Slow-release compositions and methods for inflammatory airway obstruction

Abstract

The present disclosure provides a sustained-release pharmaceutical composition for prevention or treatment of asthma in a subject in need thereof; and a method of preventing or treating asthma in a subject in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition as described herein.

Description

SLOW-RELEASE COMPOSITIONS AND METHODS FOR INFLAMMATORY AIRWAY OBSTRUCTIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application No. 63 / 587,964, filed October 4, 2023.FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under HL158507 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD

[0003] The present disclosure provides compositions and methods for prevention or treatment of inflammatory airway obstruction.BACKGROUND

[0004] Asthma is one of the most common diseases in the United States, with nearly 26 million individuals diagnosed. Asthma is a chronic disorder characterized by inflammation and swelling of the airways, leading to respiratory obstruction, which may thereby cause discomfort, pain, hyperventilation, hypoxia, and even death. Common symptoms include trouble breathing, severe shortness of breath, coughing, wheezing and tightness or pain of chest, with many patients experiencing changes in frequency and intensity of symptoms throughout their lifetime. (See, e.g., Rehman A, et al. Prevalence of asthma and its management: A review. J Pak Med Assoc. 2018 Dec;68(12): 1823-1827. PMID: 30504949.)

[0005] Treatment options for asthma are presently limited to symptom management. However, managing asthma symptoms can be complicated, as asthma has various different pathologies, and presents differently from patient to patient due to various environmental, lifestyle, physical, psychological, neurological, genetic, and other factors. Further, existing treatment options come with certain drawbacks, including low systemic bioavailability and negative side effects. Additionally, emerging research has found patient response to common treatments tends to vary according to patient genotype. (See Zein, J. et al. (2020). HSD3B1 genotype identifies glucocorticoid responsiveness insevere asthma. Proceedings of the National Academy of Sciences, 117(4), 2187-2193.) Accordingly, there exists an ongoing unmet need for new approaches for preventing, treating, and managing asthma. The present disclosure addresses this need.BRIEF SUMMARY

[0006] The present disclosure relates to compositions for prevention or treatment of inflammatory airway obstruction, methods of preparing such a composition, methods of treating or preventing inflammatory airway obstruction, methods of reducing the frequency of asthma attacks, and a kit comprising the composition.

[0007] In an aspect, the present disclosure provides a sustained-release pharmaceutical composition for prevention or treatment of asthma in a mammalian subject in need thereof composing a pharmaceutically effective dose of dehydroepiandrosterone (DHEA). In any embodiment of the composition, the composition may further comprise a magnesium salt. In any embodiment, the magnesium salt may comprise magnesium glycinate.

[0008] In any embodiment, the composition may comprise about Img to about 200mg of dehydroepiandrosterone. In any embodiment, the composition may comprise about lOmg to about 150mg of dehydroepiandrosterone. In any embodiment, the composition may comprise about 50mg to about 125mg of dehydroepiandrosterone. In any embodiment, the composition may comprise about 90mg to about 1 lOmg of dehydroepiandrosterone. In any embodiment, the composition may comprise about lOOmg of dehydroepiandrosterone. In any embodiment, the composition may comprise about 50mg of dehydroepiandrosterone.

[0009] In any embodiment, the composition may further comprise about lOOmg to about 600mg of magnesium glycinate. In any embodiment, the composition may further comprise about 200mg to about 500mg of magnesium glycinate. In any embodiment, the composition may further comprise about 300mg to about 400mg of magnesium glycinate. In any embodiment, the composition may further comprise about 360mg to about 390mg of magnesium glycinate. In any embodiment, the composition may further comprise about 385mg of magnesium glycinate.

[0010] In any embodiment, the composition may further comprise one or more carriers. In any embodiment, the one or more carriers may comprise methylcellulose, microcrystalline cellulose, or a combination of methylcellulose and microcrystalline cellulose. In any such embodiment, the methylcellulose may comprise hydroxypropyl methylcellulose. In any such embodiment, the methylcellulose may be METHOCEL™ E4M. In any embodiment of the composition, the compositionmay comprise about lOOmg to about 120mg methyl cellulose. In any embodiment, the composition may comprise about lOmg to about 40mg microcrystalline cellulose.

[0011] In any embodiment, the composition may comprise a pharmaceutically acceptable buffer. In any embodiment, the composition may comprise a pharmaceutically acceptable pH modulator. In any embodiment, the composition may comprise a pharmaceutically acceptable salt. In any embodiment, the composition may comprise a pharmaceutically acceptable preservative. In any embodiment, the composition may comprise a pharmaceutically acceptable antioxidant. In any embodiment, the composition may comprise a pharmaceutically acceptable excipient. In any embodiment, the composition may comprise a pharmaceutically acceptable adjuvant. In any embodiment, the composition may comprise a pharmaceutically acceptable lubricant. In any embodiment, the composition may comprise a pharmaceutically acceptable binder. In any embodiment, the composition may comprise a pharmaceutically acceptable humectant. In any embodiment, the composition may comprise a pharmaceutically acceptable flavorant.

[0012] In any embodiment, the mammalian subject may be a human.

[0013] In another aspect, the present disclosure provides a sustained-release capsule comprising the pharmaceutical composition as described herein. In any embodiment of the sustained-release capsule, the capsule may be a sustained-release double-gel capsule. In any embodiment, the capsule size may be 00 standard. In any embodiment, the capsule size may be #1 standard. In any embodiment, the capsule size may be #3 standard. In any embodiment, the capsule may be a 3D-printed capsule.

[0014] In another aspect, the present disclosure provides a method of preventing or treating asthma in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition as described herein. In a further aspect, the present disclosure provides a method of preventing asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition as described herein. In still another aspect, the present disclosure provides a method of increasing baseline serum concentration of dehydroepiandrosterone in a human patient in need thereof, the method comprising: administering to the subject to the composition as described herein.

[0015] In further still another aspect, the present disclosure provides a method of reducing the frequency of asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective regimen of the sustained-release capsule as described herein. In any embodiment, the pharmaceutically effective regimen may comprise the human patient ingesting one capsule per 12 hours.

[0016] In any embodiment of the methods described herein, the human patient may express C / A at position 1245 of the gene Hsd3bl on one or both alleles or A / A at position 1245 of the gene Hsd3bl on one or both alleles. In any embodiment of the methods described herein, the human patient may be a biological female who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 45 pg / dL. In any embodiment of the methods described herein, the human patient may be a biological male who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 90 pg / dL. In any embodiment of the methods described herein, the human patient may be a patient who has been diagnosed with moderate asthma. In any embodiment of the methods described herein, the human patient may be a patient who has been diagnosed with severe asthma.

[0017] In any embodiment of the methods described herein, the method may result in a sustained blood serum concentration of dehydroepiandrosterone sulfate of from about 490 pg / dL to about 1,020 pg / dL.

[0018] In any embodiment of the methods described herein, the method may further comprise administering to the human patient a pharmaceutically effective dose of albuterol.

[0019] In yet another aspect, the present disclosure provides a sustained-release double-gel capsule for prevention or treatment of asthma in a human patient having C / A 1245 variant of the gene Hsd3bl gene or A / A1245 variant of the gene Hsd3bl, the capsule comprising: a capsule shell containing a plurality of ingredients in its interior, the shell comprising a sustained-release formulation; and the ingredients comprising 50mg to lOOmg dehydroepiandrosterone, 350mg to 400mg magnesium glycinate; lOOmg to 120mg methylcellulose E4M; and 20mg to 30mg microcrystalline cellulose.

[0020] In a further aspect, the present disclosure provides a kit comprising: the sustained release capsule as described herein; a container; and instructions providing information on how to administer the capsule to a subj ect in need thereof.

[0021] In an additional aspect, the present disclosure provides the use of the composition as described herein for the manufacture of a medicament for prevention or treatment of asthma in a human patient.

[0022] In still another aspect, the present disclosure provides a composition or method substantially as described in the present disclosure.

[0023] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The teachings of some embodiments of the present disclosure will be better understood by reference to the description taken in conj unction with the accompanying drawings, wherein:

[0025] Figure 1 depicts a proposed model for Hsd3bl genotype and glucocorticoid response. Glucocorticoid drug treatment suppresses adrenal dehydroepiandrosterone, which may become a limiting substrate for 3P-hydroxysteroid dehydrogenase- 1 (3P-HSD1) enzyme responsible for metabolizing dehydroepiandrosterone to potent downstream androgen biomolecules, depending on patient Hsd3bl genotype. Adrenal permissive and adrenal restrictive alleles enable and limit metabolic flux through 3P-HSD1 and recovery of lung airway airflow.

[0026] Figures 2A-2B are 2-dimensional chemical structures for dehydroepiandrosterone and dehydroepiandrosterone sulfate, respectively.

[0027] Figures 3A-3B show the correlation between serum dehydroepiandrosterone sulfate concentration and FEViPP. Figure 3A is a graph showing that in subjects diagnosed with asthma, FEViPP correlates with serum dehydroepiandrosterone sulfate concentration in biological males and biological females. Figure 3B is a bar graph showing that chronic daily glucocorticoid use is correlated with serum dehydroepiandrosterone sulfate concentration suppression.

[0028] Figure 4 is a graph depicting a TopMD™ pathway analysis result following treatment with 50mg and lOOmg slow-release dehydroepiandrosterone. Both doses decreased circulating expression of IL4 and / / .- / -pathway genes in humans when analyzed by RNASeq, followed by TopMD™ pathway analysis.DETAILED DESCRIPTION

[0029] Although the concepts of the present disclosure are susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and will be described herein in detail. It should be understood, however, that there is no intent to limit the concepts of the present disclosure to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives consistent with the present disclosure and the appended claims.

[0030] References in the specification to “one embodiment,” “an embodiment,” “another embodiment,” “some embodiments,” “an illustrative embodiment,” etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may or may not necessarily include that particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. It should be further appreciated that although reference to a “preferred” component or feature may indicate the desirability of a particular component or feature with respect to an embodiment, the disclosure is not so limiting with respect to otherembodiments, which may omit such a component or feature. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to implement such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described. Additionally, it should be appreciated that items included in a list in the form of “at least one of A, B, and C” can mean (A); (B); (C); (A and B); (B and C); (A and C); or (A, B, and C). Similarly, items listed in the form of “at least one of A, B, or C” can mean (A); (B); (C); (A and B); (B and C); (A and C); or (A, B, and C). Further, with respect to the claims, the use of words and phrases such as “a,” “an,” “at least one,” and / or “at least one portion” should not be interpreted so as to be limiting to only one such element unless specifically stated to the contrary, and the use of phrases such as “at least a portion” and / or “a portion” should be interpreted as encompassing both embodiments including only a portion of such element and embodiments including the entirety of such element unless specifically stated to the contrary.

[0031] Throughout this disclosure, various quantities, such as amounts, sizes, dimensions, proportions and the like, are presented in a range format. It should be understood that the description of a quantity in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of any embodiment. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as all individual numerical values within that range unless the context clearly dictates otherwise. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual values within that range, for example, 1.1, 2, 2.3, 4.62, 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, unless the context clearly dictates otherwise.

[0032] Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers + / - 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.

[0033] The disclosed embodiments may, in some cases, be implemented in hardware, firmware, software, or a combination thereof. The disclosed embodiments may also be implemented asinstructions carried by or stored on one or more transitory or non-transitory machine-readable (e.g., computer-readable) storage media, which may be read and executed by one or more processors. A machine-readable storage medium may be embodied as any storage device, mechanism, or other physical structure for storing or transmitting information in a form readable by a machine (e.g., a volatile or non-volatile memory, a media disc, or other media device).

[0034] In the description and / or the drawings, some structural or method features may be described and / or shown in specific arrangements and / or orderings. However, it should be appreciated that such specific arrangements and / or orderings may not be required. Rather, in some embodiments, such features may be arranged in a different manner and / or order than described and / or shown in the illustrative figures unless indicated to the contrary. Additionally, the inclusion of a structural or method feature in a particular embodiment is not meant to imply that such feature is required in all embodiments and, in some embodiments, may not be included or may be combined with other features.

[0035] All publications referenced and cited in the present disclosure are incorporated by reference in there entireties.

[0036] One of the current standards of care for management of asthma is administration of corticosteroids, especially inhaled administration. Despite the effectiveness of these drugs in managing asthma, they can lead to persistent and adverse side effects. Poor systemic bioavailability of inhaled corticosteroids can minimize side effects compared to oral use. However, chronic use of inhaled corticosteroids can lead to adrenal suppression (the inability to produce adequate amounts of certain hormones), reduced growth and growth velocity, increased risk of osteoporosis and diabetes, ophthalmic defects such as increased risk of cataracts, and reoccurrence of viral or atypical infections. (See Heffler E, et al. Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):776-781. doi: 10. 1016 / j .jaip.2018.01.025. Epub 2018 Feb 3. PMID: 29408385 ). Other documented side effects of inhaled corticosteroids include headache, sore throat, muscle aches, bronchitis, and higher susceptibility to cold or flu. Oral corticosteroids can cause more severe forms of above side effects, as well as dizziness, nausea, acne, weight gam, swelling or numbness of extremities and irregular heartbeat. Additionally, recent findings show that patient response to common treatments, such as glucocorticoids (such as prednisone and fluticasone), as genotype dependent. (See Zein, J. et al. (2020). HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma. Proceedings of the National Academy of Sciences, 117(4), 2187-2193.)

[0037] In addition to these findings, magnesium therapy has been shown to function as both an anti-inflammatory agent and an inhibitor of the effect of calcium to contract smooth muscle in lung passageways. (See, e.g., Landon, R. A. & Young, E. A. Role of magnesium in regulation of lung function. J. Am. Diet. Assoc. 93, 674-677 (1993).)

[0038] With the above principles in mind, the present disclosure provides compositions and methods for prevention, treatment, and management of pulmonary obstructive disease such as asthma. In an aspect, the present disclosure provides a sustained-release pharmaceutical composition for prevention or treatment of asthma in a mammalian subject in need thereof comprising a pharmaceutically effective dose of dehydroepiandrosterone (DHEA).

[0039] Dehydroepiandrosterone (DHEA, also sometimes called androstenolone) (Fig. 4A) is an endogenous steroid hormone precursor produced in the adrenal glands, gonads, and brain. Although dehydroepiandrosterone is a precursor to more potent androgens, it is known to possess mild androgenic activity in itself. Dehydroepiandrosterone is transformed into dehydroepiandrosterone sulfate (DHEA-S, also sometimes called androstenolone sulfate) by sulfation of the C3 [3 carbon (Fig. 4B). Dehydroepiandrosterone sulfate is believed to be hormonally inert, and circulates in blood serum in much higher concentrations (approximately 2 orders of magnitude) than endogenous dehydroepiandrosterone. Levels of dehydroepiandrosterone sulfate are considered a read-out for dehydroepiandrosterone. Levels of each vary between biological males and biological females, and rise and fall throughout life. Biological males and biological females from birth to around age 14 have approximately the same expected levels, after which biological males are expected to have higher levels than biological females.

[0040] Dehydroepiandrosterone has anti-inflammatory effects, and suppresses production of many proinflammatory molecules, such as cytokines, associated with asthma symptoms. Evidence shows patients diagnosed with severe asthma tend to have very low dehydroepiandrosterone sulfate levels compared to non-asthmatic populations. (See Kasperska-Zajac A. Asthma and dehydroepiandrosterone (DHEA): facts and hypotheses. Inflammation. 2010 Oct;33(5):320-4.; Pesce G, et al. Low serum DHEA-S is associated with impaired lung function in women. EClinicalMedicine . 2020 Jun 6;23: 100389.)

[0041] Dehydroepiandrosterone plays a role in the mechanism leading to corticosteroid resistance in moderate-to-severe asthma patients. (Figs. 1, 3A-3B.) Patients with severe asthma can also express a mutated variant of the Hsd3bl gene, which encodes the enzyme 3[3-HDSl that metabolizes dehydroepiandrosterone into downstream androgens, such as testosterone. Certain Hsd3bl mutations restrict the enzyme to the adrenal gland, thereby reducing metabolic flux of dehydroepiandrosteroneinto other biomolecules such as androgens. The adrenal restrictive Hsd3b / ( \ 245A) allele limits conversion, whereas the adrenal permissive Hsd3b 7(1245C) allele increases dehydroepiandrosterone metabolism to potent androgens. The genotype effect is dose-dependent, i.e., homozygous H. 'C / J / ? / I 215 l2 l5Agenotype patients have more restricted dehydroepiandrosterone metabolism than heterozygous 77sc / 3 / ? / l245A 12451patients, who in turn have more restricted dehydroepiandrosterone metabolism than homozygous Hsd3b y1245C / 1245Cpatients. When administered glucocorticoids, patients with an enzyme restrictive Hsd3bl genotype show a significant decrease in lung function, as measured through spirometry testing such as forced expiratory volume (FEVi) or maximum amount of air that can forcefully be exhaled, compared to patients not treated with glucocorticoids.

[0042] In any embodiment of the composition, the composition may further comprise an ionic component. In any embodiment of the composition, the ionic component may comprise a magnesium salt. In any embodiment, the magnesium salt may comprise magnesium glycinate. In any embodiment, the magnesium salt may comprise magnesium sulfate. In any embodiment, the magnesium salt may comprise magnesium chloride. In any embodiment, the magnesium salt may comprise a mixture of magnesium glycinate and magnesium sulfate. In any embodiment, the magnesium salt may comprise a mixture of magnesium sulfate and magnesium chloride. In any embodiment, the magnesium salt may comprise a mixture of magnesium glycinate, magnesium sulfate, and magnesium chloride.

[0043] In any embodiment, the composition may comprise about Img to about 200mg of dehydroepiandrosterone. For example, in any embodiment, the composition may comprise about Img, 5mg, lOmg, I5mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, lOOmg, 105mg, HOmg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, or even greater of dehydroepiandrosterone. In any embodiment, the composition may comprise about lOmg to about 150mg of dehydroepiandrosterone. In any embodiment, the composition may comprise about 50mg to about 125mg of dehydroepiandrosterone. In any embodiment, the composition may comprise about 90mg to about 1 lOmg of dehydroepiandrosterone. In any embodiment, the composition may compnse about lOOmg of dehydroepiandrosterone. In any embodiment, the composition may comprise about 50mg of dehydroepiandrosterone.

[0044] In any embodiment, the composition may comprise about lOOmg to about 600mg of magnesium salt. In any embodiment, the composition may comprise about lOOmg to about 600mg of magnesium glycinate. For example, in any embodiment, the composition may comprise lOOmg, HOmg, 120mg, HOmg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg,230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg,350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg,470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg,590mg, or 600mg of magnesium glycinate. In any embodiment, the composition may comprise about200mg to about 500mg of magnesium glycinate. In any embodiment, the composition may comprise about 300mg to about 400mg of magnesium glycinate. In any embodiment, the composition may comprise about 360mg to about 390mg of magnesium glycinate. In any embodiment, the composition may comprise about 385mg of magnesium glycinate. In any embodiment, the composition may comprise 385mg of magnesium glycinate.

[0045] In any embodiment, the composition may further comprise one or more carriers. In any embodiment, the one or more carriers may comprise methylcellulose, microcrystalline cellulose, or a combination of methylcellulose and microcrystalline cellulose. In any such embodiment, the methylcellulose may comprise hydroxypropyl metbylcellulose (HPMC, also sometimes called hypromellose). In any such embodiment, the methylcellulose may be METHOCEL™ E4M. Methylcellulose carriers such as hydroxypropyl methylcellulose provide a matrix material in oral controlled delivery of therapeutics, for controlling rate of release of hydrophobic and hydrophilic molecules. In any embodiment of the composition, the composition may comprise about lOOmg to about 120mg methylcellulose. In any embodiment, the composition may comprise lOOmg, 105mg, l lOmg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, or 200mg of methylcellulose. In any embodiment, the composition may comprise about lOmg to about 40mg microcrystalline cellulose. In any embodiment, the composition may comprise 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, or 40mg of microcrystalline cellulose.

[0046] In any embodiment, the composition may comprise a pharmaceutically acceptable buffer. In any embodiment, the composition may comprise a pharmaceutically acceptable pH modulator. In any embodiment, the composition may comprise a pharmaceutically acceptable salt. In any embodiment, the composition may comprise a pharmaceutically acceptable preservative. In any embodiment, the composition may comprise a pharmaceutically acceptable antioxidant. In any embodiment, the composition may comprise a pharmaceutically acceptable excipient. In any embodiment, the composition may comprise a pharmaceutically acceptable adjuvant. In any embodiment, the composition may comprise a pharmaceutically acceptable lubricant. In any embodiment, the composition may comprise a pharmaceutically acceptable binder. In any embodiment, the compositionmay comprise a pharmaceutically acceptable humectant. In any embodiment, the composition may comprise a pharmaceutically acceptable flavorant.

[0047] In any embodiment, the mammalian subject may be a human.

[0048] In another aspect, the present disclosure provides a sustained-release capsule comprising the pharmaceutical composition as described herein. In any embodiment of the sustained-release capsule, the capsule may be a sustained-release double-gel capsule. In any embodiment, the capsule size may be 00 standard. In any embodiment, the capsule size may be #1 standard. In any embodiment, the capsule size may be #3 standard. In any embodiment, the capsule may be a 3D-printed capsule. The 3D-printed capsule may contain two or more microcompartments within the capsule. In such embodiments, the microcompartments may be of different volume, or may all be of about the same volume.

[0049] In another aspect, the present disclosure provides a method of preventing or treating asthma in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition as described herein. In a further aspect, the present disclosure provides a method of preventing asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition as described herein. In still another aspect, the present disclosure provides a method of increasing baseline serum concentration of dehydroepiandrosterone in a human patient in need thereof, the method comprising: administering to the subject to the composition as described herein.

[0050] In yet another aspect, the present disclosure provides a method of preparing a composition for preventing or treating asthma, the method comprising the steps of: mixing dehydroepiandrosterone with an ionic component, and packing the mixture in a sustained-release capsule. In an embodiment, the ionic component may be a magnesium salt. In an embodiment, the magnesium salt may be magnesium glycinate. In an embodiment, the method may further comprise mixing one or more carriers with the dehydroepiandrosterone and the ionic component. The one or more carriers may comprise methylcellulose, microcrystalline cellulose, or a combination of methylcellulose and microcrystalline cellulose. In an embodiment, the sustained-release capsule may be filed with a mixture comprising 50mg dehydroepiandrosterone or lOOmg dehydroepiandrosterone, and 385mg magnesium glycinate.

[0051] In further still another aspect, the present disclosure provides a method of reducing the frequency of asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective regimen of the sustained-release capsule as described herein. In any embodiment, the pharmaceutically effective regimen may comprise the human patient ingestingone capsule per 12 hours. In any embodiment, the pharmaceutically effective regimen results in a sustained blood serum concentration of at least about 400 pg / dL for at least 12 hours following administration.

[0052] In any embodiment of the methods described herein, the human patient may express C / A at position 1245 of the gene Hsd3bl on one or both alleles or A / A at position 1245 of the gene Hsd3bl on one or both alleles. In any embodiment of the methods described herein, the human patient may be a biological female who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 45 pg / dL. In any embodiment of the methods described herein, the human patient may be a biological male who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 90 pg / dL.

[0053] In any embodiment of the methods described herein, the human patient may be a patient who has been diagnosed with moderate asthma. In any embodiment of the methods described herein, the human patient may be a patient who has been diagnosed with severe asthma.

[0054] In any embodiment of the methods described herein, the method may result in a sustained blood serum concentration of dehydroepiandrosterone sulfate of from about 490 pg / dL to about 1,020 pg / dL.

[0055] In any embodiment of the methods described herein, the method may further comprise administering to the human patient a pharmaceutically effective dose of albuterol.

[0056] In yet another aspect, the present disclosure provides a sustained-release double-gel capsule for prevention or treatment of asthma in a human patient having C / A 1245 variant of the gene Hsd3bl gene or A / A1245 variant of the gene Hsd3bl, the capsule comprising: a capsule shell containing a plurality of ingredients in its interior, the shell comprising a sustained-release formulation; and the ingredients comprising 50mg to lOOmg dehydroepiandrosterone, 350mg to 400mg magnesium glycinate; lOOmg to 120mg methylcellulose E4M; and 20mg to 30mg microcrystalline cellulose.

[0057] In a further aspect, the present disclosure provides a kit comprising: the sustained release capsule as described herein; a container; and instructions providing information on how to administer the capsule to a subject in need thereof.

[0058] In an additional aspect, the present disclosure provides the use of the composition as described herein for the manufacture of a medicament for prevention or treatment of asthma in a human patient.

[0059] In still another aspect, the present disclosure provides a composition or method substantially as described in the present disclosure.

[0060] Embodiments.

[0061] The subject matter may be understood, without limitation, by reference to the following clauses:

[0062] Clause 1. A sustained-release pharmaceutical composition for prevention or treatment of asthma in a mammalian subject in need thereof comprising a pharmaceutically effective dose of dehydroepiandrosterone.

[0063] Clause 2. The sustained-release pharmaceutical composition of clause 1, further comprising a magnesium salt.

[0064] Clause 3. The sustained-release pharmaceutical composition of clause 2, wherein the magnesium salt comprises magnesium glycinate.

[0065] Clause 4. The sustained-release pharmaceutical composition of any of clauses 1-3, comprising about Img to about 200mg of dehydroepiandrosterone.

[0066] Clause 5. The sustained-release pharmaceutical composition of any of clauses 1-3, comprising about lOmg to about 150mg of dehydroepiandrosterone.

[0067] Clause 6. The sustained-release pharmaceutical composition of any of clauses 1-3, comprising about 50mg to about 125mg of dehydroepiandrosterone.

[0068] Clause 7. The sustained-release pharmaceutical composition of any of clauses 1-3, comprising about 90mg to about 1 lOmg of dehydroepiandrosterone.

[0069] Clause 8. The sustained-release pharmaceutical composition of any of clauses 1-3, comprising about lOOmg of dehydroepiandrosterone.

[0070] Clause 9. The sustained-release pharmaceutical composition of any of clauses 2-8, comprising about lOOmg to about 600mg of magnesium glycinate.

[0071] Clause 10. The sustained-release pharmaceutical composition of any of clauses 2-8, comprising about 200mg to about 500mg of magnesium glycinate.

[0072] Clause 11. The sustained-release pharmaceutical composition of any of clauses 2-8, comprising about 300mg to about 400mg of magnesium glycinate.

[0073] Clause 12. The sustained-release pharmaceutical composition of any of clauses 2-8, comprising about 360mg to about 390mg of magnesium glycinate.

[0074] Clause 13. The sustained-release pharmaceutical composition of any of clauses 2-8, comprising about 385mg of magnesium glycinate.

[0075] Clause 14. The sustained-release pharmaceutical composition of any of clauses 1-13, further comprising one or more carriers.

[0076] Clause 15. The sustained-release pharmaceutical composition of clause 14, wherein theone or more carriers comprise methylcellulose, microcrystalline cellulose, or a combination of methylcellulose and microcrystalline cellulose.

[0077] Clause 16. The sustained-release pharmaceutical composition of clause 15, wherein the methylcellulose comprises hydroxypropyl methylcellulose.

[0078] Clause 17. The sustained-release pharmaceutical composition of either clause 15 or 16, wherein the methylcellulose is METHOCEL™ E4M.

[0079] Clause 18. The sustained-release pharmaceutical composition of any of clauses 14-17, comprising about lOOmg to about 120mg methylcellulose.

[0080] Clause 19. The sustained-release pharmaceutical composition of any of clauses 14-18, comprising about lOmg to about 40mg microcrystalline cellulose.

[0081] Clause 20. The sustained-release pharmaceutical composition of any of clauses 1-19, further comprising a pharmaceutically acceptable buffer.

[0082] Clause 21. The sustained-release pharmaceutical composition of any of clauses 1-20, further comprising a pharmaceutically acceptable pH modulator.

[0083] Clause 22. The sustained-release pharmaceutical composition of any of clauses 1-21, further comprising a pharmaceutically acceptable salt.

[0084] Clause 23. The sustained- release pharmaceutical composition of any of clauses 1-22, further comprising a pharmaceutically acceptable preservative.

[0085] Clause 24. The sustained-release pharmaceutical composition of any of clauses 1-23, further comprising a pharmaceutically acceptable antioxidant.

[0086] Clause 25. The sustained-release pharmaceutical composition of any of clauses 1-24, further comprising a pharmaceutically acceptable excipient.

[0087] Clause 26. The sustained-release pharmaceutical composition of any of clauses 1-25, further comprising a pharmaceutically acceptable lubricant.

[0088] Clause 27. The sustained-release pharmaceutical composition of any of clauses 1-26, further comprising a pharmaceutically acceptable binder.

[0089] Clause 28. The sustained-release pharmaceutical composition of any of clauses 1-27, further comprising a pharmaceutically acceptable humectant.

[0090] Clause 29. The sustained-release pharmaceutical composition of any of clauses 1-28, further comprising a pharmaceutically acceptable flavorant.

[0091] Clause 30. The sustained-release pharmaceutical composition of any of clauses 1-29, wherein the mammalian subject is a human.

[0092] Clause 31. A sustained-release capsule comprising the pharmaceutical composition of any of clauses 1-30.

[0093] Clause 32. The sustained-release capsule of clause 31, wherein the capsule is a sustained- release double-gel capsule.

[0094] Clause 33. The sustained-release capsule of either clause 31 or clause 32, wherein the capsule is a size 00 standard capsule.

[0095] Clause 34. The sustained-release capsule of either clause 31 or clause 32, wherein the capsule is a size 1 standard capsule.

[0096] Clause 35. The sustained-release capsule of either clause 31 or clause 32, wherein the capsule is a size 3 standard capsule.

[0097] Clause 36. The sustained-release capsule of any of clauses 31-35, wherein the capsule is a 3D-prmted capsule.

[0098] Clause 37. A method of preventing or treating asthma in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition of any of clauses 1-30.

[0099] Clause 38. A method of preventing asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition of any of clauses 1-30.

[0100] Clause 39. A method of increasing baseline serum concentration of dehydroepiandrosterone in a human patient in need thereof, the method comprising: administering to the subject to the composition of any of clauses 1-30.

[0101] Clause 40. A method of reducing the frequency of asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective regimen of the sustained-release capsule of any of clauses 31-36.

[0102] Clause 41. The method of clause 40, wherein the pharmaceutically effective regimen comprises the human patient ingesting one capsule per 12 hours.

[0103] Clause 42. The method of any of clauses 37-41 , wherein the human patient expresses C / A at position 1245 of the gene Hsd3bl on one or both alleles or A / A at position 1245 of the gene Hsd3bl on one or both alleles.

[0104] Clause 43. The method of any of clauses 37-42, wherein the human patient is a biological female who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 45 pg / dL.

[0105] Clause 44. The method of any of clauses 37-42, wherein the human patient is a biological male who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 90 pg / dL.

[0106] Clause 45. The method of any of clauses 37-44, wherein the human patient has been diagnosed with moderate asthma.

[0107] Clause 46. The method of any of clauses 37-44, wherein the human patient has been diagnosed with severe asthma.

[0108] Clause 47. The method of any of clauses 37-46, wherein the method results in a sustained blood serum concentration of dehydroepiandrosterone sulfate of from about 490 pg / dL to about 1,020 pg / dL.

[0109] Clause 48. The method of any of clauses 37-47, further comprising administering to the human patient a pharmaceutically effective dose of albuterol.

[0110] Clause 49. A sustained-release double-gel capsule for prevention or treatment of asthma in a human patient having C / A1245 variant of the gene Hsd3bl gene or A / A1245 variant of the gene Hsd3bl, the capsule comprising: a capsule shell containing a plurality of ingredients in its interior, the shell comprising a sustained-release formulation; and the ingredients comprising 50mg to lOOmg dehydroepiandrosterone, 350mg to 400mg magnesium glycinate; lOOmg to 120mg methylcellulose E4M; and 20mg to 30mg microcrystalline cellulose.[oni] Clause 50. A kit comprising: the sustained release capsule of any of clauses 31-35; a container; and instructions providing information on how to administer the capsule to a subject in need thereof.

[0112] Clause 51. Use of the composition of any of clauses 1-30 for the manufacture of a medicament for prevention or treatment of asthma in a human patient.

[0113] Clause 52. A composition or method substantially as described in the present disclosure.

[0114] Additional embodiments, features, and advantages of the disclosure will be apparent from the detailed description above and through practice of the disclosure.EXAMPLES

[0115] The subj ect matter of the present disclosure may be further understood, without limitation, by reference to the following examples.

[0116] Example 1. Clinical Study of Dehydroepiandrosterone

[0117] In a clinical study of dehydroepiandrosterone (DHEA) treatment in asthmatic adult female human patients, selection criteria for study participation was as follows in Table 1, below:

[0118] Table 2, below, shows pilot study results for spirometry for fourteen clinical subjects. “FEVi” refers to the 1 -second forced expiratory volume spirometry test, i.e., a test of the volume of air, following a maximal inhaled breath, a person is capable of forcing out of their lungs. Experimental results are measured in liters (L).

[0119] Lung function of asthmatic children aged 6-18 years is shown in Tables 3 A, 3B, and 3C, below:

[0120] The data illustrate an observed relationship between lung function and progression of puberty. For males, there was a tendency for lung function and the maximum bronchodilator response to improve with pubertal maturation. By contrast in females, both the post-bronchodilator FEVi% and FVC% were significantly lower (by 8.9% and 9.1% respectively, p = 0.01 each) from pre- / early to mid- / late puberty as determined by breast development. In an analysis limited to severe females alone (n = 44), the lower FEVi (%) from early to late puberty remained significant. “FVC” refers to forced vital capacity, a test of the volume of air that a person can forcibly exhale from their lungs after a maximal inhaled breath. FEVi% and FVC% refers to expression of FEVi and FVC, respectively, as a percentage of a predicted value in a patient, as a means of expressing severity of obstructive lung disease. The predicted FEVi and FVC value is calculated according to methods known in the art, e.g., according to the method of Quanjer PhH et al. ‘Lung volume and forced ventilatory flows. Report Working Party Standardization of lung function tests.’ Official Statement European Respiratory Society. Eur Respir J. 1993; 6 Suppl 16: 5-40.

[0121] Example 2.

[0122] Two cohorts of subjects were treated with both 50mg and lOOmg sustained-release dehydroepiandrosterone, respectively, given by mouth twice daily. Subjects achieved steady-state dehydroepiandrosterone sulfate concentrations in plasma after 36 hours. No between-dose decreases in dehydroepiandrosterone sulfate concentrations were observed.

[0123] Example 3.

[0124] Two cohorts of subjects were treated with 50mg and lOOmg sustained-release dehydroepiandrosterone, respectively. Both doses decreased circulating expression of IL4 and 11.4- pathway genes in humans when analyzed by RNASeq, followed by TopMD™ pathway analysis. (Figure 4.) TopMD™ is an analysis tool known in the art of measuring the topological shape of gene expression relative to gene interaction maps. TopMD™ maps of global pathway activity are plotted using standard global gene expression data (microarray, RNAseq, proteomics etc.).

Claims

IN THE CLAIMS:

1. A sustained-release pharmaceutical composition for prevention or treatment of asthma in a mammalian subject in need thereof comprising a pharmaceutically effective dose of dehydroepiandrosterone.

2. The sustained-release pharmaceutical composition of claim 1 , further comprising a magnesium salt.

3. The sustained-release pharmaceutical composition of claim 2, wherein the magnesium salt comprises magnesium glycinate.

4. The sustained-release pharmaceutical composition of any of claims 1-3, comprising about 1 mg to about 200mg of dehydroepiandrosterone.

5. The sustained-release pharmaceutical composition of any of claims 1-3, comprising about lOmg to about 150mg of dehydroepiandrosterone.

6. The sustained-release pharmaceutical composition of any of claims 1-3, comprising about 50mg to about 125mg of dehydroepiandrosterone.

7. The sustained-release pharmaceutical composition of any of claims 1-3, comprising about 90mg to about 1 lOmg of dehydroepiandrosterone.

8. The sustained-release pharmaceutical composition of any of claims 1-3, comprising about 1 OOmg of dehydroepiandrosterone.

9. The sustained-release pharmaceutical composition of any of claims 2-8, comprising about lOOmg to about 600mg of magnesium glycinate.

10. The sustained-release pharmaceutical composition of any of claims 2-8, comprising about200mg to about 500mg of magnesium glycinate.

11. The sustained-release pharmaceutical composition of any of claims 2-8, comprising about300mg to about 400mg of magnesium glycinate.The sustained-release pharmaceutical composition of any of claims 2-8, comprising about360mg to about 390mg of magnesium glycinate.

13. The sustained-release pharmaceutical composition of any of claims 2-8, comprising about385mg of magnesium glycinate.

14. The sustained-release pharmaceutical composition of any of claims 1-13, further comprising one or more carriers.

15. The sustained-release pharmaceutical composition of claim 14, wherein the one or more carriers comprise methylcellulose, microcrystalline cellulose, or a combination of methylcellulose and microcrystalline cellulose.

16. The sustained-release pharmaceutical composition of claim 15, wherein the methyl cellulose comprises hydroxypropyl methylcellulose.

17. The sustained-release pharmaceutical composition of either claim 15 or 16, wherein the methylcellulose is METHOCEL™ E4M.

18. The sustained-release pharmaceutical composition of any of claims 14-17, comprising about lOOmg to about 120mg methylcellulose.

19. The sustained-release pharmaceutical composition of any of claims 14-18, comprising about lOmg to about 40mg microcrystalline cellulose.

20. The sustained-release pharmaceutical composition of any of claims 1-19, further comprising a pharmaceutically acceptable buffer.

21. The sustained-release pharmaceutical composition of any of claims 1-20, further comprising a pharmaceutically acceptable pH modulator. . The sustained-release pharmaceutical composition of any of claims 1-21, further comprising a pharmaceutically acceptable salt.

23. The sustained-release pharmaceutical composition of any of claims 1-22, further comprising a pharmaceutically acceptable preservative.

24. The sustained-release pharmaceutical composition of any of claims 1-23, further comprising a pharmaceutically acceptable antioxidant.

25. The sustained-release pharmaceutical composition of any of claims 1-24, further comprising a pharmaceutically acceptable excipient.

26. The sustained-release pharmaceutical composition of any of claims 1-25, further comprising a pharmaceutically acceptable lubricant.

27. The sustained-release pharmaceutical composition of any of claims 1-26, further comprising a pharmaceutically acceptable binder.

28. The sustained-release pharmaceutical composition of any of claims 1-27, further comprising a pharmaceutically acceptable humectant.

29. The sustained-release pharmaceutical composition of any of claims 1-28, further comprising a pharmaceutically acceptable flavorant.

30. The sustained-release pharmaceutical composition of any of claims 1-29, wherein the mammalian subject is a human.

31. A sustained-release capsule comprising the pharmaceutical composition of any of claims 1-32. The sustained-release capsule of claim 31, wherein the capsule is a sustained-release doublegel capsule.

33. The sustained-release capsule of either claim 31 or claim 32, wherein the capsule is a size 00 standard capsule.

34. The sustained-release capsule of either claim 31 or claim 32, wherein the capsule is a size 1 standard capsule.

35. The sustained-release capsule of either claim 31 or claim 32, wherein the capsule is a size 3 standard capsule.

36. The sustained-release capsule of any of claims 31-35, wherein the capsule is a 3D-printed capsule.

37. A method of preventing or treating asthma in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition of any of claims 1-30.

38. A method of preventing asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective dose of the composition of any of claims 1-30.

39. A method of increasing baseline serum concentration of dehydroepiandrosterone in a human patient in need thereof, the method comprising: administering to the subject to the composition of any of claims 1-30.

40. A method of reducing the frequency of asthma attacks in a human patient in need thereof, the method comprising: administering to the subject a pharmaceutically effective regimen of the sustained- release capsule of any of claims 31-36.

41. The method of claim 40, wherein the pharmaceutically effective regimen comprises the human patient ingesting one capsule per 12 hours.

42. The method of any of claims 37-41 , wherein the human patient expresses C / A at position 1245 of the gene Hsd3bl on one or both alleles or A / A at position 1245 of the gene Hsd3bl on one or both alleles.

43. The method of any of claims 37-42, wherein the human patient is a biological female who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 45 pg / dL.

44. The method of any of claims 37-42, wherein the human patient is a biological male who has a baseline serum concentration of dehydroepiandrosterone sulfate of less than 90 pg / dL.

45. The method of any of claims 37-44, wherein the human patient has been diagnosed with moderate asthma.

46. The method of any of claims 37-44, wherein the human patient has been diagnosed with severe asthma.

47. The method of any of claims 37-46, wherein the method results in a sustained blood serum concentration of dehydroepiandrosterone sulfate of from about 490 pg / dL to about 1,020 pg / dL.

48. The method of any of claims 37-47, further comprising administering to the human patient a pharmaceutically effective dose of albuterol.

49. A sustained-release double-gel capsule for prevention or treatment of asthma in a human patient having C / A1245 variant of the gene Hsd3bl gene or A / A1245 variant of the gene Hsd3bl, the capsule comprising: a capsule shell containing a plurality of ingredients in its interior, the shell comprising a sustained-release formulation; andthe ingredients comprising 50mg to lOOmg dehydroepiandrosterone, 350mg to 400mg magnesium glycinate; lOOmg to 120mg methylcellulose E4M; and 20mg to 30mg microcrystalline cellulose.

50. A kit comprising: the sustained release capsule of any of claims 31-35; a container; and instructions providing information on how to administer the capsule to a subject in need thereof.

51. Use of the composition of any of claims 1-30 for the manufacture of a medicament for prevention or treatment of asthma in a human patient.

52. A composition or method substantially as described in the present disclosure.

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