Compositions and methods for intranasal delivery of hydrocortisone

Abstract

An intranasal composition generally includes hydrocortisone, a hydrocortisone derivative, or a salt thereof. A method of administering an intranasal composition that includes hydrocortisone, a hydrocortisone derivative, or a salt thereof to a subject. A method of treating adrenal insufficiency in a subject, the method includes administering to a subject, a dose of a composition comprising hydrocortisone, a hydrocortisone derivative, or a salt thereof in an amount effective to treat adrenal insufficiency.

Description

[0001]Patent COMPOSITIONS AND METHODS FOR INTRANASAL DELIVERY OF HYDROCORTISONE CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Patent Application No. 63 / 615,954, filed December 29, 2023, which is incorporated herein by reference in its entirety. GOVERNMENT FUNDING This invention was made with government support under TR002494 awarded by the National Institutes of Health. The government has certain rights in the invention. SUMMARY This disclosure describes, in one aspect, an intranasal composition that includes hydrocortisone, a hydrocortisone derivative, or a salt thereof. In one or more embodiments, the hydrocortisone derivative includes hydrocortisone succinate or a salt thereof. In one or more embodiments, the composition includes hydrocortisone sodium succinate. In one or more embodiments, the composition includes hydrocortisone. In one or more embodiments, the composition does not include any ingredients in addition to the hydrocortisone, hydrocortisone derivative, or salt thereof. In one or more embodiments, the composition does include one or more ingredients in addition to the hydrocortisone, hydrocortisone derivative, or salt thereof. In one or more embodiments, the composition is a dry powder composition. In another aspect, the disclosure describes a method of administering a composition that includes hydrocortisone, a hydrocortisone derivative, or a salt thereof to a subject. In one or more embodiments, composition may be any composition of any aspect or embodiment described herein. In another aspect, the disclosure describes a method of treating adrenal insufficiency in a subject. The method includes administering to a subject, a dose of a composition that includes hydrocortisone, a hydrocortisone derivative, or a salt thereof in an amount effective to treat adrenal insufficiency. In one or more embodiments, composition may be any composition of any aspect or embodiment described herein. The above summary is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, 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. DEFINITIONS In the disclosure 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.). In the disclosure, 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. 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. In several places throughout the disclosure, 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. 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. 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. 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. BRIEF DESCRIPTION OF THE FIGURES FIG.1. Mean concentration-time profiles following 100 mg subcutaneous, 100 mg intramuscular, or split 100 mg intranasal. Arrows indicate times at which 50 mg administrations were given for the split 100 mg intranasal delivery. Data for subcutaneous administration and intramuscular administration are from Hahner et al., 2013, Eur J Endocrinol 169(2):147-154. FIG.2. Individual plasma concentration-time profiles. Traces represent the observed plasma concentrations of cortisol (µg / dL) in three participants (IN01, IN02, and IN03) after intranasal administration of 25 mg, 50 mg, or 100 mg hydrocortisone sodium succinate. FIG.3. Microscopic image of hydrocortisone raw material. FIG.4. Microscopic image of hydrocortisone sodium succinate raw material. FIG.5. Microscopic image of milled hydrocortisone sodium succinate raw material. FIG.6. Particle size distribution of hydrocortisone raw powders (hydrocortisone micronized and hydrocortisone USP neat), hydrocortisone sodium succinate raw powder (hydrocortisone Na succinate), and milled hydrocortisone sodium succinate (hydrocortisone and sec 8 sec). The distribution density q 3 presents the probability of a particle with diameter d to be found in the population. FIG.7. Hydrocortisone dissolution calibration curve. FIG.8. Hydrocortisone sodium succinate dissolution calibration curve. FIG.9. Concentration in hydrocortisone equivalence during a low-volume dissolution test of hydrocortisone raw powder (HC), hydrocortisone sodium succinate raw powder (HSS Control) and milled hydrocortisone sodium succinate (HHS-M). The Error bars represent the standard deviation of n=3 for HC and HC Control and n= 2 for HSS-M. FIG.10. Zoomed in plot of FIG.9 focusing on HC. FIG.11. Structures of hydrocortisone and hydrocortisone succinate. FIG.12. Individual plasma concentration-time profiles in dogs. Traces represent the observed plasma concentrations of cortisol (pg / mL) in two dogs after intranasal administration of 10 mg hydrocortisone dry powder and a bolus dose of 10 mg hydrocortisone sodium succinate solution. Dogs were administered dexamethasone prior to study drug administration to suppress cortisol production. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS This disclosure describes intranasal compositions of hydrocortisone, hydrocortisone derivatives, or salts thereof. In one or more embodiments, the intranasal composition is a pharmaceutical composition. Hydrocortisone is the name of the hormone cortisol when supplied as a medication. As used herein, cortisol and hydrocortisone are used interchangeably. The compositions may be used for treating medical conditions that involve adrenal insufficiency, both primary and secondary (see Table 1 for causes of adrenal insufficiency). Adrenal insufficiency is characterized by impaired adrenal synthesis of cortisol and can be categorized as primary, where the defect is in the adrenal gland, or secondary (central), where the defect is due to hypothalamic and / or pituitary dysfunction. In the secondary forms deficient secretion of ACTH leads to atrophy of the zona fasciculata in the adrenal cortex (the source of cortisol). Table 1. Causes of Adrenal Insufficiency Primary Secondary Congenital adrenal hyperplasia Isolated ACTH deficiency Ad l k d t h i l di t l PCSK1 d fi i F F S I cies r I Subjects with primary and secondary adrenal insufficiency may be at risk for life- threatening adrenal crises because they do not produce enough cortisol during periods of acute physical stress, for example during infection, trauma, illness, and the like . Adrenal crisis is a life-threatening emergency characterized by circulatory collapse in patients with cortisol deficiency. Each year, approximately 6% to 8% of patients with adrenal insufficiency experience a life-threatening adrenal crisis (see Rushworth et al., New England Journal of Medicine. 2019;381(9):852-61; and Hahner et al. European Journal of Endocrinology 2010;162(3):597- 602). Prospective studies report an incidence rate of 8 adrenal crises per 100 patient-years, while a retrospective U.S. study found a higher rate of 24 per 100 patient-years, with 44% of patients having experienced at least one adrenal crisis since diagnosis (see Hahner S et al., J Clin Endocrinol Metab.2015;100(2):407-16; Tschaidse L, et al., European Journal of Endocrinology 2024;190(4):275-83; and Li Det al., J Clin Endocrinol Metab.2021;106(3):e1408-e19. Mortality associated with adrenal crises is 0.5 per 100 patient-years, indicating that 1 in 200 patients with adrenal insufficiency experiencing an adrenal crisis will die, despite its preventable nature (see Hahner Set al., J Clin Endocrinol Metab.2015;100(2):407-16; and Allolio B. Extensive expertise in endocrinology. European Journal of Endocrinology 2015;172(3):R115-24). To reduce the likelihood or extent of an adrenal crisis, subjects are typically instructed to increase their cortisol replacement dosing when sick (“stress dosing”) either orally with hydrocortisone or, if not tolerated orally, through intramuscular injection of hydrocortisone sodium succinate. However, intramuscular injections can be intimidating for subjects (especially children) and / or caregivers who prepare the intramuscular injection. Preparing an intramuscular injection of hydrocortisone is a multi-step process that takes time and subjects / caregivers may struggle to handle glass ampoules with powder and separate solvent and needles in cases of emergency. Further, subjects (and / or caregivers) sometimes hesitate to administer an intramuscular injection when symptoms of adrenal crisis appear because of needle anxiety and / or fear of experience or inflicting pain associated with injection. Subjects or caregivers who wait too long before giving or receiving an intramuscular injection or opt not to give or receive an intramuscular injection at all, can require an emergency room visit or hospitalization for medical treatment of adrenal crisis. For this reason, intramuscular injections are not an ideal route of administration for subjects with adrenal insufficiency outside the medical setting. There is a critical need for a less invasive and intimidating route of administration such as intranasal delivery. Intranasal administration of hydrocortisone, a hydrocortisone derivative, or a salt thereof can permit rapid attainment of cortisol concentrations needed for stress dosing to prevent adrenal crisis in subjects who are unable to maintain appropriate concentrations with the use of oral hydrocortisone for example, during acute illness, trauma, and surgery, etc. Hydrocortisone, a corticosteroid with a molecular weight of 362.46 grams per mole, is white to practically white, odorless, crystalline powder known to be sparingly soluble in water and soluble in alcohol. The structure of hydrocortisone is shown in FIG.11. Hydrocortisone is accessible in various formulations. For example, hydrocortisone is available as a solid powder in vials in amounts of 100 mg, 250 mg, 500 mg, or 1000 mg. Hydrocortisone is also formulated as capsules (hydrocortisone granules) of 0.5 mg, 1 mg, 2 mg, or 5 mg, and tablets of 5 mg, 10 mg, or 20 mg Additionally, hydrocortisone is commonly used to treat a spectrum of medical conditions across multiple systems, including endocrine, respiratory, dermatological, rheumatological, and oncological diseases. Hydrocortisone succinate is succinate ester of hydrocortisone. The structure of hydrocortisone succinate is shown in FIG.11. Hydrocortisone succinate can exist as the free acid or as a salt. Example salts of hydrocortisone succinate salts include hydrocortisone sodium succinate, hydrocortisone cesium succinate, and hydrocortisone lithium succinate. Hydrocortisone sodium succinate is a white or nearly white odorless power with a molecular weight of 484.51 grams per mole. Hydrocortisone sodium succinate is soluble in water and in alcohol. Hydrocortisone has a solubility of ~ 125 ug / mL in water and ~290 ug / mL in ethanol. Hydrocortisone sodium succinate has a solubility of ~100 ug / mL in water and ~25 ug / mL in ethanol. The sodium salt of hydrocortisone succinate, hydrocortisone sodium succinate, is commonly available as a solid power of 100 mg, 250 mg, 500 mg, or 1000 mg hydrocortisone. It can be used to treat allergic states, dermatologic diseases, endocrine disorders, gastrointestinal diseases, hematologic disorders, neoplastic diseases, ophthalmic diseases, renal diseases, respiratory diseases, and rheumatic disorders when oral therapy is not feasible. This disclosure describes a composition that includes hydrocortisone, a hydrocortisone derivate, or a salt thereof. Hydrocortisone, hydrocortisone derivative, or a salt thereof are described herein as an active ingredient. The composition may be pharmaceutical compositions. The composition may be intranasal delivery composition, also called an intranasal composition. An intranasal delivery composition is a composition suitable for intranasal delivery or intranasal administration of at least an active ingredient to a subject. The composition may be formulated with one or more ingredients in addition to the active ingredient. This disclosure therefore describes a formulation for intranasal delivery of hydrocortisone, hydrocortisone succinate, or a salt thereof. The disclosure also describes methods for intranasal delivery of hydrocortisone, hydrocortisone succinate, or a salt thereof. For example, the disclosure describes methods for intranasal delivery of a composition of the present disclosure. The compositions and methods described herein satisfy a need for routes of administering hydrocortisone, a hydrocortisone derivative, or a salt thereof, that are less painful and less intimidating than intramuscular injections. The compositions and methods described herein provide an easy-to-handle pre-packaged product, enabling a subject or caregiver to quickly and easily administer a sufficient amount of hydrocortisone, a hydrocortisone derivative, or a salt thereof that can effectively reduce the likelihood and / or extent of incipient adrenal crisis. Intranasal hydrocortisone, hydrocortisone derivative, or a salt thereof delivery system is a route of administration that has not been used before for treating adrenal crises during periods of acute stress. The tolerability of intranasal hydrocortisone sodium succinate formulations (compositions) was evaluated. Additionally, the absorption and pharmacokinetics of hydrocortisone sodium succinate were characterized following intranasal administration. An open-label dose escalation pilot study was performed where participants received three escalating intranasal doses (25 mg, 50 mg, and 100 mg hydrocortisone equivalents) of hydrocortisone sodium succinate as a liquid formulation (see Example 1). Following administration of each dose, pharmacokinetic data were gathered with cortisol concentrations measured pre-dose, and at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, and 360 minutes after the intranasal dose of hydrocortisone sodium succinate to evaluate drug absorption. To assess subject tolerability, a Global Pain and Tolerability Analog Scale was administered at administration and at 5 minutes, 30 minutes, 60 minutes, 120 minutes, and 360 minutes after administration. A secondary objective was comparing intranasal pharmacokinetic (PK) variables to previously reported values following intramuscular (IM) and subcutaneous (SQ) administration (Hahner et al., 2013, Eur J Endocrinol 169(2):147-154). FIG.1 displays the mean cortisol concentration-time profiles in the dose escalation study. Cortisol reached similar plasma concentrations and peaked within the first two hours following dose administration for all three participants. The subcutaneous and intramuscular data in FIG.1 are from Hahner et al., 2013, Eur J Endocrinol 169(2):147-154. For the intranasal 100 mg dose, the dose was split into two 50 mg administrations given one hour apart, which explains the delay in peak cortisol concentration compared to intramuscular and subcutaneous administrations, where the 100 mg dose was not split. Table 2 presents the mean for pharmacokinetic variables for the three participants where AUC0–∞ is the area under the plasma concentration‐time curve from time zero extrapolated to infinity, AUC0–6 h is the area under the plasma concentration‐ time curve from time zero to six hours, Cmax: maximum observed plasma concentration, Tmax is the time to reach maximum plasma concentration, T1 / 2is the terminal half‐life. The 100 mg dose was divided into two doses (50 mg) given one hour apart. Table 2. Mean pharmacokinetic variables for intranasal hydrocortisone sodium succinate administration. Dose AUC0–∞AUC0–6CmaxTmaxT1 / 2(mg eq (µg*hour / dL) (µg*hour / dL) (µg / dL) (hour) (hour) hydrocortisone) owing escalating doses of 25 mg, 50 mg, and 100 mg of intranasal hydrocortisone sodium succinate administration in three participants (INO1, INO2, and INO3), each of whom were diagnosed with primary adrenal insufficiency due to the severe, salt-wasting form of congenital adrenal hyperplasia. As shown in Table 3, the three doses can be seen to have comparable pharmacokinetic parameter estimates. To compare the intranasal route of administration to Hanher et al. (Hahner et al., 2013, Eur J Endocrinol 169(2):147-154), pharmacokinetics were evaluated over four hours following administration of the 100 mg dose. Since the intranasal 100 mg dose was split into two 50 mg administrations given one hour apart, the Tmax for the 100 mg dose was delayed. In Table 3, Cmaxis the maximum observed plasma concentration, Tmaxis the time to reach maximum concentration, T1 / 2 is the terminal half-life, AUC0-4 is the area under the plasma concentration from time zero to four hours, * indicates the standard deviations and statistical comparisons are not calculated for a sample size of three, and ** indicates historical data from Hahner et al., 2013, Eur J Endocrinol 169(2):147-154. Table 3. Mean pharmacokinetic variables for different formulation after 100 mg dose of hydrocortisone equivalents. L) SC (n=12)**96.8 + / - 27.5 1.5 + / - 0.5 4.7 + / - 4.7 272.3 + / - 60.1IN (n=3)*95.6 2.2 2.1 318.8. e Global pain and tolerability scale ranges from 0 to 10 with 0 representing no nasal discomfort, pain, or discomfort. Mild discomfort, burning / irritation, and bitter taste in the back of the throat were reported immediately after nasal administration of hydrocortisone sodium succinate in all three subjects and resolved within an hour. Table 4. Global pain and tolerability analog scale. Time (min) 25 mg 50 mg 100 mg -1 0.0 0.0 0.0 Thus, in one aspect, this disclosure describes a composition of an active ingredient that includes hydrocortisone, a hydrocortisone derivative, or a salt thereof. The composition can be suitable for intranasal administration. As such, the composition can be an intranasal delivery composition. The hydrocortisone or hydrocortisone derivative may be provided in any pharmaceutically acceptable salt. Examples of hydrocortisone derivative include, but are not limited to, hydrocortisone succinate, hydrocortisone phosphate, hydrocortisone acetate, hydrocortisone maleate, hydrocortisone nitrate, hydrocortisone mesylate, hydrocortisone citrate, hydrocortisone phosphate, hydrocortisone maleate. Example salts of hydrocortisone derivatives include, but are not limited to hydrocortisone sodium succinate, hydrocortisone sodium phosphate, hydrocortisone sodium acetate, hydrocortisone sodium maleate, hydrocortisone sodium nitrate, hydrocortisone sodium mesylate, hydrocortisone sodium citrate, hydrocortisone potassium phosphate, hydrocortisone potassium succinate, hydrocortisone potassium acetate, hydrocortisone potassium maleate, hydrocortisone potassium nitrate, hydrocortisone potassium mesylate, or hydrocortisone potassium citrate. In one or more embodiments, the composition includes hydrocortisone. In one or more embodiments, the active ingredient includes hydrocortisone. In one or more embodiments, the active ingredient is hydrocortisone. In one or more embodiments, the composition includes hydrocortisone succinate or a pharmaceutically acceptable salt thereof. In one or more embodiments, the active ingredient in the composition includes hydrocortisone succinate or a pharmaceutically acceptable salt thereof. In one or more embodiments, the active ingredient in the composition is hydrocortisone succinate or a pharmaceutically acceptable salt thereof. In one or more embodiments the composition includes hydrocortisone sodium succinate, hydrocortisone potassium succinate, or both. In one or more embodiments, the active ingredient of the composition includes hydrocortisone sodium succinate, hydrocortisone potassium succinate, or both. In one or more embodiments, the active ingredient of the composition is hydrocortisone sodium succinate, hydrocortisone potassium succinate, or both. In one or more embodiments the composition includes hydrocortisone sodium succinate. In one or more embodiments, the active ingredient of the composition includes hydrocortisone sodium succinate. In one or more embodiments, the active ingredient of the composition is hydrocortisone sodium succinate. In one or more embodiments the composition includes hydrocortisone potassium succinate. In one or more embodiments the active ingredient of the composition includes hydrocortisone potassium succinate. In one or more embodiments the active ingredient of the composition is hydrocortisone potassium succinate. In one or more embodiments, the composition is excipient free. For example, in one or more embodiments, the hydrocortisone, a derivative of hydrocortisone, or a salt thereof, formulation is excipient free. In one or more embodiments, the composition is carrier free. For example, in one or more embodiments, active ingredient is not formulated with a pharmaceutically acceptable carrier. In one or more embodiments, the composition is not formulated with any ingredients in addition to the active ingredient. In one or more embodiments, the composition is excipient and carrier free. In one or more embodiments, the composition consists of the active ingredient. In one or more embodiments, the composition is a dry powder that includes the active ingredient. For example, in one or more embodiments, the active ingredient may be a dry powder. In one or more embodiments, a dry powder composition may include one or more other ingredients in addition to the active ingredient. As such, a dry powder composition may be formulated with one or more ingredients in addition to the active ingredient. For example, a dry powder composition may include one or more excipients or dried other chemical agents. In one or more embodiments, the composition is a dry powder that consists of the active ingredient. In one or more embodiments, the composition may be formulated with a pharmaceutically acceptable carrier to provide a pharmaceutical composition. It is understood that a composition or a pharmaceutical composition may or may not include one or more ingredients in addition to the active ingredient. As such, in one or more embodiments, the composition may include a pharmaceutically acceptable carrier. When formulated with one or more ingredients (for example, a carrier, an excipient, or the like) in addition to the active ingredient, the composition or pharmaceutical composition can be referred to as a formulation. For example, in one or more embodiments the active ingredient is formulated with a pharmaceutically acceptable carrier. As used herein, “carrier” includes any solvent, dispersion medium, vehicle, coating, diluent, antibacterial, and / or antifungal agent, isotonic agent, absorption modifying agent, buffer, carrier solution, suspension, colloid, and the like. The use of such media and / or agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the composition is contemplated. Supplementary active ingredients also can be incorporated into the compositions. As used herein, “pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, that is, the material may be administered to an individual along with the active ingredient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. In one or more embodiments, the composition may be formulated into a pharmaceutical composition for intranasal delivery of the active ingredient. In one or more embodiments, the carrier is a liquid carrier. In one or more embodiments, the pharmaceutically acceptable carrier can include water. The pH of a composition disclosed herein may be from about pH 4.0 to about pH 10.0. In one or more embodiments, the pH of a composition is 4.0 to pH 10.0. In one or more embodiments, the pH of the composition is 4 to 7. In one or more embodiments, the pH of the composition pH is 4.5 to 6.5. In one or more embodiments, the pH of a composition is 5.0 to pH 8.0. In one or more embodiments, the pH of a composition is 6.0 to pH 8.0. In one or more embodiments, the pH of a composition is 7.0 to pH 8.0. The pH of a formulation disclosed herein may be maintained at the desired level by the presence of a material that maintains the pH of a solution within a desired range. Illustrative materials that maintain the pH of a solution within a desired range include, but are not limited to, a buffer, a pH control agent, a buffering agent, a buffering system, or any combination of two or more such materials. Suitable buffers include, but are not limited to, phosphate, ascorbate, arginine, acetate, citrate, acetic acid, hydrochloric acid, tartrate, glutamate, tris(hydroxymethyl)aminomethane, acetate, borate, sulfate, lactate, sodium hydroxide, or any combination thereof. The buffer or buffering system may be formed by dissolving one or more buffering agents in the carrier. As such, the carrier and the composition may include one or more buffering agents. Examples of buffering agents include, but are not limited to, sodium phosphate (monobasic and / or dibasic), potassium phosphate, sodium citrate, potassium citrate, sodium acetate, potassium acetate, sodium borate, potassium borate, magnesium sulfate, sodium lactate, potassium lactate, or any combination thereof. In one or more embodiments, the pharmaceutically acceptable carrier includes water and a salt. Example salts include, but are not limited to, sodium chloride, potassium chloride, calcium chloride, or any combination thereof. In one or more embodiments, the pharmaceutically acceptable carrier can include or be normal saline. In other embodiments, the pharmaceutically acceptable carrier can be or include a dextrose solution and / or sodium lactate solutions such as Lactated Ringer’s solution (includes sodium chloride, sodium lactate, potassium chloride, and calcium chloride) instead of or in combination with normal saline. In one or more embodiments, the pharmaceutically acceptable carrier can include or be saline. In one or more embodiments, the pharmaceutically acceptable carrier can include phosphate. In one or more embodiments, the pharmaceutically acceptable carrier can be or include phosphate buffered saline. The concentration of the active ingredient in a liquid formulation, such as a solution, suspension, or emulsion, can vary. In one or more embodiments, the composition includes 10 mg / mL or greater, 25 mg / mL or greater, 50 mg / mL or greater, 75 mg / mL or greater, 100 mg / mL or greater, 125 mg / mL or greater, 150 mg / mL or greater, 175 mg / mL or greater, 200 mg / mL or greater, 225 mg / mL or greater, 250 mg / mL or greater, 275 mg / mL or greater, 300 mg / mL or greater, 325 mg / mL or greater, 350 mg / mL or greater, 375 mg / mL or greater, 400 mg / mL or greater, 425 mg / mL or greater, 500 mg / mL or greater, 525 mg / mL or greater, 550 mg / mL or greater, 575 mg / mL or greater, 600 mg / mL or greater, 625 mg / mL or greater, 650 mg / mL or greater, 675 mg / mL or greater, 700 mg / mL or greater, 725 mg / mL or greater, 750 mg / mL or greater, 775 mg / mL or greater, 800 mg / mL or greater, 825 mg / mL or greater, 850 mg / mL or greater, 875 mg / mL or greater, 900 mg / mL or greater, 925 mg / mL or greater, 950 mg / mL or greater, 975 mg / mL or greater, 1000 mg / mL or greater, 1100 mg / mL or greater, 1200 mg / mL or greater, 1300 mg / mL or greater, or 1400 mg / mL or greater of the active ingredient. In one or more embodiments, the composition includes 1500 mg / mL or less, 1400 mg / mL or less, 1300 mg / mL or less, 1200 mg / mL or less, 1100 mg / mL or less, 1000 mg / mL or less, 975 mg / mL or less, 950 mg / mL or less, 925 mg / mL or less, 900 mg / mL or less, 875 mg / mL or less, 850 mg / mL or less, 825 mg / mL or less, 800 mg / mL or less, 775 mg / mL or less, 750 mg / mL or less, 725 mg / mL or less, 700 mg / mL or less, 675 mg / mL or less, 650 mg / mL or less, 625 mg / mL or less, 600 mg / mL or less, 575 mg / mL or less, 550 mg / mL or less, 525 mg / mL or less, 500 mg / mL or less, 475 mg / mL or less, 450 mg / mL or less, 425 mg / mL or less, 400 mg / mL or less, 375 mg / mL or less, 350 mg / mL or less, 325 mg / mL or less, 300 mg / mL or less, 275 mg / mL or less, 250 mg / mL or less, 225 mg / mL or less, 200 mg / mL or less, 175 mg / mL or less, 150 mg / mL or less, 125 mg / mL or less, 100 mg / mL or less 75 mg / mL or less, 50 mg / mL or less, or 25 mg / mL or less of the active ingredient. In one or more embodiments, the composition includes 800 mg / mL to 1500 mg / mL, such as 800 mg / mL to 1200 mg / mL, 900 mg / mL to 1100 mg / mL, or 1000 mg / mL of the active ingredient. The concentration of the hydrocortisone equivalents in a liquid formulation, such as a solution, suspension, or emulsion, can vary. In one or more embodiments, the composition includes 10 mg / mL or greater, 25 mg / mL or greater, 50 mg / mL or greater, 75 mg / mL or greater, 100 mg / mL or greater, 125 mg / mL or greater, 150 mg / mL or greater, 175 mg / mL or greater, 200 mg / mL or greater, 225 mg / mL or greater, 250 mg / mL or greater, 275 mg / mL or greater, 300 mg / mL or greater, 325 mg / mL or greater, 350 mg / mL or greater, 375 mg / mL or greater, 400 mg / mL or greater, 425 mg / mL or greater, 500 mg / mL or greater, 525 mg / mL or greater, 550 mg / mL or greater, 575 mg / mL or greater, 600 mg / mL or greater, 625 mg / mL or greater, 650 mg / mL or greater, 675 mg / mL or greater, 700 mg / mL or greater, 725 mg / mL or greater, 750 mg / mL or greater, 775 mg / mL or greater, 800 mg / mL or greater, 825 mg / mL or greater, 850 mg / mL or greater, 875 mg / mL or greater, 900 mg / mL or greater, 925 mg / mL or greater, 950 mg / mL or greater, 975 mg / mL or greater, 1000 mg / mL or greater, 1100 mg / mL or greater, 1200 mg / mL or greater, 1300 mg / mL or greater, or 1400 mg / mL or greater hydrocortisone equivalents. In one or more embodiments, the composition includes 1500 mg / mL or less, 1400 mg / mL or less, 1300 mg / mL or less, 1200 mg / mL or less, 1100 mg / mL or less, 1000 mg / mL or less, 975 mg / mL or less, 950 mg / mL or less, 925 mg / mL or less, 900 mg / mL or less, 875 mg / mL or less, 850 mg / mL or less, 825 mg / mL or less, 800 mg / mL or less, 775 mg / mL or less, 750 mg / mL or less, 725 mg / mL or less, 700 mg / mL or less, 675 mg / mL or less, 650 mg / mL or less, 625 mg / mL or less, 600 mg / mL or less, 575 mg / mL or less, 550 mg / mL or less, 525 mg / mL or less, 500 mg / mL or less, 475 mg / mL or less, 450 mg / mL or less, 425 mg / mL or less, 400 mg / mL or less, 375 mg / mL or less, 350 mg / mL or less, 325 mg / mL or less, 300 mg / mL or less, 275 mg / mL or less, 250 mg / mL or less, 225 mg / mL or less, 200 mg / mL or less, 175 mg / mL or less, 150 mg / mL or less, 125 mg / mL or less, 100 mg / mL or less 75 mg / mL or less, 50 mg / mL or less, or 25 mg / mL or less hydrocortisone equivalents. In one or more embodiments, the composition includes 800 mg / mL to 1500 mg / mL, such as 800 mg / mL to 1200 mg / mL, 900 mg / mL to 1100 mg / mL, or 1000 mg / mL hydrocortisone equivalents. The composition may be provided in any suitable form including but not limited to a solution, a suspension, an emulsion, a spray, an aerosol, a powder, or any form of mixture suitable for intranasal delivery. The composition may be delivered in a formulation with any pharmaceutically acceptable excipient, carrier, or vehicle. For example, the composition may be delivered in a conventional intranasal dosage form such as, for example, an aerosol , a non- aerosol spray, a nebulized composition, and the like. In one or more embodiments the composition is an aerosol composition. An aerosol composition can be used in conjunction with a delivery device. Example delivery devices include inhalers such as aerosol inhalers and dry-powder inhalers. Upon actuation of the delivery device, an amount of a composition or a dose of an active ingredient is delivered to a subject in the form of an aerosol. In one or more embodiments, the composition is a liquid aerosol composition. For example, in one or more embodiments, the composition is a solution, suspension, or an emulsion liquid aerosol composition. In one or more embodiments, the composition is a dry powder aerosol composition. Aerosol composition may include propellants. Example propellants include, but are not limited to, hydrofluorocarbon propellants. As such, in one or more embodiments, the composition includes a propellant. In one or more embodiments, an aerosol formulation includes a propellant. In one or more embodiments the composition is a non-aerosol spray composition. A non- aerosol spray composition can be used in conjunction with a delivery device. A non-aerosol spray composition can be used in conjunction with a delivery device. Examples of non-aerosol spray nasal delivery devices include, but are not limited to, nasal spray devices and nebulizer. A nasal spray device may be an atomizer device having a spray tip. Upon actuation of the delivery device, an amount of a composition or a dose of an active ingredient is delivered to a subject in the form of a spray, such as a mist. In one or more embodiments, the composition is a liquid non- aerosol spray composition. For example, in one or more embodiments, the composition is a solution, suspension, or an emulsion liquid non-aerosol spray composition. The composition may further include one or more additives including such as, for example, vitamin E (which can improve tolerability and / or absorption), an adjuvant, a skin penetration enhancer, a colorant, a fragrance, a flavoring, and the like. As another example, preservative or absorption enhancing agents may be used to enhance stability of the product and nasal permeability. Excipients that increase permeability and stability include, but are not limited to, cyclodextrins, surfactants (e.g., bile salts, fatty acids, phospholipids, etc.), cationic polymers, tight junction modulators, enzyme inhibitors, or amino acids. In one or more embodiments, the formulation includes a cyclodextrin. Cyclodextrins are cyclic oligosaccharides often including glucose or dextrose subunits covalently joined via an α- 1,4-glycosic bonds to form a macrocycle. Cyclodextrins can be described by the number of glucose / dextrose subunits. For example, a cyclodextrin may have six (α-cyclodextrin; α-CD), seven (β-cyclodextrin; β-CD), eight (γ-cyclodextrin), nine, or ten glucose / dextrose subunits. Cyclodextrins may be unsubstituted or substituted. An unsubstituted cyclodextrin is a cyclodextrin where none of the hydroxyl groups of the glucose / dextrose subunits are replaced with a different moiety. A substituted cyclodextrin is a cyclodextrin where one or more of the hydroxyl groups of the glucose / dextrose subunits of the cyclodextrin are substituted with a different moiety. The substituent may be described as the entire group that replaces the hydroxyl or as an R group where the location of the substituent can be described as -OR or -OCH2R where R is a moiety other than H. Example substitutions include 2-hydroxypropyl (R = - CH2CH(OH)(CH3)), methoxy (R = -OCH3), acetate (-O(CO)CH3), 3,5-dimethylphenyl carbamate, and sulfobutylether (R = CH2CH2CH2CH2(SO3)-). Examples of substituted cyclodextrins include hydroxypropyl-β-cyclodextrin (HP-β-CD; CAS No.128446-35-5), hydroxypropyl-γ-cyclodextrin (HP-γ-CD; CAS No.128446-34-3), methyl-β-cyclodextrin (M-β- CD; CAS No.128446-36-6), sulfobutylether-β-cyclodextrin (SBE-β-CD; CAS No.182410-00- 0), and 1(1-napthyl)ethyl carbamoyl-β-cyclodextrin. The pattern of cyclodextrin substitution may vary. A single hydroxyl on the entire cyclodextrin may be substituted or two or more hydroxyls on the cyclodextrin may be substituted. In some cases where two or more hydroxyls are substituted, the two or more hydroxyls may be on the same glucose subunit, different glucose subunits, or both. A cyclodextrin may be randomly substituted. When a plurality of substituted cyclodextrin compounds from the same class are included in a formulation, the number and pattern of the substitution on each cyclodextrin in the plurality may be the same or different. In one or more embodiments, the formulation includes α-cyclodextrin. In one or more embodiments, the formulation includes β-cyclodextrin. In one or more embodiments, the formulation includes γ-cyclodextrin. In one or more embodiments, the formulation includes hydroxypropyl-β-cyclodextrin. In one or more embodiments, the formulation includes sulfobutylether-β-cyclodextrin. In one or more embodiments, the formulation includes methylated-β-cyclodextrin such as randomly methylated-β-cyclodextrin. Hydrocortisone formulations that included cyclodextrin were developed for nasal administration. The cyclodextrin may act as a solubility and / or stability enhancer. Formulations (n=30 vials / formulation) were prepared at various hydrocortisone sodium succinate concentrations (125 mg / mL to 1000 mg / mL hydrocortisone equivalents) at varying pH values and with varying sulfobutylether-β-cyclodextrin (CAPTISOL available from Ligand Pharmaceuticals, San Diego, CA) amounts. Rigorous stability assessment over two weeks revealed insolubility at the targeted 500 mg / mL concentration in sterile water. The 125 mg / mL and 250 mg / mL hydrocortisone solutions showed pH changes and concentration declines over a two-week period. The 500 mg / mL hydrocortisone solution with 10-20% weight per volume (w / v) sulfobutylether-β-cyclodextrin demonstrated favorable solubility but faced precipitation issues after 2-3 weeks. These findings highlight challenges in hydrocortisone liquid formulation for nasal administration, emphasizing solubility and stability. The composition may include a dispersing agent. A dispersing agent may be used to maintain the homogeneity of a suspension formulation disclosed herein by, for example, minimizing or preventing settling of suspension particles. Examples of dispersing agents include lactose, trehalose, magnesium stearate, and the like. Plasma cortisol levels delivered by intranasal administration and intravenous administration were compared. Two dogs were intranasally administered a 10 mg ( 0.67 mg / kg) dry powder dose of hydrocortisone. The dogs received dexamethasone the night prior and 1 hr prior to the study to suppress cortisol production. Following intranasal delivery (7 to 14 days), dogs were intravenously administered a 10 mg dose of hydrocortisone sodium succinate. No signs of pain or discomfort was observed. FIG.12 shows the cortisol plasma concentration at various time point post administration. The intranasal absolute bioavailability values were 84% and 96%. When a dry powder composition is prepared by solvent precipitation, buffers and salts may be used to stabilize the hydrocortisone in solution prior to particle formation. Suitable buffers include, but are not limited to, the buffers listed above. In the context of embodiments in which the dry powder is prepared by solvent precipitation, preferred buffers include, but are not limited to, ascorbate, phosphate, citrate, acetate, and tris(hydroxymethyl)aminomethane. Suitable salts include, but are not limited to, sodium chloride, sodium carbonate, and calcium chloride. Additional excipients may be used to, for example, improve the taste associated with intranasal administration of the active ingredient, which can improve compliance. A composition may be conveniently presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Methods of preparing a composition with a pharmaceutically acceptable carrier include the step of bringing the active ingredient into association with a carrier that constitutes one or more accessory ingredients. For example, a composition for intranasal delivery may be prepared by uniformly and / or intimately bringing the active ingredient into association with a liquid carrier and any accessory ingredient. In a composition, such as a powder composition, the particle size distribution may vary. For intranasal delivery compositions, particle size may affect the active ingredient absorption properties. For example, larger particles may settle near the front of the nasal cavity and small particles may pass through the nasal cavity into the throat and / or lungs. The particle size may be expressed in terms of the number of particles that have a particle size small than a stated particular particle size. For example, the particle size distribution may be described in terms of D10, D50, and D90 where a D10 value is the particle size that 10% of the of the particles in a sample are smaller than, a D50 value is the particle size that 50% of the of the particles in a sample are smaller than, and a D90value is the particle size that 90% of the of the particles in a sample are smaller than. The effective particle size for nasal delivery is dictated by the size of the particle aggregates as they are dispensed from the delivery device. The primary particle size described by D10, D50, and D90represents the lower bounds of particle size distribution upon complete disaggregation during the aerosol dispersion process. In one or more embodiments, the particle D10 may be 0.01 micrometers (µm) or greater, 0.1 µm or greater, 1 µm or greater, 5 µm or greater, 10 µm or greater, 15 µm or greater, 20 µm or greater, 30 µm or greater, 40 µm or greater, 50 µm or greater, 75 µm or greater, 100 µm or greater, 125 µm or greater, 150 µm or greater, 175 µm or greater, 200 µm or greater, 250 µm or greater, 300 µm or greater, or 400 µm or greater. In one or more embodiments, the hydrocortisone D10may be 500 µm or less, 400 µm or less, 300 µm or less, 250 µm or less, 200 µm or less, 175 µm or less, 150 µm or less, 125 µm or less, 75 µm or less, 50 µm or less, 40 µm or less, 30 µm or less, 20 µm or less, 15 µm or less, 10 µm or less, 5 µm or less, 1 µm or less, or 0.1 µm or less. In one or more embodiments, the particle D50may be 1 micrometers (µm) or greater, 5 µm or greater, 10 µm or greater, 15 µm or greater, 20 µm or greater, 30 µm or greater, 40 µm or greater, 50 µm or greater, 60 µm or greater, 70 µm or greater, 80 µm or greater, or 90 µm or greater, 100 µm or greater, 125 µm or greater, 150 µm or greater, 175 µm or greater, or 200 µm or greater. In one or more embodiments, the hydrocortisone D50 may be 250 µm or less, 200 µm or less, 175 µm or less, 150 µm or less, 125 µm or less,100 µm or less, 90 µm or less, 80 µm or less, 70 µm or less, 60 µm or less, 50 µm or less, 40 µm or less, 30 µm or less, 20 µm or less, 15 µm or less, 10 µm or less, or 5 µm or less. In one or more embodiments, the particle D90 may be 50 micrometers (µm) or greater, 60 µm or greater, 70 µm or greater, 80 µm or greater, 90 µm or greater, 100 µm or greater, 110 µm or greater, 120 µm or greater, 130 µm or greater, 140 µm or greater, 150 µm or greater, 160 µm or greater, 170 µm or greater, 180 µm or greater, 190 µm or greater, 2000 µm or greater, 250 µm or greater, 300 µm or greater, or 350 µm or greater. In one or more embodiments, the hydrocortisone D90 may be 400 µm or less, 350 µm or less, 300 µm or less, 250 µm or less, 200 µm or less, 190 µm or less, 180 µm or less, 170 µm or less, 160 µm or less, 150 µm or less, 140 µm or less, 130 µm or less, 120 µm or less, 110 µm or less, 100 µm or less, 90 µm or less, 80 µm or less, 70 µm or less, or 60 µm or less. The effect of hydrocortisone particle size distribution on dissolution was assessed. The samples tested included USP hydrocortisone (CO137) raw powder used as obtained from the supplier (Spectrum Chemical, New Brunswick, NJ), hydrocortisone raw powder used as obtained from the supplier (Sigma-Aldrich, St. Louis, MO), and bulk hydrocortisone sodium succinate milled after obtaining from the supplier (H1340; Spectrum Chemical, New Brunswick, NJ). The hydrocortisone raw powders had particle sizes above the desired range. Both raw powders had a D90 of about 20 µm, an D50 of about 3.5 µm, and an D10 of about 0.93 µm (FIG. 6). This size distribution indicates that these powders have primary particles that are already smaller than the desired size range for delivery into the nasal cavity. The unprocessed hydrocortisone sodium succinate powder from was visually determined to be coarse and heterogenous. The size analysis found a D90of 150 µm (FIG.6). The D50was 55 µm and the D10was 10 µm both of which are desirable (FIG.6). Following milling, the D90was reduced to 110 µm and the D50 reduced to 35 µm. However, the D10 was reduced 6 µm thus increasing the respirable fraction of this powder if in fact these fine particles completely disaggregate during actuation of an intranasal delivery device (FIG.6). Microscopic photographs were taken of hydrocortisone and hydrocortisone sodium succinate materials used in the study, depicting the very fine nature of the micronized hydrocortisone material compared to the starting hydrocortisone sodium succinate material. In agreement with the particle size distribution data, the milled hydrocortisone sodium succinate (FIG.3) had decreased size compared to the hydrocortisone sodium succinate material (FIG.4) but was much larger that than the micronized hydrocortisone material (FIG.5). Low volume dissolution studies were performed on the raw hydrocortisone powders, the raw bulk hydrocortisone sodium succinate powder, and the milled hydrocortisone sodium succinate powder as described in the Examples. During the course of the dissolution analysis, it was visually observed that both of the hydrocortisone sodium succinate powders were very easily wet upon addition to the filter membrane as compared the hydrocortisone powder. It was also observed that there was considerable variance in the piling of the powders onto the membrane (the powders were not evenly dispersed across the filter membrane). This represents a worse-case scenario as powders administered in this manner would experience no dispersion which is unlike what would be encountered during a dispense from a powder delivery device. Nonetheless, the dissolution kinetics are relevant and represent a conceptual lower limit for dissolution. FIG.7 and FIG.8 depict the calibration curves used to analyze the dissolution results. The resulting dissolution curves depicted in FIG.9 and FIG.10 show the rapid and complete dissolution of hydrocortisone sodium succinate powder from both the milled (HSS-M) and starting material tested (HSS control). High variability in dissolution was observed for the milled hydrocortisone sodium succinate material as a result of one of the wells having completely dissolved the material by the first time point. Hydrocortisone sodium succinate exhibited a dissolution rate that was much faster than hydrocortisone (HC), reaching a concentration 20 times higher at the 30-minute mark. Milling size reduction did not enhance the dissolution rate of hydrocortisone sodium succinate beyond that of the not processed starting material (HSS Control), with both materials showing nearly complete dissolution within 30 minutes. Both hydrocortisone sodium succinate (HSS) and hydrocortisone (HC) displayed first- order dissolution kinetics, but their dissolution rates and concentrations differed significantly. In another aspect, the present disclosure describes a method of administering a composition that includes hydrocortisone, a hydrocortisone derivative, or a slat thereof to a subject. For example, in some embodiments, the method includes administering a compostion of the present disclosure to a subject. 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). In one or more embodiments, the subject is a human. In one or more embodiments, the human is 2 years or old or older, 5 years old or older, 7 years old or older, 10 years old or older, or 12 years old or older. In one or more embodiments, the human is 12 years old or less, 10 years old or less, 7 years old or less, 5 years old or less, or 2 years old or less. In one or more embodiments, the subject is a livestock animal, a laboratory animal, or a companion animal. In one or more embodiments, the subject is a livestock animal. In one or more embodiments, the subject is a laboratory animal. In one or more embodiments, the subject is a companion animal. In one or more embodiments, administering the composition includes intranasal administration of the composition. For example, administering the composition can include administering the composition into the nose of the subject. Intranasal administration can include contacting the composition with mucous membranes of the nasal cavity of a subject. In one or more embodiments, administering the composition includes using a delivery device to administer the composition. In one or more embodiments, administering the composition includes using a delivery device to intranasally deliver the composition to the subject. Example delivery devices include, but are not limited to, inhalers such as metered dose inhalers, dry powder inhalers, soft mist inhalers; nebulizers, nasal spray device; and the like. The amount of the active ingredient administered can vary depending on various factors including, but not limited to, the weight, physical condition, and / or age of the subject. Thus, the absolute weight of the active ingredient 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. Accordingly, it is not practical to set forth generally the amount that constitutes an amount of the active ingredient effective for all possible applications. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors. In one or more embodiments, the method can include administering a sufficient amount of the composition to provide a dose of, for example, from about 5 mg to 1000 mg of the active ingredient to the subject, although in some embodiments the methods may be performed by administering the composition to achieve a dose outside this range. In one or more embodiments, the method includes administering a sufficient amount of a composition disclosed herein to provide a minimum dose of at least 2 mg, such as, for example, at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, or at least 250 mg of the active ingredient. In one or more embodiments, the method includes administering a sufficient amount of a composition disclosed herein to provide a minimum dose of at least 5 mg such as, for example, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, or at least 250 mg hydrocortisone equivalents. In one or more embodiments, the method includes administering a sufficient amount of a composition disclosed herein to provide a maximum dose of no more than 1000 mg such as, for example, no more than 500 mg, no more than 250 mg, no more than 200 mg, no more than 100 mg, no more than 75 mg, no more than 50 mg, or no more than 25 mg of the active ingredient. In one or more embodiments, the method includes administering a sufficient amount of a composition disclosed herein to provide a maximum dose of no more than 1000 mg such as, for example, no more than 500 mg, no more than 250 mg, no more than 200 mg, no more than 100 mg, no more than 75 mg, no more than 50 mg, or no more than 25 mg hydrocortisone equivalents. The active ingredient or hydrocortisone equivalents is said to be present in amounts “no more than” a reference amount or concentration when the active ingredient is not absent but is present in an amount up or including to the reference amount or concentration. In one or more embodiments, the method includes administering a sufficient amount of a composition disclosed herein to provide a dose that falls within a range having endpoints defined by any a minimum dose identified above and any maximum dose identified above that is greater than the selected minimum dose. For example, the method can include administering a sufficient amount of a composition disclosed herein to provide a dose of from 5 mg to 25 mg, from 50 mg to 75 mg, from 5 mg to 100 mg, from 5 mg to 500 mg, or from 100 mg to 500 mg of the active ingredient. Thr method can include administering a sufficient amount of a composition disclosed herein to provide a dose of from 5 mg to 25 mg, from 50 mg to 75 mg, from 5 mg to 100 mg, from 5 mg to 500 mg, or from 100 mg to 500 mg hydrocortisone equivalents. In certain embodiments, the dose can be equal to any minimum dose or any maximum listed dose above. Thus, for example, the method can include administering a sufficient amount of the composition to provide a dose of 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 250 mg, or 500 mg of the active ingredient. The method can include administering a sufficient amount of the composition to provide a dose of 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 250 mg, or 500 mg hydrocortisone equivalents. In some instances, the dose of the active ingredient may be at least partially determined by the age or medical history of the subject. For example, in some cases, a dose of from 5 mg to 25 mg of the active ingredient may be an appropriate starting point for a subject up to two years of age; a dose of 50 mg of the active ingredient may be an appropriate starting point for a subject from two years of age to seven years of age; a dose of 75 mg of the active ingredient may be an appropriate starting point for a subject from seven years of age to twelve years of age; and a dose of 100 mg of the active ingredient may be an appropriate starting point for a subject twelve years of age or older. Such doses may be modified based on the subject’s medical condition or medical history. As one nonlimiting example, certain subjects may have increased cortisol clearance and may, therefore, require that the listed starting pint doses be increased in order to achieve the desired therapeutic effect. A single dose may be administered all at once or in multiple discrete administrations. When multiple administrations are used, the amount of each administration may be the same or different. For example, a dose of 100 mg of the active ingredient may be administered as a single administration of 100 mg, as two 50 mg administrations, or as a first administration of 75 mg followed by a second administration of 25 mg. When multiple administrations are used to deliver a single dose, the interval between administrations may be the same or different. In one or more embodiments, a composition of the present disclosure may be administered, for example, to achieve from a single dose to multiple doses per day or per week of the active ingredient, although in some embodiments the method can involve a course of treatment that includes administering doses at a frequency outside this range. When a course of treatment involves administering multiple doses within a certain period, the amount of each dose may be the same or different. For example, a course of treatment can include a loading dose initial dose, followed by a maintenance dose that is lower than the loading dose. 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 composition of the present disclosure may be administered from about once to several time per day over one day or several days while the patient is in acute illness. In another aspect, the present disclosure describes a method of treating adrenal insufficiency in a subject. The method includes administering composition that includes hydrocortisone, a derivative of hydrocortisone, or a salt thereof to a subject in an amount to provide a dose of the active ingredient in an amount effective to treat adrenal insufficiency. For example, the method can include administering to a subject a dose of a composition that includes hydrocortisone, a hydrocortisone derivative, in an amount effective to treat adrenal insufficiency. In one or more embodiments, the composition includes hydrocortisone. In one or more embodiments, the composition includes hydrocortisone succinate. In one or more embodiments, the composition includes hydrocortisone sodium succinate. In one or more embodiments, the composition is a composition described herein. In one or more embodiments, the composition is administered to the subject intranasally. “Treat” or variations thereof refer to reducing, limiting progression, ameliorating, or resolving, to any extent, the symptoms or signs related to adrenal insufficiency. 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 adrenal insufficiency. “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 adrenal insufficiency. Generally, a “therapeutic” treatment is initiated after the condition (e.g., adrenal insufficiency) manifests in a subject, while “prophylactic” treatment is often initiated before a condition (e.g., adrenal insufficiency) manifests in a subject. Treating a condition can be prophylactic or, alternatively, can be initiated after the subject exhibits one or more symptoms or clinical signs of adrenal insufficiency. Treatment that is prophylactic—e.g., initiated before a subject manifests a symptom or clinical sign of the adrenal insufficiency such as is referred to herein as treatment of a subject that is “at risk” of having adrenal insufficiency. 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 adrenal insufficiency is a subject possessing one or more risk factors associated with adrenal insufficiency such as, for example, genetic predisposition, ancestry, age, sex, geographical location, lifestyle, or medical history. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Accordingly, a composition can be administered before, during, or after the subject first exhibits a symptom or clinical sign of adrenal insufficiency. Treatment initiated before the subject first exhibits a symptom or clinical sign associated with adrenal insufficiency may result in decreasing the likelihood that the subject experiences clinical evidence of the condition compared to a subject to which the composition is not administered, decreasing the severity of symptoms and / or clinical signs of adrenal insufficiency, and / or completely resolving the condition. Treatment initiated after the subject first exhibits a symptom or clinical sign associated with adrenal insufficiency may result in decreasing the severity of symptoms and / or clinical signs of the condition compared to a subject to which the composition is not administered, and / or completely resolving the condition. Thus, in one or more embodiments, the method includes administering an effective amount of the composition to a subject having, or at risk of having adrenal insufficiency. In this aspect, an “effective amount” is an amount effective to reduce, limit progression, ameliorate, or resolve, to any extent, a symptom or clinical sign related to adrenal insufficiency. In one or more embodiments, the method includes treating primary adrenal insufficiency. In one or more embodiments, the method includes treating primary adrenal insufficiency associated with one or more of congenital adrenal hyperplasia, adrenoleukodystrophy, neonatal adrenoleukodystrophy, familial glucocorticoid deficiency type 1, familial glucocorticoid deficiency type 2, triple A or Allgrove syndrome, Wolman disease, Kearns-Sayre syndrome, Smith-Lemli-Opitz syndrome, isolated autoimmune adrenalitis, autoimmune polyglandular syndrome, APS1, autoimmune polyglandular syndrome (APS2), glucocorticoid resistance, an infection (e.g., HIV, tuberculosis, meningococcemia), adrenal hemorrhage, or congenital adrenal hypoplasia, autoimmune adrenalitis (Addison disease), glucocorticoid resistance, Zellweger, multiple endocrine neoplasia Type 2 A & B. In one or more embodiments, the method includes treating secondary adrenal insufficiency. In one or more embodiments, the method includes treating secondary adrenal insufficiency associated with one or more of isolated ACTH deficiency, PCSK1 deficiency, prohormone convertase 1 / 3 deficiency, congenital proopiomelanocortin deficiency, combined pituitary hormone deficiency, X-linked panhypopituitarism, Prader Willi, hypothalamic pituitary tumors, hypothalamic surgery, hypothalamic irradiation, pituitary apoplexy (Sheehan syndrome), or iatrogenic (secondary to steroid treatment for rheumatologic diseases, chemotherapy, etc.), multiple anterior pituitary hormone deficiencies due to pituitary aplasia / hypoplasia, holoprosencephaly, corticotropin release factor deficiency. In one or more embodiments, the method includes treating adrenal crisis. An adrenal crisis is acute deterioration and profound impairment of general health, with at least two of the following signs and symptoms: arterial hypotension with systolic blood pressure <100 mm Hg or relative hypotension (≥20 mm Hg lower than usual), nausea or vomiting, severe weakness or fatigue, fever, somnolence, confusion or impaired consciousness, hyponatremia (≤ 132 mmol / L), hyperkalemia, and / or hypoglycemia (more common in children). EXEMPLARY EMBODIMENTS Below there is provided a non-exhaustive listing of non-limiting exemplary embodiments. Any one or more of the features of these embodiments may be combined with any one or more features of another example, embodiment, or aspect described herein. Embodiment 1 is an intranasal delivery composition comprising hydrocortisone, a hydrocortisone derivative, or a salt thereof. Embodiment 2 is the intranasal delivery composition of Embodiment 1, where the hydrocortisone derivative includes hydrocortisone succinate or a salt thereof. Embodiment 3 is the intranasal delivery composition of claim Embodiment 1 or 2, where the composition includes hydrocortisone sodium succinate. Embodiment 4 is the intranasal delivery composition of any one of Embodiments 1 or 2, further comprising one or more excipients. Embodiment 5 is the intranasal delivery composition of Embodiment 4, where the excipient includes a material that enhances stability of the hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 6 is the intranasal delivery composition of Embodiment 4, where the excipient includes a material that enhances permeation of the hydrocortisone, the hydrocortisone derivative, or the salt thereof across nasal mucosa of a subject. Embodiment 7 is the intranasal delivery composition of Embodiment 6, where material that enhances permeation of the hydrocortisone, the hydrocortisone derivative, or the salt thereof across the nasal mucosa includes a surfactant, vitamin E, a hydrophilic small molecule, a cyclodextrin, a surfactant, a cationic polymer, a tight junction modulator, an enzyme inhibitor, or an amino acid. Embodiment 8 is the intranasal delivery composition of Embodiment 4, where the excipient includes a material that enhances tolerability of the hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 9 is the intranasal delivery composition of Embodiment 8, where the material that enhances tolerability of the hydrocortisone, the hydrocortisone derivative, or the salt thereof includes a flavoring, a fragrance, or vitamin E. Embodiment 10A is the intranasal delivery composition of Embodiment 1, where the composition is excipient free. Embodiment 10B is the intranasal delivery composition of Embodiment 1, where the composition consists of hydrocortisone, a hydrocortisone derivative, or a salt thereof. Embodiment 11 is the intranasal delivery composition of any of Embodiment 1 to 10B, where the composition is a solid. Embodiment 12 is the intranasal delivery composition of Embodiment 11, where the composition is a dry powder, the dry powder comprising particles, the particles comprising the hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 13 is the intranasal delivery composition of Embodiment 12, where the particles have a D90of 50 µm to 200 µm. Embodiment 14 is the intranasal delivery composition of Embodiment 12, where the particles have a D90 of 50 µm to 150 µm. Embodiment 15 is the intranasal delivery composition of Embodiment 12, where particles the have a D9050 µm to 120 µm. Embodiment 16 is the intranasal delivery composition of any one of Embodiment 12 to 16, where the particles have a D50 of 1 µm to 100 µm. Embodiment 17 is the intranasal delivery composition of any one of Embodiment 12 to 16, where the particles have a D50 of 5 µm to 50 µm. Embodiment 18 is the intranasal delivery composition of any one of Embodiment 12 to 16, where the particles have a D50of 5 µm to 20 µm. Embodiment 19 is the intranasal delivery composition of any one of Embodiment 12 to 18, where the particles have a D10 of 0.01 µm to 20 µm. Embodiment 20 is the intranasal delivery composition of any one of Embodiment 12 to 18, where the particles have a D10 of 0.1 µm to 10 µm. Embodiment 21 is the intranasal delivery composition of any one of Embodiment 12 to 18, where the particles have a D10 of 0.1 µm to 5 µm. Embodiment 22 is the intranasal delivery composition of any one of Embodiment 1 to 10B, where the composition further includes a pharmaceutically acceptable liquid carrier. Embodiment 23 is the intranasal delivery composition of Embodiment 22, where the pharmaceutically acceptable liquid carrier includes water. Embodiment 24 is the intranasal delivery composition of Embodiment 22, where the pharmaceutically acceptable carrier includes Lactated Ringer’s solution. Embodiment 25 is the intranasal delivery composition of any one of Embodiments 22 to 24, where the pharmaceutically acceptable carrier includes saline. Embodiment 26 is the intranasal delivery composition of any one of Embodiments 22 to 24, where the pharmaceutically acceptable carrier includes phosphate buffered saline. Embodiment 27 is the intranasal delivery composition of any one of Embodiments 22 to 26, where the composition includes 1 mg / mL to 1000 mg / mL of the hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 28 is the intranasal delivery composition of any one of Embodiments 22 to 26, where the composition includes 50 mg / mL to 1000 mg / mL of the hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 29 is the intranasal delivery composition of any one of Embodiments 22 to 26, where the composition includes 250 mg / mL to 1000 mg / mL of the hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 30 is the intranasal delivery composition of any one of Embodiments 22 to 29, where the composition is a solution. Embodiment 31 is the intranasal delivery composition of any one of Embodiments 22 to 29, where the composition is a suspension. Embodiment 32 is the intranasal delivery composition of any one of Embodiments 22 to 29, where the composition is an emulsion. Embodiment 33 is the intranasal delivery composition of any one of Embodiments 1 to 32, where the composition is an aerosol composition. Embodiment 34 is the intranasal delivery composition of any one of Embodiments 1 to 32, where the composition is a non-aerosol spray composition. Embodiment 35 is a method of administering a composition comprising hydrocortisone, a hydrocortisone derivative, or a salt thereof to a subject. Embodiment 36 is the method of Embodiment 35, where the composition is the intranasal delivery composition of any one of Embodiments 1 to 34. Embodiment 37 is the method of claim 35, where the composition includes hydrocortisone. Embodiment 38 is the method of Embodiment 35, where the composition includes hydrocortisone succinate or a salt thereof. Embodiment 39 is the method of Embodiment 35, where the composition includes hydrocortisone sodium succinate. Embodiment 40 is the method of any one of Embodiments 35 to 39, where the method includes intranasally administering the composition to the subject. Embodiment 41 is the method of any one of Embodiments 35 to 41, where the subject is a human. Embodiment 42 is a method of treating adrenal insufficiency in a subject, the method comprising administering to a subject, a dose of a composition comprising hydrocortisone, a hydrocortisone derivative, or a salt thereof in an amount effective to treat adrenal insufficiency. Embodiment 43 is the method of Embodiment 42, where the composition includes hydrocortisone. Embodiment 43 is the method of Embodiment 42, where the composition includes hydrocortisone succinate or a salt thereof. Embodiment 44 is the method of Embodiment 42, where the composition includes hydrocortisone sodium succinate. Embodiment 45 is the method of Embodiment 42, where the composition includes the intranasal delivery composition of any one of Embodiments 1 to 35. Embodiment 46 is the method of any one of Embodiments 42 to 45, where the method includes intranasally administering the dose of the composition to the subject. Embodiment 47 is the method of any one of Embodiments 42 to 45, where the dose includes 5 mg to 1000 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 48 is the method of claim any one of Embodiments 42 to 45, where the dose includes 25 mg to 100 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 49 is the method of claim any one of Embodiments 42 to 45, where the dose includes 5 mg to 25 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 50 is the method of claim any one of Embodiments 42 to 45, where the dose includes 50 mg to 75 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 51 is the method of claim any one of Embodiments 42 to 45, where the dose includes 5 mg to 100 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 52 is the method of claim any one of Embodiments 42 to 45, where the dose includes 5 mg to 500 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 53 is the method of claim any one of Embodiments 42 to 45, where the dose includes 100 mg to 500 mg hydrocortisone, the hydrocortisone derivative, or the salt thereof. Embodiment 54 is the method of claim any one of Embodiments 42 to 53, where the adrenal insufficiency results from a primary cause of adrenal insufficiency. Embodiment 55 is the method of Embodiment 54, where the primary cause of adrenal insufficiency includes congenital adrenal hyperplasia. Embodiment 56 is the method of any one of Embodiments 42 to 54, where the adrenal insufficiency results from a secondary cause of adrenal insufficiency. Embodiment 57 is the method of any one of Embodiments 42 to 56, where the dose of hydrocortisone is delivered through multiple administrations. Embodiment 58 is the method of any one of claims 42 to 57, where the method includes administering multiple doses of hydrocortisone. EXAMPLES The present invention 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. Example 1 Data were prospectively collected from a total of three participants who met inclusion criteria and were enrolled in a three-arm pilot trial. All participants had a diagnosis of congenital adrenal hyperplasia (CAH), which was confirmed by hormonal and / or molecular testing. Participants with allergies or nasal discharge or on intranasal and / or inhaled steroids were excluded from the study. All participants were 18 years or older and not in adrenal crisis at the time of the study. Study Design An open-label dose escalation pilot study was performed to characterize and evaluate the tolerability and pharmacokinetics of intranasal hydrocortisone in response to intranasal stress dosing in adult participants with congenital adrenal hyperplasia. Three adults were recruited into the study. Each participant made three visits over the course of the study. At the first visit, each participant received 25 mg hydrocortisone sodium succinate intranasally. At the second visit, each participant received 50 mg hydrocortisone sodium succinate intranasally. At the third visit, each participant received 100 mg hydrocortisone sodium succinate intranasally. At each visit, a six-hour cortisol pharmacokinetics study was performed with cortisol concentrations measured pre-dose, and at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, and 360 minutes hours after the intranasal dose of hydrocortisone sodium succinate to evaluate drug absorption. Participants were instructed to take their evening glucocorticoid dose by 8 pm the night before the study. On the day of the study, participants withheld the usual morning dose of glucocorticoids. Participants were evaluated to ensure that they did not experience any allergy or nasal discharge, were on any current intranasal and / or inhaled steroids, or on any long-acting steroids that would exclude them from participating. Participants in the low dose group were admitted into the out subject research unit for approximately six hours. An indwelling catheter was inserted in the participants arm for blood collection. A single intranasal stress dose of 25 mg of hydrocortisone sodium succinate was administered. Blood samples (7 mL per sample, with 63 mLs total) were obtained prior to the dose and at approximately 30 minutes, 60 minutes, 90 minutes, two hours, three hours, four hours, five hours, and six hours after the stress dose. Saliva samples were collected prior to the dose and at approximately 30 minutes, 60 minutes, 90 minutes, two hours, three hours, four hours, five hours, and six hours after the stress dose, for a total of nine salivary samples collected during the study visit. The syringe with drug solution and atomizer were weighed prior to and after administration and volume of solution in the syringe were visually monitored. Participants were administered a Global Pain and Tolerability Analog Scale to assess overall nasal discomfort prior to nasal administration, immediately after nasal administration, and at five minutes, 15 minutes, 60 minutes, 120 minutes, and six hours after nasal administration. After completing the six-hour pharmacokinetic study, participants were discharged from the research facility and continued their usual glucocorticoid oral dosing schedule. After the three participants completed the low dose group study, they moved to the intermediate dose arm. The same sampling design was used for the six-hour pharmacokinetic study. The 50 mg hydrocortisone sodium succinate was administered by splitting the dose into two administrations of 25 mg doses (one for each nostril). After the three participants completed the intermediate dose group study, they moved to the high dose arm. For intranasal administration of the 100 mg, the dose was split into two 50 mg administrations given one hour apart. Preparation of Intranasal Hydrocortisone sodium succinate solution SOLU-CORTEF (hydrocortisone sodium succinate for injection, USP, Pharmacia & Upjohn Company LLC, Kalamazoo, MI) product was purchased. The 100 mg plain-vials contain hydrocortisone sodium succinate equivalent to 100 mg hydrocortisone, 0.8 mg monobasic sodium phosphate anhydrous, 8.73 mg dibasic sodium phosphate dried. For the study, hydrocortisone sodium succinate (100 mg plain-vial) was solubilized in sterile water as directed in the package insert to achieve final concentration a 125 mg / mL. A total volume of 200 µl of the final concentration was used to deliver a total dose of 25 mg. To deliver a total dose of 50 mg and 100 mg, a total volume of 400 µL and 800 µL were used, respectively. The intranasal dose was delivered using an atomizer device having a spray tip (atomizer) attached to a 1 ml or 3 ml syringe (MAD Nasal, Teleflex Medical, Inc., Wayne, PA). The syringe carries the medication (200 µl) and enables the accurate measurement of drugs to be delivered. The spray tip attaches to the syringe via the luer lock connector. The spray tip fragments the medication into a fine mist of particles 30 micrometers to100 micrometers in size as it is being sprayed into a subject’s nose. Determination of cortisol concentration in serum and saliva De-identified blood and salivary samples were evaluated for cortisol concentrations by liquid chromatography tandem mass spectrometry (LC-MS / MS). Adrenocorticotropic hormone (ACTH) concentrations were also measured to assess hypothalamic-pituitary-adrenal axis (HPA) activity and to show the recovery of the HPA axis in response to intranasal dosing. Pharmacokinetic Analysis Descriptive statistics of cortisol concentrations and pharmacokinetics parameters were generated. Cortisol concentration-time data were analyzed by non-compartmental method. WinNonLin Phoenix (Pharsight, Certara, Inc., Princeton, NJ) was used to calculate cortisol area under the curve (AUC) using the linear trapezoidal rule, maximum concentration (Cmax), time taken to reach the maximum concentration (Tmax), elimination half-life, and cortisol clearance. Results of the hydrocortisone sodium succinate new formula were compared with the mean pharmacokinetic variables (maximum concentration, Cmax; time to Cmax, Tmax; area under the curve, AUC) for subcutaneous (SC) and intramuscular (IM) cortisol as previously described (Hanher et al., Eur. J. Endocrinol. Aug 2013;169(2):147-154). The mean concentration-time profiles for the subcutaneous and intramuscular formulation were digitized using WebPlotDigitizer v4.4 (https: / / automeris.io / WebPlotDigitizer). Particle size and low-volume dissolution studies Materials: Micronized USP Hydrocortisone (CO137) and the Hydrocortisone Sodium Succinate (H1340) were procured from Spectrum Chemicals (New Brunswick, NJ) and the Hydrocortisone (3867) was purchased from Sigma-Aldrich (St. Louis, MO). Phosphate Buffered Saline (ABI-102-03) (“PBS”) used in the dissolution testing was obtained from American Bioinnovations (Sparks, MD). Milling of hydrocortisone sodium succinate: One gram of hydrocortisone sodium succinate (HSS) was milled in 8-10 second intervals using an electric benchtop rotary blade mill. Visual inspection was performed after each interval to confirm adequate milling and to ensure the material was not caking on the equipment. After each milling interval a small aliquot of the powder was taken for sizing analysis using laser diffraction. Upon reaching desired particle size distribution, no further milling steps will be conducted. In these studies, one milling interval was used and additional milling was halted to ensure the particles were not reduced to a size smaller than the target minimum cut-off of 10 µm. Particle size analysis: To measure the geometric size of the dispersed raw material powders, approximately 5 mg to 10 mg of each test sample was dispensed in the hopper of the Sympatec RODOS laser diffraction apparatus (RODOS; available from Sympatec, Germany). The dispersing pressure was set to 2 barr and 5 millisecond time-slices with an optical concentration (Copt) between 3% to 30% were analyzed for particle size distribution and the averages are reported in FIG.6. Low volume dissolution evaluation: Low-volume dissolution was performed according to Brunaugh et al. (Brunaugh AD, Seo H, Warnken Z, Ding L, Seo SH, Smyth HD. Development and evaluation of inhalable composite niclosamide-lysozyme particles: A broad-spectrum, patient-adaptable treatment for coronavirus infections and sequalae. PloS one.2021 Feb 11;16(2):e0246803) and Rohrschneider et al (Rohrschneider M, Bhagwat S, Krampe R, Michler V, Breitkreutz J, Hochhaus G. Evaluation of the Transwell System for Characterization of Dissolution Behavior of Inhalation Drugs: Effects of Membrane and Surfactant. Mol Pharm. 2015;12(8):2618–24. Epub 2015 / 06 / 20. pmid:26091361) with some modification. Whatman GF / C glass microfiber filters (24 mm diameter) were placed onto TRANSWELL (Corning Inc, Corning, NY) inserts with a base membrane pore size of 8 μm. The inserts were placed into a 6 well TRANSWELL plate (Corning), each containing 1.5 mL phosphate-buffered saline (PBS, pH 7.4) in the receptor compartment and allowed to equilibrate to 34 °C in a water bath. Around 2 mg of test article was placed on the pre-wetted glass microfiber filters followed by an additional pipetting of 0.5 mL PBS onto the filter to initiate the dissolution study. At each time point, 0.2 mL of the receptor fluid was removed for analysis and replaced with fresh media. Studies were performed in triplicate with time points at 5, 10, 15, 20, 25, and 30 minutes after initiation. A 60 min timepoint was taken for the slower dissolving micronized hydrocortisone material. Concentration in the receptor fluid was quantitated by absorbance at 260 nm using a TECAN F200 plate reader (TECAN, Switzerland) with UV Star 96 well plates (Greiner Bio- One, Germany) with dilutions made as required to result in area within the calibration curve range. The concentration measured of from the hydrocortisone sodium succinate materials was converted based on the molar ratio to hydrocortisone for direct comparison. Example 2: Intranasal delivery of dry powder Study Design For this study, no anesthesia was used. Prior to study initiation, cortisol production was suppressed using by administering 0.1 mg / kg of dexamethasone sodium phosphate intramuscularly the day prior to the study and at least 1- 2 hours prior to starting the PK study. A 10 mg dose of hydrocortisone dry powder was administered intranasally. Blood samples (~2 mL) were be collected via a catheterized vein pre-dose and at 0, 10, 20, 30, 45, 60, 90, 120, 240, and 360 min post-dose. Tolerability was assessed at similar timepoints. Following a 7-14 day washout period, hydrocortisone sodium succinate was administered via a bolus intravenous dose of 10 mg. De-identified plasma samples were evaluated for cortisol concentrations by liquid chromatography tandem mass spectrometry (LC-MS / MS). Pharmacokinetic Analysis Descriptive statistics of cortisol concentrations and pharmacokinetics parameters were generated. Cortisol concentration-time data were analyzed by non-compartmental method. WinNonLin Phoenix (Pharsight, Certara, Inc., Princeton, NJ) was used to calculate cortisol area under the curve from time 0 to infinity (AUC) using the linear trapezoidal rule, maximum concentration (Cmax), time taken to reach the maximum concentration (Tmax), elimination half- life, and cortisol clearance. The intranasal bioavailability was determined by dividing the AUC (IN) by the AUC (IV). The complete disclosure of all patents, patent applications, and publications, and electronically available material (including, for instance, nucleotide sequence submissions in, e.g., GenBank and RefSeq, and amino acid sequence submissions in, e.g., SwissProt, PIR, PRF, PDB, and translations from annotated coding regions in GenBank and RefSeq) 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. 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. 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. 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

What is claimed is:

1. An intranasal composition comprising hydrocortisone, a hydrocortisone derivative, or a salt thereof.

2. The intranasal composition of claim 1, wherein the hydrocortisone derivative comprises hydrocortisone succinate or a salt thereof.

3. The intranasal composition of claim 1 or 2, wherein the composition comprises hydrocortisone sodium succinate.

4. The intranasal composition of any one of claims 1 to 3, further comprising one or more excipients.

5. The intranasal composition of claim 4, wherein the excipient comprises a material that enhances stability of the hydrocortisone, the hydrocortisone derivative, or the salt thereof.

6. The intranasal composition of claim 4, wherein the excipient comprises a material that enhances permeation of the hydrocortisone, the hydrocortisone derivative, or the salt thereof across nasal mucosa of a subject.

7. The intranasal composition of claim 6, wherein material that enhances permeation of the hydrocortisone, the hydrocortisone derivative, or the salt thereof across the nasal mucosa comprises a surfactant, vitamin E, a hydrophilic small molecule, a cyclodextrin, a surfactant, a cationic polymer, a tight junction modulator, an enzyme inhibitor, or an amino acid.

8. The intranasal composition of claim 4, wherein the excipient comprises a material that enhances tolerability of the hydrocortisone, the hydrocortisone derivative, or the salt thereof.

9. The intranasal composition of claim 8, wherein the material that enhances tolerability of the hydrocortisone, the hydrocortisone derivative, or the salt thereof comprises a flavoring, a fragrance, or vitamin E.

10. The intranasal composition of claim 1, wherein the composition is excipient free.

11. The intranasal composition of any of claims 1 to 10, wherein the composition is a solid.

12. The intranasal composition of claim 11, wherein the composition is a dry powder, the dry powder comprising particles, the particles comprising the hydrocortisone, the hydrocortisone derivative, or the salt thereof.

13. The intranasal composition of claim 12, wherein the particles have a D90 of 50 µm to 200 µm.

14. The intranasal composition of claim 12, wherein the particles have a D90of 50 µm to 150 µm.

15. The intranasal composition of claim 12, wherein particles have a D9050 µm to 120 µm.

16. The intranasal composition of any one of claims 12 to 15, wherein the particles have a D50of 1 µm to 100 µm.

17. The intranasal composition of any one of claims 12 to 15, wherein the particles have a D50 of 5 µm to 50 µm.

18. The intranasal composition of any one of claims 12 to 15, wherein the particles have a D50of 5 µm to 20 µm.

19. The intranasal composition of any one of claims 12 to 18, wherein the particles have a D10 of 0.01 µm to 20 µm.

20. The intranasal composition of any one of claims 12 to 18, wherein the particles have a D10 of 0.1 µm to 10 µm.

21. The intranasal composition of any one of claims 12 to 18, wherein the particles have a D10of 0.1 µm to 5 µm.

22. The intranasal composition of any one of claims 1 to 10, wherein the composition further comprises a pharmaceutically acceptable liquid carrier.

23. The intranasal composition of claim 22, wherein the pharmaceutically acceptable liquid carrier comprises water.

24. The intranasal composition of claim 22, wherein the pharmaceutically acceptable carrier comprises Lactated Ringer’s solution.

25. The intranasal composition of any one of claims 22 to 24, wherein the pharmaceutically acceptable carrier comprises saline.

26. The intranasal composition of any one of claims 22 to 24, wherein the pharmaceutically acceptable carrier comprises phosphate buffered saline.

27. The intranasal composition of any one of claims 22 to 26, wherein the composition comprises 1 mg / mL to 1000 mg / mL of the hydrocortisone, the hydrocortisone derivative, or the salt thereof.

28. The intranasal composition of any one of claims 22 to 26, wherein the composition comprises 50 mg / mL to 1000 mg / mL of the hydrocortisone, the hydrocortisone derivative, or the salt thereof.

29. The intranasal composition of any one of claims 22 to 26, wherein the composition comprises 250 mg / mL to 1000 mg / mL of the hydrocortisone, the hydrocortisone derivative, or the salt thereof.

30. The intranasal composition of any one of claims 22 to 29, wherein the composition is a solution.

31. The intranasal composition of any one of claims 22 to 29, wherein the composition is a suspension.

32. The intranasal composition of any one of claims 22 to 29, wherein the composition is an emulsion.

33. The intranasal composition of any one of claims 1 to 32, wherein the composition is an aerosol composition.

34. The intranasal composition of any one of claims 1 to 32, wherein the composition is a non- aerosol spray composition.

35. A method of administering a composition comprising hydrocortisone, a hydrocortisone derivative, or a salt thereof to a subject.

36. The method of claim 35, wherein the composition comprises hydrocortisone.

37. The method of claim 35, wherein the composition comprises hydrocortisone succinate or a salt thereof.

38. The method of claim 35, wherein the composition comprises hydrocortisone sodium succinate.

39. The method of claim 35, wherein the composition is the intranasal composition of any one of claims 1 to 34.

40. The method of any one of claims 35 to 39, wherein the method comprises intranasally administering the composition to the subject.

41. The method of any one of claims 35 to 40, wherein the subject is a human.

42. A method of treating adrenal insufficiency in a subject, the method comprising administering to a subject, a dose of a composition comprising hydrocortisone, a hydrocortisone derivative, or a salt thereof in an amount effective to treat adrenal insufficiency.

43. The method of claim 42, wherein the composition comprises hydrocortisone.

44. The method of claim 42, wherein the composition comprises hydrocortisone succinate or a salt thereof.

45. The method of claim 42, wherein the composition comprises hydrocortisone sodium succinate.

46. The method of claim 42, wherein the composition comprises the intranasal composition of any one of claims 1 to 34.

47. The method of any one of claims 42 to 46, wherein the method comprises intranasally administering the dose of the composition to the subject.

48. The method of any one of claims 42 to 47, wherein the dose comprises 5 mg to 1000 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof.

49. The method of any one of claims 42 to 47, wherein the dose comprises 25 mg to 100 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof.

50. The method of any one of claims 42 to 47, wherein the dose comprises 5 mg to 25 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof.

51. The method of any one of claims 42 to 47, wherein the dose comprises 50 mg to 75 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof.

52. The method of any one of claims 42 to 47, wherein the dose comprises 5 mg to 100 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof.

53. The method of any one of claims 42 to 47, wherein the dose comprises 5 mg to 500 mg of hydrocortisone, the hydrocortisone derivative, or the salt thereof.

54. The method of any one of claims 42 to 47, wherein the dose comprises 100 mg to 500 mg hydrocortisone, the hydrocortisone derivative, or the salt thereof.

55. The method of any one of claims 42 to 54, wherein the adrenal insufficiency results from a primary cause of adrenal insufficiency.

56. The method of claim 55, wherein the primary cause of adrenal insufficiency comprises congenital adrenal hyperplasia.

57. The method of any one of claims 42 to 54, wherein the adrenal insufficiency results from a secondary cause of adrenal insufficiency.

58. The method of any one of claims 42 to 57, wherein the dose of hydrocortisone is delivered through multiple administrations.

59. The method of any one of claims 42 to 57, wherein the method comprises administering multiple doses of hydrocortisone.

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