Testosterone-containing pharmaceutical composition

Abstract

A pharmaceutical composition adapted for oral administration, comprising at least 10% w / w natural testosterone, at least 36% w / w sesame oil, at least 28% w / w propylene glycol monolaurate, at least 9% w / w ethanol, and at least 14% w / w benzyl alcohol. A dosing regimen for use in a human subject, comprising administering at least a first and a second pharmaceutical composition, wherein the first composition comprises 2.5-7.5% w / w natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, and the second composition comprises at least 9% w / w natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, and the first and second compositions are orally administered to the human subject at least once every 24 hours to normalize serum testosterone. 1. A method for producing a composition comprising natural testosterone, comprising: i) forming a homogenous preparation comprising sesame oil, propylene glycol monolaurate, benzyl alcohol, and ethanol; ii) adding natural testosterone to the homogenous preparation at a concentration of about 13% w / w to form a combined testosterone preparation; and iii) mixing the combined preparation to dissolve the testosterone and form a substantially clear preparation.

Description

[Technical Field]

[0001] The present disclosure relates to pharmaceutical compositions adapted for oral delivery comprising natural testosterone, pharmaceutical compositions comprising natural testosterone for use in treatment regimens comprising administration of natural testosterone compositions, and methods and uses for the treatment of hormone-related conditions that benefit from testosterone administration in male, female, and transgender subjects. [Background technology]

[0002] Testosterone is produced in the testes of males and the ovaries of females, and small amounts are secreted by the adrenal glands. Testosterone is a key steroid involved in the initiation and completion of puberty, regulating fertility, development, sexual desire, body composition, and energy metabolism in both male and female development. Testosterone exerts its effects through interaction with the androgen receptor and regulates gene expression in target tissues. Testosterone and testosterone derivatives are used to treat male hypogonadism, which results from little or no testosterone production by the testes. Other disease indications for the use of testosterone or testosterone derivatives, such as testosterone esters, include constitutional delayed puberty, delayed puberty due to diseases such as chronic renal failure or other chronic childhood diseases that cause delayed puberty, insufficient secretion of adrenal testosterone in girls and women, which results in a lack of pubic and axillary hair, and late-onset hypogonadism. Hypogonadism can lead to infertility, lack of libido in men and women, osteoporosis, reduced muscle growth, cardiovascular disease, anemia, and depression. Steroid hormone replacement therapy, particularly testosterone replacement therapy, is facilitated by several formulations and delivery routes. Currently, most testosterone regimens involve the use of parenteral injections, skin patches or gels, buccal tablets, or oral dosage forms of testosterone esters or derivatives.

[0003] Intramuscular injections every 1 to 3 weeks show little pharmacokinetic variability but are painful, extremely inconvenient to use, and do not provide any circadian variation. Testosterone patches can cause moderate to severe skin reactions due to the vehicle that promotes enhanced dermal absorption of testosterone. Testosterone gel is the most widely used product. However, the gel is expensive and inconvenient to use, and special care must be taken to avoid inadvertent exposure to women and children.

[0004] Oral testosterone compositions are desirable and do not suffer from the disadvantages associated with the above delivery methods. However, oral administration of native testosterone has poor bioavailability, necessitating the use of alkylated or esterified testosterone. This is because a significant amount of orally administered native testosterone is metabolized both through the intestinal wall and during the first hepatic pass, which represents an approximately 98% reduction in bioavailability.

[0005] Alkylated or esterified testosterone derivatives offer increased stability but have undesirable side effects. For example, testosterone esters require conversion to testosterone in the body, which results in variable pharmacokinetic (PK) profiles that often exceed the physiological range of testosterone. Testosterone esters also have low solubility and require a high-fat diet for absorption. Furthermore, testosterone esters are converted to dihydrotestosterone (DHT) more readily than native testosterone, and high DHT levels can have a variety of potential side effects, including prostate enlargement and increased cardiovascular risk.

[0006] Male hypogonadism has a complex etiology and can occur at any time during a male subject's life due to several conditions. In boys and adult men, hypogonadism can be primary or secondary. Primary hypogonadism is a problem originating in the testes and involving reduced or absent testosterone production. A common cause of primary hypogonadism is Klinefelter's syndrome, which occurs when a subject has two X chromosomes and one Y chromosome. Primary hypogonadism can also result from mumps orchitis, hemochromatosis, cancer treatment, and physical injury to the testes. Secondary hypogonadism results from the failure of the pituitary gland in the brain, which normally releases gonadotropins to stimulate the testes. Secondary hypogonadism can be congenital or acquired due to insufficiency or damage to either the hypothalamus or pituitary gland. Kallmann syndrome is a congenital syndrome in which a deficiency in secondary hypothalamic signaling results in insufficient gonadotropin secretion and, therefore, testosterone secretion. Pituitary tumors, craniopharyngiomas, brain tumors, brain radiation therapy and neurosurgery, HIV / AIDS, and inflammatory diseases such as sarcoidosis, histiocytosis, and tuberculosis can all cause secondary hypogonadism.

[0007] Constitutional growth retardation and delayed puberty (CDGP) describes a condition in developing children that results in a temporary delay in puberty and a concomitant growth spurt. It is the most common cause of short stature and delayed puberty and is typically treated by pediatric endocrinologists. CDGP affects all organ systems as well as bone development. Although affected subjects eventually enter puberty normally, they are shorter than their peers and experience delayed sexual maturation, which can lead to bullying and teasing, as well as long-term psychological effects requiring medical intervention. In females, insufficient adrenal secretion of testosterone can result in a lack of pubic and axillary hair and a decreased libido.

[0008] Oral testosterone formulations that purport to increase the bioavailability of testosterone or testosterone esters by delivering them in an oily vehicle are known in the art. See WO 2006 / 113505 or U.S. Patent Application Publication No. 2007 / 0026066. Bioavailability is increased by including additional components, such as finasteride and dutasteride, which inhibit the conversion of testosterone to dihydrotestosterone. See WO 2005 / 076899. WO 2009 / 133352 discloses a composition adapted for oral administration containing a lipid carrier, benzyl alcohol, ethanol, and lauroglycol, which exhibits improved testosterone stability and absorption in fasted and fed states compared to commercially available testosterone undecanoate compositions.

[0009] The present disclosure relates to treatment regimens for the delivery of natural testosterone in the treatment of male hypogonadism, the induction of puberty in CDGP, the induction and continued treatment of puberty in primary and secondary hypogonadism, the treatment of adults with hypogonadism, and the treatment of late-onset hypogonadism, which provide effective hormone replacement using a lipid-based formulation adapted for oral administration. Additionally, the testosterone compositions provided herein are concentrated, reducing the number of capsules to be swallowed, for example, in high testosterone dosing regimens, thereby improving patient compliance and treatment outcomes. Summary of the Invention

[0010] According to an aspect of the present invention, there is provided a pharmaceutical composition adapted for oral administration, the composition comprising at least 10% w / w natural testosterone, at least 35% w / w sesame oil, at least 27% w / w propylene glycol monolaurate, at least 9% w / w ethanol, and at least 14% w / w benzyl alcohol.

[0011] In a preferred embodiment of the present invention, there is provided a composition comprising at least 10% w / w natural testosterone, at least 36% w / w sesame oil, at least 28% w / w propylene glycol monolaurate, at least 9% w / w ethanol, and at least 14% w / w benzyl alcohol.

[0012] In a preferred embodiment of the present invention, the aforementioned composition comprises or consists essentially of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 16% w / w benzyl alcohol.

[0013] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.74% w / w sesame oil, 28.06% w / w of propylene glycol monolaurate, 9% w / w ethanol, and 16.20% w / w benzyl alcohol.

[0014] In an alternative preferred embodiment of the present invention, the aforementioned composition comprises or consists essentially of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0015] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.64% w / w sesame oil, 28.05% w / w of propylene glycol monolaurate, 11.25% w / w ethanol, and 14.06% w / w benzyl alcohol. DETAILED DESCRIPTION OF THE INVENTION

[0016] According to an aspect of the present invention, there is provided a dosing regimen for use in a human subject in need of treatment that would benefit from the administration of natural testosterone, the dosing regimen comprising administering a pharmaceutical composition comprising natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, the composition being orally administered to said human subject at least once in a 24-hour period to normalize serum testosterone.

[0017] Preferably, the aforementioned regimen is for the treatment of hypogonadism.

[0018] Testosterone levels in men decline with age, especially after age 40, and can vary depending on the assay used. The Endocrine Society guidelines (2018) cite harmonized reference ranges for total testosterone in healthy, non-obese young men (19-39 years of age) as 264-916 ng / dL (9.2-31.8 nmol / L) using the 2.5th and 97.5th percentiles, and 303-852 ng / dL (10.5-29.5 nmol / L) using the 5th and 95th percentiles. In infants and prepubertal boys, testosterone levels are very low, <20 ng / dL (<0.8 nmol / L), and gradually increase to adult levels throughout adolescence. In reproductive-age women, testosterone levels range from 14-87 ng / dL (0.5-3.0 nmol / L). Typically, replacing serum testosterone in an adult male subject requires a total dose of 40 mg to 600 mg of natural testosterone over a 24-hour period. These doses can be varied over time and can be administered one, two, three, or four times, for example, in doses of 80 mg to 300 mg. The subject's response can be monitored, for example, 2 to 6 hours after administration, and adjustments can be made as needed.

[0019] For example, for boys with primary or secondary hypogonadism, a typical dosage regimen of 40 mg per 24 hours for at least 3 months is appropriate for treating delayed puberty or inducing puberty, and is monitored and adjusted accordingly.Typically, the dosage regimen for inducing puberty is extended to adulthood by gradually increasing the dosage of natural testosterone to an adult dosage.The dosage of natural testosterone administered to a subject can be selected according to different parameters, such as the subject's pubertal status, its body surface area, and its body weight.Other factors include the desired treatment period, which in the case of delayed puberty or pubertal induction, can be from the onset of puberty to adulthood, which can be several years.If the subject does not respond adequately to the initial dosage applied, a higher dosage or even a substantially higher dosage can be adopted, as long as the patient's tolerance allows and improves clinical outcome.

[0020] In a preferred embodiment of the present invention, the composition contains 2-10% w / w of natural testosterone.

[0021] In a preferred embodiment of the present invention, the composition contains 2 to 7.5% w / w of natural testosterone.

[0022] In a preferred embodiment of the present invention, the aforementioned composition comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10% w / w of natural testosterone.

[0023] In a preferred embodiment of the present invention, the aforementioned composition comprises 9, 10, or 11% w / w of natural testosterone.

[0024] In a preferred embodiment of the present invention, the composition comprises about 10% w / w of natural testosterone.

[0025] In a preferred embodiment of the present invention, the aforementioned human subject receives one, two, three, or four doses of a composition according to the present invention, the compositions being separated in time over a 24 hour period.

[0026] In a preferred embodiment of the present invention, the subject is administered the composition according to the present invention once every 24 hours.

[0027] In a preferred embodiment of the present invention, the subject is administered two temporally separated compositions according to the present invention within a 24 hour period.

[0028] In a preferred embodiment of the present invention, the aforementioned subject is administered three temporally separated compositions according to the present invention within a 24 hour period.

[0029] In a more preferred embodiment of the present invention, the three temporally separated compositions are separated at 8 hour intervals within a 24 hour period.

[0030] In a further preferred embodiment of the present invention, the aforementioned subject is administered four temporally separated compositions according to the present invention within a 24 hour period.

[0031] In a preferred embodiment of the present invention, the aforementioned subject is administered a total native testosterone dose of between 10 and 800 mg of native testosterone over a 24 hour period.

[0032] In a further preferred embodiment of the present invention, the aforementioned subject is administered a total native testosterone dosage of between 10 and 600 mg of native testosterone over a 24 hour period.

[0033] In a preferred embodiment of the present invention, the total native testosterone dose is 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg of native testosterone over a 24 hour period.

[0034] In a further preferred embodiment of the present invention, the aforementioned subject is administered a dose of 400 mg of total native testosterone over a 24 hour period.

[0035] In a further preferred embodiment of the present invention, the aforementioned subject is administered a total native testosterone dosage of between 400 and 800 mg over a 24 hour period.

[0036] In a more preferred embodiment of the present invention, the aforementioned total dose is 640 mg, 680 mg, 720 mg, 760 mg, 800 mg of natural testosterone over a 24 hour period.

[0037] In a more preferred embodiment of the present invention, the total dose is 40 mg of natural testosterone over a 24 hour period.

[0038] In a preferred embodiment of the present invention, two-thirds of the total native testosterone dose is administered between 00:00 and 12:00 hours, and one-third of the total native testosterone dose is administered between 12:00 and 24:00 hours.

[0039] In an alternative preferred embodiment of the present invention, 50% to 90% of the total native testosterone dose is administered between 00:00 and 12:00 hours, and 50% to 10% of the total native testosterone dose is administered between 12:00 and 24:00 hours.

[0040] Preferably, 55% to 70% of the total native testosterone dose is administered between 00:00 and 12:00 hours, and 45% to 30% of the total native testosterone dose is administered between 12:00 and 24:00 hours.

[0041] In a preferred embodiment of the present invention, 50% of the total native testosterone dose is administered between 00:00 and 12:00 hours, and 50% of the total native testosterone dose is administered between 12:00 and 24:00 hours.

[0042] In a preferred embodiment of the present invention, the aforementioned dose of total native testosterone is administered in three temporally separated doses within a 24 hour period.

[0043] In a preferred embodiment of the present invention, the aforementioned dose of total native testosterone is administered in three temporally separated doses within a 24 hour period, spatially separated by eight hours.

[0044] In a preferred embodiment of the invention, the aforementioned composition comprises at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40 or 41% w / w of sesame oil.

[0045] In a preferred embodiment of the invention, the aforementioned composition comprises at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30 or 31% w / w propylene glycol monolaurate.

[0046] In a preferred embodiment of the invention, the aforementioned composition comprises at least 5, 6, 7, 8, 9, or 10% w / w ethanol.

[0047] In a preferred embodiment of the invention, the aforementioned composition comprises at least 15, 16, 17, 18, 19, or 20% w / w of benzyl alcohol.

[0048] In a preferred embodiment of the present invention, the aforementioned composition comprises: 2-10% w / w natural testosterone, at least 40% w / w sesame oil, at least 30% w / w of propylene glycol monolaurate, at least 5% w / w ethanol, and At least 15% w / w benzyl alcohol.

[0049] Preferably, the aforementioned composition consists of testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol as set forth in Table 1.

[0050] In alternative preferred embodiments of the present invention, the aforementioned compositions comprise at least 35%, 36%, 37%, or 38% w / w sesame oil.

[0051] In alternative embodiments of the present invention, the aforementioned compositions comprise at least 27%, 28%, or 29% w / w propylene glycol monolaurate.

[0052] In alternative embodiments of the invention, the aforementioned compositions comprise at least 8, 9, 10, or 11% w / w ethanol.

[0053] In alternative embodiments of the invention, the aforementioned compositions comprise at least 13, 14, 15, 16, 17, 18, or 19% w / w of benzyl alcohol.

[0054] In an alternative embodiment of the present invention, the aforementioned composition comprises or consists essentially of: 9-11% w / w natural testosterone, at least 35% w / w sesame oil, at least 27% w / w of propylene glycol monolaurate, at least 8% w / w ethanol, and At least 13% w / w benzyl alcohol.

[0055] In a further alternative embodiment of the present invention, the aforementioned composition comprises or consists essentially of: 9-11% w / w natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0056] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists essentially of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 16% w / w benzyl alcohol.

[0057] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.74% w / w sesame oil, 28.06% w / w of propylene glycol monolaurate, 9% w / w ethanol, and 16.20% w / w benzyl alcohol.

[0058] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists essentially of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0059] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.64% w / w sesame oil, 28.05% w / w of propylene glycol monolaurate, 11.25% w / w ethanol, and 14.06% w / w benzyl alcohol.

[0060] In a preferred embodiment of the present invention, the aforementioned dosing regimen is for the treatment of delayed puberty.

[0061] In a preferred embodiment of the invention, the treatment for delayed puberty is a dosing regimen of 40 mg to 120 mg daily for 3 to 6 months, more preferably 3 months.

[0062] In an alternative preferred embodiment of the present invention, the dosing regimen is for the induction of puberty.

[0063] In a preferred embodiment of the present invention, the induction of puberty is a dosing regimen of 40 mg of natural testosterone in a 24-hour period for at least three months.

[0064] In preferred embodiments of the present invention, the aforementioned dosing regimens for induction of puberty span 3-6 months, 6-12 months, 1-2 years, or 3-4 years.

[0065] In a preferred embodiment of the present invention, pubertal induction is monitored for at least three months and the dose of natural testosterone is adjusted to an adult dose of up to 600 mg natural testosterone in 24 hours.

[0066] In a preferred embodiment of the present invention, pubertal induction is monitored for at least three months and the dosage of natural testosterone is adjusted to an adult dose of up to 800 mg natural testosterone in 24 hours.

[0067] In the treatment of primary or secondary hypogonadism, pubertal induction is necessary. Typically, a low dose of natural testosterone, such as 40 mg daily, is initially administered, followed by small increments throughout the teenage years, e.g., from age 12 to 18, to an adult dose of between 600 and 800 mg daily. Typically, pubertal induction is monitored every 3 to 6 months, preferably for 3 to 12 months, more preferably for 3 to 24 months, even more preferably for 3 to 48 months, or even 3 to 84 months, with dosage adjustments made if necessary. Subjects with hypogonadism require testosterone replacement throughout their lives.

[0068] In a preferred embodiment of the invention, the aforementioned dosing regimen is given throughout the life of the human subject.

[0069] In a preferred embodiment of the invention, the dosing regimen is for use in treating primary hypogonadism in a human subject as described above.

[0070] In a preferred embodiment of the invention, the primary hypogonadism is associated with or caused by a condition selected from the following group: Klinefelter's syndrome, anorchia, mumps orchitis, hemochromatosis, cancer treatment, and physical injury to the testes.

[0071] In an alternative preferred embodiment, the dosing regimen is for use in treating secondary hypogonadism in a human subject as described above.

[0072] In a preferred embodiment of the invention, the secondary hypogonadism is associated with or caused by a condition selected from the following group: congenital hypopituitarism, Kallmann syndrome, a pituitary tumor, craniopharyngioma, an inflammatory disease such as sarcoidosis, histiocytosis, and tuberculosis, and HIV / AIDS, or a late effect of cancer therapy.

[0073] In a preferred embodiment of the invention, the aforementioned dosing regimen is associated with pubertal failure resulting from either primary or secondary hypogonadism, or chronic diseases including Duchenne muscular dystrophy, or glucocorticoid therapy.

[0074] In a preferred embodiment of the present invention, the aforementioned dosing regimen is associated with constitutional growth retardation and delayed puberty.

[0075] In a preferred embodiment of the present invention, the constitutional growth retardation and pubertal delay is familial constitutional growth retardation and pubertal delay.

[0076] In an alternative preferred embodiment of the present invention, the constitutional growth retardation and delayed puberty is idiopathic.

[0077] In a preferred embodiment of the present invention, subjects being treated for constitutional growth retardation and delayed puberty are administered doses of 40 mg to 120 mg of natural testosterone within a 24-hour period for at least three months.

[0078] In a preferred embodiment of the present invention, subjects being treated for constitutional growth retardation and delayed puberty are administered doses of 40 mg to 120 mg of natural testosterone within a 24-hour period for a period of 3 to 12 months, or preferably for a period of 3 to 6 months.

[0079] In an alternative embodiment of the invention, the aforementioned regimen is for use in treating cardiovascular disease or a condition related to cardiovascular disease.

[0080] Cardiovascular disease (CVD) is a disorder of the heart and blood vessels, including coronary heart disease, deep vein thrombosis, pulmonary embolism, and cerebrovascular disease. Risk factors for CVD include smoking, excessive alcohol use, physical inactivity, and obesity. Coronary heart disease occurs when fatty deposits build up in the arteries of the heart, reducing or blocking blood supply to the heart and leading to heart attacks and heart failure. The accumulation of fatty deposits is a process known as atherosclerosis, and is typically elevated in individuals with high cholesterol, hypertension, or diabetes. Cholesterol, like other lipids, is transported throughout the body via lipoproteins, such as lipoprotein(a), which form various high-, medium-, or low-density lipoprotein complexes. Lipoprotein(a) and low-density lipoprotein (LDL) are known risk factors for CVD. Testosterone therapy has been reported to reduce lipoprotein(a) and cholesterol levels, particularly in hypogonadal and elderly cohorts, thereby reducing the risk of CVD. 1,2

[0081] In a preferred embodiment of the invention, the cardiovascular disease is selected from the group consisting of coronary heart disease, deep vein thrombosis, pulmonary embolism, cerebrovascular disease, atherosclerosis, stroke prevention, hyperlipidemia, peripheral arterial disease, hypertension, metabolic syndrome, and type I and type II diabetes.

[0082] In a preferred embodiment of the present invention, the treatment of cardiovascular disease or cardiovascular related disorders is a daily dosage regimen of 40 mg to 120 mg for at least 6 months.

[0083] In a preferred embodiment of the present invention, the reduction in lipoprotein(a), LDL, and / or cholesterol in the aforementioned cardiovascular or cardiovascular-related diseases is monitored, for example, for a period of three months, and the dose of native testosterone is eventually adjusted to an adult dose of up to 600 mg of native testosterone in 24 hours.

[0084] In a preferred embodiment of the present invention, the reduction in lipoprotein(a), LDL, and / or cholesterol in the aforementioned cardiovascular or cardiovascular-related diseases is monitored, for example, for a period of three months, and the dose of native testosterone is eventually adjusted to an adult dose of up to 800 mg of native testosterone in 24 hours.

[0085] In an alternative embodiment of the invention, the aforementioned regimen is for the treatment of non-alcoholic steatohepatitis (NASH).

[0086] In one preferred embodiment of the invention, the aforementioned regimen is for the treatment of non-alcoholic fatty liver disease (NAFLD).

[0087] NASH and NAFLD are liver diseases. NASH is an inflammatory condition that can lead to fibrosis, cirrhosis, and liver cancer. NAFLD similarly results in liver tissue damage. Approximately 20% of patients with NAFLD also have NASH. Causes of both NASH and NAFLD include obesity, glucocorticoid use, viral infections such as hepatitis C, and excessive alcohol consumption. Currently, there are no approved medications for the treatment of NASH or NAFLD. Medical advice is weight loss and lifestyle changes. An associated condition is metabolic syndrome, which is more likely when a subject has NASH or NAFLD. Metabolic syndrome results from high serum triglycerides, high blood pressure, and an inability to control blood sugar levels.

[0088] In a preferred embodiment of the invention, the aforementioned regimen is a treatment for metabolic syndrome.

[0089] In a preferred embodiment of the invention, the aforementioned regimen is for the treatment of type II diabetes.

[0090] In a preferred embodiment of the present invention, said human subject is male or female.

[0091] In an alternative preferred embodiment of the present invention, the subject is transgender and undergoing gender reassignment treatment.

[0092] In an alternative preferred embodiment of the present invention, said subject is transgender and has transitioned from a female to a male subject.

[0093] In a preferred embodiment of the present invention, converting subjects are administered 40 mg to 280 mg of natural testosterone twice daily for 6 to 12 months.

[0094] Alternatively, converting subjects are administered 120 mg to 280 mg of natural testosterone twice daily for 6 to 12 months.

[0095] In a preferred embodiment of the present invention, a converting subject is administered a dose selected from the group consisting of 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, or 280 mg of native testosterone twice daily for 6 to 12 months.

[0096] In practice, conversion of female subjects to male subjects is monitored for serum testosterone to achieve a serum testosterone of 10-35 nmol / L (300-1000 ng / dL), and the dose of natural testosterone is adjusted to achieve the desired serum testosterone levels to ensure safe and effective conversion.

[0097] In a preferred embodiment of the present invention, the subject is middle-aged or elderly.

[0098] Middle-aged and elderly people as referred to in the context of this application are those aged approximately 40-65 and 66-100 years, respectively.

[0099] In a further preferred embodiment of the present invention, testosterone administration is for treating decreased libido in a male or female human subject.

[0100] In a preferred embodiment of the present invention, said testosterone administration is for the treatment of erectile dysfunction.

[0101] In a preferred embodiment of the present invention, said human subject is in a fasted state prior to administration of said therapeutic regimen.

[0102] In an alternative embodiment of the invention, said human subject is in a fed state prior to administration of said therapeutic regimen.

[0103] In an alternative embodiment of the invention, the aforementioned composition is for use in a male human subject for the prevention or amelioration of azoospermia or infertility.

[0104] According to an aspect of the present invention, there is provided a dosing regimen for use in a human subject in need of treatment that would benefit from the administration of natural testosterone, the dosing regimen comprising administering at least first and second pharmaceutical compositions:

[0105] The first composition comprises 2.5 to 7.5% w / w of natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol; The second composition comprises at least 9% w / w of natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol; The first and second compositions are orally administered to the human subject at least once every 24 hours to normalize serum testosterone.

[0106] In a preferred embodiment of the present invention, the aforementioned first composition comprises: 2.5 to 7.5% w / w natural testosterone, at least 40% w / w sesame oil, at least 30% w / w of propylene glycol monolaurate, at least 5% w / w ethanol, and At least 15% w / w benzyl alcohol.

[0107] Preferably, the first composition consists of testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol as set forth in Table 1.

[0108] In a preferred embodiment of the present invention, said second composition comprises at least 9, 10, or 11% w / w testosterone.

[0109] In a preferred embodiment of the present invention, said second composition comprises or consists essentially of: 9-11% w / w natural testosterone, at least 35% w / w sesame oil, at least 27% w / w of propylene glycol monolaurate, at least 8% w / w ethanol, and At least 13% w / w benzyl alcohol.

[0110] In a further preferred embodiment of the present invention, the aforementioned composition comprises or consists essentially of: 9-11% w / w natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0111] In a preferred embodiment of the present invention, said second composition comprises or consists essentially of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 16% w / w benzyl alcohol.

[0112] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.74% w / w sesame oil, 28.06% w / w of propylene glycol monolaurate, 9% w / w ethanol, and 16.20% w / w benzyl alcohol.

[0113] In an alternative preferred embodiment of the present invention, said second composition comprises or consists essentially of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0114] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.64% w / w sesame oil, 28.05% w / w of propylene glycol monolaurate, 11.25% w / w ethanol, and 14.06% w / w benzyl alcohol.

[0115] In a preferred embodiment of the present invention, the human subject is administered the first and second compositions either simultaneously or temporally separated over a 24 hour period.

[0116] In a preferred embodiment of the present invention, the human subject is administered a dose of between 10 and 800 mg of total native testosterone over a 24 hour period.

[0117] In a further preferred embodiment of the present invention, the aforementioned human subject is administered a dose of between 10 and 600 mg of total native testosterone over a 24 hour period.

[0118] In a preferred embodiment of the present invention, the human subject is administered a dose of between 160 and 800 mg of total native testosterone over a 24 hour period.

[0119] In a further preferred embodiment of the present invention, the aforementioned human subject is administered a dose of between 160 and 600 mg of total native testosterone over a 24 hour period.

[0120] In a preferred embodiment of the present invention, the total native testosterone dosage is 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg over a 24 hour period.

[0121] In preferred embodiments of the present invention, the aforementioned total native testosterone dosage is 160 mg, 200 mg, 240 mg, 280 mg, 320 mg, 360 mg, 400 mg, 440 mg, 480 mg, 520 mg, 560 mg, 600 mg, 640 mg, 680 mg, 720 mg, 760 mg, or 800 mg over a 24 hour period.

[0122] In a further preferred embodiment of the present invention, the aforementioned human subject is administered a dose of 400 mg of total native testosterone over a 24 hour period.

[0123] In a further preferred embodiment of the present invention, the aforementioned human subject is administered a dose of between 400 and 800 mg of total native testosterone over a 24 hour period.

[0124] In further preferred embodiments of the present invention, the aforementioned total native testosterone dosages are 640 mg, 680 mg, 720 mg, 760 mg, and 800 mg over a 24 hour period.

[0125] In a more preferred embodiment of the present invention, the total native testosterone dosage is 40 mg over a 24 hour period.

[0126] In a preferred embodiment of the present invention, two-thirds of the total native testosterone dose is administered between 00:00 and 12:00 hours, and one-third of the total dose is administered between 12:00 and 24:00 hours.

[0127] In an alternative preferred embodiment of the present invention, 50% to 90% of the total native testosterone dose is administered between 00:00 and 12:00 hours, and 50% to 10% of the total dose is administered between 12:00 and 24:00 hours.

[0128] Preferably, 55% to 70% of the total dose of natural testosterone is administered between 00:00 and 12:00, and 45% to 30% of the total dose of natural testosterone is administered between 12:00 and 24:00.

[0129] In a preferred embodiment of the present invention, 50% of the total native testosterone dose is administered between 00:00 and 12:00 hours, and 50% of the total dose is administered between 12:00 and 24:00 hours.

[0130] In a preferred embodiment of the present invention, the aforementioned dose of 240 mg of total native testosterone is administered between 00:00 and 12:00 hours, and the dose of 160 mg of total native testosterone is administered between 12:00 and 24:00 hours.

[0131] In a preferred embodiment of the present invention, the aforementioned dose of 280 mg of total native testosterone is administered between 00:00 and 12:00 hours, and the dose of 120 mg of total native testosterone is administered between 12:00 and 24:00 hours.

[0132] In a preferred embodiment of the present invention, the aforementioned dose of 400 mg of total native testosterone is administered between 00:00 and 12:00 hours, and the dose of 400 mg of total native testosterone is administered between 12:00 and 24:00 hours.

[0133] In a preferred embodiment of the present invention, the aforementioned dose of 320 mg of total native testosterone is administered between 00:00 and 12:00 hours, and the dose of 280 mg of total native testosterone is administered between 12:00 and 24:00 hours.

[0134] In a preferred embodiment of the present invention, the aforementioned dosing regimen is for the treatment of delayed puberty.

[0135] In a preferred embodiment of the invention, the treatment for delayed puberty is a dosing regimen of 40 mg to 120 mg daily for 3 to 6 months, more preferably 3 months.

[0136] In an alternative preferred embodiment of the present invention, the dosing regimen is for the induction of puberty.

[0137] In a preferred embodiment of the present invention, the induction of puberty is a dosing regimen of 40 mg of natural testosterone in a 24-hour period for at least three months.

[0138] In preferred embodiments of the present invention, the aforementioned dosing regimens for induction of puberty span 3-6 months, 6-12 months, 1-2 years, or 3-4 years.

[0139] In a preferred embodiment of the present invention, pubertal induction is monitored for at least three months and the dose of natural testosterone is adjusted to an adult dose of up to 600 mg natural testosterone in 24 hours.

[0140] In a preferred embodiment of the present invention, pubertal induction is monitored for at least three months and the dosage of natural testosterone is adjusted to an adult dose of up to 800 mg natural testosterone in 24 hours.

[0141] In a preferred embodiment of the invention, the aforementioned dosing regimen is given throughout the life of the human subject.

[0142] In a preferred embodiment of the invention, the dosing regimen is for use in treating primary hypogonadism in a human subject as described above.

[0143] In a preferred embodiment of the invention, the primary hypogonadism is associated with or caused by a condition selected from the following group: Klinefelter's syndrome, anorchia, mumps orchitis, hemochromatosis, cancer treatment, and physical injury to the testes.

[0144] In an alternative preferred embodiment, the dosing regimen is for use in treating secondary hypogonadism in a human subject as described above.

[0145] In a preferred embodiment of the invention, the secondary hypogonadism is associated with or caused by a condition selected from the following group: congenital hypopituitarism, Kallmann syndrome, a pituitary tumor, craniopharyngioma, an inflammatory disease such as sarcoidosis, histiocytosis, and tuberculosis, and HIV / AIDS, or a late effect of cancer therapy.

[0146] In a preferred embodiment of the invention, the aforementioned dosing regimen is associated with pubertal failure resulting from either primary or secondary hypogonadism, or chronic diseases including Duchenne muscular dystrophy, or glucocorticoid therapy.

[0147] In a preferred embodiment of the present invention, the aforementioned dosing regimen is associated with constitutional growth retardation and delayed puberty.

[0148] In a preferred embodiment of the present invention, the constitutional growth retardation and pubertal delay is familial constitutional growth retardation and pubertal delay.

[0149] In an alternative preferred embodiment of the present invention, the constitutional growth retardation and delayed puberty is idiopathic.

[0150] In a preferred embodiment of the present invention, treatment of constitutional growth retardation and delayed puberty involves administering to a human subject a dose of 40 mg to 120 mg of natural testosterone within a 24-hour period for at least three months.

[0151] In a preferred embodiment of the present invention, the treatment of constitutional growth retardation and delayed puberty is administered to a human subject at a dose of 40 mg to 120 mg of natural testosterone within a 24-hour period for a period of 3 to 12 months, or preferably for a period of 3 to 6 months.

[0152] In an alternative embodiment of the invention, the aforementioned regimen is for use in treating cardiovascular disease or a condition related to cardiovascular disease.

[0153] In a preferred embodiment of the invention, the cardiovascular disease is selected from the group consisting of coronary heart disease, deep vein thrombosis, pulmonary embolism, cerebrovascular disease, atherosclerosis, stroke prevention, hyperlipidemia, peripheral arterial disease, hypertension, metabolic syndrome, and type I and type II diabetes.

[0154] In a preferred embodiment of the present invention, the treatment of cardiovascular disease or cardiovascular related disorders is a daily dosage regimen of 40 mg to 120 mg for at least 6 months.

[0155] In a preferred embodiment of the present invention, the reduction in lipoprotein(a), LDL, and / or cholesterol in the aforementioned cardiovascular or cardiovascular-related diseases is monitored, for example, for a period of three months, and the dose of native testosterone is eventually adjusted to an adult dose of up to 600 mg of native testosterone in 24 hours.

[0156] In a preferred embodiment of the present invention, the reduction in lipoprotein(a), LDL, and / or cholesterol in the aforementioned cardiovascular or cardiovascular-related diseases is monitored, for example, for a period of three months, and the dose of native testosterone is eventually adjusted to an adult dose of up to 800 mg of native testosterone in 24 hours.

[0157] In an alternative embodiment of the invention, the aforementioned regimen is for the treatment of non-alcoholic steatohepatitis (NASH).

[0158] In one preferred embodiment of the invention, the aforementioned regimen is for the treatment of non-alcoholic fatty liver disease (NAFLD).

[0159] In a preferred embodiment of the invention, the aforementioned regimen is a treatment for metabolic syndrome.

[0160] In a preferred embodiment of the invention, the aforementioned regimen is for the treatment of type II diabetes.

[0161] In a preferred embodiment of the present invention, said human subject is male or female.

[0162] In an alternative preferred embodiment of the present invention, the subject is transgender and undergoing gender reassignment treatment.

[0163] In an alternative preferred embodiment of the present invention, said subject is transgender and has transitioned from a female to a male human subject.

[0164] In a preferred embodiment of the present invention, converting subjects are administered 40 mg to 280 mg of natural testosterone twice daily for 6 to 12 months.

[0165] Alternatively, converting subjects are administered 120 mg to 280 mg of natural testosterone twice daily for 6 to 12 months.

[0166] In a preferred embodiment of the present invention, a converting subject is administered a dose selected from the group consisting of 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, or 280 mg of native testosterone twice daily for 6 to 12 months.

[0167] In practice, conversion of female human subjects to male human subjects is monitored for serum testosterone to achieve a serum testosterone of 10-35 nmol / L (300-1000 ng / dL), and the dose of native testosterone is adjusted to achieve the desired serum testosterone level to ensure safe and effective conversion.

[0168] In a preferred embodiment of the present invention, said human subject is middle-aged or elderly.

[0169] Middle-aged and elderly people as referred to in the context of this application are those aged approximately 40-65 and 66-100 years, respectively.

[0170] In a further preferred embodiment of the present invention, testosterone administration is for treating decreased libido in a male or female human subject.

[0171] In a preferred embodiment of the present invention, said testosterone administration is for the treatment of erectile dysfunction.

[0172] In a preferred embodiment of the present invention, said human subject is in a fasted state prior to administration of said therapeutic regimen.

[0173] In an alternative embodiment of the invention, said human subject is in a fed state prior to administration of said therapeutic regimen.

[0174] In an alternative embodiment of the invention, the aforementioned composition is for use in a male human subject for the prevention or amelioration of azoospermia or infertility.

[0175] Azoospermia is a condition that causes a decrease or cessation of sperm production, and can be the result of several clinical conditions.For example, the administration of androgens such as testosterone undecanoate can cause a decrease in sperm production.The composition of the present invention does not cause azoospermia and maintains sperm count within normal range.

[0176] The composition may be combined with additional pharmaceutically acceptable carriers, if desired, to preserve the testosterone and protect the lipid-based carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more suitable solid or liquid fillers, diluents, or encapsulants suitable for human administration and compatible with testosterone and the lipid-based carrier. In this context, the term "pharmaceutically acceptable carrier" refers to a natural or synthetic organic or inorganic component with which an active ingredient is combined to facilitate application or protect the active agent. For example, these include, but are not limited to, stabilizers, preservatives, antioxidants, and plasticizers to protect the lipid vehicle (or its outer packaging unit) from chemical degradation and / or to maintain the stability of the steroid hormone. Such pharmaceutically acceptable materials may include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), mixed tocopherols, and aromatic phenols.

[0177] The components of the pharmaceutical compositions also are capable of being commingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0178] The compositions may be conveniently provided in unit dosage form and may be prepared by any method well known in the art of pharmacy.All methods include the step of bringing the active agent into association with a carrier, which constitutes one or more accessory ingredients.In general, the compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0179] Compositions suitable for oral administration are provided as discrete units such as capsules, tablets, lozenges, or as liquids, e.g., administered via syringe, each containing a predetermined amount of the active hormone. Carrier formulations suitable for oral administration can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

[0180] According to an aspect of the present invention, there is provided a dosing regimen for a human female subject in need of treatment that would benefit from the administration of natural testosterone, the dosing regimen comprising administering a pharmaceutical composition comprising natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, the composition being orally administered to said human subject at least once within a 24-hour period to normalize serum testosterone.

[0181] In a preferred embodiment of the invention, the aforementioned composition comprises at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or 41% w / w of sesame oil.

[0182] In a preferred embodiment of the invention, the aforementioned composition comprises at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30 or 31% w / w propylene glycol monolaurate.

[0183] In a preferred embodiment of the invention, the aforementioned composition comprises at least 5, 6, 7, 8, 9, or 10% w / w ethanol.

[0184] In a preferred embodiment of the invention, the aforementioned composition comprises at least 15, 16, 17, 18, 19, or 20% w / w of benzyl alcohol.

[0185] In a preferred embodiment of the present invention, the aforementioned composition comprises: 2-10% w / w natural testosterone, at least 40% w / w sesame oil, at least 30% w / w of propylene glycol monolaurate, at least 5% w / w ethanol, and At least 15% w / w benzyl alcohol.

[0186] Preferably, the aforementioned composition consists of testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol as set forth in Table 1.

[0187] In alternative preferred embodiments of the present invention, the aforementioned compositions comprise at least 35%, 36%, or 37% w / w sesame oil.

[0188] In alternative embodiments of the present invention, the aforementioned compositions comprise at least 27%, 28%, or 29% w / w propylene glycol monolaurate.

[0189] In alternative embodiments of the invention, the aforementioned compositions comprise at least 8, 9, 10, or 11% w / w ethanol.

[0190] In alternative embodiments of the invention, the aforementioned compositions comprise at least 13, 14, 15, 16, or 17% w / w of benzyl alcohol.

[0191] In an alternative embodiment of the present invention, the aforementioned composition comprises: 9-11% w / w natural testosterone, at least 35% w / w sesame oil, at least 27% w / w of propylene glycol monolaurate, at least 8% w / w ethanol, and At least 13% w / w benzyl alcohol.

[0192] In a further alternative embodiment of the present invention, the aforementioned composition comprises or consists essentially of: 9-11% w / w natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0193] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 16% w / w benzyl alcohol.

[0194] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.74% w / w sesame oil, 28.06% w / w of propylene glycol monolaurate, 9% w / w ethanol, and 16.20% w / w benzyl alcohol.

[0195] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0196] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.64% w / w sesame oil, 28.05% w / w of propylene glycol monolaurate, 11.25% w / w ethanol, and 14.06% w / w benzyl alcohol.

[0197] In a preferred embodiment of the present invention, the aforementioned subject is administered a composition comprising at least 2 mg of natural testosterone.

[0198] In a preferred embodiment of the present invention, the subject is administered between 2 mg and 40 mg of a composition of natural testosterone.

[0199] In an alternative embodiment of the present invention, the aforementioned subject is administered the composition at a dose selected from the group consisting of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, or 40 mg of native testosterone.

[0200] In one embodiment of the invention, said female subject has adrenal insufficiency.

[0201] In one embodiment of the present invention, the adrenal insufficiency is the result of a condition selected from the group consisting of primary, secondary, or tertiary adrenal insufficiency, polycystic ovarian failure, and glucocorticoid-repairing aldosteronism (GRA).

[0202] In an alternative embodiment of the present invention, said female subject has cardiovascular disease or a disease related to cardiovascular disease.

[0203] In a preferred embodiment of the present invention, the aforementioned disease is selected from the group consisting of coronary heart disease, deep vein thrombosis, pulmonary embolism, cerebrovascular disease, atherosclerosis, stroke prevention, hyperlipidemia, peripheral arterial disease, hypertension, metabolic syndrome, and type I and type II diabetes.

[0204] According to an aspect of the present invention, there is provided a dosing regimen for use in a human subject suffering from frailty, the dosing regimen comprising administering a pharmaceutical composition comprising natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, wherein the composition is orally administered to said human subject to increase serum testosterone.

[0205] In a preferred embodiment of the present invention, the aforementioned compositions are administered daily, or every other day, weekly, or monthly.

[0206] In a preferred embodiment of the present invention, the subject is administered the composition two or three times daily.

[0207] In a preferred embodiment of the present invention, the aforementioned composition is administered for at least three months.

[0208] In a preferred embodiment of the present invention, the subject is administered the composition in spatially separated doses spaced 6-8 hours apart.

[0209] In a preferred embodiment of the present invention, the subject is administered the composition in spatially separated doses at 8 hour intervals.

[0210] In a preferred embodiment of the present invention, the composition contains 2-10% w / w of natural testosterone.

[0211] In a preferred embodiment of the present invention, the aforementioned composition comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10% w / w of natural testosterone.

[0212] In a preferred embodiment of the present invention, the aforementioned composition comprises at least 9, 10, or 11% w / w of natural testosterone.

[0213] In a preferred embodiment of the present invention, the composition comprises about 10% w / w of natural testosterone.

[0214] In a preferred embodiment of the invention, the aforementioned composition comprises at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or 41% w / w of sesame oil.

[0215] In a preferred embodiment of the invention, the aforementioned composition comprises at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or 31% w / w propylene glycol monolaurate.

[0216] In a preferred embodiment of the invention, the aforementioned composition comprises at least 5, 6, 7, 8, 9, or 10% w / w ethanol.

[0217] In a preferred embodiment of the invention, the aforementioned composition comprises at least 15, 16, 17, 18, 19, or 20% w / w benzyl alcohol.

[0218] In a preferred embodiment of the present invention, the aforementioned composition comprises: 2-10% w / w natural testosterone, at least 40% w / w sesame oil, at least 30% w / w of propylene glycol monolaurate, at least 5% w / w ethanol, and At least 15% w / w benzyl alcohol.

[0219] Preferably, the aforementioned composition consists of testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol as set forth in Table 1.

[0220] In alternative preferred embodiments of the present invention, the aforementioned compositions comprise at least 35%, 36%, or 37% w / w sesame oil.

[0221] In alternative embodiments of the present invention, the aforementioned compositions comprise at least 27%, 28%, or 29% w / w propylene glycol monolaurate.

[0222] In alternative embodiments of the invention, the aforementioned compositions comprise at least 8, 9, 10, or 11% w / w ethanol.

[0223] In alternative embodiments of the invention, the aforementioned compositions comprise at least 13, 14, 15, 16, or 17% w / w of benzyl alcohol.

[0224] In an alternative embodiment of the present invention, the aforementioned composition comprises: 9-11% w / w natural testosterone, at least 35% w / w sesame oil, at least 27% w / w of propylene glycol monolaurate, at least 8% w / w ethanol, and At least 13% w / w benzyl alcohol.

[0225] In a further alternative embodiment of the present invention, the aforementioned composition comprises or consists essentially of: 9-11% w / w natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0226] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 16% w / w benzyl alcohol.

[0227] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.74% w / w sesame oil, 28.06% w / w of propylene glycol monolaurate, 9% w / w ethanol, and 16.20% w / w benzyl alcohol.

[0228] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0229] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.64% w / w sesame oil, 28.05% w / w of propylene glycol monolaurate, 11.25% w / w ethanol, and 14.06% w / w benzyl alcohol.

[0230] In a preferred embodiment of the present invention, the aforementioned dosage is between 10 and 200 mg of natural testosterone.

[0231] In an alternative preferred embodiment of the present invention, the aforementioned dosage is between 30 mg and 200 mg of natural testosterone.

[0232] In an alternative preferred embodiment of the present invention, the aforementioned dosage is between 30 mg and 50 mg of natural testosterone.

[0233] In alternative embodiments of the present invention, the aforementioned dosage is selected from the group consisting of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, and 200 mg of native testosterone.

[0234] In a preferred embodiment of the present invention, the aforementioned dosage is between 10 and 40 mg of natural testosterone.

[0235] In an alternative preferred embodiment of the present invention, the aforementioned dosage is between 30 mg and 50 mg of natural testosterone.

[0236] In alternative embodiments of the present invention, the aforementioned dosage is selected from the group consisting of 10 mg, 20 mg, 30 mg, 40 mg, and 50 mg of natural testosterone.

[0237] In preferred embodiments of the present invention, the aforementioned treatments may be provided short-term or long-term. Short-term in the context of the present invention is defined as the provision of a natural testosterone composition according to the present invention over a period of weeks or months. Long-term treatment is defined as the provision of a testosterone composition according to the present invention throughout one's life.

[0238] In one embodiment of the present invention, said subject is a female subject.

[0239] In one embodiment of the present invention, said subject is a male subject.

[0240] Frailty is an age-related biological syndrome characterized by diminished physical and mental reserves, reduced tolerance to external stressors, and increased risk of disability, hospitalization, and ultimately death. The prevalence of frailty increases with age and is typically more common in women than men; in Europe, frailty is estimated to affect 5-10% of the population over 65 years of age and 25-50% of those over 85 years of age. Postmenopausal women have a significantly higher prevalence. Frailty is characterized, for example, by increased protein catabolism and muscle atrophy.

[0241] According to a further aspect of the present invention, there is provided a dosage regimen for use in treating Turner syndrome in a female human subject, the dosage regimen comprising administering a pharmaceutical composition comprising natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, wherein the composition is orally administered to said human female subject to increase serum testosterone.

[0242] In a preferred embodiment of the present invention, the aforementioned administration regimen comprises the administration of growth hormone.

[0243] In a preferred embodiment of the invention, the aforementioned administration regimen precedes and / or is concurrent with the administration of growth hormone.

[0244] In a preferred embodiment of the present invention, the composition contains 2-10% w / w of natural testosterone.

[0245] In a preferred embodiment of the present invention, the aforementioned composition comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10% w / w of natural testosterone.

[0246] In a preferred embodiment of the present invention, the aforementioned composition comprises 9, 10, or 11% w / w of natural testosterone.

[0247] In a preferred embodiment of the present invention, the composition comprises 10% w / w of natural testosterone.

[0248] In a preferred embodiment of the invention, the aforementioned composition comprises at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or 41% w / w of sesame oil.

[0249] In a preferred embodiment of the invention, the aforementioned composition comprises at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or 31% w / w propylene glycol monolaurate.

[0250] In a preferred embodiment of the invention, the aforementioned composition comprises at least 5, 6, 7, 8, 9, or 10% w / w ethanol.

[0251] In a preferred embodiment of the invention, the aforementioned composition comprises at least 15, 16, 17, 18, 19, or 20% w / w benzyl alcohol.

[0252] In a preferred embodiment of the present invention, the aforementioned composition comprises: 2-10% w / w natural testosterone, at least 40% w / w sesame oil, at least 30% w / w of propylene glycol monolaurate, at least 5% w / w ethanol, and At least 15% w / w benzyl alcohol.

[0253] Preferably, the aforementioned composition consists of testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol as set forth in Table 1.

[0254] In alternative preferred embodiments of the present invention, the aforementioned compositions comprise at least 35%, 36%, or 37% w / w sesame oil.

[0255] In alternative embodiments of the present invention, the aforementioned compositions comprise at least 27%, 28%, or 29% w / w propylene glycol monolaurate.

[0256] In alternative embodiments of the invention, the aforementioned compositions comprise at least 8, 9, 10, or 11% w / w ethanol.

[0257] In alternative embodiments of the invention, the aforementioned compositions comprise at least 13, 14, 15, 16, or 17% w / w of benzyl alcohol.

[0258] In an alternative embodiment of the present invention, the aforementioned composition comprises: 9-11% w / w natural testosterone, at least 35% w / w sesame oil, at least 27% w / w of propylene glycol monolaurate, at least 8% w / w ethanol, and At least 13% w / w benzyl alcohol.

[0259] In an alternative embodiment of the present invention, the aforementioned composition comprises or consists essentially of: 9-11% w / w natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0260] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and At least 16% w / w benzyl alcohol.

[0261] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.74% w / w sesame oil, 28.06% w / w of propylene glycol monolaurate, 9% w / w ethanol, and 16.20% w / w benzyl alcohol.

[0262] In a further alternative and preferred embodiment of the present invention, the aforementioned composition comprises or consists of: Approximately 10% w / w of natural testosterone, at least 36% w / w sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and At least 14% w / w benzyl alcohol.

[0263] In a further preferred embodiment of the present invention, the aforementioned composition consists of: 10% w / w natural testosterone, 36.64% w / w sesame oil, 28.05% w / w of propylene glycol monolaurate, 11.25% w / w ethanol, and 14.06% w / w benzyl alcohol.

[0264] In a preferred embodiment of the present invention, the aforementioned dosage is between 10 and 40 mg of natural testosterone.

[0265] In an alternative preferred embodiment of the present invention, the aforementioned dosage is between 30 mg and 50 mg of natural testosterone.

[0266] In alternative embodiments of the present invention, the aforementioned dosage is selected from the group consisting of 10 mg, 20 mg, 30 mg, 40 mg, and 50 mg of natural testosterone.

[0267] In a preferred embodiment of the present invention, the aforementioned compositions are administered daily, or every other day, weekly, or monthly.

[0268] In a preferred embodiment of the present invention, the aforementioned composition is administered daily or every other day from about age 9 until completion of bone growth.

[0269] Completion of bone growth is defined as a bone age greater than 14 years and a growth rate greater than approximately 2 cm per year.

[0270] In a preferred embodiment of the present invention, the aforementioned composition is administered for at least three months.

[0271] In a preferred embodiment of the present invention, the aforementioned composition is administered during puberty.

[0272] Puberty is the process of physical changes that occur as a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in girls and the testes in boys. On average, girls begin puberty at age 10-11 and complete puberty at age 15-17. Boys typically begin puberty at age 11-12 and complete puberty at age 16-17.

[0273] According to an aspect of the present invention, there is provided a method for producing a composition comprising natural testosterone, the method comprising: i) forming a homogeneous preparation comprising sesame oil, propylene glycol monolaurate, benzyl alcohol, and ethanol; ii) adding native testosterone to said homogenous preparation at a concentration of about 13% w / w to form a combined testosterone preparation; and iii) mixing the combined preparation to dissolve the testosterone and form a substantially clear preparation.

[0274] In a preferred method of the present invention, the preparation contains native testosterone at a final dissolved concentration of 9-13% w / w.

[0275] In a preferred method of the present invention, the preparation contains native testosterone at a final dissolved concentration of 9-11% w / w.

[0276] In a preferred embodiment of the present invention, the preparation contains native testosterone at a final dissolved concentration of about 10% w / w.

[0277] According to an aspect of the present invention, there is provided a composition obtained or obtainable by a method according to the present invention.

[0278] Throughout the description and claims of this specification, the words "comprise" and "contain," as well as variations of those words, such as "comprising" and "comprises," mean "including but not limited to," and are not intended to (and do not) exclude other parts, addenda, components, wholes, or steps.

[0279] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating singularity as well as plurality, unless the context otherwise requires.

[0280] It is to be understood that any feature, integer, property, compound, chemical moiety, or group described in connection with any aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith.

[0281] Embodiments of the present invention will now be described, by way of example only, with reference to the following figures and tables: [Brief explanation of the drawings]

[0282] [Figure 1] FIG. 1 shows serum total testosterone following a single dose of either 80 mg testosterone undecanoate or 120 mg DITEST in the fed state, or 200 mg DITEST in the fasted or fed state. [Figure 2] FIG. 2 shows serum DHT following a single dose of either 80 mg testosterone undecanoate or 120 mg DITEST in the fed state, or 200 mg DITEST in the fasted or fed state. [Example]

[0283] material and method DITEST contains testosterone as its sole active ingredient. A chemical description of the active ingredient is provided below.

[0284] [Table 1]

[0285] [Table 2]

[0286] Testosterone is a Schedule 4 Part II controlled substance (an androgenic anabolic steroid) in the UK. It belongs to the androgenic pharmacological therapy group (ATC code G03B A03).

[0287] DITEST Formula [Table 3]

[0288] [Table 4]

[0289] [Table 5]

[0290] [Table 6]

[0291] [Table 7]

[0292] [Table 8]

[0293] formulation DITEST is an oral immediate-release gelatin capsule containing 40 mg of natural testosterone and the following excipients: sesame oil, ethanol, benzyl alcohol, and propylene glycol monolaurate. The capsule shell also contains glycerin. Fractionated coconut oil, isopropyl alcohol, lecithin, and Phosal 53 MCT (lecithin in caprylic / capric triglyceride, alcohol, glyceryl stearate, oleic acid, and ascorbyl palmitate) are used as processing aids during encapsulation and may be present in trace amounts. DITEST is supplied as a liquid fill in opaque soft gelatin capsules. The testosterone drug substance is USP / EP grade and manufactured in accordance with Good Manufacturing Practice (GMP). All excipients are European Pharmacopoeia grade and approved for use in adult humans at the amounts administered within the clinical development program. The gelatin used to form the capsule shell is certified as Bovine Spongiform Encephalopathy (BSE) / Transmissible Spongiform Encephalopathy (TSE)-free (European Directorate for the Quality of Medicines and Healthcare Products [EDQM] Certificate of Conformity [CEP]). DITEST is manufactured in accordance with GMP.

[0294] DITEST is packaged, for example, in an aluminum-aluminum blister pack. The blisters are contained within a cardboard box. DITEST is labelled in compliance with the requirements of EudraLex (Regulations for Medicinal Products for the European Union) Volume 4: Annex 13 of the European GMP guidelines (Investigational Medicinal Products Manufacturing).

[0295] Method for preparing a composition containing 10% by weight of natural testosterone 1. All excipients were weighed and added in order of decreasing mass (sesame oil, propylene glycol, benzyl alcohol, and ethanol) into an amber glass bottle (this approach was taken to reduce evaporation losses due to the volatility of ethanol). 2. The mixture was mixed by hand until uniform. 3. Testosterone was added to an amber glass bottle at a target weight of 2.667 g (133.3 mg / g target concentration) and a stir bar was placed in the bottle. 4. The formulation was mixed using a magnetic stirrer (setting 5) and initially mixed for 48 minutes. 5. The formulations were allowed to continue mixing at ambient temperature for a total of 4 days before solubility evaluation was completed.

[0296] Solubility evaluation of 10% w / w testosterone compositions was performed as follows: 1. The formulation was transferred to a centrifuge tube. 2. The formulation was centrifuged at 15,000 rpm for 15-20 minutes. 3. The supernatant was analyzed by assay to determine the testosterone content.

[0297] Softgel Filling Validation Method for Preparation of Compositions Containing 10% Ethanol by Weight 1. All excipients were weighed and added in order of decreasing mass (sesame oil, propylene glycol, benzyl alcohol, and ethanol) into an amber glass bottle. 2. Testosterone was added to a brown glass bottle and a stir bar was placed in the bottle. 3. The formulation was mixed using a magnetic stirrer initially at 300 rpm and gradually increased to 500 rpm over a mixing time of 3 hours and 20 minutes. The placebo was prepared as follows: The excipients were combined in aa bottle and mixed by hand for 1 minute.

[0298] Storage conditions DITEST must be stored in a dry place between 5°C and 25°C, with temperature controlled and monitored. Temperature monitoring equipment is included with DITEST shipments to ensure acceptable transport conditions.

[0299] There is an unmet need for oral natural testosterone therapy in men with androgen (testosterone) deficiency. Current therapy for most hypogonadal patients in Europe and the United States (US) is administered either by intramuscular injection or gel. These therapies have drawbacks, including injection-related pain, skin reactions, and the potential for transmission to partners via the gel. At the time this study was designed, only one oral formulation of oral testosterone undecanoate was available in the UK, but it was not approved in the US at the time. DITEST is a novel formulation of natural testosterone. In preclinical studies, DITEST demonstrated good absorption after oral administration, and this study further investigated its safety and pharmacokinetics (PK) in adult men with hypogonadism. Testosterone undecanoate is thought to be absorbed primarily via the intestinal lymphatics with dietary lipids, whereas DITEST was formulated to allow absorption without the need for dietary lipids. To determine the proportion absorbed via the lymphatics, aqueous and lipid fractions of serum were separated for serum testosterone measurements. Because this was a first-in-human trial, participants were closely monitored as hospitalized patients during treatment.

[0300] method This study was conducted in male participants aged 18 to 80 years who required testosterone replacement therapy for primary or secondary hypogonadism. The study was a randomized, active-controlled, single-dose, two-way crossover study in two cohorts. Participants in each cohort who met the entry criteria at screening and baseline were randomized to one of two sequences:

[0301] Cohort 1: A single dose of 120 mg (3 × 40 mg) DITEST followed by a single dose of 80 mg (2 × 40 mg) testosterone undecanoate, or a single dose of 80 mg (2 × 40 mg) testosterone undecanoate followed by a single dose of 120 mg (3 × 40 mg) DITEST. The two treatments were separated by a minimum 7-day washout period, and both treatments were administered in the fed state.

[0302] Cohort 2: A single dose of 200 mg (5 × 40 mg) DITEST (fed) followed by a single dose of 200 mg DITEST (fasted) or a single dose of 200 mg DITEST (fasted) followed by a single dose of 200 mg (5 × 40 mg) DITEST (fed). The two treatments were separated by a minimum 7-day washout period.

[0303] Twelve participants were recruited into each cohort. (Note: Participants in Cohort 1 were eligible to enter Cohort 2 after a washout period of at least 3 months between cohorts.) Participants were not to be recruited into Cohort 2 until the outcomes of participants treated in Cohort 1 were evaluated (this review determined whether the planned dose for Cohort 2 needed to be adjusted). No other testosterone treatments were permitted during each cohort, including the washout period. (Note: Participants entering Cohort 1 were allowed to return to their usual testosterone treatment, if applicable, upon completion of this cohort and before screening for Cohort 2.) Each participant was required to visit the investigational site at least four or five times per cohort, as follows: screening assessment, assessment of baseline testosterone levels after the washout period from the participant's current medication (only for participants currently receiving testosterone replacement therapy), both dosing dates, and a follow-up visit at the end of the study. On each dosing day, participants remained at the investigational site, and PK blood and saliva samples were collected at -0.5, -0.25 (Cohort 1 only), 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, and 10 hours. PK blood and saliva samples could be collected at up to two additional time points per period if deemed necessary based on accrued data. This was documented in the Trial Master File (TMF) and notified to the Independent Ethics Committee (IEC). If necessary and for practical reasons, participants were allowed to stay overnight at the investigational site or a nearby hotel the night before and / or the night after the dosing day. In Cohort 2, participants could request to reschedule their treatment visit if they were unable to fast overnight.

[0304] Diagnosis and main criteria for inclusion and exclusion: Main selection criteria: Male participants aged 18-80. · Diagnosis of primary testicular failure or secondary hypogonadism due to known pituitary disease or congenital defect. ·Body mass index (BMI)>18kg / m2 and <35 kg / m 2 . · Testosterone levels <8nmol / L after washout of current testosterone treatment, if applicable. · Normal prostate-specific antigen (PSA) levels based on the participant's age.

[0305] Key exclusion criteria: Participants with a past or current history of prostate cancer, male breast cancer, or liver neoplasms. Participants with a past or current history of myocardial infarction (MI), unstable cardiovascular disease, or a clinically significant finding on a screening electrocardiogram (ECG) (as determined by the investigator). Participants with other unstable or inadequately treated endocrine conditions. · Baseline hematocrit >0.5.

[0306] Investigational drug, dose, administration method, batch number: DITEST as immediate-release soft gelatin capsules for oral administration. Each capsule contains 40 mg of natural testosterone in a lipid formulation. Cohort 1 Low Dose: 120 mg (3 x 40 mg capsules). Batch No. 137001-03A Cohort 2 High Dose: 200 mg (5 x 40 mg capsules). Batch number 137001-F1.

[0307] Treatment duration In each cohort, participants received two single doses of the study intervention separated by a washout period of at least 7 days.

[0308] Control product, dose, method of administration, batch number: Testosterone undecanoate 40 mg capsules for oral administration. Each capsule contains 40 mg of testosterone undecanoate, equivalent to 25.3 mg of testosterone. Cohort 1 dose: 80 mg (2 x 40 mg capsules). Batch numbers 193376 and 198015.

[0309] Evaluation items: Primary endpoint ·Maximum serum concentration (C max ) and area under the curve (AUC 0~10 ) Testosterone serum concentrations following administration of a single dose of 120 mg or 200 mg DITEST and 80 mg testosterone undecanoate in the fed state as measured by the primary PK parameter.

[0310] Secondary endpoints C max and AUC 0~10 Testosterone serum concentrations after administration of a single 200 mg dose of DITEST in the fed and fasted states as measured by the primary PK parameter of AEs observed throughout the study. · Changes during the study in vital signs, ECG, and safety laboratory data.

[0311] Exploratory endpoints: To assess serum testosterone and DHT levels. To assess levels of testosterone and testosterone undecanoate (testosterone undecanoate measured only in participants in the testosterone undecanoate arm) in the lipid and aqueous fractions of blood. To assess serum intact testosterone undecanoate levels in participants receiving testosterone undecanoate. Testosterone concentrations in venous and capillary blood samples collected using the Mitra microsampling device will be compared with serum concentrations. To compare salivary testosterone concentrations with serum concentrations. To assess salivary androstenedione concentrations.

[0312] statistical methods Descriptive statistics (n, mean, standard deviation [SD], median and range for continuous variables, frequency and percentage for categorical variables) were obtained by treatment group and / or visit and sequence, where applicable. Geometric means and coefficients of variation were also presented for PK parameters. For each cohort, the primary PK endpoint was analyzed using an analysis of variance (ANOVA) model corresponding to a two-way crossover design with factors of sequence, treatment, period, and participants within sequence. Analyses were performed on log-transformed values. 90% confidence intervals (CIs) for treatment effect ratios were calculated using the mean squared error obtained from the ANOVA model. Ratios were calculated for DITEST (test) versus testosterone undecanoate (reference). Safety and tolerability variables, including vital signs, ECG, AEs / SAEs, and clinical laboratory variables, as well as demographic information (including age, BMI, weight, and height), detailed medical history, and current medical conditions, were summarized descriptively only.

[0313] Demographic and baseline characteristics: In the entire safety set (N = 25), participants had a mean age of 53.8 years (SD: 13.90), a mean weight of 91.7 kg (SD: 13.04), and a mean BMI of 29.1 kg / m 2 The mean baseline serum testosterone level was 3.00 nmol / L (SD: 2.59). Most participants were white (92.0%).

[0314] Pharmacokinetics Testosterone: Serum testosterone levels were within the physiological range after administration of DITEST (both fed and fasted at 200 mg) and after fed administration of testosterone undecanoate. DITEST 120 mg was significantly higher than testosterone undecanoate. max and AUC 0‐10 DITEST 200mg has a lower C than testosterone undecanoate. max and AUC 0‐10 DITEST was shown to have a similar T-cell response compared to testosterone undecanoate. maxAn exploratory comparison between the two DITEST doses (both in the fed state) showed a significant difference in C for the 120 mg dose compared to the 200 mg dose. max and AUC 0‐10 DITEST 200 mg showed the same C in both fasted and fed states, suggesting dose proportionality. max and AUC 0~10 This demonstrated that food has no effect on the absorption of DITEST.

[0315] DHT: DITEST was associated with lower serum concentrations of DHT compared with testosterone undecanoate. Mean serum DHT concentrations remained below the upper limit of normal (2.65 nmol / L) with DITEST 120 mg.

[0316] Testosterone Undecanoate: Serum testosterone undecanoate levels after administration of 80 mg testosterone undecanoate were 10 times greater than testosterone levels, suggesting that most of the testosterone undecanoate was not converted to testosterone.

[0317] Aqueous and lipid fractions: The concentration-time curves for the aqueous and lipid fractions of testosterone were similar to those for both DITEST and testosterone undecanoate serum levels, with the lipid fraction being approximately 1 / 10 of the serum concentrations for both DITEST and testosterone undecanoate. In contrast, the lipid fraction of serum testosterone undecanoate accounted for more than half of the total serum testosterone undecanoate measurements, suggesting that the majority of testosterone undecanoate was present in the lipid fraction.

[0318] Mitra Microsampling Device: Venous sampling using the Mitra device showed similar but lower concentration-time curves for testosterone compared with serum samples. The concentrations were higher when the results were corrected for hematocrit, but were still lower than serum concentrations. Capillary testosterone levels measured using the Mitra device were 3-4 times higher than when venous samples were measured with the Mitra device.

[0319] safety A total of 10 TEAEs were reported after DITEST (120 mg fed, 200 mg fed, and 200 mg fasted) and 8 TEAEs were reported after testosterone undecanoate. The number of TEAEs was similar between DITEST and testosterone undecanoate and between the fasted and fed states of DITEST. TEAEs were most frequently reported in the following SOCs: infections and infestations, skin and subcutaneous tissue disorders, and nervous system disorders.

[0320] One participant experienced QT prolongation after administration of both study interventions in Cohort 1 (testosterone undecanoate and DITEST 120 mg). The investigator reported these findings as related to the study intervention. All other TEAEs were reported as unrelated to the study intervention. There were no SAEs or severe AEs after administration of DITEST. One SAE was reported after testosterone undecanoate (severe urinary retention, unrelated to testosterone undecanoate). No participants discontinued due to an AE.

[0321] The mean changes in laboratory variables from pre-dose to 10 hours post-dose were small, with large standard deviations. Overall, there were no clinically relevant differences in laboratory results between DITEST and testosterone undecanoate or between the fed and fasted states of DITEST.

[0322] The mean changes in vital signs were small (mean changes with DITEST ranged from -2.1 to 4.3 mmHg for systolic blood pressure, -5.5 to -0.3 mmHg for diastolic blood pressure, and 2.8 to 10.5 bpm for heart rate, compared with mean changes of 12.8 mmHg, 1.5 mmHg, and 8.5 bpm, respectively, with testosterone undecanoate). No individual clinically significant abnormalities were noted in any vital sign.

[0323] In adult male participants with primary or secondary hypogonadism, serum testosterone levels were within the physiological range after administration of DITEST in both the fed and fasted states and after administration of testosterone undecanoate in the fed state. DITEST 120 mg significantly increased serum testosterone levels compared to testosterone undecanoate. max and AUC 0‐10 DITEST 200mg has a lower C than testosterone undecanoate. max and AUC 0‐10 The C of testosterone from DITEST was similar. max and AUC 0~10 There was no effect of food on DHT. DITEST was associated with lower serum concentrations of DHT compared with testosterone undecanoate. Measurement of capillary testosterone and salivary testosterone using the Mitra microsampling device showed very poor correlation with serum testosterone. There was no difference in the lipid fraction of testosterone between DITEST and testosterone undecanoate.

[0324] Figures 1-2 and Tables 3-5 show the results of administering DITEST at 120 mg and 200 mg doses to hypogonadal men. Using these results, dosing regimen modeling predicts the average total testosterone (Cavg) over 24 hours and the minimum (Cmin) and maximum (Cmax) levels over 24 hours required for a physician to prescribe a dosing regimen. Based on this, a 70 kg man taking 200 mg of DITEST every 12 hours with food would have a Cmin of 6.65, a Cavg of 15.00, and a Cmax of 29.30, which are acceptable levels for testosterone replacement and may allow dose titration by collecting samples approximately 4 hours after administration. DITEST was well tolerated when administered as a single dose of 120 mg and 200 mg, with no serious or severe adverse events. One participant experienced two "long QT syndrome" AEs, reportedly related to testosterone undecanoate and DITEST 120 mg, respectively. All other TEAEs were reported as unrelated to the study intervention. There were no safety signals from vital signs or clinical laboratory data. Therefore, it can be concluded that DITEST offers the potential for oral natural testosterone supplementation, with the advantage of not requiring food or a high-fat meal to aid absorption.

[0325] References 1.CJMALKIN,PJPUGH,THJONES and KSCHANNER,Testosterone for secondary prevention in men with ischaemic heart disease?,QJ Med 2003;96:521-529 2.Joseph M.Zmuda,MS,Paul D.Thompson,MD,Roberta Dickenson,BS,Linda L.Bausserman,PhD;Testosterone Decreases Lipoprotein(a) in Men;The American Journal of Cariology,Volume 77,Issue 14,June 1996,1244-1247.

Claims

1. (1) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and at least 16% w / w benzyl alcohol, or (2) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and at least 14% w / w benzyl alcohol 1. A pharmaceutical composition adapted for oral administration comprising:

2. The composition comprises: 10% w / w natural testosterone, at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and at least 16% w / w benzyl alcohol 2. The pharmaceutical composition of claim 1, consisting essentially of:

3. The composition comprises: 10% w / w natural testosterone, at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and at least 14% w / w benzyl alcohol 2. The pharmaceutical composition of claim 1, consisting essentially of:

4. 1. A pharmaceutical composition for use in treating hypogonadism in a human subject in need thereof, comprising: the treatment comprising orally administering the composition to the human subject at least once every 24 hours to normalize serum testosterone; the human subject is in a fasted state prior to administration of the composition; The composition comprises: (1) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and at least 16% w / w benzyl alcohol, or (2) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and at least 14% w / w benzyl alcohol A pharmaceutical composition comprising:

5. The composition comprises: 10% w / w natural testosterone, at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and at least 16% w / w benzyl alcohol 5. The composition of claim 4 consisting essentially of:

6. The composition comprises: 10% w / w natural testosterone, at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and at least 14% w / w benzyl alcohol 5. The composition of claim 4 consisting essentially of:

7. 7. The composition of any one of claims 4 to 6, wherein the human subject is administered the composition once, twice, three or four times in a 24 hour period, the administrations being separated temporally over the 24 hour period.

8. 8. The composition of any one of claims 4 to 7, wherein the human subject is administered a total native testosterone dose of 10 to 800 mg of native testosterone over a 24 hour period.

9. (i) two-thirds of the total native testosterone dose in a 24-hour period is administered between 00:00 and 12:00 hours, and one-third of the total native testosterone dose is administered between 12:00 and 24:00 hours; or (ii) 50% to 90% of the total native testosterone dose in a 24-hour period is administered between 00:00 and 12:00 hours, and 50% to 10% of the total native testosterone dose is administered between 12:00 and 24:00 hours; or (iii) 55% to 70% of the total native testosterone dose in a 24-hour period is administered between 00:00 and 12:00 hours, and 45% to 30% of the total native testosterone dose is administered between 12:00 and 24:00 hours; or (iv) 50% of the total native testosterone dose in a 24 hour period is administered between 00:00 and 12:00 hours, and 50% of the total native testosterone dose is administered between 12:00 and 24:00 hours. The composition according to any one of claims 4 to 8.

10. 7. The composition of any one of claims 4 to 6, wherein the hypogonadism is Turner's syndrome in a female human subject, and the treatment comprises orally administering the composition to the human female subject to increase serum testosterone.

11. 1. A first pharmaceutical composition for use in treating primary or secondary hypogonadism in a human subject in need thereof, comprising: the treatment comprising orally administering the first composition and the second composition to the human subject at least once every 24 hours to normalize serum testosterone; the human subject is in a fasted or fed state prior to administration of the first and second compositions; The first composition comprises: 2.5 to 7.5% w / w of natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, the second composition comprising: (1) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and at least 16% w / w benzyl alcohol, or (2) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and A first pharmaceutical composition comprising at least 14% w / w benzyl alcohol.

12. A second pharmaceutical composition for use in treating primary or secondary hypogonadism in a human subject in need thereof, comprising: the treatment comprising orally administering to the human subject a first composition and a second composition at least once every 24 hours to normalize serum testosterone; the human subject is in a fasted or fed state prior to administration of the first and second compositions; The first composition comprises: 2.5 to 7.5% w / w of natural testosterone, sesame oil, propylene glycol monolaurate, ethanol, and benzyl alcohol, the second composition comprising: (1) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and at least 16% w / w benzyl alcohol, or (2) 10% w / w natural testosterone; at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and A second pharmaceutical composition comprising at least 14% w / w benzyl alcohol.

13. The first composition comprises: 2.5 to 7.5% w / w of natural testosterone, at least 40% w / w sesame oil, at least 30% w / w of propylene glycol monolaurate, at least 5% w / w ethanol, and 13. The first composition of claim 11 or the second composition of claim 12, comprising at least 15% w / w benzyl alcohol.

14. the second composition comprising: 10% w / w natural testosterone, at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 9% w / w ethanol, and 14. The first composition of claim 11 or 13 or the second composition of claim 12 or 13, consisting essentially of at least 16% w / w benzyl alcohol.

15. the second composition comprising: 10% w / w natural testosterone, at least 36% w / w of sesame oil, at least 28% w / w of propylene glycol monolaurate, at least 11% w / w ethanol, and 14. The first composition of claim 11 or 13 or the second composition of claim 12 or 13, consisting essentially of at least 14% w / w benzyl alcohol.

16. The first composition of any one of claims 11 and 13 to 15 or the second composition of any one of claims 12 to 15, wherein the human subject is administered the first composition and the second composition simultaneously or temporally separated over the 24 hour period.

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