Ploroglucinol formulations and methods of use

Abstract

The present disclosure provides a pharmaceutical composition comprising an active pharmaceutical ingredient (API) in a total amount of from about 50 mg to about 1000 mg, the active pharmaceutical ingredient being phloroglucinol, trimethylphloroglucinol, a pharmaceutically acceptable salt thereof, or a combination thereof. The pharmaceutical composition comprises an immediate release moiety, a first modified release moiety, and a second modified release moiety. Also provided are oral dosage units comprising the pharmaceutical compositions, and methods of treating spasmodic conditions using the pharmaceutical compositions or oral dosage units in a subject in need thereof.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 351,572, filed on June 13, 2022, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to pharmaceutical compositions comprising an active pharmaceutical ingredient (API) which is phloroglucinol, trimethylphloroglucinol, a pharmaceutically acceptable salt thereof, or a combination thereof, and methods of use thereof. Background Art

[0004] Phloroglucinol is an antispasmodic drug, known in French as Spasfon TM ) and several other countries for the relief of pain in gastrointestinal disorders. In placebo-controlled trials, phloroglucinol demonstrated statistically significant improvements in pain and stool frequency in patients with irritable bowel syndrome (IBS). Despite its proven efficacy, the PK properties of phloroglucinol do make it difficult to administer daily over the long term. After administration of existing formulations, the maximum plasma concentration (C max ), followed by a rapid decline. Therefore, frequent dosing (up to 6 times a day) is required.

[0005] There is a need for formulations that maintain efficacy with less frequent dosing. Summary of the invention

[0006] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an active pharmaceutical ingredient (API) in a total amount of about 50 mg to about 1000 mg, wherein the active pharmaceutical ingredient is phloroglucinol, trimethylphloroglucinol, a pharmaceutically acceptable salt thereof, or a combination thereof. The pharmaceutical composition comprises an immediate release portion comprising about 20-40% by weight of the total amount of the API, wherein at least about 90% by weight of the API in the immediate release portion is released from the pharmaceutical composition within about 2 hours as measured by a USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution at about 37° C. The pharmaceutical composition also comprises a first modified release portion comprising about 20-40% by weight of the total amount of the API, wherein at least about 90% by weight of the API in the first modified release portion is released from the pharmaceutical composition after at least about 2 hours to about 4 hours as measured by a USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution at about 37° C. The pharmaceutical composition further comprises a second modified release portion comprising about 20-40% by weight of the total amount of the API, wherein at least about 90% by weight of the API in the second modified release portion is released from the pharmaceutical composition after about 4 hours or more as measured by USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution at about 37° C. An oral dosage unit comprising a pharmaceutical composition according to any one of the preceding claims.

[0007] In other embodiments, the present disclosure provides a method of treating a spastic disorder in a subject in need thereof, the method comprising orally administering to the subject an oral dosage unit described herein, (i) wherein oral administration to the subject in the fed state results in: a median T value of the API of max from about 0.5 to about 1.75 hours; the average C max From about 269 to about 1512 ng / mL; the average AUC of the API tau from about 879 to about 4695 h*ng / mL; and / or the mean t1 / 2 of the API is from about 1.6 hours to about 2.4 hours; or (ii) wherein oral administration to the subject in the fasting state results in: a median T1 / 2 of the API max is about 0.5 hours; the average C max From about 2745 to about 4874 ng / mL; the average AUC of the API tau is about 4567 to about 6853 h*ng / mL; and / or the average t1 / 2 of the API is about 2 hours. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The present application may be further understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the subject matter, exemplary embodiments of the subject matter are shown in the accompanying drawings; however, the subject matter of the present disclosure is not limited to the specific compositions, methods, devices, and systems disclosed. In addition, the drawings are not necessarily drawn to scale.

[0009] Figures 1A-1C Figure 1 is a graph of the mean (+SD) of plasma phloroglucinol concentrations on Day 1 plotted by dose level on a semi-log scale - PK population. In these graphs, LLOQ for phloroglucinol = 10 ng / mL; at any single time point, the mean concentration was calculated only if at least half of the subjects had a valid value (i.e., quantifiable and not missing) at that time point for each treatment.

[0010] Figure 2A-2C Plots of mean (+SD) plasma phloroglucinol trough concentrations by dose level plotted on a semi-log scale - PK population. In these plots, LLOQ for phloroglucinol = 10 ng / mL; BID tau = 10 h, AM dosing only on Day 6. At any single time point, the mean concentration was calculated only if at least half of the subjects had a valid value (i.e., quantifiable and not missing) at that time point for each treatment.

[0011] Figure 3 is a flow chart of a manufacturing process for preparing the dosage forms of the present disclosure.

[0012] Figure 4 is the dissolution curve of the capsule of Example 1. DETAILED DESCRIPTION

[0013] The present disclosure provides a pharmaceutical composition capable of releasing an active pharmaceutical ingredient within a predetermined time period. The composition contains an immediate release and a delayed release portion, thereby providing sustained release of the API. In this way, the patient does not need to continuously administer an oral dosage form of the API throughout the day. Therefore, the API is administered on a more regular basis, and the condition is treated more reliably.

[0014] In this disclosure, unless the context clearly dictates otherwise, references to no specific number include plural referents, and references to a specific value include at least that specific value. Thus, for example, a reference to "a material" is a reference to at least one of such material and equivalents thereof known to those skilled in the art, and so forth.

[0015] The modifier "about" should be considered to disclose a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses a range of "2 to 4". When used to modify a single number, the term "about" may mean plus or minus 10% of the indicated number, and includes the indicated number. For example, "about 10%" may mean a range of 9% to 11%, and "about 1" means 0.9 to 1.1.

[0016] When a list is presented, it should be understood that each individual element of the list and each combination of the list should be interpreted as a separate embodiment unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0017] It should be understood that certain features of the invention, which are described herein in the context of separate embodiments for the sake of clarity, may also be provided in combination in a single embodiment. That is, unless clearly incompatible or exclusive, each individual embodiment is considered to be combinable with any other embodiment, and such combination is considered to be another embodiment. Conversely, the various features of the invention, which are described in the context of a single embodiment for the sake of brevity, may also be provided separately or in any sub-combination. It should also be noted that the drafting of the claims may exclude any optional elements. Therefore, this statement is intended to serve as a prior basis for the use of exclusive terms such as "only", "only" and the like in conjunction with the recitation of claim elements, or the use of "negative" limitations. Finally, although an embodiment may be described as part of a series of steps or part of a more general structure, each of the steps may also be considered an independent embodiment in itself.

[0018] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the U.S. Federal or a state government, or equivalent agencies in countries outside the U.S., or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0019] As used herein, the terms "patient" or "subject" refer to mammals and are used interchangeably. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary or farm animal, livestock or pet, or an animal commonly used in clinical research.

[0020] In some embodiments, "treating" any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or alleviating the development of the disease or at least one of its clinical symptoms). "Treatment" refers to the use of phloroglucinol, trimethylphloroglucinol, or a combination thereof to ameliorate a disease or disorder. In some embodiments, "treating" refers to improving at least one physical parameter that may not be discernible by the subject. In other embodiments, "treating" refers to modulating the disease or disorder, whether physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In other embodiments, "treating" refers to delaying the onset of a disease or disorder.

[0021] The present disclosure provides a pharmaceutical composition comprising an active pharmaceutical ingredient (API), wherein the API is phloroglucinol, trimethyl phloroglucinol, a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the API is phloroglucinol or a pharmaceutically acceptable salt thereof. In other embodiments, the API is trimethyl phloroglucinol or a pharmaceutically acceptable salt thereof.

[0022] As used herein, the term "phloroglucinol" refers to the following compound.

[0023]

[0024] Phloroglucinol also includes any tautomeric forms thereof, including its known keto tautomer as shown below.

[0025]

[0026] Likewise, the term "trimethylphloroglucinol" as used herein refers to the following compound.

[0027]

[0028] Phloroglucinol and trimethylphloroglucinol can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids, bases, alkali metals and alkaline earth metals. In some embodiments, pharmaceutically acceptable salts can be formed from organic and inorganic acids, including for example acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and similar known acceptable acids. In other embodiments, pharmaceutically acceptable salts can also be formed from inorganic bases, and it is desirable to be alkali metal salts, including for example sodium, lithium or potassium, for example alkali metal hydroxides. The example of inorganic bases includes but is not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide. Pharmaceutically acceptable salts can also be formed from organic bases such as ammonium salts, mono-, di- and tri-methylammonium, mono-, di- and tri-ethylammonium, mono-, di- and tri-propylammonium, ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and tri-ethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium, diethanolamine, ethylenediamine, etc. In one example, the base is sodium hydroxide, lithium hydroxide, potassium hydroxide or a mixture thereof.

[0029] The pharmaceutical composition contains a total amount of about 50 mg to about 1000 mg of the API. In some embodiments, the pharmaceutical composition contains a total amount of about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, or about 1000 mg of the API. In other embodiments, the pharmaceutical composition contains about 100 to about 1000, about 100 to about 900, about 100 to about 800, about 100 to about 700, about 100 to about 600, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 1000, about 200 to about 900, about 200 to about 800, about 200 to about 700, about 200 to about 600, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 1000, about 300 to about 900, about 300 to about 800, about 300 to about 700, about 300 to about 600, about 200 to about 500, about 200 to about 400 or about 900 to about 1000 mg of the API.

[0030] The pharmaceutical composition comprises an immediate release portion, a first modified release portion, and a second modified release portion. In some embodiments, the immediate release portion and the first modified release portion contain the same API. In other embodiments, the immediate release portion and the second modified release portion contain the same API. In other embodiments, the first and second modified release portions contain the same API. In other embodiments, the immediate release, the first modified release, and the second modified release portions contain the same API.

[0031] The immediate release portion comprises about 20 to about 40 wt % of the API based on the weight of the pharmaceutical composition. In some embodiments, the immediate release portion contains about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 wt % of the API based on the weight of the pharmaceutical composition. In other embodiments, the immediate release portion contains about 20 to about 40, about 20 to about 38, about 20 to about 36, about 20 to about 35, about 20 to about 34, about 20 to about 32, about 20 to about 30, about 20 to about 28, about 20 to about 26, about 20 to about 25, about 20 to about 24, about 20 to about 22, about 22 to about 40, about 22 to about 38, about 22 to about 36, about 22 to about 35, about 22 to about 34, about 22 to about 32, about 22 to about 30, about 22 to about 28, about 22 to about 26, about 22 to about 24, about 24 to about 40, about 24 to about 38, about 24 to about 36, about 24 to about 35, about 22 to about 34, about 22 to about 32, about 22 to about 32, about 28 to about 30, about 24 to about 26, about 26 to about 40, about 26 to about 38, about 26 to about 36, about 26 to about 35, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 40, about 28 to about 38, about 28 to about 36, about 28 to about 35, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 40, about 30 to about 38, about 30 to about 36, about 30 to about 35, about 30 to about 34, about 30 to about 32, about 32 to about 40, about 32 to about 38, about 32 to about 36, about 32 to about 34, about 34 to about 40, about 34 to about 38, about 34 to about 36, about 36 to about 40, about 36 to about 38, or about 38 to about 40 wt % of the API.

[0032] The immediate release portion may contain about 50 mg to about 500 mg of the API. In some embodiments, the immediate release portion contains about 50, about 75, about 100, about 125, about 150, about 160, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 400, about 425, about 450, about 475, or about 500 mg of the API. In other embodiments, the immediate release portion contains about 50 to about 450, about 50 to about 400, about 50 to about 350, about 50 to about 300, about 50 to about 250, about 50 to about 200, about 50 to about 150, about 50 to about 100, about 100 to about 500, about 100 to about 450, about 100 to about 400, about 100 to about 350, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 500, about 150 to about 450, about 150 to about 400, about 150 to about 350, about 150 to about 300, about 150 to about 250. In some embodiments, the immediate release portion contains about 50 mg to about 400 mg of the API. In other embodiments, the immediate release portion contains about 160 mg of the API.

[0033] According to the present disclosure, at least about 90% by weight of the API in the immediate release portion is released from the pharmaceutical composition, for example, within about 2 hours from administration of the API, as measured by USP 2 paddles at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution at about 37° C. In some embodiments, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 100% by weight of the API in the immediate release portion is released from the pharmaceutical composition, for example, within about 2 hours from administration of the API, as measured by USP 2 paddles at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution at about 37° C. In other embodiments, at least about 90% by weight of the API in the immediate release portion is released from the pharmaceutical composition, for example, within about 2 hours from administration of the API, as measured by USP 2 paddles at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution at about 37° C. The immediate release portion comprises about 90 to about 100, about 90 to about 99, about 90 to about 98, about 90 to about 97, about 90 to about 96, about 90 to about 95, about 90 to about 94, about 90 to about 93, about 90 to about 92, about 90 to about 91, about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 91 to about 96, about 91 to about 95, about 91 to about 94, about 90 to about 93, about 90 to about 92, about 90 to about 91, about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 91 to about 96, about 91 to about 95, about 91 to about 94, about 91 to about 93, about 91 to about 92, about 92 to about 100, about 92 to about 99, about 92 to about 98, about 92 to about 97, about 92 to about 96, about 92 to about 95, about 92 to about 94, about 92 to about 93, about 93 to about 100 or about 99 to about 100 weight percent of the API is released from the pharmaceutical composition, for example, within about 2 hours from administration of the API.

[0034] The term "within about 2 hours" refers to a time frame from about 1 minute to about 2 hours. In certain aspects, the API is released within about 2 hours from administration of the API. In some embodiments, the API is released from the immediate release portion within, for example, about 1, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 minutes from administration of the API. In other embodiments, the API is administered within, for example, about 1 to about 120 minutes, about 1 to about 110, about 1 to about 100, about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 10 to about 120, about 10 to about 110, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 ... 0, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 120, about 20 to about 110, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 120, about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about about 60, about 30 to about 50, about 30 to about 40, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 120, about 50 to about 110, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 40 to about 50, about 50 to about 120, about 50 to about 110, about 60 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 120, about 60 to about 110, about 60 to about 100, about The immediate-release portion is released from the immediate-release portion within 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 120, about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 120, about 80 to about 110, about 80 to about 100, about 80 to about 90, about 90 to about 120, about 90 to about 110, about 90 to about 100, about 100 to about 120, about 100 to about 110, or about 110 to about 120 minutes.

[0035] According to the present disclosure, the first modified release portion comprises about 20 to about 40 wt % of the API based on the weight of the pharmaceutical composition. In some embodiments, the first modified release portion contains about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 wt % of the API based on the weight of the pharmaceutical composition. In other embodiments, the first modified release portion comprises about 20 to about 40, about 20 to about 38, about 20 to about 36, about 20 to about 35, about 20 to about 34, about 20 to about 32, about 20 to about 30, about 20 to about 28, about 20 to about 26, about 20 to about 25, about 20 to about 24, about 20 to about 22, about 22 to about 40, about 22 to about 38, about 22 to about 36, about 22 to about 34, about 22 to about 32, about 22 to about 30, about 22 to about 38, about 22 to about 36, about 22 to about 34, about 22 to about 32, about 22 to about 30, about 22 to about 28, about 22 to about 26, about 22 to about 24, about 24 to about 40, about 24 to about 38, about 24 to about 36, % by weight of the API.

[0036] The first modified release portion may contain about 25 mg to about 200 mg of the API. In some embodiments, the first modified release portion contains about 25, about 50, about 75, about 80, about 100, about 125, about 150, about 160, about 175, or about 200 mg of the API. In other embodiments, the first modified release portion comprises about 25 to about 200, about 25 to about 175, about 25 to about 160, about 25 to about 150, about 25 to about 125, about 25 to about 100, about 25 to about 75, about 25 to about 60, about 25 to about 50, about 50 to about 200, about 50 to about 175, about 50 to about 160, about 50 to about 150, about 50 to about 125, about 50 to about 100, about 50 to about 80, about 50 to about 75, about 75 to about 200, about 75 to about 175, about 75 to about 160, about 75 to about 150, about 75 to about 125, about 75 to about 100. In some embodiments, the first modified release portion contains about 50 mg to about 200 mg of the API. In other embodiments, the first modified release portion contains about 160 mg of the API. In other embodiments, the first modified release portion contains about 160 mg of the API. In other embodiments, the first modified release portion contains about 80 mg of the API.

[0037] At least about 90 weight percent of the API in the first modified release portion is released from the pharmaceutical composition, e.g., after at least about 2 hours to about 4 hours from administration of the API, as measured by USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution at about 37°C. In some embodiments, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 100 weight percent of the API in the first modified release portion is maintained at, e.g., at least about 2 hours to about 4 hours from administration of the API, e.g., about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, or about 4 hours or e.g., about 2 to about 3.75, about 2 to about 3.5, about 2 to about 3.25, about 2 to about 3.75, about 2 to about 3.25, about 2 to about 3.75, about 2 to about 3.25, about 2 to about 3.75, about 2 to about 3.25, about 2 to about 3.75, about 2 to about 3.25, about 2 to about 3.75, about 2 to about 3.25, about 2 to about 3.75, about 2 to about 3.25, about 2 to about 3. From the pharmaceutical composition, the dosage form may be released after 2.25 to about 3, about 2.25 to about 2.75, about 2.25 to about 2.5, about 2.5 to about 4, about 2.5 to about 3.75, about 2.5 to about 3.5, about 2.5 to about 3.25, about 2.5 to about 3, about 2.5 to about 2.75, about 2.75 to about 4, about 2.75 to about 3.75, about 2.75 to about 3.5, about 2.75 to about 3.25, about 2.75 to about 3, about 3 to about 4, about 3 to about 3.75, about 3 to about 3.5, about 3 to about 3.25, about 3.25 to about 4, about 3.25 to about 3.75, about 3.25 to about 3.5, about 3.5 to about 4, about 3.5 to about 3.75, or about 3.75 to about 4 hours.In other embodiments, as described above, the method comprises preparing a 0.1 N aqueous solution of about 0.1 N aqueous solution by USP 2 paddle method at about 50 rpm in about 750 mL at about 37°C. about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 90 to about 96, about 90 to about 95, about 90 to about 94, about 90 to about 93, about 90 to about 92, about 90 to about 91, about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 91 to about 96, about 91 to about 95, about 91 to about 94, about 90 to about 93, about 90 to about 92, about 90 to about 91, about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 91 to about 96, about 91 to about 95, about 91 to about 94, about 92 to about 93, about 93 to about 100, about 92 to about 99, about 92 to about 98, about 92 to about 97, about 92 to about 96, about 92 to about 95, about 92 to about 94, about 92 to about 93 9, about 93 to about 98, about 93 to about 97, about 93 to about 96, about 93 to about 95, about 93 to about 94, about 94 to about 100, about 94 to about 99, about 94 to about 98, about 94 to about 97, about 94 to about 96, about 94 to about 95, about 95 to about 100, about 95 to about 99, about 95 to about 98, about 95 to about 97, about 95 to about 96, about 96 to about 100, about 96 to about 99, about 96 to about 98, about 96 to about 97, about 97 to about 100, about 97 to about 99, about 97 to about 98, about 98 to about 100, about 98 to about 99, or about 99 to about 100 weight % of the API is released from the pharmaceutical composition, for example, after at least about 2 hours to about 4 hours from administration of the API.

[0038] According to the present disclosure, the second modified release portion comprises about 20 to about 40 wt % of the API based on the weight of the pharmaceutical composition. In some embodiments, the second modified release portion contains about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 wt % of the API based on the weight of the pharmaceutical composition. In other embodiments, the second modified release portion comprises about 20 to about 40, about 20 to about 38, about 20 to about 36, about 20 to about 35, about 20 to about 34, about 20 to about 32, about 20 to about 30, about 20 to about 28, about 20 to about 26, about 20 to about 25, about 20 to about 24, about 20 to about 22, about 22 to about 40, about 22 to about 38, about 22 to about 36, about 22 to about 36, by weight of the pharmaceutical composition. , about 22 to about 35, about 22 to about 34, about 22 to about 32, about 22 to about 30, about 22 to about 38, about 22 to about 36, about 22 to about 34, about 22 to about 32, about 22 to about 30, about 22 to about 28, about 22 to about 26, about 22 to about 24, about 24 to about 40, about 24 to about 38, about 24 to about 36, about 24 to about 35, about 24 to about 34, about 24 to about 32, about 24 to about 30, about 24 to about 28, about 24 to about 26, about 26 to about 40, about 26 to about 38, about 26 to about 36, about 26 to about 35, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 40, about 28 to about 38, about 28 to about 36, about 28 to about 35, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 40, about 30 to about 38, about 30 to about 36, about 30 to about 35, about 30 to about 34, about 30 to about 32, about 32 to about 40, about 32 to about 38, about 32 to about 36, about 32 to about 35, about 32 to about 34, about 34 to about 40, about 34 to about 38, about 34 to about 36, about 34 to about 35, about 35 to about 40, about 35 to about 36, about 36 to about 40, about 36 to about 38, or about 38 to about 40 wt % of the API.

[0039] The second modified release portion may contain about 25 mg to about 200 mg of the API. In some embodiments, the second modified release portion contains about 25, about 50, about 75, about 80, about 100, about 125, about 150, about 160, about 175, or about 200 mg of the API. In other embodiments, the second modified release portion comprises about 25 to about 200, about 25 to about 175, about 25 to about 160, about 25 to about 150, about 25 to about 125, about 25 to about 100, about 25 to about 75, about 25 to about 60, about 25 to about 50, about 50 to about 200, about 50 to about 175, about 50 to about 160, about 50 to about 150, about 50 to about 125, about 50 to about 100, about 50 to about 80, about 50 to about 75, about 75 to about 200, about 75 to about 175, about 75 to about 160, about 75 to about 150, about 75 to about 125, about 75 to about 100. In some embodiments, the second modified release portion contains about 50 mg to about 200 mg of the API. In other embodiments, the second modified release portion contains about 150 mg to about 200 mg of the API. In other embodiments, the second modified release portion contains about 160 mg of the API. In other embodiments, the second modified release portion contains about 80 mg of the API.

[0040] At least about 90% by weight of the API in the second modified release portion is released from the pharmaceutical composition, e.g., after 4 hours or more from administration of the API, as measured by a USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution at about 37° C. In some embodiments, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 100% by weight of the API in the second modified release portion is released, e.g., after 4 hours or more from administration of the API, e.g., about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours from administration of the API, or e.g., about 4 to 12, about 4 to 11, about 4 to 10, about 4 to 9, about 4 to 8, about 4 to 7, about 4 to 6, about 4 to 5, about 5 to 12 , about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 12, about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 hours, is released from the pharmaceutical composition.In other embodiments, as described above, the method comprises preparing a 0.1 N aqueous solution of about 0.1 N aqueous solution by USP 2 paddle method at about 50 rpm in about 750 mL at about 37°C. about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 90 to about 96, about 90 to about 95, about 90 to about 94, about 90 to about 93, about 90 to about 92, about 90 to about 91, about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 91 to about 96, about 91 to about 95, about 91 to about 94, about 90 to about 93, about 90 to about 92, about 90 to about 91, about 91 to about 100, about 91 to about 99, about 91 to about 98, about 91 to about 97, about 91 to about 96, about 91 to about 95, about 91 to about 94, about 92 to about 93, about 93 to about 100, about 92 to about 99, about 92 to about 98, about 92 to about 97, about 92 to about 96, about 92 to about 95, about 92 to about 94, about 92 to about 93, about 93 to about 100 About 99, about 93 to about 98, about 93 to about 97, about 93 to about 96, about 93 to about 95, about 93 to about 94, about 94 to about 100, about 94 to about 99, about 94 to about 98, about 94 to about 97, about 94 to about 96, about 94 to about 95, about 95 to about 100, about 95 to about 99, about 95 to about 98, about 95 to about 97, about 95 to about 96, about 96 to about 100, about 96 to about 99, about 96 to about 98, about 96 to about 97, about 97 to about 100, about 97 to about 99, about 97 to about 98, about 98 to about 100, about 98 to about 99, or about 99 to about 100 weight percent of the API is released from the pharmaceutical composition, for example, after 4 hours or more from administration of the API.

[0041] As used herein, the release of the API from the immediate release portion, the first modified release portion, the second modified release portion, or a combination thereof is measured at about 37°C by a USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution.

[0042] Dosage Unit

[0043] As discussed herein, the present disclosure provides dosage units containing pharmaceutical compositions described herein. In some embodiments, the oral dosage unit is formulated for oral administration, i.e., an oral dosage unit. The oral dosage unit can take various delivery forms. In some embodiments, the dosage unit is a tablet, a capsule (hard or soft), a bag, a soft gel, a liquid, a gel, a strip, a film, or a tablet in a capsule. In other embodiments, the dosage unit is a tablet, a capsule, or a bag. In other embodiments, the oral dosage unit is a tablet. In other embodiments, the oral dosage unit is a capsule. In other embodiments, the oral dosage unit is a bag.

[0044] The term "tablet" as used herein refers to a solid dosage unit. The tablet may have any shape or size that is convenient for oral administration, such as round, oval, etc. Depending on the base of the tablet, it may be coated with a layer comprising the immediate release portion or the modified release portion. In some embodiments, the tablet is a double-layer tablet containing an immediate release (IR) and a modified release layer adjacent to each other. In other embodiments, the tablet is a three-layer tablet containing an immediate release and a modified release layer separated by a layer such as a buffer layer. In other embodiments, the tablet contains particles coated with the immediate release portion embedded in the tablet and beads coated with the first modified release portion and / or the second modified release portion. In other embodiments, the tablet contains a tablet comprising the first modified release portion and / or the second modified release portion embedded in a tablet comprising the immediate release portion. In other embodiments, the tablet contains a tablet comprising the first modified release portion and / or the second modified release portion suspended in a liquid solution comprising the immediate release portion, wherein the liquid solution is contained in a capsule. In other embodiments, the capsule of the present disclosure contains a solution comprising the immediate release portion and beads or particles coated with the first modified release portion and / or the second modified release portion. In other embodiments, the soft gel of the present disclosure contains a solution comprising the immediate release portion and beads or particles coated with the first modified release portion and / or the second modified release portion.

[0045] The term "capsule" as used herein refers to a solid dosage unit. The shape of the capsule is generally oval, but other forms determined by those skilled in the art may be used. The capsule may be a hard or soft gelatin capsule as desired. In some embodiments, the capsule contains a tablet comprising the immediate release portion and a tablet comprising the first modified release portion and / or the second modified release portion. In other embodiments, the capsule contains an immediate release tablet, a plug, and a modified release tablet comprising the first modified release portion and / or the second modified release portion. In other embodiments, the capsule contains beads coated with the immediate release portion and beads coated with the first modified release portion and / or the second modified release portion. In other embodiments, the capsule contains an immediate release mini-tablet and a modified release mini-tablet comprising the first modified release portion and / or the second modified release portion. In other embodiments, the capsule contains immediate release granules and granules coated with the first modified release portion and / or the second modified release portion. In other embodiments, the capsule contains a plurality of beads coated with the first modified release and / or the second modified release portion and an immediate release portion as a layer.

[0046] The term "bag" as used herein refers to a package containing a mixture of immediate release and modified release particles or beads comprising the immediate release portion and particles or beads comprising the first modified release portion and / or the second modified release portion. The package can be selected by those skilled in the art.

[0047] Regardless of the form of the dosage unit, it may optionally or additionally contain beads, particles, or a combination thereof. "Beads" as used herein are solid particles prepared by extrusion and spheronization of the immediate release portion, the first modified release portion, and / or the second modified release portion, or a combination thereof. In some embodiments, the pharmaceutical composition takes the form of a plurality of beads. In other embodiments, the pharmaceutical composition takes the form of a plurality of particles. The beads or particles contain a core and an optional layer on the core. Similarly, the "particles" are solid particles, but they are prepared by granulation. Those skilled in the art will be able to select a suitable granulation method to prepare the particles used herein. In some embodiments, the granulation method includes high shear granulation, melt granulation, dry granulation, or wet granulation, etc. In some embodiments, the dosage unit contains beads comprising the immediate release portion. In other embodiments, the dosage unit contains beads comprising the first modified release portion. In other embodiments, the dosage unit contains beads comprising the second modified release portion. In other embodiments, the dosage unit contains beads comprising the immediate release portion and the first modified release portion. In other embodiments, the dosage unit contains beads comprising the first modified release portion and the second modified release portion. In other embodiments, the dosage unit contains beads comprising the immediate release portion, the first modified release portion and the second modified release portion.

[0048] Regardless of the specific presentation, the dosage form contains about 10 to about 60 weight % of the immediate release portion based on the weight of the oral dosage unit. In some embodiments, the dosage form contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 55 or about 60 weight % of the immediate release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 10 to about 55, about 10 to about 50, about 10 to about 45, about 10 to about 40, about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 60, about 15 to about 55, about 15 to about 50, about 15 to about 45, about 15 to about 40, about 15 to about 35, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 60, about 20 to about 55, about 20 to about 50, about 20 to about 45, about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, The immediate release portion is about 25 to about 60, about 25 to about 55, about 25 to about 50, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 60, about 30 to about 55, about 30 to about 50, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 60, about 35 to about 55, about 35 to about 50, about 35 to about 45, about 35 to about 40, about 40 to about 60, about 40 to about 55, about 40 to about 50, about 40 to about 45, about 45 to about 60, about 45 to about 55, about 45 to about 50, about 50 to about 60, about 50 to about 55, or about 55 to about 60% by weight of the immediate release portion. In other embodiments, the dosage form contains about 30 to about 50% by weight of the immediate release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 43 weight % of the immediate release portion based on the weight of the oral dosage unit.

[0049] The dosage form may also contain about 10 to about 40 weight % of the first modified release portion based on the weight of the oral dosage unit. In some embodiments, the dosage form contains about 10, about 15, about 20, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, or about 40 weight % of the first modified release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 10 to about 40, about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 40, about 15 to about 35, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 40, about 30 to about 35, about 25 to about 30, about 30 to about 40, about 30 to about 35, or about 35 to about 40 weight % of the first modified release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 20 to about 30 weight % of the first modified release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 28 weight % of the first modified release portion based on the weight of the oral dosage unit.

[0050] The dosage form further comprises about 10 to about 40 weight % of the second modified release portion based on the weight of the oral dosage unit. In some embodiments, the dosage form comprises about 10, about 15, about 20, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, or about 40 weight % of the second modified release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 40, about 15 to about 35, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 40, about 30 to about 35, or about 35 to about 40 weight % of the second modified release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 20 to about 30 weight % of the second modified release portion based on the weight of the oral dosage unit. In other embodiments, the dosage form contains about 28 weight % of the second modified release portion based on the weight of the oral dosage unit.

[0051] Typically, a plurality of beads or particles are incorporated into the dosage units described herein. As used herein, the term "plurality" refers to a plurality of beads or particles that provide the amount of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt required for the dosage unit. In some embodiments, the dosage unit comprises a plurality of beads. In other embodiments, the dosage unit comprises a plurality of particles. In other embodiments, the dosage unit comprises a plurality of beads and a plurality of particles.

[0052] The beads and / or particles contain one or both of the immediate release or modified release portions. In some embodiments, the beads comprise the immediate release portion. In other embodiments, the beads comprise the modified release portion. In other embodiments, the beads comprise the immediate release and modified release portions. In other embodiments, the particles comprise the immediate release portion. In other embodiments, the particles comprise the modified release portion. In other embodiments, the particles comprise the immediate release and modified release portions.

[0053] The dosage forms or pharmaceutical compositions described herein may contain one or more different types of beads or particles. In certain aspects, the dosage forms contain three types of beads or particles. For example, the dosage forms or pharmaceutical compositions described herein contain (i) an immediate release portion, which includes beads or particles containing the immediate release portion, (b) a first modified release portion, which includes beads or particles containing the first modified release portion, (c) and a second modified release portion, which includes beads or particles containing the second modified release portion. In other aspects, the dosage forms or pharmaceutical compositions described herein contain two types of beads or particles. In some embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or particles, which include an immediate release portion coated on the first modified release portion. In other embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or particles, which include an immediate release portion coated on the second modified release portion. In other embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or particles, which include an immediate release portion coated on a combination of the first release portion and the second release portion. In other aspects, the dosage forms or pharmaceutical compositions described herein contain one type of beads or particles. In some embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or particles comprising a first modified release portion coated on the second release portion. In other embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or particles comprising a first modified release portion coated on the second release portion and an immediate release portion coated on the first modified release portion.

[0054] Any of the beads or particles can be coated with a topcoat. In some embodiments, the beads or particles can be coated with a topcoat that is an enteric polymer that modulates the release of the API. For example, the first modified release portion comprises an API-containing core coated with a first enteric polymer that is soluble at a pH of about 5.5. The first enteric polymer can be selected by one skilled in the art. In some embodiments, the first enteric polymer is a methacrylic acid copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or a methacrylic acid:ethyl acrylate copolymer, such as a 1:1 copolymer, or a L 30D-55 polymer. In some embodiments, the first enteric polymer is methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate, or cellulose acetate phthalate. In other embodiments, the first enteric polymer is a 1:1 methacrylic acid:ethyl acrylate copolymer. In other embodiments, the first enteric polymer is L 30D-55 polymer. In other embodiments, the API-containing core coated with the first enteric polymer takes the form of beads or granules.

[0055] In other examples, the second modified release portion comprises an API-containing core coated with a second enteric polymer that is soluble at a pH of 6.8 or higher. In some embodiments, the second enteric polymer is a methacrylic acid copolymer, methyl acrylate, or a methyl methacrylate copolymer. In other embodiments, the second enteric polymer is methacrylic acid. In other embodiments, the enteric polymer is methyl acrylate. In other embodiments, the second enteric polymer is a methyl methacrylate copolymer. In other embodiments, the second enteric polymer is FS 30D copolymer. In other embodiments, the API-containing core coated with the second enteric polymer takes the form of beads or granules.

[0056] Ideally, the dosage form described herein releases all API within a specified time period. In some aspects, at least about 30% by weight of the total amount of API in the composition is released from the composition, for example, within a time period of about 5 minutes to about 2 hours from the application of the API. For example, about 30 to about 60% by weight of the total amount of API in the composition is released from the composition, for example, within a time period of about 5 minutes to about 2 hours from the application of the API. In some embodiments, about 30, about 35, about 40, about 45, about 50, about 55 or about 60% by weight of the total amount of API in the composition is released from the composition, for example, within a time period of about 5 minutes to about 2 hours from the application of the API. In other embodiments, about 30 to about 60, about 30 to about 55, about 30 to about 50, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 60, about 35 to about 55, about 35 to about 50, about 35 to about 45, about 35 to about 40, about 40 to about 60, about 40 to about 55, about 40 to about 50, about 40 to about 45, about 45 to about 60, about 45 to about 55, about 45 to about 50, about 50 to about 60, about 50 to about 55, or about 55 to about 60 weight percent of the total amount of API in the composition is released from the composition, e.g., within a period of about 5 minutes to about 2 hours from administration of the API.

[0057] In other aspects, at least about 60% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 2 hours to about 4 hours from the application of the API. For example, about 60 to about 80% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 2 hours to about 4 hours from the application of the API. In some embodiments, about 60, about 65, about 70, about 75 or about 80% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 2 hours to about 4 hours from the application of the API. In other embodiments, about 60 to about 75, about 60 to about 70, about 65 to 80, about 65 to about 75, about 65 to about 70, about 70 to about 80, about 70 to about 75 or about 75 to about 80% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 2 hours to about 4 hours from the application of the API.

[0058] In other aspects, at least about 80% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 3 hours to about 6 hours from the application of the API. For example, about 80 to about 100% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 3 hours to about 6 hours from the application of the API. In some embodiments, about 80, about 85, about 90, about 95 or about 100% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 3 hours to about 6 hours from the application of the API. In other embodiments, about 80 to about 95, about 80 to about 90, about 80 to about 85, about 85 to about 100, about 85 to about 95, about 85 to about 90, about 90 to about 100 or about 95 to about 100% by weight of the total amount of API in the composition is released from the pharmaceutical composition, for example, within a time period of about 3 hours to about 6 hours from the application of the API.

[0059] As used herein, "release of API" is measured at about 37°C by USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution.

[0060] The immediate release portion, the first modified release portion, or the second modified release portion, or a combination thereof, further contains an inactive pharmaceutical agent such as an excipient described herein. In some embodiments, one or more of the immediate release portion, the first modified release portion, or the second modified release portion further comprises one or more of a filler, a binder, a disintegrant, an emulsifier, an antistatic agent, or a solvent.

[0061] The beads and / or particles of the present disclosure may have a diameter of about 50 to about 1500 μm. In some embodiments, the core has a diameter of about 50 to about 1300 μm, about 50 to about 1100 μm, about 50 to about 900 μm, about 50 to about 800 μm, about 50 to about 700 μm, about 50 to about 600 μm, about 50 to about 500 μm, about 50 to about 400 μm, about 50 to about 300 μm, about 50 to about 200 μm, about 100 to about 1500 μm, about 100 to about 1300 μm, about 100 to about 1100 μm, about 100 to about 900 μm, about 100 to about 800 μm, about 100 to about 700 μm, about 100 to about 600 μm, about 100 to about 500 μm, about 100 to about 400 μm, about 100 to about 300 μm, about 100 to about 200 μm. In other embodiments, the core has a diameter of about 100 to about 800 μm.

[0062] The dosage unit may have multiple API-containing cores with different dissolution properties. Thus, the core may be coated with one or more layers. In some embodiments, the core is coated with two or more layers, i.e., a multilayer tablet. In other embodiments, the core is coated with an immediate release layer. In other embodiments, the core is coated with a modified release layer. In other embodiments, the core is coated with an immediate release layer and coated with a modified release layer.

[0063] The other layers may be applied as a topcoat or between the other layers. The layers may contain pharmaceutically inert components (ie, as a buffer layer) or pharmaceutically active components, as determined by one skilled in the art.

[0064] The oral dosage unit comprises one or more of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt of phloroglucinol or trimethylphloroglucinol. In some embodiments, the oral dosage unit comprises phloroglucinol or a pharmaceutically acceptable salt thereof. In other embodiments, the oral dosage unit comprises trimethylphloroglucinol or a pharmaceutically acceptable salt thereof. In other embodiments, the oral dosage unit comprises phloroglucinol or a pharmaceutically acceptable salt thereof and trimethylphloroglucinol or a pharmaceutically acceptable salt thereof.

[0065] Treatment

[0066] The pharmaceutical compositions and dosage units and formulations described herein can be used to treat spastic conditions in a subject. The method comprises administering a pharmaceutical composition or oral dosage unit described herein to the subject. In some embodiments, the spastic condition is a sudden involuntary muscle contraction of a body part of the subject, such as an organ or muscle. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of a bronchial, stomach, intestine, ureter, gallbladder, kidney, or bile duct. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of a bronchial. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of a stomach. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of an intestine. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of a ureter. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of a gallbladder. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of a kidney. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of a bile duct. In other embodiments, the spastic disorder is urinary tract spasm, gallstones, gastrointestinal disorders, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), renal colic or biliary spastic disorder. In other embodiments, the spastic disorder is urinary tract spasm. In other embodiments, the spastic disorder is gastrointestinal disorders. In other embodiments, the spastic disorder is IBD. In other embodiments, the spastic disorder is IBS. In other embodiments, the spastic disorder is IBS with diarrhea (IBS-D). In other embodiments, the spastic disorder is renal colic. In other embodiments, the spastic disorder is biliary spastic disorder. In other embodiments, the spastic disorder is mixed IBS (IBS-M). In other embodiments, the spastic disorder is constipation-predominant IBS (IBS-C). In other embodiments, the spastic disorder is Crohn's disease. In other embodiments, the spastic disorder is ulcerative colitis.

[0067] The pharmaceutical composition or oral dosage unit can be administered to the human subject in a fed or fasted state. In some embodiments, the pharmaceutical composition or oral dosage unit is administered to the subject in a fed state. In other embodiments, the pharmaceutical composition or oral dosage unit is administered to the subject in a fasted state.

[0068] In certain aspects, oral administration of the pharmaceutical composition or oral dosage unit to the subject in the fed state results in: a median T of the API max from about 0.5 to about 1.75 hours; the average C max From about 269 to about 1512 ng / mL; the average AUC of the APItau is about 879 to about 4695 h*ng / mL; and / or the average t1 / 2 of the API is about 1.6 hours to about 2.4 hours.

[0069] In some embodiments, the median T of the API in the fed state is max is about 0.5, about 0.75, about 1, about 1.25, about 1.5, or about 1.75 hours. In other embodiments, the median T of the API in the fed state is about 0.5, about 0.75, about 1, about 1.25, about 1.5, or about 1.75 hours. max From about 0.5 to about 1.5, from about 0.5 to about 1, from about 0.5 to about 0.75, from about 0.75 to about 1.75, from about 0.75 to about 1.5, from about 0.75 to about 1.25, from about 0.75 to about 1, from about 1 to about 1.75, from about 1 to about 1.5, from about 1 to about 1.25, from about 1.25 to about 1.75, from about 1.25 to about 1.5, or from about 1.5 to about 1.75 hours.

[0070] In other embodiments, the average C of the API in the fed state is max is about 269, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1512, or about 1550 ng / mL. In other embodiments, the C of the API in the fed state is about 269, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1512, or about 1550 ng / mL. maxFrom about 269 to about 1550, from about 269 to about 1512, from about 269 to about 1500, from about 269 to about 1400, from about 269 to about 1300, from about 269 to about 1200, from about 269 to about 1100, from about 269 to about 1000, from about 269 to about 900, from about 269 to about 800, from about 269 to about 700, from about 269 to about 600, from about 269 to about 500, from about 269 to about 400, from about 300 to about 1550, from about 300 to about 1500, from about 300 to about 1512, from about 300 to about 1500, from about 300 to about 1400, from about 300 to about 1400, from about 300 to about 1200, from about 300 to about 1100, from about 300 to about 1000, from about 269 to about 900 about 300 to about 900, about 300 to about 800, about 300 to about 700, about 300 to about 600, about 300 to about 500, about 300 to about 400, about 400 to about 1550, about 400 to about 1512, about 400 to about 1500, about 400 to about 1400, about 400 to about 1300, about 400 to about 1200, about 400 to about 1100, about 400 to about 1000, about 400 to about 900, about 400 to about 800, about 400 to about 700, about 400 to about 600, about 400 to about 500, about 500 to about 1550, about 500 to about 1512, about 500 to about 1500, about 500 to about 1400, about 500 to about 1300 0, about 500 to about 1200, about 500 to about 1100, about 500 to about 1000, about 500 to about 900, about 500 to about 800, about 500 to about 700, about 500 to about 600, about 600 to about 1550, about 600 to about 1512, about 600 to about 1500, about 600 to about 1400, about 600 to about 1300, about 600 to about 1200, about 600 to about 1100, about 600 to about 1000, about 600 to about 900, about 600 to about 800, about 600 to about 700, about 700 to about 1550, about 700 to about 1512, about 700 to about 1500, about 700 to about 1400, about 700 to about 1300, about From about 700 to about 1200, from about 700 to about 1100, from about 700 to about 1000, from about 700 to about 900, from about 700 to about 800, from about 800 to about 1550, from about 800 to about 1512, from about 800 to about 1500, from about 800 to about 1400, from about 800 to about 1300, from about 800 to about 1200, from about 800 to about 1100, from about 800 to about 1000, from about 800 to about 900, from about 900 to about 1550, from about 900 to about 1512, from about 900 to about 1500, from about 900 to about 1400, from about 900 to about 1300, from about 900 to about 1200, from about 900 to about 1100, from about 900 to about 1000, from about 1000 to about 1550,about 1000 to about 1512, about 1000 to about 1500, about 1000 to about 1400, about 1000 to about 1300, about 1000 to about 1200, about 1000 to about 1100, about 1100 to about 1550, about 1100 to about 1512, about 1100 to about 1500, about 1100 to about 1400, about 1100 to about 1300, about 1100 to about 1200, about 1200 to about 1 1500, about 1200 to about 1500, about 1200 to about 1500, about 1200 to about 1400, about 1200 to about 1300, about 1300 to about 1550, about 1300 to about 1512, about 1300 to about 1500, about 1300 to about 1400, about 1400 to about 1550, about 1400 to about 1512, about 1400 to about 1500, or about 1500 to about 1550 ng / mL.

[0071] In other embodiments, the average AUC of the API in the fed state is tau In other embodiments, the average AUC of the API in the fed state is about 879 to about 4695 h*ng / mL. tau is about 879, about 1000, about 1500, about 2000, about 2500, about 3000, about 3500, about 4000, about 4500, or about 4695 h*ng / mL. In other embodiments, the average AUC of the API in the fed state is about 879, about 1000, about 1500, about 2000, about 2500, about 3000, about 3500, about 4000, about 4500, or about 4695 h*ng / mL. tauFrom about 879 to about 4500, from about 879 to about 4000, from about 879 to about 3500, from about 879 to about 3000, from about 879 to about 2500, from about 879 to about 2000, from about 879 to about 1500, from about 879 to about 1000, from about 1000 to about 4695, from about 1000 to about 4500, from about 1000 to about 4000, from about 1000 to about 3500, from about 1000 to about 3000, from about 1000 to about 2500, from about 1000 to about 2000, from about 1000 to about 1500, from about 1500 to about 4695, from about 1500 to about 4500, from about 1500 to about 4000, from about 1500 to about 3500, from about 1500 to about 3000, from about 1500 to about 2500 From about 1500 to about 2000, about 2000 to about 4695, about 2000 to about 4500, about 2000 to about 4000, about 2000 to about 3500, about 2000 to about 3000, about 2000 to about 2500, about 2500 to about 4500, about 2500 to about 4695, about 2500 to about 4000, about 2500 to about 3500, about 2500 to about 3000, about 3000 to about 4695, about 3000 to about 4500, about 3000 to about 4000, about 3000 to about 3500, about 3500 to about 4695, about 3500 to about 4500, about 3500 to about 4000, about 4000 to about 4500, or about 4000 to about 4695 h*ng / mL.

[0072] In other embodiments, the average t1 / 2 of the API in the fed state is about 1.6 hours to about 2.4 hours. In other embodiments, the average t1 / 2 of the API in the fed state is about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3 or 2.4 hours. In other embodiments, the average t1 / 2 of the API in the fed state is about 1.7 to about 2.3, about 1.6 to about 2.2, about 1.6 to about 2.1, about 1.6 to about 2, about 1.6 to about 1.9, about 1.6 to about 1.8, about 1.6 to about 1.7, about 1.7 to about 2.4, about 1.7 to about 2.3, about 1.7 to about 2.2, about 1.7 to about 2.1, about 1.7 to about 2, about 1.7 to about 1.9, about 1.7 to about 1.8, about 1.8 to about 2.4, about 1.8 to about 2. 3, about 1.8 to about 2.2, about 1.8 to about 2.1, about 1.8 to about 2, about 1.8 to about 1.9, about 1.9 to about 2.4, about 1.9 to about 2.3, about 1.9 to about 2.2, about 1.9 to about 2.1, about 1.9 to about 2, about 2 to about 2.4, about 2 to about 2.3, about 2 to about 2.2, about 2 to about 2.1, about 2.1 to about 2.4, about 2.1 to about 2.3, about 2.1 to about 2.2, about 2.2 to about 2.4, about 2.2 to about 2.3, or about 2.3 to about 2.4 hours.

[0073] In other aspects, oral administration to the human subjects in the fasting state results in: a median T of the API max is about 0.5 hours; the average C max From about 2745 to about 4874 ng / mL; the average AUC of the API tau is about 4567 to about 6853 h*ng / mL; and / or the average t1 / 2 of the API is about 2 hours.

[0074] In some embodiments, oral administration to the human subjects in the fasting state results in a median T of the API of max It is about 0.5 hours.

[0075] In other embodiments, oral administration to said human subjects in the fasting state results in an average C max In other embodiments, the average C of the API in the fasting state is about 2745 to about 4874 ng / mL. max In other embodiments, the average C of the API in the fasting state is about 2745, about 3000, about 3500, about 4000, about 4500, or about 4874 ng / mL. maxAbout 2745 to about 4500, about 2745 to about 4000, about 2745 to about 3500, about 2745 to about 3000, about 3000 to about 4874, about 3000 to about 4500, about 3000 to about 4000, about 3000 to about 3500, about 3500 to about 4874, about 3500 to about 4500, about 3500 to about 4000, about 4000 to about 4874, about 4000 to about 4500, or about 4500 to about 4874 ng / mL.

[0076] In other embodiments, oral administration to said human subjects in the fasting state results in a mean AUC of said API of tau In other embodiments, the average AUC of the API is about 4567 to about 6853 h*ng / mL. tau is about 4567, about 5000, about 5500, about 6000, about 6500, or about 6853 h*ng / mL. In other embodiments, the average AUC of the API is about 4567, about 5000, about 5500, about 6000, about 6500, or about 6853 h*ng / mL. tau About 4567 to about 6500, about 4567 to about 6000, about 4567 to about 5500, about 4567 to about 5000, about 5000 to about 6853, about 5000 to about 6500, about 5000 to about 6000, about 5000 to about 5500, about 5500 to about 6853, about 5500 to about 6500, about 5500 to about 6000, about 6000 to about 6853, about 6000 to about 6500, or about 6500 to about 6853 h*ng / mL.

[0077] In other embodiments, the average t1 / 2 of the API in the fasting state is about 2 hours. In some embodiments, the average t1 / 2 of the API in the fasting state is about 2, about 2.1, or about 2.2 hours. In other embodiments, the average t1 / 2 of the API in the fasting state is about 2 to about 2.2, about 2 to about 2.1, or about 2.1 to about 2.2 hours.

[0078]

[0079]

[0080]

[0081] Example 1: Modified Release Formulation

[0082] The dosage form of the present disclosure contains three types of beads. One type of beads releases phloroglucinol almost immediately after administration, a second type of beads releases phloroglucinol about 2 to 4 hours after administration, and a third type of beads releases phloroglucinol about 4 to about 6 hours after administration.

[0083] The amount and quantity of each component are shown in Tables 1A and 1B.

[0084]

[0085]

[0086] The beads are Figure 3 Prepared as described in the flowchart.

[0087] A. The core beads (i.e., immediate release beads) were prepared as follows:

[0088] 1. Sift phloroglucinol, microcrystalline cellulose, hypromellose and croscarmellose sodium through a suitable grinder.

[0089] 2. Blend the milled mixture from step 1 in a suitable granulator / mixer and prepare a wet mass using purified water.

[0090] 3. The wet mass was passed through an extruder / spheronizer to produce wet beads.

[0091] 4. Dry the wet beads using a suitable dryer to obtain core beads.

[0092] 5. Screen all core beads through a 16 / 30 mesh screen and collect the beads retained on the 30 mesh screen as uncoated beads.

[0093] 6. Divide the beads from step 5 into 3 parts: part 1, part 2 and part 3.

[0094] B. Preparation of Eudragit L30D-55 beads

[0095] 7. Prepare coating solution using Eudragit L30D-55, triethyl citrate, talc and purified water.

[0096] 8. Coat the Part 2 core beads from Step 6 using the coating solution from Step 7 to prepare Eudragit L30D-55 coated beads.

[0097] 9. Screen all beads from step 8 through a 16 / 30 mesh screen and collect the beads retained on the 30 mesh screen as Eudragit L30D-55 coated beads.

[0098] C. Preparation of Eudragit FS30D beads

[0099] 10. Prepare coating solution using Eudragit FS30D, triethyl citrate, talc and purified water.

[0100] 11. Coat the Part 3 core beads from Step 6 using the coating solution from Step 10 to prepare Eudragit FS30D coated beads.

[0101] 12. Screen all beads from step 11 through a 16 / 30 mesh screen and collect beads retained on the 30 mesh screen as Eudragit FS30D coated beads.

[0102] D. Lubrication

[0103] 13. Combine the Eudragit L30D-55 coated beads from step 9 and the Eudragit FS30D coated beads from step 12 with the talc in a suitable blender.

[0104] E. Encapsulation

[0105] 14. Encapsulate the Part 1 uncoated beads from step 6 and the blend from step 13 in size 00 opaque white gelatin capsules using a suitable capsule filling machine.

[0106] 15. Transfer the filled capsules through a dust collector and metal detector.

[0107] As previously described, the IR beads were coated with a suspension containing Eudragit L30D55 ​​(to produce DR beads intended for release at pH 5.5) or Eudragit FS30D-55 (to produce DR beads intended for release at pH 7.0).

[0108] The coated beads were blended and lubricated with talc as described above and encapsulated with the IR beads in size 00 capsules. The Eudragit L30D-55 and Eudragit FS30D coated beads were blended together before encapsulation.

[0109] Example 2

[0110] The immediate release beads, 2-hour modified release beads, and 4-hour modified release beads were prepared as described in Example 1. A placebo batch of sugar spheres coated with Eudragit L30D-55 and Eudragit FS30D was prepared using sugar spheres as core beads and coated as described for phloroglucinol core beads in Example 1. The composition of the placebo capsules is shown in

[0111] Table 2.

[0112]

[0113] The IR beads, Eudragit L30D-55 coated beads and Eudragit FS30D coated beads were assayed prior to the blending and encapsulation steps.

[0114] Finished capsules were tested using a validated method. Acceptance criteria for active batches are shown in Table 3. All batches met the acceptance criteria. Dissolution profiles for single filled capsules are shown in Figure 4 middle.

[0115]

[0116] Example 3

[0117] This was a randomized, double-blind, placebo-controlled, multiple ascending dose study to characterize the safety and PK of Formulation A when administered to healthy adult subjects. Formulation A was prepared as described in Example 1. A preliminary food effect assessment was also performed.

[0118] A. Goal

[0119] The objectives of this study are as follows:

[0120] To evaluate the safety and tolerability of Formulation A after multiple oral doses in healthy subjects; and

[0121] • To characterize the PK of Formulation A after multiple oral doses to healthy subjects.

[0122] As described below, subjects were randomized into 1 of 8 cohorts, with 6 subjects in each cohort scheduled to receive Formulation A and 2 subjects in each cohort scheduled to receive placebo.

[0123] Cohort 1a: 320 mg Formulation A or matching placebo, starting in the morning of Day 1 and continuing through the morning of Day 6, with a daily high-fat breakfast (0 hours) and daily high-fat dinner (10 hours);

[0124] Cohort 1b: 320 mg of Formulation A or matching placebo, starting on the morning of Day 1 and continuing through the morning of Day 6, with a daily low-fat breakfast (0 hours) and daily low-fat dinner (10 hours);

[0125] Cohort 2a: 640 mg Formulation A or matching placebo, starting on the morning of Day 1 and continuing through the morning of Day 6, with a daily high-fat breakfast (0 hours) and daily high-fat dinner (10 hours);

[0126] Cohort 2b: 640 mg of Formulation A or matching placebo, starting on the morning of Day 1 and continuing through the morning of Day 6, with a daily low-fat breakfast (0 hours) and daily low-fat dinner (10 hours);

[0127] Cohort 3a: 1280 mg Formulation A or matching placebo, starting on the morning of Day 1 and continuing through the morning of Day 6, with a daily high-fat breakfast (0 hours) and daily high-fat dinner (10 hours);

[0128] Cohort 3b: 1280 mg of Formulation A or matching placebo, starting on the morning of Day 1 and continuing through the morning of Day 6, with a daily low-fat breakfast (0 hours) and daily low-fat dinner (10 hours);

[0129] Cohort 3c: 960 mg of Formulation A or matching placebo twice daily (BID) (at 0 and 10 hours) on an empty stomach, starting in the morning of Day 1 and continuing through the morning of Day 6; and

[0130] • Cohort 3d: Starting in the morning of Day 1 and continuing through the morning of Day 6, take 1280 mg of Formulation A or matching placebo BID (at 0 and 10 hours) on an empty stomach.

[0131] The dietary definitions are consistent with the U.S. Food and Drug Administration guidance for the evaluation of food effects on drugs in investigational new drug applications and new drug applications. See Table 4.

[0132]

[0133] For each subject, the study consisted of the following periods:

[0134] A screening period of up to 26 days before starting inpatient confinement (Day -1);

[0135] A single 7-day inpatient treatment period consisting of administration of blinded study drug (Formulation A or matching placebo capsules) from the morning of Day 1 to the morning of Day 6, followed by 24-hour PK sampling; and

[0136] Follow-up telephone call 3 days (± 1 day) after discharge from the clinical unit.

[0137] For each cohort, the sentinel dose group consisting of the first 2 subjects (1 subject receiving Formulation A and 1 subject receiving placebo) will start the dosing regimen first. At least 48 hours later, the remaining members of the cohort will start the dosing regimen. These remaining subjects in each cohort may start dosing on the same day or may be divided into smaller groups and start dosing on multiple days.

[0138] For Cohorts 3c and 3d, in which subjects received Formulation A or placebo on an empty stomach, the following order was followed:

[0139] The sentinel subject in Cohort 3c (taking 3 capsules on an empty stomach) starts dosing at least 48 hours after the last subject in Cohort 3b has started dosing; and

[0140] The sentinel subject in Cohort 3d (taking 4 capsules on an empty stomach) started dosing at least 48 hours after the last subject in Cohort 3c had started dosing.

[0141] Progression from Cohort 1 to Cohort 2 and from Cohort 2 to Cohort 3 will be allowed only after it is determined that adequate safety and tolerability have been demonstrated to allow continuation.

[0142] Safety was assessed throughout the study on the basis of AEs, physical examinations, skin and oral mucosal assessments, ECGs, vital sign assessments, and clinical laboratory evaluations. Beginning in Cohort 2, the number of daily bowel movements was recorded. Unscheduled procedures or visits and / or additional follow-up may be required for subjects with clinically significant abnormal laboratory findings, unresolved TEAEs, SAEs requiring follow-up labs and review, or clinically significant AEs.

[0143] B. Inclusion Criteria

[0144] Based on the screening and enrollment results, subjects who met all of the following criteria were eligible to participate in this study:

[0145] 1. Healthy subjects aged between 18 and 55 years (inclusive), in good health based on medical and psychiatric history, physical examination, ECG, vital signs and routine laboratory tests (blood chemistry, hematology, coagulation and urine tests);

[0146] 2. Body mass index (BMI) between 18 and 30 kg / m 2 Between (inclusive);

[0147] 3. Non-smokers who have not used nicotine-containing products for at least 6 months before screening;

[0148] 4. Male subjects with female partners of childbearing potential must agree to use two medically acceptable and highly effective birth control methods from day 1 to 90 days after the last dose of the study drug. For male subjects with female partners of childbearing potential, medically acceptable and highly effective birth control methods include: latex condoms containing spermicide, diaphragms containing intravaginal spermicide, cervical caps containing spermicide, indwelling intrauterine devices (hormonal or non-hormonal), implantable contraceptives, and oral contraceptives;

[0149] 5. Male subjects must agree to give up sperm donation within 90 days from day 1 to the last dose of study drug;

[0150] 6. Female subjects with male partners must have undergone surgical sterilization (hysterectomy and / or bilateral oophorectomy), be at least 1 year postmenopausal (FSH is within the postmenopausal range), or agree to use 2 medically acceptable and highly effective birth control methods from Day -14 to 60 days after the last dose of study drug. For female subjects with male partners, medically acceptable and highly effective birth control methods include: latex condoms with spermicide, diaphragms with intravaginal spermicide, cervical caps with spermicide, and non-hormonal indwelling intrauterine devices; and

[0151] 7. Able to understand and willing to comply with study procedures and restrictions (including confinement to clinical units, fasting and meal requirements, restrictions on physical activity, use of recreational drugs or alcohol, and medications) and provide written informed consent in accordance with institutional and regulatory guidelines.

[0152] C. Exclusion criteria

[0153] Based on the screening and enrollment results, subjects who met any of the following criteria were excluded from the study:

[0154] 1. Actively participate in experimental therapy research; receive experimental therapy using small molecules within 30 days or 5 half-lives of the first dose of study drug (whichever is longer); or receive experimental therapy using large molecules within 90 days or 5 half-lives of the first dose of study drug (whichever is longer);

[0155] 2. Personal or family history of long QT syndrome, torsades de pointes or other complex ventricular arrhythmias, or family history of sudden death;

[0156] 3. A history of clinically significant arrhythmias or current clinically significant arrhythmias, including ventricular tachycardia, ventricular fibrillation, atrial fibrillation, sinus node dysfunction, or clinically significant heart block. Subjects with mild forms of ectopy (e.g., atrial premature beats) are not necessarily excluded;

[0157] 4. QTcF prolonged >450msec based on the average of three ECGs;

[0158] 5. Sitting systolic blood pressure ≥140 mmHg and / or diastolic blood pressure ≥90 mmHg, or systolic blood pressure <100 mmHg and / or diastolic blood pressure <50 mmHg;

[0159] 6. Resting heart rate (HR) higher than 100 beats per minute (bpm) or lower than 60 bpm;

[0160] 7. Body temperature higher than 37.6°C (99.7°F, measured orally), respiratory rate less than 12 times or greater than 20 times / minute;

[0161] 8. Positive for human immunodeficiency virus antibody, hepatitis C virus antibody, hepatitis B surface antigen or SARS-CoV-2 RNA;

[0162] 9. Any other clinical laboratory value significantly outside the normal limit (based on the laboratory normal range);

[0163] 10. Evidence or history of the following diseases: any clinically significant immune, blood, kidney, endocrine, lung, gastrointestinal, cardiovascular, musculoskeletal, liver, psychiatric, neurological (including history of epileptic seizures or convulsions) or allergic disease (including clinically significant or multiple drug allergies); surgical conditions; cancer (except basal or squamous cell carcinoma of the skin and cancer that has regressed or remitted for more than 5 years before screening); or any condition that may confuse the study procedures or results, affect the safety of the subjects, or interfere with the absorption, distribution, metabolism or excretion of the study drugs (appendectomy is allowed, cholecystectomy is prohibited);

[0164] 11. Use of any prescription drugs (including topical drugs) or OTC drugs (except for occasional use of acetaminophen or NSAIDs such as ibuprofen or naproxen according to the package insert), herbal supplements, dietary supplements, or nutritional supplements within 14 days or 5 half-lives before the first dose of study drug (whichever is longer), or unwillingness to refrain from using these drugs until final discharge from the clinical unit. OTC topical drugs may be allowed. In addition, drugs with a half-life of more than 14 days must be approved before the subject is enrolled;

[0165] 12. Positive drug or alcohol test results or history of alcoholism or drug abuse within 2 years before the first dose of study medication, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition: DSM-IV;

[0166] 13. Typical weekly intake of ≥14 alcoholic drinks. Note: 1 serving of alcohol is equivalent to 1 / 2 pint of beer (285 mL), 1 glass of liquor (25 mL) or 1 glass of wine (125 mL);

[0167] 14. History or evidence of illegal drug use in the past 2 years;

[0168] 15. Underwent surgery within 4 weeks of registration or planned to undergo elective surgery during the study period;

[0169] 16. Any disease within 4 weeks before registration, unless considered by the investigator to be of no clinical significance;

[0170] 17. Known allergy to any ingredient of Preparation A. Any history of severe allergic reaction (including drugs, food, insect bites or environmental allergens);

[0171] 18. Inadequate venous access;

[0172] 19. Currently receiving weight loss medication or previous weight loss surgery (such as gastric bypass surgery);

[0173] 20. Pregnancy, breastfeeding or planning to become pregnant during the study period; or

[0174] 21. Is considered unsuitable for any other reason that may expose the subjects to increased risk during participation or interfere with the interpretation of the research results.

[0175] D. Treatment

[0176] Study subjects were orally administered Formulation A or placebo capsules. Study subjects were randomized in a 6:2 ratio to receive Formulation A or placebo.

[0177] Each capsule of Formulation A contains 320 mg of phloroglucinol in the following configurations: 160 mg in IR beads, 80 mg in 2-hour DR beads, and 80 mg in 4-hour DR beads. Inactive ingredients used in the formulation include: microcrystalline cellulose, hypromellose, croscarmellose sodium, triethyl citrate, Eudragit L 30D-55, and talc.

[0178] For a given dose cohort, placebo consisted of the same number of matching placebo capsules as subjects receiving Formulation A. See Table 5.

[0179]

[0180] (i) Dose selection and scheduling for each subject

[0181]

[0182] All subjects received multiple oral doses of blinded study drug (Formulation A or matching placebo capsules).

[0183] All subjects in all cohorts were required to observe an overnight fast of at least 10 hours starting in the evening before the first and last doses of study medication.

[0184] For subjects in the feeding cohort, the relevant meal type was administered 30 minutes before the corresponding dose, and all meals must be completed before administration. Subjects had lunch at least 4 hours after the morning study drug administration every day. No study drug was administered at lunch. The lunch content was standard, but not strictly limited to high-fat or low-fat standards.

[0185] For cohorts that required fasting to take study drug, no food was consumed for at least 2 hours before or 1 hour after each interim dose. Subjects had lunch at least 4 hours after study drug administration each day. All meals were standardized.

[0186] Subjects must take all study drug capsules within ≤5 minutes.Study drug is administered with approximately 240 mL of water.

[0187] All subjects received a standardized meal at approximately the same time each day during confinement (when protocol-mandated fasting was not in effect). The subject was encouraged to remain sedentary and to be accompanied if he / she needed to use the restroom during the first 3.5 hours after dosing.

[0188] (ii) Excluded Drugs and / or Procedures

[0189] Any prescription (including topical) or OTC medications (except occasional use of acetaminophen or NSAIDs such as ibuprofen or naproxen, as per package insert), herbal supplements, dietary supplements, or nutraceuticals are prohibited for 14 days before the first dose of study drug or 5 half-lives, whichever is longer, until discharge, except for medications required for treatment of the AE. OTC topical medications may be permitted. In addition, drugs with 5 half-lives greater than 14 days may be approved.

[0190] Participants could not be taking weight loss medications during the study period, nor had they previously undergone weight loss surgery (eg, gastric bypass surgery).

[0191] Subjects cannot be participating in any other investigational therapy study concurrently with this study, receive an experimental therapy using a small molecule within 30 days or 5 half-lives of the first dose of study drug (whichever is longer), or receive an experimental therapy using a large molecule within 90 days or 5 half-lives of the first dose of study drug (whichever is longer) while participating in this study.

[0192] (iii) General and dietary restrictions

[0193] All subjects in all cohorts were required to observe an overnight fast of at least 10 hours starting in the evening before the first and last doses of study medication.

[0194] All interim doses were administered on an empty stomach (at least approximately 1 hour before or approximately 2 hours after a meal). Water was permitted during the fasting period, except for 1 hour before and 1 hour after dosing (except for water used to administer study drug). Subjects were required to take all study drug capsules within ≤5 minutes. Study drug was administered with approximately 240 mL of water.

[0195] Subjects received standardized meals at approximately the same time each day during confinement (when protocol-mandated fasting was not in effect). Subjects were encouraged to remain sedentary and were accompanied if he / she needed to use the restroom during the first 3.5 hours after dosing.

[0196] Subjects must abstain from alcohol, caffeine and / or xanthine-containing products (i.e., coffee, tea, chocolate, and caffeinated sodas, cola, energy drinks, etc.), grapefruit, grapefruit products, star fruit, star fruit products, and limes, and vitamin water from 48 hours prior to study drug administration on Day 1 until final discharge from the clinical unit. Subjects must avoid contact sports and strenuous exercise starting 5 days prior to the first dose of study drug and throughout the confinement period. Subjects must be nonsmokers who have not used nicotine-containing products for at least 6 months prior to screening.

[0197] (iii) Pharmacokinetic endpoints

[0198] Where data permitted, the following plasma PK parameters of phloroglucinol were determined after the first dose of Formulation A in the morning of Day 1:

[0199] ·C max ;

[0200] ·T max ;

[0201] AUC tau ;and

[0202] ·C min

[0203] Where data permitted, the following plasma PK parameters of phloroglucinol were determined after the last dose of Formulation A on the morning of Day 6:

[0204] ·C max ;

[0205] ·T max ;

[0206] AUC tau ;

[0207] AUC 0-inf and the associated extrapolated percentages;

[0208] AUC 0-t ;

[0209] t1 / 2;

[0210] ·λz;

[0211] CL / F (based on AUC tau );and

[0212] Vd / F (based on AUC tau ).

[0213] Additionally, trough samples were used to assess the achievement of steady state.

[0214] Also based on the relevant C maxThe accumulation at steady state was characterized by the AUC values.

[0215] When data allowed, the urinary concentration of phloroglucinol was also used to calculate the cumulative amount of phloroglucinol excreted in urine (Ae), renal clearance (calculated as Ae / AUC tau ) and the fraction of dose excreted by the kidneys (Fe).

[0216] Exploratory analyses may also be performed to characterize the plasma and urine PK profiles of the sulfate and glucuronic acid conjugates of phloroglucinol.

[0217] (iv) Safety endpoints

[0218] The safety of Formulation A was evaluated from the time of informed consent until completion of study participation. Safety endpoints included the following:

[0219] Physical examination, skin and oral mucosal assessment, ECG, vital sign assessment (in both sitting and supine positions), and clinical laboratory evaluation;

[0220] TEAEs were graded according to the severity of CTCAE version 5.0;

[0221] Treatment-emergent SAEs;

[0222] TEAEs leading to early discontinuation of the study;

[0223] Significant laboratory abnormalities that emerge during treatment; and

[0224] Obvious abnormalities in vital signs occur during treatment.

[0225] (v) Statistical and analytical plan

[0226] Categorical data are usually summarized with the count and percentage of subjects. The denominator used for percentage calculation is clearly defined. Continuous data (quantitative safety data or difference from baseline) are usually summarized with descriptive statistics, including n (number of non-missing values), mean, median, standard deviation, minimum and maximum. For the summary of concentration and PK parameters, geometric mean (GM) and GM coefficient of variation (CV) % are also provided. Subjects with a value of 0 are excluded from the calculation of GM and GM CV %.

[0227] The summary by cohort included all eight cohorts separately, while the summary by dose level combined the corresponding cohorts at the total dose levels of 320 mg, 640 mg, 960 mg, and 1280 mg.

[0228] Analysis days are calculated from the date of the first dose of study drug. The day of the first dose of study drug is treatment period day 1, and the day before day 1 is day -1. There is no day 0.

[0229] Baseline was defined as the last measurement before the first dose of study drug.

[0230] (a) Analytical Group

[0231] The safety population consisted of all randomized subjects who received at least 1 dose of Formulation A.

[0232] The PK population included all subjects who received Formulation A and had at least 1 quantifiable post-dose plasma concentration of phloroglucinol.

[0233] The PK evaluable population includes subjects with sufficient plasma concentration data to characterize at least 1 PK parameter of phloroglucinol.

[0234] The counts and percentages of subjects in each analysis population were summarized by cohort, dose level, and based on the total number of subjects across all randomizations.

[0235] (b) Disposition of subjects

[0236] Subject disposition is presented for all randomized subjects. The number and percentage of subjects in each of the following categories are summarized by cohort and overall, as appropriate:

[0237] Randomized;

[0238] ·Administering medication;

[0239] ·Completed research;

[0240] · premature withdrawal from the study and the main reason for premature withdrawal; and

[0241] · Withdrew from the study early due to the COVID-19 pandemic.

[0242] (ii) Project Deviation

[0243] Protocol deviations for all randomized subjects were summarized with frequency distribution (counts and percentages) by cohort, dose level, and category.

[0244] For all randomized subjects, subjects with protocol deviations are listed by cohort.

[0245] Any impact of COVID-19 on study visits (e.g., not completed, partially completed in-person, performed virtually, performed outside of the time window) is listed for all subjects in the safety population.

[0246] (c) Demographics and baseline characteristics

[0247] The following demographic and baseline characteristics are tabulated and summarized by cohort, dose level, and overall, using descriptive statistics or counts and percentages of subjects for the safety population and repeated for all other analysis populations if they were different from the safety population:

[0248] Age (years);

[0249] ·gender;

[0250] Fertility potential;

[0251] Race (Asian, American Indian or Alaska Native, Black or African American, Native Hawaiian or Other Pacific Islander, White, Other);

[0252] · Race (Hispanic or Latino, non-Hispanic or Latino, not reported, unknown);

[0253] Height (cm);

[0254] Body weight (kg); and

[0255] BMI (kg / m 2 ).

[0256] Medical history

[0257] (d) Medical history was coded into SOC and PT using MedDRA version 23.1. The counts and percentages of subjects with medical history by SOC and PT were summarized and presented by cohort, dose level, and based on the total number of subjects across all randomized groups.

[0258] (e) Previous and concomitant medications

[0259] Prior and concomitant medications were coded into ATC categories and PTs using the WHO Drug Dictionary GB3 September 2020 version. For summary purposes, a medication was considered a prior medication if it was discontinued prior to administration of study drug and a concomitant medication if it was taken at any time after the first dose of study drug (i.e., started before the first dose of study drug and continued, or started after the first dose of study drug).

[0260] The counts and percentages of subjects taking prior and concomitant medications by ATC category and PT were tabulated and summarized by cohort, dose level, and total based on safety population. (vi) Study Drug Exposure and Adherence

[0261] Exposure was defined as the number of days between the first and last dose of study drug, inclusive, and summarized by treatment in the safety population.Study drug administration data for all subjects in the safety population are presented by treatment group.

[0262] (f) Pharmacokinetic analysis

[0263] Sample collection for pharmacokinetic analysis

[0264] Pre-dose blood samples for PK were collected within 60 minutes prior to the first administration of study drug and within 5 minutes prior to any designated subsequent study drug administration. The following windows were allowed for the collection of PK samples: ±1 minute for samples collected ≤8 hours after dosing, ±2 minutes for samples collected >8 and ≤16 hours after dosing, and ±5 minutes for samples collected >16 hours after dosing. The planned blood sample collection times (hours after dosing) were:

[0265] Day 1 (first dose): predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, and 9;

[0266] Day 1 (evening dosing): pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, and 6;

[0267] Day 2 (morning dosing): Before dosing

[0268] Days 4 and 5 (morning and evening dosing): prior to dosing; and

[0269] Day 6: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 16, and 24.

[0270] Urine samples for PK were collected to measure phloroglucinol concentrations at the following time intervals after the first and last doses of study drug: 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 10 hours, 10 to 12 hours, 12 to 14 hours, 14 to 16 hours, and 16 to 24 hours. Urine aliquots were also obtained from the morning void before the first and last doses of study drug.

[0271] Pharmacokinetic concentration

[0272] Individual plasma concentrations of phloroglucinol by cohort at each nominal time point in the PK population are summarized descriptively. Individual plasma concentrations of the PK population are also listed.

[0273] Individual plasma concentrations by cohort were plotted on a linear and semi-log scale for the actual sampling time points relative to the dosing time. In both cases, the lower limit of quantitation was plotted as a reference line. The troughs on days 4, 5, and 6 were plotted in a similar manner.

[0274] A plot of mean plasma phloroglucinol concentration versus time was generated for each cohort. A plot of mean and individual cumulative Ae versus time was also presented. Similar outputs were provided for any measured metabolite if data permitted.

[0275] Actual sampling times that fall outside the sampling time window may be excluded from concentration summaries and mean concentration plots but are still used in calculations of PK parameters and individual concentration plots. Exclusion of concentrations outside the window is evaluated on a case-by-case basis.

[0276] Pharmacokinetic parameters

[0277] Where data permitted, the following plasma PK parameters of phloroglucinol were determined after the first dose of Formulation A on the morning of Day 1 (using a non-compartmental analysis):

[0278] ·C max ——determined directly from the concentration-time curve; if C max If it occurs at more than one time point, C max Defined as the first maximum value;

[0279] ·T max If the maximum value occurs at more than one time point, T max Defined as the first time point with this value;

[0280] AUC tau ;and

[0281] ·C min .

[0282] Where data permitted, the following plasma PK parameters of phloroglucinol were determined (using a non-compartmental analysis) after the last dose of Formulation A on the morning of Day 6:

[0283] ·C max ——determined directly from the concentration-time curve; if C max If it occurs at more than one time point, C max Defined as the first maximum value;

[0284] ·T max If the maximum value occurs at more than one time point, T max Defined as the first time point with this value;

[0285] AUC tau ;

[0286] AUC 0-inf ——is calculated as ([AUC 0-t ] + the last quantifiable plasma concentration [C last ] / λ z );

[0287] AUC 0-t ——From before drug administration (0 o'clock) to C last AUC of

[0288] ·λ z - Calculated from semi-log plots of plasma concentration versus time. The parameters were calculated by linear least squares regression analysis using points in the late log phase-linear phase;

[0289] ·t 1 / 2 ——is calculated as the natural logarithm (2) / λ z ;

[0290] CL / F – calculated as dose / AUC tau ;

[0291] Vd / F - calculated as dose / [λ z AUC tau ];

[0292] ·RC max - Accumulation ratio evaluation only on day 6; calculated as C on day 6 max / Day 1 C max ;

[0293] ·R AUCtau - Accumulation ratio assessed only on day 6; calculated as AUC on day 6 tau / AUC on day 1 tau ;as well as

[0294] AUC extrap - The area under the extrapolated plasma concentration-time curve; expressed as (1-AUC 0-t / AUC 0-inf )·100.

[0295] The following urine PK parameters of phloroglucinol were determined using non-compartmental methods, as appropriate:

[0296] The constant excretion in urine from hour 0 to hour 2 (Ae 0-2 );

[0297] · Constant excretion in urine from hour 0 to hour 4 (Ae 0-4 );

[0298] · Constant excretion in urine from hour 0 to hour 6 (Ae 0-6 );

[0299] · Constant excretion in urine from hour 0 to hour 10 (Ae 0-10 );

[0300] · Constant excretion in urine from hour 0 to hour 12 (Ae 0-12 );

[0301] · Constant excretion in urine from hour 0 to hour 14 (Ae 0-14 );

[0302] · Constant excretion in urine from hour 0 to hour 16 (Ae 0-16 );

[0303] · Constant excretion in urine from hour 0 to hour 24 (Ae 0-24 );

[0304] The fraction of unchanged excreted dose in urine from hour 0 to hour 2 (Fe 0-2 );

[0305] The fraction of unchanged excreted dose in urine from hour 0 to hour 4 (Fe 0-4 );

[0306] The fraction of unchanged excreted dose in urine from hour 0 to hour 6 (Fe 0-6 );

[0307] The fraction of unchanged excreted dose in urine from hour 0 to hour 10 (Fe 0-10 );

[0308] The fraction of unchanged excreted dose in urine from hour 0 to hour 12 (Fe 0-12 );

[0309] The fraction of unchanged excreted dose in urine from hour 0 to hour 14 (Fe 0-14 );

[0310] The fraction of unchanged excreted dose in urine from hour 0 to hour 16 (Fe 0-16 );

[0311] The fraction of unchanged excreted dose in urine from hour 0 to hour 24 (Fe 0-24 );and

[0312] Renal clearance; calculated as Ae / AUC tau .

[0313] The actual collection times were used in the PK parameter calculations.

[0314] E. Study Subjects (i) Disposition of Subjects

[0315] Table 7 presents the subject disposition for the safety population.

[0316] A total of 65 subjects were randomized to 1 of 8 cohorts. Six subjects in each cohort received Formulation A at one of the following dose levels, with a high-fat or low-fat meal (fed state): 320 mg, 640 mg, or 1280 mg. Two subjects in each cohort received placebo in the corresponding fed state. Six subjects received Formulation A 960 mg fasting and 6 subjects received Formulation A 1280 mg fasting; 2 subjects in each of these cohorts received placebo fasting. One additional subject in Cohort 3c who received 960 mg Formulation A BID fasting withdrew from the study early due to concerns about being able to tolerate the number of blood draws during treatment. The remaining 64 subjects completed the study.

[0317]

[0318]

[0319] (ii) Demographics and other baseline characteristics

[0320] The demographic and baseline characteristics of the safety population are summarized in Table 8. The mean age of the subjects was 32.3 to 42.5 years, and the mean BMI was 22.64 to 28.63 kg / m 2 The majority of participants were not Hispanic or Latino. Demographics and baseline characteristics were generally well matched across treatment groups.

[0321]

[0322]

[0323]

[0324] F. Pharmacokinetic and Pharmacodynamic Results (i) Plasma Pharmacokinetics of Formulation A

[0325] Error! Reference source not found. Plots showing mean (+SD) day 1 plasma phloroglucinol concentrations by dose level for the PK population by food state are shown on linear and semi-log scales, respectively.

[0326] Phloroglucinol was rapidly absorbed following administration of Formulation A in the fed state. Two periods of slower decline in mean plasma phloroglucinol concentrations were observed at approximately 2 and 4 hours after dosing. Systemic exposure to phloroglucinol generally increased with increasing dose across treatment groups in the high-fat, low-fat, and fasting states; however, relatively blunted and sustained exposure was evident with food.

[0327] Error! Reference source not found. 2 Plots showing mean (+SD) plasma phloroglucinol trough concentrations by dose level for the PK population on linear and semi-log scales, respectively.

[0328] No noticeable accumulation of phloroglucinol was observed following each morning and evening (nominal times 0 and 10 hours) administration of Formulation A, beginning on the morning of Day 1 and continuing through the morning of Day 6. Given the short dosing interval of 10 hours between the morning and evening doses, the evening trough concentrations were generally higher than the morning trough concentrations for the subsequent 14-hour interval.

[0329] Table 9 summarizes the plasma Formulation A PK parameters for the Day 1 PK population. Formulation A was rapidly absorbed following administration of Formulation A on Day 1. In the fasting state, the median T max In the fed state, consistent with the more blunted sustained shape of the curve, the median T max The values ​​ranged from 0.52 to 1.75 hours. The average C max The exposure increased with increasing dose, ranging from 269.17 to 1201.00 ng / mL and 506.83 to 1074.83 ng / mL in the high-fat and low-fat treatment groups, respectively. The exposure was significantly higher in the absence of food, with the mean C in the fasting 960 mg and 1280 mg treatment groups being 2.34 and 3.33 ng / mL, respectively. max The values ​​were 2745.71 and 4873.33 ng / mL respectively. max The changes are similar to those of tau The determined systemic exposures followed a similar trend.

[0330]

[0331]

[0332]

[0333] Table 1 summarizes the plasma Formulation A PK parameters for the Day 6 PK population. Given the lack of accumulation at steady state following each morning and evening dose of Formulation A (nominal times 0 and 10 hours), the Day 6 PK profile was qualitatively and quantitatively similar to that observed following the initial dose on Day 1. The t1 / 2 was similar across treatment groups, ranging from 1.6 hours to 2.4 hours in all treatment groups. The t1 / 2 was similar across treatment groups based on AUC 1.0 and 1.5 hours in all treatment groups. tau (R AUCtau ) and C max (R Cmax ) were similar and close to 1, indicating that there was no appreciable accumulation of Formulation A at steady state following the administered dosing regimen.

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340] (ii) Dose ratio of formulation A

[0341] Dose proportionality results were assessed using the Smith criterion (90% CI: 0.839 to 1.161) and the Hummel criterion (90% CI: 0.50 to 1.50) across the dose range in both high-fat and low-fat conditions. Overall, no general trends indicating departures from dose proportionality were observed across the dose range studied.

[0342] Table 4 summarizes the power model analysis of Formulation A dose proportionality for the Day 1 PK evaluable population for the 320 mg, 640 mg, and 1280 mg high fat and low fat Formulation A treatment groups.

[0343] The estimated slopes (with 90% CI) of the dose-exposure relationships for the high fat 320 mg, 640 mg, and 1280 mg Formulation A treatment groups on Day 1 were max For tau The two parameters evaluated (C max and AUC tau) all met the Hummel criteria but did not meet the more stringent Smith criteria. The estimated slopes (with 90% CI) of the dose-exposure relationships for the low-fat 320 mg, 640 mg, and 1280 mg Formulation A treatment groups on Day 1 were max For tau For the AUC, it was 1.145 (0.964, 1.325). tau Meets Hummel's criteria but not Smith's.

[0344]

[0345]

[0346] Table 5 summarizes the power model analysis of Formulation A dose proportionality for the Day 6 PK evaluable population for the 320 mg, 620 mg, and 1280 mg high fat and low fat Formulation A treatment groups.

[0347] The estimated slopes (with 90% CI) of the dose-exposure relationships for the high fat 320 mg, 640 mg, and 1280 mg Formulation A treatment groups on Day 6 were max For 0-inf 1.062 (0.896, 1.227) for the AUC 0-t For the AUC, it is 1.068 (0.902, 1.234). 0-t and AUC 0-inf The estimated slopes (with 90% CI) of the dose-exposure relationship for the low-fat 320 mg, 640 mg, and 1280 mg Formulation A treatment groups on Day 6 for C max For 0-inf 1.174 (0.988, 1.361) for the AUC 0-t For all parameters evaluated (C max , AUC 0-t and AUC 0-inf ) all meet the Hummel criterion but not the Smith criterion.

[0348]

[0349]

[0350] (iii) Urinary pharmacokinetics of Formulation A

[0351] Table 13 summarizes the urine Formulation A PK parameters for the PK population on Day 1. Consistent with the rapid clearance of Formulation A from plasma, Formulation A was rapidly excreted in urine. For all dosing regimens studied, the PK profile of Formulation A in urine on Day 1 generally followed a dose-dependent trend similar to the corresponding plasma PK profile.

[0352]

[0353]

[0354]

[0355] Table 6 summarizes the urine Formulation A PK parameters for the PK population on Day 6. Urinary excretion on Day 6 followed a similar pattern to that observed on Day 1 for all dosing regimens.

[0356]

[0357]

[0358]

[0359] (iv) Pharmacokinetic and pharmacodynamic conclusions

[0360] Following administration of Formulation A, phloroglucinol was rapidly absorbed and subsequently declined. Systemic exposure to phloroglucinol generally increased with increasing dose across treatment groups; evidence of IR / DR / DR kinetics was observed in the current study, with a slowing of the rate of decline in plasma phloroglucinol concentrations observed approximately 2 hours after administration of Formulation A and then again approximately 4 hours after administration of Formulation A. Given the overall fairly rapid half-life, no notable accumulation was observed at steady state. When administered with food, the PK profile of Formulation A demonstrated a blunted but sustained exposure, regardless of meal type. Exposures observed in this study met or exceeded those observed with Spasfon for all dosing regimens. TM The mean C after administration of 1 to 2 capsules of Formulation A was max Value with use 1 to 2 tablets of Spasfon TM The average C obtained for the tablets max The mean C values ​​after administration of 3 to 4 capsules of Formulation A were similar, but AUC was higher in all conditions studied. max and AUC values ​​are much higher than those using Spasfon TM The value obtained.

[0361] Consistent with the rapid clearance of Formulation A from plasma, Formulation A was rapidly excreted into the urine. The PK profiles of Formulation A in urine on Days 1 and 6 generally followed a dose-dependent trend similar to the corresponding plasma PK profiles for all dosing regimens studied.

[0362] Exploratory dose proportionality assessments showed no overall trend away from proportionality across the dose range studied.

[0363] In general, subjects generally had relatively few bowel movements per day (average 0 to 2) throughout the study. Overall, the data showed no clear or consistent trends in bowel movements. However, data from selected cohorts and isolated subjects within individual cohorts suggest that Formulation A may produce a reduction in the number of bowel movements per day during treatment, with a return to baseline after completion of the treatment period.

[0364] G. Safety Results (i) Exposure

[0365] A total of 65 subjects were randomized into 1 of 8 cohorts. Starting on the morning of Day 1 and continuing through the morning of Day 6, 6 subjects in each cohort received formulation A administered each morning and evening (nominal times 0 and 10 hours). The following dose levels were studied with a high or low fat meal (fed state): 320 mg, 640 mg, or 1280 mg. Two subjects in each cohort received placebo in the corresponding fed state. Six subjects received 960 mg formulation A on an empty stomach and six subjects received 1280 mg formulation A on an empty stomach; 2 subjects in each of these cohorts received placebo on an empty stomach. An additional subject began fasting dosing with 960 mg formulation A, but withdrew from the study early after the first dose due to concerns about the number of blood draws that could be tolerated during treatment.

[0366] (ii) Adverse events

[0367] Table 7 provides a summary of AEs for the safety population.

[0368] There were no TEAEs related to COVID-19. There were no treatment-emergent SAEs, study drug-related treatment-emergent SAEs, TEAEs leading to death, TEAEs leading to study discontinuation, or study drug-related TEAEs leading to study discontinuation.

[0369] Overall, 3 (25.0%), 5 (41.7%), 2 (28.6%), 6 (33.3%), and 4 (25.0%) subjects in the 320 mg, 640 mg, 960 mg, 1280 mg, and combined placebo groups experienced TEAEs of mild or moderate severity, respectively.

[0370] Overall, TEAEs considered to be related to study drug were experienced by 1 (8.3%), 1 (8.3%), and 2 (11.1%) subjects in the 320 mg, 640 mg, and 1280 mg Formulation A treatment groups, respectively. Of these study drug-related TEAEs, all were mild in severity.

[0371] No dose-dependent increase in the frequency or severity of AEs was observed, and there were no clear differences in the incidence or severity of AEs based on dietary conditions.

[0372]

[0373]

[0374]

[0375] Table 9 summarizes the TEAEs by SOC and PT for the safety population. In the 320 mg, 640 mg, 960 mg, 1280 mg and combined placebo groups, 3 (25.0%), 5 (41.7%), 2 (28.6%), 6 (33.3%) and 4 (25.0%) subjects experienced TEAEs, and there was no obvious dose-dependent increase in the frequency of AEs. In addition, there was no significant difference in the incidence or severity of AEs according to dietary conditions. The most commonly reported SOCs for TEAEs were gastrointestinal disorders and nervous system disorders. There were no TEAEs related to COVID-19 during the study, and no TEAEs resulted in death.

[0376]

[0377]

[0378]

[0379]

[0380] Drug-related adverse events

[0381] Error! Reference source not found. Study drug-related TEAEs by SOC and PT for the safety population are shown. Overall, 1 (8.3%), 1 (8.3%), 2 (11.1%), and 1 (6.3%) subjects experienced drug-related TEAEs in the 320 mg, 640 mg, 1280 mg, and combined placebo groups, respectively. In the overall formulation A 320 mg treatment group, 1 (8.3%) subject experienced dyspepsia, fatigue, myalgia, and headache. In the overall formulation A 640 mg treatment group, 1 (8.3%) subject experienced ventricular tachycardia. In the overall formulation A 1280 mg treatment group, 2 (11.1%) subjects experienced abdominal pain and diarrhea. One of these subjects (5.6%) also experienced dyspepsia and flatulence. In the combined placebo group, 1 (6.3%) subject experienced constipation.

[0382]

[0383]

[0384]

[0385] H. Safety Conclusion

[0386] The results of this study showed that Formulation A was safe and well tolerated in healthy subjects when administered orally in doses ranging from 320 mg to 1280 mg daily in the morning and evening (nominal times 0 and 10 hours) starting on the morning of Day 1 and continuing until the morning of Day 6. No subject died, experienced a SAE that emerged during treatment, or discontinued the study due to a TEAE. The incidence of TEAEs was roughly comparable between subjects receiving Formulation A (25.0%, 41.7%, 28.6%, and 33.3% of subjects in the 320 mg, 640 mg, 960 mg, and 1280 mg Formulation A treatment groups, respectively) and subjects receiving placebo treatment (25.0% of placebo subjects). All TEAEs were mild or moderate in severity. No dose-dependent increase in the frequency or severity of AEs was observed, and there was no significant difference in the incidence or severity of AEs based on dietary conditions.

[0387] During the study period, there were no meaningful changes from baseline in laboratory parameters, vital signs, 12-lead ECG results, or skin and mucosal assessments.

[0388] No dose-dependent increase in the frequency or severity of AEs was observed, and there were no clear differences in the incidence or severity of AEs based on meal conditions. During the study, there were no meaningful changes from baseline in laboratory parameters, vital signs, 12-lead ECG results, or skin and mucosal assessments.

[0389] I. Overall Conclusion

[0390] Based on this study, the following conclusions can be drawn:

[0391] Formulation A was safe and well tolerated in healthy subjects at single oral doses ranging from 320 mg to 1280 mg administered each morning and evening (nominal times 0 and 10 hours) starting on the morning of Day 1 and continuing through the morning of Day 6 under all conditions studied (including the fasting state which resulted in a rapid increase to high exposure);

[0392] Evidence of IR / DR / DR kinetics was observed following administration of Formulation A, with no noticeable accumulation following daily morning and evening dosing; and

[0393] In the presence of food, the PK profile of Formulation A showed a blunted but sustained exposure, regardless of meal type.

[0394] The embodiments shown and described in this specification are merely specific embodiments of the inventor as a person skilled in the art and are not limiting in any way. Therefore, various changes, modifications or alterations may be made to these embodiments within the scope of the following claims without departing from the spirit of the invention. The cited references are expressly incorporated herein by reference in their entirety.

Claims

1. A pharmaceutical composition comprising a total amount of about 50 mg to about 1000 mg of an active pharmaceutical ingredient (API), wherein the active pharmaceutical ingredient is phloroglucinol, trimethylphloroglucinol, a pharmaceutically acceptable salt thereof, or a combination thereof, wherein the pharmaceutical composition comprises: an immediate release portion comprising about 20 to about 40 weight percent of the total amount of the API, wherein at least about 90 weight percent of the API in the immediate release portion is released from the pharmaceutical composition within about 2 hours as measured by a USP 2 paddle method at about 50 rpm at about 37° C. in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution; a first modified release portion comprising about 20 to about 40 weight percent of the total amount of the API, wherein at least about 90 weight percent of the API in the first modified release portion is released from the pharmaceutical composition after at least about 2 hours to about 4 hours as measured by a USP 2 paddle method at about 50 rpm at about 37° C. in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution; and A second modified release portion comprising about 20 to about 40 weight percent of the total amount of the API, wherein at least about 90 weight percent of the API in the second modified release portion is released from the pharmaceutical composition after about 4 hours or longer as measured by a USP 2 paddle method at about 50 rpm at about 37°C in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution.

2. The pharmaceutical composition according to claim 1, wherein the API is phloroglucinol or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition according to any one of the preceding claims, wherein the API is trimethylphloroglucinol or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition according to any one of the preceding claims, in the form of a plurality of beads.

5. The pharmaceutical composition according to any one of claims 1 to 3, which is in the form of a plurality of particles.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the first modified release portion comprises an API-containing core coated with a first enteric polymer capable of dissolving at a pH of about 5.

5.

7. The pharmaceutical composition according to claim 6, wherein the first enteric polymer is a methacrylic acid copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or a 1:1 methacrylic acid:ethyl acrylate copolymer, or L 30D-55 polymer.

8. The pharmaceutical composition according to claim 6 or 7, wherein the API-containing core coated with the first enteric polymer is in the form of beads or granules.

9. The pharmaceutical composition according to any one of the preceding claims, wherein the second modified release portion comprises an API-containing core coated with a second enteric polymer capable of dissolving at a pH of 6.8 or higher.

10. The pharmaceutical composition according to claim 9, wherein the enteric polymer is a methacrylic acid copolymer, such as methacrylic acid, methyl acrylate, methyl methacrylate copolymer, or such as FS 30D copolymer.

11. The pharmaceutical composition according to claim 9 or 10, wherein the API-containing core coated with the second enteric polymer is in the form of beads or granules.

12. A pharmaceutical composition according to any one of the preceding claims, wherein the immediate release portion is in the form of beads or granules.

13. The pharmaceutical composition according to any one of claims 1 to 5, wherein The immediate release portion is coated on the first modified release portion, or The immediate release portion is coated on the second modified release portion, or The immediate release portion is coated on a combination of the first release portion and the second release portion.

14. The pharmaceutical composition according to any one of claims 1-5, wherein the first modified release portion is coated on the second release portion.

15. The pharmaceutical composition according to claim 14, wherein the immediate release portion is coated on the first modified release portion.

16. The pharmaceutical composition of any of the preceding claims, wherein at least about 30 weight percent of the total amount of API in the composition is released from the composition within a period of about 5 minutes to about 2 hours as measured by USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution at about 37°C.

17. The pharmaceutical composition of any of the preceding claims, wherein at least about 60 weight percent of the total amount of API in the composition is released from the pharmaceutical composition within a period of about 2 hours to about 4 hours as measured by USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution at about 37°C.

18. The pharmaceutical composition of any of the preceding claims, wherein at least about 80 weight percent of the total amount of API in the composition is released from the pharmaceutical composition within a period of about 3 hours to about 6 hours as measured by USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution comprising about 0.1 N HCl solution at about 37°C.

19. A pharmaceutical composition according to any one of the preceding claims, comprising from about 50 mg to about 500 mg of the API in the immediate release portion, such as from about 50 mg to about 400 mg, or such as about 160 mg.

20. A pharmaceutical composition according to any one of the preceding claims, comprising from about 25 mg to about 200 mg of the API in the first modified release portion, such as from about 50 mg to about 200 mg, or such as about 160 mg, or such as about 80 mg.

21. A pharmaceutical composition according to any one of the preceding claims, comprising from about 25 mg to about 300 mg of the API in the second modified release portion, such as from about 25 mg to about 200 mg, or such as about 160 mg, or such as about 80 mg.

22. The pharmaceutical composition of any of the preceding claims, wherein one or more of the immediate release portion, the first modified release portion, or the second modified release portion further comprises one or more of a filler, a binder, a disintegrant, an emulsifier, an antistatic agent, or a solvent.

23. An oral dosage unit comprising a pharmaceutical composition according to any one of the preceding claims.

24. The oral dosage unit according to claim 23, comprising from about 10 to about 60 wt%, or such as from about 30 to about 50 wt%, or such as about 43 wt% of the immediate release portion, based on the weight of the oral dosage unit.

25. The oral dosage unit according to claim 23 or 24, comprising from about 10 to about 40 wt%, or such as from about 20 to about 30 wt%, or such as about 28 wt% of the first modified release portion, based on the weight of the oral dosage unit.

26. The oral dosage unit of any one of claims 23-25, comprising from about 10 to about 40 wt%, or such as from about 20 to about 30 wt%, or such as about 28 wt% of said second modified release portion, based on the weight of the oral dosage unit.

27. An oral dosage unit according to any one of claims 23 to 26 in the form of a tablet, capsule or sachet.

28. A method of treating a spastic disorder in a subject in need thereof, the method comprising orally administering to the subject an oral dosage unit according to any one of claims 23-27, wherein oral administration to the subject in the fed state results in The median value T of the API max From about 0.5 to about 1.75 hours; The average C of the API max From about 269 to about 1512 ng / mL; The mean AUC of the API tau From about 879 to about 4695 h*ng / mL; and / or The API has a mean t1 / 2 of about 1.6 hours to about 2.4 hours; or wherein oral administration to said subject in a fasting state results in The median value T of the API max About 0.5 hours; The average C of the API max From about 2745 to about 4874 ng / mL; The mean AUC of the API tau From about 4567 to about 6853 h*ng / mL; and / or The mean t1 / 2 of the API was about 2 hours.

29. The method of claim 28, wherein the spastic disorder is a sudden involuntary muscle contraction of the bronchi, stomach, intestines, ureters, gall bladder, kidneys, or bile ducts.

30. The method of claim 28, wherein the spastic disorder is urinary tract spasm, gallstones, gastrointestinal disorders, inflammatory bowel syndrome, renal colic, or biliary spastic disorder.

31. An oral dosage unit according to any one of claims 23-27 for use in treating a spastic disorder in a subject in need thereof, comprising orally administering the oral dosage unit to the subject, and wherein the oral administration in the fed state results in: The median value T of the API max From about 0.5 to about 1.75 hours; The average C of the API max From about 269 to about 1512 ng / mL; The mean AUC of the API tau From about 879 to about 4695 h*ng / mL; and / or The API has a mean t1 / 2 of about 1.6 hours to about 2.4 hours; or wherein said oral administration in the fasting state results in: The median value of the API is T max About 0.5 hours; The average C of the API max From about 2745 to about 4874 ng / mL; The mean AUC of the API tau From about 4567 to about 6853 h*ng / mL; and / or The mean t1 / 2 of the API was about 2 hours.

32. The oral dosage unit of claim 31, wherein the spastic disorder is a sudden involuntary muscle contraction of the bronchi, stomach, intestines, ureters, gall bladder, kidneys, or bile ducts.

33. The oral dosage unit of claim 31, wherein the spastic disorder is urinary tract spasm, gallstones, gastrointestinal disorders, inflammatory bowel syndrome, renal colic, or biliary spastic disorder.

34. An oral dosage unit according to any one of claims 23-27 for use in treating a spastic disorder in a subject in need thereof, comprising orally administering the oral dosage unit to the subject, and wherein the oral administration in the fed state results in: The median value T of the API max From about 0.5 to about 1.75 hours; The average C of the API max From about 269 to about 1512 ng / mL; The mean AUC of the API tau From about 879 to about 4695 h*ng / mL; and / or The API has a mean t1 / 2 of about 1.6 hours to about 2.4 hours; or wherein said oral administration in the fasting state results in: The median value T of the API max About 0.5 hours; The average C of the API max From about 2745 to about 4874 ng / mL; The mean AUC of the API tau From about 4567 to about 6853 h*ng / mL; and / or The mean t1 / 2 of the API was about 2 hours.

35. The oral dosage unit of claim 34, wherein the spastic disorder is a sudden involuntary muscle contraction of the bronchi, stomach, intestines, ureters, gall bladder, kidneys, or bile ducts.

36. The oral dosage unit of claim 34, wherein the spastic disorder is urinary tract spasm, gallstones, gastrointestinal disorders, inflammatory bowel syndrome, renal colic, or biliary spastic disorder.

37. Use of an oral dosage unit according to any one of claims 23-27 for treating a spastic disorder in a subject in need thereof, comprising orally administering the oral dosage unit to the subject, and wherein the oral administration in the fed state results in: The median value of the API is T max From about 0.5 to about 1.75 hours; The average C of the API max From about 269 to about 1512 ng / mL; The mean AUC of the API tau From about 879 to about 4695 h*ng / mL; and / or The API has a mean t1 / 2 of about 1.6 hours to about 2.4 hours; or wherein said oral administration in the fasting state results in: The median value of the API is T max About 0.5 hours; The average C of the API max From about 2745 to about 4874 ng / mL; The mean AUC of the API tau From about 4567 to about 6853 h*ng / mL; and / or The mean t1 / 2 of the API was about 2 hours.

38. Use according to claim 37, wherein the spastic disorder is a sudden involuntary muscle contraction of the bronchi, stomach, intestines, ureters, gall bladder, kidneys or bile ducts.

39. The use according to claim 37, wherein the spastic disorder is urinary tract spasm, gallstones, gastrointestinal disorders, inflammatory bowel syndrome, renal colic or biliary spastic disorder.

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