Urea compositions and methods of use

Abstract

Disclosed herein are compositions of urea, such as edible urea compositions for the treatment of hyponatremia. Further disclosed herein are methods for preparing such compositions of edible urea. Also disclosed are methods for administering the disclosed compositions to a subject in need thereof, such as a subject suffering from hyponatremia.

Description

UREA COMPOSITIONS AND METHODS OF USE

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 515,521, filed on July 25, 2023, and entitled “UREA COMPOSITIONS AND METHODS OF USE,” the entire disclosure of which is expressly incorporated by reference herein. FIELD OF THE INVENTION

[0002] This disclosure generally relates to compositions of urea, such as edible compositions of urea. The disclosure further relates to methods of using disclosed compositions of urea, such as administering the compositions to a subject with hyponatremia. BACKGROUND

[0003] Compositions of edible urea are useful to treat hyponatremia, a condition wherein sodium levels in the body become abnormally low. Sodium is an electrolyte that plays a role in regulating extracellular and intracellular fluid volume, e.g., the amount of water surrounding and inside cells. Accordingly, a reduction of sodium below certain levels can lead to increased water content within cells and cell swelling. Symptoms of hyponatremia range from mild physiological disturbances to life-threatening effects, such as rapid swelling of the brain, which can result in a coma and death. Several factors may contribute to the development of hyponatremia, including underlying conditions that affect various organs, certain medications, and drinking too much water. The dangers posed by hyponatremia necessitate improved oral urea compositions for use at home and in the clinic.

[0004] Edible or oral formulations of urea are available to treat hyponatremia. However, improved formulations are necessary to provide compositions having advantageous pharmaceutical properties, e.g., enhanced stability, and organoleptic properties, e.g., desirable 1 DMS_US.364752221.1taste. Regarding formulations of edible urea, there exists a need for compositions having improved stability, e.g., reduced degradation upon exposure to moisture, light, and heat, to enhance shelf-life and storage stability. Compositions containing additional components that improve free water excretion are also needed. Further, to improve the adherence of subjects to such treatment, there is a need to provide stable edible urea compositions with improved organoleptic characteristics. Aspects of the invention disclosed herein address these needs. INCORPORATION BY REFERENCE

[0005] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually, and as if each is fully set forth herein. However, where such reference is made, and whether to patents, publications, non-patent literature, or other sources of information, it is for the general purpose of providing context for discussing features of the invention. Accordingly, unless specifically stated otherwise, the reference is not to be construed as an admission that the document or underlying information, in any jurisdiction, is prior art, or forms part of the common general knowledge in the art. SUMMARY OF THE INVENTION

[0006] A first aspect of the invention includes compositions of edible urea.

[0007] A second aspect of the invention includes unit dosage forms of edible urea.

[0008] A third aspect of invention includes methods of using disclosed compositions and unit dosage forms of edible urea, such as in the treatment of hyponatremia.

[0009] A first embodiment is a composition including 75% to 85% (wt / wt) of urea, 5% to 15% (wt / wt) of an antioxidant, 0.5% to 5% (wt / wt) of an antacid, and 0.5% to 5% (wt / wt) of an electrolyte, where each range inclusive. 2 DMS_US.364752221.1

[0010] A second embodiment is a composition where the antioxidant is a vitamin or a mineral.

[0011] A third embodiment is a composition where the vitamin is vitamin C (ascorbic acid).

[0012] A fourth embodiment is a composition where the antacid comprises a bicarbonate salt.

[0013] A fifth embodiment is a composition where the antacid comprises calcium bicarbonate, potassium bicarbonate, sodium bicarbonate, or a combination thereof.

[0014] A sixth embodiment is a composition where the electrolyte is sodium chloride.

[0015] A seventh embodiment is a composition, which further includes further including a non-saccharide sweetener.

[0016] An eighth embodiment is a composition where the percent (wt / wt) amount of the non- saccharide sweetener in the composition is 1.5% to 8%, inclusive.

[0017] A ninth embodiment is a composition where the non-saccharide sweetener comprises a peptide.

[0018] A tenth embodiment is a composition where the peptide comprises a dipeptide methyl ester.

[0019] An eleventh embodiment is a composition where the dipeptide methyl ester is l- aspartyl-l-phenylalanine methyl ester (aspartame).

[0020] A twelfth embodiment is a composition where the composition further comprises an anti-caking agent.

[0021] A thirteenth embodiment is a composition where the % (wt / wt) amount of the anti- caking agent in the composition is 0.5% to 4%, inclusive. 3 DMS_US.364752221.1

[0022] A fourteenth embodiment is a composition where the anti-caking agent comprises a calcium salt.

[0023] A fifteenth embodiment is a composition where the anti-caking agent is calcium silicate.

[0024] A sixteenth embodiment is a composition where the calcium silicate has a particle size of greater than seven microns (7 µm).

[0025] A seventeenth embodiment is a composition which further includes a flavoring agent.

[0026] An eighteenth embodiment is a composition where the % (wt / wt) amount of the flavoring agent is 0.5% to 5%, inclusive.

[0027] A nineteenth embodiment is a composition where the flavoring agent has a fruit flavor and / or a fruity odor.

[0028] A twentieth embodiment is a composition where the flavoring agent comprises ethyl phenylglycidate and / or ethyl methylphenylglycidate.

[0029] A twenty-first embodiment is a composition where the composition is a powder mixture.

[0030] A twenty-second embodiment is a composition consisting of urea (75-85% w / w), ascorbic acid (5-15% w / w), sodium bicarbonate (0.5-5% w / w), sodium chloride (0.5-5% w / w), aspartame (1.5-8% w / w), calcium silicate (0.5-4% w / w), and ethyl phenylglycidate and / or ethyl methylphenylglycidate (0.5-5% w / w total), where the composition is a powder mixture.

[0031] A twenty-third embodiment is a composition consisting of about 79 wt% urea, 10 wt% ascorbic acid, 5 wt% aspartame, 2.1 wt% sodium bicarbonate, 1.6 wt% calcium silicate, and 1 wt% ethyl phenylglycidate. 4 DMS_US.364752221.1

[0032] A twenty-fourth embodiment is a unit dosage form consisting of 15.7 g to 16.0 g urea, 1.5 g to 2.1 g ascorbic acid, 0.5 g to 1.0 g aspartame, 0.22 g to 0.42 g sodium bicarbonate, 0.25 g to 0.32 g sodium chloride, 0.32 to 0.75 g calcium silicate, and 0.21 g to 0.85 g ethyl 3- phenylglycidate, where the unit dosage form is a powder mixture and each range is inclusive.

[0033] A twenty-fifth embodiment is a unit dosage form including 16.0 grams urea, 2.1 grams ascorbic acid, 1.0 grams aspartame, 0.42 grams sodium bicarbonate, 0.32 grams sodium chloride, 0.32 grams calcium silicate, and 0.21 grams ethyl phenylglycidate.

[0034] A twenty-sixth embodiment is a composition or a unit dosage form where a 20 gram (g) sample of the composition or the unit dosage form has a moisture content of less than 0.5%, as determined by a loss on drying assay.

[0035] A twenty-seventh embodiment is a composition or a unit dosage form where the composition is intended for oral consumption by a subject.

[0036] A twenty-eighth embodiment is a composition or a unit dosage form where the composition or the unit dosage form is dispersed into a liquid or a food colloid prior to oral consumption by the subject.

[0037] A twenty-ninth embodiment is a composition or a unit dosage form where the subject is suffering from hyponatremia.

[0038] A thirtieth embodiment is a method of treating hyponatremia including orally administering to a subject suffering from hyponatremia the composition or the unit dosage form of any of the preceding embodiments.

[0039] A thirty-first embodiment is a method of treating hyponatremia including dispersing the composition or the unit dosage form of any of the preceding embodiments into a liquid or a food colloid prior to oral administration to the subject. 5 DMS_US.364752221.1

[0040] A thirty-second embodiment is a method of treating hyponatremia where the composition or the unit dosage form is administered to the subject at least once per day. BRIEF DESCRIPTION OF THE FIGURES

[0041] The accompanying drawings are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments, and together with the description serve to explain the principles of the disclosure.

[0042] FIG 1. CHN spectrum of an exemplary composition of edible urea.

[0043] FIG 2. IR spectrum of an exemplary composition of edible urea.

[0044] FIG 3A. UV vis spectrum of an exemplary urea composition.

[0045] FIG 3B. UV vis spectrum of a commercially available edible urea composition.

[0046] FIG 4. Bar graph shows percent (%) moisture content of a commercially available edible urea composition (left) and an exemplary edible urea formulation (right) in a moisture absorption study.

[0047] FIG 5. Bar graph shows percent (%) degradation of a commercially available edible urea composition (left) and an exemplary edible urea formulation (right) in response to heat exposure. DETAILED DESCRIPTION

[0048] Hyponatremia results from the inability of the kidney to excrete a water load, or excess water intake, and is clearly evidenced by abnormally low sodium levels in the blood. Several physiological processes can contribute to the development of hyponatremia. In one example, the condition may occur if there is persistent stimulation by the anti-diuretic hormone vasopressin. Hyponatremia is more likely to develop in people living with certain diseases, like kidney failure, congestive heart failure, and diseases affecting the lungs, liver or brain. It 6 DMS_US.364752221.1often occurs with pain after surgery. Also, people taking medications like diuretics and some antidepressants are at higher risk for this condition.

[0049] Acute hyponatremia is characterized by onset of symptoms in less than 48 hours. Patients with acute hyponatremia can develop neurologic symptoms resulting from cerebral edema, which is caused by the movement of water into the brain. Such symptoms may include seizures, impaired mental status, coma, and death. In the case of symptom persistence over 48 hours, hyponatremia is considered chronic. Patients with chronic hyponatremia typically have a serum sodium concentration above 120meq / L. Idiogenic osmoles form in the brain as a protective mechanism to reduce the degree of cerebral edema. Hence, chronic hyponatremia patients may appear asymptomatic. Mild hyponatremia is characterized by gastrointestinal tract symptoms nausea, vomiting, loss of appetite. Sometimes, subtle neurologic abnormalities may be present when the serum sodium is between 120 and 130 meq / L. Hyponatremia in the elderly may manifest with frequent falls and gait disturbances (Renneboog et al., Am J Med.2006;119:71.e1– 8).

[0050] Hyponatremia may be euvolemic, hypovolemic or hypervolemic. Proper interpretation of various laboratory tests can differentiate the various types of hyponatremia, as effective treatment varies with the nature of onset, whether the condition is acute or chronic in nature, and symptom severity. See, e.g., Sterns, “Overview of the treatment of hyponatremia in adults,” 2021, UpToDate.com, Hoorn & Zietse, J Am Soc Nephrol. 2017 May; 28(5): 1340– 1349, Sahay & Sahay, Indian J Endocrinol Metab. 2014 Nov-Dec; 18(6): 760–771, and current hyponatremia treatment guidelines available to one of skill in the art. Treatment for hyponatremia depends on the underlying cause and the severity of symptoms. People with moderate to severe hyponatremia require intravenous sodium and water restriction. Certain 7 DMS_US.364752221.1medications, such as tolvaptan (Samsca), may be used to correct blood sodium levels. Oral administration of urea can also effectively treat hyponatremia.

[0051] Urea is an osmotic diuretic in nephron segments with high water permeability and low urea permeability, specifically the connecting tubule, cortical collecting duct, and outer medulla collecting duct. The effects of urea on free water excretion can be explained by the dependence of free water excretion on solute excretion. See, e.g., Table 1 of Rondon-Berrios, Blood Purif. 2020;49(1-2):212-218. The pathophysiology of hyponatremia, e.g., in the case of syndrome of inappropriate antidiuretic hormone secretion (SIADH), not only involves dilution from water accumulation but also a component of sodium loss (Verbalis, Am J Med. 2006 Jul;119(7 Suppl 1):S21–9). Administration of urea to SIADH patients has been shown to decrease natriuresis and create a state of positive sodium balance, which also contributes to the improvement of plasma sodium concentration (Verbalis et al., Metabolism. 1988 Jan;37(1):46– 54).

[0052] Oral urea, an osmotic agent increases urinary-free water excretion and is safe and effective for the treatment of hyponatremia. Commercially available edible urea compositions are available for the treatment of hyponatremia. The oral preparation of urea is typically supplied as a powder packet that is mixed with water or juice. The US Food and Drug Administration considers urea a medical food, classified as generally regarded as a safe category.

[0053] Since its introduction, certain disadvantages of commercially available oral preparations of urea, such as Ure-Na (Nephcentric, Phoenix, AZ) have been noted, e.g., unfavorable pharmaceutical properties, e.g., powder clumping, caking, and limited storage stability, and clinical characteristics, e.g., low patient compliance due to undesirable taste, which limit the utility of the composition. Provided herein are improved edible urea compositions, and 8 DMS_US.364752221.1methods and uses related to the same, which include components that drive free water excretion, while maintaining bodily Na+and K+levels in the body and have desirable organoleptic characteristics. Together, pharmaceutical formulation with these aims is anticipated to translate to reduced preparation time and improved treatment adherence. Additionally, disclosed compositions have enhanced shelf-life and storage stability under various conditions.

[0054] Composition

[0055] In some aspects, provided herein are edible compositions of urea. In some embodiments, disclosed compositions comprise urea and any one or more of an antioxidant, an antacid, and an electrolyte. In some embodiments, disclosed compositions comprise urea, an antioxidant, an antacid, and an electrolyte. In some embodiments, disclosed compositions further comprise a sweetener, an anti-caking agent, a flavoring agent, or any combination thereof. In some embodiments, disclosed compositions comprise urea, ascorbic acid, aspartame, sodium bicarbonate, sodium chloride, calcium silicate, and ethyl phenylglycidate and / or ethyl methylphenylglycidate. In some embodiments, disclosed compositions consist of urea, ascorbic acid, aspartame, sodium bicarbonate, sodium chloride, calcium silicate, and ethyl phenylglycidate and / or ethyl methylphenylglycidate.

[0056] Urea

[0057] In some embodiments, disclosed compositions comprise urea in a % (wt / wt) amount of at least about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, or 75%. In some embodiments, disclosed compositions comprise urea in a % (wt / wt) amount of less than about 75%, 76%, 77%, 78%, 79%, or 80%. In some embodiments, disclosed compositions comprise urea in a % (wt / wt) amount of about 65% to 95%, 70% to 95%, 75% to 95%, 80% to 95%, 65% to 90%, 70% to 90%, 75% to 90%, 80% to 90%, 85% to 90%, 65% to 85%, 70% to 85%, 75% to 9 DMS_US.364752221.185%, 80% to 85%, 65% to 80%, 70% to 80%, 75% to 80%, 78% to 80%, or 78% to 79%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise urea in a % (wt / wt) amount of about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85%. In preferred embodiments, disclosed compositions comprise urea in a % (wt / wt) amount of about 78%, 79%, or 80%.

[0058] Urea is known to facilitate the excretion of water from the kidneys. When water restriction is insufficient, urea is recommended in the second line treatment of moderate to severe hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). A posology of 0.25-0.5 g / kg daily is typically recommended.

[0059] Antioxidants

[0060] In some embodiments, disclosed compositions comprise urea and any one or more of an antioxidant, an antacid, and an electrolyte. In some embodiments, the antioxidant is a vitamin. In some embodiments, the antioxidant is vitamin C, vitamin E, selenium, a carotenoid, e.g., α- carotene, β-carotene, β-cryptoxanthin, lutein, lycopene, or zeaxanthin, or any combination thereof. In preferred embodiments, the antioxidant is ascorbic acid (vitamin C). In some embodiments, disclosed compositions comprise urea, ascorbic acid, an antacid, and an electrolyte.

[0061] In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of greater than about 5%, 6%, 7%, 8%, 9%, 10%, 11% 12%, 13%, 14%, or 15%. In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of less than about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, or 10%. In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of 5% to 15%, 6% to 15%, 7% to 15%, 8% to 15%, 9% to 15%, 10% to 15%, 11% to 15%, 12% to 15%, 10 DMS_US.364752221.113% to 15%, or 14% to 15%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of 5% to 14%, 6% to 14%, 7% to 14%, 8% to 14%, 9% to 14%, 10% to 14%, 11% to 14%, 12% to 14%, or 13% to 14%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of 5% to 13%, 6% to 13%, 7% to 13%, 8% to 13%, 9% to 13%, 10% to 13%, 11% to 13%, or 12% to 13%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of 5% to 12%, 6% to 12%, 7% to 12%, 8% to 12%, 9% to 12%, 10% to 12%, or 11% to 12%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of 5% to 11%, 6% to 11%, 7% to 11%, 8% to 11%, 9% to 11%, or 10% to 11%. In some embodiments, disclosed compositions comprise the antioxidant in a % (wt / wt) amount of about 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, or 12%

[0062] In preferred embodiments, the antioxidant is ascorbic acid. In some embodiments, disclosed compositions comprise ascorbic acid in a % (wt / wt) amount of 5% to 13%, 6% to 13%, 7% to 13%, 8% to 13%, 9% to 13%, 10% to 13%, 11% to 13%, or 12% to 13%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise ascorbic acid in a % (wt / wt) amount of 5% to 12%, 6% to 12%, 7% to 12%, 8% to 12%, 9% to 12%, 10% to 12%, or 11% to 12%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise ascorbic acid in a % (wt / wt) amount of about 5% to 11%, 6% to 11%, 7% to 11%, 8% to 11%, 9% to 11%, or 10% to 11%. In some embodiments, disclosed compositions comprise ascorbic acid in a % (wt / wt) amount of about 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, or 12%. 11 DMS_US.364752221.1

[0063] Antioxidants may be used as excipients to delay or inhibit the oxidation process of molecules in a formulation. See, e.g., Celestino et al., Brazilian Journal of Pharmaceutical Sciences 2012;48(3). However, antioxidants may also react unfavorably with other excipients. In one example, ascorbic acid and sodium bicarbonate in solid form have been shown to react, resulting in hardening, clumping, and reductions in reactivity (Bruno F, “Long-term storage of Ascorbic Acid mixed with Sodium Bicarbonate,” Chemistry, StackExchange). The disclosure of US20210100743A1 notes degradation of an experimental edible urea composition that included sodium bicarbonate and citric acid upon exposure to humidity, due to a chemical reaction between the two. Surprisingly, exemplary compositions comprising ascorbic acid and sodium bicarbonate, such as the composition described in Example 1, were found to have reduced hygroscopicity and greater stability relative to the commercially available embodiment of US20210100743A1, which does not contain ingredients shown to undermine favorable pharmaceutical properties. See, e.g., examination of physical properties, including powder texture, in Example 4, and hygroscopicity and moisture content studies described in Example 5 herein.

[0064] Regarding bioactivity, low extracellular [Na+] directly activates osteoclastogenesis and osteoclastic bone resorption. Ascorbic acid has a central role in regulating the equilibrium between osteoblastic functions and osteoclastogenesis, and decreased intracellular ascorbic acid concentration can weaken cellular defense against oxidative stress, facilitating accumulation of harmful products of oxidative stress responses, including free reactive oxygen species. See, e.g., Wu et al., Arch Biochem Biophys. 2003;420:114–120, Xiao et al., J Endocrinol Invest. 2005;28:253–260, and Barsony et al., Age (Dordr).2013 Apr; 35(2): 271–288. Additionally, the 12 DMS_US.364752221.1antioxidant may be used to supplement a mammal’s vitamin C levels and defend against oxidative stress.

[0065] Sweeteners

[0066] In some embodiments, disclosed compositions comprise a sweetener. In some embodiments, the sweetener is a non-saccharide sweetener. In some embodiments, the non- saccharide sweetener comprises one or more peptides. In some embodiments, the non-saccharide sweetener comprises two peptides. In some embodiments, the non-saccharide sweetener comprises a dipeptide methyl ester. In some embodiments, the dipeptide methyl ester is l- aspartyl-l-phenylalanine methyl ester (aspartame). In some embodiments, the non-saccharide sweetener is aspartame, acesulfame-k, neotame, cyclamate, alitame, stevia, including derivatives thereof or combinations thereof.

[0067] In some embodiments, the sweetener is derived from a fruit. In some embodiments, the sweetener is derived from a swingle fruit, e.g., a luo han guo extract. In some embodiments, the sweetener is a saccharide sweetener, such as a monosaccharide, a disaccharide, or a polysaccharide. In some embodiments, the saccharide sweetener is dextrose, fructose, galactose, glucose, lactose, maltodextrin, maltose, sucralose, or a combination thereof.

[0068] Sweeteners or sweetening agents are generally used in pharmaceutical formulations to improve palatability upon oral administration to a subject. In some cases, they are also used as taste-masking agents. Sweeteners may be further classified into natural sweeteners, e.g., sucrose and sorbitol, and artificial sweeteners, e.g., aspartame and saccharin. See, e.g., Chattopadhyay et al., J Food Sci Technol. 2014 Apr; 51(4): 611–621. In preferred embodiments, disclosed compositions do not comprise a polysaccharide, e.g., polysaccharides having a dextrose equivalent (DE) of < 20, such as maltodextrin. Hyponatremia is a complication of diabetes, as 13 DMS_US.364752221.1diabetes can cause significant electrolyte disturbances. Hypoglycemic agents and other medications can also contribute to hyponatremia. See, e.g., Liamis et al., World J Clin Cases. 2014 Oct 16; 2(10): 488–496. Accordingly, disclosed compositions preferably include sweeteners that have a negligible effect on blood glucose levels, e.g., aspartame.

[0069] In some embodiments, disclosed compositions comprise the sweetener in a % (wt / wt) amount of at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8%. In some embodiments, disclosed compositions comprise the sweetener in a % (wt / wt) amount of less than 10%, 11%, 12%, 13%, 14%, or 15%.

[0070] In some embodiments, disclosed compositions comprise the sweetener in a % (wt / wt) amount of about 0.5 % to 10%, 1% to 10%, 2% to 10%, 3% to 10%, 4% to 10%, 5% to 10%, 6% to 10%, 7% to 10%, 8% to 10%, or 9% to 10%. In some embodiments, disclosed compositions comprise the sweetener in a % (wt / wt) amount of about 0.5 % to 8%, 1% to 8%, 2% to 8%, 3% to 8%, 4% to 8%, 5% to 8%, 6% to 8%, or 7% to 8%. In some embodiments, disclosed compositions comprise the sweetener in a % (wt / wt) amount of about 0.5 % to 6%, 1% to 6%, 2% to 6%, 3% to 6%, 4% to 6%, or 5% to 6%. In some embodiments, disclosed compositions comprise the sweetener in a % (wt / wt) amount of about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or 8%.

[0071] In preferred embodiments, the sweetener is aspartame. In some embodiments, disclosed compositions comprise aspartame in a % (wt / wt) amount of at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8%. In some embodiments, disclosed compositions comprise aspartame in a % (wt / wt) amount of less than 10%, 11%, 12%, 13%, 14%, or 15%.

[0072] In some embodiments, disclosed compositions comprise aspartame in a % (wt / wt) amount of about 0.5 % to 10%, 1% to 10%, 2% to 10%, 3% to 10%, 4% to 10%, 5% to 10%, 6% 14 DMS_US.364752221.1to 10%, 7% to 10%, 8% to 10%, or 9% to 10%. In some embodiments, disclosed compositions comprise aspartame in a % (wt / wt) amount of about 0.5 % to 8%, 1% to 8%, 2% to 8%, 3% to 8%, 4% to 8%, 5% to 8%, 6% to 8%, or 7% to 8%. In some embodiments, disclosed compositions comprise aspartame in a % (wt / wt) amount of about 0.5 % to 6%, 1% to 6%, 2% to 6%, 3% to 6%, 4% to 6%, or 5% to 6%. In some embodiments, disclosed compositions comprise aspartame in a % (wt / wt) amount of about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or 8%.

[0073] Aspartame, a commonly used sweetener in foods and beverages, is effective as a taste-masker in pharmaceutical compositions, e.g., it has been shown to reduce the bitterness of various pharmaceutical actives and excipients. See, e.g., Sohi et al., Drug Dev Ind Pharm. 2004 May;30(5):429-48 and Wu et al., Sens. Actuator B Chem. 2016;235:11–17. The naturally occurring amino acids aspartic acid and phenylalanine are components of aspartame. Several regulatory agencies have confirmed that aspartame and its breakdown products are safe and approved for use in the general population, infants, children, and women who are pregnant or lactating. See, e.g., U.S. FDA, “Additional Information about High Intensity Sweeteners Permitted for Use in Food in the United States.” 2018.

[0074] Antacid

[0075] In some embodiments, disclosed compositions comprise an antacid. In some embodiments, the antacid comprises a bicarbonate, such as calcium bicarbonate, potassium bicarbonate, or sodium bicarbonate, a carbonate, such as calcium carbonate or magnesium carbonate, a hydroxide, such as aluminum hydroxide or magnesium hydroxide, an aluminum– magnesium complex, such as almasilate, hydrotalcite, or magaldrate, an aluminum saccharide combination, such as sucralfate, sodium hydrogen carbonate, aluminum hydroxide, or other 15 DMS_US.364752221.1antacid agents, such as aluminum phosphate, algeldrate, or magnesium trisilicate, or any combination thereof. In preferred embodiments, the antacid is sodium bicarbonate.

[0076] In some embodiments, disclosed compositions comprise about 0.5% to 5%, 0.5% to 4.5%, 0.5% to 4%, 0.5% to 3.5%, 0.5% to 3.0%, 0.5% to 2.5%, 0.5% to 2.0%, 0.5% to 1.5%, or 0.5% to 1.0% of the antacid, wherein each range is inclusive. In some embodiments, disclosed compositions comprise about 1.0% to 5%, 1.0% to 4.5%, 1.0% to 4%, 1.0% to 3.5%, 1.0% to 3.0%, 1.0% to 2.5%, 1.0% to 2.0%, or 1.0% to 1.5% of the antacid, wherein each range is inclusive. In some embodiments, disclosed compositions comprise about 1.5% to 5%, 1.5% to 4.5%, 1.5% to 4%, 1.5% to 3.5%, 1.5% to 3.0%, 1.5% to 2.5%, or 1.5% to 2.0%, of the antacid, wherein each range is inclusive. In some embodiments, disclosed compositions comprise about 2.0% to 5%, 2.0% to 4.5%, 2.0% to 4%, 2.0% to 3.5%, 2.0% to 3.0%, or 2.0% to 2.5% of the antacid, wherein each range is inclusive.

[0077] In some embodiments, disclosed compositions comprise about 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or 4% of the antacid.

[0078] In preferred embodiments, the antacid is sodium bicarbonate. In some embodiments, disclosed compositions comprise about 0.5% to 5%, 0.5% to 4.5%, 0.5% to 4%, 0.5% to 3.5%, 0.5% to 3.0%, 0.5% to 2.5%, 0.5% to 2.0%, 0.5% to 1.5%, or 0.5% to 1.0% of sodium bicarbonate, wherein each range is inclusive. In some embodiments, disclosed compositions comprise about 1.0% to 5%, 1.0% to 4.5%, 1.0% to 4%, 1.0% to 3.5%, 1.0% to 3.0%, 1.0% to 2.5%, 1.0% to 2.0%, or 1.0% to 1.5% of sodium bicarbonate, wherein each range is inclusive. In some embodiments, disclosed compositions comprise about 1.5% to 5%, 1.5% to 4.5%, 1.5% to 4%, 1.5% to 3.5%, 1.5% to 3.0%, 1.5% to 2.5%, or 1.5% to 2.0%, of sodium bicarbonate, 16 DMS_US.364752221.1wherein each range is inclusive. In some embodiments, disclosed compositions comprise about 2.0% to 5%, 2.0% to 4.5%, 2.0% to 4%, 2.0% to 3.5%, 2.0% to 3.0%, or 2.0% to 2.5% of sodium bicarbonate, wherein each range is inclusive.

[0079] In some embodiments, disclosed compositions comprise about 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or 4% of sodium bicarbonate.

[0080] Also known as baking soda, sodium bicarbonate, it is used to relieve heartburn, sour stomach, or acid indigestion by neutralizing excess stomach acid. In addition to its antacid capabilities, sodium bicarbonate is useful in the treatment of hyponatremia. See, e.g., Farkas, “Emergent treatment of hyponatremia or elevated ICP with bicarb ampules,” PulmCrit (EmCrit), 2015, and Hootman et al., “Trick of the Trade: Sodium Bicarbonate for Acute Symptomatic Hyponatremia,” Tox & Medications, Tricks of the Trade, Academic Life in Emergency Medicine, 2020. For severe symptomatic hyponatremia, e.g., resulting in seizures or a coma, initial treatment with 2 ml / kg of 8.4% sodium bicarbonate may be recommended. For less dire situations, about 1.5 ml / kg of 8.4% sodium bicarbonate may be administered initially. 8.4% sodium bicarbonate has about the same osmolarity as 6% NaCl, making it about twice as powerful as an osmotic agent as 3% NaCl.

[0081] Electrolytes

[0082] In some embodiments, disclosed compositions comprise an electrolyte. In some embodiments, the electrolyte comprises sodium or potassium. In some embodiments, the electrolyte is sodium chloride, potassium chloride, or a combination thereof. In preferred embodiments, the electrolyte is sodium chloride. 17 DMS_US.364752221.1

[0083] In some embodiments, disclosed compositions comprise the electrolyte in a % (wt / wt) amount of at least about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, or 3%. In some embodiments, disclosed compositions comprise the electrolyte in a % (wt / wt) amount of less than about 5%, 6%, 7%, 8%, 9%, or 10%.

[0084] In some embodiments, disclosed compositions comprise the electrolyte in a % (wt / wt) amount of about 0.5% to 5%, 0.6% to 5%, 0.7% to 5%, 0.8% to 5%, 0.9% to 5%, 1% to 5%, 1.1% to 5%, 1.2% to 5%, 1.3% to 5%, 1.4% to 5%, 1.5% to 5%, 1.6% to 5%, 1.7% to 5%, 1.8% to 5%, 1.9% to 5%, 2% to 5%, 2.1% to 5%, 2.2% to 5%, 2.3% to 5%, 2.4% to 5%, 2.5% to 5%, 2.6% to 5%, 2.7% to 5%, 2.8% to 5%, 2.9% to 5%, or 3% to 5% wherein each range is inclusive.

[0085] In some embodiments, disclosed compositions comprise the electrolyte in a % (wt / wt) amount of about 0.5% to 3%, 0.6% to 3%, 0.7% to 3%, 0.8% to 3%, 0.9% to 3%, 1% to 3%, 1.1% to 3%, 1.2% to 3%, 1.3% to 3%, 1.4% to 3%, 1.5% to 3%, 1.6% to 3%, 1.7% to 3%, 1.8% to 3%, 1.9% to 3%, 2% to 3%, 2.1% to 3%, 2.2% to 3%, 2.3% to 3%, 2.4% to 3%, 2.5% to 3%, 2.6% to 3%, 2.7% to 3%, 2.8% to 3%, or 2.9% to 3%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise the electrolyte in a % (wt / wt) amount of about 0.5% to 2%, 0.6% to 2%, 0.7% to 2%, 0.8% to 2%, 0.9% to 2%, 1% to 2%, 1.1% to 2%, 1.2% to 2%, 1.3% to 2%, 1.4% to 2%, 1.5% to 2%, 1.6% to 2%, 1.7% to 2%, 1.8% to 2%, or 1.9% to 2%, wherein each range is inclusive.

[0086] In some embodiments, disclosed compositions comprise the electrolyte in a % (wt / wt) amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3%.

[0087] In preferred embodiments, the electrolyte is sodium chloride. In other preferred embodiments, sodium chloride is the only electrolyte in the composition. In some embodiments, 18 DMS_US.364752221.1disclosed compositions comprise sodium chloride in a % (wt / wt) amount of at least about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, or 3%. In some embodiments, disclosed compositions comprise sodium chloride in a % (wt / wt) amount of less than about 5%, 6%, 7%, 8%, 9%, or 10%.

[0088] In some embodiments, disclosed compositions comprise sodium chloride in a % (wt / wt) amount of about 0.5% to 3%, 0.6% to 3%, 0.7% to 3%, 0.8% to 3%, 0.9% to 3%, 1% to 3%, 1.1% to 3%, 1.2% to 3%, 1.3% to 3%, 1.4% to 3%, 1.5% to 3%, 1.6% to 3%, 1.7% to 3%, 1.8% to 3%, 1.9% to 3%, 2% to 3%, 2.1% to 3%, 2.2% to 3%, 2.3% to 3%, 2.4% to 3%, 2.5% to 3%, 2.6% to 3%, 2.7% to 3%, 2.8% to 3%, or 2.9% to 3%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise sodium chloride in a % (wt / wt) amount of about 0.5% to 2%, 0.6% to 2%, 0.7% to 2%, 0.8% to 2%, 0.9% to 2%, 1% to 2%, 1.1% to 2%, 1.2% to 2%, 1.3% to 2%, 1.4% to 2%, 1.5% to 2%, 1.6% to 2%, 1.7% to 2%, 1.8% to 2%, or 1.9% to 2%, wherein each range is inclusive.

[0089] In some embodiments, disclosed compositions comprise sodium chloride in a % (wt / wt) amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3%.

[0090] Replacement of salt and water through intravenous infusion of a sodium chloride solution is one treatment option proposed for patients with hypovolemic hyponatremia. For example, sodium chloride is permissible up to 3% NaCl in a peripheral vein to treat severe hyponatremia. In conditions of hyponatremia and low salt syndrome, sodium chloride for injection (23.4%) may be used to replenish lost water and salt in body.

[0091] However, the treatment may not be suitable for all hyponatremia patients. For example, Soiza & Talbot teach avoidance of salt tablets in most patients with euvolaemic and hypervolaemic hyponatraemia, as the resulting thirst and increased water intake and retention 19 DMS_US.364752221.1can worsen hyponatraemia (Soiza & Talbot, Ther Adv Drug Saf. 2011 Feb; 2(1): 9–17). Accordingly, preferred embodiments of disclosed compositions comprise sodium chloride in an % (wt / wt) amount of 3% or less, and more preferably 2% or less. Sodium chloride may also be used as an additive for total parenteral nutrition (TPN) and carbohydrate-containing IV fluids. Additionally, potassium chloride has been shown to treat hyponatremia. See, e.g., Laragh, J Clin Invest.1954 May;33(5):807-18 and Kamel & Bear, Am J Kidney Dis.1993 Apr;21(4):439-43.

[0092] Anti-Caking Agent

[0093] In some embodiments, disclosed compositions comprise an anti-caking agent. In some embodiments, the anti-caking agent comprises silica. In some embodiments, the anti- caking agent comprises a calcium salt. In preferred embodiments, the anti-caking agent is calcium silicate.

[0094] In some embodiments, disclosed compositions comprise the anti-caking agent in a % (wt / wt) amount of at least about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, or 4%. In some embodiments, disclosed compositions comprise the anti-caking agent in a % (wt / wt) amount of less than about 5%, 6%, 7%, 8%, 9%, or 10%.

[0095] In some embodiments, disclosed compositions comprise the anti-caking agent in a % (wt / wt) amount of about 0.5% to 4.5%, 0.6% to 4.5%, 0.7% to 4.5%, 0.8% to 4.5%, 0.9% to 4.5%, 1% to 4.5%, 1.1% to 4.5%, 1.2% to 4.5%, 1.3% to 4.5%, 1.4% to 4.5%, 1.5% to 4.5%, 1.6% to 4.5%, 1.7% to 4.5%, 1.8% to 4.5%, 1.9% to 4.5%, 2% to 4.5%, 2.1% to 4.5%, 2.2% to 4.5%, 2.3% to 4.5%, 2.4% to 4.5%, 2.5% to 4.5%, 2.6% to 4.5%, 2.7% to 4.5%, 2.8% to 4.5%, or 2.9% to 4.5%, wherein each range is inclusive.

[0096] In some embodiments, disclosed compositions comprise the anti-caking agent in a % (wt / wt) amount of about 0.5% to 4%%, 0.6% to 4%%, 0.7% to 4%%, 0.8% to 4%%, 0.9% to 20 DMS_US.364752221.14%%, 1% to 4%%, 1.1% to 4%%, 1.2% to 4%%, 1.3% to 4%%, 1.4% to 4%%, 1.5% to 4%%, 1.6% to 4%%, 1.7% to 4%%, 1.8% to 4%%, 1.9% to 4%%, 2% to 4%%, 2.1% to 4%%, 2.2% to 4%%, 2.3% to 4%%, 2.4% to 4%%, 2.5% to 4%%, 2.6% to 4%%, 2.7% to 4%%, 2.8% to 4%%, 2.9% to 4%, or 3% to 4%, wherein each range is inclusive.

[0097] In some embodiments, disclosed compositions comprise the anti-caking agent in a % (wt / wt) amount of about 0.5% to 3.5%, 0.6% to 3.5%, 0.7% to 3.5%, 0.8% to 3.5%, 0.9% to 3.5%, 1% to 3.5%, 1.1% to 3.5%, 1.2% to 3.5%, 1.3% to 3.5%, 1.4% to 3.5%, 1.5% to 3.5%, 1.6% to 3.5%, 1.7% to 3.5%, 1.8% to 3.5%, 1.9% to 3.5%, 2% to 3.5%, 2.1% to 3.5%, 2.2% to 3.5%, 2.3% to 3.5%, 2.4% to 3.5%, 2.5% to 3.5%, 2.6% to 3.5%, 2.7% to 3.5%, 2.8% to 3.5%, or 2.9% to 3.5%, wherein each range is inclusive.

[0098] In some embodiments, disclosed compositions comprise the anti-caking agent in a % (wt / wt) amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5%.

[0099] In preferred embodiments, the anti-caking agent is calcium silicate. In some embodiments, disclosed compositions comprise calcium silicate in a % (wt / wt) amount of at least about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, or 3%. In some embodiments, disclosed compositions comprise calcium silicate in a % (wt / wt) amount of less than about 5%, 6%, 7%, 8%, 9%, or 10%.

[0100] In some embodiments, disclosed compositions comprise calcium silicate in a % (wt / wt) amount of about 0.5% to 4.5%, 0.6% to 4.5%, 0.7% to 4.5%, 0.8% to 4.5%, 0.9% to 4.5%, 1% to 4.5%, 1.1% to 4.5%, 1.2% to 4.5%, 1.3% to 4.5%, 1.4% to 4.5%, 1.5% to 4.5%, 21 DMS_US.364752221.11.6% to 4.5%, 1.7% to 4.5%, 1.8% to 4.5%, 1.9% to 4.5%, 2% to 4.5%, 2.1% to 4.5%, 2.2% to 4.5%, 2.3% to 4.5%, 2.4% to 4.5%, 2.5% to 4.5%, 2.6% to 4.5%, 2.7% to 4.5%, 2.8% to 4.5%, or 2.9% to 4.5%, wherein each range is inclusive.

[0101] In some embodiments, disclosed compositions comprise calcium silicate in a % (wt / wt) amount of about 0.5% to 4%%, 0.6% to 4%%, 0.7% to 4%%, 0.8% to 4%%, 0.9% to 4%%, 1% to 4%%, 1.1% to 4%%, 1.2% to 4%%, 1.3% to 4%%, 1.4% to 4%%, 1.5% to 4%%, 1.6% to 4%%, 1.7% to 4%%, 1.8% to 4%%, 1.9% to 4%%, 2% to 4%%, 2.1% to 4%%, 2.2% to 4%%, 2.3% to 4%%, 2.4% to 4%%, 2.5% to 4%%, 2.6% to 4%%, 2.7% to 4%%, 2.8% to 4%%, 2.9% to 4%, or 3% to 4%, wherein each range is inclusive.

[0102] In some embodiments, disclosed compositions comprise calcium silicate in a % (wt / wt) amount of about 0.5% to 3.5%, 0.6% to 3.5%, 0.7% to 3.5%, 0.8% to 3.5%, 0.9% to 3.5%, 1% to 3.5%, 1.1% to 3.5%, 1.2% to 3.5%, 1.3% to 3.5%, 1.4% to 3.5%, 1.5% to 3.5%, 1.6% to 3.5%, 1.7% to 3.5%, 1.8% to 3.5%, 1.9% to 3.5%, 2% to 3.5%, 2.1% to 3.5%, 2.2% to 3.5%, 2.3% to 3.5%, 2.4% to 3.5%, 2.5% to 3.5%, 2.6% to 3.5%, 2.7% to 3.5%, 2.8% to 3.5%, or 2.9% to 3.5%, wherein each range is inclusive.

[0103] In some embodiments, disclosed compositions comprise calcium silicate in a % (wt / wt) amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5%.

[0104] In some embodiments, the anti-caking agent has a peak particle diameter size of greater than about 5 µm, 7 µm, 10 µm, 15 µm, 20 µm, 25 µm, 30 µm, 35 µm, 40 µm, or 45 µm. 22 DMS_US.364752221.1In some embodiments, the anti-caking agent has peak particle diameter size of less than about 75 µm, 80 µm, 85 µm, 90 µm, 95 µm, or 100 µm.

[0105] In some embodiments, the anti-caking agent has a peak particle diameter size within range from about 10 µm to 200 µm, 15 µm to 200 µm, 20 µm to 200 µm, 25 µm to 200 µm, 30 µm to 200 µm, 35 µm to 200 µm, 40 µm to 200 µm, 45 µm to 200 µm, 50 µm to 200 µm, 55 µm to 200, 60 µm to 200 µm, 65 µm to 200 µm, 70 µm to 200 µm, 75 µm to 200 µm, 80 µm to 200 µm, 85 µm to 200 µm, 90 µm to 200 µm, 95 µm to 200 µm, or 100 µm to 200 µm, wherein each range is inclusive.

[0106] In some embodiments, the anti-caking agent has a peak particle diameter size within range from about 10 µm to 100 µm, 15 µm to 100 µm, 20 µm to 100 µm, 25 µm to 100 µm, 30 µm to 100 µm, 35 µm to 100 µm, 40 µm to 100 µm, 45 µm to 100 µm, 50 µm to 100 µm, 55 µm to 100, 60 µm to 100 µm, 65 µm to 100 µm, 70 µm to 100 µm, 75 µm to 100 µm, 80 µm to 100 µm, 85 µm to 100 µm, 90 µm to 100 µm, or 95 µm to 100 µm, wherein each range is inclusive.

[0107] In some embodiments, the anti-caking agent has a peak particle diameter size of about 7 µm, 8 µm, 9 µm, 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm, 17 µm, 18 µm, 19 µm, 20 µm, 21 µm, 22 µm, 23 µm, 24 µm, 25 µm, 26 µm, 27 µm, 28 µm, 29 µm, 30 µm, 31 µm, 32 µm, 33 µm, 34 µm, 35 µm, 36 µm, 37 µm, 38 µm, 39 µm, 40 µm, 41 µm, 42 µm, 43 µm, 44 µm, 45 µm, 46 µm, 47 µm, 48 µm, 49 µm, 50 µm, 51 µm, 52 µm, 53 µm, 54 µm, 55 µm, 56 µm, 57 µm, 58 µm, 59 µm, 60 µm, 61 µm, 62 µm, 63 µm, 64 µm, 65 µm, 66 µm, 67 µm, 68 µm, 69 µm, 70 µm, 71 µm, 72 µm, 73 µm, 74 µm, 75 µm, 76 µm, 77 µm, 78 µm, 79 µm, or 80 µm.

[0108] In some embodiments, calcium silicate in a disclosed composition has a peak particle diameter size of greater than 5 µm, 7 µm, 10 µm, 15 µm, 20 µm, 25 µm, 30 µm, 35 µm, 40 µm, 23 DMS_US.364752221.1or 45 µm. In some embodiments, the anti-caking agent has a particle size distribution where the peak value of particle diameter is less than about 75 µm, 80 µm, 85 µm, 90 µm, 95 µm, or 100 µm.

[0109] In some embodiments, calcium silicate in a disclosed composition has a peak particle diameter size within range from about 10 µm to 200 µm, 15 µm to 200 µm, 20 µm to 200 µm, 25 µm to 200 µm, 30 µm to 200 µm, 35 µm to 200 µm, 40 µm to 200 µm, 45 µm to 200 µm, 50 µm to 200 µm, 55 µm to 200, 60 µm to 200 µm, 65 µm to 200 µm, 70 µm to 200 µm, 75 µm to 200 µm, 80 µm to 200 µm, 85 µm to 200 µm, 90 µm to 200 µm, 95 µm to 200 µm, or 100 µm to 200 µm, wherein each range is inclusive.

[0110] In some embodiments, calcium silicate in a disclosed composition has a peak particle diameter size within range from about 10 µm to 100 µm, 15 µm to 100 µm, 20 µm to 100 µm, 25 µm to 100 µm, 30 µm to 100 µm, 35 µm to 100 µm, 40 µm to 100 µm, 45 µm to 100 µm, 50 µm to 100 µm, 55 µm to 100, 60 µm to 100 µm, 65 µm to 100 µm, 70 µm to 100 µm, 75 µm to 100 µm, 80 µm to 100 µm, 85 µm to 100 µm, 90 µm to 100 µm, or 95 µm to 100 µm, wherein each range is inclusive.

[0111] In some embodiments, calcium silicate in a disclosed composition has a peak particle diameter size of about 7 µm, 8 µm, 9 µm, 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm, 17 µm, 18 µm, 19 µm, 20 µm, 21 µm, 22 µm, 23 µm, 24 µm, 25 µm, 26 µm, 27 µm, 28 µm, 29 µm, 30 µm, 31 µm, 32 µm, 33 µm, 34 µm, 35 µm, 36 µm, 37 µm, 38 µm, 39 µm, 40 µm, 41 µm, 42 µm, 43 µm, 44 µm, 45 µm, 46 µm, 47 µm, 48 µm, 49 µm, 50 µm, 51 µm, 52 µm, 53 µm, 54 µm, 55 µm, 56 µm, 57 µm, 58 µm, 59 µm, 60 µm, 61 µm, 62 µm, 63 µm, 64 µm, 65 µm, 66 µm, 24 DMS_US.364752221.167 µm, 68 µm, 69 µm, 70 µm, 71 µm, 72 µm, 73 µm, 74 µm, 75 µm, 76 µm, 77 µm, 78 µm, 79 µm, or 80 µm.

[0112] Calcium silicate (Ca2SiO4) is a pharmaceutical anti-caking agent derived from limestone. In optimal levels and particle size, it absorbs moisture and allows products to flow freely during the manufacturing process. For example, US20210100743A1 notes that appropriate selection of calcium silicate is important to avoid clumping. Calcium silicate particles having an average diameter between 3.0 and 7.0 microns are noted as preferred, and more preferably between 4.0 and 6.0 microns, as particles larger than the upper end of these ranges are described as needing more time to disperse or dissolve in water, whereas particles below the lower end of the ranges are taught to contribute to powder clumping. Use of calcium silicate particle sizes above the thresholds taught in US20210100743A1, such as 200 mesh or 74 µm, and subsequent ultrasonication, contributed to favorable pharmaceutical properties of the edible urea compositions described herein. See, e.g., analysis of an exemplary edible urea composition, including powder texture, in Example 4 herein.

[0113] Flavoring Agent

[0114] In some embodiments, disclosed compositions comprise a flavoring agent. In some embodiments, the flavoring agent has a sweet flavor, a salty flavor, a sour flavor, a bitter flavor, or any combination thereof. In some embodiments, the flavoring agent has a fruit flavor and / or a fruity odor. In some embodiments, the fruit flavor is apple, banana, blueberry, cherry, grape, lemon, lime, orange, pineapple, peach, raspberry, strawberry, tangerine, or any combination thereof.

[0115] In some embodiments, the flavoring agent has a vanilla flavor, a caramel flavor, a chocolate flavor, a clove flavor, a coffee flavor, a cotton candy flavor, a honey flavor, a licorice 25 DMS_US.364752221.1flavor, a mint flavor, a peppermint flavor, a spearmint flavor, a tea flavor, a green tea flavor, a black tea flavor , a chai tea flavor, a matcha flavor, a chamomile tea flavor, a vinegar flavor, an apple cider vinegar flavor, or any combination thereof. In some embodiments, the flavoring agent has a vanilla flavor. In some embodiments, the flavoring agent has a chocolate flavor. Alternative or additional flavoring agents which may be used in disclosed compositions are described in, e.g., US20130252985A1, US20140127370A1, US20020182270A1, US20060249167A1, US20040151815A1, and US20080233056A1.

[0116] In preferred embodiments, the flavoring agent has a strawberry flavor. In preferred embodiments, the flavoring agent with a strawberry flavor is ethyl phenylglycidate (ethyl 3- phenylglycidate) or ethyl methylphenylglycidate.

[0117] In some embodiments, disclosed compositions comprise the flavoring agent in a % (wt / wt) amount of at least about 0.5%, 1%, 2%, 3%, 4%, or 5%. In some embodiments, disclosed compositions comprise the flavoring agent in a % (wt / wt) amount of less than about 5%, 6%, 7%, 8%, 9% or 10%.

[0118] In some embodiments, disclosed compositions comprise the flavoring agent in a % (wt / wt) amount of 0.1% to 8%, 0.5% to 8%, 1% to 8%, 1.5% to 8%, 2% to 8%, 2.5% to 8%, 3% to 8%, 3.5% to 8%, 4% to 8%, 4.5% to 8%, 5% to 8%, 5.5% to 8%, 6% to 8%, 6.5% to 8%, 7% to 8%, or 7.5% to 8%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise the flavoring agent in a % (wt / wt) amount of about 0.1% to 5%, 0.5% to 5%, 1% to 5%, 1.5% to 5%, 2% to 5%, 2.5% to 5%, 3% to 5%, 3.5% to 5%, 4% to 5%, or 4.5% to 5%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise the flavoring agent in a % (wt / wt) amount of 0.1% to 4.5%, 0.5% to 4.5%, 1% to 4.5%, 1.5% to 26 DMS_US.364752221.14.5%, 2% to 4.5%, 2.5% to 4.5%, 3% to 4.5%, 3.5% to 4.5%, or 4% to 4.5%, wherein each range is inclusive.

[0119] In some embodiments, disclosed compositions comprise the flavoring agent in a % (wt / wt) amount of about 0.5 %, 0.6 %, 0.7 %, 0.8 %, 0.9 %, 1 %, 1.1 %, 1.2 %, 1.3 %, 1.4 %, 1.5 %, 1.6 %, 1.7 %, 1.8 %, 1.9 %, 2 %, 2.1 %, 2.2 %, 2.3 %, 2.4 %, 2.5 %, 2.6 %, 2.7 %, 2.8 %, 2.9 %, 3 %, 3.1 %, 3.2 %, 3.3 %, 3.4 %, 3.5 %, 3.6 %, 3.7 %, 3.8 %, 3.9 %, 4 %, 4.1 %, 4.2 %, 4.3 %, 4.4 %, 4.5 %, 4.6 %, 4.7 %, 4.8 %, 4.9 %, or 5 %.

[0120] In preferred embodiments, disclosed compositions comprise ethyl phenylglycidate (ethyl 3-phenylglycidate) and / or ethyl methylphenylglycidate. In some embodiments, disclosed compositions comprise ethyl phenylglycidate (ethyl 3-phenylglycidate) and / or ethyl methylphenylglycidate in a % (wt / wt) amount of at least about 0.5%, 1%, 2%, 3%, 4%, or 5%. In some embodiments, disclosed compositions comprise ethyl phenylglycidate (ethyl 3- phenylglycidate) and / or ethyl methylphenylglycidate in a % (wt / wt) amount of less than about 5%, 6%, 7%, 8%, 9% or 10%.

[0121] In some embodiments, disclosed compositions comprise ethyl phenylglycidate (ethyl 3-phenylglycidate) and / or ethyl methylphenylglycidate in a % (wt / wt) amount of 0.1% to 8%, 0.5% to 8%, 1% to 8%, 1.5% to 8%, 2% to 8%, 2.5% to 8%, 3% to 8%, 3.5% to 8%, 4% to 8%, 4.5% to 8%, 5% to 8%, 5.5% to 8%, 6% to 8%, 6.5% to 8%, 7% to 8%, or 7.5% to 8%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise ethyl phenylglycidate (ethyl 3-phenylglycidate) and / or ethyl methylphenylglycidate in a % (wt / wt) amount of 0.1% to 5%, 0.5% to 5%, 1% to 5%, 1.5% to 5%, 2% to 5%, 2.5% to 5%, 3% to 5%, 3.5% to 5%, 4% to 5%, or 4.5% to 5%, wherein each range is inclusive. In some embodiments, disclosed compositions comprise ethyl phenylglycidate (ethyl 3-phenylglycidate) and / or ethyl 27 DMS_US.364752221.1methylphenylglycidate in a % (wt / wt) amount of 0.1% to 4.5%, 0.5% to 4.5%, 1% to 4.5%, 1.5% to 4.5%, 2% to 4.5%, 2.5% to 4.5%, 3% to 4.5%, 3.5% to 4.5%, or 4% to 4.5%, wherein each range is inclusive.

[0122] In some embodiments, disclosed compositions comprise ethyl phenylglycidate (ethyl 3-phenylglycidate) and / or ethyl methylphenylglycidate in a % (wt / wt) amount of about 0.5 %, 0.6 %, 0.7 %, 0.8 %, 0.9 %, 1 %, 1.1 %, 1.2 %, 1.3 %, 1.4 %, 1.5 %, 1.6 %, 1.7 %, 1.8 %, 1.9 %, 2 %, 2.1 %, 2.2 %, 2.3 %, 2.4 %, 2.5 %, 2.6 %, 2.7 %, 2.8 %, 2.9 %, 3 %, 3.1 %, 3.2 %, 3.3 %, 3.4 %, 3.5 %, 3.6 %, 3.7 %, 3.8 %, 3.9 %, 4 %, 4.1 %, 4.2 %, 4.3 %, 4.4 %, 4.5 %, 4.6 %, 4.7 %, 4.8 %, 4.9 %, or 5 %.

[0123] The term “flavor” describes the taste of any particular food or drink, and the sensation of taste, such as a chemical sense, can be expressed by the sensation an individual feels upon tasting the flavor. Four fundamental sensations of taste have been described: sweet, salty, sour, and bitter. See, e.g., Sohi et al., Drug Dev Ind Pharm. 2004 May;30(5):429-48 Organoleptic properties, such as product appearance, smell and texture may affect medication adherence (Kardas & Muras, Wiad. Lek. 2005;58:15–20). Taste-masking strategies, e.g., to reduce bitterness, are described in, e.g., Coupland & Hayes, Pharm Res.2014 Nov; 31(11): 2921–2939 and Menella & Beauchamp, Clin Ther. 2008 Nov; 30(11): 2120–2132. Flavoring agents may be used in pharmaceutical products to impart salty, sour, bitter, and sweet flavors to a formulation. In some examples, low-molecular-weight volatile compounds generated during ripening of a fruit, e.g., esters, lactones, aldehydes, and furanones, can contribute to strawberry aroma and flavor (Fan et al., Hortic Res.2021 Apr 1;8(1):66).

[0124] Unit Dosage Form 28 DMS_US.364752221.1

[0125] In some aspects, provided herein are unit dosage forms of edible urea. In some embodiments, disclosed compositions comprise urea, an antioxidant, a sweetener, an antacid, and a salt, such as sodium chloride.

[0126] In some embodiments, the total weight of ingredients in the unit dosage form is less than 19 g, 20 g, 21 g, 22 g, 23 g, 24 g, or 25 g. In some embodiments, the total weight of ingredients in the unit dosage form ranges from about 17 g to 25 g, 18 g to 22 g, 19 g to 22 g, 20 g to 22 g, or 21 g to 22 g, wherein each range is inclusive. In some embodiments, the total weight of ingredients in the unit dosage form is about 18.6 g, 18.7 g, 18.8 g, 18.9 g, 19.0 g, 19.1 g, 19.2 g, 19.3 g, 19.4 g, 19.5 g, 19.6 g, 19.7 g, 19.8 g, 19.9 g, 20.0 g, 20.1 g, 20.2 g, 20.3 g, 20.4 g, 20.5 g, 20.6 g, 20.7 g, 20.8 g, 20.9 g, 21.0 g, 21.1 g, 21.2 g, 21.3 g, 21.4 g, 21.5 g, 21.6 g, 21.7 g, 21.8 g, 21.9 g, 22.0 g, 22.1 g, 22.2 g, 22.3 g, 22.4 g, 22.5 g, 22.6 g, 22.7 g, 22.8 g, 22.9 g, 23.0 g, 23.1 g, 23.2 g, 23.3 g, 23.4 g, 23.5 g, 23.6 g, 23.7 g, 23.8 g, 23.9 g, 24.0 g, 24.1 g, 24.2 g, 24.3 g, 24.4 g, 24.5 g, 24.6 g, 24.7 g, 24.8 g, 24.9 g, or 25.0 g. In preferred embodiments, the total weight of ingredients in the unit dosage form is about 20.0 grams.

[0127] In some embodiments, the unit dosage form is a powder mixture that is suitable for dissolution in a liquid, e.g., water, fruit juice, or other beverage, prior to administration to a subject in need thereof, such as a subject suffering from hyponatremia. In some embodiments, the powder mixture is dissolved in a volume of liquid, e.g., water, that is at least 40 ml, 50 ml, 60 ml, 70 ml, or 80 ml. In some embodiments, the powder mixture is dissolved in a volume of liquid, e.g., water, that is less than 100 ml, 120 ml, 140 ml, 160 ml, 180 ml, or 200 ml. In some embodiments, the powder mixture is dissolved in a volume of liquid, e.g., water, that is about 60 ml, 65 ml, 70 ml, 75 ml, 80 ml, 85 ml, 90 ml, 95 ml, or 100 ml. In preferred embodiments, the powder mixture is dissolved in 80 ml of water. 29 DMS_US.364752221.1

[0128] In some examples, the powder mixture unit dosage form is dissolved in 80 ml water. The presence of water-soluble ingredients in the unit dosage form, like ascorbic acid, sodium bicarbonate and sodium chloride, facilitate quick dissolution. In comparison to commercially available edible urea formulations, the minimum volume of liquid needed for dissolution is reduced by 20%. This reduced volume is advantageous in the treatment of certain subjects suffering from hyponatremia, specifically those with hypervolemia, where water restriction, e.g., to volumes of less than 1.25 L / d, is essential (Yeates et al., CMAJ. 2004 Feb 3; 170(3): 365– 369).

[0129] In some embodiments, the unit dosage form is a powder mixture that is suitable for addition to a food colloid, e.g., dairy products, pudding, and other foods one of skill in the art would recognize as suitable for administration to a subject.

[0130] Unit Dosage Form Ingredients

[0131] In some embodiments, disclosed compositions comprise a unit dosage form comprising urea in an amount that is greater than 10, 11, 12, 13, 14, 15, 16, 17, or 18 grams. In some embodiments, disclosed compositions comprise urea in an amount that is less than 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 grams. In some embodiments, disclosed compositions comprise urea in an amount of 10 to 20 grams, 11 to 19 grams, 12 to 18 grams, 13 to 17 grams, or 14 to 16 grams. In some embodiments, disclosed compositions comprise urea in an amount of 15 to 20 grams, 15 to 19 grams, 15 to 18 grams, or 15 to 17 grams.

[0132] In some embodiments, disclosed unit dosage forms comprise urea in an amount of 15.60 to 16.05, 15.61 to 16.05, 15.62 to 16.05, 15.63 to 16.05, or 15.64 to 16.05 g. In some embodiments, disclosed unit dosage forms comprise urea in an amount of 15.60 to 16.04, 15.61 to 16.04, 15.62 to 16.04, 15.63 to 16.04, 15.64 to 16.04, or 15.65 g to 16.04 g, wherein each 30 DMS_US.364752221.1range is inclusive. In some embodiments, disclosed compositions comprise urea in an amount of 15.60 to 16.03, 15.61 to 16.03, 15.62 to 16.03, 15.63 to 16.03, 15.64 to 16.03, or 15.65 g to 16.03 g, wherein each range is inclusive.

[0133] In some embodiments, disclosed unit dosage forms comprise a unit dosage form comprising the antioxidant in an amount of at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 g. In some embodiments, disclosed unit dosage forms comprise the antioxidant in an amount of less than 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 g. In some embodiments, disclosed unit dosage forms comprise the antioxidant in an amount of 1.5 g to 2.5 g, 1.6 to 2.5 g, 1.7 g to 2.5 g, 1.8 g to 2.5 g, 1.9 g to 2.5 g, 2.0 g to 2.5 g, 2.1 g to 2.5 g, 2.2 g to 2.5 g, 2.3 g to 2.5 g, or 2.4 g to 2.5 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the antioxidant in an amount of 1.5 g to 2.4 g, 1.6 to 2.4 g, 1.7 g to 2.4 g, 1.8 g to 2.4 g, 1.9 g to 2.4 g, 2.0 g to 2.4 g, 2.1 g to 2.4 g, 2.2 g to 2.4 g, or 2.3 g to 2.4 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the antioxidant in an amount of 1.5 g to 2.3 g, 1.6 to 2.3 g, 1.7 g to 2.3 g, 1.8 g to 2.3 g, 1.9 g to 2.3 g, 2.0 g to 2.3 g, 2.1 g to 2.3 g, or 2.2 g to 2.3 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the antioxidant in an amount of 1.5 g to 2.2 g, 1.6 to 2.2 g, 1.7 g to 2.2 g, 1.8 g to 2.2 g, 1.9 g to 2.2 g, 2.0 g to 2.2 g, or 2.1 g to 2.2 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the antioxidant in an amount of 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 g.

[0134] In preferred embodiments, the antioxidant is ascorbic acid. In some embodiments, disclosed unit dosage forms comprise a unit dosage form comprising ascorbic acid in an amount of at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 grams. In 31 DMS_US.364752221.1some embodiments, disclosed unit dosage forms comprise ascorbic acid in an amount of less than 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 grams. In some embodiments, disclosed unit dosage forms comprise ascorbic acid in an amount of 1.5 g to 2.5 g, 1.6 to 2.5 g, 1.7 g to 2.5 g, 1.8 g to 2.5 g, 1.9 g to 2.5 g, 2.0 g to 2.5 g, 2.1 g to 2.5 g, 2.2 g to 2.5 g, 2.3 g to 2.5 g, or 2.4 g to 2.5 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise ascorbic acid in an amount of 1.5 g to 2.4 g, 1.6 to 2.4 g, 1.7 g to 2.4 g, 1.8 g to 2.4 g, 1.9 g to 2.4 g, 2.0 g to 2.4 g, 2.1 g to 2.4 g, 2.2 g to 2.4 g, or 2.3 g to 2.4 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise ascorbic acid in an amount of 1.5 g to 2.3 g, 1.6 to 2.3 g, 1.7 g to 2.3 g, 1.8 g to 2.3 g, 1.9 g to 2.3 g, 2.0 g to 2.3 g, 2.1 g to 2.3 g, or 2.2 g to 2.3 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise ascorbic acid in an amount of 1.5 g to 2.2 g, 1.6 to 2.2 g, 1.7 g to 2.2 g, 1.8 g to 2.2 g, 1.9 g to 2.2 g, 2.0 g to 2.2 g, or 2.1 g to 2.2 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise ascorbic acid in an amount of 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2.0 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, or 2.5 g.

[0135] In some embodiments, disclosed unit dosage forms comprise the sweetener in an amount of about 0.1 g to 2 g, 0.2 g to 2 g, 0.3 g to 2 g, 0.4 g to 2 g, 0.5 g to 2 g, 0.6 g to 2 g, 0.7 g to 2 g, 0.8 g to 2 g, 0.9 g to 2 g, 1.0 g to 2 g, 1.1 g to 2 g, 1.2 g to 2 g, 1.3 g to 2 g, 1.4 g to 2 g, 1.5 g to 2g, 1.6 g to 2 g, 1.7 g to 2 g, 1.8 g to 2 g, 1.9 g, to 2 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the sweetener in an amount of about 0.1 g to 1.5 g, 0.2 g to 1.5 g, 0.3 g to 1.5 g, 0.4 g to 1.5 g, 0.5 g to 1.5 g, 0.6 g to 1.5 g, 0.7 g to 1.5 g, 0.8 g to 1.5 g, 0.9 g to 1.5 g, 1.0 g to 1.5 g, 1.1 g to 1.5 g, 1.2 g to 1.5 g, 1.3 g to 1.5 g, or 1.4 g to 1.5 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the sweetener in an amount of about 0.1 g to 1.0 g, 0.2 g to 1.0 g, 0.3 g to 1.0 g, 32 DMS_US.364752221.10.4 g to 1.0 g, 0.5 g to 1.0 g, 0.6 g to 1.0 g, 0.7 g to 1.0 g, 0.8 g to 1.0 g, or 0.9 g to 1.0 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the sweetener in an amount of at least 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1.0 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, or 1.5 g.

[0136] In preferred embodiments, disclosed unit dosage forms comprise the sweetener aspartame. In some embodiments, disclosed compositions comprise a unit dosage form comprising aspartame in an amount of at least 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, or 1.5 g. In some embodiments, disclosed compositions comprise a unit dosage form comprising aspartame in an amount of at least 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, or 1.5 g.

[0137] In some embodiments, disclosed unit dosage forms comprise an antacid. In some embodiments, the antacid comprises a bicarbonate, such as calcium bicarbonate, potassium bicarbonate, or sodium bicarbonate, a carbonate, such as calcium carbonate or magnesium carbonate, a hydroxide, such as aluminum hydroxide or magnesium hydroxide, an aluminum– magnesium complex, such as almasilate, hydrotalcite, or magaldrate, an aluminum saccharide combination, such as sucralfate, sodium hydrogen carbonate, aluminum hydroxide, or other antacid agents, such as aluminum phosphate, algeldrate, or magnesium trisilicate, or any combination thereof. In preferred embodiments, the antacid is sodium bicarbonate.

[0138] In some embodiments, disclosed unit dosage forms comprise the antacid in an amount of at least about 0.05 g, 0.1g, 0.15g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, or 0.5 g. In some embodiments, disclosed unit dosage forms comprise the antacid in an amount of less than about 0.5 g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, or 1g. In some embodiments, disclosed unit dosage forms comprise the antacid in an amount of 0.10 g to 0.54 g, 33 DMS_US.364752221.10.12 g to 0.52 g, 0.14 g to 0.50 g, 0.16 g to 0.48 g, 0.18 g to 0.46 g, 0.20 to 0.44 g, or 0.22 g to 0.42 g. In some embodiments, disclosed unit dosage forms comprise the antacid in an amount of about 0.1g, 0.12g, 0.14g, 0.16g, 0.18g, 0.2g, 0.22g, 0.24g, 0.26g, 0.28g, 0.3g, 0.32g, 0.34g, 0.36g, 0.38g, 0.4g, 0.42g, 0.44g, 0.46g, 0.48g, 0.5g.

[0139] In preferred embodiments, disclosed unit dosage forms comprise the antacid sodium bicarbonate. In some embodiments, disclosed unit dosage forms comprise sodium bicarbonate in an amount of at least about 0.05 g, 0.1g, 0.15g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, or 0.5 g. In some embodiments, disclosed unit dosage forms comprise sodium bicarbonate in an amount of less than about 0.5 g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, or 1g. In some embodiments, disclosed unit dosage forms comprise sodium bicarbonate in an amount of about 0.10 g to 0.54 g, 0.12 g to 0.52 g, 0.14 g to 0.50 g, 0.16 g to 0.48 g, 0.18 g to 0.46 g, 0.20 to 0.44 g, or 0.22 g to 0.42 g. In some embodiments, disclosed unit dosage forms comprise sodium bicarbonate in an amount of about 0.1g, 0.12g, 0.14g, 0.16g, 0.18g, 0.2g, 0.22g, 0.24g, 0.26g, 0.28g, 0.3g, 0.32g, 0.34g, 0.36g, 0.38g, 0.4g, 0.42g, 0.44g, 0.46g, 0.48g, or 0.5g.

[0140] In preferred embodiments, disclosed unit dosage forms comprise an electrolyte. In some embodiments, the electrolyte comprises sodium or potassium. In some embodiments, the electrolyte is sodium chloride, potassium chloride, or a combination thereof. In preferred embodiments, the electrolyte is sodium chloride.

[0141] In some embodiments, disclosed unit dosage forms comprise the electrolyte in an amount of at least 0.1g, 0.2g, 0.3g, 0.4g, or 0.5g. In some embodiments, disclosed unit dosage forms comprise the electrolyte in an amount of less than 0.4g, 0.5g, 0.6g, 0.7g, 0.8g, 0.9g, or 1g.

[0142] In some embodiments, disclosed unit dosage forms comprise the electrolyte in an amount of 0.1g to 0.50 g, 0.15g to 0.50 g, 0.2g to 0.50 g, 0.25g to 0.50 g, 0.3g to 0.50 g, 0.35g to 34 DMS_US.364752221.10.50 g, 0.4g to 0.50 g, or 0.45g to 0.50 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the electrolyte in an amount of about 0.1g to 0.45 g, 0.15g to 0.45 g, 0.2g to 0.45 g, 0.25g to 0.45 g, 0.3g to 0.45 g, 0.35g to 0.45 g, 0.4g to 0.45 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the electrolyte in an amount of about 0.1g to 0.40 g, 0.15g to 0.40 g, 0.2g to 0.40 g, 0.25g to 0.40 g, 0.3g to 0.40 g, 0.35g to 0.40 g, 0.4g to 0.40 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the electrolyte in an amount of about 0.1g to 0.35 g, 0.15g to 0.35 g, 0.2g to 0.35 g, 0.25g to 0.35 g, or 0.3g to 0.35 g, wherein each range is inclusive.

[0143] In some embodiments, disclosed unit dosage forms comprise the electrolyte in an amount of about 0.15g, 0.16g, 0.17g, 0.18g, 0.19g, 0.2g, 0.21g, 0.22g, 0.23g, 0.24g, 0.25g, 0.26g, 0.27g, 0.28g, 0.29g, 0.3g, 0.31g, 0.32g, 0.33g, 0.34g, 0.35g, 0.36g, 0.37g, 0.38g, 0.39g, 0.4g, 0.41g, 0.42g, 0.43g, 0.44g, 0.45g, 0.46g, 0.47g, 0.48g, 0.49g, or 0.5g.

[0144] In preferred embodiments, disclosed unit dosage forms comprise the electrolyte sodium chloride. In some embodiments, disclosed unit dosage forms comprise sodium chloride in an amount of at least 0.1g, 0.2g, 0.3g, 0.4g, or 0.5g. In some embodiments, disclosed unit dosage forms comprise sodium chloride in an amount of less than 0.4g, 0.5g, 0.6g, 0.7g, 0.8g, 0.9g, or 1g.

[0145] In some embodiments, disclosed unit dosage forms comprise sodium chloride in an amount of 0.1g to 0.50 g, 0.15g to 0.50 g, 0.2g to 0.50 g, 0.25g to 0.50 g, 0.3g to 0.50 g, 0.35g to 0.50 g, 0.4g to 0.50 g, or 0.45g to 0.50 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise sodium chloride in an amount of about 0.1g to 0.45 g, 0.15g to 0.45 g, 0.2g to 0.45 g, 0.25g to 0.45 g, 0.3g to 0.45 g, 0.35g to 0.45 g, 0.4g to 0.45 g, 35 DMS_US.364752221.1wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise sodium chloride in an amount of about 0.1g to 0.40 g, 0.15g to 0.40 g, 0.2g to 0.40 g, 0.25g to 0.40 g, 0.3g to 0.40 g, 0.35g to 0.40 g, 0.4g to 0.40 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise sodium chloride in an amount of about 0.1g to 0.35 g, 0.15g to 0.35 g, 0.2g to 0.35 g, 0.25g to 0.35 g, or 0.3g to 0.35 g, wherein each range is inclusive.

[0146] In some embodiments, disclosed unit dosage forms comprise sodium chloride in an amount of about 0.15g, 0.16g, 0.17g, 0.18g, 0.19g, 0.2g, 0.21g, 0.22g, 0.23g, 0.24g, 0.25g, 0.26g, 0.27g, 0.28g, 0.29g, 0.3g, 0.31g, 0.32g, 0.33g, 0.34g, 0.35g, 0.36g, 0.37g, 0.38g, 0.39g, 0.4g, 0.41g, 0.42g, 0.43g, 0.44g, 0.45g, 0.46g, 0.47g, 0.48g, 0.49g, or 0.5g.

[0147] In some embodiments, disclosed unit dosage forms comprise an anti-caking agent. In some embodiments, the anti-caking agent comprises silica. In some embodiments, the anti- caking agent comprises a calcium salt. In preferred embodiments, the anti-caking agent is calcium silicate.

[0148] In some embodiments, disclosed unit dosage forms comprise the anti-caking agent in an amount of at least about 0.1g, 0.2g, 0.3g, 0.4g, or 0.5g. In some embodiments, disclosed unit dosage forms comprise the anti-caking agent in an amount of less than about 0.8 g, 0.9 g, 1.0 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, or 1.5 g.

[0149] In some embodiments, disclosed unit dosage forms comprise the anti-caking agent in an amount of about 0.1 g to 0.9 g, 0.2 g to 0.9 g, 0.3 g to 0.9 g, 0.4 g to 0.9 g, 0.5 g to 0.9 g, 0.6 g to 0.9 g, or 0.7 g to 0.9 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise the anti-caking agent in an amount of about 0.1 g to 0.8 g, 0.2 g to 0.8 g, 36 DMS_US.364752221.10.3 g to 0.8 g, 0.4 g to 0.8 g, 0.5 g to 0.8 g, 0.6 g to 0.8 g, or 0.7 g to 0.8 g, wherein each range is inclusive.

[0150] In some embodiments, disclosed unit dosage forms comprise the anti-caking agent in an amount of about 0.1 g, 0.2 g, 0.3 g, 0.4g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, or 1 g. In some embodiments, disclosed unit dosage forms comprise the anti-caking agent in an amount of about 0.25 g, 0.26 g, 0.27 g, 0.28 g, 0.29 g, 0.3 g, 0.31 g, 0.32 g, 0.33 g, 0.34 g, 0.35 g, 0.36 g, 0.37 g, 0.38 g, 0.39 g, 0.4 g, 0.41 g, 0.42 g, 0.43 g, 0.44 g, 0.45 g, 0.46 g, 0.47 g, 0.48 g, 0.49 g, 0.5 g, 0.51 g, 0.52 g, 0.53 g, 0.54 g, 0.55 g, 0.56 g, 0.57 g, 0.58 g, 0.59 g, 0.6 g, 0.61 g, 0.62 g, 0.63 g, 0.64 g, 0.65 g, 0.66 g, 0.67 g, 0.68 g, 0.69 g, 0.7 g, 0.71 g, 0.72 g, 0.73 g, 0.74 g, 0.75 g, 0.76 g, 0.77 g, 0.78 g, 0.79 g, or 0.8 g.

[0151] In preferred embodiments, the anti-caking agent is calcium silicate. In some embodiments, disclosed unit dosage forms comprise calcium silicate in an amount of at least about 0.1g, 0.2g, 0.3g, 0.4g, or 0.5g. In some embodiments, disclosed unit dosage forms comprise calcium silicate in an amount of less than about 0.8 g, 0.9 g, 1.0 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, or 1.5 g.

[0152] In some embodiments, disclosed unit dosage forms comprise calcium silicate in an amount of about 0.1 g to 0.9 g, 0.2 g to 0.9 g, 0.3 g to 0.9 g, 0.4 g to 0.9 g, 0.5 g to 0.9 g, 0.6 g to 0.9 g, or 0.7 g to 0.9 g, wherein each range is inclusive. In some embodiments, disclosed unit dosage forms comprise calcium silicate in an amount of about 0.1 g to 0.8 g, 0.2 g to 0.8 g, 0.3 g to 0.8 g, 0.4 g to 0.8 g, 0.5 g to 0.8 g, 0.6 g to 0.8 g, or 0.7 g to 0.8 g, wherein each range is inclusive.

[0153] In some embodiments, disclosed unit dosage forms comprise calcium silicate in an amount of about 0.1 g, 0.2 g, 0.3 g, 0.4g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, or 1 g. In some 37 DMS_US.364752221.1embodiments, disclosed unit dosage forms comprise calcium silicate in an amount of about 0.25 g, 0.26 g, 0.27 g, 0.28 g, 0.29 g, 0.3 g, 0.31 g, 0.32 g, 0.33 g, 0.34 g, 0.35 g, 0.36 g, 0.37 g, 0.38 g, 0.39 g, 0.4 g, 0.41 g, 0.42 g, 0.43 g, 0.44 g, 0.45 g, 0.46 g, 0.47 g, 0.48 g, 0.49 g, 0.5 g, 0.51 g, 0.52 g, 0.53 g, 0.54 g, 0.55 g, 0.56 g, 0.57 g, 0.58 g, 0.59 g, 0.6 g, 0.61 g, 0.62 g, 0.63 g, 0.64 g, 0.65 g, 0.66 g, 0.67 g, 0.68 g, 0.69 g, 0.7 g, 0.71 g, 0.72 g, 0.73 g, 0.74 g, 0.75 g, 0.76 g, 0.77 g, 0.78 g, 0.79 g, or 0.8 g.

[0154] In some embodiments, disclosed unit dosage forms comprise a flavoring agent. n some embodiments, disclosed unit dosage forms comprise a flavoring agent having a sweet flavor, a salty flavor, a sour flavor, a bitter flavor, or any combination thereof. In some embodiments, the flavoring agent has a fruit flavor and / or a fruity odor. In some embodiments, the fruit flavor is apple, banana, blueberry, cherry, grape, lemon, lime, orange, pineapple, peach, raspberry, strawberry, tangerine, or any combination thereof.

[0155] In some embodiments, disclosed unit dosage forms comprise a vanilla flavor, a caramel flavor, a chocolate flavor, a clove flavor, a coffee flavor, a cotton candy flavor, a honey flavor, a licorice flavor, a mint flavor, a peppermint flavor, a spearmint flavor, a tea flavor, a green tea flavor, a black tea flavor , a chai tea flavor, a matcha flavor, a chamomile tea flavor, a vinegar flavor, an apple cider vinegar flavor, or any combination thereof. In some embodiments, disclosed unit dosage forms comprise a vanilla flavor. In some embodiments, the disclosed unit dosage forms comprise a chocolate flavor. Alternative or additional flavoring agents which may be used in disclosed unit dosage forms are described in, e.g., US20130252985A1, US20140127370A1, US20020182270A1, US20060249167A1, US20040151815A1, and US20080233056A1. 38 DMS_US.364752221.1

[0156] In preferred embodiments, the flavoring agent has a strawberry flavor. In preferred embodiments, the flavoring agent with a strawberry flavor is ethyl phenylglycidate (ethyl 3- phenylglycidate) or ethyl methylphenylglycidate.

[0157] In some embodiments, disclosed unit dosage forms comprise the flavoring agent in an amount of at least about 0.05 g, 0.1 g, 0.15 g, 0.2 g, 0.2 g, 0.3 g, 0.35 g, or 0.4 g. In some embodiments, disclosed unit dosage forms comprise the flavoring agent in an amount of less than about 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, or 5 g.

[0158] In some embodiments, disclosed unit dosage forms comprise the flavoring agent in an amount of about 0.05 g to 2 g, 0.1 g to 2 g, 0.3 g to 2 g, 0.4 g to 2 g, 0.5 g to 2 g, 0.6 g to 2 g, 0.7 g to 2 g, 0.8 g to 2 g, 0.9 g to 2 g, 1 g to 2 g, 1.1 g to 2 g, 1.2 g to 2 g, 1.3 g to 2 g, 1.4 g to 2 g, 1.5 g to 2 g, 1.6 g to 2 g, 1.7 g to 2 g, 1.8 g to 2 g, or 1.9 g to 2 g. In some embodiments, disclosed unit dosage forms comprise the flavoring agent in an amount of about 0.05 g to 1 g, 0.1 g to 1 g, 0.3 g to 1 g, 0.4 g to 1 g, 0.5 g to 1 g, 0.6 g to 1 g, 0.7 g to 1 g, 0.8 g to 1 g, or 0.9 g to 1 g.

[0159] In some embodiments, disclosed unit dosage forms comprise the flavoring agent in an amount of about 0.1 g, 0.12 g, 0.14 g, 0.16 g, 0.18 g, 0.2 g, 0.22 g, 0.24 g, 0.26 g, 0.28 g, 0.3 g, 0.32 g, 0.34 g, 0.36 g, 0.38 g, 0.4 g, 0.42 g, 0.44 g, 0.46 g, 0.48 g, 0.5 g, 0.52 g, 0.54 g, 0.56 g, 0.58 g, 0.6 g, 0.62 g, 0.64 g, 0.66 g, 0.68 g, 0.7 g, 0.72 g, 0.74 g, 0.76 g, 0.78 g, 0.8 g, 0.82 g, 0.84 g, 0.86 g, 0.88 g, 0.9 g, 0.92 g, 0.94 g, 0.96 g, 0.98 g, 1 g, 1.02 g, 1.04 g, 1.06 g, 1.08 g, 1.1 g, 1.12 g, 1.14 g, 1.16 g, 1.18 g, 1.2 g, 1.22 g, 1.24 g, 1.26 g, 1.28 g, 1.3 g, 1.32 g, 1.34 g, 1.36 g, 1.38 g, 1.4 g, 1.42 g, 1.44 g, 1.46 g, 1.48 g, 1.5 g, 1.52 g, 1.54 g, 1.56 g, 1.58 g, 1.6 g, 1.62 g, 1.64 g, 1.66 g, 1.68 g, 1.7 g, 1.72 g, 1.74 g, 1.76 g, 1.78 g, 1.8 g, 1.82 g, 1.84 g, 1.86 g, 1.88 g, 1.9 g, 1.92 g, 1.94 g, 1.96 g, 1.98 g, or 2 g. 39 DMS_US.364752221.1

[0160] In preferred embodiments, the flavoring agent is ethyl phenylglycidate and / or ethyl methylphenylglycidate. In some embodiments, disclosed unit dosage forms comprise ethyl phenylglycidate and / or ethyl methylphenylglycidate in an amount of at least about 0.05 g, 0.1 g, 0.15 g, 0.2 g, 0.2 g, 0.3 g, 0.35 g, or 0.4 g. In some embodiments, disclosed unit dosage forms comprise ethyl phenylglycidate and / or ethyl methylphenylglycidate in an amount of less than about 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, or 5 g.

[0161] In some embodiments, disclosed unit dosage forms comprise ethyl phenylglycidate and / or ethyl methylphenylglycidate in an amount of about 0.05 g to 2 g, 0.1 g to 2 g, 0.3 g to 2 g, 0.4 g to 2 g, 0.5 g to 2 g, 0.6 g to 2 g, 0.7 g to 2 g, 0.8 g to 2 g, 0.9 g to 2 g, 1 g to 2 g, 1.1 g to 2 g, 1.2 g to 2 g, 1.3 g to 2 g, 1.4 g to 2 g, 1.5 g to 2 g, 1.6 g to 2 g, 1.7 g to 2 g, 1.8 g to 2 g, or 1.9 g to 2 g. In some embodiments, disclosed unit dosage forms comprise ethyl phenylglycidate and / or ethyl methylphenylglycidate in an amount of about 0.05 g to 1 g, 0.1 g to 1 g, 0.3 g to 1 g, 0.4 g to 1 g, 0.5 g to 1 g, 0.6 g to 1 g, 0.7 g to 1 g, 0.8 g to 1 g, or 0.9 g to 1 g.

[0162] In some embodiments, disclosed unit dosage forms comprise ethyl phenylglycidate and / or ethyl methylphenylglycidate in an amount of about 0.1 g, 0.12 g, 0.14 g, 0.16 g, 0.18 g, 0.2 g, 0.22 g, 0.24 g, 0.26 g, 0.28 g, 0.3 g, 0.32 g, 0.34 g, 0.36 g, 0.38 g, 0.4 g, 0.42 g, 0.44 g, 0.46 g, 0.48 g, 0.5 g, 0.52 g, 0.54 g, 0.56 g, 0.58 g, 0.6 g, 0.62 g, 0.64 g, 0.66 g, 0.68 g, 0.7 g, 0.72 g, 0.74 g, 0.76 g, 0.78 g, 0.8 g, 0.82 g, 0.84 g, 0.86 g, 0.88 g, 0.9 g, 0.92 g, 0.94 g, 0.96 g, 0.98 g, 1 g, 1.02 g, 1.04 g, 1.06 g, 1.08 g, 1.1 g, 1.12 g, 1.14 g, 1.16 g, 1.18 g, 1.2 g, 1.22 g, 1.24 g, 1.26 g, 1.28 g, 1.3 g, 1.32 g, 1.34 g, 1.36 g, 1.38 g, 1.4 g, 1.42 g, 1.44 g, 1.46 g, 1.48 g, 1.5 g, 1.52 g, 1.54 g, 1.56 g, 1.58 g, 1.6 g, 1.62 g, 1.64 g, 1.66 g, 1.68 g, 1.7 g, 1.72 g, 1.74 g, 1.76 g, 1.78 g, 1.8 g, 1.82 g, 1.84 g, 1.86 g, 1.88 g, 1.9 g, 1.92 g, 1.94 g, 1.96 g, 1.98 g, or 2 g.

[0163] Method of Manufacturing 40 DMS_US.364752221.1

[0164] In some aspects, provided herein are methods of manufacturing disclosed compositions and unit dosage forms. An exemplary method of manufacture is provided in Example 1 herein.

[0165] In some embodiments, disclosed methods of manufacture comprise mixing powder ingredients together, thereby forming blended ingredients. In some examples, mixing may be performed using a mortar and pestle or other apparatus available to one of skill in the art and suitable for mixing solids and powders. Pharmaceutical mixing and blending equipment are described in, e.g., Pharmaceutical Blending and Mixing, 2015 John Wiley & Sons, Ltd, such as Dickey’s “Powder Blending Equipment,” pg.287-310.

[0166] In some embodiments, the powder ingredients comprise urea and any one or more of an antioxidant, an antacid, and an electrolyte. In some embodiments, the powder ingredients comprise urea, an antioxidant, an antacid, and an electrolyte. In some embodiments, the powder ingredients further comprise a sweetener, an anti-caking agent, a flavoring agent, or any combination thereof. In some embodiments, the powder ingredients comprise urea, ascorbic acid, aspartame, sodium bicarbonate, sodium chloride, calcium silicate, and ethyl phenylglycidate and / or ethyl methylphenylglycidate. In some embodiments, the powder ingredients consist of urea, ascorbic acid, aspartame, sodium bicarbonate, sodium chloride, calcium silicate, and ethyl phenylglycidate and / or ethyl methylphenylglycidate.

[0167] In some embodiments, the blended ingredients are then subjected to ultrasonic mixing, thereby forming a homogenous mixture. In some embodiments, the blended ingredients are subjected to ultrasonic mixing for at least 1 hour. In some embodiments, the blended ingredients are subjected to ultrasonic mixing for less than about 12 hours, 18 hours, or 24 hours. In some embodiments, the blended ingredients are subjected to ultrasonic mixing for about 1 41 DMS_US.364752221.1hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours. Ultrasonic mixing may be performed by, e.g., placing the blended ingredients into an ultrasonic receptacle, such as an ultrasonic bath, without water.

[0168] In some embodiments, the blended ingredients or the homogenous mixture are dried to remove moisture, thereby forming a dried composition. In some embodiments, drying is performed at a temperature of less than about 75oC, 100oC, 125oC, 150oC, 175oC, or 200oC. In preferred embodiments, drying is performed at a temperature of or below 100oC to prevent melting. Drying may be accomplished with use of, e.g., a vacuum oven.

[0169] In some embodiments, the dried composition is packaged in a container. In preferred embodiments, the dried composition is packaged in an airtight container. Airtight containers may be composed of plastic and / or glass. An airtight container is preferred to prevent moisture penetration. In other preferred embodiments, the dried composition is packaged in a container suitable to hold a disclosed unit dosage form, such as a vial, a pouch, or a sachet.

[0170] In additional preferred embodiments, the container is resistant to light penetration, such as a light-resistant container. In some embodiments, the light-resistant container comprising disclosed compositions and unit dosage forms comprises an opaque covering.

[0171] As noted by the United States Pharmacopeia, a light-resistant container protects the contents from the effects of light by virtue of the specific properties of the material of which it is composed, including any coating applied to it. See Light Transmission Test under Containers— Performance Testing 671. Alternatively, a clear, colorless, or a translucent container may be made light-resistant by means of an opaque covering, in which case the label of the container bears a statement that the opaque covering is needed until the contents are to be used or 42 DMS_US.364752221.1administered. Where it is directed to “protect from light” in an individual monograph, preservation in a light-resistant container is intended.

[0172] Where an article is required to be packaged in a light-resistant container, and if the container is made light-resistant by means of an opaque covering, a single-use, unit-dose container or mnemonic pack for dispensing may not be removed from the outer opaque covering before dispensing.

[0173] Method of Treatment

[0174] In some aspects, provided herein are methods of treating hyponatremia. In some embodiments, disclosed methods comprise administering, such as orally administering, disclosed compositions, including disclosed unit dosage forms, to a subject suffering from hyponatremia. In some embodiments, the subject in need thereof is a human suffering from euvolemic, hypovolemic or hypervolemic hyponatremia.

[0175] In some embodiments, disclosed compositions are dispersed into liquid prior to oral administration to the subject. In some embodiments, disclosed compositions are dispersed into a food colloid prior to oral administration to the subject.

[0176] In some embodiments, disclosed compositions are orally administered to a subject in need thereof once per day. In some embodiments, disclosed compositions are orally administered to a subject in need thereof at least once per day and up to four, five, or six times per day, inclusive. In some embodiments, disclosed compositions are orally administered to a subject in need thereof once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times per day.

[0177] In some embodiments, disclosed methods comprise administering a disclosed composition or unit dosage form to a subject in need thereof in combination with an additional 43 DMS_US.364752221.1hyponatremia treatment. In some embodiments, an additional hyponatremia treatment comprises water restriction, administration of a pharmaceutical agent, e.g., a vasopressin antagonist, salt tablets, potassium replacement, or any combination thereof.

[0178] In hyponatremia, blood sodium levels are below normal levels (about 135 to 145 milliequivalents / liter), which threatens fluid balance and control of blood pressure, nerves, and muscles. Hyponatremia may be categorized as mild (plasma sodium: 130–134 mmol / L), moderate (plasma sodium: 120–129 mmol / L), or severe (plasma sodium: <120 mmol / L), and as acute (duration of less than 48 h), or chronic (duration of 48 h or more). Pre-treatment evaluation of hyponatremia, treatment options, and patient monitoring are described in, e.g., Sterns, “Overview of the treatment of hyponatremia in adults,” 2021, UpToDate.com.

[0179] Oral urea is generally administered at a dose of 0.25–0.5 g / kg / day with typical doses of 15, 30, or 60 g / day. In general, the higher the urine osmolality (a surrogate for negative electrolyte free-water clearance), the higher the urea dose needed to correct hyponatremia. For example, a disclosed composition or unit dosage form comprising about 16 grams of urea may be administered to a subject in need thereof, such as a human suffering from hyponatremia up to four or five times a day, inclusive. EXAMPLES

[0180] Example 1: Preparation and Storage of an Exemplary Edible Urea Formulation

[0181] Contents in the amounts described in the table below were mixed and ground using a mortar pestle. The total amount of combined ingredients was about 20.4 grams. Prior to preparation, the chemical constituents were stored in a cool and dry place. Use of a liquid flavouring agent was avoided to prevent the powder from clumping. The blended ingredients were then subjected to ultrasonic mixing using an ultrasonic bath without water. The mixture 44 DMS_US.364752221.1was sonicated at 25oC for 5 hours to ensure homogeneous mixing of all components. Ultrasonication was found to reduce particle size, improve mixing and blending, and even improve the appearance of the powder, e.g., the color. The mixture was then dried under a vacuum oven with a temperature below 100oC to prevent the urea from melting.

[0182] Table 1. Ingredients of an Exemplary Formulation of Edible Urea Ingredient Amount (g) % (wt / wt) Urea 16 79formulation is at about 20oC in cool and dark places, away from moisture and corrosive chemicals. The product should be sealed tightly preferably in a plastic bag or an air-tight glass bottle to prevent moisture due to the presence of hygroscopic components in the composition. Moisture penetration was found to result in powder agglomeration. Further relating to moisture content, hygroscopicity studies are described in Example 5. Leaching was not observed until after 6 months of storage under ambient conditions, and none of the components was chemically reactive with plastic containers.

[0184] Example 2: Physical Analysis of an Exemplary Urea Composition

[0185] The physical properties of the exemplary urea formulation of Example 1 were analyzed, including density, viscosity, and solubility. Tests were performed according to known methods, e.g., as described by the American Standard for Testing and Materials (ASTM). For 45 DMS_US.364752221.1example, density was determined according to ASTM-D7481:Standard Test Methods for Determining Loose and Tapped Bulk Densities of Powders using a Graduated Cylinder.

[0186] Density: The density of the formulation, along with additional physical characteristics were determined.

[0187] Table 2. Density and Physical Properties of an Exemplary Formulation of Edible Urea Property Unit / Characteristic Density 1.01 g / ml for 0.5 g 1.02 g / ml for 1 g Specific 0.015 for 0.5 g gravity 1.02 for 1 g Net weight 20.7 g Color White Texture Fine powder

[0188] Viscosity: The viscosity of the formulation, at levels from 3.2 % to 4% in water were tested.

[0189] Table 3. Viscosity of an Exemplary Formulation of Edible Urea Formulation Flow time Relative viscosity Viscosity Reduced Concentration (g / ml) Specific Viscosity (%) 3.2 105 1.05 0.05 0.018 3.4 107 1.07 0.07 0.022 3.6 110 1.10 0.10 0.030 3.8 113 1.13 0.13 0.038

[0190] Solubility: The solubility of the formulation was tested in various organic solvents, including water, methanol, and chloroform. For reference, the pH of 1 gram of the formulation in 50 ml of water was 4.20.

[0191] Table 4. Solubility of an Exemplary Formulation of Edible Urea Exemplary Water (1ml) Ethanol (1ml) Methanol (1ml) Chloroform46 DMS_US.364752221.1(mg) (1ml) [0

[0193] The exemplary composition of Example 1 was analyzed using CHN analysis and Fourier Transform Infrared Spectroscopy (FTIR). CHN analysis measures carbon, hydrogen, and nitrogen elemental content, whereas FTIR is used to definitively identify compounds by measuring the absorbance of a sample’s infrared radiation.

[0194] CHN Analysis

[0195] The sample was precisely weighed before analysis in the CHN instrument (Vario EL cube, CHNS Elemental Analyzer). A Cahn Model C-33 or C-25 microbalance was used to measure a 1 mg sample of the exemplary composition. The weight was recorded, along with sample ID, sample type, and position in the sample wheel. The sample was then placed in the sample wheel of the instrument for analysis of Carbon, Hydrogen and Nitrogen via combustion. 47 DMS_US.364752221.1

[0196] FIG. 1 shows the CHN spectrum of the exemplary urea composition of Example 1. Additionally, the elemental composition is provided in Table 5.

[0197] FTIR

[0198] The exemplary edible urea composition was prepared for analysis in powder form by mixing with potassium bromide pellets. The concentration of the sample in KBr ranged from 0.2% to 1%, inclusive. After a homogeneous mixture was prepared, it was pressed under hydraulic press to form a pellet. FTIR analysis was performed using the spectrophotometer Shimadzu IR Affinity.

[0199] FIG.2 shows the IR spectrum of the exemplary edible urea composition of Example 1. Regarding the IR spectrum, peaks around 3000 cm-1correlate to the NH group, while the carbonyl peak is visible at 1600 cm-1. The methyl bending peaks are present around 1200-1000 cm-1.

[0200] Table 5. Elemental Composition of an Exemplary Urea Composition Peak Number (#) Element Name Retention Time Element Percent

[0201] Example 4: Comparative Physical Properties of an Exemplary Urea Composition and a Commercially Available Edible Urea Composition 48 DMS_US.364752221.1

[0202] Physical properties of the exemplary composition of Example 1 and a commercially available edible urea composition were determined and compared. The commercially available composition contains synthetically derived urea powder, maltodextrin, citric acid, calcium silicate, sucralose, and natural flavors.

[0203] The exemplary composition of Example 1 and the commercial formulation were compared by appearance, viscosity, density, and caloric value, as shown in Table 6. Physical properties were assessed according to known methods, e.g., as described in Halonen et al., Emission Control Science and Technology, 2016.

[0204] Table 6. Comparative Physical Properties of an Edible Urea Compositions Property Exemplary Composition Commercial Composition Color White powder Pale yellow powder Relative viscosity (4% ) 1.17 1.22 Reduced viscosity (4%) 0.049 0.067 Density (1 g ) 1.02 g / ml for 1 g 1.02 g / ml Net weight 20.04 g (16 g urea) 15 g urea Calories > 5% >15%

[0205] The urea and moisture content of each formulation were also compared using UV-vis spectroscopy. UV-vis analysis was performed using a Shimadzu UV 1800. 1 mg of the exemplary composition was dissolved in 10 ml of distilled water prior to analysis, and the sample was analyzed at a spectrum from 200 nm to 800 nm.

[0206] Relative to current commercially available urea compositions, the urea content of the exemplary composition was higher, whereas the moisture content was lower. The electronic transitions of urea in the exemplary composition of Example 1 (FIG. 3A) are sharper in comparison to the commercial formulation (FIG. 3B) and indicative of a greater urea content. The relative broadness of the commercial formulation’s absorbance spectrum may be due to absorption of water. Peak broadness is usually related to hydrogen bonding tendency, which 49 DMS_US.364752221.1indicates greater moisture entrapment in the sample of a commercially available composition. In contrast, the sharpness of the electronic transitions of the exemplary composition around 190 nm and 270 nm, which correlate to the electronic transitions of urea, indicate a relatively reduced moisture content. This result is consistent with visible examination of powder textures. The texture of the exemplary composition was fine and dispersed in contrast to the clumped texture of the commercially available edible urea composition.

[0207] Example 5: Comparative Moisture Content Studies

[0208] A standard loss on drying assay was conducted to compare the hygroscopicity of the exemplary formulation of Example 1 and the commercially available edible urea formulation. Equipment included an electric oven, maintained at a temperature range between 50oC to 80oC, a desiccator with a balance of sufficient sensitivity, and a non-corrodible air-tight container. Briefly, approximately 2 g of the exemplary composition of Example 1 and the commercially available edible urea formulation were accurately weighed and spread on a watch glass before placement in a desiccator at 25° / 75% RH. Saturated sodium chloride solution was used to provide a 75% RH.

[0209] Weight gain was measured at intervals for 72 hours. The weight change was computed using the following equation: [(M3 − M2) ∗ 100] / [M2 − M1], where M1= weight of empty Petri plate; M2= initial weight of both Petri plate and sample together; M3= weight of both Petri plate and sample together after 6 hours. Moisture content was determined by subtracting total weight after drying from the original total weight: Moisture content = total value – total value after drying.

[0210] At completion of the assay, the moisture content of the commercial composition was nearly doubled in comparison to the exemplary formulation. Results were extrapolated to 20 50 DMS_US.364752221.1grams and 100 grams of each formulation. As shown in FIG. 4, at an amount of 20 grams, the moisture content of the exemplary formulation was 0.48%, and the moisture content of the commercial composition was 0.88%. Extrapolating this data, a moisture content of 2.4% was determined for 100 grams of the exemplary formulation, whereas a moisture content of 4.4% was determined for 100 grams of the commercial formulation.

[0211] Example 6: Comparative Stability Studies

[0212] The stability of the exemplary formulation described in Example 1 was determined in response to various degradants, including acidic conditions, light, and heat.

[0213] Ambient stability: After storage in a cool and dark place for about 8 to 12 months (20°C to 25°C with a humidity level of about 30%), the texture of the exemplary composition of Example 1 appeared fine and dispersed, not indicative of absorbing moisture. In contrast, after 3 months of storage under comparable conditions, the commercial composition showed signs of moisture absorption, such as powder clumping. The commercially available edible urea formulation contains ingredients that are known to be hygroscopic, such as maltodextrin and sucralose. Accordingly, the exemplary formulation had improved stability and hygroscopicity, as evidenced by reduced moisture content, in comparison to the commercial composition.

[0214] Accelerated chemical stability: The stabilities of the exemplary formulation of Example 1 and a commercially available edible urea formulation were determined and compared in the presence of 0.1 N hydrochloric acid (HCl) and 0.1 N sodium hydroxide. Two crucibles, filled with either 1 gram of the exemplary formulation or the commercial composition, and a beaker were placed in a desiccator for six hours with the acid and the base, separately. After this time period, the samples were removed and their weights were determined, and the weight change was computed using the following equation: 51 DMS_US.364752221.1[(M3 − M2) ∗ 100] / [M2 − M1], where M1= weight of empty Petri plate; M2= initial weight of both Petri plate and sample together; and M3= weight of both Petri plate and sample together after 6 hours. Stability was determined in terms of weight, by subtracting the weight after dessication in the presence of the acid or the base from the original weight: original value of the sample – total value after removal from the desiccator. The degradation observed for each gram of sample was then extrapolated to 20 grams and 100 grams of each formulation.

[0215] The chemical stability of the exemplary formulation was enhanced compared to the commercial composition. Following exposure to HCl under desiccant conditions at 25°C, the weight of the exemplary formulation was reduced by 5 mg, whereas that of the commercial composition was reduced by 7 mg. Extrapolated to 20 and 100 gram samples, degradation of the exemplary formulation (0.1% degradation per 20 grams; 0.5% degradation per 100 grams) was reduced relative to the commercial composition (0.14% degradation per 20 grams; 0.7% degradation per 100 grams).

[0216] Photostability: The stabilities of the exemplary formulation of Example 1 and commercially available urea composition were determined and compared following exposure to a halogen lamp (1000 W). Samples (1 gram) of each formulation were exposed to six hours of light exposure under a halogen lamp.

[0217] Degradation was determined by differences in weight prior to and following light exposure, along with visible changes in color. Slight changes in weight and color were evident after six hours of exposure to a halogen lamp. In contrast, changes in neither weight nor color were observed under dark conditions for the same period of time.

[0218] Heat Stability: The stabilities of the exemplary formulation of Example 1 and commercially available urea formulation in response to increasing temperatures were determined 52 DMS_US.364752221.1and compared. Samples of each formulation were exposed to 30°C, 40°C, 50°C, and 60°C for two hours. FIG. 5 shows enhanced stability of the exemplary composition relative to the commercial composition. For example, at 50°C, the degradation of the commercial composition was about 633% greater than that of the exemplary composition.

[0219] Example 7: Administering a Disclosed Urea Composition

[0220] A urea composition, such as an edible urea composition, is prepared according to the methods described herein, e.g., Example 1. The powder is mixed in a volume of liquid, such as water or juice, or a food colloid, prior to administration to a subject in need thereof, such as a subject experiencing hyponatremia. For example, a disclosed composition containing about 16 grams of urea is mixed in 100 mL water prior to ingestion by a subject in need thereof. The minimum volume for mixing and dissolution is 80 ml, which is advantageous for subjects requiring liquid restriction, such as subjects suffering from hypervolemic hyponatremia. EQUIVALENTS AND SCOPE

[0221] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present invention is not intended to be limited to the above, but rather is as set forth in the appended claims.

[0222] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. 53 DMS_US.364752221.1The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0223] Furthermore, it is to be understood that the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses and descriptive terms, from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.

[0224] Where elements are presented as lists, e.g., in Markush group format, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the invention, or aspects of the invention is / are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the term “comprising” is intended to be open and permits the inclusion of additional elements or steps.

[0225] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranged can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. 54 DMS_US.364752221.1

[0226] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5% or up to 1% of a given value. Alternatively, the term can mean within an order of magnitude, for example within 5-fold, or within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0227] In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the method of the invention can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art. 55 DMS_US.364752221.1

Claims

CLAIMS I claim Claim 1. A composition comprising 75% to 85% (wt / wt) of urea, 5% to 15% (wt / wt) of an antioxidant, 0.5% to 5% (wt / wt) of an antacid, and 0.5% to 5% (wt / wt) of an electrolyte, wherein each range inclusive. Claim 2. The composition of claim 1, wherein the antioxidant is a vitamin or a mineral. Claim 3. The composition of claim 2, wherein the vitamin is vitamin C (ascorbic acid). Claim 4. The composition of claim 1, wherein the antacid comprises a bicarbonate salt. Claim 5. The composition of claim 4, wherein the antacid comprises calcium bicarbonate, potassium bicarbonate, sodium bicarbonate, or a combination thereof. Claim 6. The composition of claim 1, wherein the electrolyte is sodium chloride. Claim 7. The composition of any one of claims 1 to 6, further comprising a non-saccharide sweetener. Claim 8. The composition of claim 7, wherein the percent (wt / wt) amount of the non-saccharide sweetener in the composition is 1.5% to 8%, inclusive. 56 DMS_US.364752221.1Claim 9. The composition of claim 8, wherein the non-saccharide sweetener comprises a peptide. Claim 10. The composition of claim 9, wherein the peptide comprises a dipeptide methyl ester. Claim 11. The composition of claim 10, wherein the dipeptide methyl ester is l-aspartyl-l- phenylalanine methyl ester (aspartame). Claim 12. The composition of any one of claims 1 to 11, wherein the composition further comprises an anti-caking agent. Claim 13. The composition of claim 12, wherein the % (wt / wt) amount of the anti-caking agent in the composition is 0.5% to 4%, inclusive. Claim 14. The composition of claim 12 or claim 13, wherein the anti-caking agent comprises a calcium salt. Claim 15. The composition of claim 14, wherein the anti-caking agent is calcium silicate. Claim 16. The composition of claim 15, wherein the calcium silicate has a particle size of greater than seven microns (7 µm). Claim 17. The composition of any one of claims 1 to 16, wherein the composition further comprises a flavoring agent. 57 DMS_US.364752221.1Claim 18. The composition of claim 17, wherein the % (wt / wt) amount of the flavoring agent is 0.5% to 5%, inclusive. Claim 19. The composition of claim 17 or claim 18, wherein the flavoring agent has a fruit flavor and / or a fruity odor. Claim 20. The composition of any one of claims 17 to 19, wherein the flavoring agent comprises ethyl phenylglycidate and / or ethyl methylphenylglycidate. Claim 21. The composition of any one of claims 1 to 20, wherein the composition is a powder mixture. Claim 22. A composition consisting of: a. 75-85 wt% urea, b. 5-15 wt% ascorbic acid; c. 0.5-5 wt% sodium bicarbonate; d. 0.5-5 wt% sodium chloride; e. 1.5-8 wt% aspartame; f. 0.5-4 wt% calcium silicate; and g. 0.5-5 wt% ethyl phenylglycidate and / or ethyl methylphenylglycidate, wherein the composition is a powder mixture. 58 DMS_US.364752221.1Claim 23. The composition of claim 26, consisting of about 79 wt% urea, 10 wt% ascorbic acid, 5 wt% aspartame, 2.1 wt% sodium bicarbonate, 1.6 wt% calcium silicate, and 1 wt% ethyl phenylglycidate. Claim 24. A unit dosage form comprising: a) 15.7 g to 16.0 g urea; b) 1.5 g to 2.1 g ascorbic acid; c) 0.5 g to 1.0 g aspartame; d) 0.22 g to 0.42 g sodium bicarbonate; e) 0.25 g to 0.32 g sodium chloride; f) 0.32 to 0.75 g calcium silicate; and g) 0.21 g to 0.85 g ethyl 3-phenylglycidate; wherein the unit dosage form is a powder mixture and each range is inclusive. Claim 25. The unit dosage form of claim 24, comprising 16.0 grams urea, 2.1 grams ascorbic acid, 1.0 grams aspartame, 0.42 grams sodium bicarbonate, 0.32 grams sodium chloride, 0.32 grams calcium silicate, and 0.21 grams ethyl phenylglycidate. Claim 26. The composition or the unit dosage form of any one of claims 1 to 25, wherein a 20 gram (g) sample of the composition or the unit dosage form has a moisture content of less than 0.5%, as determined by a loss on drying assay. 59 DMS_US.364752221.1Claim 27. The composition or the unit dosage form of any one of claims 1 to 26, wherein the composition is intended for oral consumption by a subject. Claim 28. The composition or the unit dosage form of any one of claims 1 to 27, wherein the composition or the unit dosage form is dispersed into a liquid or a food colloid prior to oral consumption by the subject. Claim 29. The composition or the unit dosage form of any one of claims 1 to 28, wherein the subject is suffering from hyponatremia. Claim 30. A method of treating hyponatremia comprising orally administering to a subject suffering from hyponatremia the composition or the unit dosage form of any one of claims 1 to 29. Claim 31. The method of claim 30, comprising dispersing the composition or the unit dosage form of any one of claims 1 to 29 into a liquid or a food colloid prior to oral administration to the subject. Claim 32. The method of claim 30 or claim 31, wherein the composition or the unit dosage form is administered to the subject at least once per day. 60 DMS_US.364752221.1

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