AU2022467882B2 - (17-)-3-oxoandrost-4-en-17-yl dodecanoate compositions and methods of preparation and use - Google Patents

Abstract

Disclosed are bioavailable solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate compositions and methods of use in administration to mammals in need of thereof. The (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate is preferably provided in a solid state crystalline form having a plurality of peaks corresponding to the peaks shown in FIG. 2, a plurality of crystallites ranging in size from about 40 nm to about 60 nm based as identified via powder x-ray diffraction spectra, and a melting point in the range of about 51 °C to about 63 °C. The compositions may be provided in oral or injectable administration form for the treatment of conditions such as in need of testosterone therapy. An exemplary chemical structure of a (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate composition disclosed herein is as follows (I).

Description

(17-)-3-OXOANDROST-4-EN-17-YL DODECANOATE COMPOSITIONS AND METHODS OF PREPARATION AND USE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This PCT patent application claims the benefit under PCT Rule 4.10 to co-

pending US patent application No. 16/953,607 filed November 20, 2020 and anticipated to

issue on June 28, 2022 as US patent 11,370,811, and which is expressly incorporated herein

in its entirety by this reference.

FIELD OF THE INVENTION

[0002] Disclosed herein are solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate (see: https://pubchem.ncbi.nlm.nih.gov/compound/Dodecanoate) a novel

ester of dodecanoic fatty acid, and its methods of pharmaceutical compositions suitable for

pharmaceutical uses and administration to mammals (e.g., humans) in need of (17-B)-

Hydroxy-4-Androsten-3-one.

BACKGROUND OF THE INVENTION

[0003] Various bioavailable solid state esters suitable for pharmaceutical uses and

administration to mammals in need thereof are disclosed in the following US patents and

applications, all of which are expressly incorporated herein in their entirety by reference:

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, 9,757,389 filed September 26, 2016 and issued September 12, 2017, 2016/0184320

filed August 28, 2015 and published June 30, 2016, 2017/0035781 filed June 22, 2016 and

published February 9, 2017, 2018/0125858 filed August 8, 2017 and published May 10,

2018, 2019,0275060 filed August 6, 2018 and published September 12, 2019, 2020/0046731 filed February 12, 2019 and published February 13, 2020 (the Patents).

[0004] Different solid state forms of an ester of an active pharmaceutical ingredient

(API) or esterified active pharmaceutical ingredient (EAPI) may possess different

properties that can provide a formulation, in which the EAPI is included, with specific

advantages, for example, by facilitating better processing or handling characteristics,

changing the dissolution profile in a favorable direction, or improving stability (polymorph

as well as chemical stability) and shelf-life. These variations in the properties of different

solid state forms may also translate to benefits to a final dosage form, for instance, by providing or contributing to improved bioavailability. Different solid state forms of an

EAPI may also give rise to a variety of polymorphs or crystalline forms, which may in turn

provide additional opportunities to assess variations in the properties and characteristics of

a solid EAPI.

[0005] An important characteristic of EAPI is that its dissolution or release rate

does not change substantially over time period. Changes in dissolution or release rate of

EAPI over time period can result from otherwise identical products except for the solid

state form (e.g., having the same EAPI, formulations components and amounts thereof),

but can result in different pharmacokinetic properties which can change or alter the efficacy

or safety of a drug product.

[0006] The stability of EAPI in pharmaceutical preparations (e.g., compositions

and unit dosage forms) is also important. For example, if the EAPI changes physical form

(e.g., crystal form or amount thereof) in a pharmaceutical composition or unit dosage form,

this can also affect pharmacokinetic properties and therefore related safety and efficacy

15 parameters.

[0007] To be useful, the solid state has to be stable. A number of examples of bulk

drug substance and pharmaceutical compositions/dosage forms that have changed physical

form are known in the literature and have resulted in substantial problems to patients

receiving these drugs. A well-known example is ritonavir which underwent a change in

crystal form resulting in the product failing dissolution tests and being pulled off the market

for a period of time (see Morissette et al. Proc Natl Acad Sci U S A. 2003 Mar

4;100(5):2180-4). Other high profile cases include the recall of batches of Neupro

(rotigotine) due to the appearance of a new polymorph in 2008, recall of 1.5 million tablets

of warfarin in 2010 due to concerns over 2-propanol levels, which potentially could affect

API crystallinity, and in 2010 the recall of 60 million tablets of Avalide over concerns in

variability in the amounts of the less soluble polymorph of irbesartan in 2010. See Lee et

al. Annu. Rev. Chem. Biomol. Eng. 2011, 2, 259-280.

[0008] Absorption of any prodrug such as an ester derivative of an API (EAPI)

needs to be managed to provide adequate and sustained levels of the API derived from

EAPI in vivo without adding any safety issues associated with the ester or its metabolite.

Solubility, release, dissolution and partitioning of EAPI in a particular solvent is a function

of lipophilicity and is related to solid state characteristics e.g., the physical form of the drug

substance such as crystal form, solvation, whether or not amorphous material is present,

etc. Therefore, the solid state physical form is one of the key properties with respect to ease manufacturing, storage, and performance of the EAPI for enabling safe and effective levels 22 Jan 2026 of API.

[0009] Esters of (17-β)-Hydroxy-4-Androsten-3-one, which themselves are not thought to be biological active, are known to be transformed to the biologically active 5 molecule ((17-β)-Hydroxy-4-Androsten-3-one in vivo and other related metabolites like (17-β)-hydroxy-5α-androstan-3-one, and therefore can be used for treating patients in need of (17-β)-Hydroxy-4-Androsten-3-one treatment. However, inadequate solubility, release, 2022467882

dissolution, partitioning, and/or physical stability of the solid state of the EAPI can result in poor bioavailability of (17-β)-Hydroxy-4-Androsten-3-one, a useful hormone for the 10 treatment of disease states related to need of (17-β)-Hydroxy-4-Androsten-3-one, such as e.g., male or female hypogonadism, lung disease, or 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 solubility challenges with esters of (17-β)-Hydroxy-4-Androsten-3-one, 15 adequate absorption and conversion rate into the parent drug remain an important design element in preparing and identifying solid state esters of (17-β)-Hydroxy-4-Androsten-3- one. Approaches to date have failed to disclose or adequately characterize specific solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate used for ease in development of pharmaceutical compositions. 20 [0011] Steroids including steroid esters, such as testosterone and testosterone esters, are known to exhibit different solid state forms that have different properties including dissolution, bioavailability and absorption (See e.g., Ballard BE, Biles J, Steroids, 1964; 4: 273; Bouche R, Draguet-Brughmans M, J Pharm Belg, 1977; 32: 347; Carless et al. Journal of Pharmacy and Pharmacology Volume 20, Issue 8, pages 630–638, August 25 1968; Borka & Haleblian (1990) Acta Pharm. Jugosl. 40:71-94).

[0012] Esterification of testosterone with dodecanoic acid (lauric acid) are more suitable and preferred for therapy since lauric acid is a saturated medium chain fatty acid (MCFA) with 12 carbon atoms associated with certain health benefits. There is a need for stable and bioavailable solid state forms of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate, 30 a candidate of new drug products on male or female hypogonadism, lung disease, sarcopenia (see: https://society-scwd.org/sarcopenia/), cachexia (see: https://society- scwd.org/cachexia/), muscle wasting (see: https://society-scwd.org/muscle-wasting/), or liver disease that would be suitable for use in treatment of subjects in need of (17-β)- Hydroxy-4-Androsten-3-one. It is an object of the present invention to meet these needs, or at least go some way to providing the public with a useful choice. 22 Jan 2026

[0012A] In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless 5 specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art. 2022467882

SUMMARY OF THE INVENTION 10 [0013] It was found that not all solid state forms of the dodecanoate ester derivative of ((17-β)-Hydroxy-4-Androsten-3-one are alike and suitable for treatment of mammals in need of (17-β)-Hydroxy-4-Androsten-3-one. It was found that a specific solid state dodecanoate ester derivative of (17-β)-Hydroxy-4-Androsten-3-one, wherein at least 0.001% (e.g., at least 0.01, 0.1 1.0 or 10%) of the solid state (17-β)-3-Oxoandrost-4-en-17- 15 yl dodecanoate dissolves in 1000 mL 8% Triton X100 containing aqueous solution in 30 minutes in a USP Type 2 apparatus at 37 °C at 100 rpm, are more suitable for administering to a human (e.g., treating or preventing a disease, condition or disorder).

[0014] Additionally, it was found that compositions of the selected solid forms described herein are adequately bioavailable. In one embodiment, a composition for 20 administration to a human subject in need of ((17-β)-Hydroxy-4-Androsten-3-one therapy is provided: e.g., the composition comprising or made from a) a solid state of (17-β)-3- Oxoandrost-4-en-17-yl dodecanoate and b) a pharmaceutically acceptable carrier, wherein upon oral administration of the solid state of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate to the human subject, at least about 0.1% 0.5%, 1%, 2%, 3%, 5%,8% or 10% of the (17- 25 β)-Hydroxy-4-Androsten-3-one (testosterone) equivalent dose is bioavailable to the human subject.

[0015] Thus, in one embodiment, a solid state EAPI which is (17-β)-3-Oxoandrost- 4-en-17-yl dodecanoate is provided. The solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate is crystalline. In a specific aspect, the crystalline solid state (17-β)-3- 30 Oxoandrost-4-en-17-yl dodecanoate is a crystal form substantially free of other non-crystal forms. In another specific aspect, the crystalline solid state (17-β)-3-Oxoandrost-4-en-17- yl dodecanoate described herein is substantially free of amorphous forms.

[FOLLOWED BY PAGE 4a]

[0015A] In a first particular aspect, the present invention provides a 22 Jan 2026

pharmaceutical composition comprising or prepared from: a crystalline form of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate having an XRD pattern comprising a plurality of peaks selected from the group of angles consisting of 5 10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2, and 23.2±0.2 measured relative to two-theta (2θ), and having a melting point in the range of about 58.3±10 °C. 2022467882

[0016] The solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate provided herein has a characteristics of particle size distribution. In specific aspects, the particle 10 sizes of the solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate are less than 200 nm (“nanometer”), from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 µm (“micrometer”), from 50 to 250 µm, from 250 to 500 µm, from 500 to 1000 µm, or greater than 1000 µm. In another aspect, the solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate has a d50 of greater than 1000 µm, from 355 to 1000 µm, from 180 to 355 µm, from 125 to 180 µm, 90 15 to 125 µm, from 1 to 90 µm, or less than 1 µm. In another related aspect, the solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate has a D10, D50, or D90 that is less than 200

[FOLLOWED BY PAGE 5]

4a nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 um, from 50 to 250 um, from

250 to 500 um, from 500 to 1000 um, or greater than 1000 um. In one particular aspect,

the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate having a characteristics of

particle size distribution or size characteristics is crystalline. In another particular aspect,

the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate having a characteristics of

particle size distribution or size characteristics is a crystal form substantially free of other

non-crystalline forms.

[0017] Pharmaceutical compositions provided herein comprise or are prepared

from a solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate as described in the

paragraphs above. For example, the pharmaceutical composition is prepared from or

comprises a solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate and one or more

pharmaceutically acceptable excipients, carriers, or additives. The pharmaceutical

composition described herein can comprise or be prepared from crystalline solid state (17-

B)-3-Oxoandrost-4-en-17-yl dodecanoate. In some aspects, the pharmaceutical

composition comprises or is prepared from solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate, where is not-milled or is milled, micronized or nanosized. In specific aspects,

the pharmaceutical composition comprises or is prepared from solid state (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate wherein the particle size is less than 200 nm, from 200

to 500 nm, from 500 to 1000 nm, from 1 to 50 um, from 50 um to 250 um, from 250 um

to 500 um, from 500 um to 1000 um, or greater than 1000 um. In another aspect, the

pharmaceutical composition comprises or is prepared from solid state (17-3)-3-

Oxoandrost-4-en-17-y} dodecanoate having a d50 of greater than 1000 um, from 355 to

1000 um, from 180 to 355 um, from 125 to 180 um, from 90 to 125 um, from 1 to 90 um,

or less than 1 um. In another related aspect, the pharmaceutical composition comprises or

is prepared from solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate having a D10, D50,

or D90 that is less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50

um, from 50 to 250 um, from 250 to 500 um, from 500 to 1000 um, or greater than 1000

um. In some specific aspects, the pharmaceutical composition of solid state (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate is formulated for topical, enteral or parenteral

administration. In some aspects, the pharmaceutical composition of solid state (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate is formulated for buccal, sublingual, or sublabial

administration. In some specific aspects, the pharmaceutical composition of solid state (17-

B)-3-Oxoandrost-4-en-17-yl dodecanoate is formulated for nasal, rectal or vaginal

administration. In some specific aspects, the pharmaceutical composition of solid state (17- β)-3-Oxoandrost-4-en-17-yl dodecanoate is formulated for intravenous, subcutaneous, 22 Jan 2026 intramuscular, intradermal, intraspinal, intrathecal, or intra-arterial administration. In some specific aspects, the pharmaceutical composition of solid state (17-β)-3-Oxoandrost-4-en- 17-yl dodecanoate is formulated as liquid, solution, suspension, dispersion (see: 5 https://en.wikipedia.org/wiki/Dispersion_(chemistry)), solid, semi-solid, gel, lotion, paste, foam, spray, suspension, dispersion, syrup, or ointment. In some specific aspects, the pharmaceutical composition of solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate is 2022467882 formulated as a tincture, patch, injectable, or oral dosage form. In some aspects, the pharmaceutical composition of solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate 10 comprises solubilized or partially solubilized (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate. In one aspect, the pharmaceutical composition or unit dosage form is suitable for oral administration (e.g., capsule or tablet).

[0018] Provided herein are pharmaceutically compositions or unit dosage forms comprising or prepared from solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate as 15 described in the paragraphs above.

[0019] Additionally, described herein are methods of using solid state (17-β)-3- Oxoandrost-4-en-17-yl dodecanoate for pharmaceutical compositions wherein the method can treat males or females in need of (17-β)-Hydroxy-4-Androsten-3-one (testosterone).

[0019A] In another particular aspect, the present invention provides a method 20 of treating or substantially inhibiting development of at least one of carcinoma, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, end-stage lung disease, end-stage kidney disease, end-stage musculoskeletal system disease, end-stage cardiovascular disease, end-stage blood disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage genital organ disease, end-stage 25 central nervous system disease, hepatic fibrosis, hepatic inflammation, hepatic steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre/post liver transplant, cirrhosis, primary biliary cholangitis (PBC), lung disease affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle mass wasting, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes, 30 hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, a metabolic syndrome, visceral adiposity, obesity, impaired wound healing, large waist, hereditary angioedema, and a symptom thereof, the method comprising administering a pharmaceutical composition comprising or prepared from a crystalline form of (17-β)-3-

[FOLLOWED BY PAGE 6a]

Oxoandrost-4-en-17-yl dodecanoate having an XRD pattern comprising a plurality of peaks 22 Jan 2026

selected from the group of angles consisting of 10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2, and 23.2±0.2 measured relative to two-theta (2θ).

[0019B] In the description in this specification reference may be made to 5 subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims. 2022467882

BRIEF DESCRIPTION OF THE FIGURES 10 [0020] FIG. 1 shows a first heat cycle heat enthalpy change plot for a solid state form of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate measured by differential scanning calorimetry as disclosed herein;

[0021] FIG. 2 shows a result of an XRD measure for a solid state (17-β)-3- Oxoandrost-4-en-17-yl dodecanoate as disclosed herein with 8 distinguishable peaks for a 15 crystalline structure;

[0022] FIG. 3 shows general formulation processes for producing a variety of different forms of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate in a pharmaceutical composition or dosage form to improve physical, chemical, pharmacokinetic, and pharmacodynamic properties for enhancing bioavailability as disclosed herein, and; 20 [0023] FIG. 4 shows two microscopic images with 20 µm and 5 µm scales of particles of the solid state (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate used for a pharmaceutical composition or dosage form described herein, wherein said particles of the

[FOLLOWED BY PAGE 7]

6a solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate has a specific shape, such as flat thin panel shape.

DETAILED DESCRIPTION

[0024] Before invention embodiments are described, it is to be understood that this

disclosure is not limited to the particular structures, process steps, or materials disclosed

herein, but is extended to equivalents thereof as would be recognized by those ordinarily

skilled in the relevant arts. It should also be understood that terminology employed herein

is used for the purpose of describing particular examples or embodiments only and is not

intended to be limiting.

[0025] Furthermore, the described features, structures, or characteristics can be

combined in any suitable manner in one or more embodiments. In the following

description, numerous specific details are provided, such as examples of compositions,

dosage forms, treatments, etc., to provide a thorough understanding of various invention

embodiments. One skilled in the relevant art will recognize, however, that such detailed

embodiments do not limit the overall inventive concepts articulated herein, but are merely

representative thereof.

[0026] It should be noted that, the singular forms "a," "an," and, "the" include

plural referents unless the context clearly dictates otherwise. Thus, for example, reference

to "an excipient" includes reference to one or more of such excipients, and reference to "the

carrier" includes reference to one or more of such carriers.

[0027] As used herein, the terms "treat," "treatment," or "treating" and the like

refers to administration of a therapeutic agent to a pathogen-infected subject who is either

asymptomatic or symptomatic. In other words, "treat," "treatment," or "treating" can refer

to reducing, ameliorating or eliminating symptoms associated with a condition present in

an infected subject.

[0028] As used herein, "androgen receptor agonists" refers to compounds,

molecules, or agents such as testosterone that bind and activate an androgen receptor.

Examples of androgen receptor agonists include, but are not limited to, dihydrotestosterone,

mibolerone, testosterone, alkylated testosterone, derivatives of testosterone esters,

methyltrienolone, oxandrolone, nandrolone and fluoxymesterone. Where appropriate, fatty

acid esters of these androgen receptor agonists can be used herein accordingly.

[0029] As used herein, "testosterone ester" refers to testosterone esterified with a

fatty acid. Exemplary testosterone esters include without limitation testosterone

WO wo 2024/005770 PCT/US2022/034463

undecanoate, testosterone decanoate, testosterone dodecanoate, testosterone tridecanoate,

testosterone decanoate, testosterone enanthate, testosterone palmitate, testosterone

cypionate, and testosterone propionate.

[0030] As used herein, "testosterone agent" refers to an active pharmaceutical agent

that produces a physiologic action or effect of testosterone in-vivo. Examples of

testosterone agents are found throughout the present application. One example of a

testosterone agent is testosterone (T). Another example is a testosterone ester, such as

testosterone undecanoate or testosterone tridecanoate.

[0031] As used herein, the terms "therapeutic agent," "active agent," and the like

can be used interchangeably and refer to agent that can have a beneficial or positive effect

on a subject when administered to the subject in an appropriate or effective amount. In one

aspect, the therapeutic or active agent can be an androgenic steroid. The terms "additional

active agent," "supplemental active agent," "secondary active agent," and the like can be

used interchangeably and refer to a compound, molecule, or material other than an

androgenic steroid that has physiologic activity when administered to a subject in an

effective amount.

[0032] As used herein, the terms "formulation" and "composition" are used

interchangeably and refer to a mixture of two or more compounds, elements, or molecules.

In some aspects, the terms "formulation" and "composition" may be used to refer to a

mixture of one or more active agents with a carrier or other excipients. Furthermore, the

term "dosage form" can include one or more formulation(s) or composition(s) provided in

a format for administration to a subject. For example, an "oral dosage form" can be suitable

for administration to a subject's mouth. A "topical dosage form" can be suitable for

administration to a subject's skin by rubbing, etc.

[0033] As used herein, a "subject" refers to an animal. In one aspect the animal

may be a mammal. In another aspect, the mammal may be a human.

[0034] As used herein, "in need of treatment" refers to a subject that has a disease

or is suspected of having the disease according to various diagnostic criteria typically used

in practice, or desires treatment or is indicated for treatment. Thus, "in need of treatment"

can include the step of identifying a subject in need of treatment.

[0035] As used herein, "identifying a subject in need of treatment" can include the

step of obtaining a biological sample from the subject and determining the level of one or

more biomarkers as described herein (RT-PCR detection of a virus gene), assessing a

biological sample obtained from said subject, performing an imaging analysis on the subject, assessing one or more clinical characteristics of said subject (e.g., assessing symptoms or overt symptoms), or a combination thereof.

[0036] As used herein, an "acute" condition refers to a condition that can develop

rapidly and have distinct symptoms needing urgent or semi-urgent care. By contrast, a

"chronic" condition refers to a condition that is typically slower to develop and lingers or

otherwise progresses over time. Some examples of acute conditions can include without

limitation, an asthma attack, bronchitis, a heart attack, pneumonia, and the like. Some

examples of chronic conditions can include without limitation, arthritis, diabetes,

hypertension, high cholesterol, and the like.

[0037] The terms "serum testosterone" or "serum (17-B)-Hydroxy-4-Androsten-3-

one levels," "serum T levels," "serum testosterone concentration," "plasma testosterone

concentration," "testosterone concentration in the blood," and "serum testosterone

concentration," are used interchangeably and refer to the "total" serum testosterone

concentration which is the sum of the bioavailable testosterone including free and bound

testosterone fractions or concentrations. As with any bioanalytical measure, for increased

consistency, the method employed to measure initial serum testosterone levels may be

consistent with the method used to monitor and re-measure serum testosterone levels during

clinical testing and testosterone therapy for a subject. Unless otherwise stated,

"testosterone concentration" refers to serum total testosterone concentration.

[0038] Average serum testosterone concentrations can be determined using

methods and practices known in the art. For example, the average baseline plasma

testosterone concentration of a human male is the arithmetic mean of the total plasma

testosterone concentration determined on at least two consecutive time points that are

reasonably spaced from each other, for example from about 1 hour to about 168 hours apart.

In a particular case, the plasma testosterone concentration can be determined on at least

two consecutive times that are about 12 hours to about 48 hours apart. In another particular

method, the plasma testosterone concentration of the human male can be determined at a

time between about 5 o'clock and about 11 o'clock in the morning. Further, the plasma

testosterone concentration can be the determined by standard analytical procedures and

methods available in the art, such as for example, automated or manual immunoassay

methods, liquid chromatography or liquid chromatography-tandem mass spectrometry

(LC-MSMS) etc.

[0039] As use herein with respect to physiologic levels of a given substance, the

term "baseline" refers to a level or concentration of the substance in a subject prior to administration of an active agent. For example, the baseline level of serum testosterone in a subject would the subject's testosterone serum level prior (e.g. just prior) to the commencement of testosterone administration or therapy.

[0040] As used herein, "free testosterone serum concentration", refers to the

fraction of total testosterone that is not bound to a protein e.g., SHBG (see:

https://en.wikipedia.org/wiki/Sex_hormone-bindingglobulin) or albumin. In some

aspects of the methods described herein, free testosterone serum concentrations are used

instead of serum total testosterone concentrations. For example, a subject can appear to

have total serum testosterone levels in the normal range, but can be still considered

testosterone deficient based on free testosterone levels. It should be understood that as used

herein, the term testosterone serum levels or concentrations can provide express support

for free testosterone serum concentrations, unless the context or recitation clearly dictates

otherwise.

[0041] The term "oral administration" represents any method of administration in

which an active agent can be administered by swallowing, chewing, or sucking of the

dosage form. Oral administration can be intended for enteral delivery of an active agent or

transmucosal delivery of the active agent. In some embodiments, the composition of the

current inventions can be admixed with food or drink prior to being orally consumed.

[0042] As used herein, a "dosing regimen" or "regimen" such as an "initial dosing

regimen" or "starting dose" or a "maintenance dosing regimen" refers to how, when, how

much, and for how long a dose of the compositions of the present invention can be

administered to a subject. For example, an initial or starting dose regimen for a subject

may provide for a total daily dose of from about 15 mg to about 1500 mg administered in

two divided doses at least 12 hours apart (e.g. once with breakfast and once with dinner)

with meals repeated daily for 30 days.

[0043] As used herein, "daily dose" refers to the amount of active agent (e.g. a

testosterone ester) administered to a subject over a 24-hour period of time. The daily dose

can be administered one or more administrations during the 24-hour period. In one

embodiment, the daily dose provides for two administrations in a 24-hour period. With

this in mind, an "initial dose" or initial daily dose" refers to a dose administered during the

initial regimen or period of a dosing regimen.

[0044] As used herein, an "effective amount" or a "therapeutically effective

amount" of a drug refers to a non-toxic, but sufficient amount of the drug, to achieve

therapeutic results in treating a condition for which the drug is known to be effective. It is

10 understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an "effective amount" or a "therapeutically effective amount" may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine. See, for example, Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis," Monographs in

Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein by reference.

[0045] As used herein "single when used to describe dosing of a subject refers

to the dosage form being a single dosage form, e.g. a single tablet, capsule, pump or squirt

of gel or solution, etc. In contrast, "multiple unit" when used to describe dosing of a subject

refers to the dosage including two or more dosage forms, e.g. 2 capsules, 3 tablets, 2-4

pumps or squirts, etc. It is noteworthy that multiple unit dosage forms generally will be the

same type of dosage forms (i.e. tablet or capsule) but are not required to be the same dosage

form type.

[0046] In this disclosure, "comprises," "comprising," "containing" and "having"

and the like can have the meaning ascribed to them in U.S. Patent law and can mean

"includes," "including," and the like, and are generally interpreted to be open ended terms.

The terms "consisting of" or "consists of" are closed terms, and include only the

components, structures, steps, or the like specifically listed in conjunction with such terms,

as well as that which is in accordance with U.S. Patent law. "Consisting essentially of" or

"consists essentially of" have the meaning generally ascribed to them by U.S. Patent law.

In particular, such terms are generally closed terms, with the exception of allowing

inclusion of additional items, materials, components, steps, or elements, that do not

materially affect the basic and novel characteristics or function of the item(s) used in

connection therewith. For example, trace elements present in a composition, but not

affecting the compositions nature or characteristics would be permissible if present under

the "consisting essentially of" language, even though not expressly recited in a list of items

following such terminology. When using an open-ended term, like "comprising" or

"including," in the written description it is understood that direct support should be afforded

also to "consisting essentially of" language as well as "consisting of" language as if stated

explicitly and vice versa.

[0047] The terms "first," "second," "third," "fourth," and the like in the description

and in the claims, if any, are used for distinguishing between similar elements and not

necessarily for describing a particular sequential or chronological order. It is to be

understood that any terms SO used are interchangeable under appropriate circumstances

such that the embodiments described herein are, for example, capable of operation in

sequences other than those illustrated or otherwise described herein. Similarly, if a method

is described herein as comprising a series of steps, the order of such steps as presented

herein is not necessarily the only order in which such steps may be performed, and certain

of the stated steps may possibly be omitted and/or certain other steps not described herein

may possibly be added to the method.

[0048] As used herein, comparative terms such as "increased," "decreased,"

"better," "worse," "higher," "lower," "enhanced," "improved," "maximized," "minimized," and the like refer to a property of a device, component, composition, biologic

response, biologic status, or activity that is measurably different from other devices,

components, compositions, biologic responses, biologic status, or activities that are in a

surrounding or adjacent area, that are similarly situated, that are in a single device or

composition or in multiple comparable devices or compositions, that are in a group or class,

that are in multiple groups or classes, or as compared to an original (e.g. untreated) or

baseline state, or the known state of the art. For example, a composition that "increases"

testosterone serum levels provides a testosterone serum level in a subject that is elevated as

compared to a serum level at a previous point in time, such as a baseline level (e.g. prior to

treatment), or as compared to an earlier treatment with a different (e.g. lower dose).

[0049] As used herein, the term "substantially" refers to the complete or nearly

complete extent or degree of an action, characteristic, property, state, structure, item, or

result. For example, an object that is "substantially" enclosed would mean that the object

is either completely enclosed or nearly completely enclosed. The exact allowable degree

of deviation from absolute completeness may in some cases depend on the specific context.

However, generally speaking the nearness of completion will be SO as to have the same

overall result as if absolute and total completion were obtained. The use of "substantially"

is equally applicable when used in a negative connotation to refer to the complete or near

complete lack of an action, characteristic, property, state, structure, item, or result. For

example, a composition that is "substantially free of" particles would either completely lack

particles, or SO nearly completely lack particles that the effect would be the same as if it

completely lacked particles. In other words, a composition that is "substantially free of" an ingredient or element may still actually contain such item as long as there is no measurable effect thereof.

[0050] As used herein, the term "about" is used to provide flexibility to a numerical

range endpoint by providing that a given value may be "a little above" or "a little below"

the endpoint. Unless otherwise stated, use of the term "about" in accordance with a specific

number or numerical range should also be understood to provide support for such numerical

terms or range without the term "about". For example, for the sake of convenience and

brevity, a numerical range of "about 50 langstroms to about 80 langstroms" should also be

understood to provide support for the range of "50 langstroms to 80 langstroms."

Furthermore, it is to be understood that in this specification support for actual numerical

values is provided even when the term "about" is used therewith. For example, the

recitation of "about" 30 should be construed as not only providing support for values a little

above and a little below 30, but also for the actual numerical value of 30 as well.

[0051] As used herein, a plurality of items, structural elements, compositional

elements, and/or materials may be presented in a common list for convenience. However,

these lists should be construed as though each member of the list is individually identified

as a separate and unique member. Thus, no individual member of such list should be

construed as a de facto equivalent of any other member of the same list solely based on

their presentation in a common group without indications to the contrary.

[0052] Concentrations, amounts, levels and other numerical data may be expressed

or presented herein in a range format. It is to be understood that such a range format is

used merely for convenience and brevity and thus should be interpreted flexibly to include

not only the numerical values explicitly recited as the limits of the range, but also to include

all the individual numerical values or sub-ranges or decimal units encompassed within that

range as if each numerical value and sub-range is explicitly recited. As an illustration, a

numerical range of "about 1 to about 5" should be interpreted to include not only the

explicitly recited values of about 1 to about 5, but also include individual values and sub-

ranges within the indicated range. Thus, included in this numerical range are individual

values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as

well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only

one numerical value as a minimum or a maximum. Furthermore, such an interpretation

should apply regardless of the breadth of the range or the characteristics being described.

[0053] Reference throughout this specification to "an example" means that a

particular feature, structure, or characteristic described in connection with the example is included in at least one embodiment. Thus, appearances of the phrases "in an example" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0054] The term "API" refers to active pharmaceutical ingredient or drug and

means (17-B)-Hydroxy-4-Androsten-3-one (also known as testosterone) which is

considered the biologically active agent for the purpose of this disclosure. It is noted that

(17-B)-3-Oxoandrost-4-en-17-yl dodecanoate can be converted in vivo to (17-B)-hydroxy-

5a-androstan-3-one (directly or via the corresponding ester) which is also biological

activity as well as other metabolites. The term "EAPI" means an ester of (17-B)-Hydroxy-

4-Androsten-3-one, a prodrug of the biologically active agent. It is understood that the

EAPI can also have biological activity without cleavage of the ester, but for the purpose of

this invention the API is considered the pharmacological agent, which is (17-B)-Hydroxy-

4-Androsten-3-one (testosterone).

[0055] As used herein, the term AUCt1-t2 is the area under the curve of a plasma-

versus-time graph determined for the analyte from the time "t1 to t2" wherein t1 and t2 are

times (in hours) post dosing. For Example, t1 could be 1 hour and t2 could be 2 hours post

dose.

[0056] As used herein, the term "Cavg," "Cave," or "C-average" are used

interchangeably and determined as the mean values obtained from AUCt1-t2 divided by the

time period (t1-t2|). For example, Cavg t0-t8 is the average plasma concentration over a

period of 8 hours from t1=0 to t2=8 hours post-dosing determined by dividing the AUCto-

t8 value by 8 hours. Similarly, Cavg t0-t1 is the average plasma concentration over a period

of 12 hours post-dosing determined by dividing the AUCt0-t12 value by 12 hours (t1=0 and

t2=12). Similarly, Cavg t12-t24 is the average plasma concentration over a period of 12 hours

post-dosing determined by dividing the AUCt12-t24 value by 12 hours (t1=12 and t2=24);

Cavgt0-t24 is the average plasma concentration over a period of 24 hours post-dosing

determined by dividing the AUCt0-t24 value by 24 hours (t1=0 and t2=24), and SO on. Unless

otherwise stated, all Cavg values are considered to be Cavgt0-t24 and unless otherwise stated,

all the time values are expressed in hours (h). For example, the term Cavg t0-t24 denotes Cavg

from time zero (0) to 24 hours post dosing.

[0057] As used herein, "Ct" refers to the serum concentration of testosterone at time

"t" after administration of the dosage of the current invention. The time "t" is generally in

hours post administration, unless otherwise specified. For example, a Ct of "C(-2 to 0) refers

to serum testosterone concentration measured in sample collected between the time of about 2 hours before and just immediately prior to dosage administration to the subject tested. Similarly, Ct of "C(2 to 4)" refers to serum testosterone concentration measured in sample collected between the time of about 2 hours and 4 hours after administration of a dosage to the subject tested.

[0058] As used herein, the term (17-B)-Hydroxy-4-Androsten-3-one refers to a

chemical having an IUPAC name of (8R,9S,10R,13S,14S,17S)-17-Hydroxy-10,13-

dimethyl- 1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[alphenanthren-3-one

and a CAS number of 58-22-0. (17-3)-3-Oxoandrost-4-en-17-yl dodecanoate generically

refers to compounds having the (17-B)-Hydroxy-4-Androsten-3-one structure but the

hydroxyl group at the 17th carbon site on the testosterone structure is esterified with lauric

acid (e.g., 12-carbon chain saturated alkanoic acid). For example, (8R,9S,10R,13S,14S,17S)-10,13-dimethy1-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-

dodecahydrocyclopenta[alphenanthren-17-yl dodecanoate is the IUPAC name for (17-B)-

Hydroxy-4-Androsten-3-one esterified with a straight chain saturated 12 carbon long

alkanoic acid called lauric acid. Dodecanoic acid, alternatively named lauric acid as well,

is the IUPAC name for the saturated alkanoic acid having CAS number 143-07-7. In a

more specific aspect, (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate refers to those of (17-

B)-3-Oxoandrost-4-en-17-yl laurate specifically disclosed herein. In one specific aspect, it

refers to the dodecanoic (17-B)-Hydroxy-4-Androsten-3-one ester (referred to herein as

(17-B)-3-Oxoandrost-4-en-17-yl dodecanoate, (17-B)-3-Oxoandrost-4-en-17-y1 laurate, or

the dodecanoic ester of (17-B)-Hydroxy-4-Androsten-3-one and the such (CAS No. 59232-

78-9)). (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate has the following chemical structure

as shown in Exhibit 1:

Exhibit 1

O H

o

15

[0059] Solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate can exist in

different crystalline forms as well as in non-crystalline forms. A non-crystalline solid form

is referred to herein as an "amorphous form", which is a disordered arrangement of (17-3)-

3-Oxoandrost-4-en-17-yl dodecanoate molecules. Different crystalline forms of (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate arise from different packing of the (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate molecules in the solid state, resulting in different

crystal symmetries and/or unit cell parameters. Crystalline forms are identified or

characterized by any suitable methods, e.g., x-ray diffraction (see, e.g., Remington's

Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa., p 173 (1990); The United

States Pharmacopeia, 23rd ed., pp. 1843-1844 (1995)). Such different crystalline forms are

referred to herein as "polymorphic forms" or "non-solvated forms", which mean that they

are essentially free of residual solvents, e.g., organic solvents. If the substances incorporate

stoichiometric or non-stoichiometric amounts of water ("hydrate" as used herein), or any

other solvent ("solvate" as used herein), in the crystal structure, these are referred to herein

as a "pseudopolymorphic form."

[0060] The term "amorphous form" as used herein in connection with solid state

refers to a non-crystalline solid form (i.e., not in a crystalline form), which is a disordered

arrangements of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate molecules. Typically, an

amorphous solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate has no long-range

periodic molecular packing structure as determined by Powder X-ray Diffraction ("PXRD"

or "XRD"). The XRD pattern of amorphous (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

appears as a halo with no distinctive peaks. Amorphous forms for some compounds can be

obtained by a number of methods known in the art, including, but not limited to, heating,

melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation,

desolvation, sublimation, grinding, cryo-grinding, spray-cooling or freeze-drying.

[0061] The term "crystal", "crystallite", or "crystalline" as used herein refers to a

solid structure, typically formed by a solidification or crystallization, that generally has an

ordered molecular packing structure (characteristic shapes and cleavage planes formed by

the arrangement of molecules in a pattern referred to as a "lattice"). In an aspect, a number

of crystallites agglomerate and then form any grains, which can be packed to form any

particles. That is, particle size is greater than grain size, which is greater than any crystal

size.

[0062] The term "seeding" as used herein refers to starting or promoting a

crystallization event using a small amount of materials.

[0063] As used herein, the term "Triton X100" or Triton "X-100" is a non-ionic

detergent and refers to a composition as known as polyethylene glycol p-(1,1,3,3-

tetramethylbutyl)-phenyl ether, octyl phenol ethoxylate, polyoxyethylene octyl phenyl

ether, 4-octylphenol polyethoxylate, Mono 30, TX-100, t-octylphenoxypolyethoxyethanol,

or Octoxynol-9 and associated with CAS NO. 9002-93-1.

[0064] A "pharmaceutical composition" or "formulation" as used herein refers to a

composition comprising or prepared from a solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate and one or more pharmaceutically acceptable carriers, excipients, or additives.

Moreover, an exemplary composition may be any of the compositions taught in the Patents.

A "unit dosage form" as used herein refers to a medicament prepared from or comprising

a pharmaceutical composition and includes tablets, capsules, caplets, gelcaps, ampoules,

suspensions, solutions, gels, dispersions and other dosage units typically associated with

parenteral, enteral, topical or other forms of administration of (17-B)-3-Oxoandrost-4-en-

17-y1 dodecanoate to a subject in need thereof.

[0065] A "pharmaceutically acceptable carrier", "pharmaceutically acceptable

excipient", "pharmaceutically acceptable additive", or similar term refers to one or multiple

components or ingredients that are acceptable (1) as being compatible with the other

ingredients in compositions or formulations comprising (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate and (2) are not deleterious nor overly deleterious to a subject to whom the

composition or formulation is to be administered. Excipients include any of the excipients

disclosed in the Patents.

[0066] Carriers (e.g., pharmaceutically acceptable excipients or additives) and

methods of preparing oral pharmaceutical compositions comprising (17-B)-3-Oxoandrost-

4-en-17-yl dodecanoate are available to the skilled artisan in view of this application which

typically involve a specific solid state form of the (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate.

[0067] Reference will now be made in detail to specific embodiments of the

invention. While the invention will be described in conjunction with such embodiments, it

will be understood that it is not intended to limit the invention to those embodiments. To

the contrary, it is intended to cover alternatives, variants, modifications, and equivalents as

may be included within the spirit and scope of the invention as defined by the appended

claims.

Solid state forms of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

[0068] The specific solid state forms of (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate disclosed herein have one or more advantageous properties compared to other

forms such as chemical or polymorphic purity, increased crystallinity, flowability,

solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface

and pycnometric density, bulk/tap density, stability (e.g., such as chemical stability as well

as thermal and mechanical stability with respect to polymorphic conversion), stability

towards hydration and/or storage stability, a lower degree of hygroscopicity, low content

of residual solvents and advantageous processing and handling characteristics such as

compressibility and bulk density. Specific solid state forms of (17-3)-3-Oxoandrost-4-en-

17-y1 dodecanoate are provided herein.

[0069] (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate can be prepared by a number

of synthetic routes (as well as other corresponding esters in an analogous fashion). For

example, (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is prepared under the

corresponding alcohol via an esterification reaction with (17-B)-Hydroxy-4-Androsten-3-

one and an activated fatty acid of n-dodecanoic acid (IUPAC name as lauric acid, CAS

number 143-07-7): e.g., a lauroyl chloride or anhydride, in a suitable solvent under suitable

conditions to produce the product (e.g., pyridine as a catalyst of esterification). In one

aspect, the (17-B)-Hydroxy-4-Androsten-3-one (testosterone) is prepared from a

phytosterol or cholesterol or any other suitable starting material. The product is worked up

via any number of techniques. For example, the product is dissolved in a solvent (e.g.,

organic solvent such as heptanes or any other solvent); washed successively with e.g., cold

water (2X), 0.05 N NaOH, saturated NaHCO3 (2X), water, brine, then dried over anhydrous

Na2SO4 (~50 g), followed by drying process (e.g., rotavap/Tbath < 30 °C). Without wishing

to be bound by theory, the inventors have unexpectedly found that crystallization or

recrystallization of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate provides solid state forms

with one or more advantageous properties as described herein.

[0070] Thus, according to one embodiment, an example of recrystallized or

crystallized solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is provided here.

According to this embodiment, (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is dissolved

in a solvent (e.g., heptane) and allowed to crystallize or recrystallize or after a first

crystallization is transferred to another solvent and allowed to crystallize or recrystallize.

The crystalline mass can be isolated (e.g., filtered by suction), optionally washed (e.g., with

water), optionally dried (e.g., over phosphorous pentoxide) and optionally re-crystallized from another solvent e.g., oleic acid, hexane, heptanes, etc. In one aspect, the solvent (for crystallization or recrystallization) is an alcohol (e.g., ethanol, methanol, or propanol), fatty acid (e.g., oleic acid, linoleic acid, or linoeladic acid), alkane (e.g., hexane, heptane, pentane, or halogenated alkane), oil (e.g., vegetable oil, castor oil, or hydrogenated oil), or any other suitable solvent (e.g., pyridine, benzene, or toluene). In this context, a solvent refers to a liquid in which (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is soluble.

[0071] Crystalline forms of a substance can be obtained by a number of techniques,

as is known in the art. Exemplary techniques for obtaining, producing, or manufacturing

crystalline forms of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate include melt

recrystallization, melt cooling, solvent recrystallization, recrystallization in confined

spaces such as in nanopores or capillaries, recrystallization on surfaces or templates such

as on polymers, recrystallization in the presence of additives, such as co-crystal counter-

molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor

diffusion, sublimation, grinding and solvent-drop grinding.

[0072] Typically, specific crystalline forms of active pharmaceutical ingredients

(API) (e.g., testosterone esters) can be distinguished from each other by one or more

physical or chemical properties such as rate of dissolution, infrared or Raman spectroscopy,

x-ray diffraction techniques (e.g., single crystal and powder diffraction techniques), solid

state-NMR (see: https://en.wikipedia.org/wiki/Solid- (SS-NMR) state nuclear magnetic resonance), thermal techniques such as melting point, differential

thermal analysis (DTA) (see: https://en.wikipedia.org/wiki/Differential_thermal analysis),

differential scanning calorimetry (see: (DSC)

https://en.wikipedia.org/wiki/Differentialscanning_calorimetry), thermal gravimetric

analysis (TGA) (see: : https://en.wikipedia.org/wiki/Thermogravimetric_analysis) and other

methods as disclosed elsewhere in the specification or available to the skilled artisan. Other

methods to characterize or distinguish a pseudopolymorphic form from another

isostructural polymorphs, pseudopolymorphs, desolvates or anhydrates include elemental

analysis, Karl-Fisher titration, dynamic vapor sorption analysis, thermogravimetric-

infrared spectroscopic analysis (TG-IR), residual solvent gas chromatography (see:

https://www.restek.com/Technical-Resources/Technical-

Library/Pharmaceutical/pharm_A005), (see: 1H-NMR https://en.wikipedia.org/wiki/Protonnuclear_magneticresonance) etc.

[0073] Thus, in one embodiment, a solid state form of (17-B)-3-Oxoandrost-4-en-

17-y1 dodecanoate is provided wherein the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate has one or more advantageous properties compared to other forms, such as chemical properties, crystalline, or polymorphic purity, increased crystallinity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability (e.g., such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion), stability towards hydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvent(s) and advantageous processing and handling characteristics such as compressibility and bulk density. In the specific aspect of this embodiment, the solid state

(17-B)-3-Oxoandrost-4-en-17-yl dodecanoate in this disclosure is a crystalline form. In

further aspect, the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is useful for

administration to a human. In one aspect, the solid state (17-B)-3-Oxoandrost-4-en-17-y1

dodecanoate is a specific crystalline form characterized by an analytical techniques known

in the ordinary skilled artisan (e.g., substantially similar to that characterized in the

Examples and Figures by XRD and DSC).

[0074] In one aspect, the solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate

found here has two endothermic transition peaks, that can represent change of a kind of

crystalline form to a different form of solid state or phase changes (e.g., solid to liquid).

FIG. 1 displays a first cycle heat enthalpy change plot for the solid state form of (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate measured by differential scanning calorimetry as

disclosed herein. In another aspect, one small endothermic peak showing at 35 to 45 °C in

FIG. 1 can be a glass transition peak, which can be a stable solid form to a meta-state solid

from (e.g., amorphous form). In further aspect, one small endothermic peak showing at 35

to 45 °C in FIG. 1 can be a lattice-form transition peak, which can be a crystalline form to

a different crystalline from. In an aspect, the other large endothermic peak showing at 45

to 70 °C represents the melting point (e.g., the phase change from solid state to liquid state)

of the solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate disclosed herein as

determined by differential scanning calorimetry. In one aspect, the solid state (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate is a crystalline form having a melting point in the

range of 45 to 70 °C, 50 to 70 °C, or 50 to 65 °C as determined by differential scanning

calorimetry. In one aspect, the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is

a crystalline form having a melting point in the specific range of 51 to 63 °C as determined

by differential scanning calorimetry as shown in See FIG. 1.

[0075] In one aspect, the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

is a crystalline form having at least 1, 2, 3, 4, 5, 6 or more distinguished peaks as determined by XRD corresponding to those in FIG. 2. In one aspect, the solid state (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate is a crystalline form which is not milled or is milled,

micronized, or nanosized. In one aspect, the particle size of the solid state (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate has a d50 of greater than 1000 um, from 355 to 1000

um, from 180 to 355 um, from 125 to 180 um, from 90 to 125 um, from 1 to 90 um, or

less than 1 um. In one aspect, the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

has particle size distribution of less than 200 nm, from 200 to 500 nm, from 500 to 1000

nm, from 1 to 50 um, from 50 um to 250 um, from 250 um to 500 um, from 500 um to

1000 um, or greater than 1000 um. In one aspect, the particle size of the solid state (17-B)-

3-Oxoandrost-4-en-17-yl dodecanoate has a D10, D50, or D90 that is less than 200 nm, from

200 to 500 nm, from 500 to 1000 nm, from 1 to 50 um, from 50 to 250 um, from 250 to

500 um, from 500 to 1000 um, or greater than 1000 um. In one aspect, the release profile

of the (17-3)-3-Oxoandrost-4-en-17-yl dodecanoate does not change substantially as a

function of storage time.

Production of Different Forms of (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate in

a Pharmaceutical Composition from the Solid State

[0076] Described herein are different solid state forms of (17-B)-3-Oxoandrost-4-

en-17-y1 dodecanoate created by compositions with any excipients or carriers (e.g.,

solubilizers, surfactants, additives, and SO on). The identification of different forms of (17-

B)-3-Oxoandrost-4-en-17-yl dodecanoate yields improvement related to physical,

chemical, pharmacokinetic, and pharmacodynamic properties.

[0077] A number of different forms including crystalline forms of (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate may exist. A solid state crystalline form of (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate having the melting point at 55 to 65 °C shown in FIG.

1 and at least 1, 2, 3, 4, 5, 6 or more distinguished peaks as determined by XRD shown in

FIG. 2 described herein can be transformed to at least one of a single crystalline form,

amorphous form, polymorphic crystalline form, meta-stable solid form, or liquid form of

(17-B)-3-Oxoandrost-4-en-17-yl dodecanoate by making a pharmaceutical composition

comprising at least one of pharmaceutically acceptable excipients, carriers, or ingredients.

In specific aspect, a variety of different forms of (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate in a pharmaceutical composition can be provided by methods available to the

ordinary skilled artisan in view of this disclosure: see FIG. 3.

21

Experimental Instrumentation and Conditions for Analyzing Solid State (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate

[0078] A variety of techniques may be used to identify or characterize solid state

(17-B)-3-Oxoandrost-4-en-17-yl dodecanoate.

[0079] Fourier Transform-Raman Spectroscopy ("FT-Raman") (see:

https://www.sciencedirect.com/topics/chemistry/fourier-transform-raman-

spectroscopy#:s:text=Near%2Dinfrared%20Fourier%20Transform%20Raman,advantag

%20of%20the%20optical%20interferometer.) is useful for characterizing and identifying

solid state forms of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate. For example, different

solid state forms of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate may be characterized

using a Bruker RFS100 instrument, with Nd:YAG 1064 nm excitation, 300 mW laser

power, Ge detector, using 64 scans over the range of 25-3500 cm and with 2 cm 1

resolution. As is understood by the ordinary skilled artisan, the parameters and

instrumentation for FT-Raman may be modified depending on the instrument, the solid

state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate, and goal(s) of the analysis.

[0080] Another useful technique for characterization is XRD (see

https://en.wikipedia.org/wiki/Powder_diffraction). For example, XRD can be performed

with a Bruker D8 Advance X-ray diffractometer with CuKa-radiation. The standard

measuring conditions are e.g., tube power 40 kV/40 mA; step size 0.010° (20); step time

57.6 sec; scanning range 3°-40° (20); divergence slit 0.600 mm; antiscatter slit 4.800 mm;

slit mode fixed; sample rotation speed 15.000 %min; detector LYNXEYE_XE (1D mode);

goniometer radius 280.0 nm; wavelength for display 1.54060 À. As is understood by the

ordinary skilled artisan, the parameters and instrumentation for XRD may be modified

depending on the instrument, the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

and goal(s) of the analysis. In one embodiment, the solid state (17-B)-3-Oxoandrost-4-en-

17-y1 dodecanoate is crystalline or substantially crystalline as indicated by XRD. An

example of an XRD spectra is shown in FIG. 2 for a crystalline from of solid state (17-B)-

3-Oxoandrost-4-en-17-yl dodecanoate. FIG. 2 shows well defined peaks corresponding to

the crystalline from of the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate with

little or no characteristics of amorphous forms of the solid state (17-B)-3-Oxoandrost-4-en-

17-yl dodecanoate (as indicated by the absence of an "amorphous halo" in the spectra in

the 5-30 degree 20 range and peaks not broadened). In one aspect, the solid state (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate described herein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or

12 or more of the peaks that correspond to those in FIG. 2 that have an intensity of above

25, 50, 100, 150, or 200 counts. The intensity can be a random relative value compared to

one measured from the control.

[0081] 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 the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate. For example, TG-

FTIR can be performed with a Netzsch Thermo-Microbalance TG 209 coupled with a

Bruker FT-IR Spectrometer Vector 22, using an aluminum crucible (open or with a

microhole), under a nitrogen atmosphere, and e.g., at a heating rate of 10 °C/min over the

range of 25 °C to 350 °C. As is understood by the ordinary skilled artisan, the parameters

and instrumentation for TG-FTIR may be modified depending on the instrument, the solid

state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate and goal(s) of the analysis.

[0082] Characterization/Analysis of a solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate can also be performed using Differential Scanning Calorimetry ("DSC"). For

example, DSC can be performed with a Perkin Elmer Differential Scanning Calorimeter,

using closed Pan Al crucibles, a heating rate of 10 °C min-1 over a range from 0 °C to 100

°C (or e.g., over a range from 5 °C to 150 °C): For example, see FIG. 1. As is understood

by the ordinary skilled artisan, the parameters and instrumentation for DSC may be

modified depending on the instrument, the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate and goal(s) of the analysis. Thus, in yet another embodiment, the solid state

(17-B)-3-Oxoandrost-4-en-17-yl dodecanoate provided herein has a melting point in the

range of about 45 to 70 °C, as determined by DSC. In a specific embodiment, the solid

state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate provided herein has a melting point in

the range of about 50 to 65 °C, as determined by DSC. In a more specific embodiment, the

solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate provided herein has a melting

point in the range of about 55 to 65 °C, as determined by DSC. In one aspect of this

embodiment, the melting point of the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate is a characteristics of solid state forms of (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate: See FIG. 1.

[0083] Dynamic Sorption (see: Vapor (DVS) https://en.wikipedia.org/wiki/Dynamic vapor sorption) analysis is another technique for

characterizing and analyzing (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate. For example,

DVS can be performed with a Surface Measurement Systems DVS-1 water vapor sorption

analyzer. The experiments can be run by placing the sample on a quartz holder on top of a microbalance, and allowing the sample to equilibrate at 50% relative humidity (RH) before starting the pre-defined humidity program. The program can proceed e.g., in the following steps: 1 hour at 50% RH; 50% to 0% RH at a rate of 5% RH change per hour; 5 hours at

0% RH; 0% RH to 96% RH at 5% RH change per hour; 5 hours at 95% RH; 95% RH to

50% RH at a rate of 5% RH change per hour, and followed by one hour at 50% RH As is

understood by the ordinary skilled artisan, the parameters and instrumentation for DVS

may be modified depending on the instrument, the solid state (17-B)-3-Oxoandrost-4-en-

17-yl dodecanoate and goal(s) of the analysis.

[0084] High performance liquid chromatography (see: (HPLC) https://en.wikipedia.org/wiki/High-performance liquid chromatography) is also useful for

analyzing or characterizing (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate. In some of the

embodiments, the purity of crystalline forms of (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate as measured by HPLC is greater than about 90%, about 90.5%, about 91.0%,

about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about

94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%,

about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9% based on total area

under the curve as observed at a suitable wavelength e.g., about 240 nm or about 250 nm.

In some embodiments, the crystalline form of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate disclosed herein is about 98.0% to 100.0% pure as measured by HPLC as area

under the curve as observed at a suitable wavelength, e.g., at a wavelength of from about

200 nm to about 300 nm, e.g., about 240 nm or 250 nm.

[0085] In some of the embodiments, the purity of different forms of (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate in a pharmaceutical composition as measured by

HPLC is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%,

about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about

95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%,

about 99.0%, about 99.5%, or about 99.9% based on total area under the curve as observed

at a suitable wavelength e.g., about 200 nm to about 300 nm, or about 240 nm to about 250

nm. In some embodiments of the invention, different forms of (17-6)-3-Oxoandrost-4-en-

17-yl dodecanoate in a pharmaceutical composition is about 98.0% to 100.0% pure as

measured by HPLC based on area under the curve as observed at a suitable wavelength,

e.g., at a wavelength of from about 200 nm to about 300 nm, e.g., about 240 nm or 250

nm.

[0086] As is understood by the ordinary skilled artisan, solid state NMR and other

techniques can be used to analyze or characterize the solid state (17-3)-3-Oxoandrost-4-en-

17-yl dodecanoate and forms thereof in view of this disclosure.

Production of Different Particle Size Distributions of Solid State (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate

[0087] Compositions having different particles sizes or distributions of particles

sizes can be produced by any suitable method. Micronization techniques can be based on

friction to reduce particle size; such methods include milling, bashing and grinding.

Another technique of producing different sized (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate particles involves supercritical fluids where the (17-3)-3-Oxoandrost-4-en-17-

yl dodecanoate is dissolved in a solvent at high temperature and pressure and the mixture

is sprayed out of a nozzle, causing the formation of particles of particular sizes or within

particular size ranges/distributions. Some basic supercritical fluid techniques are RESS

of (see: process (Rapid Expansion of Supercritical Solutions) https://hightechextracts.com/the-science/rapid-expansion-of-supercritical-

solution/#:~:text=Rapid%20Expansion%20of%20Supercritical%20Solution%20(RESS)

%20is%20used%20generally%20to,solution%20through%20an%20expansion%20nozzle. ), (see: the method (Supercritical Anti-Solvent) SAS http://hpp.uva.es/technology/formulation/supercritical-antisolvent-

sas/#:-:text=The%20Supercritical%20Anti%20Solvent%20technique,solution%20with9

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)%20

s%20a%20technique%20for.of%20CO2%20at%20moderate%20pressures. Particle Size Distribution and Morphology Analysis

[0088] Particle size distribution of solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate particles can be analyzed by a number of techniques. For example, particle

size distribution can be analyzed by photon correlation spectroscopy (PCS) (see:

https://www.sciencedirect.com/topics/chemical-engineering/photon-correlation-

spectroscopy): e.g., Malvern ZetaSizer 2000 HS (Malvern Instruments, Malvern, UK). The

measuring mode applied can be e.g., Contin-Auto mode. PCS yields the mean diameter of

the bulk population (z-average) and a polydispersity index (PI) ranging from 0

(monodisperse) through 0.10-0.20 (relatively monodisperse) to > 0.5 for a broad size distribution. The measuring range of PCS is approximately 3 nm - 3 um. As is understood by the ordinary skilled artisan, the parameters and instrumentation for PCS may be modified depending on the instrument, the solid state (17-3)-3-Oxoandrost-4-en-17-yl dodecanoate and goal(s) of the analysis.

[0089] Particles of solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate can

also be visually analyzed by Scanning Electron Microscopy (SEM) (see: https://en.wikipedia.org/wiki/Scanning electron microscope). Solid particles are

deposited on metallic stubs then placed in liquid nitrogen and dried under vacuum. The

metal stubs are coated uniformly with gold or palladium. All samples are examined for

morphology and surface properties using a scanning electron microscope (e.g., Joel, SEM,

JSM-25 SII, Tokyo, Japan). Particle size, polydispersity index and zeta potential can be

initially measured by a laser particle size analyzer (Submicron Particle Size Analyser 90

plus, Brookhaven Instrument Co., Holtsville, NY, USA). An aliquot of solid state (17-B)-

3-Oxoandrost-4-en-17-yl dodecanoate particles can be diluted with e.g., 3 ml of deionized

water. The diluted (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate samples are loaded into a

4 ml cuvette and the particle size and zeta potential measurement can be conducted at

ambient temperature. For example, particles of the solid state (17-B)-3-Oxoandrost-4-en-

17-yl dodecanoate characterized as shown in FIG. 1 and 2 were measured by a scanning

electron microscope. FIG. 4 shows the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate particles exist as one or more crystallites, grains, and particles with a shape of

flat thin panel. As shown in FIG. 4, those size ranges over one or more of about less than 1

um, about 1 - 5 um and about 5 - 50 um. As is understood by the ordinary skilled artisan,

the parameters and instrumentation for electron microscopy may be modified depending

on the instrument, the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate and goal(s)

of the analysis.

[0090] The crystallite sizes of the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate disclosed here, which agglomerate to particles of the solid state (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate as seen in FIG. 4, can also be estimated by XRD e.g.,

by applying the Sherrer equation (see: https://en.wikipedia.org/wiki/Scherrer_equation)

where the size of crystallites agglomerated to build particles of the solid state (e.g., crystal

particles or crystallites) can be calculated, in a solid to the broadening of a peak in a

diffraction pattern. Typically, particles are made from agglomeration of grains, which are

agglomerated from many crystallites of the solid state. Based on XRD diffractogram shown in FIG. 4, the mean crystallite size of the solid state (17-B)-3-Oxoandrost-4-en-17- yl dodecanoate disclosed here was measured about 50 nm with standard deviation of about

7 nm. The mean crystallite size was measured using Scherrer equation as:

K X A

wherein D is the crystallite size of the ordered domains, K is a dimensionless Scherrer

constant (=0.9), a is the X-ray wavelength (=0.15406 nm), is the line broadening at half

the maximum intensity (FWHM) in radians for each peak, and 0 is the peak position in 20.

For example, Table 1 summarizes the crystallite sizes measured from each peak (8

distinguishable peaks) as shown in FIG. 2 using the Scherrer equation.

Table 1. Crystallite size measured using Scherrer equation based on peaks in XRD (FIG. 2)

Peak ID Peak position (20) Crystallite size FWHM (0) (nm)

1 10.9 0.17 46.9

2 13.6 0.17 47.1

3 14.0 0.14 57.2

4 15.3 0.19 42.2

5 17.3 0.14 57.4

6 18.0 0.15 53.6

7 19.2 0.13 60.2

8 23.2 0.19 42.7

Mean 0.16 51.1

0.023 7.4 SD

Release Profile of the Solid State (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

[0091] In one embodiment, the release profile (e.g., a profile comprising 2, 3, 4, 5,

or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of

the solid state (17-B)-3-oxoandrost-4-en-17-yl1 dodecanoate found here does not change

substantially as a function of storage time. Additionally, the release amount of the solid

state crystalline (17-B)-3-oxoandrost-4-en-17-yl dodecanoate is less than 10%, 9%, 8%,

7%, 6%, or 5% up to at least 60 min, 120 min, 180 min, 240 min, 360 min, 24 hours, or 48

hours in a USP type 2 apparatus at 100 rpm in about 1000 mL 8% Triton X-100 solution in

water at a specific temperature e.g., 20.0, 37.0 or 40.0 °C ( 0.5). In one aspect, the release

profile of the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate does not

substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16

weeks. In one aspect, the release profile of the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,

12, 13, 14, 15, or 16 months. In one aspect, the release test is performed using a USP type

2 apparatus at 100 rpm in about 1000 mL 8% Triton X-100 solution in water at a specific

temperature e.g., 20.0, 37.0 or 40.0 °C (+ 0.5). In one aspect, a release profile that does not

substantially change over a period of time refers to a release profile that changes by less

than plus/minus 50%, 40%, 30%, 20%, or 10% or less of the amount of (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate released at one or more specific time point under

specific conditions.

Pharmaceutical Compositions Comprising or Prepared from the Solid State (17-B)-

3-Oxoandrost-4-en-17-yl dodecanoate

[0092] The pharmaceutical compositions and dosage forms (e.g. capsule or tablet)

described herein comprising or prepared from the solid state (17-B)-3-Oxoandrost-4-en-17-

yl dodecanoate can include a variety of pharmaceutically acceptable carriers known in the

common art. Non-limiting examples of components that can be included as components of

the pharmaceutical carrier include lipophilic surfactants, hydrophilic surfactants,

triglycerides, fatty acid (C8 to C22), fatty acid glycerides (mono-, di-, tri-, or a combination

thereof), additives or a combination thereof.

[0093] In one embodiment, the pharmaceutical composition or dosage form

comprising or prepared from the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

is as described herein. In an aspect, the pharmaceutical composition or dosage form is

prepared from solid state crystalline (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate. In

another aspect, the pharmaceutical composition or dosage form is prepared from specific

crystalline forms of solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate. In yet

another aspect, the pharmaceutical composition or dosage form is prepared from the

crystalline form of the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate as

characterized by DSC and XRD as shown in FIG. 1, 2, and 4.

[0094] In another embodiment, the crystalline form of the solid state (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate can be transformed to amorphous, substantially amorphous, partially amorphous, or amorphous-like forms in the pharmaceutical composition or dosage formulation post processes for making the compositions or dosage formulations with pharmaceutically acceptable carriers. Amorphous-like refers to one of physical states of (17-B)-3-Oxoandrost-4-en-17-yl1 dodecanoate in a dosage form or pharmaceutical composition in which a substantial amount of the (17-3)-3-Oxoandrost-4- en-17-y1 dodecanoate is not in a structured crystalline form (e.g., dissolved or dispersed in a solvent). In another specific aspect of this embodiment, the solid state (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate in the pharmaceutical composition or dosage form can

be semi-solid forms or substantially free of crystalline forms. In further aspect of this

embodiment, the solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate in the

pharmaceutical composition or dosage form can be partially maintained with the same

crystalline forms as intact.

[0095] In yet another aspect, the pharmaceutical composition or dosage form is

prepared from crystalline forms of the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate and the pharmaceutical composition comprises amorphous or amorphous-like

solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate. In yet another aspect, the

pharmaceutical composition or dosage form is prepared from crystalline forms of the solid

state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate and the pharmaceutical composition

comprises substantially free of amorphous solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate. In yet another aspect, the pharmaceutical composition or dosage form is

prepared from crystalline forms of the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate and the pharmaceutical composition comprises solubilized (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate.

[0096] In one embodiment, the pharmaceutical composition or unit dosage form

comprising or prepared from the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

has improved release properties as compared to the release from the crystalline forms of

the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate without any carriers or

excipients. According to this embodiment, a pharmaceutical composition or unit dosage

form comprising or prepared from the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate releases more (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate than do

crystalline forms of the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate release at

a specified time point (e.g., 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min,

10 min, 11 min, 12 min, 15 min, 20 min, 25 min, 30 min, 35 min, 45 min, 60 min, 75 min,

90 min, 105 min, 120 min, 180 min, and 240 min.) in a USP Type 2 apparatus in about

1000 mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or

40.0 °C (+ 0.5)) at 100 rpm. Releasing more (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

from the pharmaceutical composition or unit dosage form refers to releasing more than

10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or more than the crystalline

forms of solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate in the dissolution

aqueous media (e.g., 8% Triton X100 solution in water).

[0097] In one embodiment, the pharmaceutical composition or unit dosage form

having (or made from) the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate has a

release profile (e.g., single time point or multiple time points) of (17-B)-3-Oxoandrost-4-

en-17-yl dodecanoate that does not change substantially as a function of storage time as

measured using a USP type 2 apparatus in about 1000 mL 8% Triton X100 solution in

water at specific temperature (e.g., 20.0, 37.0 or 40.0 °C (+ 0.5)) at 100 rpm. In one aspect,

the release profile does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

11, 12, 13, 14, 15, or 16 weeks. In one aspect, the release profile does not substantially

change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. In one

aspect, a release profile that does not substantially change over a period of time refers to a

release profile that changes by less than plus/minus 50%, 40%, 30%, 20%, or 10% or less

of the amount of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate released at one or more

specific time point under specific conditions.

[0098] In one embodiment, the unit dosage form or pharmaceutical composition as

described herein comprising, or prepared from the solid state (17-B)-3-Oxoandrost-4-en-

17-yl dodecanoate and a pharmaceutically acceptable carrier, wherein the dosage form or

pharmaceutical composition releases 20% or more (17-B)-3-Oxoandrost-4-en-17-y1

dodecanoate as measured with a USP Type 2 apparatus having 1000 mL 8% Triton X100

solution in water at thirty minutes at a specific temperature at 100 RPM than an equivalent

release amount of crystalline solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate

without any excipient or carrier that does not release more than 1% of the (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate amount as measured with a USP Type 2 apparatus

having 1000 mL 8% Triton X100 solution in water at thirty minutes, is provided.

[0099] In some embodiments, the pharmaceutically acceptable carrier of the

composition can include a lipophilic additive. Non-limiting examples of lipophilic

additives can include lipophilic surfactants, mono, di, or triglycerides, tocopherol,

tocopherol succinate, tocopherol acetate, tocopherol derivatives, a sterol, a phytosterol and

combinations thereof. In one embodiment, the lipophilic additive can include a fatty acid or fatty acid glyceride. In another embodiment, the lipophilic additive can include the fatty acid glyceride which can be a monoglyceride, a diglyceride, a triglyceride or mixtures thereof. Non-limiting examples of fatty acid glycerides that can be used in the oral pharmaceutical compositions and dosage forms of the present invention include monoglycerides and/or diglycerides derived from sources such as maize oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil, and mixtures thereof. In a specific embodiment, the pharmaceutical composition or dosage form thereof, comprises one or more maize oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil, or combination thereof. In another embodiment, the composition includes one or more triglycerides. In one aspect, the lipophilic additive is a C8-C22 saturated fatty acid

(or has 1, 2, or 3 unsaturations on ester chain), a mono-, di-, or triglyceride thereof

(including mixtures), or a combination thereof. 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, vaccenic acid, linoleic acid, or

linoelaidic acid. In another specific aspect, the mono-, di-, or triglyceride is a glyceride of

caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic

acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, or linoelaidic acid

or a combination thereof.

[00100] In another embodiment, the lipophilic additive can include a

lipophilic surfactant.

[00101] As used herein a lipophilic surfactant is considered when it has a

Hydrophilic-Lipophilic Balance (HLB) value of 10 or less. Various lipophilic surfactants

can be used including, but not limited to mono-, di- glycerides of fatty acids like glyceryl

monolinoleate (e.g. MAISINE 35-1), mono- and di glycerides of caprylic-capric acid (e.g.

CAPMUL MCM), glyceryl monooleate, mixtures of alcohols or polyalcohols with a variety

of natural and/or hydrogenated oils such as PEG-5 hydrogenated castor oil, PEG-7

hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g. LABRAFIL

M 1 2125 CS), PEG-6 almond oil (e.g. LABRAFIL M 1966 CS), PEG-6 apricot kernel oil

(e.g. LABRAFIL M 1944 CS), PEG-6 olive oil (e.g. LABRAFIL M 1980 CS), PEG-6

peanut oil (e.g. LABRAFIL M 1969 CS), PEG-6 hydrogenated palm kernel oil (e.g.

LABRAFIL M 2130 BS), PEG-6 palm kernel oil (e.g. LABRAFIL M 2130 CS), PEG-6

triolein (e.g. LABRAFIL M 2735 CS), PEG-8 corn oil (e.g. LABRAFIL WL 2609 BS),

PEG-20 corn glycerides (e.g. CROVOL M40), PEG-20 almond glycerides (e.g. CROVOL

A40), lipophilic polyoxyethylene-polyoxypropylene block co-polymers (e.g. PLURONIC

L92, L101, L121 etc.); propylene glycol fatty acid esters, such as propylene glycol

monolaurate (e.g. Lauroglycol FCC), propylene glycol ricinoleate (e.g. Propymuls),

propylene glycol monooleate (e.g. Myverol P-O6), propylene glycol dicaprylate/dicaprate

(e.g. CAPTEX 200), and propylene glycol dioctanoate (e.g. CAPTEX 800), propylene

glycol mono- caprylate (e.g. CAPRYOL 90); propylene glycol oleate (e.g. LUTROL

OP2000); propylene glycol myristate; propylene glycol mono stearate; propylene glycol

hydroxy stearate; propylene glycol ricinoleate ; propylene glycol isostearate; propylene

glycol mono-oleate; propylene glycol dicaprylate/dicaprate; propylene glycol dioctanoate;

propylene glycol caprylate-caprate; propylene glycol dilaurate; propylene glycol distearate;

propylene glycol dicaprylate; propylene glycol dicaprate; mixtures of propylene glycol

esters and glycerol esters such as mixtures composed of the oleic acid esters of propylene

glycol and glycerol (e.g. ARLACEL 186); sterol and sterol derivatives such as cholesterol,

sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soya sterol, PEG-10 soya sterol,

PEG-20 soya sterol, and the like; glyceryl palmitostearate, glyceryl stearate, glyceryl

distearate, glyceryl monostearate, or a combination thereof; sorbitan fatty acid esters such

as sorbitan monolaurate (e.g. ARLACEL 20), sorbitan monopalmitate (e.g. Span-40),

sorbitan monooleate (e.g. Span-80), sorbitan monostearate, and sorbitan tristearate,

sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate,

sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate,

and the like; fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic

acid, menthol, menthol derivatives, lecithin, phosphatidyl choline, bile salts, and the like,

and mixtures thereof. It is important to note that some lipophilic surfactants may also

function as the solubilizer component of the compositions and oral dosage forms.

[00102] In one embodiment, the lipophilic surfactant can be selected from

the group consisting of glyceryl monolinoleate (e.g. MAISINE 35-1), mono- and di

glycerides of caprylic, capric acid (e.g. CAPMUL MCM), glyceryl monooleate, propylene

glycol mono caprylate, propylene glycol oleate, propylene glycol monostearate, propylene

glycol monolaurate, propylene glycol mono-oleate, propylene glycol dicaprylate/dicaprate,

sorbitan monooleate, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-

9 hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil,

PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, sorbitan

monolaurate (e.g. ARLACEL 20), sorbitan monopalmitate, sorbitan monooleate, sorbitan

monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, and combinations thereof. It should be noted that the combinations of two or more lipophilic surfactants from the same or different classes therein are also within the scope of this invention and are together can be referred to as the lipophilic surfactant, unless otherwise stated.

[00103] In embodiments of the present invention, the oral pharmaceutical

compositions or dosage forms (e.g. capsule or tablet) can include a hydrophilic additive.

In one embodiment, hydrophilic additive is selected from the group consisting of

hydrophilic surfactants, e.g., celluloses - such as hydroxypropyl celluloses with low

molecular weight, low viscosity types (e.g. METHOCEL E5, E6, E10 E15, LV100 etc.

grades) and hydroxypropyl celluloses having higher molecular weight, medium to high

viscosity (e.g. METHOCEL K4M, K15M, K100M etc.); polyvinylpyrrolidones (e.g.

KOLLIDON k17, K30 etc.); polyvinyl acetates and combinations thereof.

[00104] In one embodiment, the hydrophilic additive can be a hydrophilic

surfactant. A hydrophilic surfactant is considered when it has an HLB value of greater than

10. Non-limiting examples of hydrophilic surfactants include non-ionic surfactants, ionic

surfactants and zwitterionic surfactants. Specifically the hydrophilic surfactants suitable

for the current invention include, but not limited to, alcohol-oil transesterification products;

polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl

sulphate salts, dioctyl sulfosuccinate salts; polyethylene glycol fatty acids esters;

polyethylene glycol fatty acids mono- and di- ester mixtures; polysorbates, polyethylene

glycol derivatives of tocopherol and the like. It should be noted that the combinations of

two or more hydrophilic surfactants from the same or different classes are within the scope

of this invention and are together can be referred to as the hydrophilic surfactant unless

explicitly specified. In one embodiment, the hydrophilic additive can be a hydrophilic

surfactant. Non-limiting examples of hydrophilic surfactants can include PEG-8

caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride,

PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium lauryl sulfate, sodium dioctyl

sulfosuccinate, polyethylene glycol fatty acids mono- and di- ester mixtures, polysorbate

80, polysorbate 20, polyethylene glycol 1000 tocopherol succinate, phytosterols,

phytosterol fatty acid esters, and mixtures thereof.

[00105] In some embodiments, surfactants utilized in the pharmaceutical

compositions described herein include sterols and derivatives of sterols. In various

embodiments, these surfactants are hydrophilic or lipophilic. Examples of hydrophilic

PCT/US2022/034463

sterol surfactants are lanosterol PEG-24 cholesterol ether (e.g. SOLULAN C-24,

Amerchol), PEG-30 soya sterol (e.g. Nikkol BPS-30, from Nikko), PEG-25 phyto sterol

(e.g. Nikkol BPSH-25 from Nikko), PEG-30 cholestanol (e.g. Nikkol DHC, from Nikko).

Examples of lipophilic sterol surfactants are cholesterol, sitosterol, phytosterol (e.g.

GENEROL series from Henkel), PEG-5 soya sterol (e.g. Nikkol BPS-S, from Nikko), PEG-

10 soya sterol (e.g. Nikkol BPS-10 from Nikko), PEG-20 soya sterol (e.g. Nikkol BPS-20

from Nikko).

[00106] In one embodiment, the pharmaceutical composition or unit dosage

form includes an additive as described in the following paragraphs.

[00107] Suitable additives utilized in various embodiments described herein

include, by way of non-limiting example, adsorbing agents, anti-adherents, anticoagulants,

antifoaming agents, antioxidants, anti-caking agents, anti-static agents, binders, bile acids,

bufferants, bulking agents, chelating agents, coagulants, colorants, co-solvent, opaquants,

congealing agents, coolants, cryoprotectants, diluents, dehumidifying agents, desiccants,

desensitizers, disintegrants, dispersing agents, enzyme inhibitors, glidants, fillers,

hydrating agent, super disintegrants, gums, mucilages, hydrogen bonding agents, enzymes,

flavorants, humectants, humidifying agents, lubricant oils, ion-exchange resins, lubricants,

plasticizers, pH modifying agents, preservatives, solidifying agent, solvents, solubilizers,

spreading agent sweeteners, stabilizers, surface area enhancing agents, suspending agent,

thickeners, viscosity increasing agents, waxes, solidifier, and mixtures thereof.

[00108] In one embodiment, the oral pharmaceutical composition or the

dosage form comprises or is prepared from solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate and a pharmaceutically acceptable carrier. In another embodiment, the

compositions or the dosage form of the current invention includes solid state (17-B)-3-

Oxoandrost-4-en-17-yl dodecanoate and a pharmaceutically acceptable carrier, wherein the

solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is not solubilized at 30 °C, or

above 30 °C, or at a temperature range above 30°C, including 30 °C to about 40 °C. In one

aspect, the unit dosage form is a hard gel or soft gel capsule or a tablet.

Methods of Use for Treatment of Disease

[00109] The pharmaceutical compositions or unit dosage forms comprising

or prepared from the solid state (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate have a

number of methods for use.

[00110] Subjects that can be treated by administration of pharmaceutical

compositions and unit dosage forms of the present disclosure (e.g., comprising or prepared from solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate) can be any mammal (e.g., a human male or female) in need thereof. In particular, in one embodiment, the human male may be at least 14 years of age. In another embodiment, the human male is an adult of at least age 16, 18, or 20. In another embodiment, the human male is an adult of at least age

21, 23, or 25. In another embodiment, the human male is an adult of at least age 30. In a

further embodiment, the subject can be an adult male of at least age 50. In yet a further

embodiment, the subject can be an adult male of at least age 60. Subjects that can be treated

by pharmaceutical compositions and unit dosage forms of the present disclosure (e.g.,

comprising or prepared from the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

characterized as shown in FIG 1, 2, and 4) can be any human female in need thereof. In

particular, in one embodiment, the human female may be at least 14 years of age. In another

embodiment, the human female is an adult of at least age 30. In a further embodiment, the

subject can be an adult female of at least age 50. In a further embodiment, the subject can

be an adult female who has deficient endogenous serum testosterone levels. In a further

embodiment, the subject can be an adult female who has undergone unilateral or bilateral

oophorectomy. In yet 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 post-menopausal woman. In an additional aspect, the subjects having diseases

related to lack of therapeutically effective testosterone levels, such as, but no limited to,

hypogonadism (e.g., testosterone deficiency or absence of testosterone), liver disease or

lung disease related to steatosis, inflammatory or fibrotic cytokines, chemokines, enzymes,

or biomarkers can be treated with the pharmaceutical compositions or formulations

prepared from or comprising the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

in this disclosure.

[00111] As discussed above, the present invention also provides for a method

of treating a human subject in need of testosterone therapy is provided. The method can

include the steps of administering any of the pharmaceutical compositions or dosage forms

(e.g., capsule or tablet) disclosed herein. The pharmaceutical compositions and the dosage

forms of the present invention can be used to treat any condition associated with

testosterone deficiency, including complete absence, of endogenous testosterone in male or

female subjects. Examples of conditions associated with testosterone deficiency that can

be treated using the dosage forms (e.g., capsule or tablet) and/or compositions of the present

invention include, but are not limited to, congenital or acquired primary hypogonadism,

hypogonadotropic hypogonadism, cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter's syndrome, post castration, eunuchoidism, hypopituitarism, endocrine impotence, infertility due to spermatogenic disorders, impotence, male sexual dysfunction (MSD) including conditions such as premature ejaculation, erectile dysfunction, decreased libido, and the like, micropenis and constitutional delay, penile enlargement, appetite stimulation, testosterone deficiency associated with chemotherapy, testosterone deficiency associated with toxic damage from alcohol, testosterone deficiency associated with toxic damage from heavy metal, osteoporosis associated with androgen deficiency, and combinations thereof.

[00112] Other conditions that can be treated by the compositions and dosage

forms disclosed herein include idiopathic gonadotropin, LHRH (luteinizing hormone-

releasing hormone) deficiency, or pituitary hypothalamic injury from tumors, trauma, or

radiation. Typically, these subjects have low serum testosterone levels but have

gonadotropins in the normal or low range. In one embodiment, the compositions or oral

dosage forms may be used to stimulate puberty in carefully selected males with clearly

delayed puberty not secondary to a pathological disorder. In another embodiment, the

compositions and oral dosage forms may be used in female-to-male transsexuals in order

to maintain or restore male physical and sexual characteristics including body muscle mass,

muscle tone, bone density, body mass index (BMI), enhanced energy, motivation and

endurance, restoring psychosexual activity etc. In some embodiments, pharmaceutical

compositions and unit dosage forms of the present disclosure (e.g., prepared from or

comprising the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate disclosed here) can

be useful in providing hormonal male contraception. In some embodiments,

pharmaceutical compositions and unit dosage forms of the present disclosure (e.g.,

prepared from or comprising the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

in this disclosure) can be used to provide treatment of one or more symptoms associated

with female sexual dysfunction, anorgasmia, osteoarthritis, hormonal male contraception.

Additionally, pharmaceutical compositions and unit dosage forms of the present disclosure

(e.g., prepared from or comprising the solid state (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate in this finding) can be used to treat and/or improve the patient related

outcomes including the quality of life and wellbeing of the subjects suffering from

deficiency of endogenous testosterone. In some embodiments, pharmaceutical

compositions and unit dosage forms of the present disclosure (e.g., prepared from or

comprising the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate in this disclosure)

can be used to treat or improve the symptoms of subjects suffering from conditions such as carcinoma, sarcoma, melanoma, lymphoma, leukemia, an end-stage condition related to liver disease, an end-stage condition related to lung disease, an end-stage condition related to kidney disease, an end-stage condition related to musculoskeletal system disease, an end- stage condition related to cardiovascular disease, an end-stage condition related to blood disease, an end-stage condition related to endocrine gland disease, an end-stage condition related to gastrointestinal disease, an end-stage condition related to skin disease, an end- stage condition related to genital organ disease, an end-stage condition related to central nervous system disease, hepatic fibrosis, hepatic inflammation, hepatic steatosis, non- alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre/post liver transplant, cirrhosis, primary biliary cholangitis (PBC), lung disease affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis

(IPF), muscle mass wasting, cachexia, sarcopenia, frailty, type 1 diabetes, type 2 diabetes,

hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism,

metabolic syndromes, visceral adiposity, obesity, impaired wound healing, large waist, and

hereditary angioedema.

[00113] The following examples are provided to promote a clearer

understanding of certain embodiments of this disclosure and are in no way meant as a

limitation thereon.

EXAMPLE 1: Preparation of Solid State (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate

[00114] A non-limiting exemplary synthetic scheme for producing a solid

state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate as disclosed herein and is outlined in

more detail below. The (17-B)-3-Oxoandrost-4-en-17-y1 dodecanoate can be produced

utilizing the generalized scheme set forth below:

[00115] 1) (17-B)-Hydroxy-4-Androsten-3-one (0.1 mol) is weighed and

placed into a 1000 mL 4N RB flask containing a stir bar.

[00116] 2) Pyridine (160 mL) is added to the flask.

[00117] 3) The flask is placed in an ice-water bath and fitted with a nitrogen

inlet, addition funnel, thermocouple, and stopper. Stirring and nitrogen flow are started.

[00118] 4) The funnel is charged with a solution of acid chloride (1.56 equiv.

e.g., lauroyl chloride) in heptane (160 mL), then fitted with an adapter connected to a

bubbler.

[00119] 5) The contents of the funnel are added dropwise over 30-40 min

(Note: the internal temperature increases 5-7 °C during the addition.)

PCT/US2022/034463

[00120] 6) When the dropwise addition is complete, the bath is removed and

stirring is continued.

[00121] 7) After 1 hour, the reaction mixture is transferred to a large

separatory funnel and diluted with heptane (1000 mL) (Note: TLC at 1 hour indicates a

complete reaction).

[00122] 8) The heptane solution is washed successively with 800 mL

portions of: cold water (2X), 0.05 N NaOH, saturated NaHCO3 (2X), water, brine, then

dried over anhydrous Na2S04 (~50 g). Then concentrated to dryness (rotavap/Tbath 30

°C).

EXAMPLE 2: Preparation of Solid State (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate

Crystals

[00123] A reaction mixture or product of Example 1 (or material produced

by another route) can be transferred into water, ethanol, or methanol (or any other

appropriate solvent) and allowed to crystallize. The crystalline mass can be filtered by

suction, washed with water, dried over phosphorous pentoxide and re-crystallized from

another solvent (although this step is not necessary) e.g., oleic acid, hexane, heptanes, etc.

EXAMPLE 3: Differential Scanning Calorimetry of Solid State (17-B)-3-Oxoandrost-4-en-

17-yl dodecanoate

[00124] This example demonstrates that the solid state (17-B)-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 forms of the solid state (17-

B)-3-Oxoandrost-4-en-17-yl dodecanoate was placed in a closed Pan Al crucible of a

differential scanning calorimeter instrument and was heated from 0 to 100 °C. The result

is shown in the first heating cycle (FIG. 1), which shows two endothermic transition peaks

for the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate disclosed here at about 30-

40 °C and about 50-65 °C. In a specific aspect, the melting point of the specific crystalline

forms of the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is identified at 51 -

63 °C based on the DSC results.

EXAMPLE 4: XRD Crystallography of Solid State (17-B)-3-Oxoandrost-4-en-17-yl

dodecanoate

[00125] The solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate is

crystalline or substantially crystalline as indicated by XRD as shown in an example of an

XRD spectra in FIG. 2 for the crystalline forms of the solid state (17-3)-3-Oxoandrost-4-

en-17-y1 dodecanoate. FIG. 2 displays well defined peaks corresponding to the crystalline

forms of the solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate with little or no

amorphous forms of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate (as indicated by the

absence of an "amorphous halo" in the spectra in the 5-30 O of 20 range and no broadening

of the peaks).

EXAMPLE 5: Pharmaceutical compositions or dosage forms having a variety of different

forms of (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate prepared by typical formulation

methods

[00126] Pharmaceutical compositions or dosage forms described herein are

formulated or prepared from a specific crystalline forms of the solid state (17-3)-3-

Oxoandrost-4-en-17-yl dodecanoate characterized by DSC and XRD, as shown in FIG. 1

and 2. Pharmaceutical compositions or dosage forms disclosed herein are prepared from

the specific solid state (17-B)-3-Oxoandrost-4-en-17-yl dodecanoate and at least one of

pharmaceutical acceptable carriers by any suitable process including one or more steps of,

by way of non-limiting example, agglomeration, air suspension chilling, air suspension

drying, balling, coacervation, comminution, compression, pelletization, cryopelletization,

encapsulation, extrusion, granulation, homogenization, inclusion complexation,

lyophilization, nanoencapsulation, melting, mixing, molding, grinding, milling, pan

coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing,

spray drying, or the like, as shown in FIG. 3, known to the skilled artisan or developed in

view of the teachings herein.

[00127] It is understood that the above-described compositions, dosage

forms and/or modes of applications are only illustrative of preferred embodiments of the

present invention. Numerous modifications and alternative arrangements 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

arrangements. Thus, while the present invention has been described above with

particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiments of the invention, it will be apparent to those of ordinary skill in the art that variations including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.

Claims (1)

1. CLAIMS 13 Feb 2025 2022467882 13 Feb 2025

   The claims defining the invention are as follows:

   55 1. 1. A pharmaceutical composition comprising or prepared from: a crystalline form of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate having an XRD pattern comprising a plurality of peaks selected from the group of angles consisting of 2022467882

   10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2, and 23.2±0.2 measured relative to two-theta (2θ), and 10 10 having a melting point in the range of about 58.3±10 °C.

   2. 2. The pharmaceutical composition of claim 1, wherein said plurality of peaks comprises at least one of 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, and more than 7 peaks, and wherein said crystalline form comprises a plurality of crystallites 15 ranging in size from about 40 nm to about 60 nm, and wherein said pharmaceutical composition further comprises a pharmaceutical composition for an oral or injectable administration.

   3. 3. The pharmaceutical composition of claim 1, wherein said pharmaceutical 20 composition further comprises at least one additive.

   4. 4. The pharmaceutical composition of claim 3, wherein said at least one additive comprises at least one of a solubilizer and a surfactant.

   25 25 5. 5. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition further comprises at least one of a tablet, a capsule, a caplet, a gelcap, 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 said pharmaceutical composition for injectable administration further comprises at 30 least one of an intravenous injectable, an intramuscular injectable, a subcutaneous injectable, an intradermal injectable, an intraspinal injectable, an intrathecal injectable, and an intra-arterial injectable comprising at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

   41

   6. The pharmaceutical composition of claim 1, wherein said pharmaceutical 13 Feb 2025 2022467882 13 Feb 2025

   6.

   composition further comprises at least one carrier.

   7. 7. The pharmaceutical composition of claim 6, wherein said at least one 5 carrier, further comprises at least one of a lipophilic carrier and a hydrophilic carrier.

   8. The pharmaceutical composition of claim 7, wherein said at least one 2022467882

   lipophilic carrier further comprises at least one of a lipophilic surfactant and a lipophilic additive, and wherein said hydrophilic carrier further comprises at least one of a hydrophilic 10 surfactant and a hydrophilic additive.

   9. The pharmaceutical composition of claim 8, wherein said at least one lipophilic carrier comprises at least one of a fatty acid, a derivative of a fatty acid, a vegetable oil, a derivative of a vegetable oil, a monoglyceride, a diglyceride, a triglyceride, 15 a derivative of a monoglyceride, a derivative of a diglyceride, a derivative of a triglyceride, a sterol, a phytosterol, a tocopherol, a tocopherol succinate, a tocopherol acetate and a fish oil, and wherein said 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 20 fatty acid diglyceride mixture, a polysorbate, a polyethylene glycol derivative of tocopherol, an alcohol, and an alcohol derivative.

   10. The pharmaceutical composition of claim 9, wherein said at least one fatty acid comprises at least one of an oleic acid, a lauric acid, a stearic acid, and a derivative 25 thereof, and wherein said vegetable oil comprises at least one of a peppermint oil, a sesame oil, a borage oil, a castor oil, a maize oil, a cottonseed oil, and a derivative thereof, and wherein said derivative of monoglyceride comprises at least one of glyceryl monolinoleate, and sorbitan mono-fatty acid, and wherein said derivative of diglyceride comprises glyceryl palmitostearate, and wherein said polyoxyethylene hydrogenated vegetable oil comprises 30 PEG hydrogenated castor oil, and wherein said alcohol comprises at least one of ethyl alcohol and benzyl alcohol, and wherein said alcohol derivative comprises benzyl benzoate.

   42

   11. A method of treating or substantially inhibiting development of a condition 22 Jan 2026

   for which testosterone is needed, the method comprising administering the pharmaceutical composition of claim 1.

   5 12. A method of treating or substantially inhibiting development of at least one of carcinoma, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, end-stage lung disease, end-stage kidney disease, end-stage musculoskeletal system disease, end- 2022467882

   stage cardiovascular disease, end-stage blood disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage genital organ disease, 10 end-stage central nervous system disease, hepatic fibrosis, hepatic inflammation, hepatic steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre/post liver transplant, cirrhosis, primary biliary cholangitis (PBC), lung disease affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle mass wasting, cachexia, sarcopenia, frailty, type 1 15 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, a metabolic syndrome, visceral adiposity, obesity, impaired wound healing, large waist, hereditary angioedema, and a symptom thereof, the method comprising administering the pharmaceutical composition of claim 1.

   20 13. A method of treating or substantially inhibiting development of at least one of carcinoma, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, end-stage lung disease, end-stage kidney disease, end-stage musculoskeletal system disease, end- stage cardiovascular disease, end-stage blood disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage genital organ disease, 25 end-stage central nervous system disease, hepatic fibrosis, hepatic inflammation, hepatic steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), pre/post liver transplant, cirrhosis, primary biliary cholangitis (PBC), lung disease affecting the interstitium, interstitial lung disease (ILD), pneumonia, idiopathic pulmonary fibrosis (IPF), muscle mass wasting, cachexia, sarcopenia, frailty, type 1 30 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, a metabolic syndrome, visceral adiposity, obesity, impaired wound healing, large waist, hereditary angioedema, and a symptom thereof, the method comprising administering a pharmaceutical composition comprising or prepared from a crystalline form of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate having an XRD pattern comprising a plurality of peaks selected from the group of angles consisting of 22 Jan 2026

   10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2, and 23.2±0.2 measured relative to two-theta (2θ).

   5 14. The method of claim 13, wherein said pharmaceutical composition further comprises or is prepared from at least one of: a) a crystalline form of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate having an 2022467882

   XRD pattern comprising at least three peaks selected from the group of angles consisting of 10.9±0.2, 13.6±0.2, 14.0±0.2, 15.3±0.2, 17.3±0.2, 18.0±0.2, 19.2±0.2, and 23.2±0.2 10 measured relative to two-theta (2θ), b) a crystalline form of (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate having a melting point in the range of about 58.3±10 °C, and c) a fluent substance consisting essentially of a crystalline form of (17-β)-3- Oxoandrost-4-en-17-yl dodecanoate. 15 15. The method of claim 13, wherein said plurality of peaks comprises at least one of 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, and more than 7 peaks, and wherein said crystalline form comprises a plurality of crystallites ranging in size from about 40 nm to about 60 nm, and 20 wherein said pharmaceutical composition further comprises a pharmaceutical composition for an oral or injectable administration.

   16. The method of claim 13, wherein said pharmaceutical composition further comprises at least one additive. 25 17. The method of claim 16, wherein said at least one additive comprises at least one of a solubilizer and a surfactant.

   18. The method of claim 13, wherein said pharmaceutical composition further 30 comprises at least one of a tablet, a capsule, a caplet, a gelcap, 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 said pharmaceutical composition for injectable administration further comprises at least one of an intravenous injectable, an intramuscular injectable, a subcutaneous injectable, an intradermal injectable, an intraspinal injectable, an intrathecal injectable, and an intra-arterial injectable 22 Jan 2026 comprising at least one of an implant, a solution, a suspension, an emulsion, a microemulsion, a nanoemulsion, a gel, a liposome, and a pellet.

   5 19. The method of claim 13, wherein said pharmaceutical composition further comprises at least one carrier. 2022467882

   20. The method of claim 19, wherein said at least one carrier, further comprises at least one of a lipophilic carrier and a hydrophilic carrier. 10 21. The method of claim 20, wherein said at least one lipophilic carrier further comprises at least one of a lipophilic surfactant and a lipophilic additive, and wherein said hydrophilic carrier further comprises at least one of a hydrophilic surfactant and a hydrophilic additive. 15 22. The method of claim 21, wherein said at least one lipophilic carrier comprises at least one of a fatty acid, a derivative of a fatty acid, a vegetable oil, a derivative of a vegetable oil, a monoglyceride, a diglyceride, a triglyceride, a derivative of a monoglyceride, a derivative of a diglyceride, a derivative of a triglyceride, a sterol, a 20 phytosterol, a tocopherol, a tocopherol succinate, a tocopherol acetate and a fish oil, and wherein said 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 of tocopherol, an 25 alcohol, and an alcohol derivative.

   23. The method of claim 22, wherein said at least one fatty acid comprises at least one of an oleic acid, a lauric acid, a stearic acid, and a derivative thereof, and wherein said vegetable oil comprises at least one of a peppermint oil, a sesame oil, a borage oil, a 30 castor oil, a maize oil, a cottonseed oil, and a derivative thereof, and wherein said derivative of monoglyceride comprises at least one of glyceryl monolinoleate, and sorbitan mono- fatty acid, and wherein said derivative of diglyceride comprises glyceryl palmitostearate, and wherein said polyoxyethylene hydrogenated vegetable oil comprises PEG hydrogenated castor oil, and wherein said alcohol comprises at least one of ethyl alcohol 22 Jan 2026 and benzyl alcohol, and wherein said alcohol derivative comprises benzyl benzoate.

   24. The method of claim 13, wherein said pharmaceutical composition treats or 5 substantially inhibits development of a condition for which testosterone is needed. 2022467882