Testosterone ester dodecanoate compositions and methods

Abstract

Disclosed are methods and oral compositions for treating a variety of end-stage diseases, such as end-stage kidney disease, chronic kidney disease, cirrhosis, chronic liver failure, end-stage liver disease, cancer, congestive heart failure, pulmonary fibrosis, chronic obstructive pulmonary disease. In the embodiment of the invention, the composition comprises testosterone ester dodecanoate.

Description

[0001] United States Patent and Trademark Office International patent applications Composition and method of testosterone dodecanoate Inventor M.V. Patel K. Papencohn J. Ogler N. Chidambaram B.J. Bruno July 18, 2024 Volume number LPC-011PCT-1

[0002] Cross-reference to related applications This PCT patent application claims the benefit of co-pending U.S. Provisional Patent Application No. 63 / 516,015, filed July 27, 2023, and U.S. Non-Provisional Patent Application No. 18 / 654,926, filed May 3, 2024, pursuant to PCT Rule 4.10, the entire contents of which are expressly incorporated herein by reference. Technical Field

[0003] This disclosure relates to compositions, dosage forms, and regimens, as well as methods of treating subjects requiring testosterone dodecanoate (TD). Therefore, this disclosure is relevant to the fields of chemistry, pharmaceutical science, medicine, and other health sciences. Background Technology

[0004] Testosterone dodecanoate (also known as testosterone laurate, testosterone duodecanoate, or TD) is an ester of testosterone, as shown. Testosterone is the primary sex hormone and anabolic steroid in men. End-stage disease (ESD) is a general term for any condition that may lead to death within a short period of time. ESD can include conditions such as end-stage renal disease (ESRD), chronic kidney disease (CKD), cirrhosis, chronic liver failure, end-stage liver disease (ESLD), cancer, congestive heart failure (CHF), pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Endocrine disorders are commonly associated with ESD. Insufficient testosterone levels in men, especially those with ESD, can lead to abnormalities including hypogonadism, sarcopenia, weakness, increased hospitalizations, poor quality of life, low survival rates, and increased mortality. Exogenous hormone therapy can be used to treat men to combat this endocrine dysfunction. Because testosterone has low oral bioavailability, the most commonly used form of testosterone in testosterone therapy is testosterone ester.

[0005] Various treatments and compositions thereof related to various liver diseases are known in the art. These methods and compositions are disclosed in the following U.S. patent applications, all entitled "Liver Disease," which are incorporated herein by reference in their entirety: 20200022991, entitled "Liver Disease," filed August 28, 2019 and published January 23, 2020; 20200155570, entitled "Liver Disease," filed July 19, 2019 and published May 21, 2020; 2020038399, entitled "Liver Disease," filed August 25, 2020 and published December 10, 2020; 20200390785, entitled "Liver Disease," filed August 25, 2020 and published December 17, 2020; and 63 / 136,185, entitled "Method and Composition for Treating Non-Cirrhotic..." "Nash" was submitted on January 11, 2021.

[0006] Cirrhosis is an essential liver disease (ESD), and liver transplantation is its only cure (see the Wikipedia entry for "Cirrhosis"). Cirrhosis is typically caused by a variety of factors, such as alcohol, non-alcoholic fatty liver disease (NAFLD - see the Wikipedia entry for "NAFLD"), drug abuse, chronic viral hepatitis, and autoimmune diseases. Cirrhosis is one of the leading causes of death in the United States. The number of liver disease cases is rapidly increasing in the United States and globally, with an estimated prevalence of between 6 and 7 million cases of chronic liver disease in the U.S. Decompensated cirrhosis is estimated to affect more than 500,000 Americans, with men being twice as likely as women to be affected, and causing approximately 45,000 deaths annually. The only cure, liver transplantation, has a high economic burden (approximately $878,500 per transplant).

[0007] In patients with advanced cirrhosis, the hypothalamic-pituitary-gonadal axis undergoes significant alterations, leading to endocrine dysfunction. Compared to subjects with normal liver function, men with chronic non-alcoholic liver disease have decreased levels of total and free testosterone, and elevated levels of sex hormone-binding globulin (SHBG). Cirrhosis patients experience impaired hepatocyte function due to protein homeostasis disturbances and reduced albumin synthesis. Cirrhosis is an inflammatory disease state characterized by elevated inflammatory markers, increased intestinal permeability (leakage), worsening portal hypertension, and abnormal serum alkaline phosphatase (ALP) levels, indicating impaired liver function. Bone health impairment, such as osteopenia and osteoporosis, is also extremely common in patients with cirrhosis.

[0008] Sarcopenia (loss of muscle mass / area) has been observed in 60-80% of men with cirrhosis, and frailty (a state of reduced physiological reserves) is associated with an increased risk of hospitalization and liver dysfunction events, a doubling of waiting list mortality, and poor post-transplant outcomes (see the Wikipedia entry on "Sarcopenia"). Furthermore, myosteatosis (excessive fat in muscle tissue—see the Wikipedia entry on "myosteatosis") has been shown to be associated with decreased muscle mass, strength, and mobility, elevated MELD (Model for End-Stage Liver Disease) scores (see the Wikipedia entry on "Model for End-Stage Liver Disease"), shortened median survival, and increased mortality in patients with cirrhosis.

[0009] Hepatic encephalopathy (HE - see the Wikipedia entry for "Hepatic encephalopathy") occurs frequently in patients with cirrhosis because their liver disease is already in its end stage. Approximately 30-50% of individuals with cirrhosis have overt HE (symptomatic). It has been reported that approximately 200,000 patients in the United States have overt HE. Clinically, overt HE is significantly more common in cirrhotic patients with muscle wasting, decreased muscle strength, or endocrine dysfunction. During the course of cirrhosis, approximately 30% to 40% of patients will develop overt hepatic encephalopathy (neurological and neuropsychiatric abnormalities detected through bedside examination and testing) at some stage. In relapsing HE, patients experience episodes of neurological dysfunction that can last from hours to days, followed by remission to baseline neurological function levels within 6 months.

[0010] HE is an important decompensated event, a metabolically induced, potentially reversible brain dysfunction leading to “brain fog” associated with elevated systemic ammonia levels. In patients with cirrhosis, myotoxic ammonia accumulates due to impaired ability of the liver (major organ) and muscles (minor organ) to clear ammonia from the systemic circulation. Furthermore, HE is a known risk factor for hospitalization, accidental trauma, and death. Additionally, anemia is a predictor of HE in liver transplant candidates with cirrhosis. Potential risk factors for HE include a history of mild or overt HE, sarcopenia, hyponatremia (see the Wikipedia entry on hyponatremia), epilepsy (see the Wikipedia entry on epilepsy), type 2 diabetes, elevated creatinine and bilirubin levels, and decreased albumin levels.

[0011] Rifaximin is a semi-synthetic, non-systemic antibiotic currently approved for reducing the risk of relapse in overt hepatic encephalopathy (HE). It is marketed as XIFAXAN® 550 mg tablets for oral administration twice daily. Reports indicate that patients with a history of HE have an average rifaximin exposure (AUC) approximately 12 times higher than observed in healthy subjects after taking XIFAXAN®.

[0012] Currently, testosterone undecanoate (TU) is the only FDA-approved orally administered testosterone ester. Other orally approved products including TU include (e.g., JATENZO®, KYZATREX). TM Both JATENZO® and KYZATREX carry a black box warning from the FDA, indicating that these products may increase blood pressure. TM Prescribing TLANDO® may increase the risk of adverse cardiovascular events. It has been reported that, based on ambulatory blood pressure monitoring (ABPM), oral TU products cause a range of systolic BP increases from 1.7 mmHg to 5.4 mmHg, while the average diastolic BP, based on ABPM, ranges from 1.2 mmHg to 3.2 mmHg.

[0013] Furthermore, these oral approved products, including TU, tend to lower high-density lipoprotein (HDL) cholesterol levels in patients receiving testosterone-based therapy (TRT). In patients treated with JATENZO® and TLANDO®, the mean reduction in HDL-cholesterol was found to be 6.9 mg / dL and 5.7 mg / dL, respectively. For example, after a period of testosterone treatment, 29% of JATENZO® treatment subjects and 22% of TLANDO® treatment subjects experienced a shift in HDL levels from baseline (normal HDL cholesterol levels) to below the normal range.

[0014] In addition, benign prostatic hyperplasia (BPH) and worsening of BPH signs and symptoms are known in patients receiving testosterone therapy. Clinical studies have shown that elevated prostate-specific antigen (PSA) levels (defined as serum PSA concentration >4 ng / mL), prostatic induration (see Wikipedia entry for "induration"), and prostate cancer are some of the most frequently reported adverse reactions, occurring in approximately 4.6%, 1.3%, and 1.3% of patients receiving injectable TU compositions, respectively. Prostate infections and prostate abnormalities have also been reported with TU injections—see the FDA-approved AVEED® label.

[0015] Therefore, the risks of cardiovascular disease, benign prostatic hyperplasia (BPH), and prostate cancer are the main safety concerns for transurethral resection of the prostate (TRT). Lauric acid (LA – see the Wikipedia entry for "lauric acid") has been reported to be associated with beneficial effects on the cardiovascular system because it increases HDL levels and reduces blood pressure and heart rate in both normotensive and hypertensive rats. Furthermore, studies have shown that LA can prevent testosterone-induced benign prostatic hyperplasia in rats.

[0016] Reports indicate that the use of rifaximin, the current standard-of-care treatment for hepatic cirrhosis (HE), has resulted in frequent adverse events (≥10%) in HE-affected subjects, including peripheral edema, nausea, dizziness, fatigue, and ascites. Elevated levels of alanine aminotransferase (ALT), a liver injury marker, have also been observed with oral rifaximin. Furthermore, concerns remain regarding long-term rifaximin use, its potential to alter gut microbiota and lead to resistance, and its possible inhibition of P-glycoprotein transporters. Given these limitations, there is an urgent need for an oral therapy that overcomes some of these limitations in the treatment and management of cirrhosis, an end-stage disease.

[0017] We believe that oral testosterone therapy may provide a multimodal basis for the treatment of end-stage diseases such as cirrhosis. However, the current efficacy and approval of oral TUs are limited to those approved for use in subjects with hypogonadism. Due to limitations in their pharmacokinetics and pharmacodynamics, including risks associated with cardiovascular and prostate health, TUs are considered a suboptimal testosterone therapy for the treatment / management of end-stage diseases such as cirrhosis.

[0018] There remains an unmet need in testosterone therapy (methods and compositions) for a treatment option with a more favorable benefit-risk profile to treat / manage end-stage disease with a lower risk of adverse events compared to other oral testosterone therapies with acceptable efficacy. TD esters exhibit unique physicochemical and biopharmaceutical properties compared to other T esters.

[0019] We unexpectedly discovered that, in the treatment / management of end-stage diseases such as cirrhosis, oral compositions of TD and their delivery methods produce unique pharmacokinetic and pharmacodynamic (PD) characteristics compared to oral TU, regardless of the patient's gonadal status. The oral bioavailability of TD is at least 20% higher than that of other testosterone homologs (such as TU and testosterone tridecanoate (TT)). Summary of the Invention

[0020] This disclosure covers compositions, oral dosage forms, and regimens including TD and related methods. The compositions and oral dosage forms may be formulated to include a therapeutically effective amount of TD and a variety of pharmaceutically acceptable additives. On one hand, when orally administered to a subject, the pharmaceutically acceptable additives in the composition or dosage form can provide sufficient amounts of TD to treat ESDs such as ESRD, CKD, cirrhosis, chronic liver failure, ESLD, cancer, CHF, pulmonary fibrosis, COPD, particularly hypogonadism, sarcopenia, asthenia, increased hospitalizations, poor quality of life, low survival, and increased mortality. On the other hand, the composition or dosage form may include a rapidly releasing, dissolved, or solubilized form of TD that, when orally administered to a subject, can enhance, improve, or maximize the bioavailability of TD (e.g., C). max (and / or AUC). For example, on the one hand, when administered orally to a subject using the compositions and methods of the present invention, the in vitro release, in vivo solubilization, and absorption of TD are all increased. On the other hand, when administered orally to a subject using the compositions and methods of the present invention, the absorption of TD is relatively increased compared to when administered orally to a subject using a composition comprising an equal amount of non-testosterone dodecanoate ester composition.

[0021] In a first embodiment, the present invention includes a method of administering (preferably orally) to a subject a disclosed pharmaceutical composition comprising TD (TDPC) or prepared therefrom, wherein, compared to the subject's pre-TDPC administration state or placebo administration, the method prevents or improves at least one of the subject's cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay.

[0022] The administration may also result in the subject having at least one of the following: decreased SHBG levels, increased albumin levels, reduced weakness, reduced sarcopenia, reduced intramuscular fat deposition, reduced fat mass, decreased systemic ammonia levels, reduced portal hypertension, reduced abnormally high levels of at least one of ALT, AST, GGT, and ALP, increased lean body mass, increased free T, and increased total TC. avg An increase of at least 100 ng / dL, elevated hematocrit levels, elevated hemoglobin levels, and decreased inflammatory markers.

[0023] During the administration, the subject may have liver fibrosis and at least one of the following: MELD score of at least 12, at least one decompensated event, BMI > 20, L3 musculoskeletal index < 55 cm. 2 / m 2The following are considered abnormal indicators: liver frailty index >3, ALT / AST ratio approximately 1, AST >40 U / L, abnormal ALT levels, and abnormal ALP levels. The L3 musculoskeletal index, also known as "L3 SMI," is defined as the cross-sectional area of ​​muscle tissue at the L3 level (see the NCBI / NLM / NIH website, article titled "Correlation between L3 skeletal muscle index and prognosis of patients with stage IV gastric cancer," also accessible at: https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC8576239 / #:~:text=L3%20SMI%20%3D%20cross%2Dsectional%20area,status%20of%20patients%20with%20GC).

[0024] During the administration, the subject may have at least one of the following: disordered protein homeostasis, abnormally high SHBG levels, and abnormally low albumin levels, and may require testosterone intervention based on at least one of the following: morning baseline testosterone levels of <400 ng / dL, <350 ng / dL, <300 ng / dL, and <250 ng / dL.

[0025] During the administration of this drug, cardiovascular risk may include the risk of adverse changes in at least one of SBP, DBP, HDL levels, ascites occurrence, homocysteine ​​levels, and myocardial mass or strength. Deterioration of cardiovascular health may include adverse changes in at least one of SBP, DBP, HDL, ascites occurrence, homocysteine ​​levels, cardiac reactive protein levels, and myocardial mass or strength, and improvement of cardiovascular health may include favorable changes. Deterioration of prostate health may include adverse changes in at least one of prostate size, prostate weight, and BPH symptoms, and improvement of prostate health may include favorable changes. Deterioration of muscle health may include adverse changes in at least one of muscle mass, muscle strength, muscle function, and myotoxicity, and improvement of muscle health may include favorable changes in these aspects. Deterioration of CNS health may include adverse changes in at least one of depression, seizures, cognition, risk of HE occurrence, risk of recurrence of overt HE, breakthrough HE episode, HE-related hospitalization, duration before the onset of overt HE episode, reversal of HE recurrence, occurrence of asterixis, mental state, intellectual function, psychometric test results, and neurophysiological test results, and improvement of CNS health may include favorable changes in these aspects. A decline in GI health may include at least one of the following adverse changes: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH (also known as MASH—see the Wikipedia entry for "Metabolic dysfunction-associated steatotic liver disease"), NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC, and PBC, and an improvement in GI health may include its favorable changes.

[0026] In the application, adverse changes in SBP may include an increase in SBP of at least 1.7 mmHg, and favorable changes in SBP may include a decrease in SBP of at least 1 mmHg.

[0027] In the application of this treatment, the condition may include at least one of the following: cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, advanced liver disease, chronic liver disease, end-stage lung disease, chronic kidney disease, end-stage renal disease, end-stage musculoskeletal system disease, end-stage cardiovascular disease, end-stage hematologic disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage reproductive organ disease, end-stage central nervous system disease, liver fibrosis, liver inflammation, hepatic steatosis, hepatic encephalopathy (HE), relapse of overt HE. NASH, NAFLD, pre- / post-liver transplant, decompensated cirrhosis, PBC, PSC, ILD, pneumonia, IPF, muscle loss, cachexia, sarcopenia, asthenia, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral obesity, obesity, impaired wound healing, lumbar disc herniation, intramuscular fat deposition syndrome, cancer, CHF, pulmonary fibrosis, COPD, and hereditary angioedema.

[0028] In the application, the pharmaceutical composition may include at least one additive, which may include at least one lipophilic additive and / or at least one hydrophilic additive. The at least one lipophilic additive may include at least one of a surfactant and a non-surfactant, and the at least one hydrophilic additive may include at least one of a surfactant and a non-surfactant.

[0029] In the application, the pharmaceutical composition may include at least one carrier, which may include at least one of a lipophilic carrier and a hydrophilic carrier. The lipophilic carrier may include at least one of a lipophilic surfactant and a lipophilic additive, and the hydrophilic carrier may include at least one of a hydrophilic surfactant and a hydrophilic additive. The lipophilic carrier may include at least one of fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherols, tocotrienols or their derivatives, tocopherol succinate, tocopherol acetate, and fish oil, and wherein the hydrophilic carrier includes at least one of polyoxyethylene hydrogenated vegetable oil, polyoxyethylene vegetable oil, polyethylene glycol fatty acid esters, mixtures of polyethylene glycol fatty acid monoglycerides, mixtures of polyethylene glycol fatty acid diglycerides, polysorbate esters, polyethylene glycol derivatives of tocopherol, alcohols, and alcohol derivatives. The fatty acids may include at least one of oleic acid, lauric acid, stearic acid, and their derivatives, and the vegetable oils include at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and their derivatives, and the monoglyceride derivatives include at least one of monolinoleic acid glyceride and sorbitol monofatty acid, and the diglyceride derivatives include glyceryl palmitate stearate, and the polyoxyethylene hydrogenated vegetable oils include PEG-hydrogenated castor oil, and the alcohols include at least one of ethanol and benzyl alcohol; and the alcohol derivatives include benzyl benzoate.

[0030] In the application, the pharmaceutical composition may include at least one of tablets, capsules, pouches, gel capsules, suspensions, solutions, beverages, gels, syrups, dispersions, emulsions, sprays, lozenges, microemulsions, nanoemulsions, elixirs, pastes, powders, and granules.

[0031] In the administration, administration may include a dosing regimen, which may include at least one of a QD regimen and a BID regimen. The dosing regimen may include at least one of a titration regimen and a non-titeration regimen. Administration may include at least one of a total daily dose of TD of about 200 mg to about 1000 mg, about 350 mg to about 850 mg, and about 500 mg to about 700 mg. TDPC dosage forms may include single-dose unit dosage forms, two-dose unit dosage forms, three-dose unit dosage forms, and four-dose unit dosage forms.

[0032] In the application described, the pharmaceutical composition may include at least one of the following: adsorbent, anti-adhesion agent, anticoagulant, defoamer, antioxidant, anti-caking colorant, antistatic agent, binder, bile acid, buffer, filler, chelating agent, coagulant, colorant, cosolvent, opaque agent, coagulant, coolant, cryoprotectant, diluent, dehumidifier, drying agent, desensitizer, disintegrant, dispersant, enzyme inhibitor, flow aid, filler, humectant, hyperdisintegrant, gum, mucilage, hydrogen bonding agent, enzyme, flavoring agent, humectant, moisturizer, lubricant, ion exchange resin, lubricant, plasticizer, pH adjuster, preservative, curing agent (coagulant), solvent, solubilizer, spreading agent, sweetener, stabilizer, surface area enhancer, suspending agent, thickener, viscous agent, wax, and mixtures thereof. As non-limiting examples, anti-adhesion agents (anti-sticking agents, flow aids, flow promoters, lubricants) include: talc, magnesium stearate, fumed silica (Carbsil, Aerosil), micronized silica (Syloid No. FP 244, Grace USA), polyethylene glycol, surfactants, waxes, stearic acid, stearates, stearic acid derivatives, starch, hydrogenated vegetable oil, sodium benzoate, sodium acetate, leucine, PEG-4000, and magnesium dodecyl sulfate. As non-limiting examples, antioxidants include BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbate palmitate, 4-hydroxymethyl-2,6-di-tert-butylphenol, and tocopherol. Binders (adhesives), which are agents that impart cohesiveness to powdered materials through particle-to-particle bonding, include, as non-limiting examples: matrix binders (dry starch, dry sugar), film binders (PVP, starch paste, cellulose, bentonite, sucrose), and chemical binders (polymeric cellulose derivatives, such as carboxymethyl cellulose, HPC and HPNC; syrups; corn syrup; water-soluble polysaccharides, such as gum arabic, tragacanth, guar gum and alginate; gelatin, gelatin hydrolysate; agar; sucrose; glucose; and non-cellulose binders, such as PVP, PEG, vinylpyrrolidone copolymers, pregelatinized starch, sorbitol and glucose).Buffers include acids and bases, where the acids are pharmaceutically acceptable, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkyl sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid, and the bases are pharmaceutically acceptable, such as amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, and carbonic acid. Sodium hydrogen, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, or pharmaceutically acceptable cations salts of the following acids: acetic acid, acrylic acid, adipic acid, alginic acid, alkyl sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. As a non-limiting example, chelating agents include EDTA and EDTA salts. As non-limiting examples, colorants or opacifiers include titanium dioxide, food colorings, lakes, natural plant colorants, iron oxide, silicates, sulfates, magnesium hydroxide, and aluminum hydroxide. As non-limiting examples, diluents or fillers include lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starch, directly compressible starch, microcrystalline cellulose, cellulose, sorbitol, sucrose, sucrose-based materials, calcium sulfate, dicalcium phosphate, and glucose. As non-limiting examples, disintegrants and hyperdistegrants include croscarmellose sodium, starch, starch derivatives, clay, gums, cellulose, cellulose derivatives, alginate, croscarmellose, sodium starch glycolate, and microcrystalline cellulose. As non-limiting examples, flavoring agents or desensitizers include spray-dried flavorings, essential oils, and ethyl vanillin. As non-limiting examples, plasticizers include polyethylene glycol, citrates (e.g., triethyl citrate, tributyl citrate, triethyl acetate), acetylated monoglycerides, glycerol, triacetyl glycerol, propylene glycol, phthalates (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol, and dibutyl sebacate. As non-limiting examples, preservatives include ascorbic acid, boric acid, sorbic acid, benzoic acid and its salts, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds. As non-limiting examples, solvents include alcohols, ketones, esters, chlorinated hydrocarbons, and water.As non-limiting examples, sweeteners include natural sweeteners such as maltose, sucrose, glucose, sorbitol, glycerol, and dextrin, as well as artificial sweeteners such as aspartame, saccharin, and saccharin salt. As non-limiting examples, thickeners (viscosity modifiers, thickening agents) include sugars, polyvinylpyrrolidone, cellulose, polymers, high molecular weight polyethylene glycol (e.g., PEG 8000), and alginate. As non-limiting examples, additives also include proteins (e.g., collagen, gelatin, corn protein, gluten, mussel protein, lipoprotein); carbohydrates (e.g., alginate, carrageenan, cellulose derivatives, pectin, starch, chitosan); gums (e.g., xanthan gum, gum arabic); cetacean; natural or synthetic waxes; carnauba wax. Wax), fatty acids (e.g., stearic acid, hydroxystearic acid), fatty alcohols; sugars; shellac, such as sugar-based (e.g., lactose, sucrose, glucose) or starch-based shellac; polysaccharide-based shellac (e.g., maltodextrin and maltodextrin derivatives, dextrin, cyclodextrin and cyclodextrin derivatives); cellulose-based shellac (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, cellulose acetate butyrate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose phthalate); inorganic substances, such as dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc, and titanium dioxide; polyols, such as mannitol, xylitol, and sorbitol; polyethylene glycol esters; and polymers, such as alginate, poly(lactide-co-lactide), gelatin, cross-linked gelatin, and agar.

[0033] In a second embodiment, the invention includes a (preferably oral) method of administering to a subject a disclosed pharmaceutical composition comprising TD (TDPC) or prepared therefrom, which, compared to a substantially equivalent administration of a pharmaceutical composition comprising at least one non-TD testosterone ester and substantially free of TD (NDPC), results in a lower deterioration or a greater improvement in at least one of the subject's cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay.

[0034] The administration may also result in the subject having at least one of the following: a lower reduction in HDL level relative to HDL levels caused by substantially equivalent NDPC administration, increased bacterial inhibitory activity, a reduction in HbA1c level by at least 0.2 units, a decrease in SBP, and a decrease in DBP.

[0035] During the administration, the subject may have liver fibrosis and at least one of the following: a MELD score of at least 12, at least one decompensated event, a BMI > 20, and an L3 musculoskeletal index < 55 cm. 2 / m 2 The liver weakness index is >3, the ALT / AST ratio is approximately 1, AST is >40 U / L, there are abnormal ALT levels, and abnormal ALP levels.

[0036] During the administration, the subject may have at least one of the following: disordered protein homeostasis, abnormally high SHBG levels, and abnormally low albumin levels, and may require testosterone intervention based on at least one of the following: morning baseline testosterone levels of <400 ng / dL, <350 ng / dL, <300 ng / dL, and <250 ng / dL.

[0037] In the administration of this product, cardiovascular risk may include the risk of adverse changes in at least one of SBP, DBP, HDL levels, ascites occurrence, homocysteine ​​levels, and myocardial mass or strength. Deterioration of cardiovascular health may include adverse changes in at least one of SBP, DBP, HDL, ascites occurrence, homocysteine ​​levels, cardiac reactive protein levels, and myocardial mass or strength, and improvement of cardiovascular health may include favorable changes. Deterioration of prostate health may include adverse changes in at least one of prostate size, prostate weight, and BPH symptoms, and improvement of prostate health may include favorable changes. Deterioration of muscle health may include adverse changes in at least one of muscle mass, muscle strength, muscle function, and myotoxicity, and improvement of muscle health may include favorable changes in these aspects. Deterioration of CNS health may include adverse changes in at least one of the following: depression, seizures, cognition, risk of HE occurrence, risk of recurrence of overt HE, breakthrough HE episode, HE-related hospitalization, duration before the onset of overt HE episode, reversal of HE recurrence, occurrence of asterixis, mental state, intellectual function, psychometric test results, and neurophysiological test results, and improvement of CNS health may include favorable changes in these aspects. A deterioration in GI health may include at least one of the following adverse changes: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH, NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC, and PBC, and an improvement in GI health may include its favorable changes.

[0038] In the application, adverse changes in SBP may include an increase in SBP of at least 1.7 mmHg, and favorable changes in SBP may include a decrease in SBP of at least 1 mmHg.

[0039] In the application, the condition may include at least one of the following: cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, advanced liver disease, chronic liver disease, end-stage lung disease, chronic kidney disease, end-stage renal disease, end-stage musculoskeletal system disease, end-stage cardiovascular disease, end-stage hematologic disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage reproductive organ disease, end-stage central nervous system disease, liver fibrosis, liver inflammation, hepatic steatosis, hepatic encephalopathy (HE), and relapse of dominant HE. NASH, NAFLD, pre- / post-liver transplant, decompensated cirrhosis, PBC, PSC, ILD, pneumonia, IPF, muscle loss, cachexia, sarcopenia, asthenia, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral obesity, obesity, impaired wound healing, lumbar disc herniation, intramuscular fat deposition syndrome, cancer, CHF, pulmonary fibrosis, COPD, and hereditary angioedema.

[0040] In the administration, the pharmaceutical composition may include at least one additive, which may be a lipophilic additive or a hydrophilic additive. The lipophilic additive may include at least one of a surfactant and a non-surfactant, and the hydrophilic additive may include at least one of a surfactant and a non-surfactant.

[0041] In the application, the pharmaceutical composition may include at least one carrier, which may include at least one of a lipophilic carrier and a hydrophilic carrier. The lipophilic carrier may include at least one of a lipophilic surfactant and a lipophilic additive, and the hydrophilic carrier may include at least one of a hydrophilic surfactant and a hydrophilic additive. The lipophilic carrier may include at least one of fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherols, tocopherol succinate, tocopherol acetate, and fish oil, and wherein the hydrophilic carrier includes at least one of polyoxyethylene hydrogenated vegetable oil, polyoxyethylene vegetable oil, polyethylene glycol fatty acid esters, mixtures of polyethylene glycol fatty acid monoglycerides, mixtures of polyethylene glycol fatty acid diglycerides, polysorbate esters, polyethylene glycol derivatives of tocopherol, alcohols, and alcohol derivatives. The fatty acids may include at least one of oleic acid, lauric acid, stearic acid, and their derivatives, and the vegetable oils include at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and their derivatives, and the monoglyceride derivatives include at least one of monolinoleic acid glyceride and sorbitol monofatty acid, and the diglyceride derivatives include glyceryl stearate palmitate, and the polyoxyethylene hydrogenated vegetable oils include PEG-hydrogenated castor oil, and the alcohols include at least one of ethanol and benzyl alcohol; and the alcohol derivatives include benzyl benzoate.

[0042] In the application, the pharmaceutical composition may include at least one of tablets, capsules, pouches, gel capsules, suspensions, solutions, beverages, gels, syrups, dispersions, emulsions, sprays, lozenges, microemulsions, nanoemulsions, elixirs, pastes, powders, and granules.

[0043] In the administration, administration may include a dosing regimen, which may include at least one of a QD regimen and a BID regimen. The dosing regimen may include at least one of a titration regimen and a non-titeration regimen. Administration may include at least one of a total daily dose of TD of about 200 mg to about 1000 mg, about 350 mg to about 850 mg, and about 500 mg to about 700 mg. TDPC dosage forms may include single-dose unit dosage forms, two-dose unit dosage forms, three-dose unit dosage forms, and four-dose unit dosage forms.

[0044] In a third embodiment, the invention includes a (preferably orally) method of treating a subject's condition, comprising administering TDPC to the subject, wherein the TDPC comprises or is prepared from at least one lipophilic additive, said at least one lipophilic additive comprising at least one of fatty acids, fatty acid derivatives and combinations thereof, and wherein, compared to at least one of the subject's pre-TDPC administration state and placebo administration, the administration results in no worsening of at least one of the subject's cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health and median hospitalization duration, or improves at least one of the subject's cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health and median hospitalization duration.

[0045] The administration may also result in the subject having at least one of the following: decreased SHBG levels, increased albumin levels, reduced weakness, reduced sarcopenia, reduced intramuscular fat deposition, reduced fat mass, decreased systemic ammonia levels, reduced portal hypertension, reduced abnormally high levels of at least one of ALT, AST, GGT, and ALP, increased lean body mass, increased free T, and increased total TC. avg An increase of at least 100 ng / dL, elevated hematocrit levels, elevated hemoglobin levels, and decreased inflammatory markers.

[0046] In the application, the pharmaceutical composition may include at least one of oleic acid or a derivative thereof, lauric acid or a derivative thereof, stearic acid or a derivative thereof, and combinations thereof.

[0047] In the application, TDPC comprises at least one of a w / w ratio of TD to a lipophilic additive of at least about 0.38, about 0.52, and about 0.60. In the application, TDPC comprises at least one of a w / w ratio of TD to a hydrophilic additive of at least about 4.0, about 5.4, and about 6.5.

[0048] During the administration, the subject may have liver fibrosis and at least one of the following: a MELD score of at least 12, at least one decompensated event, a BMI > 20, and an L3 musculoskeletal index < 55 cm. 2 / m 2 The liver weakness index is >3, the ALT / AST ratio is approximately 1, AST is >40 U / L, there are abnormal ALT and ALP levels.

[0049] During the administration, the subject may have at least one of the following: disordered protein homeostasis, abnormally high SHBG levels, and abnormally low albumin levels, and may require testosterone intervention based on at least one of the following: morning baseline testosterone levels of <400 ng / dL, <350 ng / dL, <300 ng / dL, and <250 ng / dL.

[0050] In the administration of this product, cardiovascular risk may include the risk of adverse changes in at least one of SBP, DBP, HDL levels, ascites occurrence, homocysteine ​​levels, and myocardial mass or strength. Deterioration of cardiovascular health may include adverse changes in at least one of SBP, DBP, HDL, ascites occurrence, homocysteine ​​levels, cardiac reactive protein levels, and myocardial mass or strength, and improvement of cardiovascular health may include favorable changes. Deterioration of prostate health may include adverse changes in at least one of prostate size, prostate weight, and BPH symptoms, and improvement of prostate health may include favorable changes. Deterioration of muscle health may include adverse changes in at least one of muscle mass, muscle strength, muscle function, and myotoxicity, and improvement of muscle health may include favorable changes in these aspects. Deterioration of CNS health may include adverse changes in at least one of the following: depression, seizures, cognition, risk of HE occurrence, risk of recurrence of overt HE, breakthrough HE episode, HE-related hospitalization, duration before the onset of overt HE episode, reversal of HE recurrence, occurrence of asterixis, mental state, intellectual function, psychometric test results, and neurophysiological test results, and improvement of CNS health may include favorable changes in these aspects. A deterioration in GI health may include at least one of the following adverse changes: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH, NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC, and PBC, and an improvement in GI health may include its favorable changes.

[0051] In the application, adverse changes in SBP may include an increase in SBP of at least 1.7 mmHg, and favorable changes in SBP may include a decrease in SBP of at least 1 mmHg.

[0052] In the application, the condition may include at least one of the following: cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, advanced liver disease, chronic liver disease, end-stage lung disease, chronic kidney disease, end-stage renal disease, end-stage musculoskeletal system disease, end-stage cardiovascular disease, end-stage hematologic disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage reproductive organ disease, end-stage central nervous system disease, liver fibrosis, liver inflammation, hepatic steatosis, hepatic encephalopathy (HE), and relapse of dominant HE. NASH, NAFLD, pre- / post-liver transplant, decompensated cirrhosis, PBC, PSC, ILD, pneumonia, IPF, muscle loss, cachexia, sarcopenia, asthenia, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral obesity, obesity, impaired wound healing, lumbar disc herniation, intramuscular fat deposition syndrome, cancer, CHF, pulmonary fibrosis, COPD, and hereditary angioedema.

[0053] In the administration, the pharmaceutical composition may include at least one additive, which may be a lipophilic additive or a hydrophilic additive. The lipophilic additive may include at least one of a surfactant and a non-surfactant, and the hydrophilic additive may include at least one of a surfactant and a non-surfactant.

[0054] In the application, the pharmaceutical composition may include at least one carrier, which may include at least one of a lipophilic carrier and a hydrophilic carrier. The lipophilic carrier may include at least one of a lipophilic surfactant and a lipophilic additive, and the hydrophilic carrier may include at least one of a hydrophilic surfactant and a hydrophilic additive. The lipophilic carrier may include at least one of fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherol, tocopherol succinate, tocopherol acetate, and fish oil, and wherein the hydrophilic carrier includes at least one of polyoxyethylene hydrogenated vegetable oil, polyoxyethylene vegetable oil, polyethylene glycol fatty acid esters, mixtures of polyethylene glycol fatty acid monoglycerides, mixtures of polyethylene glycol fatty acid diglycerides, polysorbate esters, polyethylene glycol derivatives of tocopherol, alcohols, and alcohol derivatives. The fatty acids may include at least one of oleic acid, lauric acid, stearic acid, and their derivatives, and the vegetable oils include at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and their derivatives, and the monoglyceride derivatives include at least one of monolinoleic acid glyceride and sorbitol monofatty acid ester, and the diglyceride derivatives include glyceryl stearate palmitate, and the polyoxyethylene hydrogenated vegetable oils include PEG-hydrogenated castor oil, and the alcohols include at least one of ethanol and benzyl alcohol; and the alcohol derivatives include benzyl benzoate.

[0055] In the application, the pharmaceutical composition may include at least one of tablets, capsules, pouches, gel capsules, suspensions, solutions, beverages, gels, syrups, dispersions, emulsions, sprays, lozenges, microemulsions, nanoemulsions, elixirs, pastes, powders, and granules.

[0056] In the administration, the dosing may include a dosing regimen, which may include at least one of a QD regimen and a BID regimen. The dosing regimen may include at least one of a titration regimen and a non-titeration regimen. Administration may include at least one of a total daily dose of TD of about 200 mg to about 1000 mg, about 350 mg to about 850 mg, and about 500 mg to about 700 mg. The dosage form of TDPC may include a single-dose unit dosage form, a two-dose unit dosage form, a three-dose unit dosage form, and a four-dose unit dosage form.

[0057] In a fourth embodiment, the invention includes a (preferably orally) method of treating a subject's condition, comprising administering TDPC to the subject, wherein the TDPC comprises or is prepared from at least one lipophilic additive, said at least one lipophilic additive comprising at least one of fatty acids, fatty acid derivatives and combinations thereof, and wherein, compared to a substantially equivalent administration of a pharmaceutical composition comprising at least one non-TD testosterone ester and substantially free of TD (NDPC), the administration results in a lower deterioration in at least one of the subject's cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health and median length of hospital stay, and a greater improvement in at least one of the subject's cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health and median length of hospital stay.

[0058] The administration may also result in the subject having at least one of the following: a lower reduction in HDL level relative to HDL levels caused by substantially equivalent NDPC administration, increased bacterial inhibitory activity, a reduction in HbA1c level by at least 0.2 units, a decrease in SBP, and a decrease in DBP.

[0059] In the application, the pharmaceutical composition may include at least one of oleic acid or a derivative thereof, lauric acid or a derivative thereof, stearic acid or a derivative thereof, and combinations thereof.

[0060] In the application, TDPC comprises at least one of a w / w ratio of TD to a lipophilic additive of at least about 0.38, about 0.52, and about 0.60. In the application, TDPC comprises at least one of a w / w ratio of TD to a hydrophilic additive of at least about 4.0, about 5.4, and about 6.5.

[0061] During the administration, the subject may have liver fibrosis and at least one of the following: MELD score of at least 12, at least one decompensated event, BMI > 20, L3 musculoskeletal index < 55 cm. 2 / m 2 Liver weakness index >3, ALT / AST ratio approximately 1, AST >40U / L, abnormal ALT level, abnormal ALP level.

[0062] During the administration, the subject may have at least one of the following: disordered protein homeostasis, abnormally high SHBG levels, and abnormally low albumin levels, and may require testosterone intervention based on at least one of the following: morning baseline testosterone levels of <400 ng / dL, <350 ng / dL, <300 ng / dL, and <250 ng / dL.

[0063] During the administration of this drug, cardiovascular risk may include the risk of adverse changes in at least one of SBP, DBP, HDL levels, ascites occurrence, homocysteine ​​levels, and myocardial mass or strength. Deterioration of cardiovascular health may include adverse changes in at least one of SBP, DBP, HDL, ascites occurrence, homocysteine ​​levels, cardiac reactive protein levels, and myocardial mass or strength, and improvement of cardiovascular health may include favorable changes. Deterioration of prostate health may include adverse changes in at least one of prostate size, prostate weight, and BPH symptoms, and improvement of prostate health may include favorable changes. Deterioration of muscle health may include adverse changes in at least one of muscle mass, muscle strength, muscle function, and myotoxicity, and improvement of muscle health may include favorable changes in these aspects. Deterioration of CNS health may include adverse changes in at least one of depression, seizures, cognition, risk of HE occurrence, risk of recurrence of overt HE, breakthrough HE episode, HE-related hospitalization, duration before the onset of overt HE episode, reversal of HE recurrence, occurrence of asterixis, mental state, intellectual function, psychometric test results, and neurophysiological test results, and improvement of CNS health may include favorable changes in these aspects. A deterioration in GI health may include at least one of the following adverse changes: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH, NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC, and PBC, and an improvement in GI health may include its favorable changes.

[0064] In the application, adverse changes in SBP may include an increase in SBP of at least 3 mmHg, and favorable changes in SBP may include a decrease in SBP of at least 1 mmHg.

[0065] In the application of this treatment, the condition may include at least one of the following: cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, advanced liver disease, chronic liver disease, end-stage lung disease, chronic kidney disease, end-stage renal disease, end-stage musculoskeletal system disease, end-stage cardiovascular disease, end-stage hematologic disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage reproductive organ disease, end-stage central nervous system disease, liver fibrosis, liver inflammation, hepatic steatosis, hepatic encephalopathy (HE), relapse of overt HE. NASH, NAFLD, pre- / post-liver transplant, decompensated cirrhosis, PBC, PSC, ILD, pneumonia, IPF, muscle loss, cachexia, sarcopenia, asthenia, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral obesity, obesity, impaired wound healing, lumbar disc herniation, intramuscular fat deposition syndrome, cancer, CHF, pulmonary fibrosis, COPD, and hereditary angioedema.

[0066] In the administration, the pharmaceutical composition may include at least one additive, which may be a lipophilic additive or a hydrophilic additive. The lipophilic additive may include at least one of a surfactant and a non-surfactant, and the hydrophilic additive may include at least one of a surfactant and a non-surfactant.

[0067] In the application, the pharmaceutical composition may include at least one carrier, which may include at least one of a lipophilic carrier and a hydrophilic carrier. The lipophilic carrier may include at least one of a lipophilic surfactant and a lipophilic additive, and the hydrophilic carrier may include at least one of a hydrophilic surfactant and a hydrophilic additive. The lipophilic carrier may include at least one of fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherol, tocopherol succinate, tocopherol acetate, and fish oil, and wherein the hydrophilic carrier includes at least one of polyoxyethylene hydrogenated vegetable oil, polyoxyethylene vegetable oil, polyethylene glycol fatty acid esters, mixtures of polyethylene glycol fatty acid monoglycerides, mixtures of polyethylene glycol fatty acid diglycerides, polysorbate esters, polyethylene glycol derivatives of tocopherol, alcohols, and alcohol derivatives. The fatty acids may include at least one of oleic acid, lauric acid, stearic acid, and their derivatives, and the vegetable oils include at least one of peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and their derivatives, and the monoglyceride derivatives include at least one of monolinoleic acid glyceride and sorbitol monofatty acid, and the diglyceride derivatives include glyceryl stearate palmitate, and the polyoxyethylene hydrogenated vegetable oils include PEG-hydrogenated castor oil, and the alcohols include at least one of ethanol and benzyl alcohol; and the alcohol derivatives include benzyl benzoate.

[0068] In the application, the pharmaceutical composition may include at least one of tablets, capsules, pouches, gel capsules, suspensions, solutions, beverages, gels, syrups, dispersions, emulsions, sprays, lozenges, microemulsions, nanoemulsions, elixirs, pastes, powders, and granules.

[0069] In the administration, administration may include a dosing regimen, which may include at least one of a QD regimen and a BID regimen. The dosing regimen may include at least one of a titration regimen and a non-titeration regimen. Administration may include at least one of a total daily dose of TD of about 200 mg to about 1000 mg, about 350 mg to about 850 mg, and about 500 mg to about 700 mg. TDPC dosage forms may include single-dose unit dosage forms, two-dose unit dosage forms, three-dose unit dosage forms, and four-dose unit dosage forms.

[0070] In a fifth embodiment, the invention includes a (preferably orally) method of treating a subject's condition, comprising administering TDPC to the subject, wherein the administration of TDPC can enhance the subject's indicators for monitoring liver disease (e.g., L3-SMI). For example, the administration of TDPC can increase the subject's L3-SMI. As other examples, the administration of TDPC can increase the subject's muscle area (e.g., muscle area monitored by the L3 region on a CT scan), reduce the subject's intramuscular adipose tissue (IMAT or intramuscular fat deposition) (e.g., IMAT monitored by the L3 region on a CT scan), and improve muscle mass (an increase in muscle area identified between 30 and 150 HU monitored by the L3 region on a CT scan). As another example, the administration of TDPC can address anemia in the subject. As yet another example, the administration of TDPC can improve the subject's perceived quality of life (e.g., the subject may use a PGI-C response to report feeling better). As another example, the administration of TDPC can reduce decompensation events in subjects (e.g., ascites, hepatic encephalopathy, varicose veins, or spontaneous bacterial peritonitis), increase the amount of time between recurrences of decompensation events, reduce the number of days per hospitalization, reduce the total number of days of hospitalization, or reduce the Stroop test time in subjects (for "Stroop effect", please visit Wikipedia: https: / / en.wikipedia.org / wiki / Stroop_effect).

[0071] For example, when TDPC was administered to 15 randomized subjects and compared to 10 subjects who received placebo, the subjects who received TDPC showed an increase in L3-SMI relative to baseline and compared to the placebo subjects. These trends remained similar at least at the previously described endpoints, including increases in subjects' muscle area, muscle mass, perceived quality of life, and decreases in IMAT, decompensated events, and Stroop test time.

[0072] Exemplary process endpoint calculations were performed using the LS mean (SE) calculated by ANOVA, taking into account baseline and change relative to baseline (L3-SMI) for the treatment group, relative to the score (PGI-C) for the treatment group, or a binomial distribution of event statistics (hepatic encephalopathy) that did not have baseline characteristics and relative to the score for the treatment group. After a given time (e.g., 12 weeks), L3-SMI increased by 2.64 (0.84) from baseline in those receiving TDPC treatment, which was statistically distinguishable from baseline. Furthermore, after a given time (e.g., 24 weeks), L3-SMI increased by 3.62 (0.93) from baseline in those receiving TDPC treatment, which was statistically distinguishable from baseline and further statistically distinguishable from those receiving placebo with an L3-SMI of -0.74 (1.14). The PGI-C score of TDPC treatment was 3.00 (0.25), which was statistically distinguishable from the placebo score of 3.85 (0.26). The TDPC treatment group had statistically fewer hepatic encephalopathy decompensation events (e.g., 2 events) compared to the placebo group (e.g., 6 events). Furthermore, recurrence of grade 1 decompensation events (e.g., HE) was delayed with TDPC treatment, with a mean recurrence time of 115 days, compared to 39 days in the placebo group. These examples demonstrate the unexpected and significant benefit of the described TDPC. Other exemplary endpoints may be statistically significant, or trends between the TDPC and placebo groups may indicate a benefit.

[0073] The benefits of TDPC administration are further supported by the lack of observed clinical benefit at lower doses (e.g., administration of a 50 mg load of TDPC once daily for subchronic treatment). For example, administration of lower doses of TDPC may not enhance indicators used by subjects to monitor liver disease (e.g., L3-SMI). For example, administration of lower doses of TDPC may not increase a subject's L3-SMI. As other examples, administration of lower doses of TDPC may not increase a subject's muscle area (e.g., muscle area monitored by the L3 region on a CT scan), may not reduce a subject's intramuscular adipose tissue (IMAT) (e.g., IMAT monitored by the L3 region on a CT scan), and may not increase muscle mass (an increase in muscle area identified between 30 and 150 HU monitored by the L3 region on a CT scan). As another example, administration of TDPC may not resolve a subject's anemia. As yet another example, administration of lower doses of TDPC may not improve a subject's perceived quality of life (e.g., a subject may report feeling better using the PGI-C response). As another example, lower doses of TDPC may not reduce decompensation events (e.g., ascites, hepatic encephalopathy, varicose veins, or spontaneous bacterial peritonitis) in subjects, will not increase the time between recurrences of decompensation events in subjects, will not reduce the number of days per hospitalization, will not reduce the total number of days of hospitalization, or will not reduce the Stroop test time in subjects.

[0074] The benefits of TDPC treatment, including improvements in muscle area, muscle mass, fat area, PGI-C questionnaire scores, and other benefits observed alone or in combination with the exemplary lower doses of TDPC, have led to and demonstrated beneficial clinical outcomes of sarcopenia and decompensation events with the exemplary TDPC treatment.

[0075] In addition to other embodiments disclosed herein, it is worth noting that in some embodiments, testosterone tridecanoate can replace TD, wherein the corresponding dosing regimen is adjusted accordingly (e.g., the total daily dose is 600 mg to 1500 mg, 300 mg to 750 mg, or 150 mg to 375 mg). Attached Figure Description

[0076] The features and advantages of embodiments of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which collectively illustrate the features of this disclosure by way of example; and wherein: Figure 1 The pharmacokinetic curve of mean serum testosterone levels after oral administration of 155 mg TD, and Figure 2This is a survival curve comparing exemplary administration of TD with administration of placebo. Detailed Implementation

[0077] Before describing embodiments of the present invention, it should be understood that this disclosure is not limited to the specific structures, processes, or materials disclosed herein, but extends to equivalents that will be recognized by those skilled in the art. It should also be understood that the terminology used herein is for describing specific examples or embodiments only and is not intended to be limiting.

[0078] Furthermore, the described features, structures, or properties can be combined in any suitable manner in one or more embodiments. Numerous specific details, such as examples of compositions, dosage forms, treatments, etc., are provided in the following description to provide a thorough understanding of various embodiments of the invention. However, those skilled in the art will recognize that such detailed embodiments do not limit the overall inventive concept set forth herein, but are merely representative examples.

[0079] definition As used herein, the terms "treat," "treatment," or "treating" refer to the administration of a therapeutic agent to a subject, whether symptomatic or asymptomatic. In other words, "treat," "treatment," or "treating" can refer to actions that reduce or eliminate a symptom (i.e., the symptoms exhibited), or it can refer to preventative treatment (i.e., administration to a subject who is not exhibiting symptoms to prevent their occurrence). Such preventative treatment may also be referred to as symptom prevention, preventative action, preventative measures, etc.

[0080] As used herein, the terms “therapeutic agent,” “active agent,” etc., are used interchangeably and refer to a reagent or substance that has measurable specific or selected physiological activity when administered to a subject in a significant or effective amount. It should be understood that the term “drug” is explicitly included in this definition because many drugs and prodrugs are known to have specific physiological activities. These technical terms are well-known in the pharmaceutical and medical fields. Furthermore, when using these terms, or when a particular active agent is specifically identified by name or category in this written description, it is understood that such expression is intended to include explicit support for the active agent itself and pharmaceutically acceptable salts, esters, or compounds significantly associated therewith, including but not limited to prodrugs, active metabolites, polymorphs, etc. For example, the expression for the active agent allopregnanolone further includes explicit support for the active metabolite.

[0081] As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms “formulation” and “composition” can be used to refer to a mixture of one or more active agents with additives or other excipients. Furthermore, the term “dosage form” can include one or more formulations or compositions to be administered to a subject in an oral manner. For example, an “oral dosage form” is suitable for administration to a subject’s mouth. A “topical dosage form” is suitable for administration to a subject’s skin by friction or the like.

[0082] As used herein, the terms "pharmaceutically acceptable additive" or "additive" are used interchangeably and refer to a pharmaceutically acceptable agent or ingredient that can be combined with an active agent as part of a composition or dosage form. In some aspects, a pharmaceutically acceptable additive can affect the form or behavior of the active agent. For example, in some aspects, a pharmaceutically acceptable additive can completely or partially dissolve or solubilize an active agent (e.g., allogestrinone) in a pharmaceutical composition, or render the active agent amorphous. In other aspects, a pharmaceutically acceptable additive can be formulated in a pharmaceutical composition with an active agent (e.g., allogestrinone), including in a crystalline form of the active agent. In one aspect, a composition wherein said allogestrinone comprises at least one form of substantially solubilized, partially solubilized, substantially insoluble, substantially crystalline, partially crystalline, substantially amorphous, amorphous, solid, dispersion, or eutectic mixture.

[0083] Furthermore, in some respects, additives can influence or control the properties and performance of a composition or dosage form. For example, in some respects, additives can influence or control the pharmacokinetic (PK) properties or characteristics of a composition and / or dosage form (e.g., the release rate and / or extent of the active agent).

[0084] As used herein, at room temperature, "semi-liquid" or "semi-solid" corresponds to a partially solubilized surfactant, and "liquid" corresponds to a fully solubilized surfactant.

[0085] As used herein, “subject” means a mammal that may benefit from the administration of the pharmaceutical composition, dosage form, or dosage regimen or method disclosed herein. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals. In one particular aspect, the subject is a human. In another aspect, the subject is a female. In another aspect, the subject is a woman of reproductive age. In another aspect, the woman has given birth within the past 1–12 months. In another aspect, the subject is a male.

[0086] As used herein, "in need of treatment" refers to a subject who, according to various diagnostic criteria commonly used in practice, has a disease, condition, or disorder, or is suspected of having a disease, condition, or disorder, or who expects or needs treatment. Therefore, "in need of treatment" may include actions to identify subjects who require treatment.

[0087] As used herein, “identifying subjects requiring treatment” may include obtaining biological samples from the subject and determining the levels of one or more biomarkers described herein, evaluating the biological samples obtained from the subject, performing imaging analysis on the subject, assessing one or more clinical characteristics of the subject (e.g., assessing symptoms or obvious symptoms), or combinations thereof.

[0088] As used herein, the terms “illness,” “disease,” “condition,” “symptom,” and “disorder” are used interchangeably and refer to any abnormality or malfunction of any part, group, or system of a subject’s physiology, regardless of its causal relationship. For example, mental illness or mood disorders may be caused by environmental factors, genetic factors, physiological events, past experiences, and other influences or combinations thereof.

[0089] As used in this article, an "acute" condition is one that can develop rapidly and presents with obvious symptoms requiring urgent or semi-urgent care. In contrast, a "chronic" condition is one that typically develops more slowly and persists or otherwise progresses over time. Examples of acute conditions include, but are not limited to, asthma attacks, bronchitis, heart attacks, and pneumonia. Examples of chronic conditions include, but are not limited to, arthritis, diabetes, hypertension, and dyslipidemia.

[0090] The terms “serum level,” “serum amount,” “serum concentration,” “plasma level,” “plasma concentration,” “blood level,” and “blood concentration” are used interchangeably in this document and refer to the total amount of identified analytes (e.g., identified metabolites or active agents) in the blood of a subject, including free, bioavailable, and bound portions. For example, “serum allopregnanolone,” “serum allopregnanolone level,” “serum allopregnanolone concentration,” “plasma allopregnanolone concentration,” or “allopregnanolone concentration in the blood” refers to the total allopregnanolone concentration, which is the sum of the present allopregnanolone fractions, including substantially free and bound allopregnanolone concentrations. It should be understood that in this written description, these terms provide explicit support for the total analyte or reagent level and its various applicable fractions, including bioavailable, bound, and substantially free fractions. Unless otherwise stated, these values ​​are “observed” concentrations or amounts and do not require adjustment or correction for the subject’s baseline serum levels. As with any bioanalytical measurement, to improve consistency, the method used to measure initial serum levels should be consistent with the method used to monitor and remeasure serum levels during clinical testing and treatment of subjects. As used herein, the term "C" refers to... avg "" refers to the average serum concentration level over time 0 to t (e.g., average daily serum concentration level, daily C avg According to AUC 0-24 (calculated as a 24-hour ratio), term "C" max "" refers to the maximum serum concentration level after a single dose during this period.

[0091] In this document, the term "baseline" refers to the level or concentration of a substance in a subject's body prior to the administration of the active agent, such as the analyte of interest (e.g., allogeneinolone). For example, the baseline level of allogeneinolone in a subject would be the subject's serum allogeneinolone level prior to (e.g., just before) the initiation of allogeneinolone administration or treatment.

[0092] The term "oral administration" refers to any method of administration by which the active agent can be administered by swallowing, chewing, sucking, or drinking the composition or dosage form. Oral administration is contemplated for enteral delivery or transmucosal delivery of the active agent. In some embodiments, the compositions and dosage forms of this disclosure may be mixed with food or beverages prior to oral absorption, or may be administered with food or a meal.

[0093] As used herein, the terms “release” and “release rate” are used interchangeably to refer to the expulsion or release of a substance (including, but not limited to, a drug) from the composition or dosage form into the surrounding environment, such as in vitro or in vivo aqueous media. On the other hand, the term “disintegration” is a physical process involving the mechanical breakdown of a tablet into smaller particles / granules, as indicated by USP 43. <701> Disintegration is the breakdown of interparticle interactions that occurs during the formation of tablets by compressing granular particles of the active pharmaceutical ingredient (API) and excipients. On the other hand, the term "disintegration" is the physical process associated with the opening or rupture of a capsule. As used herein, the term "disintegration time" refers to the time required for disintegration to occur.

[0094] As used herein, “dosing regimen” or “regimen,” such as “initial dosing regimen,” “starting dose,” or “maintenance dosing regimen,” refers to how, when, in what quantity, and for how long a subject is administered the composition or dosage form of this disclosure. For example, an initial or starting dosing regimen for a subject may provide a total daily dose of about 10 mg to about 3400 mg, administered in divided doses at intervals of at least 4 hours, repeated daily with meals, for 30 days.

[0095] As used herein, “daily dose” refers to the amount of allogestrinone administered to the subject over a 24-hour period. The daily dose may be administered once or multiple times over a 24-hour period. In one embodiment, the daily dose is provided in two, three, four, six, or eight administrations over a 24-hour period. With this in mind, “initial dose” or “initial daily dose” refers to the dose administered during the initial regimen or dosing regimen.

[0096] As used herein, the “effective amount” or “therapeutic effective amount” of a drug refers to a non-toxic but sufficient quantity of the drug to achieve a therapeutic effect when used to treat a condition for which a known drug is effective. It should be understood that various biological factors can affect a substance’s ability to perform its intended function. Therefore, in some cases, the “effective amount” or “therapeutic effective amount” may depend on these biological factors. Furthermore, while the achievement of a therapeutic effect can be measured by a physician or other qualified medical professional using assessments known in the art, it should be recognized that individual differences and responses to treatment can make the achievement of a therapeutic effect a somewhat subjective decision. The determination of the effective amount is entirely within the realm of common techniques in pharmaceutical science and medicine. See, for example, Meiner and Tonascia, “Clinical Trials: Design, Conduct, and Analysis.” Monographs in Epidemiology and Biostatistics Volume 8 (1986), incorporated herein by reference.

[0097] As used herein, when “single unit” is used to describe a subject’s dosage form, it refers to a single dosage form, such as a single tablet, capsule, gel, or solution administered via a single pump or squirt. In contrast, when “multiple units” is used to describe a subject’s dose, it refers to a dose comprising two or more dosage forms, such as 2 capsules, 3 tablets, 2–4 pumps or squirts, etc. It is important to note that multiple unit dosage forms are typically of the same type (i.e., tablets or capsules), but do not need to be of the same dosage form type.

[0098] In this disclosure, terms such as “comprise,” “comprising,” “containing,” and “having” may have the meanings they are given under U.S. Patent Law and may mean “include” and “including,” and are generally interpreted as open-ended terms. The terms “consisting of” or “consists of” are closed terms and include only the components, structures, steps, etc., specifically listed with these terms, and content that conforms to U.S. Patent Law. “consisting essentially of,” “consists essentially of,” or “essentially consisting” have the meanings they are generally given under U.S. Patent Law. Specifically, these terms are generally closed terms but allow the inclusion of additional items, materials, components, steps, or elements that do not materially affect the essential and novel features or function of the item(s) associated with them. For example, if trace elements are present in the composition but do not affect the properties or characteristics of the composition, these trace elements are permissible according to the language of "consistently composed of..." even if they are not explicitly mentioned in the list of items following such terms. When open-ended terms such as "comprising" or "including" are used in this written description, it is understood that the language of "consistently composed of..." and "composed of..." should also be directly supported, as if explicitly stated, and vice versa.

[0099] The terms “first,” “second,” “third,” “fourth,” etc. (if any) used in the specification and claims are used to distinguish similar elements and are not necessarily used to describe a particular order or chronological sequence. It should be understood that any terms thus used are interchangeable where appropriate, allowing embodiments described herein to operate, for example, in an order different from that shown or otherwise described herein. Similarly, if a method is described herein as comprising a series of steps, the order of these steps described herein is not necessarily the only order in which they can be performed, and some said steps may be omitted and / or certain other steps not described herein may be added to the method.

[0100] The phrases “in one implementation” or “in one aspect” used in this article do not necessarily refer to the same implementation or aspect.

[0101] As used herein, comparative terms such as “increased,” “decreased,” “better,” “worse,” “higher,” “lower,” “enhanced,” “improved,” “maximized,” and “minimized” refer to properties that are measuredly different from those of a device, component, composition, biological response, biological state, or activity compared to those of a surrounding or adjacent area, similar location, a single device or composition or multiple comparable devices or compositions, the same group or category, multiple groups or categories, or an original (e.g., untreated) or baseline state or a known state of the prior art. For example, a composition or dosage form including eugenolone “increases” serum levels of eugenolone or increases eugenolone levels in a subject compared to serum levels at a previous time point, such as baseline levels (e.g., pre-treatment), or compared to earlier treatment with a different dose (e.g., a lower dose). Alternatively, when administered orally to a subject, a composition or dosage form of eugesterone that provides an “increased” serum level may provide such an increase compared to alternative known compositions or dosage forms, such as compositions using an equivalent amount of eugesterone with a suboptimal additive, or compositions comprising crystalline eugesterone, or compositions consisting primarily of eugesterone suspended / dissolved in edible oils (e.g., rapeseed oil or peanut oil or medium-chain triglycerides), or compositions consisting primarily of eugesterone solubilized / dissolved in an aqueous solution of non-encapsulated cyclodextrin, or compositions consisting primarily of eugesterone suspended in TWEEN-80.

[0102] As used herein, the term "substantially" refers to the extent or degree of completeness or near-completeness of an action, characteristic, property, state, structure, item, or result. For example, a "substantially" closed object means that the object is either completely closed or almost completely closed. In some cases, the exact permissible deviation from absolute completeness may depend on the specific circumstances. However, in general, near-completeness will produce the same overall result as absolute and complete completeness. When used in a negative sense, the term "substantially" is equally applicable to the complete or near-complete absence of an action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free" of particles either completely or almost completely lacks particles, and its effect is the same as that of completely lacking particles. In other words, a composition that is "substantially free" of a certain ingredient or element may actually still contain that item, provided that its measurable effect is absent.

[0103] As used herein, the term “fully” refers to the complete range or extent of an action, characteristic, nature, state, structure, item, or result.

[0104] As used herein, the term "about" provides flexibility for the endpoints of a numerical range by indicating that a given value can be "slightly above" or "slightly below" the endpoints. Unless otherwise stated, the use of the word "about" with respect to a particular number or range should also be understood as providing support for those numerical terms or ranges in the absence of the term "about." For example, for convenience and brevity, the numerical range "about 50 angstroms to about 80 angstroms" should also be understood as providing support for the range "50 angstroms to 80 angstroms." Furthermore, it should be understood that in this specification, the use of the term "about" with actual numerical values ​​also provides support for actual numerical values. For example, the expression "about" 30 should be interpreted as providing support not only for values ​​slightly above and slightly below 30, but also for the actual value 30.

[0105] As used herein, for convenience, multiple items, structural elements, constituent elements, and / or materials may be presented in a common list. However, these lists should be interpreted as each member being individually identified as a separate and unique member. Therefore, without indication to the contrary, no single member in such a list should be construed as a de facto equivalent of any other member in the same list solely based on its presence in the common group.

[0106] Concentration, amount, level, and other numerical data may be expressed or presented in range format throughout this document. It should be understood that this range format is used merely for convenience and brevity, and therefore should be flexibly interpreted to include not only the values ​​explicitly listed as range limits, but also all individual values ​​or subranges or decimal units included within that range, as if each value and subrange were explicitly listed. For example, a numerical range of “about 1 to about 5” should be interpreted to include not only the explicitly stated values ​​of about 1 to 5, but also the individual values ​​and subranges within the indicated range. Thus, the numerical range includes individual values ​​such as 2, 3, and 4, and subranges such as 1-3, 2-4, and 3-5, as well as the individual values ​​1, 2, 3, 4, and 5. The same principle applies to ranges that state only one value as a minimum or maximum value. Furthermore, this interpretation should apply regardless of the breadth of the range or the characteristics described.

[0107] The reference to "example" in this specification means that a particular feature, structure, or characteristic associated with an example is included in at least one implementation. Therefore, the phrase "in an example" appearing in various places in this specification does not necessarily refer to the same implementation.

[0108] describe Preferred embodiments of the invention will now be described in detail. While embodiments will be described in detail, this disclosure is not limited to these embodiments. Rather, it is intended to cover alternatives, variations, modifications, and equivalents that may be included within the spirit and scope of this disclosure.

[0109] The accompanying drawings presented herein are for illustrative purposes only and are not intended to be actual views of any particular oral pharmaceutical composition. The shapes and contours depicted in the drawings are expected to vary due to, for example, subject variability and / or multi-compartment bioavailability behavior. Therefore, the embodiments described herein should not be construed as limited to the specific shapes or contours illustrated, but rather include, for example, shape deviations caused by subject variability. For example, a PK curve illustrated as a smooth single-compartment model curve may include at least one of subject variability and multi-compartment response in the PK curve. Therefore, the curves illustrated in the drawings are illustrative in nature, and their shapes are not intended to illustrate the precise shape of the regions and do not limit the scope of the claims. Since the drawings are not presented to scale, they are not necessarily drawn to scale.

[0110] Exemplary Implementation In one embodiment, the invention includes administering a composition comprising TD to subjects requiring testosterone intervention at a pretreatment level, regardless of their gonadal status (hypogonadism or normal gonadal function).

[0111] In another embodiment, the invention includes administering a composition comprising TD to a subject requiring testosterone intervention based on a morning baseline testosterone level of at least one of <400, <350, <300, and <250 ng / dL.

[0112] In another embodiment, the present invention includes methods and compositions for treating / managing liver diseases such as NASH, non-alcoholic fatty liver disease, and any form of cholangitis.

[0113] In another embodiment, the present invention includes methods and compositions for treating / managing end-stage diseases, such as advanced kidney disease, end-stage renal disease (ESRD), chronic kidney disease (CKD), cirrhosis, chronic liver failure, end-stage liver disease (RSLD), cancer, congestive heart failure (CHF), pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).

[0114] Compared to comparable rifaximin administration, the methods and compositions of the present invention produce a favorable benefit-risk ratio characteristic relative to rifaximin due to fewer adverse events during oral administration. Compared to comparable non-TD oral administration, the methods and compositions of the present invention produce a favorable benefit-risk ratio characteristic relative to non-TD oral compositions due to fewer adverse events during oral administration.

[0115] The methods and compositions of this invention do not lead to an increase or decrease in cardiovascular risk. The methods and compositions of this invention do not reduce, increase, or weaken HDL levels. The methods and compositions of this invention do not cause changes in blood pressure, resulting in an increase in systolic blood pressure of no more than 3 mmHg or an increase in diastolic blood pressure of no more than 1 mmHg. The methods and compositions of this invention lead to a reduction in cardiac inflammatory markers such as cardiac reactive protein (CRP). The methods and compositions of this invention can improve myocardial health (including myocardial atrophy) or prevent the deterioration of myocardial health (including myocardial atrophy).

[0116] The methods and compositions of the present invention result in an average reduction of <5 mg / dL in HDL, reducing (<20%) the number of treated subjects whose HDL levels have decreased below the normal range from baseline after a period of testosterone treatment.

[0117] Compared to oral TU methods and compositions, the methods and compositions of the present invention result in a reduction of SBP by at least 1.0 mm hg and / or a reduction of DBP by at least 0.5 mm hg. Compared to TU or non-TD methods and compositions, the methods and compositions of the present invention result in a smaller average reduction in HDL (1 mg / dL). Compared to TU or non-TD methods and compositions, the methods and compositions of the present invention reduce the number of treated subjects whose HDL levels have decreased below the normal range from baseline after a period of testosterone treatment by 10%.

[0118] The methods and compositions of the present invention result in maintaining prostate health, preventing prostate health deterioration, reducing the increase of BPH symptoms, without an increase in BPH symptoms, and without a change in prostate size or weight.

[0119] Compared to TU and non-TD methods and compositions, the methods and compositions of the present invention reduce the potential incidence of benign prostatic hyperplasia and / or increased prostate weight or size by at least 5%. Compared to TU and non-TD methods and compositions, the methods and compositions of the present invention reduce the potential degree of increased prostate weight or size by at least 5%. Compared to other forms of T treatment including TU, the methods and compositions of the present invention reduce, for example, the prostate weight to body weight ratio and response markers of testosterone-induced benign prostatic hyperplasia by at least 5%.

[0120] Compared to TU and non-TD methods and compositions, the methods and compositions of the present invention result in a reduction in infection rate, for example, by at least 5%.

[0121] Compared to TU and non-TD methods and compositions, the methods and compositions of the present invention maintain the health of muscles, heart, lungs, kidneys, brain, liver, or any organ or prevent their further deterioration, for example, by at least 5%.

[0122] Liver diseases such as NASH and end-stage diseases such as cirrhosis are often associated with chronic inflammation in various biological tissues. Therefore, compared with TU and non-TD methods and compositions, the methods and compositions of the present invention reduce inflammation and inflammatory markers such as CRP, pro-inflammatory cytokines such as TNF-α, and interleukins by at least 5%.

[0123] Patients with cirrhosis are in a state of immune dysfunction and are at high risk of developing serious infections. Bacterial infections remain the most common cause of morbidity and mortality in these patients. The most common infections in patients with cirrhosis are spontaneous bacterial peritonitis and urinary tract infections, followed by pneumonia, spontaneous bacteremia, skin and soft tissue infections, and Clostridium difficile infection (CDI), with varying risks of death. The main pathogenic microorganisms are Gram-negative bacteria, such as Escherichia coli, Klebsiella spp., and Enterobacter spp., while Gram-positive bacteria, especially Enterococci and Staphylococcus aureus, account for about 20%, and anaerobes account for only 3%.

[0124] In one aspect, the methods and compositions of the present invention provide immunomodulation, reduced mortality and / or morbidity, lower infection rates than the placebo group, protection against Gram-negative bacteria (such as Escherichia coli), protection against Gram-positive bacteria, reduced hospitalizations, and reduced incidence of at least one of the following diseases: spontaneous bacterial peritonitis, urinary tract infection, pneumonia, spontaneous bacteremia, skin and soft tissue infections, and Clostridium difficile infection (CDI).

[0125] In another aspect of the method and composition of the present invention, the metabolite TD has antibacterial activity and reduces infection rates, lowers ammonia levels in subjects, and improves cognitive function. In another aspect of the method and composition of the present invention, TD is a pro-antibacterial agent.

[0126] Anemia is a condition in which a subject lacks sufficient healthy red blood cells to carry enough oxygen to their body tissues. Anemia, also known as hypohemoglobinemia, causes fatigue and weakness. The prevalence of anemia is common in patients with end-stage cirrhosis and is a predictor of overt or mild hepatic encephalopathy (HE) in liver transplant candidates with cirrhosis. In one aspect, in these patients, the methods and compositions of the present invention exhibit erythropoiesis-promoting effects, reducing anemia, preventing further decrease in hemoglobin, and increasing hematocrit by at least 3% or hemoglobin levels by at least about 1 g / dL.

[0127] Endocrine dysfunction is common in patients with end-stage disease. Profound changes in the hypothalamic-pituitary-gonadal axis in patients with advanced cirrhosis lead to endocrine dysfunction, accompanied by elevated serum aromatase activity. Compared to controls with normal liver function, men with chronic non-alcoholic liver disease have decreased levels of both total and free testosterone, and elevated levels of SHBG. Low total testosterone levels may also be an independent risk factor for major infections and death. Furthermore, the commonly used spironolactone treatment for managing cirrhosis is often associated with decreased circulating testosterone levels.

[0128] In one aspect, the methods and compositions of the present invention improve / counteract endocrine dysfunction, increase total testosterone, reverse the antiandrogenic effect of spironolactone, increase sex hormone-binding globulin, and increase free testosterone. In one aspect, the methods and compositions of the present invention, alone or simultaneously, normalize abnormal free testosterone, total testosterone, and SHBG. In one aspect, the methods and compositions of the present invention increase free testosterone by at least about 20% and increase total testosterone by [missing information]. avg Increase by at least approximately 100 ng / dL and reduce SHBG by at least approximately 20%.

[0129] In one aspect, the methods and compositions of the present invention provide antioxidant effects, resulting in improved levels of reactive oxygen species and improved mitochondrial function.

[0130] Albumin is primarily synthesized in the liver. In patients with cirrhosis, hepatocellular function is impaired, and albumin synthesis is reduced, decreasing by 60-80% in advanced cirrhosis. Furthermore, low serum albumin levels may be a clinical biomarker associated with cognitive impairment. Traditionally, hypoalbuminemia in adults is defined by a decrease in serum ALB levels <35 g / L, and clinically significant hypoalbuminemia can be identified by serum ALB levels <25 g / L. Serum ALB levels ≤ 31.6 g / L may be associated with a higher risk of overt hepatic encephalopathy (HE), and serum ALB levels ≤ 22.8 g / L may be associated with a higher risk of in-hospital mortality in overt HE. An increase in albumin of 0.5 mg / dL may lead to a significant reduction in mortality.

[0131] In one aspect, the methods and compositions of the present invention provide antioxidant effects, resulting in stimulation of albumin production, treatment of hypoalbuminemia, regulation of protein homeostasis or protein homeostasis, inhibition of protein hydrolysis, increase of albumin by at least 0.5 mg / dL without exogenous albumin administration, improvement of cognitive function, reduction or non-induction of HE events, reduction of hospitalization, reduction of mortality, and improvement of survival.

[0132] Sarcopenia, weakness, or intramuscular fat deposition, as well as cachexia-like muscle diseases, are very common in end-stage disease. Fat-free mass depletion is a predictor of hepatic encephalopathy (HE) in liver transplant candidates with cirrhosis. Sarcopenia leads to weakness and increases the risk of mild and overt hepatic encephalopathy (HE). Clinically, overt HE is significantly higher in cirrhotic patients with muscle exhaustion or decreased muscle strength.

[0133] Myostatin is a naturally occurring regulatory protein of the TGF-β growth factor family that is known to negatively regulate or inhibit muscle growth. Myostatin is a key regulator of protein synthesis, muscle loss, and bone mineral density, and is commonly found in patients with cirrhosis. Osteopenia, hyperalkaline phosphatase (ALP), and osteoporosis are very common in patients with cirrhosis.

[0134] In one aspect, relative to placebo administration or baseline, the methods and compositions of the present invention result in improvement or reversal of sarcopenia, improvement or prevention of ESD, weakness, intramuscular fat deposition, deterioration of sarcopenia secondary to cachexia, prevention / reduction of the risk of muscle toxicity, inhibition of myostatin, increase in lean body mass, increase in muscle mass, decrease in fat mass, increase in lean body mass and decrease in fat mass, enhancement of muscle protein synthesis, prevention of muscle wasting, improvement of appetite, increase in IGF-1 and mTOR activation, increase in sustained satellite cell activity, inhibition of myostatin secretion and signal transduction, increase in lean body mass by at least one of 1 kg, 2 kg and 3 kg, and / or decrease in fat mass by at least one of 1 kg, 2 g and 3 kg, improvement or prevention of deterioration of liver frailty index, improvement in grip strength, improvement in grip strength, improvement (increase) in 6-minute walking distance, reduction of intramuscular fat deposition, and reduction of muscle fat by at least about 10%.

[0135] In one aspect, the methods and compositions of the present invention result in improved bone health, prevent or reduce further deterioration of osteopenia, lower ALP, and reduce further deterioration of osteopenia.

[0136] In one aspect, the methods and compositions of the present invention reduce the occurrence of decompensated events while improving body composition by improving lean body mass or reducing fat mass and / or improving liver function.

[0137] In one aspect, the methods and compositions of the present invention provide remission of NASH in patients with chronic liver disease, reduce hepatic steatosis, alleviate or reduce ballooning degeneration, reduce or decrease inflammation, reduce portal hypertension, reduce portal hypertension by at least about 2 mm Hg, reduce key liver injury markers such as ALT, AST, GGT, and ALP, reduce and sustain ALT, AST, GGT, and ALP, normalize ALT, AST, GGT, and ALP, and reduce abnormal ALT, AST, and GGT levels. Liver markers decrease as early as four weeks and are reduced by at least about 10% compared to baseline or adjusted placebo administration.

[0138] In one aspect, the methods and compositions of the present invention provide a reduction in HbA1c in patients with cirrhosis, for example, a reduction of HbA1c by ~0.2 units.

[0139] In one aspect, the methods and compositions of the present invention provide patients with sexual and psychological functions.

[0140] In one aspect, the methods and compositions of the present invention halt hypermetabolic states, improve anabolic effects, provide antimetabolic effects, increase muscle protein synthesis, and reduce skeletal muscle protein breakdown.

[0141] Lowering systemic ammonia levels by improving ammonia detoxification: Patients with cirrhosis have elevated plasma and skeletal muscle ammonia levels. Skeletal muscle ammonia is a neurotoxin and myotoxin that is associated with reduced muscle mass and increased expression of myostatin.

[0142] Hyperammonemia is a persistent abnormality occurring in cirrhosis due to reduced urea synthesis, which occurs almost entirely in the liver due to hepatocellular dysfunction, with or without portosystemic shunt. Excess ammonia is a key cause of muscle loss and functional impairment in patients with cirrhosis. Hyperammonemia induces myostatin and reduces skeletal muscle mass. Hyperammonemia also activates skeletal muscle proteolysis through autophagy and upregulates the expression of myostatin, which impairs protein synthesis.

[0143] Ammonia is detoxified in the liver via the urea cycle, and skeletal muscle serves as a substitute organ for ammonia detoxification. Therefore, in cases of liver disease, the liver's ability to clear ammonia is reduced, and this, coupled with muscle loss, further diminishes the body's ammonia clearance capacity, leading to a higher risk of hyperammonemia and hepatic encephalopathy (HE). Muscle plays a crucial compensatory role in ammonia detoxification during liver disease because it contains glutamine synthase (GS), an important ammonia removal pathway during the amination of glutamate to glutamine.

[0144] Ammonia levels are lowered by reducing ammonia production through antibacterial action: In patients with cirrhosis, certain organisms in the gastrointestinal tract can lead to increased ammonia levels, increasing the risk of hyperammonemia (HE). Gram-negative anaerobes produce the largest amounts of ammonia, while Gram-positive nonspore-forming anaerobes produce adequate amounts of ammonia from peptides and amino acids within the body. Patients with cirrhosis are at high risk of infection with Clostridium difficile (CDI), an infection that causes systemic ammonia elevation and hyperammonemia.

[0145] TD is a reversible testosterone dodecanoate, believed to have antibacterial activity against Gram-negative anaerobes and Gram-positive nonspore-forming anaerobes, primarily attributed to its esterase hydrolysis product, dodecanoic acid. These specific organisms in the gastrointestinal tract can produce large amounts of ammonia from peptides and amino acids, leading to systemic increases and an increased risk of hepatitis B (HE).

[0146] In one aspect, the methods and compositions of the present invention reduce systemic ammonia levels or combat hyperammonemia or reduce HE events in patients with cirrhosis. Through antibacterial activity against Gram-negative bacteria or Gram-negative and Gram-positive bacteria in the GI tract, the methods and compositions of the present invention advantageously modulate the structure and function of intestinal bacteria, resulting in a reduction in the abundance of Veillonella, Haemophilus, Streptococcus, Parabacterium, Megamonas, Roseburia, Alistipes, Ruminococcus, Lactobacillus, Clostridium difficile, and Escherichia coli.

[0147] In one aspect, the methods and compositions of the present invention reduce systemic ammonia levels, combat hyperammonemia by restoring / improving organ ammonia detoxification function, restore / improve liver and / or muscle organ ammonia detoxification function, counteract proteolysis via autophagy, inhibit myostatin, improve skeletal muscle mass by reducing systemic ammonia levels, improve cognitive function, normalize or reduce ALP, and reduce abnormal ALP.

[0148] In one aspect, the methods and compositions of the present invention reduce systemic ammonia levels, combat hyperammonemia by reducing ammonia production, and / or restore / improve organ ammonia detoxification function, restoring / improving the ammonia detoxification function of the liver and / or muscle organs.

[0149] In one aspect, the methods and compositions of the present invention address hepatic ballooning degeneration in patients with chronic liver disease, improve hepatic steatosis, improve liver inflammation, stimulate liver regeneration, improve fibrosis, and prevent the deterioration of fibrosis.

[0150] Rifaximin is an approved HE treatment drug with extremely low gastrointestinal absorption and antibacterial activity.

[0151] In one aspect, the methods and compositions of the present invention reduce systemic ammonia levels by achieving significant systemic levels of the therapeutic agent. In another aspect, the methods and compositions of the present invention reduce systemic ammonia levels while improving muscle mass and liver function, without prostate or cardiovascular risks. In another aspect, the methods and compositions of the present invention do not significantly inhibit P-glycoprotein transporters.

[0152] In one aspect, the methods and compositions of the present invention have a preventive effect to prevent or reduce the risk of hepatic encephalopathy (HE), reduce the risk of recurrence of overt hepatic encephalopathy, reduce breakthrough attacks, reduce HE-related hospitalizations (hospitals directly caused by HE, and hospitalizations complicated by HE), delay the onset of overt HE attacks, have an ascites incidence rate of <10% in HE subjects, improve asterixis, improve mental status, improve intellectual function, improve psychometric / neurophysiological tests, increase HE reversal, and reduce mortality in HE subjects.

[0153] In one aspect, the methods and compositions of the present invention result in a reduction in HE-related hospitalizations, a reduction in hospitalizations related to any decompensation event, a reduction in all-cause hospitalizations, improved survival rates, reduced hospitalization rates, and improved quality of life (QOL).

[0154] In one aspect, the methods and compositions of the present invention treat / manage cirrhosis of various etiologies, including alcoholic, non-alcoholic fatty liver disease, viral hepatitis, drug abuse, and immune disorders.

[0155] In one aspect, the methods and compositions of the present invention treat / manage cirrhosis, resulting in a reduction in mortality or an increase in survival in patient groups.

[0156] In one aspect, the methods and compositions of the present invention treat / manage cirrhosis in patients with at least one of the following conditions: a history of mild or overt hepatic encephalopathy (HE), sarcopenia, hyponatremia, epilepsy, type 2 diabetes, high creatinine levels, high bilirubin levels, and low albumin levels.

[0157] In one aspect, the methods and compositions of the present invention treat / manage cirrhosis in subjects on the liver transplant waiting list who have decompensated cirrhosis, who have had at least one prior decompensation event; have at least one prior HE decompensation event, have at least one prior ascites decompensation event, and have a MELD score of at least one of greater than 12, less than 20, and about 12 to about 20.

[0158] In one aspect, the methods and compositions of the present invention treat / manage myogenic, bone mass index L3 SMI less than 53 (cm). 2 / m 2 The subjects had cirrhosis.

[0159] In one aspect, the methods and compositions of the present invention treat / manage cirrhosis in frail subjects with a liver weakness index greater than 3.2.

[0160] In one aspect, the methods and compositions of the present invention treat / manage cirrhosis in subjects suffering from intramuscular fat deposits and whose muscle fat content is at least about 10% as assessed by CT scan.

[0161] In one aspect, the methods and compositions of the present invention reduce or prevent an increase in MELD scores.

[0162] In one aspect, the methods and compositions of the present invention improve post-transplant outcomes, increase post-transplant survival rates, and reduce post-transplant rehabilitation requirements / costs.

[0163] In one aspect, the methods and compositions of the present invention reduce ascites and improve the survival rate of cirrhotic patients with refractory ascites.

[0164] In one aspect, the methods and compositions of the present invention can reduce the occurrence of HE events in subjects. For example, when comparing the treatment group with the placebo group, the hazard ratio for HE events may include about or less than 0.75, 0.6, 0.5, 0.4, 0.25, 0.2, and 0.1. By way of example only, the hazard ratio for HE events may be about 0.27.

[0165] In one aspect, the methods and compositions of the present invention can increase L3-SMI in subjects. For example, an increase in L3-SMI in a subject may include about or greater than 0.25 cm. 2 m -2 0.5cm 2 m -2 0.75cm 2 m -2 1cm 2 m -2 1.5cm 2 m -2 2cm 2 m -2 2.5cm 2 m -2 3cm 2 m -2 4cm 2 m -2 5cm 2 m -2 7.5cm 2 m -2 and 10cm 2 m -2 As an example only, the increase in L3-SMI in a subject could be approximately 3.6 cm.2 m -2 As another example, the increase in L3-SMI in a subject could be approximately 2.6 cm. 2 m -2 .

[0166] In one aspect, the methods and compositions of the present invention can increase L3-SMI in subjects. For example, the increase in L3-SMI in subjects compared to the placebo group may include about or greater than 0.25 cm. 2 m -2 0.5cm 2 m -2 0.75cm 2 m -2 1cm 2 m -2 1.5cm 2 m -2 2cm 2 m -2 2.5cm 2 m -2 3cm 2 m -2 4cm 2 m -2 5cm 2 m -2 7.5cm 2 m -2 and 10cm 2 m -2 As an example only, the increase in L3-SMI in a subject could be approximately 4.4 cm. 2 m -2 .

[0167] In one aspect, the methods and compositions of the present invention can increase L3-SMI in subjects over a period of time. For example, the time period for which L3-SMI increases in subjects may include approximately or less than 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 30 weeks, 36 weeks, 40 weeks, 48 ​​weeks, and 52 weeks. By way of example only, the time period for which L3-SMI increases in subjects may be approximately 12 weeks. As another example, the time period for which L3-SMI increases in subjects may be approximately 24 weeks.

[0168] In one aspect, the methods and compositions of the present invention can reduce the body weight of a subject and increase the subject's L3-SMI. For example, the reduction in body weight may include about or greater than 5%, 10%, 15%, 20%, 25%, and 30% w / w. For instance, the increase in the subject's L3-SMI may include about or greater than 0.25 cm. 2 m -2 0.5cm2 m -2 0.75cm 2 m -2 1cm 2 m -2 1.5cm 2 m -2 2cm 2 m -2 2.5cm 2 m -2 3cm 2 m -2 4cm 2 m -2 5cm 2 m -2 7.5cm 2 m -2 and 10cm 2 m -2 As an example only, the subject's weight loss could be approximately 20%, and the subject's L3-SMI could increase by approximately 3.6 cm. 2 m -2 .

[0169] In one aspect, the methods and compositions of the present invention can achieve subject PGI-C scores comprising 4, 3, 2, and 1 or less than 4, 3, 2, and 1. For example, a PGI-C score could be 3.

[0170] In one aspect, the methods and compositions of the present invention can achieve PGI-C in subjects over a period of time. For example, the time period for PGI-C in subjects may include about or less than 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 30 weeks, 36 weeks, 40 weeks, 48 ​​weeks, and 52 weeks. By way of example only, the time period for PGI-C in subjects may be about 4 weeks. As another example, the time period for PGI-C in subjects may be about 12 weeks. As another example, the time period for PGI-C in subjects may be about 24 weeks.

[0171] The compositions, additives, and dosage forms of the present invention include those disclosed in the patents incorporated herein.

[0172] Exemplary excipients include: lipophilic surfactant to hydrophilic surfactant ratios: >2:1, >3:1, >3.5:1, >5:1, >6:1, >8:1, and >10:1. Fatty acid to hydrophilic surfactant ratios: >0.3:1, >1:1, >2:1, >3:1, >3.5:1, >5:1, >6:1, >8:1, and >10:1. Hydrophilic surfactants: <20%, <15%, <12%, <10%, and <5%. TD loading is 27-32%, and the TD / fatty acid ratio w / w% is: >0.4, >1, >1.67, >2.0, >3, >4, >5, and >6. TD loading is 27-32%, and the TD / hydrophilic surfactant ratio w / w% is: >1.67, >2.0, >3, >4, >5, and >6. The TD loading is 27-32%, and the TD / hydrophilic surfactant ratio (w / w%) is >1.67, >5, >25, >50, and >75, with fatty acid content >40%, >45%, >50%, >55%, >60%, >65%, and >70%. Alternatively, the TD loading is 20-35%, containing at least 50% fatty acids (e.g., oleic acid, lauric acid).

[0173] Exemplary dosing regimens include daily doses of 200 mg to 1500 mg / day. Dosing frequency may be BID or QD. Long-term and sub-long-term use (up to 1 year).

[0174] Exemplary blood levels include: C 350 ng / ml to 1080 ng / dL avg C avg The change from baseline was 100 ng / dL.

[0175] Exemplary biomarkers of the present invention (preferably relative to pretreatment or placebo administration) include: a decrease in SHBG of at least about 10%; a decrease in portal hypertension of at least about 2 mmHg; an increase in albumin of at least about 0.5 mg / dL; a decrease in liver frailty index (LFI) of at least about 0.2 units; an increase in L2 muscle mass of at least about 5%; a decrease in muscle fat (reduction in intramuscular fat deposition) of at least about 10%; lower systemic ammonia; a decrease in abnormal levels of at least one of ALT, AST, GGT, and ALP of at least about 10%; an increase in lean body mass of at least one of about 1 kg, about 2 kg, and about 3 kg, and / or a decrease in fat mass of at least one of about 1 kg, about 2 kg, and about 3 kg; an increase in free T of at least about 20%; and total TC. avg An increase of at least approximately 100 ng / dL. An increase in hematocrit of at least approximately 3% or an increase in hemoglobin of at least approximately 1 g / dL. Lower levels of inflammatory markers.

[0176] The methods and compositions of the present invention result in an average reduction of HDL of approximately <5 mg / dL, and the number of subjects whose HDL levels decreased below the normal range from baseline after a period of testosterone treatment was reduced by <20%.

[0177] Exemplary biomarkers of the present invention (preferably relative to similar administration of non-TD testosterone esters) include: a reduced potential incidence of benign prostatic hyperplasia; a reduction in prostate weight or an increase in prostate size of at least about 5%; a reduction in HbA1c levels of at least about 0.2 units; a reduction in SBP of at least about 1 mmHg and a reduction in DBP of at least about 0.5 mmHg; a mean reduction in HDL of at least about 1 mg / dL; higher bacterial inhibitory activity; and a higher proportion of treatment participants exhibiting a moderately better or much better response in the overall impression of change in patients (PGI-C), such as at least one of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, and at least about 70%. An improvement in MSI of at least about 3 cm after at least 3 months of treatment. 2 / m 2 (Relative to the placebo group or baseline).

[0178] Example

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190] As a non-limiting example, suitable additives used in the various embodiments described herein include adsorbents, anti-adhesion agents, anticoagulants, defoamers, antioxidants, anti-caking agents, antistatic agents, binders, bile acids, buffers, fillers, chelating agents, coagulants, colorants, cosolvents, opacifiers, coagulants, coolants, cryoprotectants, diluents, dehumidifiers, scavengers, desensitizers, disintegrants, dispersants, enzyme inhibitors, flow aids, fillers, hydrating agents, hyperdisintegrants, gums, mucilages, hydrogen-bonding agents, enzymes, flavoring agents, wetting agents, humectants, lubricants, ion exchange resins, lubricants, plasticizers, pH adjusters, preservatives, curing agents (coagulants), solvents, solubilizers, spreading agents, sweeteners, stabilizers, surface area enhancers, suspending agents, thickeners, viscous agents, waxes, and mixtures thereof.

[0191] As non-limiting examples, anti-adhesion agents (anti-sticking agents, flow aids, flow promoters, lubricants) include: talc, magnesium stearate, fumed silica (Carbsil, Aerosil), micronized silica (Syloid No. FP 244, Grace U.SA), polyethylene glycol, surfactants, waxes, stearic acid, stearates, stearic acid derivatives, starch, hydrogenated vegetable oil, sodium benzoate, sodium acetate, leucine, PEG-4000, and magnesium dodecyl sulfate. As non-limiting examples, antioxidants include BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbate palmitate, 4-hydroxymethyl-2,6-di-tert-butylphenol, and tocopherol. As a non-limiting example, binders (adhesives), i.e. agents that impart cohesiveness to powder materials through particle-to-particle bonding, include: matrix binders (dry starch, dry sugar), membrane binders (PVP, starch paste, cellulose, bentonite, sucrose), and chemical binders (polymeric cellulose derivatives, such as carboxymethyl cellulose, HPC, and HPNC; syrups; corn syrup; water-soluble polysaccharides, such as gum arabic, tragacanth, guar gum, and alginate; gelatin, gelatin hydrolysate; agar; sucrose; glucose; and non-cellulose binders, such as PVP, PEG, vinylpyrrolidone copolymers, pregelatinized starch, sorbitol, and glucose). Buffers include acids and bases, where the acids are pharmaceutically acceptable, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkyl sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid, and the bases are pharmaceutically acceptable, such as amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, and carbonic acid. Sodium hydrogen, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, or pharmaceutically acceptable cations salts of the following acids: acetic acid, acrylic acid, adipic acid, alginic acid, alkyl sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. As a non-limiting example, chelating agents include EDTA and EDTA salts. As non-limiting examples, colorants or opacifiers include titanium dioxide, food colorings, lakes, natural plant colorants, iron oxide, silicates, sulfates, magnesium hydroxide, and aluminum hydroxide.As non-limiting examples, diluents or fillers include lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starch, directly compressible starch, microcrystalline cellulose, cellulose, sorbitol, sucrose, sucrose-based materials, calcium sulfate, dicalcium phosphate, and glucose. As non-limiting examples, disintegrants and hyperdistegrants include croscarmellose sodium, starch, starch derivatives, clay, gum, cellulose, cellulose derivatives, alginate, croscarmellose, sodium starch glycolate, and microcrystalline cellulose. As non-limiting examples, flavoring agents or desensitizing agents include spray-dried flavorings, essential oils, and ethyl vanillin. As non-limiting examples, plasticizers include polyethylene glycol, citrates (e.g., triethyl citrate, tributyl citrate, triethyl citrate), acetylated monoglycerides, glycerol, triacetyl glycerol, propylene glycol, phthalates (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol, and dibutyl sebacate. As non-limiting examples, preservatives include ascorbic acid, boric acid, sorbic acid, benzoic acid and its salts, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds. As non-limiting examples, solvents include alcohols, ketones, esters, chlorinated hydrocarbons, and water. As non-limiting examples, sweeteners include natural sweeteners such as maltose, sucrose, glucose, sorbitol, glycerol, and dextrin, as well as artificial sweeteners such as aspartame, saccharin, and saccharin salts. As non-limiting examples, thickeners (viscosity modifiers, thickening agents, curing agents) include sugars, polyvinylpyrrolidone, cellulose, polymers, high molecular weight polyethylene glycol (e.g., PEG 8000), and alginate. As non-limiting examples, additives also include proteins (e.g., collagen, gelatin, corn protein, gluten, mussel protein, lipoprotein); carbohydrates (e.g., alginate, carrageenan, cellulose derivatives, pectin, starch, chitosan); gums (e.g., xanthan gum, gum arabic); cetacean; natural or synthetic waxes; carnauba wax. Wax), fatty acids (e.g., stearic acid, hydroxystearic acid), fatty alcohols; sugars; shellac, such as sugar-based (e.g., lactose, sucrose, glucose) or starch-based shellac; polysaccharide-based shellac (e.g., maltodextrin and maltodextrin derivatives, dextrin, cyclodextrin and cyclodextrin derivatives); cellulose-based shellac (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, cellulose acetate butyrate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose phthalate); inorganic substances, such as dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc, and titanium dioxide; polyols, such as mannitol, xylitol, and sorbitol; polyethylene glycol esters; and polymers, such as alginate, poly(lactide-co-lactide), gelatin, cross-linked gelatin, and agar.

[0192] In some embodiments, at least one pharmaceutically acceptable carrier is any carrier suitable for delivering an effective amount of a steroidal compound (e.g., testosterone alkyl ester) to an individual. In some embodiments, at least one pharmaceutically acceptable carrier is or includes a hydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilic additive). In some embodiments, at least one pharmaceutically acceptable carrier is a lipophilic carrier (e.g., a lipophilic surfactant or lipophilic additive). In some embodiments, at least one pharmaceutically acceptable carrier is both a hydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilic additive) and a lipophilic carrier (e.g., a lipophilic surfactant or lipophilic additive). In some embodiments, the hydrophilic carrier is a hydrophilic triglyceride. In a specific embodiment, the hydrophilic triglyceride is polyoxygenated castor oil or polyoxygenated hydrogenated castor oil. In some embodiments, any pharmaceutical composition provided herein consists substantially of a lipophilic carrier or a combination of lipophilic carriers. In some embodiments, any pharmaceutical composition provided herein includes a lipophilic carrier and less than 10% w / w, less than 5% w / w, or substantially no hydrophilic carrier. In some embodiments, any pharmaceutical composition provided herein includes a lipophilic carrier and a hydrophilic carrier of less than 10% w / w, less than 5% w / w, or substantially no hydrophilic carrier. In some embodiments, the pharmaceutical composition includes a carrier (e.g., a hydrophilic carrier and / or a lipophilic carrier), and the pharmaceutical composition is a solid, semi-solid, gel, jelly, paste, etc. In some embodiments, for example, a pharmaceutical composition comprising a hydrophilic carrier and / or a lipophilic carrier, a viscosity enhancer, or a curing agent (coagulant) is used to provide a pharmaceutical composition in the form of a solid, semi-solid, gel, jelly, paste, etc. Therefore, in some embodiments, at least one pharmaceutically acceptable carrier is a hydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilic additive) and a viscosity enhancer or curing agent (coagulant). In some embodiments, at least one pharmaceutically acceptable carrier is a lipophilic carrier (e.g., a lipophilic surfactant or lipophilic additive) and a viscosity enhancer or curing agent (coagulant). In some embodiments, at least one pharmaceutically acceptable carrier is or includes a hydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilic additive), a lipophilic carrier (e.g., a lipophilic surfactant or lipophilic additive), and a viscosity enhancer or curing agent (coagulant). In some embodiments, at least one pharmaceutically acceptable carrier is or includes a hydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilic additive), a lipophilic carrier (e.g., a lipophilic surfactant or lipophilic additive), and an antioxidant.In some embodiments, at least one pharmaceutically acceptable carrier is or includes a hydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilic additive), a lipophilic carrier (e.g., a lipophilic surfactant or lipophilic additive), a thickener or curing agent (coagulant), and an antioxidant. In some embodiments, at least one pharmaceutically acceptable carrier is or includes an amphiphilic or zwitterionic carrier (e.g., an amphiphilic surfactant or amphiphilic additive). In some embodiments, a pharmaceutically acceptable carrier is any carrier suitable for achieving one or more of the pharmacokinetic and / or pharmacodynamic characteristics described herein.

[0193] As non-limiting examples, curing agents (coagulants) include PEG 3350, PEG 4000, PEG 6000, PEG8000, poloxamer 188, poloxamer 407, cetyl ester, wax, beeswax, palmitoyl stearate, stearic acid, etc.

[0194] refer to Figure 1 Absolute actual PK levels can be obtained from compositions including lipophilic and hydrophilic additives by single-dose TD administration.

[0195] refer to Figure 1 The simulated absolute value change at a daily dose of 600 mg is disclosed (however, the minimum daily dose can be as low as 200 mg / day) to support some thresholds in the implementation: TC avg Changes included increased free T, decreased SHBG, increased albumin, decreased HB1ac, decreased ammonia, increased muscle mass, decreased fat mass, and decreased TNF.

[0196] The TDPC compositions of the present invention were prepared and their performance characteristics, such as the physical form in which the TD is completely dissolved without TD crystals during preparation and storage, were evaluated. The solubilized form of TD in a single-unit dosage form is convenient and preferred for biopharmaceutical performance and stability during storage, providing sufficient shelf life. Surprisingly, the compositions described in Table F: F3, F4, F8, F9, F12, and F14, produced dissolved TD with no significant suspended undissolved crystals, at a loading of at least 25% w / w, which could be formulated into stable single-unit dosage forms. Furthermore, the ratio of lipophilic additive to hydrophilic surfactant was at least 7, and the ratio of fatty acid to hydrophilic surfactant was at least 6. It was also surprisingly found that TD compositions with a TD / fatty acid ratio of at least 4 but not more than 2 were crucial for enabling the dissolved compositions to be encapsulated into single-unit dosage forms, achieving smaller and single dosage forms that facilitate administration and performance, and without the formation of undissolved drug crystals during manufacturing and storage.

[0197] In contrast, when a single-unit dosage form is formulated with a desired drug loading of at least 25% w / w, the compositions F1, F2, F5, F6, F7, F10, F11 and F13 described in Table F contain undissolved TD crystals in the composition. Furthermore, the undesirable properties of suspensions containing undissolved TD crystals may lead to impaired solubility / absorption performance, and undissolved TD crystals exhibit undesirable physical properties during RT storage.

[0198] Exemplary markers of the present invention (preferably relative to comparable non-TD administration) may include, for example, at least about 1 unit (SBP, 1 mmHg), less HDL reduction, reversal, or even less reduction, with an average HDL reduction of at least about 1 mg / dL. Exemplary benefits of the present invention may include, for example, higher bacterial inhibitory activity relative to other fatty acid esters (e.g., with regard to Escherichia coli inhibition), or an inhibitory activity benefit of more than twice that of TU (at least 50% better than TU administration).

[0199] Modification of the composition or dosage form comprising the TD, as exemplified in this invention, can allow for a predetermined increase in antibacterial benefit. Treatment with TDPC can achieve an increase or no decrease in antibacterial benefit, an increase or no decrease in antifungal benefit, an increase or no decrease in antiviral benefit, or any combination thereof. As used herein, when describing antibacterial benefits, the description of this invention also applies to the potential for antifungal or antiviral benefits. For example, a subject anticipating a decrease in antibacterial activity may see a lower decrease in antibacterial activity, no change in antibacterial activity, or an increase. As another example, a subject may see an increase in antibacterial activity.

[0200] As a non-limiting example, treatment with TDPC can inhibit bacterial activity, including Propionibacterium acnes, Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli (Migula) Castellani and Chalmers 25922 (ATCC 25922), Group A Streptococcus, Group B Streptococcus, Group D Streptococcus, Mycobacterium tuberculosis, Streptococcus pneumoniae, Listeria monocytogenes, Helicobacter pylori, Bacteroides and Clostridium, Clostridium perfringens, CNCTC 5459 (Clostridium perfringens strain), Enterococcus faecalis, Clostridium difficile, Proteus, Proteus mirabilis, or any combination thereof.

[0201] As a non-limiting example, treatment with TDPC can inhibit fungal activity, which may include Candida albicans, Aspergillus niger, Fusarium species, or any combination thereof.

[0202] As a non-limiting example, treatment with TDPC can suppress viral activity, and the virus may include vesicular stomatitis virus, herpes simplex virus, herpes simplex virus type 1, herpes simplex virus type 2, Visna virus, respiratory syncytial virus, Junin virus, or any combination thereof.

[0203] The formulation and manufacturing of TDPC can affect its antimicrobial efficacy. For example, TDPC formulations with hydrophilic carriers (e.g., hydrogenated polyoxymethylene vegetable oils or glycerides, PEG glycerides of fatty acid esters, polyglycerol-10 fatty acid esters, polysorbate 20, poloxamer, polysorbate 80, polyoxymethylene 40 hydrogenated castor oil, polyoxymethylene 35 castor oil, sodium docusate, sodium docusate, poloxamer, polyethylene glycol 1000 tocopheryl succinate, PEG) may have a greater antimicrobial benefit than TDPCs without hydrophilic carriers. Similarly, TDPCs with less than about 40%, 30%, 20%, 10%, or 5% w / w% hydrophilic carriers may have a greater antimicrobial benefit than TDPCs with more hydrophilic carriers. As another example, TDPC formulations with lipophilic carriers (e.g., lipophilic surfactants or lipophilic additives) may have a greater antimicrobial benefit than TDPCs without lipophilic carriers. Similarly, TDPCs with a lipophilic carrier of greater than about 10%, 20%, 30%, 40%, 50%, or 60% w / w% can have a greater antimicrobial benefit than TDPCs with a lower w / w% ...

[0204] As another example, the formulation and manufacture of TDPC with an effective amount of TD can provide a greater antibacterial benefit than testosterone undecanoate pharmaceutical compositions (TUPC) with an effective amount of testosterone undecanoate (TU). Therefore, non-testosterone undecanoate pharmaceutical compositions can have a greater antibacterial benefit when compared with TUPC.

[0205] As another example, antimicrobial benefits can occur when a sufficient load of non-undecanoic acid testosterone ester is present and the ester provides an antimicrobial benefit. For instance, when comparing EHEC biofilm formation between EHEC formed in the presence of undecanoic acid and EHEC formed in the presence of lauric acid, lauric acid significantly inhibited EHEC biofilm formation differently from the control group (p<0.001), while undecanoic acid did not. Furthermore, lauric acid has been reported to have antimicrobial benefits against the following: Propionibacterium acnes, Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli (Migula) Castellani and Chalmers 25922 (ATCC 25922), Group A Streptococcus, Group B Streptococcus, Group D Streptococcus, Mycobacterium tuberculosis, Streptococcus pneumoniae, Listeria monocytogenes, Helicobacter pylori, Bacteroides and Clostridium, Clostridium perfringens, and CNCTC. 5459 (Clostridium aerogenes strain), Enterococcus faecalis, Clostridium difficile, Proteus, and Proteus mirabilis; possesses antifungal benefits against Candida albicans, Aspergillus niger, and certain Fusarium species; and possesses antiviral benefits against vesicular stomatitis virus, herpes simplex virus, herpes simplex virus type 1, herpes simplex virus type 2, Visna virus, respiratory syncytial virus, and Junin virus. The formulation and manufacture of TDPC allows for the application of biorelevant amounts of lauric acid, which can enhance the antimicrobial benefits. For example, in the formation of bioactive testosterone, the cleavage of TD laurate can provide an amount of lauric acid that allows for the antimicrobial benefits.

[0206] The exemplary oral composition was administered as a single daily dose, with serum drug levels monitored at days 1, 4, 8, 12, 16, 20, and 24 over a 24-week period. CT scans of the L3 region were also collected at weeks 12 and 24 during screening. In a double-blind trial, subjects with sarcopenia and cirrhosis awaiting liver transplantation were administered the exemplary oral composition and randomly assigned to receive either the exemplary oral formulation (LPCN 1148 (i.e., TDPC)) or placebo for 24 weeks.

[0207] Key topline results after 24 weeks of treatment showed that, compared with the placebo group, the L3-SMI of subjects in the LPCN 1148 group changed by 4.4 cm from baseline. 2 / m 2 The 95% CI was 1.3 cm. 2 / m 2 Up to 7.4 cm 2 / m 2 Key results after the 12-week treatment period showed that the L3-SMI in the LPCN 1148 group decreased by 2.6 cm from baseline.2 / m 2 The 95% CI was 0.8 cm. 2 / m 2 Up to 4.5 cm 2 / m 2 Furthermore, key results following the 24-week treatment period showed that the L3-SMI in the LPCN 1148 group decreased by 3.6 cm from baseline. 2 / m 2 The 95% CI was 1.7 cm. 2 / m 2 up to 5.5 cm 2 / m 2 .

[0208] Key outcomes following the 24-week treatment period showed that LPCN 1148 had 2 HE events with a CTAE grade greater than 1, compared to 6 in the placebo group. Similarly, survival estimates for HE events were as follows: Figure 2 As shown, this indicates that the probability of an HE event occurring over time is lower during LPCN 1148 administration compared to placebo administration. Risk outcomes can also be characterized by the hazard ratio for HE events, which shows the change in risk over time for subjects treated with LPCN 1148 and placebo. A hazard ratio less than one (e.g., LPCN 1148 divided by the placebo group) describes a lower risk or probability of the event occurring. When comparing LPCN 1148 to the placebo group, the hazard ratio was calculated to be 0.266 with a standard error of 0.298. This hazard ratio takes into account both the HE events and the timing of each HE event during the 24-week trial, with the total number of subjects decreasing with each HE event and increasing once the HE events have ended.

[0209] Key results after 24 weeks of treatment showed that hemoglobin in LPCN1148 increased by 1.30 g / dL compared to a change of -0.16 g / dL in the placebo group, and this change in LPCN1148 was statistically significant compared to both the 0 and placebo groups. Other key results after 24 weeks of treatment showed that the total number of subjects with anemia decreased from 11 subjects (73%) in LPCN1148 at baseline to 7 subjects (47%) at week 24, with 4 subjects (36%) experiencing remission of anemia and no new cases of anemia (0%). The number of subjects with anemia in the placebo group remained unchanged, from 7 subjects (50%) at baseline to 7 subjects (54%) at week 24, with 1 subject (14%) experiencing remission of anemia and 1 subject (17%) experiencing new cases of anemia. Treatment with LPCN1148 improves the resolution of anemia.

[0210] Table H1 shows the mean PGI-C in the LPCN 1148 and placebo groups during the visit.

[0211] Key results are shown in Table H1. After 4 weeks of treatment, the mean PGI-C score was 2.62 in the LPCN 1148 group and 3.69 in the placebo group. After 8 weeks of treatment, the mean PGI-C score was 3.00 in the LPCN 1148 group and 3.85 in the placebo group. After 12 weeks of treatment, the mean PGI-C score was 2.6 in the LPCN 1148 group and 3.69 in the placebo group. After 16 weeks of treatment, the mean PGI-C score was 2.53 in the LPCN 1148 group and 3.92 in the placebo group. Key results after 20 weeks of treatment showed that the mean PGI-C score of participants in the LPCN 1148 group was 3.00, while the mean PGI-C score of participants in the placebo group was 3.46. Key results after 24 weeks of treatment showed that the mean PGI-C score of participants in the LPCN 1148 group was 3.00, while the mean PGI-C score of participants in the placebo group was 3.85.

[0212] Key results following the 24-week treatment period showed that, compared to the placebo group, the IMAT area in the LPCN 1148 group decreased from baseline by 1.25 cm. 2Similarly, key results after the 24-week treatment period showed that, compared with the placebo group, the HQM area in the LPCN 1148 group changed by 10.82 cm from baseline. 2 Furthermore, when compared with the placebo group, key results after the 24-week treatment period showed that the LQM area in the LPCN 1148 group changed from baseline by 3.91 cm. 2 .

[0213] Key results after a 24-week treatment period showed a 270-foot change in the 6-minute walk test compared to -16 feet in the placebo group. Furthermore, the change in total time to complete the EncephalApp Stroop test was -4.8 seconds in the LPCN 1148 group, compared to 13.8 seconds in the placebo group. Additionally, the total hospital stay for the LPCN 1148 group was 54 days, compared to 117 days in the placebo group. Treatment with LPCN 1148 can provide benefits in both the 6-minute walk test and the Stroop test.

[0214] Through the oral pharmaceutical compositions or dosage forms exemplified in this invention, modifications to the composition or form containing a TD can result in a predetermined increase in muscle mass or prevent a predetermined decrease in muscle mass. Treatment with a TDPC can increase or prevent a decrease in L3-SMI. For example, subjects expected to lose muscle mass (e.g., subjects with end-stage liver disease) may experience an increase or prevent a decrease in L3-SMI. Treatment with a TDPC can result in subjects experiencing fewer decompensated events (e.g., HE). Treatment with a TDPC can reduce the risk of relapse of overt HE. Treatment with a TDPC can result in subjects experiencing decompensated events (e.g., HE) at the time of treatment recovering from decompensated events more quickly. Treatment with a TDPC can result in subjects experiencing a perceived improvement in their quality of life (e.g., PGI-C). Treatment with a TDPC can increase a subject's muscle mass (e.g., decreased IMAT, increased low-quality muscle (LQM), and increased high-quality muscle (HQM)).

[0215] Exemplary benefits of important outcomes indicate that overall benefits can occur at times including 4, 8, 12, 16, 20, and 24 weeks after treatment initiation. For example, benefits may appear as early as 4 weeks. As another example, benefits may appear as early as 12 weeks. As yet another example, benefits may appear as early as 24 weeks.

[0216] In individuals whose muscle mass and quality decline over time, the benefits of maintaining or improving muscle mass can be applied in combination with treatments where muscle loss may be a side effect or muscle gain may enhance the treatment. For example, GLP-1 agonist treatment is known to reduce overall weight loss; however, up to 40% of weight loss may result from fat-free weight loss (see, for example, the article “Once-Weekly Semaglutide in Adults with Overweight or Obesity” published on February 10, 2021, in the New England Journal of Medicine (NEJM), Volume 384, Issue 11, and available on the NEJM website, e.g., https: / / www.nejm.org / doi / full / 10.1056 / NEJMoa2032183). Oral medication combinations similar to those used in the LPCN 1148 treatment group can be used concurrently with GLP-1 agonist treatment. GLP-1 agonists can be selected from pemvidutide, semaglutide, liraglutide, dulaglutide, tirzepatide, natural GLP-1, dulaglutide, exenatide, exenatide ER, lixisenatide, albiglutide, or other GLP-1 agonist peptides. Combination therapy including TD or oral pharmaceutical compositions (TDPCs) containing or derived from TD can reduce the percentage of lean body mass lost during muscle loss. Combination therapy including TDPCs can maintain or increase lean body mass during muscle loss.

[0217] For example, the percentage of lean body mass loss during weight loss due to combination therapy or follow-up treatment including TDPC can be 30%, 20%, 15%, 10%, 5%, 0%, -5%, and -10% (negative % loss indicates the percentage of muscle gain during weight loss). For instance, the percentage of lean body mass loss during weight loss due to combination therapy or follow-up treatment could be 5%. As another example, the percentage of lean body mass loss during weight loss due to combination therapy or follow-up treatment could be 0%. As another example, the percentage of lean body mass gain during weight loss due to combination therapy or follow-up treatment could be 5%.

Claims

1. A method of treating a condition in a subject, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises or is prepared from TDPC, and wherein the administration results in at least one of the following, compared to at least one of the subject's pre-TDPC administration state and placebo administration: The subjects' cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay did not worsen, and The subjects showed improvement in at least one of the following: cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay.

2. The method of claim 1, wherein the administration results in the subject receiving at least one of the following: Decreased SHBG (sex hormone-binding globulin) levels Elevated albumin levels The degree of weakness has lessened. Sarcopenia has lessened. Intramuscular fat deposition has lessened. Reduced body fat Systemic ammonia levels decreased. portal hypertension has eased. Abnormally high levels of at least one of ALT, AST, GGT, and ALP decreased. Fat-free weight gain, Increased free testosterone Total testosterone C avg Increase by at least 100 ng / dL. Elevated hematocrit level Elevated hemoglobin levels Decreased inflammatory markers Increased L3-SMI (skeletal muscle index), PGI-C reduction, HE events decreased. VAT (visceral adipose tissue) is reduced. SAT (subcutaneous adipose tissue) decreases. FAT (VAT plus SAT) decreases. Increased muscle surface area, and IMAT decreased.

3. The method of claim 1, wherein the application comprises oral administration, and wherein the application results in simultaneous improvement of muscle health and CNS health.

4. The method of claim 1, wherein the subject suffers from cirrhosis and at least one of the following: A MELD score of at least 12 is required. A MELD score of no more than 25 MELD scores range from 12 to 25. At least one event of miscompensation. BMI > 20, L3 musculoskeletal index <55cm 2 / m 2 , Liver weakness index >3 The ALT / AST ratio is approximately 1. AST > 40 U / L Abnormal ALT levels, and Abnormal ALP levels.

5. The method of claim 4, wherein the total daily dose of the pharmaceutical composition comprises an amount of about 150 mg to about 600 mg administered in at least one of a once-daily or twice-daily regimen.

6. The method of claim 1, wherein the subject suffers from cirrhosis and one or more of the following: A MELD score of at least 12 is required. A MELD score of no more than 25 MELD scores range from 12 to 25. At least one event of miscompensation. BMI > 20, L3 musculoskeletal index <55cm 2 / m 2 , Liver weakness index >3 The ALT / AST ratio is approximately 1. AST > 40 U / L Abnormal ALT levels, and Abnormal ALP levels.

7. The method of claim 1, wherein the subject has at least one of dysregulated protein homeostasis, abnormally high SHBG levels, and abnormally low albumin levels, and Subjects requiring testosterone intervention are required if their morning baseline testosterone levels are <400 ng / dL, <350 ng / dL, <300 ng / dL, or <250 ng / dL.

8. The method of claim 1, wherein the cardiovascular risk includes the risk of adverse changes in at least one of SBP, DBP, HDL levels, ascites, homocysteine ​​levels, and myocardial mass or strength, and The aforementioned deterioration in cardiovascular health includes adverse changes in at least one of the following: SBP, DBP, HDL, ascites, homocysteine ​​levels, cardiac reactive protein levels, and myocardial mass or strength. The improvement in cardiovascular health mentioned above includes a favorable change in at least one of SBP, DBP, HDL levels, homocysteine ​​levels, and myocardial mass or strength, and The aforementioned deterioration in prostate health includes adverse changes in at least one of the following: prostate size, prostate weight, and BPH symptoms: The improvement in prostate health mentioned above includes favorable changes in at least one of the following: prostate size, prostate weight, and BPH symptoms: The aforementioned deterioration in muscle health includes adverse changes in at least one of muscle mass, muscle strength, muscle function, and muscle toxicity, and The improvement in muscle health mentioned above includes favorable changes in at least one of muscle mass, muscle strength, muscle function, and muscle toxicity, and The aforementioned deterioration in CNS or GI health includes at least one of the following adverse changes: depression, seizures, cognition, risk of developing HE, risk of relapse of a dominant HE event of grade 1.0 or higher, HE relapse, breakthrough HE episode, HE-related hospitalization, length of time between HE hospitalizations, reduction of at least one of the following for subjects with HE events or HE events of grade 1.0 or higher: at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, and at least about 80%; reduction of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%. At least one of the following: %, at least approximately 70% and at least approximately 80%; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; duration before the onset of dominant HE episodes; HE recurrence and reversal; occurrence of asterixis; mental state; intellectual function; psychometric test results; and neurophysiological test results. The improvement in CNS health described therein includes favorable changes in at least one of the following: depression, seizures, cognition, risk of developing HE, risk of relapse of dominant HE grade ≥1.0, HE relapse, breakthrough HE episode, HE-related hospitalization, length of time between HE hospitalizations, reduction of at least one of the following for subjects with HE events or HE grade ≥1.0: at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, and at least about 80%; reduction of at least about 20%, at least about 30%, at least about 40%, at least about 50%, and at least about 60%. At least one of the following: at least approximately 70% and at least approximately 80%; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; duration before the onset of dominant HE episodes; HE recurrence and reversal; occurrence of asterixis; mental state; intellectual function; results of psychometric tests and neurophysiological tests; and The aforementioned deterioration in GI health includes at least one of the following adverse changes: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH, NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC and PBC, and The improvement in GI health mentioned therein includes favorable changes in at least one of the following: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH, NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC, and PBC.

9. The method of claim 8, wherein the adverse change in SBP comprises an increase in SBP of at least 1.7 mmHg, and wherein the favorable change in SBP comprises a decrease in SBP of at least 1 mmHg.

10. The method according to claim 1, wherein the disease comprises at least one of the following: cancer, sarcoma, melanoma, lymphoma, leukemia, end-stage liver disease, advanced liver disease, chronic liver disease, end-stage lung disease, chronic kidney disease, end-stage renal disease, end-stage musculoskeletal system disease, end-stage cardiovascular disease, end-stage hematologic disease, end-stage endocrine gland disease, end-stage gastrointestinal disease, end-stage skin disease, end-stage reproductive organ disease, end-stage central nervous system disease, liver fibrosis, liver inflammation, hepatic steatosis, HE, and other related conditions. Relapse of hepatic encephalopathy (HE), NASH, NAFLD, pre- / post-liver transplantation, decompensated cirrhosis, PBC, PSC, ILD, pneumonia, IPF, muscle loss, cachexia, sarcopenia, asthenia, type 1 diabetes, type 2 diabetes, hyperglycemia, glucose intolerance, hypogonadism, hypogonadotropic hypogonadism, metabolic syndrome, visceral obesity, obesity, impaired wound healing, lumbar disc herniation, intramuscular fat deposition syndrome, cancer, CHF, pulmonary fibrosis, COPD, and hereditary angioedema.

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

12. The method of claim 11, wherein the at least one additive further comprises at least one of a lipophilic additive and a hydrophilic additive.

13. The method of claim 1, wherein the TDPC comprises at least one of the following: TD comprising approximately 27 wt% to approximately 32 wt% of the TDPC, A hydrophilic surfactant comprising no more than about 5 wt% of the TDPC, and The excipient comprises at least one of a minimum of 50 wt%, a minimum of 55 wt%, a minimum of 60 wt%, a minimum of 65 wt%, and a minimum of 70 wt% of the TDPC.

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

15. The method of claim 14, wherein the at least one carrier further comprises at least one of a lipophilic carrier and a hydrophilic carrier.

16. The method of claim 15, wherein the at least one lipophilic carrier further comprises at least one selected from a lipophilic surfactant and a lipophilic additive, and wherein the hydrophilic carrier further comprises at least one selected from a hydrophilic surfactant and a hydrophilic additive.

17. The method of claim 15, wherein the at least one lipophilic carrier comprises at least one selected from fatty acids, fatty acid derivatives, vegetable oils, vegetable oil derivatives, monoglycerides, diglycerides, triglycerides, monoglyceride derivatives, diglyceride derivatives, triglyceride derivatives, sterols, phytosterols, tocopherols, tocotrienols or their derivatives, tocopherol succinate, tocopherol acetate, and fish oil, and wherein the hydrophilic carrier comprises at least one selected from polyoxyethylene hydrogenated vegetable oil, polyoxyethylene vegetable oil, polyethylene glycol fatty acid esters, mixtures of polyethylene glycol fatty acid monoglycerides, mixtures of polyethylene glycol fatty acid diglycerides, polysorbate esters, polyethylene glycol derivatives of tocopherol, alcohols, and alcohol derivatives.

18. The method of claim 17, wherein the at least one fatty acid comprises at least one selected from oleic acid, lauric acid, stearic acid, and derivatives thereof, and wherein the vegetable oil comprises at least one selected from peppermint oil, sesame oil, borage oil, castor oil, corn oil, cottonseed oil, and derivatives thereof, and wherein the monoglyceride derivative comprises at least one selected from monolinoleic acid glyceride and sorbitol monofatty acid, and wherein the diglyceride derivative comprises glyceryl stearate palmitate, and wherein the polyoxyethylene hydrogenated vegetable oil comprises PEG hydrogenated castor oil, and wherein the alcohol comprises at least one selected from ethanol and benzyl alcohol; and wherein the alcohol derivative comprises benzyl benzoate.

19. The method of claim 1, wherein the pharmaceutical composition further comprises at least one of tablets, capsules, pouches, gel capsules, suspensions, solutions, beverages, gels, syrups, dispersions, emulsions, sprays, lozenges, microemulsions, nanoemulsions, elixirs, pastes, powders, and granules.

20. The method of claim 1, wherein the method comprises at least one of the following: Dosing regimens including at least one of QD and BID regimens, Dosing regimens including at least one of titration regimens and non-titeration regimens. The total daily dose of TD administration is at least one of about 150 mg to about 1000 mg, about 350 mg to about 850 mg, and about 500 mg to about 700 mg. The dosage forms of the TDPC include single-dose unit dosage forms, two-dose unit dosage forms, three-dose unit dosage forms, and four-dose unit dosage forms.

21. A method of treating a condition in a subject, the method comprising administering a TDPC to the subject, wherein the TDPC comprises or is prepared therefrom at least one lipophilic additive, the at least one lipophilic additive comprising at least one of fatty acids, fatty acid derivatives, and combinations thereof, and wherein the administration results in at least one of the following, compared to at least one of the subject's pre-TDPC administration state and placebo administration: The subjects' cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay did not worsen, and The subjects showed improvement in at least one of the following: cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay.

22. The method of claim 21, wherein the administration results in the subject receiving at least one of the following: SHBG levels decreased Elevated albumin levels The degree of weakness has lessened. Sarcopenia has lessened. Intramuscular fat deposition has lessened. Reduced body fat Systemic ammonia levels decreased. portal hypertension has eased. Abnormally high levels of at least one of ALT, AST, GGT, and ALP decreased. Fat-free weight gain, Free T increases, Total TC avg Increase by at least 100 ng / dL. Elevated hematocrit level Elevated hemoglobin levels Decreased inflammatory markers L3-SMI increases, PGI-C reduction, HE events decreased. VAT reduction SAT decreased FAT decreased, Increased muscle surface area, and IMAT decreased.

23. The method of claim 21, wherein the fatty acid comprises at least one of oleic acid or a derivative thereof, lauric acid or a derivative thereof, stearic acid or a derivative thereof, and combinations thereof.

24. The method of claim 21, wherein the TDPC comprises at least one of the following: the w / w ratio of the TD to the lipophilic additive is at least one of about 0.38, about 0.52, and about 0.60; and the w / w ratio of the TD to the hydrophilic additive is at least one of about 4.0, about 5.4, and about 6.

5.

25. The method of claim 21, wherein the application comprises oral administration, and wherein the application results in simultaneous improvement of muscle health and CNS health.

26. The method of claim 21, wherein the subject suffers from cirrhosis with a MELD score of at least 12, and at least one of the following: At least one event of miscompensation. BMI > 20, L3 musculoskeletal index <55cm 2 / m 2 , Liver weakness index >3 The ALT / AST ratio is approximately 1. AST > 40 U / L Abnormal ALT levels, and Abnormal ALP levels.

27. The method of claim 26, wherein the total daily dose of the pharmaceutical composition comprises an amount of about 150 mg to about 600 mg administered in at least one of a once-daily or twice-daily regimen.

28. The method of claim 21, wherein the subject has at least one of dysregulated protein homeostasis, abnormally high SHBG levels, and abnormally low albumin levels, and Subjects requiring testosterone intervention are required if their morning baseline testosterone levels are <400 ng / dL, <350 ng / dL, <300 ng / dL, or <250 ng / dL.

29. The method of claim 21, wherein the cardiovascular risk includes the risk of adverse changes in at least one of SBP, DBP, HDL levels, homocysteine ​​levels, and myocardial mass or strength, and The aforementioned deterioration in cardiovascular health includes adverse changes in at least one of the following: SBP, DBP, HDL, homocysteine ​​levels, cardiac reactive protein levels, and myocardial mass or strength. The improvement in cardiovascular health mentioned above includes a favorable change in at least one of SBP, DBP, HDL levels, homocysteine ​​levels, and myocardial mass or strength, and The aforementioned deterioration in prostate health includes adverse changes in at least one of the following: prostate size, prostate weight, and BPH symptoms: The improvement in prostate health mentioned above includes favorable changes in at least one of the following: prostate size, prostate weight, and BPH symptoms: The aforementioned deterioration in muscle health includes adverse changes in at least one of muscle mass, muscle strength, muscle function, and muscle toxicity, and The improvement in muscle health mentioned above includes favorable changes in at least one of muscle mass, muscle strength, muscle function, and muscle toxicity, and The aforementioned deterioration in CNS health includes at least one of the following adverse changes: depression, seizures, cognition, risk of developing HE, risk of recurrence of dominant HE grade ≥1.0, HE recurrence, breakthrough HE episode, HE-related hospitalization, length of time between HE hospitalizations, reduction of at least one of the following for subjects with HE events or HE grade ≥1.0: at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, and at least about 80%; reduction of at least about 20%, at least about 30%, at least about 40%, at least about 50%, and at least about 60%. At least one of the following: at least approximately 70% and at least approximately 80%; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; duration before the onset of dominant HE episodes; HE recurrence and reversal; occurrence of asterixis; mental state; intellectual function; results of psychometric tests and neurophysiological tests; and The improvement in CNS health described therein includes favorable changes in at least one of the following: depression, seizures, cognition, risk of developing HE, risk of relapse of dominant HE grade ≥1.0, HE relapse, breakthrough HE episode, HE-related hospitalization, length of time between HE hospitalizations, reduction of at least one of the following for subjects with HE events or HE grade ≥1.0: at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, and at least about 80%; reduction of at least about 20%, at least about 30%, at least about 40%, at least about 50%, and at least about 60%. At least one of the following: at least approximately 70% and at least approximately 80%; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; at least one of the following: a reduction of at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, and at least approximately 80% in dominant HE events; duration before the onset of dominant HE episodes; HE recurrence and reversal; occurrence of asterixis; mental state; intellectual function; results of psychometric tests and neurophysiological tests; and The aforementioned deterioration in GI health includes at least one of the following adverse changes: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH, NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC and PBC, and The improvement in GI health mentioned therein includes favorable changes in at least one of the following: diarrhea, microbial infection, Clostridium difficile infection, advanced liver disease, chronic liver disease, cirrhosis, chronic liver failure, number of liver injury markers, end-stage liver disease, liver fibrosis, liver inflammation, hepatic steatosis, NASH, NAFLD, pre-transplant liver condition, post-transplant liver condition, PSC, and PBC.

30. A method of treating a condition in a subject, the method comprising administering a TDPC to the subject, wherein the TDPC comprises or is prepared therefrom at least one lipophilic additive, the at least one lipophilic additive comprising at least one of fatty acids, fatty acid derivatives, and combinations thereof, and wherein, compared to an administration substantially equivalent to that of a pharmaceutical composition comprising TU and substantially free of TD (NDPC), the administration results in at least one of the following: The subjects had a lower incidence of deterioration in at least one of the following: cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay. The subjects had greater improvements in at least one of the following: cardiovascular risk, cardiovascular health, prostate health, muscle health, CNS health, GI health, cellular health, and median length of hospital stay.

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