3,5-Diiodothyropropionic Acid Composition and Method of Use Thereof

Abstract

The present subject matter relates to a pharmaceutical composition comprising 3,5-diiodothyropropionic acid or a salt thereof and one or more pharmaceutically acceptable excipients. Further, the present subject matter relates to a method of treating Allan-Herndon-Dudley syndrome, comprising administering to a subject in need of treatment for Allan-Herndon-Dudley syndrome one or more compositions comprising 3,5-diiodothyropropionic acid or a salt thereof and one or more pharmaceutically acceptable excipients.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 388,241, filed on July 11, 2022, the entire content of which is incorporated herein by reference.

[0002] The present subject matter relates to a pharmaceutical composition comprising 3,5 - diiodothyropropionic acid or a salt thereof and one or more pharmaceutically acceptable excipients. The present subject matter further relates to a method of treating Alan Houghton Dudley syndrome, comprising administering to a subject in need thereof a composition comprising 3,5 - diiodothyropropionic acid or a salt thereof and one or more pharmaceutically acceptable excipients.

Background Art

[0003] Alan Houghton Dudley syndrome ("AHDS") is an X - linked recessive developmental disorder that causes intellectual and motor disabilities in males. Specifically, AHDS patients have a mutated SLC16A2 gene, as a result of which the monocarboxylate transporter 8 ("MCT8") protein is abnormal. The symptoms of AHDS are usually caused by the lack of uptake of triiodothyronine ("T3"), a thyroid hormone that is normally transported across the cell membrane by MCT8, into cells. Due to this MCT8 deficiency, T3 is insufficient in the tissues where it is required for proper functioning, and T3 accumulates in the serum. Another thyroid hormone, thyroxine ("T4"), usually remains at normal serum levels in AHDS patients, although it may decrease slightly from normal levels. In AHDS patients, thyroid - stimulating hormone ("TSH") is slightly elevated from normal.

[0004] Currently, there is no treatment for AHDS approved by the US Food and Drug Administration. Clinical trials of triiodothyroacetic acid ("TRIAC"), a drug used for the treatment of AHDS, have been completed. However, since TRIAC is structurally similar to T3, it becomes difficult to accurately evaluate T3 serum levels. Furthermore, TRIAC has been shown to significantly reduce T4 serum levels.

[0005] 3,5-Diiodothyropropionic acid ("DITPA") is another thyroid hormone analog that has been studied for the treatment of AHDS. However, as previously mentioned, DITPA is still not approved for use in the treatment of AHDS. The reason for this lack of approval may be due to the absence of an effective dosing regimen, a stable and effective composition, and extensive pharmacological evaluation. International Publication No. WO 2012 / 171065, published on December 20, 2012, attempts to establish a DITPA dosing regimen for AHDS patients, but this publication only provides theoretical examples.

[0006] Therefore, there is a need in the art for a stable and effective composition containing DITPA. SUMMARY OF THE INVENTION BRIEF DESCRIPTION OF THE DRAWINGS

[0007] DISCLOSURE The present subject matter relates to a pharmaceutical composition comprising 3,5-diiodo-thyropropionic acid ("DITPA") and one or more pharmaceutically acceptable excipients.

[0008] The present subject matter further relates to a method of treating Alan Houghton Dudley Syndrome ("AHDS") or one or more symptoms of AHDS, the method comprising administering to a subject in need thereof a composition comprising DITPA and one or more pharmaceutically acceptable excipients.

[0009] BRIEF DESCRIPTION OF THE DRAWINGS

[0010]

Figure 1

Figure 2

Figure 3

DETAILED DESCRIPTION OF THE INVENTION

[0011] The applicant has discovered a composition of 3,5-diiodothyropropionic acid ("DITPA") that is surprisingly stable and surprisingly effective in the treatment of Alan Houghton Dudley Syndrome ("AHDS").

[0012] In one embodiment, the subject matter relates to a pharmaceutical composition comprising DITPA or a salt thereof and one or more pharmaceutically acceptable excipients.

[0013] In a preferred embodiment, DITPA or a salt thereof may be present in the pharmaceutical composition of the subject matter at a concentration of about 0.001% to about 10% w / w or w / v.

[0014] In a preferred embodiment, one or more pharmaceutically acceptable excipients may be present in the pharmaceutical composition of the subject matter at a concentration of about 90% to about 99.999% w / w or w / v.

[0015] Pharmaceutically acceptable excipients suitable for use in the present formulation include, but are not limited to, disintegrants, binders, fillers, plasticizers, lubricants, penetration enhancers, surfactants, sweeteners, sweetening enhancers, flavoring agents, and pH adjusters.

[0016] As used herein, the term "disintegrant" refers to a pharmaceutically acceptable excipient that promotes the disintegration of a tablet when the tablet comes into contact with water or other liquids.

[0017] Disintegrants suitable for use in this formulation include, but are not limited to, natural starches such as corn starch and potato starch, directly compressible starches such as starch 1500, modified starches such as carboxymethyl starch, sodium hydroxymethyl starch and sodium starch glycolate, as well as starch derivatives such as amylose, cross-linked polyvinylpyrrolidones such as crospovidone, cross-linked sodium carboxymethyl cellulose, sodium hydroxymethyl cellulose, calcium hydroxymethyl cellulose, modified celluloses such as low-substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, methacrylic acid divinylbenzene copolymer salts, and combinations thereof.

[0018] Binders suitable for use in this formulation include, but are not limited to, polyethylene glycol, soluble hydroxyalkyl cellulose, polyvinylpyrrolidone, gelatin, natural rubber, and combinations thereof.

[0019] Fillers suitable for use in this formulation include, but are not limited to, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate and dicalcium sulfate, lactose, sucrose, amylose, dextrose, mannitol, inositol, and combinations thereof.

[0020] Plasticizers suitable for use in this formulation include, but are not limited to, microcrystalline cellulose, triethyl citrate, polyhexanediol, acetylated monoglyceride, glyceryl triacetate, castor oil, and combinations thereof.

[0021] Lubricants suitable for use in this formulation include, but are not limited to, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, micronized polyoxyethylene glycol, talc, and combinations thereof.

[0022] Penetration enhancers suitable for use in this preparation include, but are not limited to, precipitated silica, maltodextrin, β-cyclodextrin, menthol, limonene, carvone, methyl chitosan, polysorbate, sodium lauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride, cetylpyridinium chloride, disodium edetate dihydrate, sodium deoxycholate, sodium deoxyglycocholate, sodium glycolate, sodium caprylate, sodium taurocholate, sodium hydroxybenzoyl aminocaprylate, dodecyldimethylaminopropionate, L-lysine, glyceryl oleate, glyceryl monostearate, citric acid, peppermint oil, and combinations thereof.

[0023] Surfactants suitable for use in this preparation include, but are not limited to, sorbitan esters, sodium docusate, sodium lauryl sulfate, cetrimide, and combinations thereof.

[0024] Sweeteners suitable for use in this preparation include, but are not limited to, aspartame, saccharin, acesulfame potassium, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, sucrose, dextrose, mannitol, glycerin, xylitol, and combinations thereof.

[0025] Sweetness enhancers suitable for use in this preparation include, but are not limited to, the ammonium salt forms of crude and purified glycyrrhizic acid.

[0026] Flavoring agents suitable for use in this preparation include, but are not limited to, peppermint oil, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, and combinations thereof.

[0027] pH adjusters suitable for use in the present formulation include, but are not limited to, hydrochloric acid, citric acid, fumaric acid, lactic acid, sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate, ammonium carbonate, sodium acetate, and combinations thereof. In another preferred embodiment, the pharmaceutical composition of the formulation of the present invention does not contain a preservative.

[0028] The pharmaceutical composition of the present formulation can be formulated into any dosage form including, but not limited to, measured, aerosol including powder and spray, chewable bar, beads, coated, film-coated, gel-coated capsules, liquid-filled and coated pellets, cell sheets, chewable gels, concentrates, elixirs, emulsions, films including soluble, film for solution and film for suspension, gels including measured gels, microspheres, granules including granules for solution, granules for suspension, chewing gum, inhalants, injections including foams, liposomes, emulsions, lipid complexes, powders, lyophilized powders and liposome suspensions, liquids, medicinal drops, ointments, patches, electro-controlled patches, pellets, implantable pellets, pills, powders, powders, measured powders, solutions, measured solutions, solution concentrates, gel-forming solutions / solution drops, sprays, measured sprays, suspensions, suspensions, syrups, tablets, chewable tablets, coated tablets, coated particles in tablets, film-coated tablets, tablets for solution, tablets for suspension, orally disintegrating tablets, soluble tablets, sugar-coated tablets, dispersible tablets, tablets with sensors, tapes, troches and wafers, and their sustained-release and delayed-release forms.

[0029] In a preferred embodiment, the pharmaceutical composition of the present formulation is in the form of a tablet. In a more preferred embodiment, the pharmaceutical composition of the present formulation is in the form of a dispersible tablet. In an even more preferred embodiment, the pharmaceutical composition of the formulation of the present invention is in the form of a water-dispersible tablet. In the most preferred embodiment, the pharmaceutical composition of the present formulation is in the form of a water-dispersible tablet, and the tablet is scored so that it can be divided into four equal parts.

[0030] In a preferred embodiment, when the pharmaceutical composition of the present formulation is in the form of a water-dispersible tablet, the dispersion time of the tablet when placed in at least one cup of water is within about 70 seconds, more preferably within about 60 seconds, and even more preferably within about 40 seconds.

[0031] In another embodiment, the present subject matter relates to a method of treating Alan Houghton Dudley Syndrome (“AHDS”), the method comprising administering to a subject in need thereof a composition comprising DITPA or a salt thereof and one or more pharmaceutically acceptable excipients. In another embodiment, the present subject matter relates to a method of treating one or more symptoms of AHDS, the method comprising administering to a subject in need thereof a composition comprising DITPA or a salt thereof and one or more pharmaceutically acceptable excipients.

[0032] In a preferred embodiment, the composition of the present subject matter is administered to a subject in need thereof once a day, more preferably twice a day, and most preferably three times a day. Each administration may be one or more whole tablets, or a portion of a tablet such as 1 / 2 or 1 / 4 of the whole tablet.

[0033] In another preferred embodiment, the composition of the present subject matter is administered at a dosage of about 0.1 to about 10 milligrams per kilogram of the subject's body weight per day (“mg / kg / day”), more preferably about 1 to about 5 mg / kg / day, and most preferably about 2.5 mg / kg / day.

[0034] In a preferred embodiment, DITPA is administered to a subject under 18 years of age. In another preferred embodiment, DITPA is administered to the pregnant mother of a subject in need thereof.

[0035] In a preferred embodiment, the pharmaceutical composition of the present subject matter is administered orally to a subject.

[0036] As used herein, the term “pharmaceutically acceptable” refers to components that are not biologically or otherwise undesirable in oral applications.

[0037] As used herein, all numerical values relating to amounts, weights, etc. are defined as the respective specific values “about”, i.e., plus or minus 10%. For example, the phrase “10% w / w” should be understood as “9% to 11% w / w”. Accordingly, amounts within 10% of the claimed value are included within the scope of the claims.

[0038] As used herein, “% w / w” refers to the weight percentage of the total formulation. As used herein, “% w / v” refers to the weight percentage based on the volume of the total formulation.

[0039] As used herein, the term “effective amount” refers to the amount necessary to treat a subject in need of treatment.

[0040] As used herein, the term “treatment” or “treating” refers to alleviating or improving AHDS or the symptoms of AHDS.

[0041] As used herein, the term “stable” includes, but is not limited to, physical and chemical stability. Pharmaceutically acceptable salts that can be used in accordance with the present subject matter include, but are not limited to, hydrochloride, hydrochloric acid dihydrate, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, mesylate, maleate, gentisinate, fumarate, tannate, sulfate, tosylate, esylate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0042] Throughout this application, unless the context clearly dictates otherwise, the singular forms “a”, “an”, and “the” include plural references.

[0043] The disclosed embodiments are merely exemplary embodiments of the inventive concepts disclosed herein and should not be considered limiting unless explicitly stated otherwise in the claims.

[0044] The following examples are intended to illustrate the subject matter and to teach those skilled in the art how to use the formulations of the subject matter. They are not intended to be limiting in any way.

Example

[0045] Example 1 - Sample formulation (predictive)

Table 1

[0046] Example 2 - Administration of the water-dispersible tablets (predictive) Method The water-dispersible tablets of the subject matter, such as the tablets of Example 1 (Table 1) above, typically dissolve completely in water within about 60 seconds upon mixing. The resulting dispersion is then immediately orally administered to the infant.

[0047] Results The dispersion is absorbed by the infant and is generally well tolerated.

[0048] Example 3 - Dosage regimen for pediatric subjects (predictive) Method 3,5-Diiodothyropropionic acid (“DITPA”) was administered to pediatric patients suffering from Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, the daily dose was increased to 2 mg / kg / day for an additional 2 weeks. After an additional 2 weeks, the T3 serum level was evaluated. The patient's T3 serum level was found to be 15% lower than normal. Thereafter, the patient was administered DITPA at a daily dose of 1.5 mg / kg / day for 28 days, at which point the T3 serum level was re-evaluated. As a result of the re-evaluation, the T3 serum level was normal.

[0049] Result This dosing schedule enables the appropriate dose for maintaining normal T3 serum levels in pediatric patients to be successfully identified.

[0050] Example 4 - Dosing Schedule for Pediatric Subjects (Predictive) Method DITPA was administered to pediatric patients suffering from Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, the daily dose was increased to 2 mg / kg / day for an additional 2 weeks. After an additional 2 weeks, the T3 serum level was evaluated. The patient's T3 serum level was found to be 15% higher than normal. Subsequently, the patient was administered DITPA at a daily dose of 2.5 mg / kg / day for 28 days, and the T3 serum level was re-evaluated at that time. As a result of the re-evaluation, the T3 serum level was normal.

[0051] Result This dosing schedule enables the appropriate dose for maintaining normal T3 serum levels in pediatric patients to be successfully identified.

[0052] Example 5 - Dosing Schedule for Pediatric Subjects (Predictive) Method DITPA was administered to pediatric patients suffering from Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, the daily dose was increased to 2 mg / kg / day for an additional 2 weeks. After an additional 2 weeks, the T3 serum level was evaluated. The patient's T3 serum level was found to be 15% lower than normal. Subsequently, the patient was administered DITPA at a daily dose of 1.5 mg / kg / day for 28 days, and the T3 serum level was re-evaluated at that time. As a result of the re-evaluation, the T3 serum level was again found to be 15% lower than normal. Subsequently, the patient was administered DITPA at a daily dose of 1.0 mg / kg / day for 28 days, and the T3 serum level was re-evaluated at that time. As a result of the re-evaluation, the T3 serum level was found to be normal.

[0053] Results This dosing schedule will successfully identify the appropriate dosage for pediatric patients to maintain normal T3 serum levels.

[0054] Effect of DITPA on removal of G-tube In one child who started DITPA while wearing a G-tube, the G-tube was removed because the child gained weight. The inventors designed the proposed Phase 3 trial to be robust with evaluation items aimed at determining the clinical benefits of DITPA compared to surrogate evaluation items. [Table 2-1] [Table 2-2]

[0055] The inventors' primary evaluation items were selected to ensure a high probability of NDA success based on the following factors: · The estimated PTRS to reach the primary evaluation item based on the difference in T3 levels at the end of the randomized withdrawal period has the power to detect a change of at least 100 ng / dL in serum T3 levels from baseline (start of randomized withdrawal) to week 8 (week 34 of the trial) that exceeds 99% compared to placebo. The inventors know from previous studies (such as LT3 treatment in primary hyperthyroidism) that the T3 levels in MCT8-deficient patients who discontinued SRW101 should rapidly increase within 8 weeks and have sufficient time to return to baseline high values within a few days because the LT3 levels increase within a few hours after treatment. · The main secondary evaluation items are to evaluate the dose escalation with SRW-101 and the complete total T3, free T4, and TSH response rates at the end of the maintenance therapy in the first single-group, non-blind part (week 24) of the study in the mITT population. The main secondary null hypothesis is that the proportion of patients who are complete responders for total T3, free T4, and TSH at the visit in week 24 is 0.2 or less. The alternative hypothesis is that the proportion of patients who are complete responders for total T3, free T4, and TSH at the visit in week 24 is greater than 0.2. An exact test for a proportion is used. The efficacy of SRW-101 is declared when the proportion of responders at the visit in week 24 is statistically significantly greater than 0.2 at a one-sided alpha level of 0.025. With a sample size of 40 patients aged 0 to 17 years, when using a one-sided exact test for a proportion at a target significance level of 0.025, the power to detect a difference of 100 ng / dL is approximately 100%. For secondary results, it is assumed that the proportion in the null hypothesis population is 0.2 and the alternative hypothesis is 0.80. · The number and proportion (expressed as a percentage) of total T3, free T4, and TSH responders are calculated at each scheduled time point during the OLDT period and the OLDM period (including the visit in week 24). These proportions are summarized for each scheduled time point together with the exact (Clopper-Pearson) 95% CI. Enrolled patients who missed the thyroid function test evaluation at week 24 are counted as non-responders for the main secondary evaluation items. Other secondary evaluation item analyses are specified in the statistical analysis plan (SAP), and then the approximate power is calculated.

[0056] Example 6 - Dosage Form, Route of Administration, and Administration Schedule This pharmaceutical product is a suspension tablet (i.e., dispersible tablet) designed to rapidly disintegrate in a small amount of aqueous medium before administration. The strength of each tablet can be scored into four parts to enable the administration of half or a quarter of the tablet dosage. This allows for a dosage increment of at least 1 mg, for example, in the case of a 4 mg tablet. An overview of exemplary pharmaceutical product attributes is shown in Table 2.

Table 3

[0057] One of the intended commercial products is a scored suspension tablet (dispersible tablet) that is divided into four parts so that the tablet can be divided into halves or quarters, thereby allowing a 4 mg tablet to be easily divided into 1 mg units for administration. Figure 2 is a photograph of an example of a scored tablet divided into four parts.

[0058] Two product strengths (4 and 10 mg) may be developed to allow for flexible dosing over the dosing ranges expected in the PRZ-MCT8-101 study and commercial use. These two tablets are scored into four parts, providing easy-to-administer portions of 1 mg, 2 mg, 2.5 mg, 4 mg, 5 mg, and 10 mg. Of course, additional dosing amounts can also be provided by combining multiple portions, such as combining the 1 mg portion and the 2 mg portion to provide a 3 mg dose, or combining the 5 mg portion and the 2 mg portion to provide a 7 mg dose.

[0059] The suitability of the scored tablets is characterized in accordance with FDA industry guidance. Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation (March 2013), as well as specific studies outlined in the EOP2 / Pre-Phase 3 FDA Meeting Package.

[0060] Pharmaceuticals and Administration Ingredients and Composition The pharmaceutical may be a suspension tablet (dispersible tablet) that is divided into four parts so that it can be divided into two or four equal parts. For example, refer to Figure 2. The tablet, or if divided into two or four equal parts, a portion of the tablet, is dispersed in a small amount of aqueous medium (e.g., 5 - 10 mL of water) prior to oral administration of the suspension. Two different product strengths (i.e., 4 and 10 mg) are planned and are appropriately distinguished by color debossing.

[0061] The components and composition of the pharmaceutical product are summarized in Table 3 below. All excipients are well-established for oral products and are at levels well below the respective maximum potencies listed in the FDA Inactive Ingredients (IIG) Database. Therefore, there are no new excipients involved in the manufacture of the pharmaceutical product.

[0062] The primary container closure system will be blister packaging. Based on Titan's studies of the API and the pharmaceutical product (i.e., the capsule), this drug product is stable to ambient temperature and light. Although the drug product does not appear to be hygroscopic, the formulation itself will be evaluated accordingly to assess any need for moisture mitigation. [Table 4]

[0063] Example 7 - Manufacturing Process One exemplary manufacturing process consists of stepwise compounding and blending SRW101 and the excipients in a tote bin blender to form a 10 kg common blend (commercial batch size). From the common blend, 4 and 10 mg tablets can be compressed using, for example, an IMA Comprima tablet press.

[0064] Exemplary lots are manufactured at full scale (10 kg) using the intended commercial manufacturing process. The 4 and 10 mg product strengths are manufactured from the same 10 kg blend.

[0065] Specifications and Analytical Methods The specifications for the exemplary pharmaceutical product are shown in Table 4. The specifications are developed in accordance with ICH-Q6A. All non-compendial methods (i.e., in-house HPLC for assays, degradation products, and dissolution sample testing) are fully validated prior to the release of clinical drug product lots. All compendial methods are qualified prior to the release of clinical drug product lots. The degradation products method is validated for stability as shown by forced degradation studies (i.e., heat, light, acid, base, and oxidation).

[0066] The limits of degradation products are recognized as safe according to the impurities in new pharmaceuticals of ICH-Q3B.

Table 5

[0067] Evaluation of the characteristics of tablet dispersion and tablet splitting Studies are also conducted to evaluate and ensure that not only can the tablets be dispersed in water, but also the dividable parts of the tablets can be properly dispersed in other media (i.e., powdered milk and apple sauce) (physical tests).

[0068] This tablet is intended to be divided by hand into halves or quarters by breaking along the score marks engraved on the surface of the tablet. Refer to Figure 2. The tablet can be held between the thumb and index finger on either side of the tablet or half of the tablet, with the score mark facing up. When downward pressure is applied outside the tablet or half of the tablet and upward pressure is applied in the center, the tablet is broken along the line shown in Figure 2.

[0069] Stability Pharmaceuticals manufactured using reprocessed API batches and NDA registration lots are subjected to stability studies under long-term, intermediate, and accelerated environmental conditions in accordance with ICH-Q1A(R2), as outlined in Table 19.6. Pharmaceuticals maintained under intermediate conditions are tested at all time points compared to the time point of the out-of-specification (OOS) result during the testing of the API under accelerated stability conditions.

[0070] Photostability studies are also carried out in accordance with ICH-Q1B. Six-month stability data are generated for all three stability conditions (i.e., long-term, intermediate, and accelerated conditions), together with the photostability data.

[0071] The DITPA formulations and regimens for treating AHDS or the symptoms of AHDS are not limited to the specific embodiments above, but rather include any embodiments within the scope of the general terms of the following claims enabled by the embodiments described herein, or any embodiments shown in the drawings or described in terms sufficient for one of ordinary skill in the art to make and use the claimed subject matter.

Claims

1. A pharmaceutical composition comprising 3,5-diiodothyropropionic acid or a salt thereof and one or more pharmaceutically acceptable excipients.

2. The 3,5-diiodothyropropionic acid is present at a concentration of about 0.001% to about 10% w / w or w / v, where w / w represents weight relative to the total weight of the composition and w / v represents weight relative to the total volume of the composition. The composition according to Claim 1.

3. The one or more pharmaceutically acceptable excipients are selected from the group consisting of a disintegrant, a binder, a filler, a plasticizer, a lubricant, a penetration enhancer, a surfactant, a sweetening agent, a sweetening enhancer, a flavoring agent, and a pH adjuster. The composition according to Claim 1 or 2.

4. The disintegrant is selected from the group consisting of natural starch, directly compressible starch, modified starch, starch derivatives, crosslinked polyvinylpyrrolidone, modified cellulose, alginic acid, sodium alginate, microcrystalline cellulose, methacrylic acid-divinylbenzene copolymer salt, and combinations thereof. The composition according to Claim 3.

5. The binder is selected from the group consisting of polyethylene glycol, soluble hydroxyalkyl cellulose, polyvinylpyrrolidone, gelatin, natural rubber, and combinations thereof. The composition according to Claim 3 or 4.

6. The penetration enhancer is selected from the group consisting of precipitated silica, maltodextrin, β-cyclodextrin, menthol, limonene, carvone, methyl chitosan, polysorbate, sodium lauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride, cetylpyridinium chloride, disodium edetate dihydrate, sodium deoxycholate, sodium deoxyglycocholate, sodium glycocholate, sodium caprylate, sodium taurocholate, sodium hydroxybenzoyl aminocaprylate, dodecyldimethylaminopropionate, L-lysine, glyceryl oleate, glyceryl monostearate, citric acid, peppermint oil, and combinations thereof. The composition according to any one of Claims 3 to 5.

7. The surfactant is selected from the group consisting of sorbitan esters, sodium doxsate, sodium lauryl sulfate, cetomacrogol, and combinations thereof, the composition according to any one of claims 3 to 6.

8. The composition does not contain a preservative, the composition according to any one of claims 1 to 7.

9. The composition is in the form of a tablet, the composition according to any one of claims 1 to 8.

10. The tablet is water-dispersible, the composition according to claim 9.

11. The tablet is scored so that the tablet can be divided into four equal parts, the composition according to claim 9 or 10.

12. The tablet disperses in water within about 70 seconds, the composition according to claim 10.

13. The tablet disperses in water within about 40 seconds, the composition according to claim 12.

14. A method for treating Alan Houghton Dudley syndrome, comprising administering the composition according to any one of claims 1 to 13 to a subject in need thereof.

15. A method for treating one or more symptoms of Alan Houghton Dudley syndrome, comprising administering the composition according to any one of claims 1 to 13 to a subject in need thereof.

16. The composition is administered at a dosage of about 0.1 to about 10 milligrams per kilogram of the subject's body weight per day (mg / kg / day), the method according to claim 14 or 15.

17. The composition is administered at a dosage of about 1 to about 5 mg / kg / day, the method according to claim 16.

18. The composition is administered at a dosage of about 2.5 mg / kg / day, the method according to claim 16.

19. The amount of the composition administered per day is divided into three parts, and one part is administered to the subject three times a day, the method according to any one of claims 14 to 18.

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