WO2025245024A1

WO2025245024A1 - Compositions comprising liothyronine and methods of making thereof

Info

Publication number: WO2025245024A1
Application number: PCT/US2025/030037
Authority: WO
Inventors: Raj G. Suryanarayanan; Wenqi GAI; Robert J. Schumacher; Craig M. FLORY; Timothy P. Rich; David H. Ingbar
Original assignee: University of Minnesota Twin Cities; University of Minnesota System
Current assignee: University of Minnesota Twin Cities; University of Minnesota System
Priority date: 2024-05-20
Filing date: 2025-05-19
Publication date: 2025-11-27
Anticipated expiration: 2026-11-20

Abstract

Solid pharmaceutical compositions and liquid pharmaceutical compositions that include 3,3',5'-triiodothyronine or a prodrug of 3,3',5'-triiodothyronine, a salt thereof, a hydrate thereof, or any combination thereof. The solid pharmaceutical composition includes an excipient. Methods of making the solid pharmaceutical composition. Methods of administering the solid pharmaceutical compositions and liquid pharmaceutical compositions to a subject.

Description

COMPOSITIONS COMPRISING LIOTHYRONINE AND METHODS OF MAKING

THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/649,592, filed May 20, 2024, which is incorporated herein by reference in its entirety.

SUMMARY

[0002] This disclosure describes, in one aspect, a solid pharmaceutical composition. The solid pharmaceutical composition includes T3 (3,3’5-triiodo-L-thyronine), a prodrug thereof, a salt thereof, a hydrate thereof, or any combination thereof. The solid pharmaceutical composition further includes an excipient. In one or more embodiments, the excipient is a bulking agent.

[0003] In one or more embodiments, the pharmaceutical composition includes 0.0001 wt-% to 2 wt-% T3 equivalents. In one or more embodiments, the pharmaceutical composition includes a T3 sodium salt.

[0004] In one or more embodiments, the bulking agent comprises mannitol. In one or more embodiments, solid pharmaceutical composition includes 50 wt-% to 99 wt-% of the bulking agent.

[0005] In one or more embodiments, the solid pharmaceutical composition further includes a buffer agent. In one or more embodiments, the buffer agent includes tris(hydroxymethyl)aminomethane or a salt thereof. In one or more embodiments, the pharmaceutical composition includes 1 wt-% to 5 wt-% of the buffer agent.

[0006] In one or more embodiments, the solid pharmaceutical composition includes a lyophilized solid that includes the T3, prodrug thereof, salt thereof, or any combination thereof and the bulking agent. In one or more embodiments where the solid pharmaceutical composition includes a buffer agent, the lyophilized solid further includes the buffer agent.

[0007] In another aspect, this disclosure describes a liquid pharmaceutical composition. In one or more embodiments, the liquid pharmaceutical composition includes the solid pharmaceutical composition of any one of the aspects or embodiments dissolved in carrier. In one or more embodiments where the solid pharmaceutical composition is or includes a lyophilized solid, the liquid composition includes the lyophilized solid reconstituted in a carrier.

[0008] In one or more embodiments, the carrier includes water. In one or more embodiments, the carrier includes saline. In one or more embodiments, the carrier includes dextrose.

[0009] In one or more embodiments, the liquid pharmaceutical composition has a pH of 2 to 11. In one or more embodiments, the liquid pharmaceutical composition has a pH of 4 to 8. In one or more embodiments, the liquid pharmaceutical composition has a pH of 2 to 6. In one or more embodiments, the liquid pharmaceutical composition has a pH of 3 to 6.

[0010] In another aspect, this disclosure describes a method of preparing the liquid pharmaceutical composition of any of the previous aspects or embodiments. The method includes dissolving the solid pharmaceutical composition in the carrier.

[0011] In another aspect, this disclosure describes a method of administering the liquid pharmaceutical composition of any of the aspects or embodiments to a subject. In one or more embodiments, the subject is a human.

[0012] In one or more embodiments the subject has or is at risk of having a pulmonary and/or a cardiac disease, condition, or disorder. In one or more embodiments, the subject has or is at risk of having lung inflammation, lung edema, or both, and/or lung fibrosis. In one or more embodiments, the pharmaceutical composition is administered prior to the subject manifesting any symptom or clinical sign of a pulmonary and/or cardiac disease, condition, or disorder. In one or more embodiments, the pharmaceutical composition is administered after the subject manifesting any symptom or clinical sign of a pulmonary and/or cardiac disease, condition, or disorder.

[0013] In one or more embodiments, the pharmaceutical composition is administered directly to the pulmonary tract of the subject. In one or more embodiments, the pharmaceutical composition is administered by pulmonary instillation. In one or more embodiments, the pharmaceutical composition is administered by intratracheal instillation.

[0014] In another aspect, this disclosure describes liquid composition that includes T3, a prodrug thereof, a salt thereof, a hydrate thereof, or any combination thereof; an organic solvent; water; and a bulking agent. In one or more embodiments, the liquid composition further includes a buffer agent.

[0015] In another aspect, this disclosure describes a method of preparing the solid pharmaceutical composition of any of the previous aspects or embodiments. The method includes lyophilizing the liquid composition that includes at least T3, a prodrug thereof, a salt thereof, a hydrate thereof, or any combination thereof; an organic solvent; water; and a bulking agent.

BRIEF DESCRIPTION OF DRAWINGS

[0016] FIG. 1 is a workflow diagram for preparing a lyophilized composition. Lyophilization includes freezing, primary drying, and secondary drying.

[0017] FIG. 2 is an overlay of the X-ray diffraction patterns of liothyronine sodium salt. The experimental conditions were: step size of 0.01 degrees 2 theta, speed of 4 C2 theta/min, and the range from 5 °2 theta to 35 °2 theta or 5 °2 theta 40 °2 theta.

[0018] FIG. 3 is a thermogravimetric analysis (TGA) curve of liothyronine sodium in a non- hermetically sealed pan that was heated at 10 °C/min from 25 °C to 290 °C.

[0019] FIG. 4 is a differential scanning calorimetry (DSC) heating curve of liothyronine sodium placed in a non-hermetically sealed pan at a heating rate of 10 °C/min.

[0020] FIG. 5 are DSC heating curves of liothyronine sodium in a hermetically sealed pan (1), and liothyronine sodium in a hermetically sealed pan with pinhole (2), at a heating rate of 5 °C/min.

[0021] FIG. 6 is a plot showing the automated water sorption/desorption of liothyronine sodium. The relative humidity (RH) was progressively increased from 0% to 90% and then decreased back to 0% at 25 °C.

[0022] FIG. 7 is an overlay of X-ray diffraction (XRD) patterns of lyophiles, three forms of anhydrous mannitol and mannitol hemihydrate (MHH), and liothyronine sodium. 11 = lyophile that contained 30% w/w TBA with 1% w/v mannitol and liothyronine sodium (light brown); 10 = lyophile that contained 30% w/w TBA with 0.5% w/v mannitol and liothyronine sodium; 9 = lyophile that contained 35% w/w TBA with 1% w/v mannitol and liothyronine sodium; 8 = lyophile that contained 35% w/w TBA with 0.5% w/v mannitol and liothyronine sodium; 7 = lyophile that contained 40% w/w TBA with 1% w/v mannitol and liothyronine sodium; 6 = lyophile that contained 40% w/w TBA with 0.5% w/v mannitol and liothyronine sodium; 5 = liothyronine sodium; 4 = MHH; 3 = delta-mannitol (dark green); 2 = beta-mannitol (red 3); and 1 = alpha-mannitol.

[0023] FIG. 8 is a standard curve of liothyronine sodium in a pre-lyophilization solution that included 30% w/w TBA with 1% w/v mannitol.

[0024] FIG. 9 is a is a standard curve of reconstituted liothyronine sodium from lyophilized powder that was lyophilized from a pre-lyophilization solution that included 30% w/w TBA with 1% w/v mannitol.

[0025] FIG. 10 is a plot of the concentration of liothyronine in a reconstituted solution of a lyophilized powder stored at room temperature for 14 days.

[0026] FIG. 11 is a plot of the concentration of liothyronine in a reconstituted solution of a lyophilized powder stored at room 5 °C for 14 days.

[0027] FIG. 12 is a TGA plot of liothyronine sodium that was heated at 5 °C/min from 25 °C to 290 °C.

DETAILED DESCRIPTION

[0028] This disclosure describes liquid and solid pharmaceutical compositions containing T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof. The disclosure also describes methods of administering such pharmaceutical compositions, and methods of making pharmaceutical compositions. A solid pharmaceutical composition may be a lyophilized solid pharmaceutical composition formed after the lyophilization of a pre-lyophilized solution. A liquid pharmaceutical composition may include the solid pharmaceutical composition reconstituted in a carrier. Pharmaceutical compositions of the present disclosure may be effective for treating a pulmonary disease, disorder, or condition and/or a cardiac disease disorder, or condition. For example, pharmaceutical compositions may be effective for treating pulmonary edema, acute or infant respiratory distress syndrome, lung inflammation of multiple primary causes, pre- or post-lung transplantation, acute coronary syndrome or myocardial ischemia, heart failure, or any combination thereof. Pharmaceutical compositions may be formulated to be administered directly into the lung, for example, by lung instillation.

[0029] Triiodothyronine (T3; 3,3',5'-triiodothyronine) is a thyroid hormone. The manufactured form of T3 is often called liothyronine. As used herein, the terms triiodothyronine, T3, and liothyronine all refer to the compound 3,3',5'-triiodothyronine whether naturally occurring or manufactured unless otherwise specified.

[0030] Triiodothyronine (T3; 3,3',5'-triiodo-L-thyronine) and thyroxine (T4; 3, 5,3', 5'- tetraiodothyronine) are tyrosine based thyroid hormones. T4 is a less active agent and is converted to T3 in the thyroid gland pre-secretion or in peripheral body tissue cells by deiodinase enzymes. T3 affects lung development, lung function, and repair of injury to lung tissues and a variety of cardiac-related functions. Low serum concentrations of T3 are associated with a variety of thyroid disorders and low serum levels are observed in chronic and critical illness.

[0031] Clinically, thyroid disorders are associated with diverse pulmonary symptoms. Both hypothyroidism and hyperthyroidism may cause respiratory muscle weakness and/or decreased pulmonary function. Hypothyroidism reduces respiratory drive and can also cause obstructive sleep apnea or pleural effusions. Conversely, hyperthyroidism increases respiratory drive and can cause dyspnea on exertion. Either hypothyroidism or hyperthyroidism, can be associated with idiopathic primary pulmonary arterial hypertension (IPPAH). Further, treating the underlying thyroid disorder may reverse pulmonary hypertension, although the exact mechanism involved in the pathogenesis is not established.

[0032] At the cellular level, T3 concentration affects alveolar number, the number and size of alveolar type II pneumocyte cells, and their surfactant production. T3 stimulation of alveolar fluid clearance occurs locally and rapidly in the lung. For example, T3 increases alveolar fluid clearance (AFC) in alveolar epithelial cells through augmented Na,K-ATPase activity. Active sodium resorption is involved in surfactant production, clearing pulmonary (alveolar) edema in lungs at birth, in acute lung injury (ALI), in acute respiratory distress syndrome (ARDS), and in cardiogenic edema, such as congestive heart failure. Conversely, reducing T3 levels in the lung can exacerbate alveolar edema. [0033] In one or more embodiments, a pharmaceutical composition of the present disclosure may be used to treat a pulmonary disease, disorder, or condition. In one or more embodiments, a pharmaceutical composition of the present disclosure may be used to treat alveolar edema, lung inflammation, pre- or post-transplantation lung transplant, lung fibrosis, or any combination thereof, that may be treatable using the prodrugs and methods described herein include, for example, acute respiratory distress syndrome (ARDS), infant RDS (IRDS) seen with premature birth, chest trauma, acute/chronic congestive heart failure, dilated cardiomyopathies, pre- and/or post-lung transplant, pre- and/or post- lung cancer radiotherapy or chemotherapy, pneumonia, sepsis, drug and substance-induced lung diseases such as smoking (including vaping and whether tobacco or THC), exposure to pollutants (whether environmental or occupational, e.g., asbestosis, silicosis, berylliosis, Coal Worker’s, pneumoconiosis, gas exposure, thermal injury, or other pneumoconiosis), hypersensitivity pneumonitis, reactive or obstructive lung diseases (e g., asthma, chronic bronchitis, reactive airway dysfunction syndrome, or other reactive airway diseases), aspiration chemical pneumonitis or pneumonia, pneumonia or an infection of nasosinus, intratracheal, intrabronchial or alveolar airspace (e.g., bacterial, viral, fungal), connective tissue and vasculitic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, sarcoidosis, and other related diseases), Wegener’s granulomatosis, Goodpasture disease, acute or chronic eosinophilic pneumonia, medication-related lung injury (e.g., injury from use of amiodarone, bleomycin, busulfan, mitomycin C, methotrexate, apomorphine, nitrofurantoin, or other pneumotoxic drugs), cryptogenic organizing pneumonia, pulmonary hemorrhage such as exercise induced pulmonary hemorrhage, Churg-Strauss syndrome, or congenital or structural lung disease (e.g., cystic fibrosis, bronchiectasis).

[0034] Acute respiratory distress syndrome (ARDS) is characterized, at least in part, by a lack of T3 in lung tissue. The T3 deficiency results in a decreased capability of the lung to remove fluids when inflamed or in a disease state. Further, both oxygen therapy and mechanical ventilation, each of which assists sick patients to be able to breathe and have proper blood oxygen levels, can be injurious to lung tissue (e.g., ventilator-associated lung injury, VALI), further compounding the ARDS lung injury. As such, the lack of T3 in lung tissue and the concomitant use of oxygen and ventilator therapy in ARDS patients create a difficult problem for clinicians to treat. [0035] Congestive heart failure (CHF, acute and chronic) is characterized, at least in part, by a deficit of T3 in both heart and lung tissue. Patients with CHF often have inflammation and edema in the lungs. Delivering T3 directly to the lung may allow the drug to immediately and directly acts on cellular pump mechanisms to remove the excess fluid buildup in the lungs. In addition, after the lung has absorbed the T3, its next delivery path is the heart, where T3 improves heart function (i.e., contractility).

[0036] Infant respiratory distress syndrome (IRDS) is characterized, at least in part, by a deficit of T3, often due to a premature birth. Incomplete gestation shortens the maternal-to-baby development cycle, such that lung development is incomplete with underdeveloped lung epithelium. The immature epithelium has deficiency in surfactant production/release and in the fluid absorption system. Fetal thyroid hormone levels normally increase shortly prior to birth and this is required for clearance of the airspace fluid in order for breathing to be effective in maintaining oxygen levels after birth. Thus, infants with IRDS often experience pulmonary edema, decreased gas exchange, and resulting hypoxemia.

[0037] Exercise induced pulmonary hemorrhage (EIPH) is characterized by blood in the airways associated with exercise. EPIH is commonly observed in horses such as racehorses but has also been observed in humans.

[0038] Other pulmonary and cardiac conditions involve T3 deficits. Myocardial infarction (MI) patients also have an acute, absence of T3 in infarcted myocardium. Often these patients are intubated, enabling a direct instill approach during the most critical post-MI phase of disease.

[0039] In one or more embodiments, a pharmaceutical composition of the present disclosure may be used to treat a cardiac disease, disorder, or condition. Heart failure, acute coronary syndrome, acute valvular heart disease, Takotsubo’s Syndrome, and cardiac surgery/hemodynamics can result in decreased pumping efficiency of the heart. The force of contraction by the heart muscle (myocardium), is known as inotropy. Myocardial inotropy is influenced by the active form of T3. For example, T3 contributes to myocardial gene expression by increasing the synthesis of the intracellular mechanisms that increase inotropic contractility. Decreased cardiac T3 levels may result in decreased myocardial inotropy seen in congestive heart failure, acute coronary syndrome, and in both children and adults following cardiac surgery such as cardiac bypass, cardiac valvular replacement, and heart transplant. These conditions can result in myocardial failure due to decreased inotropy and increase in systemic vascular resistance.

[0040] T3 replacement therapy for the heart has been limited to either oral or intravenous (IV) administration. Unfortunately, in critical illness there is poor absorption due to bowel wall edema, thus, blunting/ delaying the effect of T3 replacement. The IV T3 replacement, although direct and immediate, results in high serum T3 spikes, which is systemically circulated affecting all other organs and can trigger undesired side-effects (i.e., atrial arrhythmias, hypertension).

[0041] In one or more embodiments, a pharmaceutical composition of the present disclosure may be used to treat a cardiac disease, disorder, or condition. Examples of such disease, disorders, and conditions include acute coronary syndromes including unstable angina, myocardial ischemia, ST-segment elevation myocardial infarction (STEMI), Takotsubo’s Syndreom, and non-ST-segment elevation myocardial infarction (NSTEMI); acute valvular heart disease; heart failure including acute heart failure, chronic heart failure, dilated cardiomyopathies, decompensated chronic heart failure, left-sided heart failure, right-sided heart failure, and biventricular heart failure; or any combination. In one or more embodiments, a pharmaceutical composition of the present disclosure may be administered to a subject before, during, or after cardiac surgery, hemodynamics, or both.

[0042] Acute Coronary Syndromes (ACS, e.g., unstable angina, NSTEMI and STEMI), can cause post-ischemia myocardial damage. Even with early reperfusion (i.e., primary PCI angiography), further myocardial injury and inflammation (e.g., IL-6), can occur resulting in cardiac remodeling and heart failure. Cardiac cell death following ACS is propagated by dysfunctional mitochondrial potassium channels, which normally provide an antioxidant and protective role to the myocardium. T3 is a regulator of this mitochondrion, providing what is termed, a T3-dependent cardioprotective action. ACS results in rapid destruction of cardiac tissue T3 concentrations due to acute expression of deiodinase type 3 (D3), which inactivates T3 creating a local hypothyroid condition. Consequently, patients with an acute decrease in cardiac tissue T3 have an increased risk of major cardiac events, including cardiogenic shock, ventricular arrhythmias, and death. Replacing cardiac T3 in ACS may be beneficial. However, previous studies administered T3 intravenously resulting atrial fibrillation, an undesirable side-effect difficult to avoid when using intravenous administration (Pantos, et al Effects of Acute Triiodothyronine Treatment in Patients with Anterior Myocardial Infarction Undergoing Primary Angioplasty: Evidence from a Pilot Randomized Clinical Trial- ThyRepair Study. Thyroid. 2022 Nov 6; 32:714-724.).

[0043] In heart failure (acute/chronic), there is altered T3 thyroid hormone metabolism. Low serum T3 represents a strong, independent predictor of poor outcomes in heart failure. Local cardiac tissue T3 is decreased due to expression of the inactivating enzyme, deiodinase type 3 which can result in an inflammatory cytokine (i.e., IL-6, TNF -alpha) increase in heart failure altering local biochemical changes driving disease progression. Thus, it is common practice among heart failure programs to screen for subclinical hypothyroidism (SCH, TSH>7 mIU/L). SCH is characterized by decreased myocardial inotropy, impaired myocardial relaxation, decreased heart rate, resulting in decreased cardiac output. As such, SCH is an independent risk factor for heart failure among older patients. Current SCH treatment is the initiation of oral thyroid replacement for chronic heart failure (CHF). In the acute setting, a clinical trial showed hemodynamic benefits of IV T3 replacement as salvage therapy after failing conventional pharmacological and mechanical support. However, to date, no thyroid replacement is currently recommended for acute heart failure, or decompensated CHF, due to the undesired atrial arrhythmias (e.g., atrial fibrillation), which can further worsen the heart failure.

[0044] In cardiac surgery (e.g., CABG, transplant), and hemodynamics (e.g., mechanical cardiac support- ECMO, IABP), T3 may play a significant role. T3 increases the sensitivity of the heart and peripheral vascular receptors to catecholamines (e.g., epinephrine, norepinephrine, dopamine), increasing both the heart rate and blood pressure. In contrast, for profound hypothyroid state, such as in myxedema coma, patients present with bradycardia and hypotension. Treating with catecholamines alone provides only transient correction, but homeostasis may be restored when the synergistic effect of thyroid hormone replacement is added. During cardiac surgery (e.g., CABG), T3 levels decline contributing to postoperative bradycardia and hypotension. In a randomized control trial, perioperative IV T3 resulted in higher heart rate and cardiac output, and lower systemic vascular resistance. As such, cardiac surgeons may give perioperative IV T3 to hasten liberation from cardiopulmonary bypass. Children after cardiac surgery are at a specific risk of developing perioperative hypothyroid state; however, no T3 replacement is recommended due risk of atrial arrhythmias. Finally, multiple clinical studies of brain-dead potential organ donors with hemodynamic instability were given IV T3, resulting in significant reduction in the total vasopressor (catecholamine) requirement, with increased viability of solid organs for transplant.

[0045] T3 is commercially available as tablets, capsules, and liquid formulations. Table 1 shows example T3 products. Liothyronine sodium tablets have been approved for treating hypothyroidism and pituitary thyrotropin suppression. Additionally, liothyronine tablets can be used as an augmenting agent for treating major depressive disorders.

Table 1: Various commercially available T3 products

[0046] It is thought that T3 can be used to treat various pulmonary and cardiac diseases, disorders, through direct instillation of a liquid formulation into the lung. However, the aqueous solubility of T3 is relatively low. For example, the solubility of T3 in an aqueous solution at pH 7.4 is about 7 micromolar. The solubility of T3 can be increased by formulating it with an organic solvent and/or in an aqueous solution having a high pH, for example a pH of 10. However, T3 formulations that include an organic solvent and/or a high pH may potentially cause unwanted side effects when delivered to the lungs.

[0047] Commercially available liquid T3 formulations may not be suitable for certain types of administration to a patient without modification. For example, commercially available liquid formulations may include organic solvents and/or are formulated at a high pH. While commercially available T3 can be reformulated prior to use for some indications, the reformulated composition may have a limited shelf-life. Additionally, the reformulated composition may limit dose and volume flexibility.

[0048] Direct lung instillation of a lung-safe T3 liquid formulation is being explored to treat acute respiratory distress syndrome (ARDS). For example, in clinical trial number

NCT04115514, patients are treated by airway instillation of a modified commercially available T3 formulation. TRIOSTAT, Liothyronine Sodium Injection (see Table 1) or Liothyronine powder was formulated to 5 pg/mL and pH 6-8. The dose range of airway installed liothyronine sodium for Phase I was 5 pg - 50 pg and for Phase II is 50 pg to 200 pg every 12 or 24 hours over 5 days. To date, there have been no drug-related adverse events, blood T3 levels are restored to normal ranges after T3 dosing, and T3-treated patients have improved lung function.

[0049] The present disclosure describes solid and liquid pharmaceutical compositions containing T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof, that may be suitable for administration to a patient. A liquid composition of the present disclosure may have increased stability compared to present commercially available liquid T3 formulations. A solid pharmaceutical composition of the present disclosure can be reconstituted into a liquid formulation to provide flexibility in terms of the dose, volume, and formulation of the liquid pharmaceutical composition product.

[0050] In one aspect, the present disclosure describes a solid pharmaceutical composition. A solid pharmaceutical composition may be or include a lyophilized solid. A lyophilized solid is a solid composition formed from lyophilizing a pre-lyophilized solution that includes the components of the lyophilized solid. Lyophilization, also referred to as freeze-drying, is the process of removing water and/or other volatile components from a pre-lyophilized solution to from a solid composition. Lyophilization is accomplished by first freezing a pre-lyophilized solution followed by drying the frozen composition under low pressure to remove water and/or other volatile components via sublimation and/or desorption.

[0051] A solid pharmaceutical composition includes 5 wt-% or less residual moisture, for example, 4 wt-% or less, 3 wt-% or less, 2 wt-% or less, or 1 wt-% or less residual moisture. Residual moisture may be in the form of water and/or any other solvent. For example, in embodiments where a solid pharmaceutical composition is or includes a lyophilized solid, the lyophilized solid may include residual moisture in the form of water and/or any other solvent used in the pre-lyophilization solution. In one or more embodiments, a solid pharmaceutical composition includes 5 wt-% or less residual moisture. In one or more embodiments, a solid pharmaceutical composition includes 4 wt-% or less residual moisture. In one or more embodiments, a solid pharmaceutical composition includes 3 wt-% or less residual moisture. In one or more embodiments, a solid pharmaceutical composition includes 2 wt-% or less residual moisture. In one or more embodiments, a solid pharmaceutical composition includes 1 wt-% or less residual moisture.

[0052] A solid pharmaceutical composition includes T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof. A salt may also be a hydrate. Example T3 prodrugs include those described in PCT application number PCT/US25/30019 (Thyroid Hormone Prodrugs and Composition Comprising the Same; Peter Dosa; fded on May 19, 2025) and US provisional application number 63/649,530 (Thyroid Hormone Prodrugs and Composition Comprising the Same; Peter Dosa; filed on May 20, 2024), the content of both is incorporated by reference. In embodiments where a solid pharmaceutical composition includes or is a lyophilized solid, the identity of T3 compound (e.g., T3 or T3 prodrug, salt thereof, hydrate thereof, or any combination thereof) in the solid composition is described from the perspective of the T3 compound used to form the lyophilized solid. For example, in embodiments where a salt of T3 was included in a pre-lyophilization solution, the lyophilized solid can be said to include a salt of T3. Examples of T3 salts include T3 sodium salt, T3 phosphate salt, and T3 hydrochloride. In one or more embodiments, a solid pharmaceutical composition includes T3 sodium salt. A solid pharmaceutical composition also includes one or more excipients. Examples of excipients that may be included in a solid pharmaceutical composition include bulking agents and buffer agents.

[0053] The amount of T3 equivalents in a pharmaceutical composition may vary. T3 equivalents refers to the amount of T3, T3 salt, T3 hydrate, T3 hydrate/salt, T3 prodrug, T3 prodrug salt, T3 prodrug hydrate, T3 prodrug hydrate/salt, expressed as the equivalent amount of T3. When T3 is the only source of T3 in a composition, the T3 equivalents is the amount of T3 included in the composition. When a T3 salt is included, for example, the amount of T3 in the composition is expressed as T3 equivalents and is calculated as the amount of T3 provided by the amount of T3 salt included.

[0054] In one or more embodiments, a solid pharmaceutical composition may include 0.0001 weight-percent (wt-%) to 2 wt-% T3 equivalents. In one or more embodiments, a solid pharmaceutical composition includes 0.0001 wt-% or greater, 0.0005 wt-% or greater, 0.001 wt- % or greater, 0.005 wt-% or greater, 0.01 wt-% or greater, 0.05 wt-% or greater 0.1 wt-% or greater, 0.2 wt-% or greater, 0.3 wt-% or greater, 0.4 wt-% or greater, 0.5 wt-% or greater, 0.6 wt-% or greater, 0.7 wt-% or greater, 0.8 wt-% or greater, 0.9 wt-% or greater, 1 wt-% or greater, 1.1 wt-% or greater, 1.2 wt-% or greater, 1.3 wt-% or greater, 1.4 wt-% or greater, 1.6 wt-% or greater, 1.7 wt-% or greater, 1.8 wt-% or greater, or 1.9 wt-% or greater T3 equivalents. In one or more embodiments, a solid pharmaceutical composition includes 2.0 wt-% or less, 1.9 wt-% or less, 1.8 wt-% or less, 1.7 wt-% or less, 1.6 wt-% or less, 1.5 wt-% or less, 1.4 wt-% or less, 1.3 wt-% or less, 1.2 wt-% or less, 1.1 wt-% or less, 1.0 wt-% or less, 0.9 wt-% or less, 0.8 wt-% or less, 0.7 wt-% or less, 0.6 wt-% or less, 0.5 wt-% or less, 0.4 wt-% or less, 0.3 wt-% or less, 0.2 wt-% or less, 0.1 wt-% or less, 0.05 wt-% or less, 0.01 wt-% or less, 0.005 wt-% or less, 0.001 wt-% or less, or 0.0005 wt-% or less T3 equivalents. In one or more embodiments, a solid pharmaceutical composition may have an amount of T3 equivalents that falls within a range having endpoints defined by any minimum wt-% and any maximum wt-% that is greater than the minimum wt-%. Thus, for example, a solid pharmaceutical composition may have from 0.1 wt-% to 1 wt-% T3 equivalents, such as, for example, 0.3 wt-% to 1 wt-% or 0.5 wt-% to 0.9 wt-% T3 equivalents.

[0055] In one or more embodiments, a solid pharmaceutical composition includes a bulking agent. Bulking agents can be used to add mass to formulations that include a low amount of the active ingredient. The additional mass can make the formulation easier to handle. Additionally, the additional mass may prevent the loss of active ingredients that may occur when handling small quantities of material. In one or more embodiments where the solid pharmaceutical composition includes or is a lyophilized solid, the bulking agent may also serve as a stabilizer and/or cryoprotectant during the lyophilization process. Additionally, in one or more embodiments where a solid pharmaceutical composition includes or is a lyophilized solid, a bulking agent may serve to provide structure to the lyophilized solid, for example, to prevent collapse of a lyophilized cake. Examples of bulking agents include, but are not limited to, sugar such as mannitol, sugar alcohols, and as well as amino acids such as glycine. In one or more embodiments, a solid pharmaceutical composition includes mannitol. In one or more embodiments, a solid pharmaceutical composition includes glycine.

[0056] In one or more embodiments, a solid pharmaceutical composition can include a stabilizer. Examples of stabilizers include, but are not limited to sucrose and trehalose.

[0057] In one or more embodiments, a solid pharmaceutical composition may include 50 wt- % to 99 wt-% of a bulking agent. In one or more embodiments, a solid pharmaceutical composition includes 50 wt-% or greater, 60 wt-% or greater, 65 wt-% or greater, 70 wt-% or greater, 75 wt-% or greater, 80 wt-% or greater, 85 wt-% or greater, 90 wt-% or greater, or 95 wt-% or greater of a bulking agent. In one or more embodiments, a solid pharmaceutical composition includes 99 wt-% or less, 95 wt-% or less, 90 wt-% or less, 85 wt-% or less, 80 wt- % or less, 75 wt-% or less, 70 wt-% or less, 65 wt-% or less, 60 wt-% or less, or 55 wt-% or less of a bulking agent. In one or more embodiments, a solid pharmaceutical composition may have an amount of a bulking agent that falls within a range having endpoints defined by any minimum wt-% and any maximum wt-% that is greater than the minimum wt-%. Thus, for example, a solid pharmaceutical composition may include a bulking agent in an amount of 60 wt-% to 90 wt-%, such as, for example, 70 wt-% to 85 wt-% or 75 wt-% to 85 wt-%.

[0058] In one or more embodiments, a solid pharmaceutical composition includes a buffer agent. A buffer agent allows a solution to resist change in pH when exposed to certain amounts of acid and/or base. A buffer agent may be included to maintain the pH of a liquid composition that includes a reconstituted solid composition at a desired value. In one or more embodiments where a solid pharmaceutical composition includes or is a lyophilized solid, a buffer agent may be included to maintain the pH of the pre-lyophilized solution at a desired value. Buffer agents are salts of weak acids and/or salts of weak bases. Examples of buffer agents include, but are not limited to, acetic acid or salts thereof (e.g., acetate salts); monosodium and/or disodium phosphate or other phosphate salts; maleic acid or salts thereof (e.g., maleate salts); citric acid or salts thereof (e g., citrate salts); histidine or salts thereof (e.g., histidine sodium salt); tartaric acid or salts thereof (e.g., tartrate salts); lactic acid or salts thereof (e.g., lactate salts); succinic acid or salts thereof (e g., succinate salts); gluconic acid or salts thereof (e.g., gluconate salts); fumaric acid or salts thereof (e.g., fumarate salts); carbonic acid or salts thereof (e.g., bicarbonate salts), tris(hydroxymethyl)aminom ethane and salts thereof; and phthalic acid and salts thereof (e.g., hydrogen phthalate salts). In one or more embodiments, a solid composition includes tris(hydroxymethyl)aminomethane or a salt thereof.

[0059] In one or more embodiments, a solid pharmaceutical composition may include 1 wt- % to 50 wt-% of a buffer agent. In one or more embodiments, a solid pharmaceutical composition includes 1 wt-% or greater, 5 wt-% or greater, 10 wt-% or greater, 15 wt-% or greater, 20 wt-% or greater, 25 wt-% or greater, 30 wt-% or greater, 35 wt-% or greater, 40 wt-% or greater, or 45 wt-% or greater of a buffer agent. In one or more embodiments, a solid pharmaceutical composition includes 50 wt-% or less, 45 wt-% or less, 40 wt-% or less, 35 wt-% or less, 30 wt-% or less, 25 wt-% or less, 20 wt-% or less, 15 wt-% or less, 10 wt-% or less, or 5 wt-% or less of a buffer agent. In one or more embodiments, a solid pharmaceutical composition may have an amount of buffer agent that falls within a range having endpoints defined by any minimum wt-% and any maximum wt-% that is greater than the minimum wt-%. Thus, for example, a solid pharmaceutical composition may include a buffer agent in an amount of 10 wt- % to 30 wt-%, such as, for example, 10 wt-% to 25 wt-% or 15 wt-% to 25 wt-%.

[0060] In addition to a buffer agent and/or a bulking agent, a solid pharmaceutical composition may include one or more additional excipients and/or additives. In embodiments where a solid pharmaceutical composition includes or is a lyophilized solid, an additional excipient and/or additive may or may not be a part of the lyophilized solid. Example excipients include but are not limited to, dextrose and ammonium hydroxide. Example additives include, but are not limited to, adjuvants, colorants, fragrances, flavorings, and the like.

[0061 ] In another aspect, the present disclosure describes a liquid pharmaceutical composition. A liquid pharmaceutical composition may include a solid pharmaceutical composition of the present disclosure dissolved in a carrier. As such, in one or more embodiments where a solid pharmaceutical composition includes or is a lyophilized solid, a liquid pharmaceutical composition includes the solid pharmaceutical composition reconstituted in a carrier.

[0062] The relative ratio of component amounts in a liquid pharmaceutical composition may be the same as the relative ratio of component amounts in a solid pharmaceutical composition used to form the liquid pharmaceutical composition. For example, when a liquid pharmaceutical composition does not include an additional amount of an excipient already included in a solid pharmaceutical composition, the liquid pharmaceutical composition includes the same relative ratio of components that were in the solid pharmaceutical composition. In other embodiments, the relative ratio of component amounts in a liquid pharmaceutical composition may be different than the relative ratio of component amounts in a solid pharmaceutical composition used to from the liquid pharmaceutical composition. For example, when a liquid pharmaceutical composition includes an additional amount of an excipient already included in a solid pharmaceutical composition, the liquid pharmaceutical composition has a different relative ratio of component amounts that were in the solid pharmaceutical composition.

[0063] A carrier, and therefore the liquid pharmaceutical composition, may include an additional amount of an excipient already included in a solid pharmaceutical composition used to from the liquid pharmaceutical composition. For example, a carrier may include an additional amount of the buffer agent and/or bulking agent already present in a solid pharmaceutical composition. The amount of an additional excipient may be such that a liquid pharmaceutical composition includes the same concentration of the excipient as the pre-lyophilized solution used to make a solid pharmaceutical composition. For example, if a 2 mb pre-lyophilized solution included 10 millimolar (mM) of a buffer agent, an additional amount of the buffer agent may be included in a 20 milliliter (mb) liquid pharmaceutical composition such that a liquid pharmaceutical composition has a 10 mM buffer agent concentration.

[0064] A carrier of the liquid pharmaceutical composition may include water. In one or more embodiments, a carrier is a buffered aqueous solution, that is, the carrier, and therefore, a liquid pharmaceutical composition, includes a buffer agent in addition to the buffer agent included in a solid pharmaceutical composition. The additional buffer agent may be the same or different than the buffer agent included in a solid pharmaceutical composition.

[0065] A liquid pharmaceutical composition may be at a pH of 2 to 13. A liquid pharmaceutical composition may be at a pH of 2 to 11. In embodiment, a liquid pharmaceutical composition may be at a pH of 2 or greater, 3 or greater, 4 or greater, 5.5 or greater, 6 or greater, 6.5 or greater, 7 or greater, 7.5 or greater, 8 or greater, 8.5 or greater, 9 or greater, 10 or greater, 11 or greater, or 12 or greater. In embodiment, a liquid pharmaceutical composition may be at a pH of 13 or less, 12 or less, 1 1 or less, 10 or less, 9 or less, 8.5 or less, 8 or less, 7.5 or less, 7 or less, 6.5 or less, 6 or less, 5.5 or less 5 or less, 4 or less, or 3 or less. In one or more embodiments, a liquid pharmaceutical composition may be at a pH that falls within a range having endpoints defined by any minimum pH value listed above and any maximum pH value listed above that is greater than the minimum pH value. Thus, for example, a liquid pharmaceutical composition may be at a pH of 4 to 11, such as, for example, 4 to 10 or 5 to 9. In one or more embodiments, a liquid pharmaceutical composition has a pH of 3 to 10. In one or more embodiments, a liquid pharmaceutical composition has a pH of 3 to 8. In one or more embodiments, a liquid pharmaceutical composition has a pH of 3 to 7. In one or more embodiments, a liquid pharmaceutical composition has a pH of 2 to 6. In one or more embodiments, a liquid pharmaceutical composition has a pH of 3 to 6. In one or more embodiments, a liquid pharmaceutical composition has a pH of 4 to 8. In one or more embodiments, a liquid pharmaceutical composition has a pH of 4 to 6. In one or more embodiments, a liquid pharmaceutical composition has a pH of 4 to 7. In one or more embodiments, a liquid pharmaceutical composition has a pH of 4.5 to 8. In one or more embodiments, a liquid pharmaceutical composition has a pH of 4.5 to 7.5.

[0066] In one or more embodiments, a liquid pharmaceutical composition may be at a neutral pH. As used herein, the term “neutral pH” refers to a pH that is pH 7.0 + 1.5 (i.e., a pH of 5.5 to 8.5). In one or more embodiments, a liquid pharmaceutical composition has a neutral pH without the addition of an acid or a base to adjust the pH. For example, in one or more embodiments, after dissolution of a solid pharmaceutical composition with a carrier, the pH of the resultant liquid pharmaceutical composition is neutral.

[0067] Various acids and/or bases may be used to adjust the pH of a pharmaceutical composition. In the case that the pH of a pharmaceutical composition is adjusted using an acid and/or base or salt thereof, the pharmaceutical composition includes the ions of the acid and/or base or salt thereof used to adjust the pH. Examples of acids and/or bases that may be used to adjust the pH of a pharmaceutical composition include, but are not limited to, strong acids and/or strong bases or salts thereof, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, hydrobromic acid, hydroiodic acid; or weak acids and/or weak basis or salts thereof such as those described relative to the buffering agents herein.

[0068] In one or more embodiments, a carrier may include saline. In one or more embodiments, a carrier includes normal saline that includes about 0.9% (w/v) sodium chloride. In one or more embodiments, a carrier includes saline that includes from about 0.2% (w/v) to about 0.9 (w/v) sodium chloride, for example, from about 0.2% (w/v) to about 0.6 (w/v) or 0.2% (w/v) to about 0.4% (w/v) sodium chloride.

[0069] In one or more embodiments, a carrier includes dextrose. In one or more embodiments, a carrier includes from about 1% (w/v) to about 5% (w/v) dextrose. For example, in one or more embodiments, a carrier includes about 1% (w/v) to about 4 % (w/v) or about 2% (w/v) to about 5% (w/v) dextrose. In one or more embodiments, a carrier includes about 5% (w/v) dextrose.

[0070] In one or more embodiments, a carrier includes both sodium chloride and dextrose. In one or more embodiments, a carrier includes half-normal saline which includes about 0.45% (w/v) sodium chloride and about 5% (w/v) dextrose. In embodiments, a carrier includes quarternormal saline which includes about 0.22% (w/v) sodium chloride and about 5% (w/v) dextrose.

[0071] The total volume of a liquid pharmaceutical composition can be adjusted such that desired T3 equivalent concentration is achieved. For example, a liquid pharmaceutical composition may include 0.1 pg/mL to 1000 pg/mL T3 equivalents. In one or more embodiments, a liquid pharmaceutical composition includes 0.1 pg/mL or greater, 0.5 pg/mL or greater, 1 pg/mL or greater, 2 pg/mL or greater, 5 pg/mL or greater, 10 pg/mL or greater, 15 pg/mL or greater, 20 pg/mL or greater, 25 pg/mL or greater, 30 pg/mL or greater, 35 pg/mL or greater, 40 pg/mL or greater, 45 pg/mL or greater, 50 pg/mL or greater, 60 pg/mL or greater, 70 pg/mL or greater, 80 pg/mL or greater, or 90 pg/mL or greater T3 equivalents. For example, a liquid pharmaceutical composition may include 100 pg/mL or less, 90 pg/mL or less, 70 pg/mL or less, 60 pg/mL or less, 50 pg/mL or less, 45 pg/mL or less, 40 pg/mL or less, 35 pg/mL or less, 30 pg/mL or less, 25 pg/mL or less, 20 pg/mL or less, 15 pg/mL or less, 10 pg/mL or less, 5 pg/mL or less, 2 pg/mL or less, 1 pg/mL or less, or 0.5 pg/mL or less T3 equivalents. In one or more embodiments, a liquid composition may have an amount of T3 equivalents that falls within a range having endpoints defined by any minimum concentration and any maximum concentration that is greater than the minimum concentration. Thus, for example, a liquid pharmaceutical composition may have 5 pg/mL to 100 pg/mL T3 equivalents, such as, for example, 5 pg/mL to 50 pg/mL or 20 pg/mL to 50 pg/mL T3 equivalents.

[0072] In another aspect, the present disclosure describes a method of forming a liquid pharmaceutical composition of the present disclosure. A liquid pharmaceutical composition can be formed by dissolving a solid pharmaceutical composition of the present disclosure in a carrier. In one or more embodiments where a solid pharmaceutical composition includes or is a lyophilized solid, a liquid pharmaceutical composition can be formed by reconstituting the solid pharmaceutical composition.

[0073] In another aspect, the present disclosure describes a method of administering a pharmaceutical composition of the present disclosure to a subject.

[0074] The subject can be a human or a non-human animal such as, for example, a livestock animal, a laboratory animal, or a companion animal. Exemplary non-human animal subjects include, but are not limited to, animals that are hominid (including, for example chimpanzees, gorillas, or orangutans), bovine (including, for instance, cattle), caprine (including, for instance, goats), ovine (including, for instance, sheep), porcine (including, for instance, swine), equine (including, for instance, horses), members of the family Cervidae (including, for instance, deer, elk, moose, caribou, or reindeer), members of the family Bison (including, for instance, bison), feline (including, for example, domesticated cats, tigers, lions, etc.), canine (including, for example, domesticated dogs, wolves, etc.), avian (including, for example, turkeys, chickens, ducks, geese, etc.), a rodent (including, for example, mice, rats, etc.), a member of the family Leporidae (including, for example, rabbits or hares), members of the family Mustelidae (including, for example ferrets), or member of the order Chiroptera (including, for example, bats).

[0075] The subject may have or is at risk of having a pulmonary and/or cardiac disease, disorder, or condition. For example, the subject may have or is at risk of having a pulmonary and/or cardiac disease, disorder, or condition such as those described herein. As such, in one or more embodiments, the method comprises administering a pharmaceutical composition to a subject to treat a pulmonary disease, disorder, or condition. As such, in one or more embodiments, the method comprises administering a pharmaceutical composition to a subject to treat a cardiac, disorder, or condition. In one or more embodiments, a pharmaceutical composition may be administered to treat a subject that has or is at risk of lung inflammation or pulmonary edema such as alveolar edema. In one or more embodiments, a pharmaceutical composition may be administered to treat a subject that has or is at risk of having a cardiac disease, disorder or condition. In one or more embodiments, a pharmaceutical composition may be administered to treat a subject before, during, or after cardiac surgery, hemodynamic treatment, or both.

[0076] In one or more embodiments, the subject has or at risk of having exercise induced pulmonary hemorrhage (EIPH). For example, the subject may be a horse that has or is at risk of having EIPH.

[0077] “Treat” or variations thereof refer to reducing, limiting progression, ameliorating, or resolving, to any extent, the symptoms or signs related to a condition. A “treatment” may be therapeutic or prophylactic. “Therapeutic” and variations thereof refer to a treatment that ameliorates one or more existing symptoms or clinical signs associated with a condition. “Prophylactic” and variations thereof refer to a treatment that limits, to any extent, the development and/or appearance of a symptom or clinical sign of a condition. Generally, a “therapeutic” treatment is initiated after the condition manifests in a subject, while “prophylactic” treatment is initiated before a condition manifests in a subject.

[0078] Treating can be prophylactic or, alternatively, can be initiated after the subject exhibits the onset of a pulmonary or cardiac condition or the associated symptoms or clinical signs of a condition. Treatment that is prophylactic — e.g., initiated before a subject experiences an event (e.g., cancer radiotherapy) or manifests a symptom or clinical sign of the condition (e.g., while an infection remains subclinical) — is referred to herein as treatment of a subject that is “at risk” of having the condition. As used herein, the term “at risk” refers to a subject that may or may not actually possess the described risk. Thus, for example, a subject “at risk” of infectious condition is a subject present in an area where other individuals have been identified as having the infectious condition and/or is likely to be exposed to the infectious agent even if the subject has not yet manifested any detectable indication of infection by the microbe and regardless of whether the subject may harbor a subclinical amount of the microbe. As another example, a subject “at risk” of a non-infectious condition is a subject possessing one or more risk factors associated with the condition such as, for example, genetic predisposition, ancestry, age, sex, geographical location, or medical history.

[0079] Accordingly, a pharmaceutical composition of the present disclosure can be administered before, during, or after the subject first exhibits a pulmonary condition (e g., pulmonary edema, lung inflammation) and/or a cardiac condition, or other symptom or clinical sign of associated conditions or, in the case of infectious conditions, before, during, or after the subject first comes in contact with the infectious agent. Treatment initiated before the subject first exhibits a condition or another associated symptom or clinical sign may result in decreasing the likelihood that the subject experiences clinical consequences compared to a subject to whom the composition is not administered, decreasing the severity and/or completely resolving the lung or heart abnormality. Treatment initiated after the subject first exhibits clinical manifestations may result in decreasing the severity and/or complete resolution of pulmonary edema and/or lung inflammation experienced by the subject compared to a subject to whom the composition is not administered. Treatment initiated after the subject first exhibits clinical manifestations may result in decreasing the severity and/or complete resolution of the cardiac condition experienced by the subject compared to a subject to whom the composition is not administered.

[0080] For example, hyperoxic injury to rats in vivo and to alveolar type II cells in vitro is decreased when T3 is given in advance of or coincident with injurious hyperoxic exposure. In vitro, alveolar type II cell death was significantly reduced. In vivo, lung inflammation, lung injury, neutrophil infiltration and protein leakage into the alveolar space were significantly reduced.

[0081] Thus, the method includes administering an effective amount of a pharmaceutical composition of the present disclosure to a subject having, or at risk of having, a particular condition. Example conditions include pulmonary conditions such as pulmonary edema and/or lung inflammation and cardiac conditions such as those described herein. In this aspect, an “effective amount” is an amount effective to reduce, limit progression, ameliorate, or resolve, to any extent, the particular condition. For example, an “effective amount’ of a pharmaceutical composition may increase alveolar fluid clearance, increase the population of alveolar type II pneumocytes, increase the size of alveolar type II pneumocytes, increase surfactant production, increase Na,K-ATPase activity in alveolar epithelial cells, decrease or repair alveolar damage, decrease hypoxemia, and/or decrease in inflammation throughout the respiratory tract (e.g., nasosinus, intratracheal, intrabronchial and alveolar airspace ). Accordingly, a pharmaceutical composition can be administered before, during, or after the subject first exhibits a symptom or clinical sign of the condition or, in the case of infectious conditions, before, during, or after the subject first comes in contact with the infectious agent.

[0082] In one or more embodiments, the method includes identifying a subject that has a pulmonary and/or a cardiac disease, disorder, or condition. A subject that has a pulmonary and/or cardiac disease, disorder, or condition, may display one or more symptoms or clinical signs associated with a pulmonary and/or cardiac disease, disorder, or condition; may have a genetic signature associated with a pulmonary and/or cardiac disease, disorder, or condition; or both. A subject that has a pulmonary and/or cardiac disease, disorder, or condition may have low levels of serum T3 or T3 in the blood.

[0083] Identification of a subject having a pulmonary and/or cardiac disease, disorder, or condition may include diagnosing the subject with a pulmonary and/or cardiac disease, disorder, or condition. Diagnosis of a pulmonary and/or cardiac disease, disorder, or condition may be by way of a physician or other health care provider conducting tests and exams to identify a cause for symptoms displayed by a subject.

[0084] A pharmaceutical composition may be administered through any suitable route. Example routes of administration include enteral administration and parenteral administration. Enteral administration includes oral administration of tablets, capsules, or liquids. Parenteral administration includes intravenous infusions and injections.

[0085] In embodiments, a pharmaceutical composition of the present disclosure is administered directly to the pulmonary tract of the subject; that is, direct pulmonary tract administration is used introduce the pharmaceutical composition to the subject.

[0086] As used herein, the terms “directly to the pulmonary track’' and “direct pulmonary tract administration” refer to local delivery of a pharmaceutical composition first to the tissues and/or cavities of the pulmonary tract. It is understood that following local delivery to the tissues of the pulmonary tract, an active ingredient can enter the circulatory system. Direct pulmonary tract administration can include depositing an active ingredient or a composition including the same on a mucosal surface, such as a respiratory mucosa (e g., by spray, aerosol, nebulization, instillation, inhalation of aerosol or particulates). Direct pulmonary tract administration can include depositing an active ingredient or composition including the same directly within the nasosinus, intratracheal, intrabronchial, or alveolar space. Routes of direct pulmonary administration include, but are not limited to, pulmonary installation, inhalation, nebulization, or any combination thereof. Pulmonary administration may include invasive mechanical ventilation or non-invasive mechanical ventilation (BIPAP, CPAP, AV APS, BiLevel; Helmet ventilation or negative pressure ventilation). Pulmonary administration may include methods of oxygen delivery (e.g., Heated-High-Flow Nasal Cannula, High-Flow Nasal Cannula, Nasal Cannula) or ambient air.

[0087] For some pulmonary disease, disorder, or condition, direct pulmonary administration of a therapeutic may allow for a more effective treatment than systemic administration of the same therapeutic. Systemic administration, in some cases, may not achieve effective concentrations of therapeutics in the pulmonary tract due in part to systemic clearance mechanisms. Direct pulmonary administration may avoid, mitigate, or circumvent one or more systemic clearance mechanisms. Various blood-pulmonary system barriers may hinder a therapeutic from penetrating into the lungs or reaching portions of the pulmonary tract at a therapeutically relevant concentration when systemically administered. Additionally, direct pulmonary administration may result in fewer side effects than systemic administration of a therapeutic because direct pulmonary tract administration provides local delivery of the therapeutic to the location to be treated.

[0088] For some cardiac diseases, disorders, or conditions, direct pulmonary administration of a therapeutic may allow for a more effective treatment than systemic administration of the same therapeutic. Following direct pulmonary administration, the therapeutic can diffuse into the circulatory system where it interacts with heart tissue. In contrast to intravenous administration of a therapeutic to treat a heart disease, disorder, or condition, direct pulmonary administration may avoid high serum T3 spikes commonly associated with intravenous administration of T3 therapeutics.

[0089] In one or more embodiments, a pharmaceutical composition is directly delivered to the pulmonary tract via pulmonary tract instillation. Pulmonary tract installation is the administration of a liquid pharmaceutical composition to a tissue or cavity of the pulmonary tract. Pulmonary tract installation is typically accomplished in the lower respiratory tract. For example, pulmonary tract instillation includes intratracheal instillation and intrabronchial instillation.

[0090] In one or more embodiments, a pharmaceutical composition is directly delivered to the pulmonary tract by inhalation. Administration by inhalation includes inhalation by a subject of a sprayed, aerosolized, nebulized, pharmaceutical composition. Administration by inhalation may be facilitated by an inhaler device such as a metered dose inhaler, dry powder inhaler, soft- mist inhaler, or nebulizer. Administration by inhalation may be facilitated by heated high flow via a nasal cannula.

[0091] The amount of T3 equivalents administered can vary depending on various factors including, but not limited to, the weight, physical condition, and/or age of the subject; the particular clinical signs or symptoms exhibited by the subject; the type or cause of lung inflammation or pulmonary edema; and/or the method of administration. Thus, the absolute amount of T3 equivalents included in a given unit dosage form can vary widely, and depends upon factors such as the species, age, weight and physical condition of the subject, and/or the method of administration. Accordingly, it is not practical to set forth generally the amount that constitutes an amount of T3 equivalents effective for all possible applications. The physiologically active T3 concentration at the cellular level has been determined and varies depending upon the cell type and the specific hormonal target effect. Dosing of T3 can be designed to achieve either physiologic or pharmacologic local tissue T3 levels. Those of ordinary skill in the art, however, can determine the appropriate amount with due consideration of such factors.

[0092] For example, a pharmaceutical composition of the present disclosure can be administered to treat pulmonary edema or lung inflammation at the same T3 equivalent dose and frequency for which T3 has already received regulatory approval. In other cases, a pharmaceutical composition of the present disclosure may be administered for treating alveolar edema or lung inflammation at the same T3 equivalent dose and frequency at which T3 is being evaluated in clinical or preclinical studies. One can alter the dosages and/or frequency as needed to achieve a desired level of T3 equivalents. Thus, one can use standard/known dosing regimens and/or customize dosing as needed.

[0093] The primary active form of T3 — i.e., the form in which it has the greatest physiological activity — is when the T3 is “free” — e.g., not bound to large proteins such as albumin. Therefore, the physiologic effect of a given amount of T3 may be influenced by the proteins and other aspects of the environment that it is introduced into. Thus, a smaller amount of T3 equivalents may be required to achieve an effective delivered dose for the direct pulmonary administration methods herein than the dose T3 drug receiving regulatory approval from treating other conditions by intravenous delivery.

[0094] In one or more embodiments, the method can include administering sufficient amount of a pharmaceutical composition to provide a deposited dose of, for example, from about 0.5 pg to about 5.0 mg T3 equivalents to the subject, although in one or more embodiments the methods may be performed by administering a pharmaceutical composition to achieve a dose outside this range. In one or more of these embodiments, the method includes administering sufficient amount of a pharmaceutical composition to provide a deposited dose of 5 pg to 200 pg T3 equivalent to the subject. On a pg/kg basis, the calculated administered T3 equivalent dose to achieve physiologic effects could range from as low as 2 ng/kg to 1 mg/kg. As one example, a dose of 50 pg T3 equivalents can provide a pg/kg dosage range of from about 0.03 pg/kg (to a 160 kg person) to as high as 25 pg/kg (to a 2 kg preterm infant). In many instances, however, dosing on a pg/kg basis is less relevant since direct instillation to lung tissue is not as subject to systemic dilution as, for example, intravenous administration. Lung size in adults does not vary significantly with weight, so mass of T3 equivalents delivered is often the more relevant measure of an appropriate dose.

[0095] As used herein, the term “deposited dose” or “lung-delivered” dose refers to the amount T3 equivalents deposited to the surface of the respiratory tract. For instillation, the deposited dose is essentially the full dose being instilled. In an aerosol or nebulized formulation, however, the deposited dose is conventionally 10% or less of the drug being aerosolized or nebulized. 90% of the drug is expected to be lost in the delivery apparatus and/or exhaled. This may be greater in the injured ARDS lung. Thus, one may aerosolize or nebulize 500 pg of T3 equivalents to achieve an aerosolized or nebulized deposited dose of 50 pg T3 equivalents. The use the term “deposited dose” or “lung-delivered” dose normalizes the dose across different routes of administration.

[0096] A sufficient deposited dose or lung-delivered dose can provide delivery of a minimum amount of at least 5 ng T3 equivalents such as, for example, at least 100 ng, at least 1 pg, at least 10 pg, at least 50 pg, at least 100 pg, at least 250 pg, at least 500 pg, at least 1 mg, at least 1.5 mg, at least 2 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, or at least 25 mg T3 equivalent. A sufficient deposited dose or lung-delivered dose can provide delivery of a maximum amount of no more than 50 mg T3 equivalents such as, for example, no more than 30 mg, no more than 20 mg, no more than 15 mg, no more than 10 mg, no more than 5 mg, no more than 4 mg, no more than 3 mg, no more than 2 mg, no more than 1.5 mg, no more than 1 mg, no more than 500 pg, no more than 300 pg, no more than 200 pg, no more than 100 pg, no more than 50 pg, no more than 30 pg, no more than 20 pg, or no more than 10 pg T3 equivalents. A sufficient deposited dose or lung-delivered dose also can be characterized by any range that includes, as endpoints, any combination of a minimum deposited dose or lung- delivered dose and any maximum deposited dose or lung-delivered dose that is greater than the minimum deposited dose or lung-delivered dose. For example, in one or more embodiments, a deposited dose or lung-delivered dose can be from 1 pg to 2 mg T3 equivalents such as, for example, from 5 pg to 200 pg or 5 pg to 100 pg T3 equivalents.

[0097] In one or more embodiments where administration is done via lung instillation, the volume of a pharmaceutical composition delivered may be from 0.02 mL/g or wet lung weight per dose to 2 mL/g wet lung weight per dose. In one or more embodiments, a pharmaceutical composition delivered to the pulmonary tract may have a maximum volume of 2 mL/g wet lung weight per dose or less, 1.75 mL/g wet lung weight per dose or less, 1.5 mL/g wet lung weight per dose or less, 1.25 mL/g wet lung weight per dose, 1.0 mL/g wet lung weight per dose or less, 0.8 mL/g wet lung weight per dose or less, 0.6 mL/g wet lung weight per dose or less, 0.4 mL/g wet lung weight per dose or less, 0.2 mL/g wet lung weight per dose or less, 0.08 mL/g wet lung weight per dose or less, 0.06 mL/g wet lung weight per dose or less, or 0.04 mL/g wet lung weight per dose. In one or more embodiments, a pharmaceutical composition delivered to the pulmonary tract may have a minimum volume of 0.02 mL/g wet lung weight per dose or greater, 0.04 mL/g wet lung weight per dose or greater, 0.06 mL/g wet lung weight per dose or greater, 0.08 mL/g wet lung weight per dose or greater, 0.2 mL/g wet lung weight per dose or greater, 0.4 mL/g wet lung weight per dose or greater, 0.6 mL/g wet lung weight per dose or greater, 0.8 mL/g wet lung weight per dose or greater, 1.0 mL/g wet lung weight per dose or greater, 1.25 mL/g wet lung weight per dose or greater, 1.5 mL/g wet lung weight per dose or greater, or 1.75 mL/g wet lung weight per dose or greater. The maximum volume per wet lung weight per dose can be characterized by any range that includes, as endpoints, any combination of a minimum wet lung weight per dose and any maximum wet lung weight per dose that is greater than the minimum wet lung weight per dose. For example, in one or more embodiments, the volume of a liquid pharmaceutical composition delivered by lung instillation can be from 0.02 mL/g or wet lung weight per dose to 2 mL/g or wet lung weight per dose, for example, from 0.1 mL/g or wet lung weight per dose to 1 mL/g or wet lung weight per dose or 0.1 mL/g or wet lung weight per dose to 0.5 mL/g or wet lung weight per dose.

[0098] In or more embodiments, a pharmaceutical composition can be administered, for example, from a single dose to multiple doses per day, although in one or more embodiments the method can be performed by administering a pharmaceutical composition at a frequency outside this range. When multiple doses are used within a certain period, the amount of each dose may be the same or different. For example, a dose of 50 pg T3 equivalents in a day may be administered as a single dose of 50 pg, two 25 pg doses, or in multiple unequal doses. Also, when multiple doses are used within a certain period, the interval between doses may be the same or be different. In certain embodiments, a pharmaceutical composition may be administered from about once per day, four times per day, or continuously.

[0099] In one or more embodiments, a pharmaceutical composition may be administered, for example, from a single dose to a duration of multiple days, although in one or more embodiments the method can be performed by administering the pharmaceutical composition for a period outside this range. In certain embodiments, a pharmaceutical composition may be administered once, over a period of three days, or over a period of seven days. In certain embodiments, a pharmaceutical composition may be administered from about once per day, four times per day, or continuously. Usually, thyroid hormone replacement for human clinical hypothyroidism is given daily with either thyroxine T4 or combination T4 and T3. A recent study using a single oral dose of 50 micrograms of liothyronine resulted in peak serum concentration at 2.5 hours with a mean half-life of 22.5 hours. There was a lag between the peak serum concentration and the physiologic effect of increased heart rate at five hours. (Jonklaas et al., Ther Drug Monit. 37(1): 110-118, 2015). For acute severe human illness with myxedema coma, there is a wide recommended frequency of intravenous T3 administration, from every four hours to every 12-24 hours. Thus, in one or more embodiments, a pharmaceutical composition may be administered once daily by intratracheal instillation at escalating doses with frequent physiologic measurement of hemodynamic parameters and less frequently extravascular lung water (EVLW).

[0100] In another aspect, the present disclosure describes a method of making a solid pharmaceutical composition of the present disclosure. The method includes bringing the components of a solid pharmaceutical composition in contact. The components may be brought into contact as solids or in a solution.

[0101] In embodiments where a solid pharmaceutical composition includes or is a lyophilized solid, the method of forming the solid pharmaceutical composition includes lyophilizing a pre-lyophilizing solution. As such, the present disclosure further describes a liquid solution that includes T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof. A pre-lyophilizing solution includes the components of a solid pharmaceutical composition formed from the lyophilization process. As such, a pre-lyophilization solution can include T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof, a bulking agent; water; and a buffer agent. A pre-lyophilization solution can further include an organic solvent. An organic solvent may increase the solubility of T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof, in the pre-lyophilization solution. An organic solvent may decrease the lyophilization drying time. An organic solvent may increase the stability of a T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof, an organic solvent may decrease residual solvent levels in a solid pharmaceutical composition. Examples of organic solvents include, but are not limited to, tertbutanol and/or isopropanol. In one or more embodiments, the organic solvent includes tertbutanol.

[0102] The amount of each non-volatile component of a pre-lyophilized solution may be chosen such that the solid resulting from lyophilization has the desired amount of each component. Water and any organic solvents are largely or completely removed during the lyophilization process, and as such, are not present or are present at low amounts in the lyophilized solid.

[0103] In one or more embodiments, a pre-lyophilization solution may include 0.0001 wt-% to 0.1 wt-% T3 equivalents. In one or more embodiments, a pre-lyophilization solution includes a 0.0001 wt-% or greater, 0.0005 wt-% or greater, 0.001 wt-% or greater, 0.005 w-%, 0.01 wt-% or greater, or 0.05 wt-% or greater T3 equivalents. In one or more embodiments, a pre- lyophilization solution includes 0.1 wt-% or less, 0.05 wt-% or less, 0.01 wt-% or less, 0.005 wt- % or less, 0.001 wt-% or less, or 0.0005 wt-% or less T3 equivalents. In one or more embodiments, a pre-lyophilization solution may have an amount of T3 equivalents that falls within a range having endpoints defined by any minimum wt-% and any maximum wt-% that is greater than the minimum wt-%. Thus, for example, a pre-lyophilization solution may have an amount of a T3 equivalents from 0.0005 wt-% to 0.1 wt-%, such as, for example, 0.0005 wt-% to 0.005 wt-% or 0.0005 wt-% to 0.0001 wt-%.

[0104] In one or more embodiments, a pre-lyophilization solution may include 0.1 wt-% to 5 wt-% of a bulking agent. In one or more embodiments, a pre-lyophilization solution includes 0.1 wt-% or greater, 0.2 wt-% or greater, 0.3 wt-% or greater, 0.4 wt-% or greater, 0.05 wt-% or greater, 0.06 wt-% or greater, 0.7 wt-% or greater, 0.8 wt-% or greater, 0.9 wt-% or greater, 1 wt- % or greater, 2 wt-% or greater, 3 wt-% or greater, or 4 wt-% or greater of a bulking agent. In one or more embodiments, a pre-lyophilization solution includes 5 wt-% or less, 4 wt-% or less, 3 wt-% or less, 2 wt-% or less, 1 wt-% or less, 0.9 wt-% or less, 0.8 wt-% or less, 0.7 wt-% or less, 0.6 wt-% or less, 0.5 wt-% or less, 0.4 wt-% or less, 0.3 wt-% or less, or 0.2 wt-% or less of a bulking agent. In one or more embodiments, a pre-lyophilization solution may have an amount of bulking agent that falls within a range having endpoints defined by any minimum wt-% and any maximum wt-% that is greater than the minimum wt-%. Thus, for example, a pre- lyophilization solution may have an amount of a bulking agent from 0.1 wt-% to 2 wt-%, such as, for example, 0.1 wt-% to 1 wt-% or 0.1 wt-% to 0.5 wt-%.

[0105] In one or more embodiments, a pre-lyophilization solution may include 0.01 wt-% to 5 wt-% of a buffer agent. In one or more embodiments, a pre-lyophilization solution includes 0.01 wt-% or greater, 0.1 wt-% or greater, 0.2 wt-% or greater, 0.3 wt-% or greater, 0.4 wt-% or greater, 0.05 wt-% or greater, 0.06 wt-% or greater, 0.7 wt-% or greater, 0.8 wt-% or greater, 0.9 wt-% or greater, 1 wt-% or greater, 2 wt-% or greater, 3 wt-% or greater, or 4 wt-% or greater of a buffer agent. In one or more embodiments, a pre-lyophilization solution includes 5 wt-% or less, 4 wt-% or less, 3 wt-% or less, 2 wt-% or less, 1 wt-% or less, 0.9 wt-% or less, 0.8 wt-% or less, 0.7 wt-% or less, 0.6 wt-% or less, 0.5 wt-% or less, 0.4 wt-% or less, 0.3 wt-% or less, 0.2 wt-% or less, or 0.1 wt-% or less of a buffer agent. In one or more embodiments, a pre- lyophilization solution may have an amount of buffer agent that falls within a range having endpoints defined by any minimum wt-% and any maximum wt-% that is greater than the minimum wt-%. Thus, for example, a pre-lyophilization solution may have an amount of a buffer agent from 0.1 wt-% to 2 wt-%, such as, for example, 0.1 wt-% to 1 wt-% or 0.1 wt-% to 0.5 wt- %.

[0106] In one or more embodiments, a pre-lyophilization solution may include 1 mM to 100 mM of a buffer agent. In one or more embodiments, a pre-lyophilization solution may include 1 mM or greater, 5 mM or greater, 10 mM or greater, 15 mM or greater, 20 mM or greater, 25 mM or greater, 30 mM or greater, 35 mM or greater, 40 mM or greater, 45 mM or greater, 50 mM or greater, 60 mM or greater, 70 mM or greater, 80 mM or greater, or 90 mM or greater of a buffer agent. In one or more embodiments, a pre-lyophilization solution may include 100 mM or less, 90 mM or less, 80 mM or less, 70 mM or less, 60 mM or less, 50 mM or less, 45 mM or less, 30 mM or less, 25 mM or less, 20 mM or less, 15 mM or less, 10 mM or less or 5 mM or less of a buffer agent. In one or more embodiments, a pre-lyophilization solution may have an amount of buffer agent that falls within a range having endpoints defined by any minimum concentration and any maximum concentration that is greater than the minimum concentration. Thus, for example, a pre-lyophilization solution may have an amount of a buffer agent from 1 mM to 50 mM, such as, for example, 1 mM to 20 mM or 5 mM to 15 mM.

[0107] In one or more embodiments, a pre-lyophilization solution may include 5 wt-% to 50 wt-% of an organic solvent. In one or more embodiments, a pre-lyophilization solution includes 5 wt-% or greater, 10 wt-% or greater, 15 wt-% or greater, 20 wt-% or greater, 25 wt-% or greater, 30 wt-% or greater, 35 wt-% or greater, 40 wt-% or greater, or 45 wt-% or greater of an organic solvent. In one or more embodiments, a pre-lyophilization solution includes 50 wt-% or less, 45 wt-% or less, 40 wt-% or less, 35 wt-% or less, 30 wt-% or less, 25 wt-% or less, 20 wt- % or less, 15 wt-% or less, or 10 wt-% or less of an organic solvent. In one or more embodiments, a pre-lyophilization solution may have an amount of organic solvent that falls within a range having endpoints defined by any minimum wt-% and any maximum wt-% that is greater than the minimum wt-%. Thus, for example, a pre-lyophilization solution may have an amount of the organic solvent from 5 wt-% to 30 wt-%, such as, for example, 10 wt-% to 30 wt- % or 10 wt-% to 20 wt-%.

[0108] In one or more embodiments, a pre-lyophilization solution may include 5% weight by volume (w/v) to 50% w/v of an organic solvent. In one or more embodiments, a pre- lyophilization solution includes the organic solvent in an amount of 5% w/v or greater, 10% w/v or greater, 15% w/v or greater, 20% w/v or greater, 25% w/v or greater, 30% w/v or greater, 35% w/v or greater, 40% w/v or greater, or 45% w/v or greater. In one or more embodiments, a pre- lyophilization solution includes the organic solvent in an amount of 50% w/v or less, 45% w/v or less, 40% w/v or less, 35% w/v or less, 30% w/v or less, 25% w/v or less, 20% w/v or less, 15% w/v or less, or 10% w/v or less. In one or more embodiments, a pre-lyophilization solution may have an amount of organic that falls within a range having endpoints defined by any minimum % and any maximum % that is greater than the minimum %. Thus, for example, a pre- lyophilization solution may have an amount of an organic solvent from 5% w/v to 30% w/v, such as, for example, 10% w/v to 30% w/v or 10% w/v to 20%w/v.

[0109] FIG. 1 outlines the general stages of a lyophilization process. Lyophilization includes two stages, the freezing stage, and the drying stage. In the freezing stage, a pre-lyophilization solution is exposed to conditions to from ice and/or solute crystallization and/or a freeze concentrate. Ice crystallization is the primary event in the freezing step and may be followed by solute crystallization. When the solute does not crystallize it forms a freeze-concentrate. The drying stage often includes a primary drying step and a secondary drying step. Primary drying is conducted to cause ice and/or organic solvent sublimation. During secondary drying, sorbed water and/or organic solvent is removed. In general, during primary drying, the temperature is below the glass transition temperature of the freeze-concentrate or below the eutectic temperature of the frozen system. In secondary drying, temperature is below glass transition temperature of the lyophile. Primary drying, secondary drying, or both can be conducted under reduced pressure. [0110] In one or more embodiments, lyophilization includes freezing a pre-lyophilization solution to form a frozen pre-lyophilization solution. A frozen pre-lyophilization solution may include crystalline ice and/or other crystalline components as well as a freeze concentrate. Freezing a pre-lyophilization solution may include exposing the pre-lyophilization solution to a freezing temperature for a freezing time. The freezing temperature may be, for example, 0 °C or less, -10 °C or less, -20 °C or less, -30 °C or less, -40 °C or less, -50 °C or less, -60 °C or less, - 70 °C or less, or -80 °C or less. Freezing may be accomplished, for example, by exposure of a container of the pre-lyophilization solution to liquid nitrogen or using a freeze-dryer. The freezing time may be, for example, 5 minutes or greater, 0.5 hours or greater, 1 hour or greater, 2 hours or greater, 3 hours or greater, 4 hours or greater, 5 hours or greater, 6 hours or greater, 7 hours or greater, 8 hours or greater, 9 hours or greater, or 10 hours or greater. A frozen pre- lyophilization solution can be stored at a reduced temperature (e.g., -20 °C to -80 °C) until drying is conducted.

[0111] The lyophilization method includes drying a frozen pre-lyophilized solution resulting in a lyophilized solid. Drying includes removing the water and organic solvent from the frozen solution. Drying may include a primary drying stage and a secondary drying stage. The primary drying stage may include exposing a frozen pre-lyophilization solution to a primary drying temperature under a primary drying pressure for a primary drying time. During primary drying, ice and/or the organic solvent is removed from the frozen pre-lyophilization via sublimation. The primary drying temperature may be, for example, -20 °C to -80 °C such as -20 °C to -50 °C, -20 °C to -40 °C, or -25 °C to -35 °C. The primary drying pressure may be 500 millitorr (mTorr) or less, 400 mTorr or less, 300 mTorr or less, 200 mTorr or less, or 100 mTorr or less. The primary drying time may be, for example, 1 hour or greater, 12 hours or greater, 24 hours or greater, 36 hours or greater, or 48 hours or greater.

[0112] Drying may include a secondary drying stage. The secondary drying stage may include exposing a frozen pre-lyophilization solution to a secondary drying temperature under a secondary drying pressure for a secondary drying time. During secondary drying, sorbed water and/or organic solvent is removed from a frozen pre-lyophilization. The secondary drying temperature may be higher than the primary drying temperature. The secondary drying temperature, may be, for example, 0 °C to 30 °C such as 10 °C to 30 °C, 15 °C to 30°C, or -20 °C to 30 °C. The secondary drying pressure may be the same as the primary drying pressure. For example, the secondary drying pressure may be 500 millitorr (mTorr) or less, 400 mTorr or less, 300 mTorr or less, 200 mTorr or less, or 100 mTorr or less. The secondary drying time may be, for example, 30 minutes or greater, 1 hour or greater, 2 hours or greater, 3 hours or greater, 4 hours or greater, 5 hours or greater, 6 hours or greater, 7 hours or greater, 8 hours or greater, 9 hours or greater, or 10 hours or greater.

[0113] Various solid pharmaceutical compositions including T3 sodium were prepared via lyophilization. Prior to forming the pre-lyophilization solution, T3 sodium was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), automated water sorption/desorption and X-ray diffractometry (XRD).

[0114] To study the crystallinity of T3 sodium, XRD patterns were obtained (FIG. 2). Samples appear to be substantially but not completely crystalline.

[0115] Thermogravimetric analysis was used to study how the mass of the T3 sodium sample changed as the temperature it was exposed to changed. When the heating rate was 10 °C/min, there was no pronounced T3 sodium sample weight loss (~0.1 %) up to 150 °C. When the heating rate was decreased to 5 °C/min, a weight loss of 1.3% of T3 sodium sample was observed around 120 °C (FIG. 12). Thus, the weight loss depended on the heating rate (FIG. 12). Degradation may occur at elevated temperatures (FIGS. 3 and 12)

[0116] DSC was used to analyze the melting temperature of the T3 sodium sample. The T3 sodium sample melted in a non-hermetically sealed pan when the heating rate is 10 °C/min at around 200.2 °C (FIG. 4). The results were similar when the T3 sodium sample was placed in a hermetically sealed pan with pinhole at a heating rate of 5 °C/min (FIG. 5, (2)). The melting temperature observed is close to the previously reported melting point of T3 sodium, which is 205 °C. However, when a hermetically sealed pan was used, the melting point of the T3 sodium sample decreased to around 176.4 °C (FIG. 5, (1)). Hydrate formation is unlikely based on automated water sorption/desorption results of liothyronine sodium samples (FIG. 6). Pronounced weight increase was only observed at high relative humidity (85% and higher).

[0117] After baseline characterization of T3 sodium, pre-lyophilization solutions were made using tertbutanol (TBA), tris buffer, and mannitol. Current commercial products of T3 sodium are only available with T3 concentration of 10 and 20 pg/mL. Additionally, the commercially available liquid products of T3 sodium include 6.8% of alcohol by volume, ethanol, or sodium hydroxide, which may cause irritation of the respiratory tract. The solubility of T3 sodium in TBA is 27.4 pg/mL at room temperature. The solubility of T3 sodium in 10 mM pH 8.4 tris buffer is less than 9.6 pg/mL at room temperature. The pre-lyophilization formulations tested included 100 pg T3 sodium; 30%, 35%, or 40% w/w TBA; 10 mM pH 8.4 tris buffer; and 0.5% or 1% w/v mannitol. These formulations were designed to increase T3 sodium content in the pre- lyophilization solutions. A T3 sodium solubility of 59.2 pg/mL was obtained using 30% w/w TBA in 10 mM pH 8.4 tris buffer at room temperature. A T3 sodium solubility of and 66.0 /zg/mL was obtained using 40% w/w TBA in 10 mM pH 8.4 tris buffer at room temperature. Samples were lyophilized according to the procedure outlined in the Example.

[0118] After lyophilization, cakes were obtained from pre-lyophilization solutions that included T3 sodium, 0.5% and 1% w/v mannitol, 30%, 35%, and 40% w/w TBA in 10 mM pH 8.4 tris buffer. Lyophiles obtained from pre-lyophilization solutions that included 30% to 40% w/w TBA in 10 mM pH 8.4 tris buffer with 0.5% and 1% w/v mannitol and T3 sodium were subjected to synchrotron XRD analysis. Delta-, beta-, and alpha- anhydrous mannitol can be observed from the overlay of XRD patterns in FIG. 7. Possible mannitol hemihydrate (MHH) may be contained in lyophile. MHH includes 0.5 molecules of water per molecule of mannitol.

[0119] Low recovery of T3 in pre-lyophilization and reconstituted solutions (below 98%) was observed. To prevent T3 recovery loss, siliconization was done on all glassware that hold solutions containing T3 sodium. Standard curves of T3 sodium in the pre-lyophilization solution and reconstituted solutions were built (an example of such a curve is shown in FIG. 9). Due to the absence of TBA in reconstituted solutions due to freeze-drying process, slight difference in slopes could be observed (FIGS. 8 and 9). However, it does not influence the accuracy of detection.

[0120] The stability of reconstituted lyophilized solids was analyzed. For this study, lyophilized solids formed from a pre-lyophilization solution that included pre-lyophilized solutions included T3 sodium at concentration of 50 pg/mL in 30% w/w TBA in 10 mM pH 8.4 tris buffer with 1% mannitol solution were reconstituted using 20 mL of DI water with reconstitution time less than 5 minutes. The reconstituted solutions have pH values of 7.9. The amount of T3 was quantified after storing the reconstituted solutions both at room temperature and at 5 °C for 0 days, 1 day, 2 days, 3 days, 7 days, 10 days, and 14 days. Based on the standard curves of T3 sodium in the pre-lyophilization and reconstituted solutions, the concentration of T3 sodium was determined and recovery of T3 sodium was calculated. FIGS. 10 and 11 show the results. The recovery of T3 sodium is between 98.9% and 111.5% in pre-lyophilization solutions (pre-lyophilized solutions included T3 sodium at concentration of 50 pg/mL in 30% w/w TBA in 10 mM pH 8.4 tris buffer with 1% mannitol solution). The recovery of T3 sodium in freshly made reconstituted solutions (0 days) and reconstituted solutions stored up to 7 days is constantly more than 100%. As the storage time increases, the concentration of liothyronine sodium decreases (FIGS. 10 and 11). For example, for storage times longer than 7 days, recovery of T3 sodium in reconstituted solutions decreased. The decrease in T3 sodium recovery is not linear with respect to storage time.

[0121] In the preceding description and following claims, the term “and/or” means one or all of the listed elements or a combination of any two or more of the listed elements; the terms “comprises,” “comprising,” and variations thereof are to be construed as open ended — i.e., additional elements or steps are optional and may or may not be present; unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one; and the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0122] As used herein, the word “exemplary” means to serve as an illustrative example and should not be construed as preferred or advantageous over other embodiments.

[0123] As used herein, the terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

[0124] As used herein, “have,” “has,” “having,” “include,” “includes,” “including,” “comprise,” “comprises,” “comprising” or the like are used in their open-ended inclusive sense, and generally mean “include, but not limited to,” “includes, but not limited to,” or “including, but not limited to.” Further, wherever embodiments are described herein with the language “have,” “has,” “having,” “include,” “includes,” “including,” “comprise,” “comprises,” “comprising” and the like, otherwise analogous embodiments described in terms of “consisting of’ and/or “consisting essentially of’ are also provided. The term “consisting of’ means including, and limited to, that which follows the phrase “consisting of.” That is, “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present. The term “consisting essentially of’ indicates that any elements listed after the phrase are included, and that other elements than those listed may be included provided that those elements do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements.

[0125] In the description, particular embodiments may be described in isolation for clarity. Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” “one or more embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments. Thus, features described in the context of one embodiment may be combined with features described in the context of a different embodiment except where the features are necessarily mutually exclusive.

[0126] In several places throughout the above description, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

[0127] For any method disclosed herein that includes discrete steps, the steps may be performed in any feasible order. And, as appropriate, any combination of two or more steps may be performed simultaneously.

EXEMPLARY EMBODIMENTS

[0128] The following is a non-limiting list of exemplary embodiments. [0129] Embodiment 1 A is a solid pharmaceutical composition that includes T3 or a T3 prodrug, or a salt thereof, a hydrate thereof, or any combination thereof; and a bulking agent.

[0130] Embodiment IB is the solid pharmaceutical composition of Embodiment 1A, wherein the solid pharmaceutical composition includes T3, a salt thereof, a hydrate thereof, or any combination thereof.

[0131] Embodiment 1C is the solid pharmaceutical composition of Embodiment 1A, wherein the solid pharmaceutical composition includes T3 or a salt thereof.

[0132] Embodiment ID is the solid pharmaceutical composition of Embodiment 1A, wherein the solid pharmaceutical composition includes a T3 sodium salt.

[0133] Embodiment 2 is the solid pharmaceutical composition of any of Embodiment 1A- 1D, where the bulking agent includes mannitol.

[0134] Embodiment 3 is the solid pharmaceutical composition of any of Embodiments 1A to 2, where the composition further includes a buffer agent.

[0135] Embodiment 4 is the solid pharmaceutical composition of Embodiments 3, where the buffer agent includes tris(hydroxymethyl)aminomethane or a salt thereof.

[0136] Embodiment 5 is the solid pharmaceutical composition of any of Embodiments 1A to

4, where the powder includes less than 5 wt-% residual moisture.

[0137] Embodiment 6 is the solid pharmaceutical composition of any of Embodiments 1A to

5, where the solid composition includes 0.0001 wt-% to 2 wt-% T3 equivalents.

[0138] Embodiment 7 is the solid pharmaceutical composition of any of Embodiments 1A to

6, where the solid composition includes 50 wt-% to 99 wt-% of the bulking agent.

[0139] Embodiment 8 is the solid pharmaceutical composition of any of Embodiments 3 to 7, where the solid composition includes 1 wt-% to 50 wt-% of the buffer agent.

[0140] Embodiment 9 is the solid pharmaceutical composition of any of Embodiments 1A to 8, where the solid pharmaceutical composition includes T3 sodium.

[0141] Embodiment 10A is the solid pharmaceutical composition of any of Embodiments 3 to 7, where the solid pharmaceutical composition includes a lyophilized solid and the lyophilized solid includes T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof; the bulking agent; and the buffer agent (if present) in the solid pharmaceutical composition.

[0142] Embodiment 10B is the solid pharmaceutical composition of any of Embodiments 3 to 7, where the solid pharmaceutical composition includes a lyophilized solid and the lyophilized solid includes T3, a salt thereof, a hydrate thereof, or any combination thereof; the bulking agent; and the buffer agent (if present) in the solid pharmaceutical composition.

[0143] Embodiment 10C is the solid pharmaceutical composition of any of Embodiments 3 to 7, where the solid pharmaceutical composition includes a lyophilized solid and the lyophilized solid includes T3 or a salt thereof; the bulking agent; and the buffer agent if present in the solid pharmaceutical composition.

[0144] Embodiment 10D is the solid pharmaceutical composition of any of Embodiments 3 to 7, where the solid pharmaceutical composition includes a lyophilized solid and the lyophilized solid comprises T3 sodium; the bulking agent; and the buffer agent if present in the solid pharmaceutical composition.

[0145] Embodiment 11 is a liquid pharmaceutical composition that includes the solid composition of any of Embodiments 1A to 10D dissolved in a carrier.

[0146] Embodiment 12 is a liquid pharmaceutical composition that includes the solid pharmaceutical composition of any of Embodiments 10A to 10D reconstituted in a carrier.

[0147] Embodiment 13 is the liquid pharmaceutical composition of Embodiment 11 or 12, where the carrier comprises water.

[0148] Embodiment 14 is the liquid pharmaceutical composition of any of Embodiments 11 to 13, where the liquid pharmaceutical composition further comprises a bulking agent in addition to the bulking agent of the solid pharmaceutical composition.

[0149] Embodiment 15 is the liquid pharmaceutical composition of Embodiments 14, where the additional bulking agent is the same as the bulking agent of the solid pharmaceutical composition. [0150] Embodiment 16 is the liquid pharmaceutical composition of Embodiments 14, where the additional bulking agent is different than bulking agent of the solid pharmaceutical composition.

[01 1] Embodiment 17 is the liquid pharmaceutical composition of any of Embodiments 11 to 16, where the liquid pharmaceutical composition further comprises a buffer agent in addition to the buffer agent of the solid pharmaceutical composition.

[0152] Embodiment 18 is the liquid pharmaceutical composition of Embodiment 17, where the additional buffer agent is the same as the buffer agent of the solid pharmaceutical composition.

[0153] Embodiment 19 is the liquid pharmaceutical composition of Embodiment 17, where the additional buffer agent is the same as the buffer agent of the solid pharmaceutical composition.

[0154] Embodiment 20 is the liquid pharmaceutical composition of any of Embodiments 11 to 19, where the carrier comprises water.

[0155] Embodiment 21 is the liquid pharmaceutical composition of any of Embodiments 11 to 20, where the liquid pharmaceutical composition has a pH of 2 to 11.

[0156] Embodiment 22 is the liquid pharmaceutical composition of any of Embodiments 11 to 20, where the liquid pharmaceutical composition has a pH of 5 to 10.

[0157] Embodiment 23 A is the liquid pharmaceutical composition of any of Embodiments

11 to 20, where the pharmaceutical composition has a pH of 5.5 to 8.5.

[0158] Embodiment 23B is the liquid pharmaceutical composition of any of Embodiments 11 to 20, where the pharmaceutical composition has a pH of 3 to 8.

[0159] Embodiment 23C is the liquid pharmaceutical composition of any of Embodiments 11 to 20, where the pharmaceutical composition has a pH of 4 to 7.5. [0160] Embodiment 24 is a method of preparing the liquid pharmaceutical composition of any of Embodiments 11 to 23C, where the method includes dissolving the solid pharmaceutical composition in the carrier.

[0161] Embodiment 25 is a method that includes administering the pharmaceutical composition (solid pharmaceutical composition or liquid pharmaceutical composition) of any of Embodiments 1 A to 23 C to a subject.

[0162] Embodiment 26 is the method of Embodiment 25, where the subject is a human.

[0163] Embodiment 27 is the method of Embodiment 25 or 26, where the subject has or is at risk of having lung inflammation, pulmonary edema, a cardiac disease, or any combination thereof

[0164] Embodiment 28 A is the method of Embodiment 25 or 26, where the subject has or is at risk of having lung inflammation.

[0165] Embodiment 28B is the method of Embodiment 28A, where the pharmaceutical composition is administered prior to the subject manifesting any symptom or clinical sign of lung inflammation.

[0166] Embodiment 29 is the method of Embodiment 28A, where the pharmaceutical composition is administered after the subject manifesting any symptom or clinical sign of lung inflammation.

[0167] Embodiment 30 is the method of any of Embodiments 27 to 29, where the lung inflammation is a symptom or clinical sign of acute respiratory distress syndrome (ARDS).

[0168] Embodiment 31 is the method of any of Embodiments 27 to 30, where the lung inflammation is a symptom or clinical sign of premature birth, chest trauma, acute/chronic congestive heart failure, dilated cardiomyopathies, pre- and/or post-lung transplant, pre- and/or post- lung cancer radiotherapy or chemotherapy, pneumonia, sepsis, drug and substance-induced lung diseases such as smoking (including vaping and whether tobacco or THC), exposure to pollutants (whether environmental or occupational, e.g., asbestosis, silicosis, berylliosis, Coal Worker’s, pneumoconiosis, gas exposure, thermal injury, or other pneumoconiosis), hypersensitivity pneumonitis, reactive or obstructive lung diseases (e.g., asthma, chronic bronchitis, reactive airway dysfunction syndrome, or other reactive airway diseases), aspiration chemical pneumonitis or pneumonia, pneumonia or an infection of nasosinus, intratracheal, intrabronchial or alveolar airspace (e.g., bacterial, viral, fungal), connective tissue and vasculitic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, sarcoidosis, and other related diseases), Wegener’s granulomatosis, Goodpasture disease, acute or chronic eosinophilic pneumonia, medication-related lung injury (e.g., injury from use of amiodarone, bleomycin, busulfan, mitomycin C, methotrexate, apomorphine, nitrofurantoin, or other pneumotoxic drugs), cryptogenic organizing pneumonia, pulmonary hemorrhage such as exercise induced pulmonary hemorrhage, Churg-Strauss syndrome, or congenital or structural lung disease (e.g., cystic fibrosis, bronchiectasis).

[0169] Embodiment 32 is the method of any of Embodiments 25 to 31, where the subject has or is at risk of having pulmonary edema.

[0170] Embodiment 33 is the method of Embodiments 32, where the pharmaceutical composition is administered prior to the subject manifesting any symptom or clinical sign of pulmonary edema.

[0171] Embodiment 34 is the method of Embodiments 32, where the pharmaceutical composition is administered after the subject manifests any symptom or clinical sign of pulmonary edema.

[0172] Embodiment 35 is the method of any of Embodiments 32 to 34, where the pulmonary edema is a symptom or clinical sign of premature birth, chest trauma, congestive heart failure, lung transplant, lung cancer radiotherapy, lung cancer chemotherapy, smoking, exposure to a pollutant, hypersensitivity pneumonitis, a reactive/obstructive lung disease, aspiration chemical pneumonitis/pneumonia, pneumonia, an infection of the nasosinus, intratracheal, intrabronchial or alveolar airspace, a connective tissue disease, Wegener’s granulomatosis, Good pasture disease, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, medication-related lung injury, cryptogenic organizing pneumonia, Churg-Strauss syndrome, congenital lung disease, or structural lung disease.

[0173] Embodiment 36 is the method of any of Embodiments 25 or 35, wherein the subject has or is at risk of having a cardiac disease. [0174] Embodiment 37 is the method of Embodiments 36, where the cardiac disease is an acute coronary syndrome or heart failure.

[0175] Embodiment 38 is the method of Embodiments 37, where the acute coronary syndrome is unstable angina, ST-segment elevation myocardial infarction (STEMI), or non-ST- segment elevation myocardial infarction (NSTEMI).

[0176] Embodiment 39 is the method of Embodiments 37, where the heart failure acute coronary syndromes including unstable angina, myocardial ischemia, ST-segment elevation myocardial infarction (STEMI), Takotsubo’s Syndreom, and non-ST-segment elevation myocardial infarction (NSTEMI); acute valvular heart disease; heart failure including acute heart failure, chronic heart failure, dilated cardiomyopathies, decompensated chronic heart failure, leftsided heart failure, right-sided heart failure, and biventricular heart failure; or any combination.

[0177] Embodiment 40 is the method of any of Embodiments 25 to 39, where the pharmaceutical composition is administered before, during, or after the subject has cardiac surgery, a hemodynamic treatment, or both.

[0178] Embodiment 41A is the method of any of Embodiments 25 to 40, where the pharmaceutical composition is administered directly to the pulmonary tract of the subject.

[0179] Embodiment 41B is the method of any of Embodiments 25 to 41A, wherein the pharmaceutical composition is administered by inhalation of an aerosolized pharmaceutical composition, inhalation of a nebulized pharmaceutical composition, or intratracheal instillation.

[0180] Embodiment 42 is the method of any of Embodiments 25 to 41A, where the pharmaceutical composition is administered by pulmonary instillation.

[0181] Embodiment 43 is the method of any of Embodiments 25 to 41A, where the pharmaceutical composition is administered by intratracheal instillation.

[0182] Embodiment 44A is a liquid composition that includes T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof; an organic solvent; water, and a bulking agent.

[0183] Embodiment 44B is a liquid composition that includes T3, a salt thereof, a hydrate thereof, or any combination thereof; an organic solvent; water, and a bulking agent. [0184] Embodiment 44C is a liquid composition that includes a T3 salt; an organic solvent; water, and a bulking agent.

[0185] Embodiment 44D is a liquid composition that includes a T3 sodium salt; an organic solvent; water, and a bulking agent.

[0186] Embodiment 45 is the liquid composition of any of Embodiments 44A to 44D, where the bulking agent includes mannitol.

[0187] Embodiment 46 is the liquid composition of any of Embodiments 44A to 45, where the liquid composition further includes a buffer agent.

[0188] Embodiment 47 is the liquid composition of Embodiments 46, wherein the buffer agent comprises tris(hydroxymethyl)aminomethane or a salt thereof.

[0189] Embodiment 48 is the liquid composition of any of Embodiments 44A to 47, wherein the pH of the liquid composition is 5.5 to 8.5.

[0190] Embodiment 49 is the liquid composition of any of Embodiments 44A to 48, where the organic solvent includes tertbutanol.

[0191] Embodiment 50 is the liquid composition of any of Embodiments 44A to 49, where the liquid composition includes 0.0001 wt-% to 1 wt-% T3 equivalents.

[0192] Embodiment 51 is the liquid composition of any of Embodiments 44A to 50, where the liquid composition comprises 5 wt-% to 50 wt-% of the organic solvent.

[0193] Embodiment 52 is the liquid composition of any of Embodiments 44A to 51, where the liquid composition comprises 0.1 wt-% to 5 wt-% of the bulking agent.

[0194] Embodiment 53 is the liquid composition of any of Embodiments 44A to 51, where the liquid composition comprises 0.01 wt-% to 5 wt-% of the buffer agent (if present).

[0195] Embodiment 54 is a method of preparing the solid pharmaceutical composition of any of Embodiments 10A-10D, the method including lyophilizing the liquid composition of any of Embodiments 44 to 53. [0196] Embodiment 55 is the method of Embodiment 54, where lyophilizing includes freezing the liquid composition and removing at least a portion of the water and the organic solvent from the frozen liquid composition.

EXAMPLE

[0197] The present disclosure is illustrated by the following examples. It is to be understood that the particular examples, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the invention as set forth herein.

Materials and Methods

[0198] Liothyronine sodium or 3,3',5-triiodo-L-thyronine sodium salt (liothyronine sodium) was used as received from Sigma-Aldrich (Burlington, MA). The powder samples were stored in airtight and opaque containers in a freezer maintained at -20 °C. Tert-Butanol (TBA), dimethyldichlorosilane, chloroform, and D-mannitol were used as received from Sigma- Aldrich (Burlington, MA). Dimethyl Sulfoxide and tris(hydroxymethyl)aminomethane (tris base) were used as received from Fisher Scientific (Waltham, MA). Hydrochloric acid (36.5% -38%) was used as received from VWR Chemicals BDH (Solon, OH).

Differential Scanning Calorimetry (DSC)

[0199] Thermal analysis of powder samples was performed using a differential scanning calorimeter (model Q2000 TA Instruments, New Castle) equipped with a refrigerated and cooling system. The powder sample (2 mg to 5 mg) were either hermetically sealed non- hermetically sealed in an aluminum pan and measurements were performed at a heating rate of 5 °C /min from -20 °C to 250 °C. Dry nitrogen at 50 mL/min was used as the purge gas. The data were analyzed using Universal Analysis 2000, a commercial software by TA Instruments.

Thermogravimetric Analysis (TGA)

[0200] Powder samples (3 mg-5 mg) were individually placed in an aluminum pan and heated in a thermogravimetric analyzer (Q50 TGA by TA Instruments), under a dry nitrogen purge, from 25 °C to 260 °C at 5 °C/min.

Water Sorption/desorption Analysis [0201 ] Water sorption and desorption data were collected using an automated water sorption analyzer (DVS-1000 Advantage, Surface Measurement Systems, Middlesex, U.K.). Around 10 mg of the powder was placed in a quartz sample pan and equilibrated at 0% relative humidity (RH) (25 °C) for 1 h under a nitrogen flow rate of 200 mL/min. The RH was then increased at 10% increments to 90% RH. At each RH value, if the mass change (dm/dt) was less than 0.001% in 15 min, equilibrium was assumed to be achieved. The RH was then decreased at 10% decrements from 90% to 10% RH.

X-ray Diffractometry (XRD)

[0202] X-ray diffraction (XRD) patterns of liothyronine sodium were obtained by using a Rigaku Smartlab XE diffractometer with a powder diffractometer with Bragg-Brentano optics, copper X-ray sealed tube with Cu K-alphal radiation (wavelength 1.5406 A), computer controllable variable divergence slit, and the D/teX Ultra ID detector. The experiment was conducted under room temperature using the traditional 0-20 scanning method, which the step size is 0.01 degrees 2 theta, the speed is 4 degrees/min, and the range is from 5 degrees 2 theta to 35 degrees 2 theta or 5 degrees 2 theta to 40 degrees 2 theta.

Siliconizing Glassware

[0203] A I L volumetric flask with a snug-fitting glass stopper served as a storage container for the siliconizing solution which contains 2% v/v solution of dimethyldichlorosilane in chloroform. 300 mL of siliconizing solution was poured into a 600 mL glass beaker. A piece of glassware was gently placed in the siliconizing solution and the all surface was in contact with the solution. Forceps was used to remove the glassware from the solution, and it was placed on a paper towel in the hood and dried overnight. The rest of the siliconizing solution was poured back into the volumetric flask using a funnel. The dry glassware was transferred and kept into a 60 °C oven for two hours. Then the glassware was washed using soap and water and rinsed with deionized water. The glassware was air dried and ready to use for sample preparation.

Synchrotron X-ray Diffractometry (SXRD)

[0204] Samples were kept in DSC Tzero pans and were hermetically sealed. Synchrotron radiation (transmission mode) in the 17-BM-B beamline at Argonne National Laboratory (Argonne, IL) was applied on the samples. The monochromatic X-ray beam had a wavelength of 0.4512 A and a 300 pm beam diameter. An area detector (XRD- 1621, PerkinElmer) was applied and an A12O3 standard (SRM 674a, NIST) was used for calibration. A stepper motor was used to move the sample continuously (±2 mm from the center along the horizontal axis) in data collection for 30 s.

Lyophilization and Reconstitution of Various Samples

[0205] Solutions containing TBA (30%, 35%, and 40% w/w) buffered with 10 mM pH 8.4 tris buffer, mannitol (0.5% and 1% w/v), and liothyronine sodium (around 50 pg/mL) were prepared. 2 mb of these solutions were filled in 10 mL glass vials (NETA Scientific, NJ).

[0206] Freeze-drying was carried out in a benchtop freeze-dryer (VirTis Advantage, Gardiner, NY) with an organic solvent trap (VirTis). The shelf temperature was lowered to -45 °C, and samples were frozen for six hours. Primary drying was carried out for 48 hours at -30 °C under a vacuum (~200 mTorr). The temperature was then ramped to 25 °C and held for six hours. The heating and cooling rate was 0.5 °C /min. The vials were stoppered and stored at -20 °C. The lyophiles were subjected to synchrotron XRD, and 20 mL of distilled water with 1 mg/mL mannitol was used to reconstitute the lyophiles. Reconstituted solutions were kept at 5 °C for 14 days, 10 days, 7 days, 3 days, 2 days, and 1 day before quantification.

[0207] The complete disclosure of all patents, patent applications, and publications, and electronically available material cited herein are incorporated by reference in their entirety. In the event that any inconsistency exists between the disclosure of the present application and the disclosure(s) of any document incorporated herein by reference, the disclosure of the present application shall govern. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described, for variations obvious to one skilled in the art will be included within the invention defined by the claims.

[0208] Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0209] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. All numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements.

[0210] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.

Claims

CLAIMS What is claimed is:

1. A solid pharmaceutical composition comprising:

T3 or a T3 prodrug, a salt thereof, a hydrate thereof, or any combination thereof; and a bulking agent.

2. The solid pharmaceutical composition of claim 1, wherein the solid pharmaceutical composition further comprises a buffer agent.

3. The solid pharmaceutical composition of claim 1 or 2, wherein the bulking agent comprises mannitol.

4. The solid pharmaceutical composition of any of claims 2 or 3, wherein the buffer agent comprises tri s(hydroxymethyl)aminom ethane or a salt thereof.

5. The solid pharmaceutical composition of any of claims 1 to 4, wherein the solid pharmaceutical composition comprises less than 5 wt-% residual moisture.

6. The solid pharmaceutical composition of any of claims 1 to 5, wherein the solid composition comprises 0.0001 wt-% to 2 wt-% T3 equivalents.

7. The solid pharmaceutical composition of any of claims 1 to 6, wherein the solid pharmaceutical composition comprises 50 wt-% to 99 wt-% of the bulking agent.

8. The solid pharmaceutical composition of any of claims 2 to 7, wherein the solid pharmaceutical composition comprises 1 wt-% to 50 wt-% of the buffer agent.

9. The solid pharmaceutical composition of any of claims 1 to 8, wherein the solid pharmaceutical composition comprises T3 or a salt thereof.

10. The solid pharmaceutical composition of any of claims 1 to 9, wherein the solid pharmaceutical composition comprises T3 sodium.

11 . The solid pharmaceutical composition of any one of claims 1 to 10, wherein the solid pharmaceutical composition comprises a lyophilized solid and the lyophilized solid comprises the T3 or T3 prodrug, salt thereof, hydrate thereof, or any combination thereof; the bulking agent; and the buffer agent, if present, in the solid pharmaceutical composition.

12. A liquid pharmaceutical composition comprising the solid composition of any one of claims 1 to 11 dissolved in a carrier.

13. A liquid pharmaceutical composition comprising the solid pharmaceutical composition of claim 11 reconstituted in a carrier.

14. The liquid pharmaceutical composition of claim 12 or 13, wherein the carrier comprises water.

15. The liquid pharmaceutical composition of any of claims 12 to 14, wherein the liquid pharmaceutical composition has a pH of 5 to 10.

16. A method comprising administering a pharmaceutical composition to a human wherein the pharmaceutical composition is the solid pharmaceutical composition of any of claims 1 to 11 or the liquid pharmaceutical composition of any of claims 12 to 15.

17. The method of claim 16, wherein the human has or is at risk of having lung inflammation, pulmonary edema, a cardiac disease, or any combination thereof.

18. The method of claim 16 or 17, wherein the solid pharmaceutical composition is administered directly to the pulmonary tract of the human.

19. The method of any of claims 16 to 18, wherein the pharmaceutical composition is administered by inhalation of an aerosolized pharmaceutical composition or inhalation of a nebulized pharmaceutical composition.

20. The method of any of claims 16 to 18, wherein the pharmaceutical composition is administered by intratracheal instillation.