Flologlucinol formulations and methods of use

Abstract

The present disclosure provides a pharmaceutical composition comprising a total amount of about 50 mg to about 1000 mg of an active ingredient (API) that is phloroglucinol, trimethylphloroglucinol, pharmaceutically acceptable salts thereof, or combinations thereof. The pharmaceutical composition comprises an immediate release portion, a first modified release portion, and a second modified release portion. Also provided are oral dosage units comprising the pharmaceutical composition, and methods of treating a spastic condition in a subject in need thereof using the pharmaceutical composition or the oral dosage unit. TIFF2025519466000052.tif106170

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 351,572, filed on June 13, 2022. This disclosure is incorporated herein by reference.

[0002] Technical Field The present disclosure relates to pharmaceutical compositions comprising an active pharmaceutical ingredient (API) that is phloroglucinol, trimethylphloroglucinol, pharmaceutically acceptable salts thereof, or combinations thereof, and methods of using the same.

Background Art

[0003] Background Phloroglucinol is an antispasmodic drug approved in France (as Spasfon™) and several other countries for the relief of pain in gastrointestinal disorders. In placebo - controlled trials, phloroglucinol demonstrated statistically significant improvements in both pain and bowel movement frequency in patients with irritable bowel syndrome (IBS). Despite the proven efficacy of phloroglucinol, it is difficult to administer daily over a long period due to the PK profile of phloroglucinol. After administration of existing formulations, a very rapid maximum plasma concentration (C max ) is reached followed by a rapid decline. As a result, frequent dosing (up to 6 times a day) is required.

[0004] There is a need for formulations that maintain efficacy with less frequent dosing.

Summary of the Invention

[0005] Summary In one aspect, the present disclosure provides a pharmaceutical composition comprising a total amount of about 50 mg to about 1000 mg of an active ingredient (API) that is phloroglucinol, trimethylphloroglucinol, pharmaceutically acceptable salts thereof, or combinations thereof. The pharmaceutical composition comprises an immediate release portion comprising about 20 - 40 wt% of the total amount of the API, and when measured by the 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, at least about 90 wt% of the API in the immediate release portion is released from the pharmaceutical composition within about 2 hours. The pharmaceutical composition also comprises a first modified release portion comprising about 20 - 40 wt% of the total amount of the API, and when measured by the 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, at least about 90 wt% of the API in the first modified release portion is released from the pharmaceutical composition at least about 2 hours to about 4 hours later. The pharmaceutical composition further comprises a second modified release portion comprising about 20 - 40 wt% of the total amount of the API, and when measured by the 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, at least about 90 wt% of the API in the second modified release portion is released from the pharmaceutical composition about 4 hours or more later. An oral dosage unit comprising the pharmaceutical composition according to any one of the preceding claims.

[0006] In another aspect, the present disclosure is a method of treating a spastic condition in a subject in need thereof, comprising the step of orally administering to the subject the oral dosage unit described herein, wherein (i) oral administration to the subject in a fed state results in a median T of the API of about 0.5 to about 1.75 hours max ; an average C of the API of about 269 to about 1512 ng / mL max ; an average AUC of the API of about 879 to about 4695 h*ng / mL tau ; and / or an average t1 / 2 of the API of about 1.6 hours to about 2.4 hours, or (ii) oral administration to the subject in a fasting state results in a median T of the API of about 0.5 hours max ; an average C of the API of about 2745 to about 4874 ng / mL max; The average AUC of the API is about 4567 to about 6853 h*ng / mL tau ; and / or provides a method that results in an average t1 / 2 of the API of about 2 hours.

Brief Description of the Drawings

[0007] This application will be better understood when read in conjunction with the accompanying drawings. Exemplary aspects of the subject matter are shown in the drawings for purposes of illustration. However, the subject matter disclosed herein is not limited to the specific compositions, methods, devices, and systems disclosed. Further, the drawings are not necessarily drawn to scale.

[0008]

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Mode for Carrying Out the Invention

[0009] Detailed Description of Exemplary Embodiments The present disclosure provides a pharmaceutical composition capable of releasing an active ingredient over a predetermined period. The composition contains an immediate release portion and a delayed release portion, thereby providing a sustained release of the API. By doing so, patients do not need to continuously administer the oral dosage form of the API throughout the day. Therefore, the API is administered more regularly, and the condition is treated more reliably.

[0010] Unless otherwise clearly indicated by the context, in the present disclosure, the singular forms "a", "an", and "the" include plural references, and references to a particular numerical value include at least that particular value. Thus, reference to "a material" is a reference to at least one such material and its equivalents known to those skilled in the art.

[0011] 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 the range "2 to 4". When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" means 0.9 to 1.1.

[0012] When a list is presented, unless otherwise specified, each individual element of the list and all combinations of the list must be understood as separate aspects. For example, a list of aspects shown as "A, B, or C" must be interpreted as including the aspects "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0013] It should also be understood that certain features of the present invention that are described in the context of separate aspects for clarity may be provided in combination in one aspect. That is, each individual aspect is considered combinable with any other aspect, unless clearly incompatible or excluded, and such combinations are considered to be another aspect. Conversely, for the sake of brevity, the various features of the present invention described in the context of one aspect may be provided separately or in any sub - combination. Further, note that the claims may be drafted to exclude any arbitrary element. Thus, this description is intended to serve as a basis for antecedents for using exclusive terms such as "merely", "only", etc., together with an enumeration of claim elements or together with the use of "negative" limitations. Finally, although one aspect may be described as part of a series of steps or as part of a more general structure, each of the said steps may also be considered an independent aspect in itself.

[0014] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or corresponding agencies in countries other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, particularly humans.

[0015] As used herein, the terms "patient" or "subject" refer to a mammal and are used interchangeably. In some aspects, the patient or subject is a human. In other aspects, the patient or subject is a veterinary animal or livestock, a bred animal or pet, or an animal commonly used in clinical research.

[0016] To "treat" any disease or disorder, in some embodiments, refers to alleviating the disease or disorder (i.e., stopping or reducing the onset of at least one of the disease or its clinical symptoms). "Treat" refers to alleviating a disease or disorder using phloroglucinol, trimethylphloroglucinol, or a combination thereof. In some embodiments, "treat" or "treatment" refers to alleviating at least one bodily parameter that may not be distinguishable in a subject. In other embodiments, "treat" or "treatment" refers to physically (e.g., stabilizing distinguishable symptoms), physiologically (e.g., stabilizing bodily parameters), or both, adjusting a disease or disorder. In further embodiments, "treat" or "treatment" refers to delaying the onset of a disease or disorder.

[0017] The present disclosure provides a pharmaceutical composition comprising an active pharmaceutical ingredient (API) that is phloroglucinol, trimethylphloroglucinol, 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 trimethylphloroglucinol or a pharmaceutically acceptable salt thereof.

[0018] As used herein, the term "phloroglucinol" refers to the following compound. TIFF2025519466000002.tif21128

[0019] Phloroglucinol also includes any tautomeric form thereof, including its known keto tautomers shown below. TIFF2025519466000003.tif21128

[0020] Similarly, as used herein, the term "trimethylphloroglucinol" refers to the following compound. TIFF2025519466000004.tif28128

[0021] Floroglucinol and trimethylfloroglucinol may 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 other similarly known acceptable acids. In other embodiments, pharmaceutically acceptable salts may also be formed from inorganic bases, desirably, for example, sodium hydroxide, lithium hydroxide, or potassium hydroxide, such as alkali metal salts including alkali metal hydroxides. Examples of inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide. Pharmaceutically acceptable salts may also be formed from organic bases such as ammonium salts, monomethylammonium, dimethylammonium, and trimethylammonium, monoethylammonium, diethylammonium, and triethylammonium, monopropylammonium, dipropylammonium, and tripropylammonium, ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzyl-ammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1 n-butylpiperidinium, 2-methylpiperidinium, l-ethyl-2-methylpiperidinium, monoethanolammonium, diethanolammonium, and triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium, diethanolamine, ethylenediamine, and the like. In one example, the base is sodium hydroxide, lithium hydroxide, potassium hydroxide, or a mixture thereof.

[0022] The pharmaceutical composition contains a total amount of API from about 50 mg to about 1000 mg. In some embodiments, the pharmaceutical composition contains a total amount of API 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. In further embodiments, the pharmaceutical composition contains from about 100 to about 1000, from about 100 to about 900, from about 100 to about 800, from about 100 to about 700, from about 100 to about 600, from about 100 to about 500, from about 100 to about 400, from about 100 to about 300, from about 100 to about 200, from about 200 to about 1000, from about 200 to about 900, from about 200 to about 800, from about 200 to about 700, from about 200 to about 600, from about 200 to about 500, from about 200 to about 400, from about 300 to about 1000, from about 300 to about 900, from about 300 to about 800, from about 300 to about 700, from about 300 to about 600, from about 300 to about 500, from about 300 to about 400, from about 400 to about 1000, from about 400 to about 900, from about 400 to about 800, from about 400 to about 700, from about 400 to about 600, from about 400 to about 500, from about 500 to about 1000, from about 500 to about 900, from about 500 to about 800, from about 500 to about 700, from about 500 to about 600, from about 600 to about 1000, from about 600 to about 900, from about 600 to about 800, from about 600 to about 700, from about 700 to about 1000, from about 700 to about 900, from about 700 to about 800, from about 800 to about 1000, from about 800 to about 900, or from about 900 to about 1000 mg of API.

[0023] The pharmaceutical composition includes 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 further embodiments, the first modified release portion and the second modified release portion contain the same API. In still further embodiments, the immediate release portion, the first modified release portion, and the second modified release portion contain the same API.

[0024] The immediate release portion contains from about 20% to about 40% by weight 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% by weight of the API, based on the weight of the pharmaceutical composition. In further embodiments, the immediate release portion contains from about 20% to about 40%, from about 20% to about 38%, from about 20% to about 36%, from about 20% to about 35%, from about 20% to about 34%, from about 20% to about 32%, from about 20% to about 30%, from about 20% to about 28%, from about 20% to about 26%, from about 20% to about 25%, from about 20% to about 24%, from about 20% to about 22%, from about 22% to about 40%, from about 22% to about 38%, from about 22% to about 36%, from about 22% to about 35%, from about 22% to about 34%, from about 22% to about 32%, from about 22% to about 30%, from about 22% to about 28%, from about 22% to about 26%, from about 22% to about 24%, from about 24% to about 40%, from about 24% to about 38%, from about 24% to about 36%, from about 24% to about 35%, from about 24% to about 34%, from about 24% to about 32%, from about 24% to about 30, from about 24% to about 28%, from about 24% to about 26%, from about 26% to about 40%, from about 26% to about 38%, from about 26% to about 36%, from about 26% to about 35%, from about 26% to about 34%, from about 26% to about 32%, from about 26% to about 30%, from about 26% to about 28%, from about 28% to about 40%, from about 28% to about 38%, from about 28% to about 36%, from about 28% to about 35%, from about 28% to about 34%, from about 28% to about 32%, from about 28% to about 30%, from about 30% to about 40%, from about 30% to about 38%, from about 30% to about 36%, from about 30% to about 35%, from about 30% to about 34%, from about 30% to about 32%, from about 32% to about 40%, from about 32% to about 38%, from about 32% to about 36%, from about 32% to about 34%, from about 34% to about 40%, from about 34% to about 38%, from about 34% to about 36%, from about 36% to about 40%, from about 36% to about 38%, or from about 38% to about 40% by weight of the API, based on the weight of the pharmaceutical composition.

[0025] The immediate release portion may contain from about 50 mg to about 500 mg of 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 API. In further embodiments, the immediate release portion contains from about 50 to about 450, from about 50 to about 400, from about 50 to about 350, from about 50 to about 300, from about 50 to about 250, from about 50 to about 200, from about 50 to about 150, from about 50 to about 100, from about 100 to about 500, from about 100 to about 450, from about 100 to about 400, from about 100 to about 350, from about 100 to about 300, from about 100 to about 250, from about 100 to about 200, from about 100 to about 150, from about 150 to about 500, from about 150 to about 450, from about 150 to about 400, from about 150 to about 350, from about 150 to about 300 m, from about 150 to about 250, from about 150 to about 200, from about 200 to about 500, from about 200 to about 450, from about 200 to about 400, from about 200 to about 350, from about 200 to about 300, from about 200 to about 250, from about 250 to about 500, from about 250 to about 450, from about 250 to about 400, from about 250 to about 350, from about 250 to about 300, from about 300 to about 500, from about 300 to about 450, from about 300 to about 400, from about 300 to about 350, from about 350 to about 500, from about 350 to about 450, from about 350 to about 400, from about 400 to about 500, from about 400 to about 450, or from about 450 to about 500 mg of API. In still further embodiments, the immediate release portion contains from about 50 mg to about 400 mg of API. In yet further embodiments, the immediate release portion contains about 160 mg of API.

[0026] According to the present disclosure, at about 37 °C, when measured by the USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution, at least about 90 wt% of the API in the immediate release portion is released from the pharmaceutical composition within about 2 hours, for example, from the administration of the API. In some embodiments, at about 37 °C, when measured by the USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 100 wt% of the API in the immediate release portion is released from the pharmaceutical composition within about 2 hours, for example, from the administration of the API. In further embodiments, at about 37 °C, when measured by the USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution, 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 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, about 93 to 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 wt% of the API in the immediate release portion is released from the pharmaceutical composition within about 2 hours, for example, from the administration of the API.

[0027] The term "within about 2 hours" refers to a time frame of 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 at, for example, about 1 minute, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes from administration of the API. In further embodiments, the API is released from the immediate release portion at, for example, from about 1 to about 120 minutes, about 1 to about 110, about 1 to about 100 minutes, about 1 to about 90 minutes, about 1 to about 80 minutes, about 1 to about 70 minutes, about 1 to about 60 minutes, about 1 to about 50 minutes, about 1 to about 40 minutes, about 1 to about 30 minutes, about 1 to about 20 minutes, about 1 to about 10 minutes, about 10 to about 120 minutes, about 10 to about 110 minutes, about 10 to about 100 minutes, about 10 to about 90 minutes, about 10 to about 80 minutes, about 10 to about 70 minutes, about 10 to about 60 minutes, about 10 to about 50 minutes, about 10 to about 40 minutes, about 10 to about 30 minutes, about 10 to about 20 minutes, about 20 to about 120 minutes, about 20 to about 110 minutes, about 20 to about 100 minutes, about 20 to about 90 minutes, about 20 to about 80 minutes, about 20 to about 70 minutes, about 20 to about 60 minutes, about 20 to about 50 minutes, about 20 to about 40 minutes, about 20 to about 30 minutes, about 30 to about 120 minutes, about 30 to about 110 minutes, about 30 to about 100 minutes, about 30 to about 90 minutes, about 30 to about 80 minutes, about 30 to about 70 minutes, about 30 to about 60 minutes, about 30 to about 50 minutes, about 30 to about 40 minutes, about 40 to about 120 minutes, about 40 to about 110 minutes, about 40 to about 100 minutes, about 40 to about 90 minutes, about 40 to about 80 minutes, about 40 to about 70 minutes, about 40 to about 60 minutes, about 40 to about 50 minutes, about 50 to about 120 minutes, about 50 to about 110 minutes, about 50 to about 100 minutes, about 50 to about 90 minutes, about 50 to about 80 minutes, about 50 to about 70 minutes, about 50 to about 60 minutes, about 60 to about 120 minutes, about 60 to about 110 minutes, about 60 to about 100 minutes, about 60 to about 90 minutes, about 60 to about 80 minutes, about 60 to about 70 minutes, about 70 to about 120 minutes, about 70 to about 110 minutes, about 70 to about 100 minutes, about 70 to about 90 minutes, about 70 to about 80 minutes, about 80 to about 120 minutes, about 80 to about 110 minutes, about 80 to about 100 minutes, about 80 to about 90 minutes, about 90 to about 120 minutes, about 90 to about 110 minutes, about 90 to about 100 minutes, about 100 to about 120 minutes, about 100 to about 110 minutes, or about 110 to about 120 minutes from administration of the API.

[0028] According to the present disclosure, the first modified release portion comprises from about 20% to about 40% by weight 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% by weight of the API, based on the weight of the pharmaceutical composition. In further embodiments, the first modified release portion contains from about 20% to about 40%, from about 20% to about 38%, from about 20% to about 36%, from about 20% to about 35%, from about 20% to about 34%, from about 20% to about 32%, from about 20% to about 30%, from about 20% to about 28%, from about 20% to about 26%, from about 20% to about 25%, from about 20% to about 24%, from about 20% to about 22%, from about 22% to about 40%, from about 22% to about 38%, from about 22% to about 36%, from about 22% to about 34%, from about 22% to about 32%, from about 22% to about 30%, from about 22% to about 38%, from about 22% to about 36%, from about 22% to about 34%, from about 22% to about 32%, from about 22% to about 30%, from about 22% to about 28%, from about 22% to about 26%, from about 22% to about 24%, from about 24% to about 40%, from about 24% to about 38%, from about 24% to about 36%, from about 24% to about 34%, from about 24% to about 32%, from about 24% to about 30%, from about 24% to about 28%, from about 24% to about 26%, from about 26% to about 40%, from about 26% to about 38%, from about 26% to about 36%, from about 26% to about 34%, from about 26% to about 32%, from about 26% to about 30%, from about 26% to about 28%, from about 28% to about 40%, from about 28% to about 38%, from about 28% to about 36%, from about 28% to about 34%, from about 28% to about 32%, from about 28% to about 30%, from about 30% to about 40%, from about 30% to about 38%, from about 30% to about 36%, from about 30% to about 34%, from about 30% to about 32%, from about 32% to about 40%, from about 32% to about 38%, from about 32% to about 36%, from about 32% to about 34%, from about 34% to about 40%, from about 34% to about 38%, from about 34% to about 36%, from about 36% to about 40%, from about 36% to about 38%, or from about 38% to about 40% by weight of the API, based on the weight of the pharmaceutical composition.

[0029] The first modified release portion may contain from about 25 mg to about 200 mg of 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 API. In other embodiments, the first modified release portion contains from about 25 to about 200, from about 25 to about 175, from about 25 to about 160, from about 25 to about 150, from about 25 to about 125, from about 25 to about 100, from about 25 to about 75, from about 25 to about 60, from about 25 to about 50, from about 50 to about 200, from about 50 to about 175, from about 50 to about 160, from about 50 to about 150, from about 50 to about 125, from about 50 to about 100, from about 50 to about 80, from about 50 to about 75, from about 75 to about 200, from about 75 to about 175, from about 75 to about 160, from about 75 to about 150, from about 75 to about 125, from about 75 to about 100, from about 75 to about 80, from about 80 to about 200, from about 80 to about 175, from about 80 to about 160, from about 80 to about 150, from about 80 to about 125, from about 80 to about 100, from about 100 to about 200, from about 100 to about 175, from about 100 to about 160, from about 100 to about 150, from about 100 to about 125, from about 125 to about 200, from about 125 to about 175, from about 125 to about 160, from about 125 to about 150, from about 150 to about 200, from about 150 to about 175, from about 150 to about 160, from about 160 to about 200, from about 160 to about 175, or from about 175 to about 200 mg of API. In further embodiments, the first modified release portion contains from about 50 mg to about 200 mg of API. In still further embodiments, the first modified release portion contains about 160 mg of API. In yet further embodiments, the first modified release portion contains about 80 mg of API.

[0030] When measured by the 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, at least about 90 weight % of the API in the first modified release portion is released from the pharmaceutical composition, for example, at least about 2 hours to about 4 hours after administration of the API. 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 % of the API in the first modified release portion is released from the pharmaceutical composition, for example, at least about 2 hours to about 4 hours after administration of the API, for example, at 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 after administration, or for example, at about 2 to about 3.75, about 2 to about 3.5, about 2 to about 3.25, about 2 to about 3, about 2 to about 2.75, about 2 to about 2.5, about 2 to about 2.25, about 2.25 to about 4, about 2.25 to about 3.75, about 2.25 to about 3.5, about 2.25 to about 3.25, about 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 after administration.In a further aspect, at about 37 °C, when measured by the USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl solution, 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 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, about 93 to 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% by weight of the API, for example, is released from the pharmaceutical composition at least about 2 hours to about 4 hours after administration of the API.

[0031] According to the present disclosure, the second modified release portion comprises from about 20% to about 40% by weight 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% by weight of the API, based on the weight of the pharmaceutical composition. In further embodiments, the second modified release portion comprises from about 20% to about 40%, from about 20% to about 38%, from about 20% to about 36%, from about 20% to about 35%, from about 20% to about 34%, from about 20% to about 32%, from about 20% to about 30%, from about 20% to about 28%, from about 20% to about 26%, from about 20% to about 25%, from about 20% to about 24%, from about 20% to about 22%, from about 22% to about 40%, from about 22% to about 38%, from about 22% to about 36%, from about 22% to about 35%, from about 22% to about 34%, from about 22% to about 32%, from about 22% to about 30%, from about 22% to about 38%, from about 22% to about 36%, from about 22% to about 34%, from about 22% to about 32%, from about 22% to about 30%, from about 22% to about 28%, from about 22% to about 26%, from about 22% to about 24%, from about 24% to about 40%, from about 24% to about 38%, from about 24% to about 36%, from about 24% to about 35%, from about 24% to about 34%, from about 24% to about 32%, from about 24% to about 30%, from about 24% to about 28%, from about 24% to about 26%, from about 26% to about 40%, from about 26% to about 38%, from about 26% to about 36%, from about 26% to about 35%, from about 26% to about 34%, from about 26% to about 32%, from about 26% to about 30%, from about 26% to about 28%, from about 28% to about 40%, from about 28% to about 38%, from about 28% to about 36%, from about 28% to about 35%, from about 28% to about 34%, from about 28% to about 32%, from about 28% to about 30%, from about 30% to about 40%, from about 30% to about 38%, from about 30% to about 36%, from about 30% to about 35%, from about 30% to about 34%, from about 30% to about 32%, from about 32% to about 40%, from about 32% to about 38%, from about 32% to about 36%, from about 32% to about 35%, from about 32% to about 34%, from about 34% to about 40%, from about 34% to about 38%, from about 34% to about 36%, from about 34% to about 35%, from about 35% to about 40%, from about 35% to about 36%, from about 36% to about 40%, from about 36% to about 38%, or from about 38% to about 40% by weight of the API, based on the weight of the pharmaceutical composition.

[0032] The second modified release portion may contain from about 25 mg to about 200 mg of 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 API. In other embodiments, the second modified release portion contains from about 25 to about 200, from about 25 to about 175, from about 25 to about 160, from about 25 to about 150, from about 25 to about 125, from about 25 to about 100, from about 25 to about 75, from about 25 to about 60, from about 25 to about 50, from about 50 to about 200, from about 50 to about 175, from about 50 to about 160, from about 50 to about 150, from about 50 to about 125, from about 50 to about 100, from about 50 to about 80, from about 50 to about 75, from about 75 to about 200, from about 75 to about 175, from about 75 to about 160, from about 75 to about 150, from about 75 to about 125, from about 75 to about 100, from about 75 to about 80, from about 80 to about 200, from about 80 to about 175, from about 80 to about 160, from about 80 to about 150, from about 80 to about 125, from about 80 to about 100, from about 100 to about 200, from about 100 to about 175, from about 100 to about 160, from about 100 to about 150, from about 100 to about 125, from about 125 to about 200, from about 125 to about 175, from about 125 to about 160, from about 125 to about 150, from about 150 to about 200, from about 150 to about 175, from about 150 to about 160, from about 160 to about 200, from about 160 to about 175, or from about 175 to about 200 mg of API. In further embodiments, the second modified release portion contains from about 50 mg to about 200 mg of API. In still further embodiments, the second modified release portion contains about 160 mg of API. In yet further embodiments, the second modified release portion contains about 80 mg of API.

[0033] When measured by the 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, at least about 90% by weight of the API in the second modified release portion is released from the pharmaceutical composition at least 4 hours after, for example, administration of the API. 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 from the pharmaceutical composition at least about 4 hours after, for example, administration of the API, for example, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours after, or, for example, about 4 to about 12, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 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 after administration of the API.In a further aspect, when measured by the 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, 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 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, about 93 to 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 % of the API in the second modified release portion is released from the pharmaceutical composition, for example, more than about 4 hours after administration of the API.

[0034] As used herein, "release of the API" from the immediate release portion, the first modified release portion, the second modified release portion, or combinations thereof, is measured by the 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.

[0035] Dosage unit As discussed herein, the present disclosure provides dosage units containing the pharmaceutical compositions described herein. In some embodiments, an oral dosage unit is formulated for oral administration, i.e., is an oral dosage unit. Oral dosage units can take various delivery forms. In some embodiments, the dosage unit is a tablet, capsule (hard or soft), sachet, softgel, liquid, gel, wafer, film, or tablet-in-capsule. In other embodiments, the dosage unit is a tablet, capsule, or sachet. In further embodiments, the oral dosage unit is a tablet. In other embodiments, the oral dosage unit is a capsule. In still further embodiments, the oral dosage unit is a sachet.

[0036] As used herein, the term "tablet" refers to a solid dosage unit. The tablet may be of any shape or size convenient for oral administration, such as tablets in the form of circular, oval, etc. Depending on the base of the tablet, the tablet may be coated with a layer containing an immediate release portion or a modified release portion. In some embodiments, the tablet is a bilayer tablet containing an immediate release (IR) layer and a modified release layer adjacent to each other. In other embodiments, the tablet is a triple layer tablet containing an immediate release layer and a modified release layer separated by a layer, such as a buffer layer. In a further embodiment, the tablet contains an immediate release portion coated with a first modified release portion and / or a second modified release portion and granules coated with beads, which are embedded within the tablet. In yet another embodiment, the tablet contains a tablet containing a first modified release portion and / or a second modified release portion, which is embedded within a tablet containing an immediate release portion. In still further embodiments, the tablet contains a tablet containing a first modified release portion and / or a second modified release portion, which is suspended in a liquid solution containing an immediate release portion, and the liquid solution is contained within a capsule. In other embodiments, the capsules of the present disclosure contain a solution containing an immediate release portion and coated beads or granules coated with a first modified release portion and / or a second modified release portion. In a further embodiment, the softgels of the present disclosure contain a solution containing an immediate release portion and beads or granules coated with a first modified release portion and / or a second modified release portion.

[0037] As used herein, the term "capsule" refers to a solid dosage unit. Capsules are typically oval in shape, but can take other forms as determined by one of ordinary skill in the art. Capsules can be hard gelatin capsules or soft gelatin capsules as required. In some embodiments, the capsule contains a tablet containing an immediate release portion and a tablet containing a first modified release portion and / or a second modified release portion. In a further embodiment, the capsule contains an immediate release tablet, a plug, and a modified release tablet containing a first modified release portion and / or a second modified release portion. In other embodiments, the capsule contains beads coated with an immediate release portion and beads coated with a first modified release portion and / or a second modified release portion. In a further embodiment, the capsule contains immediate release mini-tablets and modified release mini-tablets containing a first modified release portion and / or a second modified release portion. In yet another embodiment, the capsule contains immediate release granules, which are coated with a first modified release portion and / or a second modified release portion. In yet another embodiment, the capsule contains, as a layer, a plurality of beads coated with a first modified release portion and / or a second modified release portion and an immediate release portion.

[0038] As used herein, the term "sachet" refers to a package containing a mixture of immediate release and modified release granules or beads containing an immediate release portion and granules or beads containing a first modified release portion and / or a second modified release portion. The package can be selected by one of ordinary skill in the art.

[0039] Regardless of the form of the dosage unit, the dosage unit may alternatively contain, or may further contain, beads, granules, or a combination thereof. As used herein, "beads" are solid particles prepared by extrusion and spheronization of an immediate release portion, a first modified release portion, and / or a 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 granules. The beads or granules contain a core and any layer on the core. Similarly, "granules" are solid particles but are prepared via granulation. One of ordinary skill in the art will be able to select an appropriate granulation method for preparing the granules used herein. In some embodiments, the granulation methods include, among others, high shear granulation, melt granulation, dry granulation, or wet granulation. In some embodiments, the dosage unit contains beads that include an immediate release portion. In other embodiments, the dosage unit contains beads that include a first modified release portion. In further embodiments, the dosage unit contains beads that include a second modified release portion. In still further embodiments, the dosage unit contains beads that include an immediate release portion and a first modified release portion. In other embodiments, the dosage unit contains beads that include a first modified release portion and a second modified release portion. In further embodiments, the dosage unit contains beads that include an immediate release portion, a first modified release portion, and a second modified release portion.

[0040] Regardless of the specific presentation, the dosage form contains an immediate release portion of about 10 to about 60 weight percent, based on the weight of the oral dosage unit. In some embodiments, the dosage form contains an immediate release portion of 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 percent, based on the weight of the oral dosage unit. In further embodiments, the dosage form contains an immediate release portion of 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, 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 50m, 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, based on the weight of the oral dosage unit. In other embodiments, the dosage form contains an immediate release portion of about 30 to about 50 weight percent, based on the weight of the oral dosage unit. In still further embodiments, the dosage form contains an immediate release portion of about 43 weight percent, based on the weight of the oral dosage unit.

[0041] The dosage form may also contain a first modified release portion of about 10 to about 40% by weight based on the weight of the oral dosage unit. In some embodiments, the dosage form contains a first modified release portion of 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% by weight based on the weight of the oral dosage unit. In further embodiments, the dosage form contains a first modified release portion of about 10 - about 40, about 10 - about 35, about 10 - about 30, about 10 - about 25, about 10 - about 20, about 10 - about 15, about 15 - about 40, about 15 - about 35, about 15 - about 30, about 15 - about 25, about 15 - about 20, about 20 - about 40, about 20 - about 35, about 20 - about 30, about 20 - about 25, about 25 - about 40, about 25 - about 35, about 25 - about 30, about 30 - about 40, about 30 - about 35, or about 35 - about 40% by weight based on the weight of the oral dosage unit. In other embodiments, the dosage form contains a first modified release portion of about 20 - about 30% by weight based on the weight of the oral dosage unit. In still further embodiments, the dosage form contains a first modified release portion of about 28% by weight based on the weight of the oral dosage unit.

[0042] The dosage form may further contain a second modified release portion of about 10 to about 40% by weight based on the weight of the oral dosage unit. In some embodiments, the dosage form contains a second modified release portion of 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% by weight based on the weight of the oral dosage unit. In further embodiments, the dosage form contains a second modified release portion of about 10 - about 35, about 10 - about 30, about 10 - about 25, about 10 - about 20, about 10 - about 15, about 15 - about 40, about 15 - about 35, about 15 - about 30, about 15 - about 25, about 15 - about 20, about 20 - about 40, about 20 - about 35, about 20 - about 30, about 20 - about 25, about 25 - about 40, about 25 - about 35, about 25 - about 30, about 30 - about 40, about 30 - about 35, or about 35 - about 40% by weight based on the weight of the oral dosage unit. In other embodiments, the dosage form contains a second modified release portion of about 20 - about 30% by weight based on the weight of the oral dosage unit. In still further embodiments, the dosage form contains a second modified release portion of about 28% by weight based on the weight of the oral dosage unit.

[0043] Typically, a plurality of beads or granules are incorporated into the dosage units described herein. As used herein, the term "plurality" refers to several beads or granules that provide the amount of phloroglucinol, trimethylphloroglucinol, or pharmaceutically acceptable salts required by the dosage unit. In some embodiments, the dosage unit comprises a plurality of beads. In further embodiments, the dosage unit comprises a plurality of granules. In other embodiments, the dosage unit comprises a plurality of beads and a plurality of granules.

[0044] The beads and / or granules contain one or both of an immediate release portion or a modified release portion. In some embodiments, the beads contain an immediate release portion. In other embodiments, the beads contain a modified release portion. In further embodiments, the beads contain both an immediate release portion and a modified release portion. In still further embodiments, the granules contain an immediate release portion. In yet further embodiments, the granules contain a modified release portion. In other embodiments, the granules contain both an immediate release portion and a modified release portion.

[0045] The dosage forms or pharmaceutical compositions described herein may contain one or more different types of beads or granules. In certain aspects, the dosage form contains three types of beads or granules. For example, the dosage forms or pharmaceutical compositions described herein may contain (i) an immediate release portion containing beads or granules that contain an immediate release portion, (b) a first modified release portion containing beads or granules that contain a first modified release portion, and (c) a second modified release portion containing beads or granules that contain a second modified release portion. In other aspects, the dosage forms or pharmaceutical compositions described herein contain two types of beads or granules. In some embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or granules that include an immediate release portion coated on a first modified release portion. In other embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or granules that include an immediate release portion coated on a second modified release portion. In further embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or granules that include an immediate release portion coated on a combination of a first release portion and a second release portion. In further aspects, the dosage forms or pharmaceutical compositions described herein contain one type of bead or granule. In some embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or granules that include a first modified release portion coated on a second release portion. In other embodiments, the dosage forms or pharmaceutical compositions described herein contain beads or granules that include a first modified release portion coated on a second release portion and an immediate release portion coated on the first modified release portion.

[0046] Any of the beads or granules can be coated with a topcoat. In some embodiments, the beads or granules may be coated with a topcoat that is an enteric polymer that modulates the release of the API. For example, the first modified release portion includes an API-containing core coated with a first enteric polymer that can elute at a pH of about 5.5. The first enteric polymer can be selected by those skilled in the art. In some embodiments, the first enteric polymer is a methacrylic acid copolymer, such as an ethyl acrylate-methacrylic acid copolymer, or, for example, a 1:1 methacrylic acid:ethyl acrylate copolymer, or, for example, an Eudragit® L 30 D-55 polymer. In some embodiments, the first enteric polymer is an ethyl acrylate-methacrylic acid 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 further embodiments, the first enteric polymer is an Eudragit® L 30 D-55 polymer. In still further embodiments, the API-containing core coated with the first enteric polymer is in the form of beads or granules.

[0047] In other examples, the second modified release portion includes an API-containing core coated with a second enteric polymer that can elute 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 further embodiments, the enteric polymer is methyl acrylate. In still further embodiments, the second enteric polymer is a methyl methacrylate copolymer. In yet further embodiments, the second enteric polymer is an Eudragit® FS 30D copolymer. In other embodiments, the API-containing core coated with the second enteric polymer is in the form of beads or granules.

[0048] The dosage forms described herein desirably release all of the API over the prescribed period. In certain aspects, at least about 30% by weight of the total amount of API in the composition is released from the composition over a period of, for example, about 5 minutes to about 2 hours from the administration 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 over a period of, for example, about 5 minutes to about 2 hours from the administration 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 over a period of, for example, about 5 minutes to about 2 hours from the administration of the API. In further 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% by weight of the total amount of API in the composition is released from the composition over a period of, for example, about 5 minutes to about 2 hours from the administration of the API.

[0049] In other aspects, at least about 60% by weight of the total amount of API in the composition is released from the pharmaceutical composition over a period of, for example, about 2 hours to about 4 hours from the administration 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 composition over a period of, for example, about 2 hours to 4 hours from the administration 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 composition over a period of, for example, about 2 hours to 4 hours from the administration 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 composition over a period of, for example, about 2 hours to 4 hours from the administration of the API.

[0050] In a further aspect, at least about 80% by weight of the total amount of API in the composition is released from the pharmaceutical composition over a period of from about 3 hours to about 6 hours, for example, from the administration of the API. For example, from about 80% to about 100% by weight of the total amount of API in the composition is released from the pharmaceutical composition over a period of from about 3 hours to about 6 hours, for example, from the administration 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 over a period of from about 3 hours to about 6 hours, for example, from the administration of the API. In a further embodiment, from about 80% to about 95%, from about 80% to about 90%, from about 80% to about 85%, from about 85% to about 100%, from about 85% to about 95%, from about 85% to about 90%, from about 90% to about 100%, or from about 95% to about 100% by weight of the total amount of API in the composition is released from the pharmaceutical composition over a period of from about 3 hours to about 6 hours, for example, from the administration of the API.

[0051] As used herein, “release of API” is measured by the 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.

[0052] The immediate release portion, the first modified release portion, or the second modified release portion, or combinations thereof, also contain inert pharmaceutical agents such as excipients 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 comprise one or more of a bulking agent, a binder, a disintegrant, an emulsifier, an anti-static agent, or a solvent.

[0053] The diameter of the beads and / or granules of the present disclosure may be from about 50 to about 1500 μm. In some embodiments, the diameter of the core is from about 50 to about 1300 μm, from about 50 to about 1100 μm, from about 50 to about 900 μm, from about 50 to about 800 μm, from about 50 to about 700 μm, from about 50 to about 600 μm, from about 50 to about 500 μm, from about 50 to about 400 μm, from about 50 to about 300 μm, from about 50 to about 200 μm, from about 100 to about 1500 μm, from about 100 to about 1300 μm, from about 100 to about 1100 μm, from about 100 to about 900 μm, from about 100 to about 800 μm, from about 100 to about 700 μm, from about 100 to about 600 μm, from about 100 to about 500 μm, from about 100 to about 400 μm, from about 100 to about 300 μm, from about 100 to about 200 μm. In other embodiments, the diameter of the core is from about 100 to about 800 μm.

[0054] The dosage unit may have a plurality of cores containing APIs with various dissolution characteristics. Accordingly, 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 a further embodiment, the core is coated with an immediate release layer. In other embodiments, the core is coated with a modified release layer. In still further embodiments, the core is coated with an immediate release layer and a modified release layer.

[0055] Other layers may be applied as a top coat or between other layers. As determined by one of ordinary skill in the art, the layer may contain a pharmaceutically inactive component, i.e., a pharmaceutically inactive component as a buffer layer, or may contain a pharmaceutically active component.

[0056] 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 further embodiments, the oral dosage unit comprises phloroglucinol or a pharmaceutically acceptable salt thereof and trimethylphloroglucinol or a pharmaceutically acceptable salt thereof.

[0057] Treatment method The pharmaceutical compositions, dosage units, and formulations described herein are useful for treating a spastic condition in a subject. The method includes administering to the subject a pharmaceutical composition or an oral dosage unit described herein. In some embodiments, the spastic condition is a sudden involuntary muscle contraction of a body part of the subject, such as an organ or a muscle. In other embodiments, the spastic condition is a sudden involuntary muscle contraction of the bronchi, stomach, intestine, ureter, gallbladder, kidney, or bile duct. In further embodiments, the spastic condition is a sudden involuntary muscle contraction of the bronchi. In still further embodiments, a sudden involuntary muscle contraction of the stomach. In yet further embodiments, a sudden involuntary muscle contraction of the intestine. In other embodiments, a sudden involuntary muscle contraction of the ureter. In further embodiments, a sudden involuntary muscle contraction of the gallbladder. In still further embodiments, a sudden involuntary muscle contraction of the kidney. In still further embodiments, a sudden involuntary muscle contraction of the bile duct. In yet further embodiments, the spastic condition is a urinary tract spasm, gallstone, gastrointestinal disorder, inflammatory bowel disorder (IBD), irritable bowel syndrome (IBS), renal colicky pain, or a spastic condition of the biliary tract. In other embodiments, the spastic condition is a urinary tract spasm. In further embodiments, the spastic condition is a gastrointestinal disorder. In still further embodiments, the spastic condition is IBD. In yet further embodiments, the spastic condition is IBS. In other embodiments, the spastic condition is diarrhea-predominant IBS (IBS-D). In further embodiments, the spastic condition is renal colicky pain. In still further embodiments, the spastic condition is a spastic condition of the biliary tract. In yet further embodiments, the spastic condition is mixed IBS (IBS-M). In other embodiments, the spastic condition is constipation-predominant IBS (IBS-C). In further embodiments, the spastic condition is Crohn's disease. In still further embodiments, the spastic condition is ulcerative colitis.

[0058] The pharmaceutical composition or oral dosage unit may be administered to a human subject in a fed state or to a human subject in a fasting state. In some embodiments, the pharmaceutical composition or oral dosage unit is administered to a subject in a fed state. In other embodiments, the pharmaceutical composition or oral dosage unit is administered to a subject in a fasting state.

[0059] In certain aspects, oral administration of a pharmaceutical composition or an oral dosage unit to a subject in a fed state results in a median T of the API of about 0.5 to about 1.75 hours max ; an average C of the API of about 269 to about 1512 ng / mL max ; an average AUC of the API of about 879 to about 4695 h*ng / mL tau ; and / or an average t1 / 2 of the API of about 1.6 hours to about 2.4 hours.

[0060] In some aspects, the median T of the API in a fed state max is about 0.5, about 0.75, about 1, about 1.25, about 1.5, or about 1.75 hours. In further aspects, the median T of the API in a fed state max is about 0.5 to about 1.5, about 0.5 to about 1, about 0.5 to about 0.75, about 0.75 to about 1.75, about 0.75 to about 1.5, about 0.75 to about 1.25, about 0.75 to about 1, about 1 to about 1.75, about 1 to about 1.5, about 1 to about 1.25, about 1.25 to about 1.75, about 1.25 to about 1.5, or about 1.5 to about 1.75 hours.

[0061] In other aspects, the average C of the API in a fed state 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 still further aspects, the C of the API in a fed state maxis from about 269 to about 1550, about 269 to about 1512, about 269 to about 1500, about 269 to about 1400, about 269 to about 1300, about 269 to about 1200, about 269 to about 1100, about 269 to about 1000, about 269 to about 900, about 269 to about 800, about 269 to about 700, about 269 to about 600, about 269 to about 500, about 269 to about 400, about 300 to about 1550, about 300 to about 1500, about 300 to about 1512, about 300 to about 1500, about 300 to about 1400, about 300 to about 1400, about 300 to about 1200, about 300 to about 1100, 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 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, 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 700 to about 1200, about 700 to about 1100, about 700 to about 1000, about 700 to about 900, about 700 to about 800, about 800 to about 1550, about 800 to about 1512, about 800 to about 1500, about 800 to about 1400, about 800 to about 1300, about 800 to about 1200, about 800 to about 1100, about 800 to about 1000, about 800 to about 900, about 900 to about 1550, about 900 to about 1512, about 900 to about 1500, about 900 to about 1400, about 900 to about 1300, about 900 to about 1200, about 900 to about 1100, about 900 to about 1000, about 1000 to about 1550,is from 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 1550, 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 from about 1500 to about 1550 ng / mL.

[0062] In other embodiments, the average AUC of the API in the fed state tau is from about 879 to about 4695 h*ng / mL. In further embodiments, the average AUC of the API in the fed state 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 still further embodiments, the average AUC of the API in the fed state tauis about 879 to about 4500, about 879 to about 4000, about 879 to about 3500, about 879 to about 3000, about 879 to about 2500, about 879 to about 2000, about 879 to about 1500, about 879 to about 1000, about 1000 to about 4695, about 1000 to about 4500, about 1000 to about 4000, about 1000 to about 3500, about 1000 to about 3000, about 1000 to about 2500, about 1000 to about 2000, about 1000 to about 1500, about 1500 to about 4695, about 1500 to about 4500, about 1500 to about 4000, about 1500 to about 3500, about 1500 to about 3000, about 1500 to about 2500, 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.

[0063] In a further aspect, the average t1 / 2 of the API in the fed state is from about 1.6 hours to about 2.4 hours. In other aspects, 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 still further aspects, the average t1 / 2 of the API in the fed state is from about 1.7 to about 2.3, from about 1.6 to about 2.2, from about 1.6 to about 2.1, from about 1.6 to about 2, from about 1.6 to about 1.9, from about 1.6 to about 1.8, from about 1.6 to about 1.7, from about 1.7 to about 2.4, from about 1.7 to about 2.3, from about 1.7 to about 2.2, from about 1.7 to about 2.1, from about 1.7 to about 2, from about 1.7 to about 1.9, from about 1.7 to about 1.8, from about 1.8 to about 2.4, from about 1.8 to about 2.3, from about 1.8 to about 2.2, from about 1.8 to about 2.1, from about 1.8 to about 2, from about 1.8 to about 1.9, from about 1.9 to about 2.4, from about 1.9 to about 2.3, from about 1.9 to about 2.2, from about 1.9 to about 2.1, from about 1.9 to about 2, from about 2 to about 2.4, from about 2 to about 2.3, from about 2 to about 2.2, from about 2 to about 2.1, from about 2.1 to about 2.4, from about 2.1 to about 2.3, from about 2.1 to about 2.2, from about 2.2 to about 2.4, from about 2.2 to about 2.3, or from about 2.3 to about 2.4 hours.

[0064] In other scenarios, when orally administered to a human subject in the fasting state, the median T of the API is about 0.5 hours max ; the average C of the API is from about 2745 to about 4874 ng / mL max ; the average AUC of the API is from about 4567 to about 6853 h*ng / mL tau ; and / or the average t1 / 2 of the API is about 2 hours.

[0065] In some aspects, when orally administered to a human subject in the fasting state, the median T of the API is about 0.5 hours max occurs.

[0066] In other aspects, when orally administered to a human subject in the fasting state, the average C of the API is from about 2745 to about 4874 ng / mL max occurs. In further aspects, the average C of the API in the fasting state maxis about 2745, about 3000, about 3500, about 4000, about 4500, or about 4874 ng / mL. In still other embodiments, the average C of the API in the fasting state max is about 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.

[0067] In yet further embodiments, when orally administered to a subject in the fasting state, the average AUC of the API is about 4567 to about 6853 h*ng / mL tau results. In other embodiments, the average AUC of the API tau is about 4567, about 5000, about 5500, about 6000, about 6500, or about 6853 h*ng / mL. In further embodiments, the average AUC of the API tau is 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.

[0068] In yet further 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 hours, about 2.1 hours, 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 hours, about 2 to about 2.1 hours, or about 2.1 to about 2.2 hours. TIFF2025519466000005.tif135146TIFF2025519466000006.tif225146

Examples

[0069] Example 1: Modified Release Formulation The dosage form of the present disclosure contains three types of beads. One type of bead releases phloroglucinol almost immediately after dosing, the second type of bead releases phloroglucinol about 2 to 4 hours after dosing, and the third type of bead releases phloroglucinol about 4 to about 6 hours after dosing. The amounts and contents of each component can be found in Tables 1A and 1B.

[0070] (Table 1A) TIFF2025519466000007.tif103146 1 Removed during processing. 2 For a 30% coating weight gain, it was prepared as a 30% dispersion containing 20% solids. The solution was prepared in excess. 3 For a 30% coating weight gain, it was prepared as a 30% dispersion containing 20% solids. The solution was prepared in excess.

[0071] (Table 1B) TIFF2025519466000008.tif159146 1 Removed during processing. 2 For a 30% coating weight gain, it was prepared as a 30% dispersion containing 20% solids. The solution was prepared in excess. 3 For a 30% coating weight gain, it was prepared as a 30% dispersion containing 20% solids. The solution was prepared in excess.

[0072] The beads were prepared as described in the flowchart of Figure 3.

[0073] A. Core beads, i.e., immediate release beads, are prepared as follows. 1. Sieve phloroglucinol, crystalline cellulose, hypromellose, and croscarmellose sodium through a suitable mill. 2. Mix the ground mixture from step 1 in a suitable granulator / mixer and prepare a wet mass using purified water. 3. Pass the wet mass through an extruder / spheronizer to prepare wet beads. 4. Dry the wet beads using a suitable dryer to obtain core beads. 5. Sieve all the core beads through a 16 / 30 mesh and collect the beads retained on the 30 mesh as uncoated beads. 6. Divide the beads from step 5 into three parts: part 1, part 2, and part 3.

[0074] B. Preparation of Eudragit L30D-55 beads 7. Prepare a coating solution using Eudragit L30D-55, triethyl citrate, talc, and purified water. 8. Coat the core beads of part 2 from step 6 using the coating solution from step 7 to prepare Eudragit L30D-55 coated beads. 9. Sieve all the beads from step 8 through a 16 / 30 mesh and collect the beads retained on the 30 mesh as Eudragit L30D-55 coated beads.

[0075] C. Preparation of Eudragit FS30D beads 10. Prepare a coating solution using Eudragit FS30D, triethyl citrate, talc, and purified water. 11. Coat the core beads of part 3 from step 6 using the coating solution from step 10 to prepare Eudragit FS30D coated beads. 12. Sieve all the beads from step 11 through a 16 / 30 mesh and collect the beads retained on the 30 mesh as Eudragit FS30D coated beads.

[0076] D. Lubrication 13. Place the Eudragit L30D-55 coated beads from step 9 and the Eudragit FS30D coated beads from step 12 into a suitable blender and combine them with talc.

[0077] E. Encapsulation 14. Using a suitable capsule filling machine, place the uncoated beads of part 1 from step 6 and the blend from step 13 into size 00 opaque white gelatin capsules. 15. Transfer the filled capsules through a deduster and a metal detector.

[0078] As previously described, the IR beads were coated with a suspension containing Eudragit L30D55, which produces DR beads intended to be released at pH 5.5, or Eudragit FS30D-55, which produces DR beads intended to be released at pH 7.0.

[0079] As previously discussed, the coated beads were combined, lubricated with talc, and placed into size 00 capsules together with the IR beads. The Eudragit L30D-55 coated beads and the Eudragit FS30D coated beads were combined together prior to encapsulation.

[0080] Example 2 Immediate release beads, 2-hour modified release beads, and 4-hour modified release beads are prepared as described in Example 1. Placebo batch coated sugar spheres using Eudragit L30D-55 and Eudragit FS30D were prepared using sugar spheres as the core beads and coated as described in Example 1 for the phloroglucinol core beads. See Table 2 for the components of the placebo capsules.

[0081] (Table 2) Placebo Capsules TIFF2025519466000009.tif89146 2It was prepared as a 30% dispersion containing 20% solids for a 30% coating weight increase. An excess of the solution was prepared. 3 It was prepared as a 30% dispersion containing 20% solids for a 30% coating weight increase. An excess of the solution was prepared.

[0082] Prior to the blending and encapsulation steps, IR beads, Eudragit L30D-55 coated beads, and Eudragit FS30D coated beads were assayed.

[0083] The completed capsules were tested using a validated method. The acceptance criteria for a valid batch are shown in Table 3. All batches met the acceptance criteria. The dissolution profiles of individual, filled capsules are shown in Figure 4.

[0084] (Table 3) TIFF2025519466000010.tif99144

[0085] Example 3 This was a randomized, double-blind, placebo-controlled, repeated-dose escalation 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 evaluation was also conducted.

[0086] A. Objectives The objectives of this study were as follows: ● To evaluate the safety and tolerability of Formulation A after administration of multiple oral doses to healthy subjects; and ● To characterize the PK of Formulation A after administration of multiple oral doses to healthy subjects.

[0087] As described below, it was planned to give Formulation A to 6 subjects per cohort and placebo to 2 subjects per cohort, and subjects were randomized into 1 of 8 cohorts. ● Cohort 1a: 320 mg of Formulation A or corresponding placebo, together with a daily high-fat breakfast (0 hours) and a daily high-fat dinner (10 hours), starting on the morning of Day 1 and continuing until the morning of Day 6; ● Cohort 1b: 320 mg of Formulation A or corresponding placebo, together with a daily low-fat breakfast (0 hours) and a daily low-fat dinner (10 hours), starting on the morning of Day 1 and continuing until the morning of Day 6; ● Cohort 2a: 640 mg of Formulation A or corresponding placebo, together with a daily high-fat breakfast (0 hours) and a daily high-fat dinner (10 hours), starting on the morning of Day 1 and continuing until the morning of Day 6; ● Cohort 2b: 640 mg of Formulation A or corresponding placebo, together with a daily low-fat breakfast (0 hours) and a daily low-fat dinner (10 hours), starting on the morning of Day 1 and continuing until the morning of Day 6; ● Cohort 3a: 1280 mg of Formulation A or corresponding placebo, together with a daily high-fat breakfast (0 hours) and a daily high-fat dinner (10 hours), starting on the morning of Day 1 and continuing until the morning of Day 6; ● Cohort 3b: 1280 mg of Formulation A or corresponding placebo, together with a daily low-fat breakfast (0 hours) and a daily low-fat dinner (10 hours), starting on the morning of Day 1 and continuing until the morning of Day 6; ● Cohort 3c: 960 mg of Formulation A or corresponding placebo, taken twice a day (BID) (0 hours and 10 hours) on an empty stomach daily, starting on the morning of Day 1 and continuing until the morning of Day 6; and ● Cohort 3d: 1280 mg of Formulation A or corresponding placebo, taken BID (0 hours and 10 hours) on an empty stomach daily, starting on the morning of Day 1 and continuing until the morning of Day 6.

[0088] The definition of the diet followed the Food and Drug Administration Guidance on Assessing the Effects of Food on Drugs in Investigational New Drug Applications and New Drug Applications. See Table 4.

[0089] (Table 4) Definition of Diet TIFF2025519466000011.tif19146

[0090] The tests for each subject consisted of the following: ● Screening period up to 26 days before the start of restraint (-1st day) for the duration of hospitalization; ● One 7-day inpatient treatment period consisting of administration of the blinded investigational drug (Formulation A or corresponding placebo capsule) from the morning of Day 1 to the morning of Day 6, followed by 24-hour PK sampling; and ● Follow-up phone call 3 (±1) days after discharge from the clinical unit.

[0091] For each cohort, first, a sentinel dose group consisting of the first 2 subjects (1 subject received Formulation A and 1 subject received placebo) started the dosing schedule. At least 48 hours later, the rest of this cohort started the dosing schedule. The remaining subjects in each cohort may start dosing on the same day or may be divided into smaller groups that start dosing on multiple days.

[0092] For cohorts 3c and 3d, where subjects received Formulation A or placebo on an empty stomach, the following order was followed: ● The sentinel subject in cohort 3c (3 capsules on an empty stomach) started dosing at least 48 hours after the last subject in cohort 3b started dosing; and ● The sentinel subject in cohort 3d (4 capsules on an empty stomach) started dosing at least 48 hours after the last subject in cohort 3c started dosing.

[0093] The progression from cohort 1 to cohort 2 and from cohort 2 to cohort 3 was carried out only after it was confirmed that sufficient safety and tolerability had been demonstrated to warrant progression.

[0094] Throughout the trial, safety was evaluated based on AEs, laboratory tests, skin and oral mucosa evaluations, ECGs, vital sign evaluations, and clinical laboratory evaluations. Starting from cohort 2, the daily frequency of bowel movements was recorded. For subjects with clinically significant abnormal test findings, unresolved TEAEs, SAE requiring follow-up clinical laboratory tests and re-examinations, or clinically significant AEs, unscheduled procedures or hospital visits and / or additional follow-up may have been required.

[0095] B. Inclusion Criteria Subjects who met all of the following criteria based on screening and check-in results were eligible to participate in this trial: 1. Healthy subjects aged 18 years or older and 55 years or younger based on medical and psychiatric history, physical examination, ECG, vital signs, and routine clinical laboratory tests (blood chemistry, hematology, coagulation, and urine tests); 2. Body mass index (BMI) of 18 kg / m 2 or more and 30 kg / m 2 or less; 3. Non-smokers who had not used nicotine-containing products for at least 6 months prior to screening; 4. Male subjects with a female partner of childbearing potential must agree to use two highly effective medically acceptable methods of contraception from day 1 to 90 days after the last dose of the investigational drug. Medically acceptable highly effective methods of contraception for male subjects with a female partner of childbearing potential included: latex condoms containing spermicide, diaphragms containing intravaginal spermicide, cervical caps containing spermicide, intrauterine devices (hormonal or non-hormonal), implantable contraceptives, and oral contraceptives; 5. Male subjects must agree to refrain from sperm donation from day 1 to 90 days after the administration of the last dose of the investigational drug; 6. Female subjects with a male partner must be surgically infertile (hysterectomy and / or bilateral oophorectomy), must be postmenopausal for at least 1 year (FSH in the postmenopausal range), or must have agreed to use two highly effective methods of contraception that are medically acceptable from day - 14 to 60 days after the last dose of the investigational drug. Medically acceptable and highly effective methods of contraception for female subjects with a male partner included: latex condoms containing spermicide, pessaries containing intravaginal spermicide, cervical caps containing spermicide, and non - hormonal intrauterine devices; and 7. Be able to understand the test procedures and restrictions (including constraints on the clinical unit, fasting and dietary requirements, restrictions on physical activity, use of recreational drugs or alcohol, and drug therapy), and be willing to comply with them, and have provided written informed consent in accordance with the facility and regulatory guidelines.

[0096] C. Exclusion Criteria Subjects who met any of the following criteria based on screening and check - in results were excluded from participating in this trial: 1. Actively participated in an experimental therapy trial, received experimental therapy with a small molecule within 30 days or 5 half - lives, whichever is longer, of the first dose of the investigational drug, or received experimental therapy with a macromolecule within 90 days or 5 half - lives, whichever is longer, of the first dose of the investigational drug; 2. Had a personal or family history of QT prolongation syndrome, torsade de pointes, or other complex ventricular arrhythmias, or a family history of sudden death; 3. Had a history of clinically significant arrhythmias or current clinically significant arrhythmias, including ventricular tachycardia, ventricular fibrillation, atrial fibrillation, sinoatrial node dysfunction, or clinically significant heart block. Subjects with minor types of ectopic excitation (e.g., atrial premature contractions) were not necessarily excluded; 4. Prolonged QTcF > 450 msec based on the average of triplicate ECGs; 5. Seated 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; 6. Resting heart rate (HR) > 100 beats per minute (bpm) or < 60 bpm; 7. Body temperature > 37.6 °C (99.7 °F, oral measurement), respiratory rate < 12 breaths per minute or > 20 breaths per minute; 8. Positive for human immunodeficiency virus antibody, hepatitis C virus antibody, hepatitis B surface antigen, or SARS-CoV 2 RNA; 9. Any other clinically significant clinical laboratory value outside the normal range (based on the test normal range); 10. Evidence or history of any clinically significant immunological, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, musculoskeletal, hepatic, psychiatric (including a history of seizures or convulsions), or allergic disorder (including clinically significant or multiple drug allergies); surgical condition; cancer (excluding basal cell or squamous cell carcinoma of the skin and cancers that have resolved or been in remission for > 5 years prior to screening); or any condition that may have affected the safety of the subject, confounded the test procedure or results, or interfered with the absorption, distribution, metabolism, or excretion of the investigational drug (appendectomy is permitted, cholecystectomy is prohibited); 11. Use of any prescription drug (including topical drugs) or OTC drug (except occasional use of acetaminophen or NSAIDs, such as ibuprofen or naproxen, in accordance with the package insert), herbal supplement, dietary supplement, or functional food within 14 days prior to the first dose of the investigational drug or within 5 half-lives, whichever is longer; or the absence of the intention to refrain from these drugs until the final discharge from the clinical unit. Use of OTC topical drugs may be permitted. Additionally, drugs with a half-life longer than 14 days must not be approved prior to subject enrollment; 12. Positive drug test result or alcohol test result, or a history of alcohol dependence or drug abuse within 2 years prior to the first dose of the investigational drug as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition: DSM-IV; 13. Typical intake of ≥14 alcoholic beverages per week. Note: One alcoholic beverage is equivalent to 1 / 2 pint of beer (285 mL), 1 glass of distilled spirits (25 mL), or 1 glass of wine (125 mL); 14. History or evidence of illegal drug use within the past 2 years; 15. Surgical procedure within 4 weeks prior to check-in or planned elective surgery during the study period; 16. Illness of any kind within the 4 weeks prior to check-in, except when considered clinically insignificant by the study responsible physician; 17. Known allergy to any component of Formulation A. Any history of severe allergic reactions (including drug, food, insect stings, or environmental allergens); 18. Inadequate venous access; 19. Currently undergoing treatment with weight loss drugs or having had previous weight loss surgery (e.g., gastric bypass); 20. Being pregnant, breastfeeding, or having a plan to become pregnant during the study; or 21. Being considered inappropriate for any other reason that may have exposed the subject to a high risk during participation or may have interfered with the interpretation of the test outcome.

[0097] D. Treatment The test subjects were orally administered Formulation A or placebo capsules. The test subjects were randomized at a 6:2 ratio to receive Formulation A or placebo.

[0098] Each Formulation A capsule contained 320 mg of phloroglucinol in the following composition: 160 mg in IR beads, 80 mg in 2-hour DR beads, and 80 mg in 4-hour DR beads. The inert ingredients used in the formulation included crystalline cellulose, hypromellose, croscarmellose sodium, triethyl citrate, Eudragit L 30 D-55, and talc.

[0099] For each predetermined dose cohort, the placebo consisted of the same number of corresponding placebo capsules as those given to the subjects receiving Formulation A. See Table 5.

[0100] (Table 5) Test drug TIFF2025519466000012.tif15128

[0101] (i) Selection and timing of the dose for each subject

[0102] (Table 6) Dose cohort TIFF2025519466000013.tif65146

[0103] All subjects were given multiple oral doses of the blinded test drug (Formulation A or the corresponding placebo capsules).

[0104] All subjects in all cohorts were required to follow an overnight fast of at least 10 hours starting from the evening before the first and last doses of the test drug.

[0105] For the dietary intake cohort, the relevant diet types were administered 30 minutes before the corresponding doses, and all meals had to be consumed before dosing. Subjects were given lunch daily, starting at least 4 hours after the morning investigational drug administration. The investigational drug was not administered with lunch. The lunch content was standard but not strictly restricted to high-fat or low-fat criteria.

[0106] For the cohort required to take the investigational drug on an empty stomach, there was no possibility of food intake for at least 2 hours before each interim dose or 1 hour after each interim dose. Subjects were given lunch daily, starting at least 4 hours after the investigational drug administration. All meals were standardized.

[0107] Subjects had to take all investigational drug capsules within ≤ 5 minutes. The investigational drug was administered with approximately 240 mL of water.

[0108] During confinement, (if the fasting specified in the protocol was not carried out,) all subjects were given a standardized meal at approximately the same time each day. Subjects were recommended to remain seated, and if they needed to use the toilet during the first 3.5 hours after dosing, they required assistance.

[0109] (ii) Excluded drug therapies and / or procedures 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; nutritional supplements; or functional foods were prohibited until discharge, except as necessary for AE treatment, within 14 days before the first dose of the investigational drug or within 5 half-lives, whichever was longer. The use of OTC topical drugs may have been permitted. Additionally, drugs with a half-life longer than 14 days may have been approved.

[0110] Subjects may not have received treatment with weight loss drugs during the trial or may not have had previous weight loss surgery (e.g., gastric bypass).

[0111] The subjects were unable to participate in any other experimental therapy trials while participating in this trial; were unable to receive experimental therapy with small molecules within 30 days or 5 half-lives, whichever was longer, of the first dose of the investigational drug; or were unable to receive experimental therapy with macromolecules within 90 days or 5 half-lives, whichever was longer, of the first dose of the investigational drug.

[0112] (iii) General restrictions and dietary restrictions All subjects in all cohorts were required to follow an overnight fast of at least 10 hours starting from the evening before the first and last doses of the investigational drug.

[0113] All provisional doses were administered on an empty stomach (at least about 1 hour before a meal or about 2 hours after a meal). Water was permitted during fasting except for 1 hour before and 1 hour after dosing (excluding the water used to administer the investigational drug). Subjects had to ingest all investigational drug capsules within ≤5 minutes. The investigational drug was administered with about 240 mL of water.

[0114] During restraint, (if the fasting specified in the protocol was not carried out,) the subjects were given a standardized diet scheduled at approximately the same time each day. The subjects were recommended to remain in a sitting position and required an attendant if they needed to use the toilet during the first 3.5 hours after dosing.

[0115] Subjects must refrain from alcohol; products containing caffeine and / or xanthine (i.e., coffee, tea, chocolate, and caffeinated sodas, colas, energy drinks, etc.); grapefruit, grapefruit products, starfruit, starfruit products, and Seville orange; and vitamin water from 48 hours before the dose of the investigational drug on Day 1 until final discharge from the clinical unit. Subjects must refrain from contact sports and strenuous exercise from 5 days before the first dose of the investigational drug and throughout the confinement period. Subjects must be non-smokers who have not used nicotine-containing products for at least 6 months prior to screening.

[0116] (iii) Pharmacokinetic endpoints Whenever the data permitted, the following plasma PK parameters for phloroglucinol were determined after the first dose of Formulation A on the morning of Day 1: ● C max ; ● T max ; ● AUC tau ; and ● C min .

[0117] Whenever the data permitted, the following plasma PK parameters for phloroglucinol were determined after the last dose of Formulation A on the morning of Day 6: ● C max ; ● T max ; ● AUC tau ; ● AUC 0-inf and extrapolated related percentage %; ● AUC 0-t ; ● t1 / 2; ● λz; ● CL / F (based on AUC tau ); and ● Vd / F (based on AUC tau ).

[0118] Furthermore, the attainment of a steady state was evaluated using trough samples.

[0119] Accumulation in the steady state was also characterized based on the relevant C max and AUC values.

[0120] To the extent permitted by the data, the cumulative amount of phloroglucinol excreted in urine (Ae), renal clearance (calculated as Ae / AUC tau ), and renal excretion rate (Fe) were also calculated using the urinary concentration of phloroglucinol.

[0121] Exploratory analyses may also have been performed to characterize the plasma and urine PK profiles of the sulfate and glucuronide conjugates of phloroglucinol.

[0122] (iv). Safety endpoints The safety of Formulation A was evaluated from the time of informed consent until the completion of participation in the study. The safety endpoints included the following: ● Physical examinations, evaluation of the skin and oral mucosa, ECG, vital sign evaluations (separately in the sitting and supine positions), and clinical laboratory evaluations; ● TEAEs graded according to CTCAE version 5.0 for severity; ● SAEs occurring during treatment; ● TEAEs that led to interruption of the study; ● Marked clinical laboratory value abnormalities occurring during treatment; and ● Marked vital sign abnormalities occurring during treatment.

[0123] (v) Statistical and analysis plan Categorical data was usually summarized using the count and percentage of the subjects. The denominator used in the percentage calculation was clearly defined. Continuous data (quantitative safety data or differences from baseline) was usually summarized using descriptive statistics including n (number of non-missing values), mean, median, standard deviation, minimum, and maximum. Geometric mean (GM) and GM% coefficient of variation (CV) were also shown for the summary of concentrations and PK parameters. Subjects with a value of 0 were excluded from the calculation of GM and GM CV%.

[0124] The summary by cohort included all eight cohorts separately, whereas the summary by dose level combined the respective cohorts for all dose levels of 320 mg, 640 mg, 960 mg, and 1280 mg.

[0125] The analysis date was calculated from the day of the first dose of the investigational drug. The day of the first dose of the investigational drug was Day 1 of the treatment period, and the day immediately preceding Day 1 was Day -1. There was no Day 0.

[0126] Baseline was defined as the last measurement before the first dose of the investigational drug.

[0127] (a) Analysis population The safety population consisted of all randomized subjects who received at least one dose of Formulation A.

[0128] The PK population included all subjects who received Formulation A and had at least one quantifiable post-dose plasma concentration for phloroglucinol.

[0129] The PK evaluable population included subjects who had plasma concentration data sufficient to characterize at least one PK parameter for phloroglucinol.

[0130] The count and percentage of subjects in each analysis population were summarized by cohort, dose level, and total based on all randomized subjects.

[0131] (b) Breakdown of the subjects The breakdown of the subjects was shown for all randomized subjects. The number and percentage of subjects in each of the following categories were summarized by cohort and overall as appropriate: ● Randomized; ● Dosed; ● Completed the trial; ● Withdrew from the trial midway. The main reasons for withdrawal midway; and ● Withdrew from the trial midway due to the COVID-19 pandemic.

[0132] (ii) Protocol violations Protocol violations were summarized by frequency distribution (count and percentage) by cohort, dose level, and category for all randomized subjects.

[0133] Subjects with protocol violations were listed by cohort for all randomized subjects.

[0134] Any impact of COVID-19 on trial visits (e.g., not completed, partially completed by the subject themselves, substantially conducted, conducted outside the window) was listed for all subjects in the safety population.

[0135] (c) Demographic and baseline characteristics The following demographic and baseline characteristics were listed and summarized by cohort, dose level, and overall using descriptive statistics or count and percentage of subjects in the safety population, and repeated for all other analysis populations if all other analysis populations differed from the safety population: ● Age (years); ● Gender; ● Pregnancy potential; ● Race (Asian, American Indian or Alaska Native, Black or African American, Native Hawaiian or Other Pacific Islander, White, Other); ● Ethnicity (Hispanic or Latino American, not Hispanic or Latino American, not reported, unknown); ● Height (cm); ● Weight (kg); and ● BMI (kg / m 2 ).

[0136] Medical history (d) Medical histories were coded to SOC and PT using MedDRA version 23.1. Counts and percentages of subjects with medical histories by SOC and PT were summarized and tabulated by cohort, dose level, and in total, based on the randomized population of all subjects.

[0137] (e) Pre-medication and concomitant medication Pre-medication and concomitant medication were coded to ATC class and PT using the WHO Drug Dictionary version September 2020 GB3. For summary purposes, drug therapy was considered pre-medication if it was discontinued before the dose of the investigational drug and concomitant medication if it was taken at any time after the first dose of the investigational drug (i.e., started before, continued during, or started after the first dose of the investigational drug).

[0138] Counts and percentages of subjects taking pre-medication and concomitant medication by ATC class and PT were tabulated and summarized by cohort, dose level, and in total, based on the safety population.

[0139] (vi) Investigational drug exposure and compliance Exposure was defined as the number of days (including the first and last doses) between the first and last doses of the investigational drug and summarized by treatment for the safety population. Investigational drug administration data were tabulated by treatment group for all subjects in the safety population.

[0140] (f) Pharmacokinetic analysis Sample collection for pharmacokinetic analysis PK pre-dose blood samples were collected within 60 minutes before the first investigational drug administration and within 5 minutes before any subsequent designated investigational drug administration. The following windows were allowed for collecting PK samples: ±1 minute for samples collected ≤8 hours after dosing, ±2 minutes for samples collected >8 hours and ≤16 hours after dosing, and ±5 minutes for samples collected ≥16 hours after dosing. The planned blood sample collection times (time from dosing) were as follows: ● Day 1 (first dose): pre-dose, 0.25 hour, 0.5 hour, 0.75 hour, 1 hour, 1.5 hours, 2 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3 hours, 3.5 hours, 4 hours, 4.25 hours, 4.5 hours, 4.75 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, and 9 hours; ● Day 1 (evening dose): pre-dose, 0.25 hour, 0.5 hour, 0.75 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, and 6 hours; ● Day 2 (morning dose): pre-dose Days 4 and 5 (morning and evening doses): pre-dose; and ● Day 6: pre-dose, 0.25 hour, 0.5 hour, 0.75 hour, 1 hour, 1.5 hours, 2 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3 hours, 3.5 hours, 4 hours, 4.25 hours, 4.5 hours, 4.75 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 16 hours, and 24 hours.

[0141] After the first and last doses of the investigational drug, PK urine samples were collected for fluoroglucinol concentration measurement between the following intervals: 0 - 2 hours, 2 - 4 hours, 4 - 6 hours, 6 - 10 hours, 10 - 12 hours, 12 - 14 hours, 14 - 16 hours, and 16 - 24 hours. Urine aliquots were also obtained from morning urinations before the first and last doses of the investigational drug.

[0142] Pharmacokinetic concentration The individual plasma concentrations of the phloroglucinol in the PK population were descriptively summarized by cohort at each nominal time point. The individual plasma concentrations in the PK population were also listed.

[0143] The individual plasma concentrations were plotted by cohort on an equal interval scale and a semi-logarithmic scale against the actual sampling time relative to the dosing time. In both cases, the lower limit of quantification was plotted as the reference line. The troughs on Day 4, Day 5, and Day 6 were plotted similarly.

[0144] For each cohort, a plot of the mean plasma phloroglucinol concentration versus time was created. Plots of the mean and individual cumulative Ae over time were also shown. To the extent the data permitted, similar outputs were shown for any measured metabolite.

[0145] Actual sampling times outside the sampling time window may have been excluded from the concentration summary and mean concentration plotting, but were still used in the calculation of PK parameters and individual concentration plotting. Exclusion of concentrations outside the window was evaluated on a case-by-case basis.

[0146] Pharmacokinetic parameters To the extent the data permitted, the following plasma PK parameters for phloroglucinol were determined (using non-compartmental analysis) after the first dose of Formulation A in the morning on Day 1: ● C max - Determined directly from the concentration-time profile; C max if occurred at multiple time points, C max was defined as the first maximum value; ● T max - If the maximum value occurred at multiple time points, T max was defined as the first time point having this value; ● AUC tau ; and ● C min .

[0147] As far as the data permitted, the following plasma PK parameters for phloroglucinol were determined (using non-compartmental analysis) after the last dose of formulation A on the morning of day 6: ●C max - Obtained directly from the concentration-time profile; C max If it occurred at multiple time points, C max was defined as the first maximum value; ●T max - If the maximum value occurred at multiple time points, T max was defined as the first time point having this value; ●AUC tau ; ●AUC 0-inf - ([AUC 0-t + Quantifiable last plasma concentration [C last / λ z ) was calculated; ●AUC 0-t - AUC from pre-dose (time 0) to C last ; ●λ z - Calculated from the semi-logarithmic plot of plasma concentration vs. time. The parameters were calculated by linear least-squares regression analysis using the points in the terminal logarithmic linear phase; ●t 1 / 2 - Calculated as natural logarithm (2) / λ z ; ●CL / F - Dose / AUC tau was calculated; ●Vd / F - Dose / [λ z ●AUC tau was calculated; ●R Cmax - Accumulation ratio evaluation on day 6 only; C on day 6 max / C on day 1 max was calculated; ●R AUCtau - Accumulation ratio evaluation on day 6 only; AUC on day 6 tau / AUC on day 1 tau was calculated; and ●AUC extrap - Percentage of the extrapolated area under the plasma concentration-time curve; (1 - AUC 0-t / AUC 0-inf) Represented as ●100.

[0148] The following urinary PK parameters of phloroglucinol were determined using the non-compartmental method as appropriate: ● Urinary unchanged excretion amount from time 0 to time 2 (Ae 0-2 ); ● Urinary unchanged excretion amount from time 0 to time 4 (Ae 0-4 ); ● Urinary unchanged excretion amount from time 0 to time 6 (Ae 0-6 ); ● Urinary unchanged excretion amount from time 0 to time 10 (Ae 0-10 ); ● Urinary unchanged excretion amount from time 0 to time 12 (Ae 0-12 ); ● Urinary unchanged excretion amount from time 0 to time 14 (Ae 0-14 ); ● Urinary unchanged excretion amount from time 0 to time 16 (Ae 0-16 ); ● Urinary unchanged excretion amount from time 0 to time 24 (Ae 0-24 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 2 (Fe 0-2 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 4 (Fe 0-4 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 6 (Fe 0-6 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 10 (Fe 0-10 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 12 (Fe 0-12 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 14 (Fe 0-14 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 16 (Fe 0-16 ); ● Fraction of dose excreted unchanged in urine from time 0 to time 24 (Fe 0-24 ); and ● Renal clearance; Ae / AUC tau was calculated as

[0149] In PK parameter calculations, the actual collection time was used.

[0150] E. Test subjects (i) Breakdown of subjects Table 7 shows the breakdown of subjects in the safety population.

[0151] A total of 65 subjects were randomized into one of eight cohorts. Six subjects in each cohort were given one formulation A of the following dose levels: 320 mg, 640 mg, or 1280 mg together with a high-fat meal or a low-fat meal (dietary intake status). Two subjects in each cohort were given a placebo in the corresponding dietary intake status. Fasting, six subjects were given 960 mg of formulation A, six subjects were given 1280 mg of formulation A. Two subjects in each of these cohorts were given a placebo fasting. An additional one subject in cohort 3c was given 960 mg of formulation A BID fasting but withdrew from the study early due to the relationship with the acceptable number of blood samplings during the treatment period. The remaining 64 subjects completed the study.

[0152] (Table 7) Breakdown of subjects - safety population TIFF2025519466000014.tif105152

[0153] (Table 7) Breakdown of subjects - safety population (continued) TIFF2025519466000015.tif93150Percent (%) was calculated as 100×n / N. In cohort 3c (960 mg fasting), subject 001 - 246 was swapped with subject 001 - 243.

[0154] (ii) Demographic and other baseline characteristics Table 8 summarizes the demographic and baseline characteristics of the safety population. The average age of the subjects was 32.3 - 42.5 years, and the average BMI was 22.64 - 28.63 kg / m 2It was not. The majority of the subjects were neither Hispanic nor Latino. Demographic and baseline characteristics were generally well-matched between treatment groups.

[0155] (Table 8) Demographic and Baseline Characteristics - Safety Population TIFF2025519466000016.tif216162

[0156] (Table 8) Demographic and Baseline Characteristics - Safety Population (continued) TIFF2025519466000017.tif227158 The baseline measurement refers to the last measurement collected before the first dose. % = 100 × n / N.

[0157] F. Pharmacokinetic and Pharmacodynamic Results (i) Plasma Pharmacokinetics of Formulation A [Error! Reference source not found.] Each shows the plot of the mean (+SD) plasma phloroglucinol concentration on Day 1 by dose level of equal and single logarithmic scales for the PK population according to the fed state.

[0158] Phloroglucinol was rapidly absorbed after administration of Formulation A in the fed state. Two periods were observed in which the mean plasma phloroglucinol concentration decreased slowly at about 2 and 4 hours after dosing. Systemic exposure to phloroglucinol generally increased with increasing dose across the treatment groups in the high-fat, low-fat, and fasting states. However, exposure was relatively blunted and sustained when taken with food.

[0159] [Error! Reference source not found.]2 shows the plot of the mean (+SD) plasma trough phloroglucinol concentration by dose level of equal and single logarithmic scales for the PK population.

[0160] No notable phloroglucinol accumulation was observed after Formulation A was administered every morning and evening (at nominal times of 0 hours and 10 hours) starting on the morning of Day 1 and continuing through the morning of Day 6. Considering the short dosing interval of 10 hours between the morning and evening doses, typically, the evening trough concentration was higher than the morning trough concentration that followed at a 14-hour interval.

[0161] Table 9 summarizes the PK parameters of Formulation A in plasma for the PK population on Day 1. After Formulation A was administered on Day 1, it was rapidly absorbed. In the fasting state, the median T max occurred at approximately 0.5 hours. In the fed state, consistent with the weaker, sustained shape of the curve, the median T max values were between 0.52 and 1.75 hours across the entire dosing range. As the dose increased, the mean C max increased, with ranges of 269.17 - 1201.00 ng / mL and 506.83 - 1074.83 ng / mL across the entire high-fat and low-fat treatment groups, respectively. In the absence of food, a fairly large exposure was evident, with mean C max values of 2745.71 ng / mL and 4873.33 ng / mL for the fasting 960 mg and 1280 mg treatment groups, respectively. Similar to the change in C max , the systemic exposure determined by AUC tau followed a similar trend.

[0162] (Table 9) Summary of Pharmacokinetic Parameters of Formulation A in Plasma - PK Population (Day 1) TIFF2025519466000018.tif135146

[0163] (Table 9) Summary of Pharmacokinetic Parameters of Formulation A in Plasma - PK Population (Day 1) (Continued) TIFF2025519466000019.tif139152

[0164] (Table 9) Summary of Pharmacokinetic Parameters of Formulation A in Plasma - PK Population (Day 1) (Continued) TIFF2025519466000020.tif102146Note: *Although λz and λz-related parameters were enumerated, they were excluded from statistical analysis if the adjusted regression coefficient was less than 0.8 or the AUC extrap was more than 20%. The AUC tau was the area under the curve for a dosing interval of 0 to 10 hours. C min was the concentration at the scheduled time point 10 hours after dosing. In this case, BLQ values were supplemented with 0. Geometric CV% = 100 * (exp(SD 2 )) - 1 0.5 , where SD was the standard deviation of the log-transformed data.

[0165] Table 1 summarizes the PK parameters of formulation A in plasma of the PK population on day 6. Considering that there was no accumulation at steady state after administration of formulation A every morning and every night (at nominal times of 0 hours and 10 hours), the PK profile on day 6 was qualitatively and quantitatively similar to that observed after the first dose on day 1. The t1 / 2 was similar across the treatment groups and was in the range of 1.6 hours to 2.4 hours across all treatment groups. The AUC tau (R AUCtau ) and the mean accumulation ratios based on C max (R Cmax ) were similar across all treatment groups and were close to 1. This indicates that there was no notable accumulation of formulation A at steady state after the administered dosing schedule.

[0166] (Table 1) Summary of the Pharmacokinetic Parameters of Formulation A in Plasma - PK Population (Day 6) TIFF2025519466000021.tif134156TIFF2025519466000022.tif224156TIFF2025519466000023.tif50156*If the adjusted regression coefficient was less than 0.8 or the AUC extrap exceeded 20%, λz and λz-related parameters were excluded from statistical analysis. ^If the adjusted regression coefficient was less than 0.8 or the AUC extrap exceeded 20% on day 1, R AUCtau was excluded from statistical analysis. The AUC tauwas the area under the curve for a dosing interval of 0 to 10 hours. Geometric CV% = 100 * (exp(SD 2 ) - 1) 0.5 , where SD was the standard deviation of the log-transformed data. R AUCtau = evaluation of the accumulation ratio only on day 6 calculated as AUC tau on day 6 / AUC tau on day 1; R Cmax = evaluation of the accumulation ratio only on day 6 calculated as C max on day 6 / C max on day 1.

[0167] (Table 2) Summary of plasma formulation A pharmacokinetic parameters - PK population (day 6) (continued) TIFF2025519466000024.tif124152TIFF2025519466000025.tif223152TIFF2025519466000026.tif65152* If the adjusted regression coefficient was less than 0.8 or AUC extrap exceeded 20%, the λz and λz-related parameters were excluded from the statistical analysis. ^ If the adjusted regression coefficient was less than 0.8 or AUC extrap exceeded 20% on day 1, R AUCtau was excluded from the statistical analysis. AUC tau was the area under the curve for a dosing interval of 0 to 10 hours. Geometric CV% = 100 * (exp(SD 2 ) - 1) 0.5 , where SD was the standard deviation of the log-transformed data. R AUCtau = evaluation of the accumulation ratio only on day 6 calculated as AUC tau on day 6 / AUC tau on day 1; R Cmax = evaluation of the accumulation ratio only on day 6 calculated as C max on day 6 / C max on day 1.

[0168] (Table 3) Summary of plasma formulation A pharmacokinetic parameters - PK population (day 6) (continued) TIFF2025519466000027.tif109150TIFF2025519466000028.tif223150TIFF2025519466000029.tif95150*If the adjusted regression coefficient is less than 0.8, or the AUC extrap exceeds 20%, λz and λz-related parameters were excluded from the statistical analysis. ^On day 1, if the adjusted regression coefficient is less than 0.8, or the AUC extrap exceeds 20%, R AUCtau was excluded from the statistical analysis. The AUC tau was the area under the curve for a dosing interval of 0 to 10 hours. Geometric CV% = 100 * (exp(SD 2 ) - 1) 0.5 , where SD was the standard deviation of the log-transformed data. R AUCtau = AUC on day 6 tau / AUC on day 1 tau was the evaluation of the accumulation ratio only on day 6 calculated as; R Cmax = C on day 6 max / C on day 1 max was the evaluation of the accumulation ratio only on day 6 calculated as.

[0169] (ii) Dose proportionality of formulation A The results of dose proportionality were evaluated using the Smith criteria (90% CI: 0.839 - 1.161) and the Hummel criteria (90% CI: 0.50 - 1.50) over the entire dose range for both the high-fat and low-fat states. Overall, no overall trend indicating deviation from dose proportionality was observed across the entire tested dose range.

[0170] Table 4 summarizes the power model analysis of dose proportionality of formulation A for the PK evaluable population on day 1 for the high-fat and low-fat formulation A treatment groups at 320 mg, 640 mg, and 1280 mg.

[0171] On day 1, the estimated slope (and 90% CI) of the dose-exposure relationship across the high-fat 320 mg, 640 mg, and 1280 mg formulation A treatment groups was C maxFor [parameter] it was 1.035 (0.705, 1.365), AUC tau For [parameter] it was 1.072 (0.887, 1.258). For both parameters (C max and AUC tau ) evaluated, they met the Hummel criteria but did not meet the more stringent Smith criteria. For the low-fat 320 mg, 640 mg, and 1280 mg formulation A treatment groups on day 1, the slope estimates (and 90% CI) of the dose-exposure relationship were, for C max it was 0.763 (0.351, 1.175), and for AUC tau it was 1.145 (0.964, 1.325). AUC tau met the Hummel criteria but did not meet the Smith criteria.

[0172] (Table 4) Power model analysis of dose proportionality of formulation A - PK evaluable population - day 1 (high-fat and low-fat) TIFF2025519466000030.tif108152

[0173] (Table 4) Power model analysis of dose proportionality of formulation A - PK evaluable population - day 1 (high-fat and low-fat) (continued) TIFF2025519466000031.tif108152 The power model was fitted by REML using SAS (trademark) Proc Mixed. The Smith and Hummel rejection regions for the dose proportionality CI were (0.839, 1.161) and (0.5, 1.5), respectively.

[0174] Table 5 summarizes the power model analysis of dose proportionality of formulation A for the PK evaluable population on day 6 for the 320 mg, 640 mg, and 1280 mg high-fat and low-fat formulation A treatment groups.

[0175] On day 6, the slope estimates (and 90% CI) of the dose-exposure relationship across the high-fat 320 mg, 640 mg, and 1280 mg formulation A treatment groups were, for C max it was 0.757 (0.287, 1.227), and for AUC0-inf was 1.062 (0.896, 1.227) for AUC 0-t was 1.068 (0.902, 1.234) for AUC 0-t and AUC 0-inf only met the Hummel criteria but not the Smith criteria. On day 6, the slope estimates (and 90% CI) of the dose-exposure relationship across the low-fat 320 mg, 640 mg, and 1280 mg formulation A treatment groups were C max was 1.131 (0.803, 1.459) for AUC 0-inf was 1.174 (0.988, 1.361) for AUC 0-t was 1.195 (1.004, 1.385) for AUC max All evaluated parameters (C 0-t , AUC 0-inf ) met the Hummel criteria but not the Smith criteria.

[0176] (Table 5) Power model analysis of dose proportionality of formulation A - PK evaluable population - day 6 (high fat and low fat) TIFF2025519466000032.tif221152

[0177] (Table 5) Power model analysis of dose proportionality of formulation A - PK evaluable population - day 6 (high fat and low fat) (continued) TIFF2025519466000033.tif84152 The power model was fitted by REML using SAS (trademark) Proc Mixed. The Smith and Hummel rejection regions for dose proportionality CI were (0.839, 1.161) and (0.5, 1.5), respectively.

[0178] (iii) Urinary pharmacokinetics of formulation A Table 13 summarizes the urine formulation A PK parameters on Day 1 for the PK population. Consistent with the rapid clearance of formulation A from plasma, formulation A was rapidly excreted into urine. For all dosing regimens tested, the urine formulation A PK profiles on Day 1 generally followed a similar dose-dependent trend as the corresponding plasma PK profiles.

[0179] (Table 13) Formulation A Pharmacokinetic Parameters - Day 1 - PK Population TIFF2025519466000034.tif156146

[0180] (Table 13) Summary of Urine Formulation A Pharmacokinetic Parameters on Day 1 - PK Population (continued) TIFF2025519466000035.tif155146

[0181] [Error! Reference source not found.] Summary of Urine Formulation A Pharmacokinetic Parameters on Day 1 - PK Population (continued) TIFF2025519466000036.tif83146 *If the adjusted regression coefficient is less than 0.8 or the AUC extrap exceeds 20%, then λ z and λ z related parameters were excluded from the statistical analysis. Fe was calculated 10 hours after dosing on Day 1 using two doses. CLr = Ae 0-10h / AUC tau , where AUC tau was the area under the curve for the dosing interval from 0 to 10 hours. Geometric CV% = 100x(exp(SD 2 ) - 1) 0.5 , where SD was the standard deviation of the log-transformed data.

[0182] Table 6 summarizes the urine formulation A PK parameters on Day 6 for the PK population. Urine excretion on Day 6 followed the same pattern as that observed on Day 1 for all dosing regimens.

[0183] (Table 6) Summary of Urine Formulation A Pharmacokinetic Parameters on Day 6 - PK Population TIFF2025519466000037.tif208146

[0184] (Table 6) Summary of the pharmacokinetic parameters of formulation A in urine on day 6 - PK population (continued) TIFF2025519466000038.tif204146

[0185] (Table 6) Summary of the pharmacokinetic parameters of formulation A in urine on day 6 - PK population (continued) TIFF2025519466000039.tif44146 * If the adjusted regression coefficient is less than 0.8, or the Auc extrap exceeds 20%, then λ z and λ z The related parameters were excluded from the statistical analysis. Fe was calculated 10 hours after the first dose on day 1 using two doses. CLr = Ae 0-10h / AUC tau , where AUC tau was the area under the curve for the dosing interval from 0 to 10 hours. Geometric CV% = 100x(exp(SD 2 ) - 1) 0.5 , where SD was the standard deviation of the log-transformed data.

[0186] (iv) Pharmacokinetic and pharmacodynamic conclusions After formulation A was administered, phloroglucinol was rapidly absorbed and then gradually decreased. The systemic exposure to phloroglucinol generally increased with increasing dose across the treatment groups. Evidence of IR / DR / DR kinetics was observed in this study, and a deceleration in the rate of decline of plasma phloroglucinol concentration was observed approximately 2 hours after administration of formulation A, and then again approximately 4 hours after administration of formulation A. Considering the overall, rather rapid half-life, no notable accumulation was observed at steady state. When administered with food, the PK profile of formulation A showed a weak but persistent exposure regardless of the meal type. For all dosing regimens, the exposure observed in this study met or exceeded that associated with the therapeutic dosing regimens of Spasfon (trademark). The average C after administration of 1 - 2 capsules of formulation A maxThe value was similar to that achieved with 1 - 2 tablets of Spasfon (trademark), whereas the AUC was large under all the conditions tested. The mean C after administration of 3 - 4 capsules of formulation A max and the AUC value both significantly exceeded the values achieved with Spasfon (trademark) under all the conditions tested.

[0187] Consistent with the rapid clearance of formulation A from plasma, formulation A was rapidly excreted in urine. For all the dosing regimens tested, the PK profiles of formulation A in urine on Day 1 and Day 6 generally followed a similar dose - dependent trend as the corresponding plasma PK profiles.

[0188] From the exploratory dose - proportionality assessment, no overall trend towards deviation from proportionality was shown across the dose range tested.

[0189] Generally, throughout the study, the number of bowel movements per day of the subjects (average 0 - 2 times) was relatively low. Overall, the data showed no clear or consistent trend in bowel movements. However, from the data of the selected cohort and isolated subjects within the various cohorts, it is suggested that formulation A may have reduced the number of bowel movements per day during the treatment period, and the number of bowel movements per day returned to baseline after completion of the treatment period.

[0190] G. Safety Results (i) Degree of Exposure A total of 65 subjects were randomized to one of eight cohorts. Six subjects in each cohort were given the dose of Formulation A from the morning of Day 1 through the morning of Day 6, continuously every morning and evening (at nominal times of 0 hours and 10 hours). The following dose levels: 320 mg, 640 mg, or 1280 mg were tested together with a high-fat meal or a low-fat meal (dietary intake status). Two subjects in each cohort were given a placebo in the corresponding dietary intake status. In the fasting state, 6 subjects were given 960 mg of Formulation A and 6 subjects were given 1280 mg of Formulation A. Two subjects in each of these cohorts were given a placebo in the fasting state. An additional 1 subject started dosing with 960 mg of Formulation A in the fasting state but withdrew from the study early after the first dose due to the relationship with the acceptable number of blood samplings during the treatment period.

[0191] (ii) Adverse events Table 7 shows an overview of AEs in the safety population.

[0192] There were no TEAE related to COVID-19. There were no SAE that occurred during treatment, no SAE that occurred during treatment related to the investigational drug, no TEAE that led to death, no TEAE that led to study discontinuation, and no TEAE related to the investigational drug that led to study discontinuation.

[0193] Overall, in the 320 mg, 640 mg, 960 mg, 1280 mg, and pooled placebo groups, 3 (25.0%) subjects, 5 (41.7%) subjects, 2 (28.6%) subjects, 6 (33.3%) subjects, and 4 (25.0%) subjects, respectively, experienced TEAEs of mild or moderate severity.

[0194] Overall, in the 320 mg, 640 mg, and 1280 mg Formulation A treatment groups, 1 (8.3%) subject, 1 (8.3%) subject, and 2 (11.1%) subjects, respectively, experienced TEAEs considered to be related to the investigational drug. All of these TEAEs related to the investigational drug were of mild severity.

[0195] 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.

[0196] (Table 7) Summary of Adverse Events - Safety Population TIFF2025519466000040.tif127146

[0197] (Table 8) Summary of Adverse Events - Safety Population (continued) TIFF2025519466000041.tif127146

[0198] (Table 7) Summary of Adverse Events - Safety Population (continued) TIFF2025519466000042.tif109146% = 100×n / N. TEAE was defined as an AE that started after the dose of the investigational drug. Subjects who reported multiple AEs were counted only once using the most severe incident. Coding was based on MedDRA version 23.1.

[0199] (Table 7) Summary of Adverse Events - Safety Population (continued) TIFF2025519466000043.tif136146% = 100×n / N. TEAE was defined as an AE that started after the dose of the investigational drug. Subjects who reported multiple AEs were counted only once using the most severe incident. Coding was based on MedDRA version 23.1.

[0200] Table 9 summarizes the treatment-emergent adverse events (TEAEs) by SOC and PT in the safety population. There was no obvious dose-dependent increase in the frequency of AEs, and 3 (25.0%), 5 (41.7%), 2 (28.6%), 6 (33.3%), and 4 (25.0%) subjects experienced TEAEs in the 320 mg, 640 mg, 960 mg, 1280 mg, and pooled placebo groups, respectively. Furthermore, there was no obvious difference in the incidence or severity of AEs based on the dietary conditions. The most frequently reported SOCs for TEAEs were gastrointestinal disorders and nervous system disorders. There were no TEAEs related to COVID-19 during this trial, and no TEAEs led to death.

[0201] (Table 9) Adverse events expressed under treatment by major organ classification and basic terms - safety population TIFF2025519466000044.tif170146

[0202] (Table 10) Adverse events expressed under treatment by major organ classification and basic terms - safety population (continued) TIFF2025519466000045.tif170145

[0203] (Table 9) Adverse events expressed under treatment by major organ classification and basic terms - safety population (continued) TIFF2025519466000046.tif190146% = 100×n / N. TEAEs were defined as AEs that started after the dose of the investigational drug. Subjects who reported multiple AEs for a given MedDRA basic term were counted only once for that basic term. Subjects who reported multiple types of events within an SOC were counted only once for that SOC.

[0204] (Table 9) Adverse events expressed under treatment by major organ classification and basic terms - safety population (continued) TIFF2025519466000047.tif199146% = 100×n / N. TEAE was defined as the AE that started after the dose of the investigational drug. Subjects who reported multiple AEs for a given MedDRA preferred term were counted only once for that preferred term. Subjects who reported multiple types of events within an SOC were counted only once for that SOC.

[0205] Adverse events related to the drug [Error! Reference source not found.] Shows TEAE related to the investigational drug by SOC and PT for the safety population. Overall, in the 320 mg, 640 mg, 1280 mg, and pooled placebo groups, 1 (8.3%) subject, 1 (8.3%) subject, 2 (11.1%) subjects, and 1 (6.3%) subject experienced drug-related TEAE, 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 pooled placebo group, 1 (6.3%) subject experienced constipation.

[0206] (Table 11) Adverse events manifested under treatment with the investigational drug by major classification and preferred term by organ - safety population TIFF2025519466000048.tif101145

[0207] [Error! Reference source not found.] Adverse events manifested under treatment with the investigational drug by major classification and preferred term by organ - safety population (continued) TIFF2025519466000049.tif101143

[0208] [Error! Reference source not found.] Adverse events manifested under treatment with the investigational drug by major classification and preferred term by organ - safety population (continued) TIFF2025519466000050.tif 106145% = 100×n / N. TEAE was defined as the AEs that started after the dose of the investigational drug. Subjects who reported multiple AEs for a given MedDRA preferred term were counted only once for that preferred term. Subjects who reported multiple types of events within an SOC were counted only once for that SOC.

[0209] [Error! Reference source not found.] Adverse events occurred under treatment with the investigational drug by major classification and preferred term by organ - Safety population (continued) TIFF2025519466000051.tif 189147% = 100×n / N. TEAE was defined as the AEs that started after the dose of the investigational drug. Subjects who reported multiple AEs for a given MedDRA preferred term were counted only once for that preferred term. Subjects who reported multiple types of events within an SOC were counted only once for that SOC.

[0210] H. Conclusions on safety From the results of this trial, it was demonstrated that formulation A was safe and well - tolerated at oral doses of 320 mg to 1280 mg administered continuously every morning and evening (at nominal times of 0 hours and 10 hours) starting from the morning of day 1 to the morning of day 6 in healthy subjects. There were no subjects who died, no subjects who experienced SAE under treatment, and no subjects whose trials were interrupted due to TEAE. The incidence of TEAE was generally equivalent between subjects given 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 given placebo (25.0% of placebo subjects). All TEAEs were of mild or moderate severity. No dose - dependent increase in the frequency or severity of AEs was observed, and there was no obvious difference in the incidence or severity of AEs based on the dietary status.

[0211] There were no significant changes from baseline in the test parameters, vital signs, findings of 12-lead ECG, or evaluation of the skin and mucosa during this trial.

[0212] No dose-dependent increase in the frequency or severity of AEs was observed, and there was no obvious difference in the incidence or severity of AEs based on the dietary conditions. There were no significant changes from baseline in the test parameters, vital signs, findings of 12-lead ECG, or evaluation of the skin and mucosa during this trial.

[0213] I. General Conclusions Based on this trial, the following conclusions can be drawn: ● Formulation A was safe and well-tolerated in healthy subjects at single oral doses in the range of 320 mg to 1280 mg, administered every morning and evening (at nominal times of 0 hours and 10 hours), starting on the morning of Day 1 and continuing until the morning of Day 6, under all test conditions, including the fasting state that caused a rapid increase to high exposure. ● Evidence of IR / DR / DR kinetics was observed after administration of Formulation A, and there was no notable accumulation after morning and evening dosing; and ● In the presence of food, the PK profile of Formulation A showed weak but sustained exposure regardless of the meal type.

[0214] The embodiments shown and described in this specification are only specific embodiments of the inventors who are those skilled in the art and do not limit in any way. Therefore, in the following claims, various changes, modifications, or amendments to these embodiments can be made without departing from the spirit of the invention. The cited references are hereby incorporated by reference in their entirety into this specification.

Claims

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

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

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

4. The pharmaceutical composition according to any one of the preceding claims, which is 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 granules.

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 that can elute 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, for example, an ethyl acrylate-methacrylic acid copolymer, or, for example, a 1:1 methacrylic acid:ethyl acrylate copolymer, or, for example, Eudragit® L 30 D-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 that can elute 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, for example, a copolymer of methacrylic acid, methyl acrylate, methyl methacrylate, or, for example, Eudragit® 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. The 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 immediate release portion is coated on top of the first modified release portion, or the immediate release portion is coated on top of the second modified release portion, or the immediate release portion is coated on top of a combination of the first release portion and the second release portion, The pharmaceutical composition according to any one of claims 1 to 5.

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

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

16. When measured by the 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, at least about 30% by weight of the total amount of API in the composition is released from the composition over a period of about 5 minutes to about 2 hours. The pharmaceutical composition according to any one of the preceding claims.

17. When measured by the 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, at least about 60% by weight of the total amount of API in the composition is released from the pharmaceutical composition over a period of about 2 to about 4 hours, the pharmaceutical composition according to any one of the preceding claims.

18. When measured by the 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, at least about 80% by weight of the total amount of API in the composition is released from the pharmaceutical composition over a period of about 3 to about 6 hours, the pharmaceutical composition according to any one of the preceding claims.

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

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

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

22. The pharmaceutical composition according to any one 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 bulking agent, a binder, a disintegrant, an emulsifier, an anti-static agent, or a solvent.

23. An oral dosage unit comprising the 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% by weight, or such as from about 30 to about 50% by weight, or such as about 43% by weight 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% by weight, or such as from about 20 to about 30% by weight, or such as about 28% by weight of the first modified release portion, based on the weight of the oral dosage unit.

26. An oral dosage unit according to any one of claims 23 to 25, comprising about 10 to about 40% by weight, or, for example, about 20 to about 30% by weight, or, for example, about 28% by weight 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, which is in the form of a tablet, capsule, or sachet.

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

29. The method according to claim 28, wherein the spastic condition is a sudden involuntary muscle contraction of the bronchus, stomach, intestine, ureter, gallbladder, kidney, or bile duct.

30. The method according to claim 28, wherein the spastic condition is a urinary tract spasm, gallstone, gastrointestinal disorder, inflammatory bowel disease, renal colicky pain, or a spastic condition of the bile duct.

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

32. The oral dosage unit according to claim 31, wherein the spastic condition is a sudden involuntary muscle contraction of the bronchus, stomach, intestine, ureter, gallbladder, kidney, or bile duct.

33. The oral dosage unit according to claim 31, wherein the spastic condition is a urinary tract spasm, gallstone, gastrointestinal disorder, inflammatory bowel disease, renal colicky pain, or a spastic condition of the bile duct.

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

35. The oral dosage unit according to claim 34, wherein the spastic state is a sudden involuntary muscle contraction of the bronchus, stomach, intestine, ureter, gallbladder, kidney, or bile duct.

36. The oral dosage unit according to claim 34, wherein the spastic state is a urinary tract spasm, gallstone, gastrointestinal disorder, inflammatory bowel disease, nephralgia, or a spastic state of the biliary tract.

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

38. The use according to claim 37, wherein the spastic state is a sudden involuntary muscle contraction of the bronchus, stomach, intestine, ureter, gallbladder, kidney, or bile duct.

39. The use according to claim 37, wherein the spastic state is a urinary tract spasm, gallstone, gastrointestinal disorder, inflammatory bowel disease, nephralgia, or a spastic state of the biliary tract. ​

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