herein, "androgen receptor agonist" refers to a compound, molecule or agent that binds and activates androgen receptors, such as testosterone. Examples of androgen receptor agonists include, but are not limited to, dihydrotestosterone, mibolerone, testosterone, alkylated testosterone, testosterone ester derivatives, methyltrienolone, oxandrolone, nandrolone and fluoxymesterone. Where appropriate, the fatty acid esters of these androgen receptor agonists can be used accordingly herein.

[0030] As used herein, "testosterone ester" refers to testosterone esterified with fatty acids. Exemplary testosterone esters include, but are not limited to, testosterone undecanoate, testosterone decanoate, testosterone dodecanoate, testosterone tridecanoate, testosterone decanoate, testosterone enanthate, testosterone palmitate, testosterone cypionate, and testosterone propionate.

[0031] As used herein, "testosterone agent" refers to an active pharmaceutical agent that produces testosterone physiological effects or effects in vivo. Examples of testosterone agents exist throughout this application. An example of a testosterone agent is testosterone (T). Another example is a testosterone ester, such as testosterone undecanoate or testosterone tridecanoate.

[0032] As used herein, the terms "therapeutic agent," "active agent," and the like are used interchangeably and refer to agents that can produce a beneficial or positive effect on a subject when administered to a subject in an appropriate or effective amount. In one aspect, the therapeutic agent or active agent can be an androgenic steroid. The terms "additional active agent," "supplemental active agent," "secondary active agent," and the like are used interchangeably and refer to compounds, molecules or materials other than androgenic steroids that are physiologically active when administered to a subject in an effective amount.

[0033] As used herein, the terms "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" can be used to refer to a mixture of one or more active agents and a carrier or other excipient. In addition, the term "dosage form" can include one or more formulations or compositions provided in a form for administration to a subject. For example, an "oral dosage form" can be suitable for administration to the mouth of a subject. A "topical dosage form" can be suitable for administration to the skin of a subject by smearing, etc.

[0034] As used herein, "subject" refers to an animal. In one aspect, the animal can be a mammal. In another aspect, the mammal can be a human.

[0035] As used herein, "needing treatment" refers to a subject who has a disease or is suspected of having a disease or who desires treatment or is suitable for treatment according to various diagnostic criteria generally used in practice. Therefore, "needing treatment" can include the step of determining the subject in need of treatment.

[0036] As used herein, "identifying a subject in need of treatment" can include the following steps: obtaining a biological sample from the subject and determining the level of one or more biomarkers described herein (RT-PCR detection of viral genes), evaluating a biological sample obtained from the subject, performing imaging analysis on the subject, evaluating one or more clinical features of the subject (e.g., evaluating symptoms or overt symptoms), or a combination thereof.

[0037] As used herein, an "acute" condition refers to a condition that may develop rapidly and have significant symptoms requiring urgent or semi-urgent care. In contrast, a "chronic" condition refers to a condition that is generally slower developing and persists or otherwise progresses over time. Some examples of acute conditions may include, but are not limited to, asthma attacks, bronchitis, heart attacks, pneumonia, etc. Some examples of chronic conditions may include, but are not limited to, arthritis, diabetes, high blood pressure, high cholesterol, etc.

[0038] The terms "serum testosterone" or "serum (17-β)-hydroxy-4-androsten-3-one level", "serum T level", "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 bioavailable testosterone, including free and bound testosterone fractions or concentrations. For any bioanalytical measurement, to improve consistency, the method used to measure the initial serum testosterone level can be consistent with the method of monitoring and re-measuring serum testosterone levels during clinical testing and testosterone treatment of the subject. Unless otherwise specified, "testosterone concentration" refers to the total serum testosterone concentration.

[0039] Mean serum testosterone concentration can be determined using methods known in the art and practice. For example, the average baseline plasma testosterone concentration of human males is the arithmetic mean of the total plasma testosterone concentration determined at least two continuous time points (e.g., intervals of about 1 hour to about 168 hours) reasonably spaced from each other. In a specific case, plasma testosterone concentration can be determined at least at continuous time points at intervals of about 12 hours to about 48 hours. In another specific method, the plasma testosterone concentration of human males can be determined at a time between about 5 and about 11 in the morning. Further, plasma testosterone concentration can be determined by standard analytical procedures and methods available in the art, such as, for example, automatic or manual immunoassay, liquid chromatography or liquid chromatography-tandem mass spectrometry (LC-MSMS) etc.

[0040] As used herein with respect to the physiological level of a given substance, the term "baseline" refers to the level or concentration of the substance in an object before an active agent is administered. For example, the baseline level of serum testosterone in an object would be the testosterone serum level of an object before (e.g., immediately before) testosterone administration or treatment is started.

[0041] As used herein, "free testosterone serum concentration" refers to the portion 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). In some aspects of the methods described herein, free testosterone serum concentration is used instead of total serum testosterone concentration. For example, a subject may present a total serum testosterone level within the normal range, but may still be considered a testosterone deficiency based on the free testosterone level. It should be understood that, as used herein, the term testosterone serum level or concentration can provide clear support (basis) for free testosterone serum concentration, unless the context or record clearly states otherwise.

[0042] The term "oral administration" represents any method of administration in which the active agent can be administered by swallowing, chewing or sucking a dosage form. Oral administration may be intended for enteral delivery of the active agent or transmucosal delivery of the active agent. In some embodiments, the compositions of the present invention may be mixed with food or beverage prior to oral administration.

[0043] As used herein, "dosage regimen" or "regimen", such as "initial dosing regimen" or "starting dosing" or "maintenance dosing regimen" refers to how, when, how much and how often the dose of the composition of the present invention can be administered to a subject. For example, an initial or starting dosing regimen for a subject can provide a total daily dose of about 15 mg to about 1500 mg, administered in two split doses, at least 12 hours apart (e.g., once at breakfast and once at dinner), with meals, repeated daily, for 30 days.

[0044] As used herein, "daily dose" refers to the amount of an active agent (e.g., testosterone ester) administered to a subject over a 24-hour period. The daily dose can be administered in one or more administrations during a 24-hour period. In one embodiment, the daily dose is administered twice within a 24-hour period. Considering this, "initial dose" or "initial daily dose" refers to the dose administered during the initial regimen or period of a medication regimen.

[0045] As used herein, an "effective amount" or "therapeutically effective amount" of a drug refers to an amount of the drug that is nontoxic but sufficient to achieve a therapeutic result in treating a condition for which the drug is known to be effective. It should be understood that various biological factors can affect the ability of a substance to perform its intended task. Therefore, an "effective amount" or "therapeutically effective amount" may depend on such biological factors in some cases. Further, although the achievement of a therapeutic effect can be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual differences and treatment responses can make the achievement of a therapeutic effect a somewhat subjective determination. The determination of an effective amount is well known to those skilled in the art of pharmaceutical science and medicine. See, e.g., Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis," Monographs in Epidemiology and Biostatistics , Volume 8 (1986), incorporated herein by reference.

[0046] As used herein, "single unit", when used to describe the administration of a subject, refers to a dosage form that is a single dosage form, such as a single tablet, capsule, a single pump or spray of a gel or solution, etc. In contrast, "multiple units", when used to describe the administration of a subject, refers to a dose that includes two or more dosage forms, such as 2 capsules, 3 tablets, 2-4 pumps or sprays, etc. It is worth noting that the multiple unit dosage form will generally be the same type of dosage form (i.e., tablet or capsule), but need not be the same dosage form type.

[0047] As used herein, "package", "comprising", "containing", and "having", etc. may have their meanings as defined in U.S. patent law and may mean "include", "comprise", etc., and are generally interpreted as open-ended terms. The term "consisting of" or "consisting of" is a closed term and includes only the components, structures, steps, etc. specifically listed in conjunction with such term and those specified in accordance with U.S. patent law. The term "consisting essentially of" or "consisting essentially of" has the meaning generally assigned to it by U.S. patent law. Specifically, such terms are generally closed terms, except that additional items, materials, components, steps, or elements that do not substantially affect the basic or novel properties or functions of the item(s) used in conjunction with it are permitted to be included. For example, trace elements present in a composition that do not affect the properties or characteristics of the composition would be permissible if present under the expression "consisting essentially of", even if not explicitly recorded in the enumeration of items following such term. When open-ended terms such as "comprising" or "including" are used in a written description, it will be understood that direct support should also be provided to the expression "consisting essentially of" as well as the expression "consisting of", as if explicitly stated, and vice versa.

[0048] The terms "first", "second", "third", "fourth", etc. (if any) in the specification and claims are used to distinguish similar elements and are not necessarily used to describe a specific order or time sequence. It should be understood that any terms so used are interchangeable where appropriate, such that the embodiments described herein are, for example, capable of operating in an order other than that illustrated or otherwise described herein. Similarly, if a method is described herein as comprising a series of steps, the order of such steps shown herein is not necessarily the only order in which such steps may be performed, and some of the steps may potentially be omitted, and / or some other steps not described herein may potentially be added to the method.

[0049] As used herein, comparative terms such as "increase", "decrease", "better", "worse", "higher", "lower", "enhance", "improve", "maximize", "minimize", etc. refer to a property of a device, component, composition, biological response, biological state, or activity that is measurably different from other devices, components, compositions, biological responses, biological states, or activities in surrounding or adjacent areas, in similar conditions, in a single device or composition, or in multiple comparable devices or compositions, in a group or class, in multiple groups or classes, or from an original (e.g., untreated) or baseline state or a state known in the art. For example, a composition that "increases" testosterone serum levels provides a testosterone serum level in a subject that is elevated compared to the serum level at a previous time point, such as a baseline level (e.g., before treatment) or compared to an earlier treatment of a different (e.g., low) dose.

[0050] As used herein, the term "substantially" refers to the complete or almost complete scope or degree of an effect, characteristic, property, state, structure, project or result. For example, an object that is "substantially" encapsulated means that the object is completely encapsulated or almost completely encapsulated. The exact allowable deviation degree relative to absolute completeness may depend on the specific environment in some cases. However, in general, complete proximity will be the degree that leads to the same overall result, as if absolute and overall completeness is achieved. The use of "substantially" is equally applicable when used for negative meanings, referring to completely or almost completely without effect, characteristic, property, state, structure, project or result. For example, a composition that is "substantially free of" particles will be completely free of particles, or almost completely free of particles---the effect is like completely free of particles. In other words, a composition that is "substantially free of" a certain component or element can actually still contain such an item, as long as there is no measurable effect thereof.

[0051] As used herein, the term "about" is used to provide flexibility for the endpoints of a numerical range by providing that a given value can be "slightly above" or "slightly below" the endpoint. Unless otherwise stated, the use of the term "about" in reference to a specific numerical value or numerical range should also be understood to provide support for such numerical terms or ranges without the term "about". For example, for convenience and brevity, a numerical range of "about 50 angstroms to about 80 angstroms" should also be understood to provide support for a range of "50 angstroms to 80 angstroms". In addition, it should be understood that in this specification, support for actual numerical values ​​is provided even when the term "about" is used. For example, a recitation of "about" 30 should be interpreted as providing support not only for values ​​slightly above and slightly below 30, but also for the actual numerical value of 30.

[0052] As used herein, for convenience, multiple items, structural elements, constituent elements, and / or materials may be presented in a common enumeration. However, these enumerations should be interpreted as if each member of the enumeration is individually identified as a separate and unique member. Therefore, in the absence of a contrary indication, no individual member of such an enumeration should be interpreted as being an actual equivalent of any other member of the same enumeration merely based on its presentation in a common group.

[0053] Concentration, amount, level and other numerical data can be expressed or appear in this article in range form.It should be understood that this range form is used only for convenience and simplicity, and therefore should be flexibly interpreted as not only including the numerical value clearly recorded as range limits, but also including all individual numerical values ​​or subranges or decimal (decimal, decimal) units covered within the range, as each numerical value and subrange are clearly recorded.As an example, the numerical range of "about 1 to about 5" should be interpreted as not only including the value of clearly recorded about 1 to about 5, but also including individual values ​​and subranges within the range.Therefore, the numerical range includes individual values ​​such as 2,3 and 4 and subranges such as 1-3,2-4 and 3-5, etc., and individually 1,2,3,4 and 5.This same principle is applicable to the scope of recording only one numerical value as minimum or maximum value.In addition, this explanation should be applicable regardless of the width of the range or characteristic.

[0054] References throughout this specification to "an example" refer to a particular feature, structure, or characteristic described in connection with the example being included in at least one embodiment. Thus, the appearances of the phrase "in one example" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0055] The term "API" refers to active pharmaceutical ingredient or drug, and means (17-β)-hydroxy-4-androsten-3-one (also known as testosterone), which is considered to be a biologically active agent for the purposes of this disclosure. Note that (17-β)-3-oxoandrost-4-ene-17-dodecanoate can be converted in vivo to (17-β)-hydroxy-5α-androstane-3-one (directly, or through the corresponding ester) - which is also biologically active, as well as other metabolites. The term "EAPI" means an ester of (17-β)-hydroxy-4-androstene-3-one - a prodrug of a biologically active agent. It should be understood that EAPI can also be biologically active without cleavage of the ester, but for the purposes of this invention, the API is considered to be a pharmacological agent, which is (17-β)-hydroxy-4-androstene-3-one (testosterone).

[0056] As used herein, the term AUC t1-t2Refers to the area under the curve of the plasma-time plot determined for the analyte from time "t1 to t2", where t1 and t2 are the times after dosing (in hours). For example, t1 can be 1 hour after dosing, and t2 can be 2 hours after dosing.

[0057] As used herein, the term “C avg ”, “C ave ” or “C-mean” can be used interchangeably and is used as the t1-t2 The average value obtained by dividing by the time period (|t1-t2|) is determined. For example, C avg t0-t8 is the average plasma concentration over an 8-hour period from t1=0 to t2=8 hours after dosing. t0-t8 The value is divided by 8 hours. Similarly, C avg t0-t12 AUC is the average plasma concentration over a 12-hour period after dosing. t0-t12 The value is determined by dividing by 12 hours (t1 = 0 and t2 = 12). Similarly, C avg t12-t24 AUC is the average plasma concentration over a 12-hour period after dosing. t12-t24 The value is determined by dividing by 12 hours (t1 = 12 and t2 = 24); C avg t0-t24 AUC is the average plasma concentration over a 24-hour period after dosing. t0-t24 The values ​​are determined by dividing by 24 hours (t1 = 0 and t2 = 24), and so on. Unless otherwise stated, all C avg Values ​​are considered to be C avg t0-t24 , and unless otherwise stated, all time values ​​are expressed in hours (h). For example, the term C avg t0-t24 Indicates C from zero (0) to 24 hours after medication avg .

[0058] As used herein, “C t " refers to the serum concentration of testosterone at time "t" after administration of a dose of the present invention. Unless otherwise specified, time "t" is generally the number of hours after administration. For example, "C (-2至0) "C t Refers to the serum testosterone concentration measured in samples collected between approximately 2 hours before and immediately before administration of a dose to a test subject. Similarly, "C (2至4) "C t Refers to serum testosterone concentrations measured in samples collected between approximately 2 hours and 4 hours after administration of a dose to a test subject.

[0059] As used herein, the term (17-β)-hydroxy-4-androsten-3-one refers to the chemical substance with the IUPAC name (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]phenanthrene-3-one and the CAS number 58-22-0. (17-β)-3-oxoandrost-4-ene-17-dodecanoate generally refers to compounds having the structure of (17-β)-hydroxy-4-androsten-3-one, but the hydroxyl group at the 17th carbon position on the testosterone structure is esterified with lauric acid (e.g., a 12-carbon chain saturated alkanoic acid). For example, (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]phenanthrene-17-ester is the IUPAC name for (17-β)-hydroxy-4-androsten-3-one esterified with a straight chain saturated 12 carbon long alkanoic acid (known as lauric acid). Dodecanoic acid (alternatively also known as lauric acid) is the IUPAC name for the saturated alkanoic acid with CAS number 143-07-7. In a more specific aspect, (17-β)-3-oxoandrost-4-ene-17-ester refers to (17-β)-3-oxoandrost-4-ene-17-ester specifically disclosed herein. In a specific aspect, it refers to dodecanoic acid (17-β)-hydroxy-4-androsten-3-one ester (referred to herein as dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester, lauric acid (17-β)-3-oxoandrost-4-ene-17-ester, or (17-β)-hydroxy-4-androstene-3-one dodecanoate, etc. (CAS No. 59232-78-9)). Dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester has the following chemical structure as shown in Exhibit 1:

[0060]

[0061] Solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester can exist in different crystalline forms and non-crystalline forms. The non-crystalline solid form is referred to herein as "amorphous form", which is a disordered arrangement of dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester molecules. The different crystalline forms of dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester are derived from the different stacking of dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester molecules in the solid state, resulting in different crystal symmetries and / or unit cell parameters. The crystalline form is identified or characterized by any suitable method, such as X-ray diffraction (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton Pa., page 173 (1990); The United States Pharmacopeia, 23rd edition, pages 1843-1844 (1995)). Such different crystalline forms are referred to herein as "polymorphic forms" or "non-solvated forms," ​​meaning that they are substantially free of residual solvents, such as organic solvents. If a substance incorporates stoichiometric or non-stoichiometric amounts of water ("hydrates" as used herein) or any other solvent ("solvates" as used herein) in the crystal structure, these are referred to herein as "pseudopolymorphic forms."

[0062] The term "amorphous form" used herein in conjunction with the solid state refers to a non-crystalline solid form (i.e., not a crystalline form) that is a disordered arrangement of (17-β)-3-oxoandrost-4-ene-17-dodecanoate molecules. Typically, amorphous solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate does not have a long-range periodic molecular stacking structure as determined by powder X-ray diffraction ("PXRD" or "XRD"). The XRD pattern of amorphous (17-β)-3-oxoandrost-4-ene-17-dodecanoate appears halo-like and has no distinct peaks. Amorphous forms of some compounds can be obtained by a variety of methods known in the art, including, but not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, cryogenic grinding, spray cooling, or freeze drying.

[0063] The terms "crystal", "microcrystal" or "crystal (body)" as used herein refer to such a solid structure: generally formed by solidification or crystallization, generally having an ordered molecular packing structure (characteristic shape and cut surface formed by the arrangement of molecules in a pattern called a "lattice"). In one aspect, a plurality of microcrystals are aggregated and then form any grains, and the grains can be accumulated to form any particles. That is, the particle size is larger than the grain size, and the grain size is larger than any crystal size.

[0064] As used herein, the term "seeding" refers to the use of a small amount of material to initiate or promote a crystallization event.

[0065] As used herein, the term "Triton X100" or Triton "X-100" is a non-ionic detergent and refers to a composition known as polyethylene glycol p-(1,1,3,3-tetramethylbutyl)-phenyl ether, octylphenol ethoxylate, polyoxyethylene octylphenyl ether, 4-octylphenol polyethoxylate, Mono 30, TX-100, t-octylphenoxypolyethoxyethanol or octoxynol-9 and associated with CAS number 9002-93-1.

[0066] As used herein, a "pharmaceutical composition" or "formulation" refers to a composition comprising solid (17-β)-3-oxoandrost-4-ene-17-ester and one or more pharmaceutically acceptable carriers, excipients or additives or prepared therefrom. In addition, the exemplary composition can be any composition taught in the patent. As used herein, a "unit dosage form" refers to a drug prepared from or including a pharmaceutical composition, and includes tablets, capsules, caplets, gelcaps, ampoules, suspensions, solutions, gels, dispersions and other dosage units, generally related to the parenteral, enteral, topical or other forms of administration of (17-β)-3-oxoandrost-4-ene-17-ester to a subject in need thereof.

[0067] "Pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "pharmaceutically acceptable additive" or similar terms refer to one or more acceptable components or ingredients that are (1) compatible with the other ingredients in the composition or formulation containing (17-β)-3-oxoandrost-4-ene-17-laurate and (2) not harmful or overly harmful to the subject to which the composition or formulation is to be administered. Excipients include any excipient disclosed in the patent.

[0068] Based on the present application (which generally relates to a specific solid form of (17-β)-3-oxoandrost-4-ene-17-olate), carriers (e.g., pharmaceutically acceptable excipients or additives) and preparation methods for oral pharmaceutical compositions containing (17-β)-3-oxoandrost-4-ene-17-olate are available to those skilled in the art.

[0069] Specific embodiments of the present invention are now described in detail. Although the present invention will be described in conjunction with such embodiments, it should be understood that it is not intended to limit the present invention to those embodiments. On the contrary, it is intended to cover alternative forms, variations, modifications and equivalent forms that may be included within the spirit and scope of the present invention, as defined by the appended claims.

[0070] Solid form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate

[0071] Specific solid forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate disclosed herein have one or more beneficial properties compared to other forms, such as chemical or polymorphic purity, improved crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface area and specific density, loose / tapped density, stability (e.g., such as chemical stability and thermal and mechanical stability - with respect to polymorphic conversion), stability towards hydration and / or storage stability, lower hygroscopicity, low levels of residual solvents, and beneficial processing and handling characteristics, such as compressibility and bulk density. Specific solid forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate are provided herein.

[0072] Dodecanoic acid (17-β)-3-oxo-androst-4-ene-17-ester can be prepared by a variety of synthetic routes (and other corresponding esters in a similar manner). For example, dodecanoic acid (17-β)-3-oxo-androst-4-ene-17-ester is prepared by esterification of (17-β)-hydroxy-4-androstene-3-one and n-dodecanoic acid (IUPAC name is lauric acid, CAS No. 143-07-7) with activated fatty acids (e.g., lauroyl chloride or lauric anhydride) in a suitable solvent under suitable conditions to produce a product (e.g., pyridine as an esterification catalyst). In one aspect, (17-β)-hydroxy-4-androstene-3-one (testosterone) is prepared from phytosterols or cholesterol or any other suitable starting material. The product is processed by any number of techniques. For example, the product is dissolved in a solvent (e.g., an organic solvent such as heptane or any other solvent); washed sequentially with, for example, cold water (2X), 0.05N NaOH, saturated NaHCO3 (2X), water, brine, and then dried over anhydrous Na2SO4 (about 50 g), followed by a drying process (e.g., rotary evaporator / T 浴 <30° C.). Without wishing to be bound by theory, the inventors have surprisingly discovered that crystallization or recrystallization of (17-β)-3-oxoandrost-4-ene-17-dodecanoate provides a solid state form having one or more of the beneficial properties described herein.

[0073] Therefore, according to one embodiment, the present invention provides an example of a recrystallized or crystallized solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester. According to this embodiment, dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester is dissolved in a solvent (e.g., heptane) and crystallized or recrystallized, or transferred to another solvent after the first crystallization and crystallized or recrystallized. The crystalline material can be separated (e.g., by suction filtration), optionally washed (e.g., with water), optionally dried (e.g., over phosphorus pentoxide) and optionally recrystallized from another solvent (e.g., oleic acid, hexane, heptane, etc.). In one aspect, the solvent (for crystallization or recrystallization) is an alcohol (e.g., ethanol, methanol or propanol), a fatty acid (e.g., oleic acid, linoleic acid or linoeladic acid), an alkane (e.g., hexane, heptane, pentane or a halogenated alkane), an oil (e.g., a vegetable oil, castor oil or a hydrogenated oil) or any other suitable solvent (e.g., pyridine, benzene or toluene). In this case, the solvent refers to a liquid in which (17-β)-3-oxoandrost-4-ene-17-dodecanoate is soluble.

[0074] As is known in the art, the crystalline form of a substance can be obtained by a variety of techniques. Exemplary techniques for obtaining, producing or manufacturing the crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate include melt recrystallization, melt cooling, solvent recrystallization, recrystallization in a confined space such as a nanopore or capillary, recrystallization on a surface or template such as a polymer, 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.

[0075] Typically, specific crystalline forms of an active pharmaceutical ingredient (API) (e.g., testosterone esters) can be distinguished from one another by one or more physical or chemical properties, such as dissolution rate, 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), thermogravimetric analysis (TGA) (see: https: / / en.wikipedia.org / wiki / Thermogravimetric_analysis), and other methods disclosed elsewhere in this specification or available to those skilled in the art. Other methods for characterizing or distinguishing one pseudopolymorphic form from other isostructural polymorphs, pseudopolymorphs, desolvates or anhydrates include elemental analysis, Karl-Fisher titration, dynamic vapor sorption analysis, thermogravimetric-infrared spectroscopy (TG-IR), residual solvent gas chromatography (see: https: / / www.restek.com / Technical-Resources / Technical-Library / Pharmaceutical / pharm_A005), 1H-NMR (see: https: / / en.wikipedia.org / wiki / Proton_nuclear_magnetic_resonance), etc.

[0076] Thus, in one embodiment, a solid state form of (17-β)-3-oxoandrost-4-ene-17-olate is provided, wherein the solid state (17-β)-3-oxoandrost-4-ene-17-olate has one or more advantageous properties compared to other forms, such as chemical properties, crystal or polymorph purity, improved crystallinity, fluidity, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface area and specific density, loose / tapped density, stability (e.g., such as chemical stability and thermal and mechanical stability - with respect to polymorphic conversion), stability towards hydration and / or storage stability, lower degree of hygroscopicity, low content of residual solvent(s) and advantageous processing and handling characteristics, such as compressibility and bulk density. In a specific aspect of this embodiment, the solid state (17-β)-3-oxoandrost-4-ene-17-olate in the present disclosure is a crystalline form. In a further aspect, solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate is useful for administration to humans. In one aspect, solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate is a specific crystalline form characterized by analytical techniques known to one of ordinary skill in the art (e.g., substantially similar to that characterized by XRD and DSC in the Examples and Figures).

[0077] In one aspect, the solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate disclosed herein has two endothermic transition peaks, which may represent a change or phase transition from one crystalline form to a different solid state form (eg, solid to liquid). Figure 1 The first cycle enthalpy change plot of the solid state form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate as disclosed herein measured by differential scanning calorimetry is shown. In another aspect, Figure 1 A small endothermic peak shown at 35 to 45° C. in the embodiment of the present invention may be a glass transition peak, which may be from a stable solid form to a meta-state solid form (eg, an amorphous form). In a further aspect, Figure 1A small endothermic peak shown at 35 to 45°C may be a lattice form transition peak, which may be from one crystal form to a different crystal form. In one aspect, another large endothermic peak shown at 45 to 70°C represents the melting point (e.g., phase transition from solid to liquid) of the solid-state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester disclosed herein, as determined by differential scanning calorimetry. In one aspect, the solid-state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester 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. In one aspect, the solid-state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester is a crystalline form having a melting point in the range of 51 to 63°C, as determined by differential scanning calorimetry, such as Figure 1 shown.

[0078] In one aspect, solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate is a Figure 2 In one aspect, the solid state (17-β)-3-oxoandrost-4-ene-17-olate is in the form of unground or ground, micronized or nanosized crystals. In one aspect, the solid state (17-β)-3-oxoandrost-4-ene-17-olate has a particle size of: d 50 In one aspect, the particle size distribution of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester is less than 200nm, 200 to 500nm, 500 to 1000nm, 1 to 50μm, 50μm to 250μm, 250μm to 500μm, 500μm to 1000μm, or greater than 1000μm. In one aspect, the particle size of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester has: D 10 , D 50 or D 90 The release profile of (17-β)-3-oxoandrost-4-ene-17-dodecanoate is less than 200 nm, 200 to 500 nm, 500 to 1000 nm, 1 to 50 μm, 50 to 250 μm, 250 to 500 μm, 500 to 1000 μm, or greater than 1000 μm. In one aspect, the release profile of (17-β)-3-oxoandrost-4-ene-17-dodecanoate does not substantially change as a function of storage time.

[0079] Different forms of dodecanoic acid (17-β)-3-oxoandrost-4-ene- in pharmaceutical compositions prepared from the solid state 17-Ester

[0080] Described herein are different solid forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate produced from compositions with any excipient or carrier (e.g., solubilizer, surfactant, additive, etc.). The identification of different forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate provides improvements associated with physical, chemical, pharmacokinetic, and pharmacodynamic properties.

[0081] A variety of different forms, including crystalline forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate, may exist. By preparing a pharmaceutical composition comprising at least one of a pharmaceutically acceptable excipient, carrier or ingredient, the pharmaceutical composition described herein having Figure 1 The melting point is shown to be between 55 and 65°C and Figure 2 The solid crystalline form of (17-β)-3-oxoandrost-4-ene-17-olate having at least 1, 2, 3, 4, 5, 6 or more distinguishing peaks as determined by XRD can be converted into at least one of a single crystalline form, an amorphous form, a polymorphic crystalline form, a metastable solid form or a liquid form of (17-β)-3-oxoandrost-4-ene-17-olate. In a specific aspect, based on the present disclosure, various different forms of (17-β)-3-oxoandrost-4-ene-17-olate in a pharmaceutical composition can be provided by methods available to those of ordinary skill in the art: see Figure 3 .

[0082] Experimental instrument for analyzing solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate set up and conditions

[0083] Various techniques can be used to identify or characterize solid state (17-β)-3-oxoandrost-4-en-17-dodecanoate.

[0084] Fourier Transform-Raman Spectroscopy ("FT-Raman") (See: https: / / www.sciencedirect.com / topics / chemistry / fourier-transform-raman-spectroscopy#:~:text=Nea r% 2Dinfrared%20Fourier%20Transform%20Raman,advantages%20of%20the% 20optical%20interferometer ) can be used to characterize and identify the solid state forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate. For example, different solid state forms of (17-β)-3-oxoandrost-4-ene-17-dodecanoate can be characterized using a Bruker RFS100 instrument, Nd:YAG 1064nm excitation, 300mW laser power, Ge detector, 25-3500cm -1 Range 64 scans, resolution 2cm -1One of ordinary skill in the art will appreciate that the parameters and instrument settings for FT-Raman can be modified depending on the instrument, the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate, and the purpose(s) of the analysis.

[0085] Another useful characterization technique is XRD (see: https: / / en.wikipedia.org / wiki / Powder_ diffraction ). For example, XRD can be performed with a Bruker D8 Advance X-ray diffractometer with CuKα irradiation. Standard measurement conditions are, for example, tube power 40 kV / 40 mA; step size 0.010° ​​(2θ); step time 57.6 seconds; scan range 3°-40° (2θ); divergence slit 0.600 mm; anti-scatter slit 4.800 mm; slit mode fixed; sample rotation speed 15.000° / min; detector LYNXEYE_XE (1D mode); goniometer radius 280.0 nm; display wavelength Those of ordinary skill in the art will appreciate that the parameters and instrument settings for XRD can be modified depending on the instrument, the solid-state (17-β)-3-oxoandrost-4-ene-17-ester, and the analytical purpose(s). In one embodiment, the solid-state (17-β)-3-oxoandrost-4-ene-17-ester is crystalline or substantially crystalline as shown by XRD. Figure 2 An example of an XRD spectrum of a crystalline form of (17-β)-3-oxoandrost-4-en-17-dodecanoate in the solid state is shown. Figure 2 The invention discloses a solid state (17-β)-3-oxoandrost-4-ene-17-ester having well-defined peaks corresponding to the crystalline form of solid state (17-β)-3-oxoandrost-4-ene-17-ester, with little or no peaks characteristic of the amorphous form of solid state (17-β)-3-oxoandrost-4-ene-17-ester) (as indicated by the absence of an "amorphous halo" and peak broadening in the 2θ range of 5-30 degrees in the spectrum). In one aspect, the solid state (17-β)-3-oxoandrost-4-ene-17-ester described herein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more peaks corresponding to the crystalline form of solid state (17-β)-3-oxoandrost-4-ene-17-ester). Figure 2 The corresponding peaks in the sample have intensities above 25, 50, 100, 150 or 200 counts. The intensities may be random relative values ​​compared to the values ​​measured by the control.

[0086] Thermogravimetric-Fourier transform infrared spectroscopy ("TG-FTIR") (see: https: / / www.eag.com / resources / appnotes / thermogravimetric-analysis-fourier-transfer-infrared-spect roscopy-tga-ftir-services / ) can also be used to characterize or analyze solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate. For example, TG-FTIR can be performed using a Netzsch Thermo-Microbalance TG 209 coupled to a Bruker FT-IR Spectrometer Vector 22, using an aluminum crucible (open or with micropores), under a nitrogen atmosphere, and, for example, at a heating rate of 10°C / min over a range of 25°C to 350°C. One of ordinary skill in the art will appreciate that the parameters and instrument settings for TG-FTIR can be modified depending on the instrument, solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate, and the purpose of analysis (one or more).

[0087] Characterization / analysis of solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate can also be performed using differential scanning calorimetry ("DSC"). For example, DSC can be performed using a Perkin Elmer differential scanning calorimeter using a closed PanAl crucible over a range of 0°C to 100°C (or, for example, over a range of 5°C to 150°C) at 10°C min -1 The heating rate is: for example, see Figure 1 . As will be appreciated by one of ordinary skill in the art, the parameters and instrument settings of the DSC may be modified according to the instrument, the solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester, and the analytical purpose (or purposes). Thus, in yet another embodiment, the solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester provided herein has a melting point in the range of about 45 to 70° C., as determined by DSC. In a specific embodiment, the solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester provided herein has a melting point in the range of about 50 to 65° C., as determined by DSC. In a more specific embodiment, the solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester provided herein has a melting point in the range of about 55 to 65° C., as determined by DSC. In one aspect of this embodiment, the melting point of the solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate is a characteristic of the solid-state form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate: Figure 1 .

[0088] Dynamic Vapor Sorption (DVS) (See: https: / / en.wikipedia.org / wiki / Dynamic_vapor_ absorption) analysis is another technique used to characterize and analyze dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester. For example, DVS can be performed using a surface measurement system DVS-1 water vapor sorption analyzer. The experiment can be performed by arranging the sample on a quartz container on a microbalance and allowing the sample to reach equilibrium at 50% relative humidity (RH) before starting a predetermined humidity program. The program can be performed, for example, in the following steps: 1 hour at 50% RH; 50% to 0% RH, at a rate of 5% RH change / hour; 5 hours at 0% RH; 0% RH to 96% RH, at a rate of 5% RH change / hour; 5 hours at 95% RH; 95% RH to 50% RH, at a rate of 5% RH change / hour, and then 1 hour at 50% RH. As one of ordinary skill in the art will appreciate, the parameters and instrument settings of the DVS can be modified depending on the instrument, solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate, and analytical purpose(s).

[0089] High Performance Liquid Chromatography (HPLC) (See: https: / / en.wikipedia.org / wiki / High- performance_liquid_chromatography ) can also be used to analyze or characterize (17-β)-3-oxoandrost-4-ene-17-dodecanoate. In some embodiments, the purity of the crystalline form of (17-β)-3-oxoandrost-4-ene-17-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 the total area under the curve observed at an appropriate wavelength (e.g., about 240 nm or about 250 nm). In some embodiments, the crystalline form of (17-β)-3-oxoandrost-4-ene-17-olate disclosed herein is about 98.0% to 100.0% pure as measured by HPLC as the area under the curve observed at an appropriate wavelength (e.g., at a wavelength of about 200 nm to about 300 nm, such as about 240 nm or 250 nm).

[0090] In some embodiments, the purity of the different forms of (17-β)-3-oxoandrost-4-ene-17-olate in the 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 the total area under the curve observed at an appropriate wavelength (e.g., about 200 nm to about 300 nm or about 240 nm to about 250 nm). In some embodiments of the invention, the different forms of (17-β)-3-oxoandrost-4-ene-17-olate in the pharmaceutical composition are about 98.0% to 100.0% pure as measured by HPLC based on the area under the curve observed at an appropriate wavelength (e.g., at a wavelength of about 200 nm to about 300 nm, such as about 240 nm or 250 nm).

[0091] As will be appreciated by one of ordinary skill in the art based on the present disclosure, solid-state NMR and other techniques may be used to analyze or characterize solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate and its forms.

[0092] Production of Solid Dodecanoic Acid (17-β)-3-Oxoandrost-4-ene-17-Ester with Different Particle Size Distribution

[0093] Compositions with different particle sizes or particle size distributions can be produced by any suitable method. Micronization techniques can reduce particle size based on friction; such methods include milling, bashing, and grinding. Another technique for producing differently sized particles of (17-β)-3-oxoandrost-4-ene-17-dodecanoate involves supercritical fluids, wherein (17-β)-3-oxoandrost-4-ene-17-dodecanoate is dissolved in a solvent at high temperature and pressure, and the mixture is ejected from a nozzle, resulting in the formation of particles within a specific size or a specific size range / distribution. Some basic supercritical fluid techniques are the RESS process (rapid expansion of supercritical solutions) (see: https: / / hightechextracts.com / the-science / rapid- expansion-of-supercritical-solution / #:~:text=Rapid%20Expansion%20of% 20Supercritical%20Solution%20(RESS)%20is%20used%20generally%20to, solution%20through%20an%20expansion%20nozzle) , SAS method (supercritical antisolvent) (see: http: / / hpp.uva.es / technology / formulation / supercritical-antisolvent-sas / #:~: text=The%20Supercritica l%20Anti%20Solvent%20technique,solution% 20with%20supercritical%20carbon%20dioxide ) and the PGSS method (Particles from Gas Saturated Solutions) (see: https: / / hightechextracts.com / the-science / particles-from-gas-saturated-solutions / #:~:text=Particles% 20from%20Gas%20Saturated%20Solutions%20(PGSS)%20is%20a%20technique% 20for,of%20CO2%20at%20moderate%20pressures) .

[0094] Particle size distribution and morphology analysis

[0095] The particle size distribution of solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate particles can be analyzed by a variety of techniques. For example, the particle size distribution can be analyzed by photon correlation spectroscopy (PCS) (see: https: / / www.sciencedirect.com / topics / chemical-engineering / photon-correlation- spectroscopy ): for example, Malvern ZetaSizer 2000HS (Malvern Instruments, Malvern, UK). The measurement mode applied can be, for example, the Contin-Auto mode. PCS gives the average diameter (z-average) and the polydispersity index (PI) of the bulk population - in the following range: from 0 (monodisperse) to 0.10-0.20 (relatively monodisperse) to greater than 0.5 (broad size distribution). The measurement range of PCS is about 3nm-3μm. As understood by a person skilled in the art, the parameters and instrument settings of PCS can be modified according to the instrument, the solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester and the analytical purpose (one or more).

[0096] Solid particles of (17-β)-3-oxoandrost-4-ene-17-dodecanoate can also be visually analyzed by scanning electron microscopy (SEM) (see: https: / / en.wikipedia.org / wiki / Scanning_electron_ microscope ). The solid particles are deposited on a metal stub, which is then placed in liquid nitrogen and dried under vacuum. The metal stub is uniformly coated with gold or palladium. The morphology and surface properties of all samples are examined using a scanning electron microscope (e.g., Joel, SEM, JSM-25SII, Tokyo, Japan). Particle size, polydispersity index, and zeta potential can be initially measured by a laser particle size analyzer (Submicron Particle Size Analyser 90plus, Brookhaven Instrument Co., Holtsville, NY, USA). An aliquot of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester particles can be diluted with, for example, 3 mL of deionized water. The diluted dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester sample is loaded into a 4 mL cuvette, and particle size and zeta potential measurements can be performed at ambient temperature. For example, by scanning electron microscopy measurements such as Figure 1 and 2 Solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate particles characterized as shown. Figure 4 The solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate particles are shown to exist as one or more microcrystals, grains, and particles, and have a flat plate shape. Figure 4 As shown, those sizes are in one or more of the following ranges: about less than 1 μm, about 1-5 μm, and about 5-50 μm. As will be appreciated by one of ordinary skill in the art, the parameters and instrument settings of the electron microscope can be modified depending on the instrument, the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate, and the purpose(s) of the analysis.

[0097] Solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester disclosed herein (which is aggregated into particles of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester, such as Figure 4 The crystallite size of the nanostructured particles (shown in FIG. 1 ) can also be estimated by XRD, for example by applying the Sherrer equation (see: https: / / en.wikipedia.org / wiki / Scherrer_ equation ), (where the size of the crystallites that aggregate to form a solid (e.g., crystalline particles or crystallites) can be calculated) is applied to the peak width in the diffraction pattern of the solid. In general, the particles are formed by the aggregation of crystallites, which are formed by the aggregation of many crystallites in the solid. Based on Figure 4 The XRD diffraction pattern shown, the average crystallite size of the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate disclosed herein was measured to be about 50 nm, with a standard deviation of about 7 nm. The average crystallite size was measured using the following Scherrer equation:

[0098]

[0099] Where D is the crystallite size of the ordered domain, κ is the dimensionless Scherrer constant (=0.9), λ is the X-ray wavelength (=0.15406 nm), β is the line width at half maximum intensity (FWHM) of each peak, and θ is the peak position (2θ). For example, Table 1 summarizes the Scherrer equation from Figure 2 Crystallite size measured for each peak shown (8 distinct peaks).

[0100] Table 1. XRD results based on Figure 2 ) using the Scherrer equation to measure the crystallite size

[0101] Peak ID Peak position (2θ) FWHM(θ) Crystallite size (nm) 1 10.9 0.17 46.9 2 13.6 0.17 47.1 3 14.0 0.14 57.2 4 15.3 0.19 42.2 5 17.3 0.14 57.4 6 18.0 0.15 53.6 7 19.2 0.13 60.2 8 23.2 0.19 42.7 average 0.16 51.1 SD 0.023 7.4

[0102] Release Spectrum of Solid Dodecanoic Acid (17-β)-3-Oxoandrost-4-ene-17-ester

[0103] In one embodiment, the release profile of the solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate disclosed herein (e.g., a profile comprising 2, 3, 4, 5 or 6 or more time points (each time point is separated by at least 5, 10 or 15 minutes) or a single time point) does not change substantially as a function of storage time. In addition, the release of the solid-state crystalline (17-β)-3-oxoandrost-4-ene-17-dodecanoate is less than 10%, 9%, 8%, 7%, 6% or 5%, up to at least 60 minutes, 120 minutes, 180 minutes, 240 minutes, 360 minutes, 24 hours or 48 hours, in a USP Type 2 apparatus at 100 rpm, in about 1000 mL of 8% Triton X-100 aqueous solution, at a specific temperature, such as 20.0, 37.0 or 40.0°C (±0.5). In one aspect, the release profile of solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate is substantially unchanged 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 solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate is substantially unchanged 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, the release test is conducted using a USP Type 2 apparatus at 100 rpm in about 1000 mL of 8% Triton X-100 aqueous solution at a specific temperature, such as 20.0, 37.0, or 40.0° C. (±0.5). In one aspect, a release profile that does not substantially change over a period of time refers to a release profile in which the amount of (17-β)-3-oxoandrost-4-ene-17-laurate released at one or more specific time points under specific conditions changes by less than plus / minus 50%, 40%, 30%, 20% or 10% or less.

[0104] Pharmaceutical composition containing solid-state (17-β)-3-oxoandrost-4-ene-17-olate or prepared therefrom

[0105] The pharmaceutical compositions and dosage forms (e.g., capsules or tablets) described herein comprising solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester or prepared therefrom may include various pharmaceutically acceptable carriers known in the art. Non-limiting examples of components that may be included as pharmaceutical carrier components include lipophilic surfactants, hydrophilic surfactants, triglycerides, fatty acids (C8 to C22), fatty acid glycerides (monoglycerides, diglycerides, triglycerides, or combinations thereof), additives, or combinations thereof.

[0106] In one embodiment, a pharmaceutical composition or dosage form comprising solid-state (17-β)-3-oxoandrost-4-ene-17-ester or prepared therefrom is as described herein. In one aspect, the pharmaceutical composition or dosage form is prepared from solid-state crystalline (crystalline) (17-β)-3-oxoandrost-4-ene-17-ester. In another aspect, the pharmaceutical composition or dosage form is prepared from a specific crystalline form of solid-state (17-β)-3-oxoandrost-4-ene-17-ester. In yet another aspect, the pharmaceutical composition or dosage form is prepared from Figure 1 , 2 Preparation of a crystalline form of solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate characterized by DSC and XRD as shown in FIG4 .

[0107] In another embodiment, after the process of preparing the composition or dosage formulation with a pharmaceutically acceptable carrier, the crystalline form of solid-state (17-β)-3-oxoandrost-4-ene-17-ester in the pharmaceutical composition or dosage formulation can be converted into an amorphous, substantially amorphous, partially amorphous or amorphous-like form. Amorphous-like refers to one of the physical states of (17-β)-3-oxoandrost-4-ene-17-ester in the dosage form or pharmaceutical composition, wherein a large amount of (17-β)-3-oxoandrost-4-ene-17-ester is not in a structured crystalline form (e.g., dissolved or dispersed in a solvent). In another specific aspect of this embodiment, the solid-state (17-β)-3-oxoandrost-4-ene-17-ester in the pharmaceutical composition or dosage form can be in a semi-solid form or substantially free of crystalline forms. In a further aspect of this embodiment, the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate in the pharmaceutical composition or dosage form may partially remain intact in the same crystalline form.

[0108] In yet another aspect, the pharmaceutical composition or dosage form is prepared from a crystalline form of solid (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the pharmaceutical composition comprises amorphous or amorphous-like solid (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. In yet another aspect, the pharmaceutical composition or dosage form is prepared from a crystalline form of solid (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the pharmaceutical composition substantially does not comprise amorphous solid (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. In yet another aspect, the pharmaceutical composition or dosage form is prepared from a crystalline form of solid (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the pharmaceutical composition comprises solubilized (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

[0109] In one embodiment, a pharmaceutical composition or unit dosage form comprising or prepared from solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate has an enhanced release profile compared to the release from a crystalline form of solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate without any carrier or excipient. According to this embodiment, a pharmaceutical composition or unit dosage form comprising or prepared from solid state (17-β)-3-oxoandrost-4-ene-17-olate releases more (17-β)-3-oxoandrost-4-ene-17-olate than a crystalline form of (17-β)-3-oxoandrost-4-ene-17-olate - at a specified time point (e.g., 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 180 minutes, and 240 minutes) in about 1000 mL of 8% Triton in a USP Type 2 apparatus. X100 aqueous solution at a specific temperature (e.g., 20.0, 37.0 or 40.0° C. (±0.5)) at 100 rpm. Releasing more dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester from a pharmaceutical composition or unit dosage form refers to releasing more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or more or more of the crystalline form of solid state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester in a dissolving aqueous medium (e.g., 8% Triton X100 aqueous solution).

[0110] In one embodiment, a pharmaceutical composition or unit dosage form having (or prepared from) solid state (17-β)-3-oxoandrost-4-ene-17-olate has a release profile (e.g., single time point or multiple time points) of (17-β)-3-oxoandrost-4-ene-17-olate that does not substantially change as a function of storage time as measured using a USP Type 2 apparatus in 1000 mL of 8% Triton X100 aqueous solution at a specific temperature (e.g., 20.0, 37.0, or 40.0° C. (±0.5)) at 100 rpm. 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 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 in which the amount of (17-β)-3-oxoandrost-4-ene-17-dodecanoate released at one or more specific time points under specific conditions changes by less than plus / minus 50%, 40%, 30%, 20%, or 10% or less.

[0111] In one embodiment, a unit dosage form or pharmaceutical composition as described herein is provided, comprising or prepared from solid (17-β)-3-oxoandrost-4-ene-17-olate and a pharmaceutically acceptable carrier, wherein the dosage form or pharmaceutical composition releases 20% or more of (17-β)-3-oxoandrost-4-ene-17-olate as measured at 100 RPM at 30 minutes at a specific temperature using a USP Type 2 apparatus with 1000 mL of 8% Triton X100 aqueous solution, as compared to an equivalent release amount of crystalline solid (17-β)-3-oxoandrost-4-ene-17-olate without any excipients or carriers that does not release more than 1% of (17-β)-3-oxoandrost-4-ene-17-olate as measured at 30 minutes using a USP Type 2 apparatus with 1000 mL of 8% Triton X100 aqueous solution.

[0112] In some embodiments, the pharmaceutically acceptable carrier of the composition may include a lipophilic additive. Non-limiting examples of lipophilic additives may include lipophilic surfactants, monoglycerides, diglycerides or triglycerides, tocopherol, tocopherol succinate, tocopherol acetate, tocopherol derivatives, sterols, phytosterols and combinations thereof. In one embodiment, the lipophilic additive may include fatty acids or fatty acid glycerides. In another embodiment, the lipophilic additive may include fatty acid glycerides, which may be monoglycerides (monoglycerides, monoglyceride), diglycerides (diglycerides, diglyceride), triglycerides (triglycerides, triglyceride) or mixtures thereof. Non-limiting examples of fatty acid glycerides that can be used for oral pharmaceutical compositions and dosage forms of the present invention include monoglycerides and / or diglycerides derived from sources such as: corn oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil and mixtures thereof. In a specific embodiment, the pharmaceutical composition or its dosage form comprises one or more corn oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil or its combination. In another embodiment, the composition includes one or more triglycerides. In one aspect, the lipophilic additive is a C8-C22 saturated fatty acid (or having 1, 2 or 3 unsaturations on the ester chain), its monoglyceride, diglyceride or triglyceride (including mixture), or its combination. In more specific aspects, the C8-C22 fatty acid is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, hexadecene acid (sapienic acid), oleic acid, elaidic acid, vaccenic acid, linoleic acid or trans-linoleic acid. In another specific aspect, the mono-, di-, or triglyceride is a glyceride of caprylic, capric, lauric, myristic, palmitic, stearic, palmitoleic, hexadecenoic, oleic, elaidic, vaccenic, linoleic, or trans-linoleic acid, or a combination thereof.

[0113] In another embodiment, the lipophilic additive may include a lipophilic surfactant.

[0114] As used herein, a lipophilic surfactant is considered when it has a hydrophile-lipophile balance (HLB) of 10 or less. Various lipophilic surfactants can be used, including, but not limited to, monoglycerides, diglycerides of fatty acids such as monolinolein (e.g., MAISINE 35-1), caprylic-capric monoglycerides and diglycerides (e.g., CAPMULMCM), monoolein; mixtures of alcohols or polyols with various 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 2125CS), PEG-6 almond oil (e.g., LABRAFIL M 1966CS), PEG-6 apricot kernel oil (e.g., LABRAFIL M 1944CS), PEG-6 olive oil (e.g., LABRAFIL M 1980CS), PEG-6 peanut oil (e.g., LABRAFIL M 1969CS), PEG-6 hydrogenated palm kernel oil (e.g., LABRAFIL M 2130BS), PEG-6 palm kernel oil (e.g., LABRAFIL M 2130CS), PEG-6 triolein (e.g., LABRAFIL M 2735CS), PEG-8 corn oil (e.g., LABRAFIL WL 2609BS), PEG-20 corn glycerides (e.g., CROVOL M40), PEG-20 almond glycerides (e.g., CROVOL A40), lipophilic polyoxyethylene-polyoxypropylene block copolymers (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-06), propylene glycol dicaprylate / dicaprate (e.g., CAPTEX 200), and propylene glycol dicaprylate (e.g., CAPTEX 800), propylene glycol monocaprylate (for example, CAPRYOL 90), propylene glycol oleate (for example, LUTROLOP 2000), propylene glycol myristate, propylene glycol monostearate, propylene glycol hydroxystearate, propylene glycol ricinoleate, propylene glycol isostearate, propylene glycol monooleate, propylene glycol dicaprylate / dicaprate, propylene glycol dicaprylate, propylene glycol caprylate-caprate, propylene glycol dilaurate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dicaprate; mixtures of propylene glycol esters with glycerol esters, such as a mixture consisting of the oleic acid esters of propylene glycol and glycerol (for example, ARLACEL 186);Sterols and sterol derivatives, such as cholesterol, sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soy sterol, PEG-10 soy sterol, PEG-20 soy sterol, and the like; palmitoyl stearin, stearin, distearin, monostearin, 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, phosphatidylcholine, bile salts, and the like, and mixtures thereof. It is important to note that some lipophilic surfactants can also serve as solubilizer components of the compositions and oral dosage forms. ;

[0115] In one embodiment, the lipophilic surfactant may be selected from the group consisting of monolinolein glyceryl (e.g., MAISINE 35-1), caprylic acid, capric acid mono- and diglycerides (e.g., CAPMUL MCM), monolinolein glyceryl, propylene glycol monocaprylate, propylene glycol oleate, propylene glycol monostearate, propylene glycol monolaurate, propylene glycol monooleate, 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., ARLACEL 20), sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate and combinations thereof. It should be noted that combinations of two or more lipophilic surfactants from the same or different classes are also within the scope of the present invention and may be collectively referred to as lipophilic surfactants unless otherwise specified.

[0116] In an embodiment of the present invention, an oral pharmaceutical composition or dosage form (e.g., capsule or tablet) may include a hydrophilic additive. In one embodiment, the hydrophilic additive is selected from: a hydrophilic surfactant; for example, cellulose-such as hydroxypropyl cellulose with a low molecular weight and a low viscosity type (e.g., METHOCEL E5, E6, E10, E15, LV100, etc.) and hydroxypropyl cellulose with a higher molecular weight and a medium to high viscosity (e.g., METHOCEL K4M, K15M, K100M, etc.); polyvinyl pyrrolidone (e.g., KOLLIDON k17, K30, etc.); polyvinyl acetate, and combinations thereof.

[0117] In one embodiment, the hydrophilic additive can be a hydrophilic surfactant. A hydrophilic surfactant is considered when it has an HLB value greater than 10. Non-limiting examples of hydrophilic surfactants include nonionic surfactants, ionic surfactants, and zwitterionic surfactants. Specifically, hydrophilic surfactants suitable for the present invention include, but are not limited to, alcohol-oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulfates, dioctyl sulfosuccinates; polyethylene glycol fatty acid esters; polyethylene glycol fatty acid monoesters and diester mixtures; polysorbates; polyethylene glycol derivatives of tocopherol, and the like. It should be noted that, unless expressly specified, combinations of two or more hydrophilic surfactants from the same or different categories are within the scope of the present invention and may be collectively referred to as hydrophilic surfactants. In one embodiment, the hydrophilic additive can be a hydrophilic surfactant. Non-limiting examples of hydrophilic surfactants can include PEG-8 caprylic / capric glycerides, lauroyl macrogol-32 glycerides, stearoyl macrogol glycerides, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyethylene glycol fatty acid mono- and diester mixtures, polysorbate 80, polysorbate 20, polyethylene glycol 1000 tocopheryl succinate, phytosterols, phytosterol fatty acid esters, and mixtures thereof.

[0118] In some embodiments, the surfactant utilized in the pharmaceutical composition described herein includes sterol and sterol derivatives. In various embodiments, these surfactants are hydrophilic or lipophilic. The example of hydrophilic sterol surfactant is lanosterol PEG-24 cholesterol ether (e.g., SOLULAN C-24, Amerchol), PEG-30 soybean sterol (e.g., Nikkol BPS-30, from Nikko), PEG-25 plant sterol (e.g., Nikkol BPSH-25, from Nikko), PEG-30 cholestanol (e.g., Nikkol DHC, from Nikko). The example of lipophilic sterol surfactant is cholesterol, sitosterol, plant sterol (e.g., GENEROL series, from Henkel), PEG-5 soybean sterol (e.g., Nikkol BPS-S, from Nikko), PEG-10 soybean sterol (e.g., Nikkol BPS-10, from Nikko), PEG-20 soybean sterol (e.g., Nikkol BPS-20, from Nikko).

[0119] In one embodiment, the pharmaceutical composition or unit dosage form includes the additives described in the following paragraphs.

[0120] Suitable additives for use in the various embodiments described herein include, by way of non-limiting example, adsorbents, antiadherents, anticoagulants, defoamers, antioxidants, anti-caking agents, antistatic agents, binders, bile acids, buffers, bulking agents, chelating agents, coagulants, colorants, cosolvents, opacifiers, freezing agents, coolants, cryoprotectants, diluents, dehumidifiers, desiccants, desensitizers, disintegrants, dispersants, enzyme inhibitors, glidants, fillers, hydrating agents, super disintegrants, gums, mucilages, hydrogen bonding agents, enzymes, flavoring agents, humectants, moisturizers, lubricating oils, ion exchange resins, lubricants, plasticizers, pH modifiers, preservatives, solidifying agents, solvents, solubilizing agents, spreading agents, sweeteners, stabilizers, surface area increasing agents, suspending agents, thickeners, viscosity increasing agents, waxes, solidifying agents, and mixtures thereof.

[0121] In one embodiment, the oral pharmaceutical composition or dosage form comprises solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester and a pharmaceutically acceptable carrier or is prepared therefrom. In another embodiment, the composition or dosage form of the present invention comprises solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester and a pharmaceutically acceptable carrier, wherein the solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester is not solubilized at 30°C, or above 30°C, or at a temperature range above 30°C (including 30°C to about 40°C). In one aspect, the unit dosage form is a hard gel or soft gel capsule or tablet.

[0122] Methods for treating diseases

[0123] The pharmaceutical composition or unit dosage form comprising or prepared from solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate has a variety of methods of use.

[0124] The subject that can be treated by administering the pharmaceutical compositions and unit dosage forms of the present disclosure (e.g., comprising solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester or prepared therefrom) can be any mammal (e.g., human male or female) in need thereof. Specifically, in one embodiment, the human male can be at least 14 years old. In another embodiment, the human male is an adult of at least 16, 18 or 20 years old. In another embodiment, the human male is an adult of at least 21, 23 or 25 years old. In another embodiment, the human male is an adult of at least 30 years old. In another embodiment, the subject can be an adult male of at least 50 years old. In yet another embodiment, the subject can be an adult male of at least 60 years old. The subject can be treated by administering the pharmaceutical compositions and unit dosage forms of the present disclosure (e.g., comprising solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester or prepared therefrom). Figure 1 , 2The subject of treatment with solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester characterized by and 4 or prepared therefrom) can be any human female in need thereof. Specifically, in one embodiment, the human female can be at least 14 years old. In another embodiment, the human female is an adult of at least 30 years old. In a further embodiment, the subject can be an adult female of at least 50 years old. In a further embodiment, the subject can be an adult female with a defect in endogenous serum testosterone levels. In a further embodiment, the subject can be an adult female who has undergone unilateral or bilateral oophorectomy. In a further embodiment, the subject can be an adult female who has undergone unilateral or bilateral oophorectomy. In yet another embodiment, the subject can be a postmenopausal woman. In another aspect, a subject suffering from a disease associated with a lack of therapeutically effective testosterone levels (such as, but not limited to, hypogonadism (e.g., testosterone deficiency or testosterone loss), liver disease or lung disease associated with steatosis, inflammatory or fibrotic cytokines, chemokines, enzymes or biomarkers) can be treated with a pharmaceutical composition or formulation prepared from or containing solid-state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester of the present disclosure.

[0125] As mentioned above, the present invention also provides a method for treating a human subject who needs testosterone therapy. The method may include the step of administering any pharmaceutical composition or dosage form (e.g., capsule or tablet) disclosed herein. Pharmaceutical compositions and dosage forms of the present invention may be used to treat any condition related to 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., capsules or tablets) 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 testicle syndrome, orchiectomy, Klinefelter's syndrome, post-castration, pseudo-anorchidism, hypopituitarism, endocrine impotence, infertility due to spermatogenesis disorders, impotence, male sexual dysfunction (MSD) (including conditions such as premature ejaculation, erectile dysfunction, loss of libido, etc.), micropenis and constitutional delayed sexual development, penis enlargement, appetite stimulation, testosterone deficiency associated with chemotherapy, testosterone deficiency associated with alcohol toxic injury, testosterone deficiency associated with heavy metal toxic injury, osteoporosis associated with androgen deficiency, and combinations thereof.

[0126] Other conditions that can be treated by the compositions and dosage forms disclosed herein include idiopathic gonadotropins, LHRH (luteinizing hormone releasing hormone) deficiency, or hypothalamic damage from tumors, trauma or radiation. Typically, these subjects have low serum testosterone levels but have gonadotropins in the normal or low range. In one embodiment, the composition or oral dosage form can be used to stimulate puberty in carefully selected males with significantly delayed puberty that is not secondary to pathological disorders. In another embodiment, the composition and oral dosage form can be used in female to male gender transition to maintain or restore male physical and gender characteristics, including body muscle mass, muscle tone, bone density, body mass index (BMI), enhance energy, motivation and endurance, restore sexual psychological activities, etc. In some embodiments, the pharmaceutical compositions and unit dosage forms of the present invention (e.g., prepared from or comprising the solid-state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester disclosed herein) can be useful in providing hormonal male contraception. In some embodiments, the pharmaceutical compositions and unit dosage forms of the present invention (e.g., prepared from or comprising the solid-state dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester disclosed herein) can be used to provide treatment for one or more symptoms associated with female sexual dysfunction, orgasmic disorders, osteoarthritis, hormonal male contraception. In addition, the pharmaceutical compositions and unit dosage forms of the present disclosure (e.g., prepared from or comprising the solid-state (17-β)-3-oxoandrost-4-ene-17-olate of the present disclosure) can be used to treat and / or improve patient-related outcomes, including the quality of life and health status of subjects suffering from endogenous testosterone deficiency.In some embodiments, the pharmaceutical compositions and unit dosage forms of the present disclosure (e.g., prepared from or comprising solid-state (17-β)-3-oxoandrost-4-ene-17-olate of the present disclosure) can be used to treat or ameliorate symptoms in a subject suffering from a condition such as cancer, sarcoma, melanoma, lymphoma, leukemia, advanced conditions associated with liver disease, advanced conditions associated with lung disease, advanced conditions associated with kidney disease, advanced conditions associated with musculoskeletal system disease, advanced conditions associated with cardiovascular disease, advanced conditions associated with blood disease, advanced conditions associated with endocrine gland disease, advanced conditions associated with gastrointestinal disease, conditions, advanced conditions related to skin diseases, advanced conditions related to reproductive organ diseases, advanced conditions related to central nervous system diseases, liver fibrosis, liver inflammation, liver steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre- / post-liver transplantation, cirrhosis, primary biliary cholangitis (PBC), lung diseases affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle wasting, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral adiposity, obesity, poor wound healing, large waist, and hereditary angioedema.

[0127] The following examples are provided to facilitate a clearer understanding of certain embodiments of the present disclosure and are not intended to be limiting thereof in any way.

[0128] Example 1: Preparation of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester

[0129] A non-limiting exemplary synthetic scheme for preparing the solid-state (17-β)-3-oxoandrost-4-ene-17-dodecanoate disclosed herein is outlined in more detail below. (17-β)-3-oxoandrost-4-ene-17-dodecanoate can be prepared using the following general scheme:

[0130] 1) Weigh (17-β)-hydroxy-4-androsten-3-one (0.1 mol) and place it in a 1000 mL 4NRB flask containing a stirring bar.

[0131] 2) Add pyridine (160 mL) to the flask.

[0132] 3) Place the flask in an ice water bath and equip it with a nitrogen inlet, addition funnel, thermocouple and stopper. Start stirring and nitrogen flow.

[0133] 4) Charge the funnel with a solution of the acid chloride (1.56 equivalents, such as lauroyl chloride) in heptane (160 mL) and assemble it with an adapter connected to a bubbler.

[0134] 5) Add the contents of the funnel dropwise over 30-40 minutes (Note: the internal temperature increases 5-7°C during the addition.)

[0135] 6) When the addition is complete, remove the bath and continue stirring.

[0136] 7) After 1 hour, the reaction mixture was transferred to a large separatory funnel and diluted with heptane (1000 mL) (Note: TLC at 1 hour indicated the reaction was complete).

[0137] 8) The heptane solution was washed with 800 mL portions of: cold water (2X), 0.05N NaOH, saturated NaHCO3 (2X), water, brine, and then dried over anhydrous Na2SO4 (about 50 g). It was then concentrated to dryness (rotary evaporator / T 浴 ≤30℃).

[0138] Example 2: Preparation of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester crystals

[0139] The reaction mixture or product of Example 1 (or material prepared by other routes) can be transferred to water, ethanol or methanol (or any other suitable solvent) and allowed to crystallize. The crystalline material can be filtered by suction, washed with water, dried over phosphorus pentoxide, and recrystallized from another solvent such as oleic acid, hexane, heptane, etc. (although this step is not required).

[0140] Example 3: Differential Scanning Calorimetry of Solid-State (17-β)-3-Oxoandrost-4-ene-17-dodecanoate

[0141] This example demonstrates that solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate has a distinctive melting point as determined using a differential scanning calorimeter. An appropriate amount of a crystalline form of solid (17-β)-3-oxoandrost-4-ene-17-dodecanoate was placed in a closed Pan Al crucible of a differential scanning calorimeter and heated from 0 to 100° C. The results of the first heating cycle are shown ( Figure 1 ), which shows two endothermic transition peaks of the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate disclosed herein at about 30-40° C. and about 50-65° C. In a specific aspect, based on the DSC results, the melting point of a specific crystalline form of the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate is identified to be at 51-63° C.

[0142] Example 4: XRD crystallography of solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate

[0143] As shown in the XRD spectrum, the solid state (17-β)-3-oxoandrost-4-ene-17-dodecanoate is crystalline or substantially crystalline, such as Figure 2 An example of a crystalline form of solid state (17-β)-3-oxoandrost-4-en-17-dodecanoate is shown in FIG. Figure 2 Well-defined peaks corresponding to the crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate in the solid state are shown, with little or no amorphous form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate (as indicated by the absence of an "amorphous halo" and peak broadening in the 2θ range of 5-30° in the spectrum).

[0144] Example 5: (17-β)-3-oxoandrost-4-ene-17-dodecanoic acid prepared by the general formulation method Pharmaceutical compositions or dosage forms of various esters

[0145] The pharmaceutical compositions or dosage forms described herein are composed of Figure 1 and 2 The specific crystalline form of solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester characterized by DSC and XRD as shown is formulated or prepared. The pharmaceutical composition or dosage form disclosed herein is prepared from a specific solid dodecanoic acid (17-β)-3-oxoandrost-4-ene-17-ester and at least one pharmaceutically acceptable carrier by any suitable method known to those skilled in the art or developed based on the teachings herein, the method comprising one or more of the following steps as non-limiting examples: aggregation, air suspension cooling, air suspension drying, spheronization, agglomeration, crushing, compression, pelletization, cryopelletization, encapsulation, extrusion, granulation, homogenization, inclusion complexation, freeze drying, nanoencapsulation, melting, mixing, molding, grinding, milling, pan coating, solvent dehydration, ultrasound, spheronization, spray cooling, spray congealing, spray drying, etc., such as Figure 3 shown.

[0146] It will be understood that the above compositions, dosage forms and / or modes of application only illustrate preferred embodiments of the present invention. Without departing from the spirit and scope of the present invention, many modifications and alternative arrangements may be envisioned by those skilled in the art, and the appended claims are intended to cover such modifications and arrangements. Therefore, although the present invention has been specifically and in detail described above in conjunction with what are currently considered to be the most practical and preferred embodiments of the present invention, it is obvious to those of ordinary skill in the art that modifications may be made without departing from the principles and ideas described herein, including but not limited to modifications in size, material, shape, form, function and mode of operation, assembly and use.

Claims

1. A pharmaceutical composition comprising at least one of the following or prepared from at least one of the following: a) a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate having an XRD pattern comprising at least five peaks selected from angles of 10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2 and 23.2±0.2 measured relative to 2θ, b) a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate having a melting point within at least one of the following ranges: about 58.3±10°C, about 58.3±9°C, about 58.3±8°C, about 58.3±7°C, about 58.3±6°C, about 58.3±5°C, about 58.3±4°C, about 58.3±3°C, about 58.3±2°C, about 58.3±1°C, about 58.3±0.5°C, and about 58.3±0.25°C, and c) A fluent material comprising a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate or prepared from a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate.

2. The pharmaceutical composition according to claim 1, wherein the at least five peaks include at least one of 6 peaks, 7 peaks, and more than 7 peaks.

3. The pharmaceutical composition of claim 1, wherein the crystalline form comprises a plurality of microcrystals having a size ranging from about 40 nm to about 60 nm.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises at least one additive.

5. The pharmaceutical composition of claim 4, wherein the at least one additive comprises at least one of a solubilizer and a surfactant. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition further comprises a pharmaceutical composition for oral or injectable administration.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises at least one of a tablet, a capsule, a caplet, a gel capsule, a suspension, a solution, a beverage, a gel, a syrup, a dispersion, an emulsion, a spray, a lozenge, a microemulsion, a nanoemulsion, an elixir, a paste, a powder, and granules, and wherein the pharmaceutical composition for injectable administration further comprises at least one of an intravenous injectable, an intramuscular injectable, a subcutaneous injectable, an intradermal injectable, an intraspinal injectable, an intrathecal injectable, and an intraarterial injectable, including at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises at least one carrier.

9. The pharmaceutical composition of claim 8, wherein the at least one carrier further comprises at least one of a lipophilic carrier and a hydrophilic carrier.

10. The pharmaceutical composition of claim 9, wherein the at least one lipophilic carrier further comprises at least one of a lipophilic surfactant and a lipophilic additive, and wherein the hydrophilic carrier further comprises at least one of a hydrophilic surfactant and a hydrophilic additive.

11. The pharmaceutical composition of claim 10, wherein the at least one lipophilic carrier comprises at least one of fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherol, tocopherol succinate, tocopherol acetate, and fish oil, and wherein the hydrophilic carrier comprises at least one of polyoxyethylene hydrogenated vegetable oils, polyoxyethylene vegetable oils, polyethylene glycol fatty acid esters, polyethylene glycol fatty acid monoglyceride mixtures, polyethylene glycol fatty acid diglyceride mixtures, polysorbates, polyethylene glycol derivatives of tocopherol, alcohols, and alcohol derivatives.

12. The pharmaceutical composition of claim 11, wherein the at least one fatty acid comprises at least one of oleic acid, lauric acid, stearic acid and derivatives thereof, and wherein the vegetable oil comprises at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil and derivatives thereof, and wherein the monoglyceride derivative comprises at least one of monolinoleyl glyceride and sorbitan monofatty acid, and wherein the diglyceride derivative comprises palmitostearin, and wherein the polyoxyethylene hydrogenated vegetable oil comprises PEG hydrogenated castor oil, and wherein the alcohol comprises at least one of ethanol and benzyl alcohol, and wherein the alcohol derivative comprises benzyl benzoate.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is used to treat a condition requiring testosterone.

14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used to treat at least one of the following: cancer, sarcoma, melanoma, lymphoma, leukemia, advanced liver disease, advanced lung disease, advanced kidney disease, advanced musculoskeletal system disease, advanced cardiovascular disease, advanced blood disease, advanced endocrine gland disease, advanced gastrointestinal disease, advanced skin disease, advanced reproductive organ disease, advanced central nervous system disease, liver fibrosis, liver inflammation, liver steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic NAFLD, pre / post liver transplantation, cirrhosis, primary biliary cholangitis (PBC), lung disease affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), sarcopenia, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral lipomatosis, obesity, poor wound healing, large waist, and hereditary angioedema.

15. A pharmaceutical composition comprising or prepared from a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate, wherein the composition is used to treat at least one of: cancer, sarcoma, melanoma, lymphoma, leukemia, advanced liver disease, advanced lung disease, advanced kidney disease, advanced musculoskeletal system disease, advanced cardiovascular disease, advanced blood disease, advanced endocrine gland disease, advanced gastrointestinal disease, advanced skin disease, advanced reproductive organ disease, advanced central nervous system disease, liver fibrosis , liver inflammation, liver steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre / post liver transplantation, cirrhosis, primary biliary cholangitis (PBC), lung disease affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), sarcopenia, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral adiposity, obesity, poor wound healing, large waist, and hereditary angioedema.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition further comprises at least one of the following or is prepared by at least one of the following: a) a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate having an XRD pattern comprising at least five peaks selected from angles of 10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2 and 23.2±0.2 measured relative to 2θ, b) a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate having a melting point within at least one of the following ranges: about 58.3±10°C, about 58.3±9°C, about 58.3±8°C, about 58.3±7°C, about 58.3±6°C, about 58.3±5°C, about 58.3±4°C, about 58.3±3°C, about 58.3±2°C, about 58.3±1°C, about 58.3±0.5°C, and about 58.3±0.25°C, and c) A fluent material comprising a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate or prepared from a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate.

17. The pharmaceutical composition of claim 16, wherein the at least five peaks include at least one of 6 peaks, 7 peaks, and more than 7 peaks.

18. The pharmaceutical composition of claim 15, wherein the crystalline form comprises a plurality of crystallites having a size ranging from about 40 nm to about 60 nm.

19. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition further comprises at least one additive.

20. The pharmaceutical composition of claim 19, wherein the at least one additive comprises at least one of a solubilizer and a surfactant.

21. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition further comprises a pharmaceutical composition for oral or injectable administration.

22. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition further comprises at least one of a tablet, a capsule, a caplet, a gel capsule, a suspension, a solution, a beverage, a gel, a syrup, a dispersion, an emulsion, a spray, a lozenge, a microemulsion, a nanoemulsion, an elixir, a paste, a powder, and granules, and wherein the pharmaceutical composition for injectable administration further comprises at least one of an intravenous injectable, an intramuscular injectable, a subcutaneous injectable, an intradermal injectable, an intraspinal injectable, an intrathecal injectable, and an intraarterial injectable, including at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

23. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition further comprises at least one carrier.

24. The pharmaceutical composition of claim 23, wherein the at least one carrier further comprises at least one of a lipophilic carrier and a hydrophilic carrier.

25. The pharmaceutical composition of claim 24, wherein the at least one lipophilic carrier further comprises at least one of a lipophilic surfactant and a lipophilic additive, and wherein the hydrophilic carrier further comprises at least one of a hydrophilic surfactant and a hydrophilic additive.

26. The pharmaceutical composition of claim 25, wherein the at least one lipophilic carrier comprises at least one of fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherols, tocopherol succinate, tocopherol acetate, and fish oils, and wherein the hydrophilic carrier comprises at least one of polyoxyethylene hydrogenated vegetable oils, polyoxyethylene vegetable oils, polyethylene glycol fatty acid esters, polyethylene glycol fatty acid monoglyceride mixtures, polyethylene glycol fatty acid diglyceride mixtures, polysorbates, polyethylene glycol derivatives of tocopherols, alcohols, and alcohol derivatives.

27. The pharmaceutical composition of claim 26, wherein the at least one fatty acid comprises at least one of oleic acid, lauric acid, stearic acid and derivatives thereof, and wherein the vegetable oil comprises at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil and derivatives thereof, and wherein the monoglyceride derivative comprises at least one of monolinoleyl glyceride and sorbitan monofatty acid, and wherein the diglyceride derivative comprises palmitostearin, and wherein the polyoxyethylene hydrogenated vegetable oil comprises PEG hydrogenated castor oil, and wherein the alcohol comprises at least one of ethanol and benzyl alcohol, and wherein the alcohol derivative comprises benzyl benzoate.

28. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is used to treat a condition requiring testosterone.

29. A method of treating a condition in a subject, the method comprising administering to the subject a pharmaceutical composition, The pharmaceutical composition comprises at least one of the following or is prepared from at least one of the following: a) a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate having an XRD pattern comprising at least five peaks selected from angles of 10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2 and 23.2±0.2 measured relative to 2θ, b) a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate having a melting point within at least one of the following ranges: about 58.3±10°C, about 58.3±9°C, about 58.3±8°C, about 58.3±7°C, about 58.3±6°C, about 58.3±5°C, about 58.3±4°C, about 58.3±3°C, about 58.3±2°C, about 58.3±1°C, about 58.3±0.5°C, and about 58.3±0.25°C, and c) a fluent material comprising a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate or prepared from a crystalline form of (17-β)-3-oxoandrost-4-ene-17-dodecanoate, And wherein the condition comprises at least one of: cancer, sarcoma, melanoma, lymphoma, leukemia, advanced liver disease, advanced lung disease, advanced kidney disease, advanced musculoskeletal system disease, advanced cardiovascular disease, advanced blood disease, advanced endocrine gland disease, advanced gastrointestinal disease, advanced skin disease, advanced reproductive organ disease, advanced central nervous system disease, liver fibrosis, liver inflammation, liver steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre / post liver transplantation, cirrhosis, primary biliary cholangitis (PBC), lung disease affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle wasting, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral fat hyperplasia, obesity, poor wound healing, thick waist and hereditary angioedema.

30. The method of claim 29, wherein the at least five peaks include at least one of 6 peaks, 7 peaks, and more than 7 peaks.

31. The method of claim 29, wherein the crystalline form comprises a plurality of crystallites having a size ranging from about 40 nm to about 60 nm.

32. The method of claim 29, wherein the pharmaceutical composition further comprises at least one additive.

33. The method of claim 32, wherein the at least one additive comprises at least one of a solubilizer and a surfactant.

34. The method of claim 29, wherein the pharmaceutical composition further comprises a pharmaceutical composition for oral or injectable administration.

35. The method of claim 29, wherein the pharmaceutical composition further comprises at least one of a tablet, a capsule, a caplet, a gel capsule, a suspension, a solution, a beverage, a gel, a syrup, a dispersion, an emulsion, a spray, a lozenge, a microemulsion, a nanoemulsion, an elixir, a paste, a powder, and granules, and wherein the pharmaceutical composition for injectable administration further comprises at least one of an intravenous injectable, an intramuscular injectable, a subcutaneous injectable, an intradermal injectable, an intraspinal injectable, an intrathecal injectable, and an intraarterial injectable, including at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

36. The method of claim 29, wherein the pharmaceutical composition further comprises at least one carrier.

37. The method of claim 36, wherein the at least one carrier further comprises at least one of a lipophilic carrier and a hydrophilic carrier.

38. The method of claim 37, wherein the at least one lipophilic carrier further comprises at least one of a lipophilic surfactant and a lipophilic additive, and wherein the hydrophilic carrier further comprises at least one of a hydrophilic surfactant and a hydrophilic additive.

39. The method of claim 38, wherein the at least one lipophilic carrier comprises at least one of fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherol, tocopherol succinate, tocopherol acetate, and fish oil, and wherein the hydrophilic carrier comprises at least one of polyoxyethylene hydrogenated vegetable oils, polyoxyethylene vegetable oils, polyethylene glycol fatty acid esters, polyethylene glycol fatty acid monoglyceride mixtures, polyethylene glycol fatty acid diglyceride mixtures, polysorbates, polyethylene glycol derivatives of tocopherol, alcohols, and alcohol derivatives.

40. The method of claim 39, wherein the at least one fatty acid comprises at least one of oleic acid, lauric acid, stearic acid, and derivatives thereof, and wherein the vegetable oil comprises at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and derivatives thereof, and wherein the monoglyceride derivative comprises at least one of monolinoleyl glyceride and sorbitan monofatty acid, and wherein the diglyceride derivative comprises palmitostearin, and wherein the polyoxyethylene hydrogenated vegetable oil comprises PEG hydrogenated castor oil, and wherein the alcohol comprises at least one of ethanol and benzyl alcohol, and wherein the alcohol derivative comprises benzyl benzoate.

41. The method of claim 29, wherein the pharmaceutical composition is used to treat a condition requiring testosterone.

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