(17-)-3-Oxoandrost-4-en-17-yl dodecanoate Compositions and Methods for Their Preparation and Use

Abstract

[Solution] Disclosed are bioavailable solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate compositions and methods for administering the same to a mammal in need thereof. The (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is preferably provided in a solid-state crystalline form having multiple peaks corresponding to those shown in Figure 2, multiple crystallites ranging in size from about 40 nm to about 60 nm as identified via powder X-ray diffraction spectroscopy, and a melting point ranging from about 51 °C to about 63 °C. The compositions can be provided in oral or injectable dosage forms for the treatment of conditions requiring testosterone therapy. Exemplary chemical structures of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate compositions disclosed herein are as follows: TIFF2025529926000005.tif25141

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This PCT patent application claims the benefit under PCT Rule 4.10 of pending U.S. patent application Ser. No. 16 / 953,607, filed November 20, 2020, and scheduled to issue as U.S. Patent No. 11,370,811 on June 28, 2022, which is expressly incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION Disclosed herein is a novel ester of dodecane fatty acid, (17-β)-3-oxoandrost-4-en-17-yl dodecanoate (see: https: / / pubchem.ncbi.nlm.nih.gov / compound / Dodecanoate), in solid form, and methods thereof for pharmaceutical use and pharmaceutical compositions suitable for administration to mammals (e.g., humans) in need thereof. [Background technology]

[0003] Various bioavailable solid esters suitable for pharmaceutical use and administration to mammals in need thereof are disclosed in the following U.S. patents and applications, all of which are expressly incorporated herein by reference in their entirety: 8,865,695, filed February 26, 2014, and issued October 21, 2014; 9,034,858, filed May 31, 2012, and issued May 19, 2015; 9,498,485, filed August 28, 2015, and issued November 22, 2016; and 9,498,485, filed September 26, 2016, and issued November 22, 2017. No. 9,757,389, filed on September 12, 2016; No. 2016 / 0184320, filed on August 28, 2015, and published on June 30, 2016; No. 2017 / 0035781, filed on June 22, 2016, and published on February 9, 2017; No. 2018 / 0125858, filed on August 8, 2017, and published on May 10, 2018; No. 2019,0275060, filed on August 6, 2018, and published on September 12, 2019; and No. 2020 / 0046731, filed on February 12, 2019, and published on February 13, 2020 (this patent).

[0004] Different solid forms of esters of active pharmaceutical ingredients (APIs) or esterified active pharmaceutical ingredients (EAPIs) can have different properties that can provide specific advantages to formulations containing EAPIs. For example, they can improve processing and handling characteristics, favorably alter dissolution properties, or improve stability (polymorphic and chemical stability) and shelf life. These changes in the properties of different solid forms can also benefit the final formulation, for example, by providing or contributing to improved bioavailability. Different solid forms of EAPIs can also give rise to diverse polymorphs and crystalline forms, which may provide additional opportunities to evaluate changes in the properties and characteristics of solid EAPIs.

[0005] An important characteristic of an EAPI is that its dissolution or release rate does not change substantially over time. Changes in the dissolution or release rate of an EAPI over time can result in different pharmacokinetic properties that can change or alter the efficacy or safety of a drug product, even if the product is identical except for its solid form (e.g., has the same EAPI, formulation ingredients, and amounts thereof).

[0006] The stability of the EAPI in the pharmaceutical formulation (e.g., composition or unit dosage form) is also important. For example, if the EAPI changes physical form (e.g., crystalline form or amount) in the pharmaceutical composition or unit dosage form, this may affect the pharmacokinetic properties and, therefore, the safety and efficacy parameters.

[0007] To be useful, solid forms must be stable. The literature is replete with examples of drug substances and pharmaceutical compositions / formulations that have changed physical form, resulting in significant problems for patients taking these drugs. A well-known example is the temporary withdrawal of ritonavir from the market after it underwent a change in crystalline form and failed dissolution tests (see Morrissette et al. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2180-4). Other notable cases include the 2008 recall of a lot of Neupro (rotigotine) due to the emergence of a new polymorph; the 2010 recall of 1.5 million warfarin tablets due to concerns about 2-propanol concentration (which could affect the crystallinity of the API); and the 2010 recall of 60 million Avalide tablets due to concerns about the variability of the amount of a less soluble polymorph of irbesartan. See Lee et al. Annu. Rev. Chem. Biomol. Eng. 2011, 2, 259-280.

[0008] The absorption of prodrugs, such as ester derivatives of APIs (EAPIs), must be managed to provide adequate and sustained concentrations of the APIs derived from the EAPI in the body and avoid additional safety issues associated with esters and their metabolites. The solubility, release, dissolution, and partitioning of EAPIs in a particular solvent depend on their lipophilicity and are related to their solid-state properties, such as crystalline form, solvation, and the presence or absence of amorphous material. Therefore, the solid-state physical form is one of the key characteristics for achieving a safe and effective concentration of the API in terms of ease of manufacturing, storage, and EAPI performance.

[0009] Although esters of (17-β)-hydroxyandrosten-3-one are considered biologically inactive, they are known to be converted in the body to related metabolites, such as (17-β)-hydroxyandrosten-3-one and (17-β)-hydroxy-5α-androstan-3-one, which are biologically active molecules. Therefore, they can be used to treat patients requiring (17-β)-hydroxyandrosten-3-one therapy. However, insufficient solubility, release, dissolution, distribution, and / or physical stability in the solid state of EAPIs can reduce the bioavailability of (17-β)-hydroxyandrosten-3-one, a useful hormone useful in the treatment of diseases requiring (17-β)-hydroxyandrosten-3-one, such as hypogonadism in men or women, pulmonary disease, and liver disease.

[0010] 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 (17-β)-hydroxy-4-androsten-3-one esters, sufficient absorption and conversion to the parent drug remain key design factors in preparing and identifying solid esters of (17-β)-hydroxy-4-androsten-3-one. Previous approaches have not disclosed or adequately characterized specific solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate compounds that could be used to facilitate the development of pharmaceutical compositions.

[0011] Steroids, including testosterone and steroid esters such as testosterone esters, are known to exhibit different solid-state properties with different properties including solubility, bioavailability, and absorption (see, e.g., Ballard BE, Biles J, Steroids, 1964; 4: 273; Bouche R, Draguet-Brughmans M, J Pharm Belg, 1977; 32: 347; Carless et al. Journal of Pharmacy and Pharmacology Volume 20, Issue 8, pages 630-638, August 1968; Borka & Haleblian (1990) Acta Pharm. Jugosl. 40: 71-94).

[0012] Esterification of testosterone with dodecanoic acid (lauric acid) is preferable because lauric acid is a saturated medium-chain fatty acid (MCFA) with 12 carbon atoms and has certain health benefits. A stable, bioavailable solid-state form of (17-β)-3-oxoandrosten-4-en-17-yl dodecanoate is needed as a potential new drug for male or female hypogonadism, pulmonary disease, sarcopenia (https: / / society-scwd.org / sarcopenia / ), cachexia (https: / / society-scwd.org / cachexia / ), muscle wasting (https: / / society-scwd.org / muscle-wasting / ), or liver disease. These forms are suitable for treating patients requiring (17-β)-hydroxy-4-androsten-3-one. Summary of the Invention

[0013] It has been found that not all solid forms of dodecanoate ester derivatives of (17-β)-hydroxy-4-androsten-3-one are suitable for treating mammals requiring (17-β)-hydroxy-4-androsten-3-one. It has been found that certain solid-state dodecanoate ester derivatives of (17-β)-hydroxy-4-androsten-3-one are more suitable for human administration (e.g., for treating or preventing a disease or condition) if at least 0.001% (e.g., 0.01%, 0.1%, 1.0%, or 10%) of the derivative dissolves in 1000 mL of aqueous solution containing 8% Triton X-100 within 30 minutes when agitated at 100 rpm at 37°C using a USP Type 2 apparatus.

[0014] Furthermore, it has been found that selected solid forms of the compositions described herein have sufficient bioavailability. In one embodiment, a composition is provided for administration to a human subject in need of (17-β)-hydroxy-4-androsten-3-one treatment. For example, the composition comprises or is made from a) solid-state (17-β)-3-oxoandrosten-4-en-17-yl dodecanoate and b) a pharmaceutically acceptable carrier, wherein when the solid-state (17-β)-3-oxoandrosten-4-en-17-yl dodecanoate is orally administered to the human subject, at least about 0.1%, 0.5%, 1%, 2%, 3%, 5%, 8%, or 10% of the (17-β)-hydroxy-4-androsten-3-one (testosterone) equivalent is bioavailable to the human subject.

[0015] Therefore, in one embodiment, a solid-state EAPI is provided which is (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. The solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is crystalline. In certain embodiments, the crystalline solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is a crystalline form that is substantially free of other non-crystalline forms. In another specific embodiment, the crystalline solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate described herein is substantially free of amorphous forms.

[0016] The solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate provided herein has a particle size distribution characteristic. In certain embodiments, the particle size of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is less than 200 nm (nanometers), 200-500 nm, 500-1000 nm, 1-50 μm (micrometers), 50-250 μm, 250-500 μm, 500-1000 μm, or greater than 1000 μm. In other embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate has a particle size distribution characteristic. 50 In a further related embodiment, the (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state has a D 10 , D 50 , or D 90 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 specific embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having the particle size distribution or size characteristics is crystalline. In another specific embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having the particle size distribution or size characteristics is a crystalline form substantially free of other amorphous forms.

[0017] The pharmaceutical compositions provided herein comprise or are prepared from the solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate described in the preceding paragraph.For example, the pharmaceutical compositions comprise or are prepared from solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and one or more pharmaceutically acceptable excipients, carriers, or additives.The pharmaceutical compositions described herein can comprise or be prepared from crystalline solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.In some embodiments, the pharmaceutical compositions comprise or are prepared from solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, which is unmilled, milled, micronized, or nanoized. In certain embodiments, pharmaceutical compositions comprise or are prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and have a particle size of less than 200 nm, 200-500 nm, 500-1000 nm, 1-50 μm, 50-250 μm, 250-500 μm, 500-1000 μm, or greater than 1000 μm. In other embodiments, pharmaceutical compositions comprise or are prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and have a particle size of greater than 1000 μm, 355-1000 μm, 180-355 μm, 125-180 μm, 90-125 μm, 1-90 μm, or less than 1 μm. 50 In further related embodiments, the pharmaceutical composition comprises or is prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and has a D of less than 200 nm, 200-500 nm, 500-1000 nm, 1-50 μm, 50-250 μm, 250-500 μm, 500-1000 μm, or greater than 1000 μm. 10 , D 50 , or D 90In some specific embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate pharmaceutical composition is formulated for topical, enteral, or parenteral administration. In some embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate pharmaceutical composition is formulated for buccal, sublingual, or sublabial administration. In some specific embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate pharmaceutical composition is formulated for nasal, rectal, or vaginal administration. In some specific embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate pharmaceutical composition is formulated for intravenous, subcutaneous, intramuscular, intradermal, intraspinal, intrathecal, or intraarterial administration. In some specific embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate pharmaceutical composition is formulated as a liquid, solution, suspension, dispersion (see https: / / en.wikipedia.org / wiki / Dispersion_(chemistry)), solid, semi-solid, gel, lotion, paste, foam, spray, suspension, dispersion, syrup, or ointment. In some specific embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate pharmaceutical composition is formulated as a tincture, patch, injectable, or oral dosage form. In some embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate pharmaceutical composition comprises dissolved or partially dissolved (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. In one embodiment, the pharmaceutical composition or unit dosage form is suitable for oral administration (eg, a capsule or tablet).

[0018] Provided herein are pharmaceutical compositions or unit dosage forms comprising or prepared from the solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate described in the paragraph above.

[0019] Additionally, described herein is a method of using solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate for pharmaceutical compositions capable of treating men or women in need of (17-β)-hydroxy-4-androsten-3-one (testosterone). [Brief explanation of the drawings]

[0020] [Figure 1] 1 is a plot of the thermal enthalpy change for the first thermal cycle of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein, measured by differential scanning calorimetry. [Figure 2] 1 shows the results of an XRD measurement of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein, including eight distinguishable peaks indicative of the crystalline structure. [Figure 3] As disclosed herein, a general formulation process is provided for producing various forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in pharmaceutical compositions or dosage forms with the goal of improving physical, chemical, pharmacokinetic, and pharmacodynamic properties to enhance bioavailability. [Figure 4] Two microscopic images of particles of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate used in the pharmaceutical compositions or dosage forms described herein are shown at 20 μm and 5 μm scales. The particles of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate have a particular shape, such as a flat, thin panel shape. DETAILED DESCRIPTION OF THE INVENTION

[0021] Before describing embodiments of the present invention, it is to be understood that the disclosure herein is not limited to the particular structures, steps, or materials described herein but extends to equivalents recognized by those skilled in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular examples or embodiments, and is not intended to be limiting.

[0022] Furthermore, the described features, structures, or characteristics may be combined as appropriate in one or more embodiments. The following description provides numerous specific details, such as compositions, dosage forms, and treatment examples, to provide a thorough understanding of various inventive embodiments. However, those skilled in the art will recognize that these detailed embodiments are merely illustrative and do not limit the overall inventive concepts presented herein.

[0023] Unless the context clearly requires otherwise, the singular forms "a," "an," and "the" are intended to include the plural. Thus, for example, reference to "an excipient" refers to one or more excipients, and reference to "the carrier" refers to one or more carriers.

[0024] As used herein, the terms "treat," "treatment," "treating," and the like refer to the administration of a therapeutic agent to a subject infected with an asymptomatic or symptomatic pathogen. In other words, "treat," "treatment," or "treating" can refer to the alleviation, amelioration, or elimination of symptoms experienced in an infected subject.

[0025] As used herein, the term "androgen receptor agonists" refers to compounds, molecules, or agents, such as testosterone, that bind to and activate the androgen receptor. Examples of androgen receptor agonists include, but are not limited to, dihydrotestosterone, mibolerone, testosterone, alkylated testosterone, testosterone ester derivatives, methyltrienolone, oxandrolone, nandrolone, fluoxymesterone, and the like. Where appropriate, fatty acid esters of these androgen receptor agonists may also be used herein.

[0026] As used herein, the term "testosterone ester" refers to testosterone esterified with a fatty acid. Exemplary testosterone esters include, but are not limited to, testosterone udecanoate, testosterone decanoate, testosterone dodecanoate, testosterone tridecanoate, testosterone decanoate, testosterone enanthate, testosterone palmitate, testosterone cypionate, and testosterone propionate.

[0027] As used herein, the term "testosterone agent" refers to an active agent that induces the physiological actions or effects of testosterone in the body. Examples of testosterone agents are described throughout this specification. One example of a testosterone agent is testosterone (T). Another example is a testosterone ester, such as testosterone undecanoate or testosterone tridecanoate.

[0028] As used herein, the terms "therapeutic agent," "active agent," and similar terms refer to an agent that provides a beneficial or positive effect to a subject when administered to the subject in an appropriate or effective amount, and can be used interchangeably. In one embodiment, the therapeutic agent or active agent can be an androgenic steroid. The terms "additional active agent," "supplemental active agent," "secondary active agent," and similar terms can be used interchangeably and refer to a compound, molecule, or substance other than an androgenic steroid that exhibits physiological activity when administered to a subject in an effective amount.

[0029] 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 embodiments, the terms "formulation" and "composition" may be used to refer to a mixture of one or more active agents with a carrier or other excipient. Additionally, the term "dosage form" may include one or more formulations or compositions provided for administration to a subject. For example, an "oral dosage form" may be suitable for administration to the mouth of a subject. A "topical dosage form" may be suitable for administration, such as by application to the skin of a subject.

[0030] As used herein, "subject" refers to an animal. In one embodiment, the animal is a mammal. In another embodiment, the mammal is a human.

[0031] As used herein, "in need of treatment" refers to a subject who is diagnosed with or suspected of having a disease, or who desires or is suggested to receive treatment, according to various diagnostic criteria used in routine medical practice. Thus, "in need of treatment" may include the step of identifying a subject who needs treatment.

[0032] As used herein, "identifying a subject in need of treatment" may include obtaining a biological sample from the subject and measuring the level of one or more biomarkers described herein (e.g., RT-PCR detection of viral genes), evaluating the biological sample obtained from the subject, performing imaging analysis on the subject, evaluating one or more clinical characteristics of the subject (e.g., evaluating symptoms or prominent symptoms), or a combination thereof.

[0033] As used herein, an "acute" condition refers to a condition that develops rapidly and has clear symptoms that require urgent or near-urgent treatment. In contrast, a "chronic" condition refers to a condition that usually develops slowly and persists or progresses over time. Examples of acute conditions include, but are not limited to, asthma attacks, bronchitis, myocardial infarction, pneumonia, etc. Examples of chronic conditions include, but are not limited to, arthritis, diabetes, high blood pressure, high cholesterol, etc.

[0034] The terms "serum testosterone" or "serum (17-β)-hydroxy-4-androsten-3-one levels," "serum T levels," "serum testosterone concentration," "plasma testosterone concentration," "testosterone concentration in the blood," and "serum testosterone concentration" are used interchangeably and refer to "total serum testosterone levels," which are the sum of bioavailable testosterone, including the percentage of free and bound testosterone. As with any biological measurement method, the method used to measure initial serum testosterone levels will be consistent with the method used to monitor and remeasure serum testosterone levels in subjects during clinical trials and testosterone therapy. Unless otherwise specified, "testosterone concentration" refers to total serum testosterone concentration.

[0035] The mean serum testosterone level can be determined using methods and techniques known in the art. For example, the mean baseline plasma testosterone concentration in a human male is the arithmetic mean of the total plasma testosterone concentration measured at at least two consecutive time points, with these time points appropriately spaced apart (e.g., about 1 hour to about 168 hours). In certain cases, the plasma testosterone concentration can be measured two or more times at intervals of about 12 hours to about 48 hours. In another specific method, the plasma testosterone concentration in a human male can be measured between 5:00 AM and 11:00 AM. Furthermore, the plasma testosterone concentration can be determined by standard analytical techniques used in the art, such as automated or manual immunoassays, liquid chromatography, or liquid chromatography-tandem mass spectrometry (LC-MSMS).

[0036] As used herein, with respect to physiological levels of a particular substance, the term "baseline" refers to the level or concentration of the substance in a subject prior to administration of an active agent. For example, a subject's baseline serum testosterone level is the subject's testosterone serum level immediately prior to (e.g., immediately prior to) initiating testosterone administration or treatment.

[0037] As used herein, "free testosterone serum concentration" refers to the fraction of total testosterone that is not bound to proteins (e.g., SHBG (see: https: / / en.wikipedia.org / wiki / Sex_hormone-binding_globulin) or albumin). In one embodiment of the methods described herein, free testosterone serum concentration may be used instead of total serum testosterone concentration. For example, a subject may be considered testosterone-deficient based on free testosterone levels even though they appear to be within the normal range for total serum testosterone levels. As used herein, the terms testosterone serum level or testosterone serum concentration should be understood to explicitly refer to free testosterone serum concentration, unless the context or description clearly indicates otherwise.

[0038] The term "oral administration" refers to any method in which an active agent is administered by swallowing, chewing, or sucking a dosage form. Oral administration may be for enteral or transmucosal administration of the active agent. In some embodiments of the invention, the composition may be mixed with food or drink before being orally ingested.

[0039] As used herein, a "dosing regimen" or "regimen," such as an "initial dosing regimen" or "starting dose" or "maintenance dosing regimen," refers to how, when, how much, and for how long a composition of the invention is administered to a subject. For example, an initial dosing regimen or starting dose for a subject may include a total daily dose of about 15 mg to about 1500 mg, administered in two divided doses at least 12 hours apart (e.g., once at breakfast and once at dinner), repeated daily with meals for 30 days.

[0040] As used herein, a "daily dose" refers to the amount of an active agent (e.g., a testosterone ester) administered to a subject over a 24-hour period. A daily dose may be administered one or more times within a 24-hour period. In one embodiment, a daily dose is administered twice within a 24-hour period. In this context, an "initial dose" or "initial daily dose" refers to the amount administered at the initial time or time of a dosing regimen.

[0041] As used herein, an "effective amount" or "therapeutically effective amount" of a drug refers to a nontoxic, sufficient amount necessary to achieve a therapeutic effect in treating a disease for which the drug is known to be effective. It is understood that various biological factors can affect the ability of a substance to achieve its intended purpose. Thus, an "effective amount" or "therapeutically effective amount" may, in some cases, depend on such biological factors. Furthermore, while the achievement of a therapeutic effect can be measured by a physician or other qualified medical professional using assessments known in the art, it is recognized that the achievement of a therapeutic effect can be somewhat subjective due to individual variations and response to treatment. Determining an effective amount is within the ordinary skill of one in the art of pharmaceutical science and medicine. See, for example, Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis," Monographs in Epidemiology and Biostatistics, Vol. 8 (1986).

[0042] As used herein, the term "single unit" refers to a dosage form that is a single unit, e.g., one tablet, capsule, pump, or spray of gel or solution, when describing administration to a subject. The term "multiple unit" refers to a dosage form that contains two or more units, e.g., two capsules, three tablets, two to four pumps or sprays, when describing administration to a subject. Note that multiple unit dosage forms are generally the same type of dosage form (i.e., tablet or capsule), but are not necessarily the same dosage form type.

[0043] As used herein, the terms "comprises," "comprising," "containing," "having," and the like have the meanings given them in U.S. patent law, similar to the terms "includes," "including," and the like, and are generally interpreted in an open-ended sense. In contrast, the terms "consisting of" or "consists of" have a closed meaning, including only the components, structures, steps, etc. specifically recited with such terms, and are subject to U.S. patent law. Furthermore, the terms "consisting essentially of" or "consists essentially of" have the meanings given them in U.S. patent law. In particular, while such terms generally have a closed meaning, they permit the inclusion of additional items, materials, components, steps, or elements so long as these do not materially affect the basic and novel characteristics or function of the item with which they are employed. For example, trace elements contained in a composition that do not affect the properties or characteristics of the composition are permissible under the phrase "consisting essentially of," but do not need to be explicitly stated in the list of items following this phrase. When open-ended terms such as "comprising" or "including" are used in the description, it is understood that direct support should likewise be given for the phrases "consisting essentially of" and "consisting of," and vice versa.

[0044] It should be understood that the terms "first," "second," "third," "fourth," and the like, used in the specification and claims are used to distinguish between similar elements and do not necessarily refer to a particular order or temporal sequence. Accordingly, the terms used herein are interchangeable under appropriate circumstances, meaning, for example, that the embodiments described herein may be operated in an order other than the order presented. Similarly, when a method is described as including a series of steps, the order of the steps presented herein is not necessarily the only order in which the steps may be performed; certain steps may be omitted, and other steps not described herein may be added to the method.

[0045] As used herein, comparative terms such as "increased," "decreased," "better," "worse," "higher," "lower," "enhanced," "improved," "maximized," and "minimized" refer to a measurably different characteristic of a device, component, composition, biological response, biological state, or activity compared to other devices, components, compositions, biological responses, biological states, or activities in the surrounding or adjacent area. This includes a single device or composition, or multiple comparable devices or compositions in a similar location, in a group or class, in multiple groups or classes, or compared to a previous state (e.g., untreated) or baseline. For example, a composition that "increases" testosterone serum levels indicates that a subject's testosterone serum levels are elevated compared to a previous time point, e.g., a baseline (e.g., pre-treatment) or a previous, different treatment (e.g., a lower dose).

[0046] As used herein, the term "substantially" refers to the complete or nearly complete extent of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed means that the object is completely or nearly completely enclosed. The acceptable degree of deviation from absolute completeness may depend on the specific context. Generally speaking, however, the degree of completeness is such that it produces the same overall result as if it were completely and comprehensively achieved. The term "substantially" also applies when used in a negative sense, referring to the complete or nearly complete absence of an action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free of particles" means that it is completely or nearly completely free of particles, thereby producing the same effect as if it were completely free of particles. In other words, a composition that is "substantially free of" a certain component or element may actually contain that component or element, but as long as the effect is not measurable, the composition is considered "substantially free."

[0047] As used herein, the term "about" is used to provide flexibility for the endpoints of a numerical range, including the possibility that a particular value may be "slightly above" or "slightly below" that endpoint. Unless otherwise specified, when the term "about" is used in connection with a particular numerical value or numerical range, it should be understood to provide support for numerical values ​​or ranges that do not include that term. For example, if a numerical range of "about 50 angstroms to about 80 angstroms" is stated for convenience and brevity, it should be interpreted as providing support for the range "50 angstroms to 80 angstroms." Furthermore, even when the term "about" is used in this specification, it should be understood as providing support for the actual numerical value. For example, when "about" 30 is stated, it should be interpreted as providing support not only for values ​​slightly above or slightly below 30, but also for the actual numerical value 30 itself.

[0048] As used herein, a "plurality" of items, structural elements, compositional elements, and / or materials may be presented in common lists for convenience. However, these lists should be construed as though each member of the list is individually identified and separate and unique. Accordingly, the individual members of such lists should not be construed as de facto equivalents of other members solely based on their presentation within a common group, unless specifically indicated to the contrary.

[0049] Concentrations, amounts, levels, and other numerical data used herein may be expressed or presented in range format. Such range formats are used for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values, subranges, or fractional units contained within that range. For example, a numerical range of "about 1 to about 5" should be interpreted as including not only the explicitly recited values ​​of about 1 to about 5, but also each individual value and subrange within that range. Thus, this numerical range also includes individual values ​​such as 2, 3, and 4, as well as subranges such as 1 to 3, 2 to 4, and 3 to 5, and even individual numerical values ​​such as 1, 2, 3, 4, and 5. This same principle applies to ranges recited with a single numerical value as the minimum or maximum value. Furthermore, this interpretation should be applied regardless of the breadth of the range or the properties described.

[0050] As used herein, the term "an example" means that a particular feature, structure, or characteristic is described with reference to that example and is included in at least one embodiment. Thus, appearances of the phrase "in an example" herein do not necessarily refer to the same embodiment.

[0051] The term "API" refers to an active pharmaceutical ingredient or drug and refers to (17-β)-hydroxy-4-androsten-3-one (also known as testosterone), which is considered herein to be the biologically active drug. Furthermore, (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is converted in the body to (17-β)-hydroxy-5α-androstan-3-one (directly or via the corresponding ester), which is also biologically active, as well as other metabolites. The term "EAPI" refers to an ester of (17-β)-hydroxy-4-androsten-3-one, i.e., a precursor to the biologically active drug. While this EAPI may be biologically active without ester cleavage, for purposes of this invention, the API is considered to be (17-β)-hydroxy-4-androsten-3-one (testosterone).

[0052] Herein, AUC t1-t2 The term refers to the area under the curve of a plasma versus time graph determined for an analyte from t1 to t2, where t1 and t2 are times in hours after administration. For example, t1 can be 1 hour after administration and t2 can be 2 hours after administration.

[0053] As used herein, "C avg "," "C ave The terms "AUC" and "C-average" are used interchangeably. t1-t2 is calculated as the average value divided by time (|t1-t2|). For example, C avg t0-t8 is the average plasma concentration over 8 hours from t1 = 0 to t2 = 8 hours after administration, and AUC t0-t8 The value is calculated by dividing the value by 8 hours. avg t0-t12 is the mean plasma concentration 12 hours after administration, and AUC t0-t12 is calculated by dividing the value by 12 hours (t1=0 and t2=12). Similarly, C avg t12-t24 is the mean plasma concentration 12 hours after administration, and AUC t12-t24 Calculated by dividing the value by 12 hours (t1=12 and t2=24). C avg t0-t24is the mean plasma concentration 24 hours after administration, and AUC t0-t24 Calculated by dividing the value by 24 hours (t1=0 and t2=24). Unless otherwise stated, all C avg The value is C avg t0-t24 and all time values ​​are expressed in hours (h) unless otherwise stated. For example, C avg t0-t24 The term C from time 0 (0) to 24 hours after administration avg means.

[0054] As used herein, "C t The term "C" refers to the serum concentration of testosterone at time "t" after administration of the present invention. Time "t" is given in hours after administration unless otherwise specified. For example, "C" (-2~0) "C" t refers to the serum testosterone concentration measured in samples taken 2 hours or immediately before administration. (2~4) "C" t refers to serum testosterone concentrations measured in samples taken between 2 and 4 hours after administration.

[0055] 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]phenanthren-3-one and CAS number 58-22-0. (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate refers to a compound with this (17-β)-hydroxy-4-androsten-3-one structure in which the hydroxyl group at the 17th carbon of the testosterone structure is esterified with lauric acid (e.g., a 12-carbon 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-yl dodecanoate is the IUPAC name for (17-β)-hydroxy-4-androsten-3-one esterified with a linear, saturated, 12-carbon alkanoic acid called lauric acid. Dodecanoic acid, also known as lauric acid, is the IUPAC name for a saturated alkanoic acid with CAS number 143-07-7. In a more specific embodiment, (17-β)-3-oxoandrost-4-en-17-yl dodecanoate specifically refers to (17-β)-3-oxoandrost-4-en-17-yl laurate, as disclosed herein. In one particular embodiment, it refers to dodecanoic acid (17-β)-hydroxy-4-androsten-3-one ester (referred to herein as (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, (17-β)-3-oxoandrost-4-en-17-yl laurate, or dodecanoic acid ester of (17-β)-hydroxy-4-androsten-3-one and the like (CAS No. 59232-78-9)). (17-β)-3-oxoandrost-4-en-17-yl dodecanoate has the following chemical structure, shown in Chemical Formula 1: [ka]

[0056] (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state can exist in different crystalline and amorphous forms. The amorphous solid form, referred to herein as an "amorphous form," is a disordered arrangement of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate molecules. The different crystalline forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate result from different packing patterns of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate molecules in the solid state, resulting in different crystal symmetries and / or unit cell parameters. Crystalline forms may be identified or characterized by suitable methods, such as X-ray diffraction (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa., p. 173 (1990); The United States Pharmacopeia, 23rd ed., pp. 1843-1844 (1995)). Such different crystalline forms are referred to herein as "polymorphic forms" or "non-solvated forms," ​​meaning that they are substantially free of residual solvent, e.g., organic solvents. In contrast, when stoichiometric or non-stoichiometric amounts of water (referred to herein as "hydrates") or other solvents (referred to herein as "solvates") are incorporated into the crystalline structure, they are referred to as "pseudopolymorphic forms."

[0057] As used herein, the term "amorphous form," when used in reference to a solid state, refers to a non-crystalline solid form (i.e., not a crystalline form) in which (17-β)-3-oxoandrost-4-en-17-yl dodecanoate molecules are randomly arranged. Typically, (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the amorphous solid state does not have a long-range periodic molecular packing structure as measured by powder X-ray diffraction ("PXRD" or "XRD"). The XRD pattern of amorphous (17-β)-3-oxoandrost-4-en-17-yl dodecanoate appears as a halo without characteristic peaks. Amorphous forms of some compounds can be obtained by several methods known in the art, including, but not limited to, heating, melt-cooling, rapid melt-cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, freeze-grinding, spray-cooling, or freeze-drying.

[0058] As used herein, the terms "crystal," "crystallite," or "crystalline" refer to a solid structure generally formed by solidification or crystallization and having an ordered molecular packing structure (a specific shape and cleavage planes formed by the arrangement of molecules called a "lattice"). In one embodiment, multiple crystallites aggregate to form any crystal grain collection, which can then pack to form any particle. That is, the particle size is larger than the crystal grain size, and the crystal grain size is larger than any crystal size.

[0059] As used herein, the term "seeding" refers to the use of a small amount of a substance to initiate or promote crystallization.

[0060] As used herein, the term "Triton X100" or "Triton X-100" refers to a nonionic surfactant also known as polyethylene glycol p-(1,1,3,3-tetramethylbutyl)-phenyl ether, octylphenol ethoxylate, polyoxyethylene octylphenyl ether, 4-octylphenol polyethoxylate, Mono30, TX-100, t-octylphenoxypolyethoxyethanol, or Octoxynol-9, and is associated with CAS number 9002-93-1.

[0061] As used herein, the term "pharmaceutical composition" or "dosage form" refers to a composition comprising or prepared from solid (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and one or more pharmaceutically acceptable carriers, excipients, or additives. Further, exemplary compositions are any of the compositions described in the patents. As used herein, the term "unit dosage form" refers to a medicament prepared from or containing a pharmaceutical composition, and includes tablets, capsules, caplets, gel capsules, ampoules, suspensions, solutions, gels, dispersions, and dosage forms typically associated with parenteral, oral, topical, or other forms of administration of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate to a subject in need thereof.

[0062] As used herein, the terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "pharmaceutically acceptable additive," or similar terms refer to one or more ingredients that are acceptable because they are (1) compatible with the other ingredients in a composition or dosage form comprising (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and (2) not deleterious or unduly deleterious to a subject receiving the composition or dosage form. Excipients include any of the excipients described in the patents.

[0063] By applying the present invention, carriers (e.g., pharmaceutically acceptable excipients or additives) and methods for their preparation for use in preparing oral pharmaceutical compositions containing (17-β)-3-oxoandrost-4-en-17-yl dodecanoate are available to those skilled in the art, and typically include specific solid-state forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

[0064] Specific embodiments of the present invention will now be described in detail. While the invention will be described in conjunction with these embodiments, it should be understood that they are not intended to limit the invention to these embodiments. On the contrary, they are intended to cover alternatives, variations, modifications, and equivalents that are included within the spirit and scope of the invention.

[0065] Solid-state form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate The particular solid-state forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein have one or more advantageous properties compared to other forms, such as improved chemical or polymorphic purity, improved crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystalline habit, specific surface area and pycnometric density, bulk / tapped density, stability (e.g., chemical stability and thermal and mechanical stability against polymorphic transformation), stability against hydration and / or storage stability, low hygroscopicity, low residual solvent content, and advantageous processing and handling properties such as compressibility and bulk density. Provided herein are particular solid-state forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

[0066] (17-β)-3-oxoandrost-4-en-17-yl dodecanoate can be prepared by several synthetic routes (as well as by methods similar to those for other corresponding esters). For example, (17-β)-3-oxoandrost-4-en-17-yl dodecanoate can be prepared by esterification of (17-β)-hydroxy-4-androsten-3-one with the corresponding alcohol, activated fatty acid n-dodecanoic acid (IUPAC name: lauric acid, CAS number: 143-07-7) (e.g., lauroyl chloride or acid anhydride), under appropriate solvent and conditions (e.g., using pyridine as an esterification catalyst). In one embodiment, (17-β)-hydroxy-4-androsten-3-one (testosterone) is prepared from phytosterol, cholesterol, or other suitable starting materials. The reaction product can be purified by any suitable technique. For example, the product can be dissolved in a solvent (e.g., an organic solvent such as heptane) and then washed sequentially with cold water (twice), 0.05 N NaOH, saturated NaHCO3 (twice), water, and brine, dried over anhydrous Na2SO4 (~50 g), and then dried (e.g., by rotary evaporation / T bath<30°C). Without being bound by theory, the inventors have unexpectedly discovered that crystallizing or recrystallizing (17-β)-3-oxoandrost-4-en-17-yl dodecanoate provides a solid-state form having one or more advantageous properties described herein.

[0067] Thus, according to one embodiment, an example of a solid-state form of recrystallized or crystallized (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is provided herein. According to this embodiment, (17-β)-3-oxoandrost-4-en-17-yl dodecanoate can be dissolved in a solvent (e.g., heptane) and crystallized or recrystallized, or transferred to another solvent after initial crystallization and crystallized or recrystallized. The crystallized solid can be isolated (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 embodiment, 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 linoleaginous acid), an alkane (e.g., hexane, heptane, pentane, or a halogenated alkane), an oil (e.g., vegetable oil, castor oil, or hydrogenated oil), or other suitable solvent (e.g., pyridine, benzene, or toluene). In this context, solvent refers to a liquid in which (17-β)-3-oxoandrost-4-en-17-yl dodecanoate dissolves.

[0068] Crystalline forms of materials can be obtained by several methods known in the art. Exemplary methods for obtaining, generating, or preparing crystalline forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate include melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on surfaces or templates such as polymers, recrystallization in the presence of additives (such as co-crystal pair molecules), desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, milling, and solvent drop milling.

[0069] Generally, a particular crystalline form of an active pharmaceutical ingredient (API) (e.g., a testosterone ester) can be distinguished from other crystalline forms by one or more physical or chemical properties found in 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 (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 herein or available to one of skill in the art. Additionally, other methods for identifying or distinguishing between structural polymorphs, pseudopolymorphs, desolvated forms, or anhydrates include elemental analysis, Karl Fischer 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.

[0070] Thus, in one embodiment, a solid-state form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is provided, which has one or more advantageous properties compared to other forms, such as improved chemical or polymorphic purity, improved crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystalline habit, specific surface area and pycnometric density, bulk / tapped density, stability (e.g., chemical stability and thermal and mechanical stability against polymorphic transformation), stability against hydration and / or storage stability, low hygroscopicity, low residual solvent content, and advantageous processing and handling properties such as compressibility and bulk density. In a particular aspect of this embodiment, the disclosed solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is in a crystalline form. In further embodiments, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is useful for administration to humans. In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is a specific crystalline form characterized by analytical techniques known to those skilled in the art (e.g., by XRD and DSC, substantially as shown in the Examples and Figures).

[0071] In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate found herein exhibits two endothermic transfer peaks, which may indicate a change from one crystalline form to another solid state or phase change (e.g., a solid-to-liquid conversion). Figure 1 shows differential scanning calorimetry results showing the first cycle of thermal enthalpy change for the solid-state form (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein. In another embodiment, the small endothermic peak appearing in Figure 1 between 35 and 45 °C may be a glass transition peak, which may indicate a transition from a stable solid form to a metastable solid (e.g., an amorphous form). In a further embodiment, the small endothermic peak appearing in Figure 1 between 35 and 45 °C may be a lattice-forming transition peak, which may indicate a transition from a crystalline form to a different crystalline form. In one embodiment, another large endothermic peak appearing at 45-70°C indicates the melting point (e.g., a phase change from the solid state to the liquid state) of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein, as determined by differential scanning calorimetry. In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is a crystalline form having a melting point in the range of 45-70°C, 50-70°C, or 50-65°C, as determined by differential scanning calorimetry. In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is a crystalline form having a melting point in the specific range of 51-63°C, as determined by differential scanning calorimetry, as shown in FIG. 1.

[0072] In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is in a crystalline form having at least one, two, three, four, five, six, or more peaks as determined by XRD corresponding to Figure 2. In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is in an unmilled crystalline form or in a milled, micronized, or nanosized crystalline form. In one embodiment, the particle size of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is d 50 In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate has a particle size distribution of 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 one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate has a particle size distribution of 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. 10 , D 50 , or D 90 is less than 200 nm, 200-500 nm, 500-1000 nm, 1-50 μm, 50-250 μm, 250-500 μm, 500-1000 μm, or greater than 1000 μm. In one embodiment, the release profile of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate does not change substantially as a function of storage time.

[0073] Preparation of different forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in pharmaceutical compositions from the solid state Described herein are different solid-state forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, which can be produced by compositions containing optional excipients and carriers (e.g., solubilizers, surfactants, additives, etc.). The identification of different forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate provides improved physical, chemical, pharmacokinetic, and pharmacodynamic properties.

[0074] Several different crystalline forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate exist. The solid-state crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having a melting point of 55-65°C shown in Figure 1 and the solid-state crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having one, two, three, four, five, six, or more peaks identified by XRD shown in Figure 2 may be converted to at least one single crystalline form, amorphous form, polymorphic crystalline form, metastable solid form, or liquid form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate by forming a pharmaceutical composition containing at least one pharmaceutically acceptable excipient, carrier, or ingredient. In certain embodiments, various different forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate can be provided in pharmaceutical compositions by methods available to those skilled in the art based on the present disclosure (see Figure 3).

[0075] Experimental equipment and conditions for the analysis of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state A variety of techniques can be used to identify or characterize solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

[0076] Fourier transform Raman spectroscopy (FT-Raman) (see: https: / / www.sciencedirect.com / topics / chemistry / fourier-transform-raman-spectroscopy#:~:text=Near%2Dinfrared%20Fourier%20Transform%20Raman,advantages%20of%20the%20optical%20interferometer.) is useful for identifying and characterizing (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state. For example, to characterize (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in different solid states, a Bruker RFS100 instrument equipped with a Nd:YAG 1064 nm excitation, 300 mW laser power, and a Ge detector was used, with a wavelength range of 25-3500 cm. -1 64 scans were performed in the range of 2cm -1 As will be understood by those of ordinary skill in the art, the FT-Raman measurement conditions and instrument settings can be varied depending on the instrument used, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the purpose of the analysis.

[0077] Another useful technique for characterization is X-ray diffraction (XRD) (see https: / / en.wikipedia.org / wiki / Powder_diffraction). For example, XRD can be performed using a Bruker D8 Advance X-ray diffractometer with CuKα radiation. Typical measurement conditions are: tube voltage 40 kV / tube current 40 mA, step size 0.010° ​​(2θ), step time 57.6 s, scan range 3°–40° (2θ), divergence slit 0.600 mm, anti-scatter slit 4.800 mm, fixed slit mode, sample rotation speed 15,000° / min, LYNXEYE_XE detector (1D mode), goniometer radius 280.0 mm, nominal wavelength 1.54060 Å. As will be understood by those skilled in the art, the XRD measurement conditions and instrument settings can be varied depending on the instrument used, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the purpose of the analysis. In one embodiment, XRD indicates that the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is crystalline or substantially crystalline. An example of an XRD spectrum of a crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is shown in Figure 2. Figure 2 shows clear peaks corresponding to the crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, with little or no characteristic of an amorphous form (as evidenced by the absence of an "amorphous halo" and no peak broadening in the 5-30° 2θ range). In one embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate described herein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more of the peaks shown in Figure 2 with intensities of greater than 25, 50, 100, 150, or 200 counts. Intensities are random relative values ​​compared to those measured from a control.

[0078] Thermogravimetric Fourier transform infrared spectroscopy (TG-FTIR) (see: https: / / www.eag.com / resources / appnotes / thermogravimetric-analysis-fourier-transfer-infrared-spectroscopy-tga-ftir-services / ) can also be used to characterize or analyze solid-state (17-β)-3-oxoandrost-4-en-17-yl 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 micro-hole type) under a nitrogen atmosphere, with a heating rate of 10 °C / min, over the range of 25 °C to 350 °C. As one skilled in the art would understand, the TG-FTIR parameters and instrumentation can vary depending on the equipment used, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the purpose of the analysis.

[0079] Characterization / analysis of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate can also be performed using differential scanning calorimetry (DSC). For example, DSC can be performed using a Perkin Elmer differential scanning calorimeter with a closed PanAl crucible at a heating rate of 10°C / min over a temperature range of 0°C to 100°C (or, for example, 5°C to 150°C). See, for example, FIG. 1. As will be appreciated by those skilled in the art, DSC parameters and instrumentation can vary depending on the equipment used, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the purpose of the analysis. Thus, in yet another embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate provided herein has a melting point, as measured by DSC, in the range of about 45°C to 70°C. In one particular embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate provided herein has a melting point in the range of about 50° C. to 65° C. as measured by DSC. In a further particular embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate provided herein has a melting point in the range of about 55° C. to 65° C. as measured by DSC. In one aspect of this embodiment, the melting point of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is one of the properties of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. See FIG. 1.

[0080] Dynamic vapor sorption (DVS) analysis (see https: / / en.wikipedia.org / wiki / Dynamic_vapor_sorption) is another technique for characterizing and analyzing (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. For example, DVS can be performed using a Surface Measurement Systems DVS-1 water vapor sorption analyzer. The experiment can be performed by placing the sample in a quartz holder on a microbalance, allowing it to equilibrate at 50% relative humidity (RH), and then initiating a predefined humidity program. For example, the program could proceed as follows: hold at 50% RH for 1 hour; ramp from 50% RH to 0% RH at 5% RH / hr; hold at 0% RH for 5 hours; ramp from 0% RH to 96% RH at 5% RH / hr; hold at 95% RH for 5 hours; ramp from 95% RH to 50% RH at 5% RH / hr; hold at 50% RH for 1 hour. As one of ordinary skill in the art would understand, DVS parameters and instrumentation can vary depending on the equipment used, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the purpose of the analysis.

[0081] High performance liquid chromatography (HPLC) (see: https: / / en.wikipedia.org / wiki / High-performance_liquid_chromatography) is also useful for the analysis and characterization of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. In some embodiments, the purity of the crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate 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% as measured by HPLC. This measurement is based on the total area under the curve (AUC) observed at an appropriate wavelength, such as about 240 nm or about 250 nm. In some embodiments, the purity of the crystalline (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein is in the range of about 98.0% to 100.0% based on the AUC measured by HPLC, where the measurement is performed at a suitable wavelength, e.g., a wavelength in the range of about 200 nm to about 300 nm, e.g., about 240 nm or about 250 nm.

[0082] In some embodiments, the purity of the different forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the pharmaceutical composition 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 (AUC) observed at an appropriate wavelength, e.g., about 200 nm to about 300 nm, or about 240 nm to about 250 nm, as measured by HPLC. In some embodiments of the present invention, the purity of the different forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the pharmaceutical composition ranges from about 98.0% to 100.0% based on the AUC observed at an appropriate wavelength, e.g., about 200 nm to about 300 nm, e.g., about 240 nm or about 250 nm, as measured by HPLC.

[0083] As will be understood by those of skill in the art, based on the disclosure herein, solid-state NMR and other techniques can be used to analyze or characterize (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and its forms in the solid state.

[0084] Preparation of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate with different particle size distributions Compositions with different particle sizes or particle size distributions can be produced by any suitable method. Micronization techniques use friction to reduce particle size, including grinding, beating, and polishing. Another technique for producing (17-β)-3-oxoandrost-4-en-17-yl dodecanoate particles of different sizes uses supercritical fluids, in which (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is dissolved in a solvent at high temperature and pressure, and the mixture is sprayed through a nozzle to form particles of a specific size or a specific size range / distribution. These basic supercritical fluid technologies include the RESS process (rapid expansion of supercritical solution) (see: https: / / hightechextracts.com / the-science / rapid-expansion-of-supercritical-solution / #:~:text=Rapid%20Expansion%20of%20Supercritical%20Solution%20(RESS)%20is%20generally%20used%20to,solution%20through%20an%20expansion%20nozzle.) and the SAS method (supercritical antisolvent method) (see: http: / / hpp.uva.es / technology / formulation / supercritical-antisolvent-sa s / #:~:text=The%20Supercritical%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.).

[0085] Particle size distribution and morphology analysis The particle size distribution of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate particles can be analyzed by various techniques. For example, particle size distribution can be analyzed by photon correlation spectroscopy (PCS) (see: https: / / www.sciencedirect.com / topics / chemical-engineering / photon-correlation-spectroscopy) using a Malvern ZetaSizer 2000 HS (Malvern Instruments, Malvern, UK). The measurement mode used is, for example, Contin-Auto mode. PCS obtains the mean diameter (z-average) of the bulk population and the polydispersity index (PI), which ranges from 0 (monodisperse) to 0.10-0.20 (relatively monodisperse) or >0.5 (wide size distribution). The measurement range of PCS is approximately 3 nm to 3 μm. As one skilled in the art will appreciate, the PCS parameters and instrumentation can be varied depending on the instrument, the solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the purpose of the analysis.

[0086] Solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate particles can also be visually analyzed by scanning electron microscopy (SEM) (see: https: / / en.wikipedia.org / wiki / Scanning_electron_microscope). Solid particles are placed on a metal stub, placed under liquid nitrogen, and dried under vacuum. The metal stub is uniformly coated with gold or palladium. All samples are examined for morphology and surface properties using a scanning electron microscope (e.g., Joel SEM, JSM-25 SII, Tokyo, Japan). Particle size, polydispersity index, and zeta potential can be initially measured using a laser particle size analyzer (Submicron Particle Size Analyser 90 plus, Brookhaven Instrument Co., Holtsville, NY, USA). A sample of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate particles can be diluted with, for example, 3 ml of deionized water. The diluted (17-β)-3-oxoandrost-4-en-17-yl dodecanoate sample is loaded into a 4 ml cuvette, and particle size and zeta potential measurements are performed at room temperature. For example, as shown in Figures 1 and 2, characterized solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate particles were measured using a scanning electron microscope. Figure 4 shows that solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate particles exist as one or more crystallites, grains, and flat, thin, plate-like particles. As shown in Figure 4, the size ranges include one or more of the following: less than about 1 μm, about 1-5 μm, and about 5-50 μm. As one skilled in the art will appreciate, the parameters and equipment for the electron microscope can be varied depending on the instrument, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, and the purpose of the analysis.

[0087] The crystalline particle size of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein, which aggregates into particles of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, can also be estimated using XRD, as shown in FIG. 4. For example, by applying the Scherrer equation (see: https: / / en.wikipedia.org / wiki / Scherrer_equation), the size of the crystallites aggregated to form particles (e.g., crystalline particles or crystallites) in the solid can be calculated based on the peak broadening in the diffraction pattern. Generally, particles are formed from aggregates of crystal grains, and crystal grains are the aggregation of many crystallites in the solid state. Based on the XRD diffractogram shown in FIG. 4, the average crystallite size of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein was determined to be approximately 50 nm, with a standard deviation of approximately 7 nm. The average crystallite size was determined using the Schreier equation: where D is the crystallite size of the ordered regions, κ is the dimensionless Schreier constant (= 0.9), λ is the X-ray wavelength (= 0.15406 nm), β is the line broadening at half maximum intensity (FWHM) of each peak in radians, and θ is the peak position at 2θ. For example, Table 1 summarizes the crystallite sizes obtained from each peak (eight distinguishable peaks) measured using the Schreier equation as shown in Figure 2. TIFF2025529926000004.tif90141

[0088] Release profile of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in solid state In one embodiment, the release profile of the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate found herein (e.g., a profile comprising 2, 3, 4, 5, 6, or more time points measured at least 5, 10, or 15 minute intervals, or a single time point profile) does not change substantially as a function of storage time. Furthermore, the release of solid-state crystalline (17-β)-3-oxoandrost-4-en-17-yl dodecanoate is less than 10%, 9%, 8%, 7%, 6%, or 5% over at least 60 minutes, 120 minutes, 180 minutes, 240 minutes, 360 minutes, 24 hours, or 48 hours when measured using a USP Type 2 apparatus in about 1000 mL of 8% aqueous Triton X100 at a specified temperature (e.g., 20.0, 37.0, or 40.0°C (±0.5)). In one embodiment, the release profile of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate remains 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 embodiment, the release profile of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate remains 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 embodiment, the release test is conducted using a USP Type 2 apparatus in approximately 1000 mL of an 8% aqueous Triton X100 solution at 100 rpm at a specific temperature (e.g., 20.0, 37.0, or 40.0°C (±0.5)). In one embodiment, a release profile that remains substantially unchanged over a period of time refers to a release profile in which the amount of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate released at a specific time point under one or more specific conditions varies by less than ±50%, 40%, 30%, 20%, or 10%.

[0089] Pharmaceutical compositions containing or prepared from (17-beta)-3-oxoandrost-4-en-17-yl dodecanoate in solid state Pharmaceutical compositions and dosage forms (e.g., capsules or tablets) containing or prepared from the solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate described herein can contain various pharmaceutically acceptable carriers known in the art. Non-limiting examples of components that can be included as components of the pharmaceutical carrier include lipophilic surfactants, hydrophilic surfactants, triglycerides, fatty acids (C8-C22), fatty acid glycerides (mono-, di-, tri-, or combinations thereof), additives, or combinations thereof.

[0090] In one embodiment, a pharmaceutical composition or dosage form is provided comprising or prepared from the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate described herein. In one aspect, the pharmaceutical composition or dosage form is prepared from solid-state crystalline (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. In another aspect, the pharmaceutical composition or dosage form is prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having a specific crystalline morphology. In yet another aspect, the pharmaceutical composition or dosage form is prepared from a crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate characterized by DSC and XRD, as shown in Figures 1, 2, and 4.

[0091] In another embodiment, the crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state can be converted to an amorphous, substantially amorphous, partially amorphous, or amorphous-like form during a post-processing step of the composition or dosage form using a pharmaceutically acceptable carrier. Amorphous-like refers to a physical state of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in a dosage form or pharmaceutical composition, in which a significant amount of the (17-β)-3-oxoandrost-4-en-17-yl dodecanoate does not have a structured crystalline form (e.g., is dissolved or dispersed in a solvent). In another specific aspect of this embodiment, the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the pharmaceutical composition or dosage form can be in a semi-solid form or a form that is substantially free of crystalline form. In a further aspect of this embodiment, the (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state in the pharmaceutical composition or dosage form can retain a partially identical crystalline morphology.

[0092] In yet another embodiment, the pharmaceutical composition or dosage form is prepared from a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state, wherein the pharmaceutical composition comprises (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in an amorphous or amorphous-like solid state. In yet another embodiment, the pharmaceutical composition or dosage form is prepared from a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state, wherein the pharmaceutical composition is substantially free of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in an amorphous solid state. In yet another embodiment, the pharmaceutical composition or dosage form is prepared from a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state, and the pharmaceutical composition comprises solubilized (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

[0093] In one embodiment, a pharmaceutical composition or unit dosage form comprising or prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate has improved release characteristics compared to the release from a crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate without a 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-en-17-yl dodecanoate is dissolved in about 1000 mL of 8% Triton X-1000 using a USP Type 2 apparatus. When measured at 100 rpm at a particular temperature (e.g., 20.0, 37.0, or 40.0°C (±0.5)) in an X100 aqueous solution, the crystalline form releases more (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in a particular time (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) than the crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state. Releasing more (17-β)-3-oxoandrost-4-en-17-yl dodecanoate from a pharmaceutical composition or unit dosage form refers to releasing 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more more in a dissolution aqueous medium (e.g., an 8% Triton X100 solution) than the crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state.

[0094] In one embodiment, a pharmaceutical composition or unit dosage form comprising (or prepared from) solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate exhibits a release profile (e.g., single or multiple time points) of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate that remains substantially unchanged as a function of storage time when measured using a USP Type 2 apparatus in approximately 1000 mL of 8% aqueous Triton X100 at a specified temperature (e.g., 20.0, 37.0, or 40.0°C (±0.5)) at 100 rpm. In one aspect, the release profile remains substantially unchanged for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In one embodiment, the release profile remains substantially unchanged for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. In one embodiment, a release profile that remains substantially unchanged over a period of time refers to a release profile in which the amount of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate released at one or more specific time points under specified conditions varies within ±50%, 40%, 30%, 20%, 10%, or less.

[0095] In one embodiment, the unit dosage form or pharmaceutical composition described herein comprises or is prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and a pharmaceutically acceptable carrier, and is a crystalline solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate (without excipients or carriers) measured in about 1000 mL of 8% Triton X100 aqueous solution at a specified temperature at 100 rpm for 30 minutes using a USP Type 2 apparatus. Provided are unit dosage forms or pharmaceutical compositions that release 20% or more of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate when measured in a 100X aqueous solution over a 30-minute period, compared to those that do not release 1% or more of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

[0096] In some embodiments, the pharmaceutically acceptable carrier of the composition can include a fat-soluble additive. Non-limiting examples of fat-soluble additives include fat-soluble surfactants, monoglycerides, diglycerides, triglycerides, tocopherol, tocopherol succinate, tocopherol acetate, tocopherol derivatives, sterols, phytosterols, and combinations thereof. In one embodiment, the fat-soluble additive can include a fatty acid or a fatty acid glyceride. In another embodiment, the fat-soluble additive can include a fatty acid glyceride, which can be a monoglyceride, a diglyceride, a triglyceride, or a mixture thereof. Non-limiting examples of fatty acid glycerides that can be used in the oral pharmaceutical compositions and dosage forms of the present invention include monoglycerides and / or diglycerides derived from 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 certain embodiments, the pharmaceutical composition or dosage form thereof comprises one or more of corn oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil, or a combination thereof. In another embodiment, the composition comprises one or more triglycerides. In one aspect, the fat-soluble additive is a C8-C22 saturated fatty acid (or one having one, two, or three unsaturated bonds in the ester chain), its monoglyceride, diglyceride, triglyceride (including mixtures), or a combination thereof. In a more specific aspect, the C8-C22 fatty acid is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, wasenic acid, linoleic acid, or linoelaidic acid. In another specific embodiment, the monoglyceride, diglyceride, or triglyceride is a glyceride of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, wascenic acid, linoleic acid, or linoelaidic acid, or a combination thereof.

[0097] In another embodiment, the fat-soluble additive may include a fat-soluble surfactant.

[0098] In this specification, the term "lipophilic surfactant" refers to a surfactant having a hydrophilic-lipoic balance (HLB) value of 10 or less. Lipophilic surfactants that may be used include, but are not limited to, mono- and diglycerides of fatty acids such as glyceryl monolinoleate (e.g., MAISINE 35-1); caprylic-capric mono- and diglycerides (e.g., CAPMUL MCM); glyceryl monooleate; PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g., LABRAFIL M 2125 CS), PEG-6 almond oil (e.g., LABRAFIL M 1966 CS), PEG-6 apricot kernel oil (e.g., LABRAFIL M 1944 CS), PEG-6 olive oil (e.g., LABRAFIL M 1980 CS), PEG-6 peanut oil (e.g., LABRAFIL M 1969 CS), PEG-6 hydrogenated palm kernel oil (e.g., LABRAFIL M 1969 CS), and PEG-6 hydrogenated palm kernel oil (e.g., LABRAFIL M 1969 CS). Mixtures of natural and / or hydrogenated oils with alcohols or polyalcohols such as PEG-6 palm kernel oil (e.g., LABRAFIL M 2130 BS), PEG-6 triolein (e.g., LABRAFIL M 2735 CS), PEG-8 corn oil (e.g., LABRAFIL WL 2609 BS), PEG-20 corn glycerides (e.g., CROVOL M40), PEG-20 almond glycerides (e.g., CROVOL A40); fat-soluble polyoxyethylene-polyoxypropylene block copolymers (e.g., PLURONIC L92, L101, L121); propylene glycol monolaurate (e.g., Lauroglycol FCC), propylene glycol ricinoleate (e.g., Propymuls), propylene glycol monooleate (e.g., Myverol P-O6), propylene glycol fatty acid esters such as propylene glycol dicaprylate / dicaprate (e.g., CAPTEX 200), and propylene glycol dioctanoate (e.g., CAPTEX 800), propylene glycol monocaprylate (e.g., CAPRYOL 90); propylene glycol oleate (e.g., LUTROL OP2000), propylene glycol myristic acid; propylene glycol monostearate;Propylene glycol hydroxystearate; Propylene glycol ricinoleate; Propylene glycol isostearate; Propylene glycol monooleate; Propylene glycol dicaprylate / dicaprate; Propylene glycol dioctanoate; Propylene glycol caprylate-caprate; Propylene glycol dilaurate; Propylene glycol distearate; Propylene glycol dicaprylate; Propylene glycol dicaprate; Mixtures of propylene glycol and oleic acid esters of glycerol (e.g., ARLACEL 186); sterols and sterol derivatives such as cholesterol, sitosterol, phytosterols, phytosterol fatty acid esters, PEG-5 soy sterol, PEG-10 soy sterol, and PEG-20 soy sterol; glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl monostearate, or combinations thereof; sorbitan monolaurate (e.g., ARLACEL 20), sorbitan monopalmitate (e.g., Span-40), sorbitan monooleate (e.g., Span-80), sorbitan monostearate, and sorbitan fatty acid esters such as sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, and sorbitan sesquistearate; fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, and myristic acid; menthol, menthol derivatives, lecithin, phosphatidylcholine, bile salts, and mixtures thereof. It should be noted that some lipid-soluble surfactants may also function as solubilizer components in the present compositions and oral dosage forms.

[0099] In one embodiment, the lipid soluble surfactant is selected from the group consisting of glyceryl monolinoleate (e.g., MAISINE 35-1), caprylic and capric monoglycerides and diglycerides (e.g., CAPMUL MCM), glyceryl monooleate, 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 (e.g., Span-40), sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, and combinations thereof. Combinations of two or more of the same or different types of fat-soluble surfactants are also included within the scope of the present invention, and such combinations are collectively referred to as fat-soluble surfactants unless otherwise specified.

[0100] In an embodiment of the present invention, the oral pharmaceutical composition or dosage form (e.g., capsule or tablet) comprises a hydrophilic excipient. In one embodiment, the hydrophilic excipient is selected from the group consisting of hydrophilic surfactants, such as celluloses (low molecular weight, low viscosity hydroxypropyl cellulose (e.g., grades such as METHOCEL E5, E6, E10, E15, and LV100) and high molecular weight, medium to high viscosity hydroxypropyl cellulose (e.g., METHOCEL K4M, K15M, and K100M)), polyvinylpyrrolidone (e.g., KOLLIDON K17 and K30), polyvinyl acetate, and combinations thereof.

[0101] In one embodiment, the hydrophilic additive can be a hydrophilic surfactant. A hydrophilic surfactant has an HLB value greater than 10. Non-limiting examples of hydrophilic surfactants include nonionic surfactants, ionic surfactants, and amphoteric surfactants. Specific examples of hydrophilic surfactants suitable for the present invention include, but are not limited to, alcohol-oil conversion products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulfates, dioctyl sulfosuccinate salts; polyethylene glycol fatty acid esters; mixtures of polyethylene glycol fatty acid monoesters and diesters; polysorbates, polyethylene glycol derivatives of tocopherol, etc. Combinations of two or more of the same or different types of hydrophilic surfactants are also within the scope of the present invention, and such combinations are collectively referred to as hydrophilic surfactants unless otherwise specified. In one embodiment, the hydrophilic additive can be a hydrophilic surfactant. Non-limiting examples of hydrophilic surfactants include PEG-8 caprylic / capric glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium lauryl sulfate, sodium dioctylsulfosuccinate, polyethylene glycol fatty acid monoester and diester mixtures, polysorbate 80, polysorbate 20, polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterol fatty acid esters, and mixtures thereof.

[0102] In some embodiments, the surfactants used in the pharmaceutical compositions described herein include sterols and their derivatives. In various embodiments, these surfactants are hydrophilic or lipophilic. Examples of hydrophilic sterol surfactants include lanosterol PEG-24 cholesterol ether (e.g., SOLULAN C-24, Amerchol), PEG-30 soybean sterol (e.g., Nikkol BPS-30, Nikko), PEG-25 plant sterol (e.g., Nikkol BPSH-25, Nikko), and PEG-30 cholestanol (e.g., Nikkol DHC, Nikko). Examples of fat-soluble sterol surfactants include cholesterol, sitosterol, phytosterol (e.g., GENEROL series, Henkel), PEG-5 soy sterol (e.g., Nikkol BPS-S, Nikko), PEG-10 soy sterol (e.g., Nikkol BPS-10, Nikko), and PEG-20 soy sterol (e.g., Nikkol BPS-20, Nikko).

[0103] In one embodiment, the pharmaceutical composition or unit dosage form comprises an excipient as described in the following paragraph.

[0104] Suitable additives for use in the various embodiments described herein include, by way of non-limiting example, adsorbents, anti-adherents, anti-caking agents, defoamers, antioxidants, anti-crystallization agents, antistatic agents, binders, bile acids, buffers, swelling agents, chelating agents, coagulants, colorants, cosolvents, opacifying agents, solidifying agents, cooling agents, anti-freeze agents, diluents, dehumidifying agents, desiccants, desensitizing agents, disintegrants, dispersing agents, enzyme inhibitors, lubricants, fillers, humectants, superdisintegrants, gums, mucilages, hydrogen bonding agents, enzymes, flavors, moisture retention agents, humidity control agents, lubricating oils, ion exchange resins, lubricants, plasticizers, pH modifiers, preservatives, solidifying agents, solvents, solubilizers, dispersing agents, sweeteners, stabilizers, surface area increasing agents, suspending agents, thickeners, viscosity increasing agents, waxes, solidifying agents, and mixtures thereof.

[0105] In one embodiment, an oral pharmaceutical composition or dosage form thereof comprises or is prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and a pharmaceutically acceptable carrier. In another embodiment, a composition or dosage form of the present invention comprises solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and a pharmaceutically acceptable carrier, wherein the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate does not dissolve at temperatures above 30°C, or above 30°C, including temperatures between 30°C and about 40°C. In one aspect, the unit dosage form is a hard gel or soft gel capsule, or a tablet.

[0106] Methods of Use for Treating Disease Pharmaceutical compositions or unit dosage forms containing or prepared from solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate have multiple methods of use.

[0107] Subjects treatable by administering the pharmaceutical compositions and unit dosage forms disclosed herein (e.g., those comprising or prepared from solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate) are any mammal (e.g., human male or female) in need thereof. In particular, in one embodiment, the human male is at least 14 years of age. In another embodiment, the human male is an adult at least 16, 18, or 20 years of age. In another embodiment, the human male is an adult at least 21, 23, or 25 years of age. In another embodiment, the human male is an adult at least 30 years of age. In a further embodiment, the subject can be an adult male at least 50 years of age. In a further embodiment, the subject can be an adult male at least 60 years of age. A subject treatable with the pharmaceutical compositions and unit dosage forms disclosed herein (e.g., those comprising or prepared from solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having the properties as shown in Figures 1, 2, and 4) can be any human female in need thereof. In particular, in one embodiment, the human female is at least 14 years of age. In another embodiment, the human female is an adult at least 30 years of age. In a further embodiment, the subject can be an adult female at least 50 years of age. In a further embodiment, the subject can be an adult female with a deficient endogenous serum testosterone level. 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 female.In additional embodiments, the subject has a disease associated with a lack of therapeutically effective testosterone levels, including, but not limited to, hypogonadism (e.g., testosterone deficiency or absence), liver or lung disease with fatty liver, or a disease associated with inflammatory or fibrotic cytokines, chemokines, enzymes, or biomarkers, and these subjects can be treated with a pharmaceutical composition or dosage form comprising or prepared from the solid-state (17-beta)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein.

[0108] As discussed above, the present invention also provides methods for treating a human subject in need of testosterone therapy. The methods can include administering any of the pharmaceutical compositions or dosage forms (e.g., capsules or tablets) disclosed herein. The pharmaceutical compositions and dosage forms of the present invention can be used to treat any condition associated with testosterone deficiency, including a complete lack of endogenous testosterone, in male or female subjects. Examples of disorders associated with testosterone deficiency treatable by 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 testicular torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, post-castration syndrome, eunuchoidism, hypopituitarism, endocrine erectile dysfunction, infertility due to impaired spermatogenesis, erectile dysfunction, male sexual dysfunction (MSD) (including disorders such as premature ejaculation, erectile dysfunction, and decreased libido), micropenis and growth retardation, penile enlargement, increased appetite, chemotherapy-related testosterone deficiency, testosterone deficiency associated with toxic injury from alcohol, testosterone deficiency associated with toxic injury from heavy metals, osteoporosis associated with androgen deficiency, and combinations thereof.

[0109] Other conditions treatable by the compositions and dosage forms disclosed herein include idiopathic gonadotropin deficiency, luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic damage caused by tumors, trauma, or radiation. These subjects typically have low serum testosterone levels, but normal or low levels of gonadotropins. In one embodiment, the compositions or oral dosage forms are used to stimulate puberty in carefully selected males whose puberty is clearly delayed and not due to a secondary pathological condition. In another embodiment, the compositions and oral dosage forms are used to maintain or restore male physical and sexual characteristics (e.g., muscle mass, muscle tone, bone density, body mass index (BMI), increased energy, improved motivation and stamina, restored psychosexual activity, etc.) in female-to-male gender transitioners. In some embodiments, the pharmaceutical compositions and unit dosage forms disclosed herein (e.g., comprising or prepared from the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein) can be useful for providing male hormonal contraception. In some embodiments, the pharmaceutical compositions and unit dosage forms disclosed herein (e.g., comprising or prepared from the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein) can be used to treat female sexual dysfunction, anorgasmia, osteoarthritis, and symptoms associated with male hormonal contraception. Additionally, the pharmaceutical compositions and unit dosage forms disclosed herein (e.g., comprising or prepared from the solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein) can be used to treat and / or improve patient-related outcomes, including quality of life and well-being, in subjects suffering from a deficiency of endogenous testosterone.In some embodiments, the pharmaceutical compositions and unit dosage forms disclosed herein (e.g., those comprising or prepared from the solid state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein) can be used to treat or ameliorate the symptoms of a subject suffering from the following diseases: cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, end-stage pulmonary disease, end-stage renal disease, end-stage musculoskeletal disease, end-stage cardiovascular disease, end-stage hematological disease, end-stage endocrine disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage inflammatory bowel ... reproductive tract disease, end-stage central nervous system disease, liver fibrosis, hepatitis, fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre- and post-liver transplant, cirrhosis, primary biliary cholangitis (PBC), lung disease involving the interstitial space, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle mass loss, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, impaired glucose tolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral fat, obesity, impaired wound healing, abdominal obesity, and hereditary angioedema.

[0110] The following examples are provided to provide a more clear understanding of certain embodiments of the present disclosure and are not intended to limit the scope of the invention. [Example]

[0111] Example 1: Preparation of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate Non-limiting exemplary synthetic routes for producing the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein are set forth in more detail below: (17-β)-3-oxoandrost-4-en-17-yl dodecanoate can be produced using the generalized route shown below.

[0112] 1) Weigh out (17-β)-hydroxy-4-androsten-3-one (0.1 mol) and place in a 1000 mL 4N RB flask equipped with a stir bar.

[0113] 2) Add pyridine (160 mL) to the flask.

[0114] 3) Place the flask in an ice-water bath and attach a nitrogen inlet, addition funnel, thermocouple, and stopper. Start stirring and nitrogen flow.

[0115] 4) The funnel is charged with a heptane solution (160 mL) of an acid chloride (1.56 equivalents, e.g., lauroyl chloride) and fitted with an adapter connected to a bubbler.

[0116] 5) Add the contents of the funnel dropwise over 30 to 40 minutes (Note: The internal temperature will rise 5 to 7°C during addition).

[0117] 6) Once the addition is complete, remove the ice-water bath and continue stirring.

[0118] 7) After 1 hour, transfer the reaction mixture to a large separatory funnel and dilute with heptane (1000 mL) (Note: TLC after 1 hour indicates the reaction is complete).

[0119] 8) Wash the heptane solution with 800 mL each of the following solutions: cold water (2 times), 0.05 N NaOH, saturated NaHCO3 (2 times), water, and brine. Then dry over anhydrous Na2SO4 (~50 g). Then concentrate to dryness on a rotary evaporator / water bath (≤30 °C). [Example]

[0120] Example 2: Preparation of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate crystals The reaction mixture or product of Example 1 (or material produced by another route) can be transferred to water, ethanol, or methanol (or other suitable solvent) and crystallized. The crystallized solid can be isolated by suction filtration, washed with water, dried over phosphorus pentoxide, and recrystallized (although this step is not essential) from another solvent (e.g., oleic acid, hexane, heptane, etc.). [Example]

[0121] Example 3: Differential scanning calorimetry of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state This example demonstrates that solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate has a distinct melting point, as determined using a differential scanning calorimeter. An appropriate amount of the crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate was placed in a sealed PanAl crucible in a differential scanning calorimeter and heated over a temperature range of 0 to 100°C. The results are shown in the first heating cycle (Figure 1), which demonstrates two endothermic transitions for the solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate disclosed herein, at approximately 30 to 40°C and approximately 50 to 65°C. In certain embodiments, the melting point of a particular crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate in the solid state was identified as 51-63° C. based on DSC results. [Example]

[0122] Example 4: XRD Crystallographic Analysis of (17-β)-3-Oxoandrost-4-en-17-yl Dodecanoate in the Solid State Solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate was shown to be crystalline or substantially crystalline by XRD. The example XRD spectrum shown in Figure 2 demonstrates the crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate. Figure 2 shows distinct peaks corresponding to the crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, with little evidence of amorphous (17-β)-3-oxoandrost-4-en-17-yl dodecanoate (as evidenced by the absence of an "amorphous halo" or peak broadening in the 2θ = 5-30° range). [Example]

[0123] Example 5: Preparation of pharmaceutical compositions or dosage forms with various forms of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate by general formulation methods The pharmaceutical compositions or dosage forms described herein are formulated or prepared using the specific crystalline form of solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate characterized by DSC and XRD, as shown in Figures 1 and 2. The pharmaceutical compositions or dosage forms disclosed herein are prepared from the specific solid-state (17-β)-3-oxoandrost-4-en-17-yl dodecanoate and at least one pharmaceutically acceptable carrier by any suitable process. As shown in Figure 3, the process may include, by way of non-limiting example, one or more of the following: aggregation, air suspension cooling, air suspension drying, spheronization, coagglomeration, grinding, compression, pelleting, freeze pelleting, encapsulation, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, dissolution, mixing, molding, grinding, milling, pan coating, solvent dehydration, sonication, spheronization, spray cooling, spray congealing, spray drying, or a similar process. These steps can be developed by one of ordinary skill in the art using known techniques or in light of the disclosure herein.

[0124] The above-described compositions, dosage forms, and / or application methods represent examples of preferred embodiments of the present invention. Numerous modifications and alternative formulations may be devised by those skilled in the art without departing from the spirit and scope of the present invention, and the appended claims are intended to cover such modifications and formulations. Thus, while the present invention has been described in specific details as being the most practical and preferred embodiment presently, it will be apparent to those skilled in the art that changes in size, material, shape, form, function, method of operation, assembly, use, and the like may be made without departing from the principles and concepts set forth herein.

Claims

1. A pharmaceutical composition comprising or prepared from at least one of the following: a) a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having an XRD pattern including at least five peaks selected from the following group of angles in two-theta (2θ) measurement: 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; b) a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having a melting point in at least one of the ranges of 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; c) A flowable material comprising or prepared from a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

2. 10. The pharmaceutical composition of claim 1, wherein the at least five peaks include at least one of six peaks, seven peaks, and more than seven peaks.

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

4. 10. The pharmaceutical composition of claim 1, further comprising at least one additive.

5. 5. The pharmaceutical composition of claim 4, wherein the at least one additive comprises at least one of a solubilizer and a surfactant.

6. 10. The pharmaceutical composition of claim 1, further comprising a pharmaceutical composition for oral or injectable administration.

7. 10. 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 drink, a gel, a syrup, a dispersion, an emulsion, a sprinkle, a lozenge, a microemulsion, a nanoemulsion, an elixir, a paste, a powder, and a granule; and wherein the pharmaceutical composition for administration by injection further comprises at least one of an intravenous injection, an intramuscular injection, a subcutaneous injection, an intradermal injection, an intraspinal injection, an epidural injection, and an intraarterial injection, wherein the intraarterial injection comprises at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

8. 10. The pharmaceutical composition of claim 1, further comprising at least one carrier.

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

11. 11. The pharmaceutical composition of claim 10, wherein the at least one lipophilic carrier comprises at least one of a fatty acid, a fatty acid derivative, a vegetable oil, a vegetable oil derivative, a monoglyceride, a diglyceride, a triglyceride, a monoglyceride derivative, a diglyceride derivative, a triglyceride derivative, a sterol, a phytosterol, a tocopherol, a tocopherol succinate, a tocopherol acetate, and a fish oil; and the hydrophilic carrier comprises at least one of a polyoxyethylene hydrogenated vegetable oil, a polyoxyethylene vegetable oil, a polyethylene glycol fatty acid ester, a polyethylene glycol fatty acid monoglyceride mixture, a polyethylene glycol fatty acid diglyceride mixture, a polysorbate, a polyethylene glycol derivative tocopherol, an alcohol, and an alcohol derivative.

12. 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; the vegetable oil comprises at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and derivatives thereof; the monoglyceride derivative comprises at least one of glyceryl monolinoleate and sorbitan mono-fatty acid; the diglyceride derivative comprises glyceryl palmitostearate; the polyoxyethylene hydrogenated vegetable oil comprises PEG-hydrogenated castor oil; the alcohol comprises at least one of ethanol and benzyl alcohol; and the alcohol derivative comprises benzyl benzoate.

13. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for the treatment of a condition requiring testosterone.

14. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for use in treating cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, end-stage lung disease, end-stage renal disease, end-stage musculoskeletal disease, end-stage cardiovascular disease, end-stage blood disease, end-stage endocrine gland disease, end-stage digestive tract disease, end-stage skin disease, end-stage reproductive tract disease, end-stage central nervous system disease, liver fibrosis, hepatitis, fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre- and post-liver transplantation, A pharmaceutical composition for treating at least one of cirrhosis of the liver, primary biliary cholangitis (PBC), interstitial lung disease, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle mass loss, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, impaired glucose tolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral fat, obesity, wound healing disorders, abdominal obesity, and hereditary angioedema.

15. A pharmaceutical composition comprising or prepared from a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate, said composition being useful in treating cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, end-stage lung disease, end-stage renal disease, end-stage musculoskeletal disease, end-stage cardiovascular disease, end-stage blood disease, end-stage endocrine gland disease, end-stage digestive tract disease, end-stage skin disease, end-stage reproductive tract disease, end-stage central nervous system disease, liver fibrosis, hepatitis, fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic steatohepatitis (NASH), and steroid-resistant liver disease (SHR). The pharmaceutical composition is for treating at least one of alcoholic fatty liver disease (NAFLD), pre- and post-liver transplantation, cirrhosis, primary biliary cholangitis (PBC), interstitial lung disease, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle mass loss, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, impaired glucose tolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral fat, obesity, wound healing disorders, abdominal obesity, and hereditary angioedema.

16. 16. The pharmaceutical composition of claim 15, further comprising or prepared from at least one of the following: a) a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having an XRD pattern including at least five peaks selected from the following group of angles in two-theta (2θ) measurement: 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; b) a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having a melting point in at least one of the ranges of 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; c) A flowable material comprising or prepared from a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate.

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

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

19. 16. The pharmaceutical composition of claim 15, further comprising at least one additive.

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

21. 16. The pharmaceutical composition of claim 15, further comprising a pharmaceutical composition for oral or injectable administration.

22. 16. 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 drink, a gel, a syrup, a dispersion, an emulsion, a sprinkle, a lozenge, a microemulsion, a nanoemulsion, an elixir, a paste, a powder, and a granule; and wherein the pharmaceutical composition for administration by injection further comprises at least one of an intravenous injection, an intramuscular injection, a subcutaneous injection, an intradermal injection, an intraspinal injection, an epidural injection, and an intraarterial injection, wherein the intraarterial injection comprises at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

23. 16. The pharmaceutical composition of claim 15, further comprising at least one carrier.

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

26. 26. The pharmaceutical composition of claim 25, wherein the at least one lipophilic carrier comprises at least one of a fatty acid, a fatty acid derivative, a vegetable oil, a vegetable oil derivative, a monoglyceride, a diglyceride, a triglyceride, a monoglyceride derivative, a diglyceride derivative, a triglyceride derivative, a sterol, a phytosterol, a tocopherol, a tocopherol succinate, a tocopherol acetate, and a fish oil; and the hydrophilic carrier comprises at least one of a polyoxyethylene hydrogenated vegetable oil, a polyoxyethylene vegetable oil, a polyethylene glycol fatty acid ester, a polyethylene glycol fatty acid monoglyceride mixture, a polyethylene glycol fatty acid diglyceride mixture, a polysorbate, a polyethylene glycol derivative tocopherol, an alcohol, and an alcohol derivative.

27. 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; the vegetable oil comprises at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and derivatives thereof; the derivative of a monoglyceride comprises at least one of glyceryl monolinoleate and sorbitan mono fatty acid; the derivative of a diglyceride comprises glyceryl palmitostearate; the polyoxyethylene hydrogenated vegetable oil comprises PEG hydrogenated castor oil; the alcohol comprises at least one of ethanol and benzyl alcohol; and the alcohol derivative comprises benzyl benzoate.

28. 16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is for the treatment of a condition in which testosterone is needed.

29. 1. A method of treating a subject for a condition, the method comprising administering to the subject a pharmaceutical composition; The pharmaceutical composition comprises or is prepared from at least one of the following: a) a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having an XRD pattern including at least five peaks selected from the following group of angles in two-theta (2θ) measurement: 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; b) a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate having a melting point in at least one of the ranges of 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; c) a flowable material comprising or prepared from a crystalline form of (17-β)-3-oxoandrost-4-en-17-yl dodecanoate; The condition may be cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, end-stage lung disease, end-stage renal disease, end-stage musculoskeletal disease, end-stage cardiovascular disease, end-stage blood disease, end-stage endocrine gland disease, end-stage digestive disease, end-stage skin disease, end-stage reproductive disease, end-stage central nervous system disease, liver fibrosis, hepatitis, fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre- and post-liver transplant, cirrhosis, primary and at least one of primary biliary cholangitis (PBC), interstitial lung disease, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle mass loss, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, hyperglycemia, impaired glucose tolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral fat, obesity, impaired wound healing, abdominal obesity, and hereditary angioedema.

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

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

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

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

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

35. 30. 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 drink, a gel, a syrup, a dispersion, an emulsion, a sprinkle, a lozenge, a microemulsion, a nanoemulsion, an elixir, a paste, a powder, and a granule; and wherein the pharmaceutical composition for administration by injection further comprises at least one of an intravenous injection, an intramuscular injection, a subcutaneous injection, an intradermal injection, an intraspinal injection, an epidural injection, and an intraarterial injection, wherein the intraarterial injection comprises at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

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

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

39. 39. The method of claim 38, wherein the at least one lipophilic carrier comprises at least one of a fatty acid, a fatty acid derivative, a vegetable oil, a vegetable oil derivative, a monoglyceride, a diglyceride, a triglyceride, a monoglyceride derivative, a diglyceride derivative, a triglyceride derivative, a sterol, a phytosterol, a tocopherol, a tocopherol succinate, a tocopherol acetate, and a fish oil, and the hydrophilic carrier comprises at least one of a polyoxyethylene hydrogenated vegetable oil, a polyoxyethylene vegetable oil, a polyethylene glycol fatty acid ester, a polyethylene glycol fatty acid monoglyceride mixture, a polyethylene glycol fatty acid diglyceride mixture, a polysorbate, a polyethylene glycol derivative tocopherol, an alcohol, and an alcohol derivative.

40. 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; the vegetable oil comprises at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and derivatives thereof; the derivative of a monoglyceride comprises at least one of glyceryl monolinoleate and sorbitan mono fatty acid; the derivative of a diglyceride comprises glyceryl palmitostearate; the polyoxyethylene hydrogenated vegetable oil comprises PEG hydrogenated castor oil; the alcohol comprises at least one of ethanol and benzyl alcohol; and the alcohol derivative comprises benzyl benzoate.

41. 30. The method of claim 29, wherein the pharmaceutical composition is for the treatment of a condition in which testosterone is indicated.

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