Pharmaceutical composition for familial benign chronic pemphigus and its use

Abstract

This invention provides a novel pharmaceutical composition for familial benign chronic pemphigus. The pharmaceutical composition for familial benign chronic pemphigus of this invention comprises 5-methyl-2-(1-piperyl)benzenesulfonic acid. The aforementioned compound is used as an anhydrous form, its salt, its hydrate or solvate, or a hydrate or solvate of its salt as the active ingredient. The aforementioned hydrate is, for example, 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate. The pharmaceutical composition of this invention can be used for the treatment or prevention of familial benign chronic pemphigus.

Description

[Technical Field]

[0001] This invention relates to pharmaceutical compositions for familial benign chronic pemphigus, and methods for the treatment or prevention of familial benign chronic pemphigus. [Previous Technology]

[0002] Familial benign chronic pemphigus is a skin disease characterized by vesicular rashes (bubbles) that frequently appear in friction areas such as the neck, armpits, and groin, resulting from acantholysis of the epidermis (Non-Patent Literature 1). These vesicles are accompanied by itching; furthermore, in severe cases, the vesicles rupture, leading to erosions that expose the mucous membrane. In these conditions, the presence of crusts, pustules, pigmentation, or secondary infections can create lesions resembling pustular eczema, producing a foul odor. Furthermore, due to the possibility of chronicity or relapse, the patient's quality of life (QOL) is reduced, and social handicap is also a worrying issue.

[0003] There is currently no fundamental treatment recommended by guidelines for familial benign chronic pemphigus. Treatment focuses on disease management and symptom management to avoid triggers for exacerbation. For example, lifestyle guidance is sometimes provided to reduce factors that exacerbate symptoms, such as friction, sweating, and sun exposure. In mild cases, treatment may involve steroid ointments or vitamin D preparations. In severe cases, immunosuppressants or retinoids may be used. Furthermore, laser therapy and surgical excision may also be performed.

[0004] Reports of side effects have emerged regarding treatments involving the administration of retinoids, steroids, vitamin D preparations, etc., indicating that these treatments are not safe and provide sustained efficacy. Therefore, there remains a high unmet medical need for safe and effective treatment for familial benign chronic pemphigus. [Prior Art Literature] [Non-Patent Literature]

[0005] Non-patent literature 1: Guidelines for the diagnosis and treatment of familial benign chronic pemphigus 2023, Journal of Japanese Dermatology: 134(2), 273-287, 2024 [Summary of the Invention]

[0006] [Problem to be Solved by the Invention] Therefore, the object of the present invention is to provide a novel pharmaceutical composition for familial benign chronic pemphigus, and a method for its treatment or prevention. [Means for Solving the Problem]

[0007] The pharmaceutical composition system for familial benign chronic pemphigus of the present invention comprises 5-methyl-2-(1-piperyl)benzenesulfonic acid (also known as 5-methyl-2-(piperyl-1-yl)benzenesulfonic acid).

[0008] The method for treating or preventing familial benign chronic pemphigus of the present invention includes the step of administering 5-methyl-2-(1-piperyl)benzenesulfonic acid to the subject.

[0009] This invention relates to 5-methyl-2-(1-piperazine)benzenesulfonic acid for the treatment or prevention of familial benign chronic pemphigus.

[0010] This invention relates to the use of 5-methyl-2-(1-piperazolyl)benzenesulfonic acid in the manufacture of pharmaceutical compositions for familial benign chronic pemphigus. [Invention Efficacy]

[0011] The pharmaceutical composition of the present invention can be used to treat or prevent familial benign chronic pemphigus by including 5-methyl-2-(1-piperyl)benzenesulfonic acid.

Implementation Method

[0013] The present invention can be exemplified by the following embodiments. [1] A pharmaceutical composition for familial benign chronic pemphigus, comprising 5-methyl-2-(1-piperyl)benzenesulfonic acid. [2] The pharmaceutical composition as described in [1], wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate or solvate, or a hydrate or solvate of its salt. [3] The pharmaceutical composition as described in [1], wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate or a hydrate of its salt. [4] The pharmaceutical composition as described in [2] or [3], wherein the aforementioned hydrate is a monohydrate of 5-methyl-2-(1-piperyl)benzenesulfonic acid. [5] The pharmaceutical composition described in any one of [1] to [4] inhibits acantholysis in the aforementioned familial benign chronic pemphigus. [6] The pharmaceutical composition described in any one of [1] to [5] improves the IGA score of the aforementioned familial benign chronic pemphigus. [7] The pharmaceutical composition described in any one of [1] to [6] inhibits or improves at least one of the groups of the aforementioned familial benign chronic pemphigus selected from the group consisting of lesion area, itching, pain and odor. [8] The pharmaceutical composition described in any one of [1] to [7] wherein the dosage of 5-methyl-2-(1-piperyl)benzenesulfonic acid is 1 to 1000 mg / day, the dosage being converted to the amount of anhydrous 5-methyl-2-(1-piperyl)benzenesulfonic acid.

[0014] [9] A method for the treatment or prevention of familial benign chronic pemphigus, comprising the step of administering 5-methyl-2-(1-piperyl)benzenesulfonic acid to a subject.

[10] The method as described in [9], wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate or solvate, or a hydrate or solvate of its salt.

[11] The method as described in [9], wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate or a hydrate of its salt.

[12] A pharmaceutical composition as described in

[10] or

[11] , wherein the aforementioned hydrate is a monohydrate of 5-methyl-2-(1-piperyl)benzenesulfonic acid.

[13] The method described in any of [9] to

[12] , wherein the administration method is oral administration.

[14] The method described in any of [9] to

[13] , wherein the daily dosage is 1 to 1000 mg / day, the dosage being converted to the amount of anhydrous 5-methyl-2-(1-piperyl)benzenesulfonic acid.

[15] The method described in any of [9] to

[14] , wherein the number of administrations per day is 1 to 3.

[16] The method described in any of [9] to

[15] , wherein the administration interval is daily administration.

[0015]

[17] A 5-methyl-2-(1-piperyl)benzenesulfonic acid, which is intended for use in the treatment or prevention of familial benign chronic pemphigus.

[18] 5-methyl-2-(1-piperyl)benzenesulfonic acid as described in

[17] , wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate or solvate, or a hydrate or solvate of its salt.

[19] 5-methyl-2-(1-piperyl)benzenesulfonic acid as described in

[17] , wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate, or a hydrate of its salt.

[20] 5-methyl-2-(1-piperyl)benzenesulfonic acid as described in

[18] or

[19] , wherein the aforementioned hydrate is a monohydrate of 5-methyl-2-(1-piperyl)benzenesulfonic acid.

[21] A 5-methyl-2-(1-piperyl)benzenesulfonic acid, which is a pharmaceutical composition for manufacturing familial benign chronic pemphigus.

[22] 5-methyl-2-(1-piperyl)benzenesulfonic acid as described in

[21] , wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate or solvate, or a hydrate or solvate of its salt.

[23] 5-methyl-2-(1-piperyl)benzenesulfonic acid as described in

[21] , wherein the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate, or a hydrate of its salt.

[24] 5-methyl-2-(1-piperyl)benzenesulfonic acid as described in

[22] or

[23] , wherein the aforementioned hydrate is a monohydrate of 5-methyl-2-(1-piperyl)benzenesulfonic acid.

[0016]

[25] A pharmaceutical composition for spinolysis comprising 5-methyl-2-(1-piperyl)benzenesulfonic acid.

[26] In the pharmaceutical composition described in

[25] , the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate, or a solvate, or a hydrate or solvate of its salt.

[27] In the pharmaceutical composition described in

[25] , the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is its anhydrous form, its salt, its hydrate, or a hydrate of its salt.

[28] In the pharmaceutical composition described in

[26] or

[27] , the aforementioned hydrate is a monohydrate of 5-methyl-2-(1-piperyl)benzenesulfonic acid.

[0017] In this specification, the term "treatment of a disease" includes, for example, the meaning of curing a disease, alleviating a disease, mitigating a disease, or inhibiting the progression of a disease. Furthermore, the term "treatment of a disease" includes, for example, the treatment of symptoms caused by the aforementioned disease (e.g., curing, alleviating, mitigating, or inhibiting symptoms). The term "prevention of a disease" includes, for example, the meaning of preventing contracting a disease, preventing the development of a disease, and preventing the recurrence of a disease. Furthermore, the term "prevention of a disease" includes, for example, the meaning of preventing symptoms caused by the aforementioned disease (e.g., preventing the occurrence of symptoms or preventing the recurrence of symptoms). In this specification, the treatment or prevention of a disease may also be referred to as, for example, the suppression of a disease. Furthermore, the treatment or prevention of symptoms caused by a disease may also be referred to as the suppression of symptoms caused by a disease.

[0018] The “epidermis” of the skin is usually composed of the stratum corneum, stratum granulosum, stratum spinosum, and stratum basale.

[0019] In this specification, treatment refers, for example, to the treatment of a subject diagnosed by a physician as having a disease or symptoms of a disease. Furthermore, in this specification, prevention means, for example, the treatment of a subject who has not yet developed a disease or symptoms of a disease, aimed at preventing the development of the disease or symptoms of a disease. The aforementioned subject is referred to, for example, as a test subject or examinee, which may be a human (patient) or a non-human animal (afflicted animal). In this specification, the term "patient" may also include, for example, the meaning of "afflicted animal" for non-human animals, and can be read as "afflicted animal." Furthermore, in the case where the aforementioned subject does not suffer from the aforementioned disease or its symptoms, the target disease or symptoms are also referred to as a healthy person (healthy human or healthy non-human animal).

[0020] Hereinafter, specific examples will be described with reference to the present invention, but the present invention is not limited to these examples. The embodiments illustrated below may be used interchangeably unless otherwise specified. Hereinafter, familial benign chronic pemphigus is also referred to as HHD.

[0021] [Pharmaceutical Composition for HHD] The pharmaceutical composition for HHD of the present invention is characterized by containing 5-methyl-2-(1-piperyl)benzenesulfonic acid. The pharmaceutical composition for HHD of the present invention is characterized by containing the aforementioned compound, and other components and conditions are not particularly limited.

[0022] The HHD pharmaceutical composition of the present invention, as described above, can be used for the treatment or prevention of HHD. The HHD pharmaceutical composition of the present invention can be used, for example, for therapeutic purposes, for preventative purposes, or for both therapeutic and preventative purposes. Hereinafter, the term "treatment / prevention" may be interpreted as treatment, prevention, or any of the following meanings: treatment and prevention. The HHD pharmaceutical composition of the present invention can, for example, provide safe treatment / prevention with fewer side effects.

[0023] In this specification, 5-methyl-2-(1-piperyl)benzenesulfonic acid will be referred to as MPBS. The aforementioned MPBS is not limited in its form and may include anhydrous MPBS (also called anhydrous MPBS), salts of MPBS (also called MPBS salts), hydrates of MPBS or hydrates of the aforementioned MPBS salts (also called MPBS hydrates), and solvates of MPBS or solvates of the aforementioned MPBS salts (also called MPBS solvates), all of which are collectively referred to as the MPBS class of the present invention. The aforementioned MPBS class contained in the pharmaceutical composition of the present invention may be, for example, the aforementioned anhydrous MPBS, the aforementioned MPBS salts, the aforementioned MPBS hydrates, or the aforementioned MPBS solvates; furthermore, it may contain only one type or any two or more types. The pharmaceutical composition of the present invention preferably contains the aforementioned MPBS class as an active ingredient.

[0024] The types of the aforementioned MPBS salts are not particularly limited, and examples include: alkali metal salts, alkaline earth metal salts, amphoteric element salts, amine salts, inorganic acid salts, or organic acid salts. Examples of alkali metal salts include: sodium salts or potassium salts; examples of alkaline earth metal salts include: magnesium salts or calcium salts; examples of amphoteric element salts include: aluminum salts. Examples of amine salts include: lower alkylamine salts such as triethylamine salts; hydroxyl lower alkylamine salts such as 2-hydroxyethylamine salts, bis-(2-hydroxyethyl)amine salts, tri(hydroxymethyl)aminomethane salts, or N-methyl-D-glucosamine salts; cycloalkylamine salts such as dicyclohexylamine salts; benzylamine salts such as N,N-dibenzylethylenediamine salts; or dibenzylamine salts. Examples of inorganic acid salts include: hydrochloride salts, hydrobromide salts, sulfate salts, or phosphate salts; examples of organic acid salts include: fumarate salts, succinate salts, oxalate salts, or lactate salts.

[0025] The type of the aforementioned MPBS hydrate is not particularly limited, for example, it may be a monohydrate. The type of the aforementioned MPBS solvate is not particularly limited. The solvent that can form the aforementioned MPBS solvate is not particularly limited, for example, it may be a non-aqueous solvent, such as methanol, ethanol, or isopropanol; acetone, ethyl acetate, or dichloromethane, etc.

[0026] In the pharmaceutical composition for HHD of the present invention, the aforementioned MPBS is preferably the aforementioned anhydrous MPBS or the aforementioned MPBS hydrate, more preferably the aforementioned MPBS hydrate, specifically the aforementioned MPBS monohydrate.

[0027] The aforementioned MPBS class of compounds are known compounds. The aforementioned MPBS class of compounds can be synthesized, for example, by the methods described in Japanese Patent Application Publication No. 3-7263, Japanese Patent Application Publication No. 9-221479, European Patent Application Publication No. 390654, European Patent Application Publication No. 779283, US Patent Publication No. 5053409, and US Patent Publication No. 5990113, and are compounds that are readily available to those skilled in the art.

[0028] The aforementioned MPBS series can be replaced by compounds or their salts, hydrates or solvates of the following general formula (I) as described in International Publication No. WO03 / 011296.

[0029] In the formula, R1 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C4 halogenated alkyl group, a halogen atom, or a C6-C12 aryl group; R2 represents a hydrogen atom, a C1-C6 alkyl group, or a C7-C12 aralkyl group, and the aforementioned aralkyl group may also have one or more substituents selected from the group consisting of cyano, nitro, C1-C6 alkoxy, halogen atom, C1-C6 alkyl group, and amino group, and n represents an integer from 1 to 4.

[0030] In the aforementioned general formula (I), the C1-C6 alkyl groups defined by R1 can be, for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dibutyl, tributyl, pentyl, isopentyl, neopentyl, tripentyl, hexyl, isohexyl. The C3-C7 cycloalkyl groups can be, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The C1-C4 halogenated alkyl groups can be, for example: trifluoromethyl, trifluoroethyl, pentafluoroethyl. The halogen atom can be, for example: fluorine atom, chlorine atom, bromine atom. The C6-C12 aryl groups can be, for example: phenyl, naphthyl.

[0031] Preferred examples of R1 may include, for example: hydrogen atom, C1-C6 alkyl, C5-C6 cycloalkyl, trifluoromethyl, halogen atom, or phenyl; more preferred examples may include, for example: C1-C3 alkyl, cyclohexyl, trifluoromethyl, chlorine atom, bromine atom, or phenyl; and even more preferred examples may include, for example: methyl or propyl, especially methyl.

[0032] Examples of C1-C6 alkyl groups defined by R2 include alkyl groups defined by R1 above. Examples of C7-C12 aralkyl groups include benzyl, phenethyl, and naphthylmethyl. This aralkyl group may also have, for example, one or more substituents selected from the group consisting of cyano, nitro, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tributoxy, pentoxy, isopentoxy, tripentoxy, hexoxy, etc., of C1-C6; halogen atoms as defined by R1 above; alkyl groups as defined by R1 above; and amino groups.

[0033] Preferred examples of R2 include, for example, a hydrogen atom, a C1-C3 alkyl group, and a C7-C12 aralkyl group, wherein the aforementioned aralkyl group may also have one or more substituents selected from C1-C3 alkyl groups, C1-C3 alkoxy groups, and halogen atoms. More preferred examples include, for example, a hydrogen atom, and a C7-C12 aralkyl group, wherein the aforementioned aralkyl group may also have one or more substituents selected from C1-C3 alkoxy groups, particularly a hydrogen atom. Furthermore, in the above general formula (I), n is preferably 2.

[0034] In the HHD pharmaceutical composition of the present invention, the aforementioned MPBS can also be, for example, in an ionized form. The HHD pharmaceutical composition of the present invention is, for example, a liquid as described below. In the case of containing aqueous solvents, non-aqueous solvents, or mixed solvents, the aforementioned MPBS can be ionized regardless of the type of anhydrous substance, salt, hydrate, or solvate. The molecular form of the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is, for example, represented by the following formula (II), and can become an ionized molecular species in proton solvents such as water. Specifically, the aforementioned molecular species can be exemplified by, for example, a monovalent cation of formula (IIIa), an amphoteric ion of formula (IIIb) having positive and negative charges, and a monovalent anion of formula (IIIc). The aforementioned monovalent cation can, for example, form a salt with an acid (anion), and the monovalent anion can, for example, form a salt with a base (cation).

[0035]

[0036] The pharmaceutical composition for HHD of the present invention can be used, for example, for the treatment or prevention of HHD, as described above. The pharmaceutical composition for HHD of the present invention can be interpreted as, for example, a pharmaceutical composition used for the symptoms of HHD; specifically, it can be interpreted as a pharmaceutical composition used for the treatment or prevention of the symptoms of HHD. Furthermore, the treatment or prevention of HHD can also be described as, for example, the suppression of HHD.

[0037] HHD, which is the subject of this invention, is a disease in which acantholysis is a pathological symptom. Acantholysis refers to the loss of intercellular adhesion in the stratum spinosum of the skin, such as keratinocytes, and can be observed, for example, as the formation of cracks or blisters within the epidermis. Furthermore, acantholytic cells (Tzanck cells), which are planktonic / rounded keratinocytes with condensed nuclei, can be observed within blisters. In the skin lesions of HHD patients, acantholysis is known to result from abnormal differentiation of keratinocytes. Acantholysis can be observed, for example, by collecting the lesioned skin of the patient and observing it according to methods known to those skilled in the art.

[0038] The pharmaceutical composition for HHD of the present invention can, for example, inhibit the aforementioned pathological symptoms of HHD. The pathological symptoms to be inhibited include, for example, acantholysis, and in addition to acantholysis, may also include abnormal keratinization. That is, the pharmaceutical composition for HHD of the present invention can, for example, inhibit acantholysis, and furthermore, can inhibit both acantholysis and abnormal keratinization. According to the pharmaceutical composition for HHD of the present invention, for example, it can inhibit acantholysis, and can inhibit both acantholysis and abnormal keratinization.

[0039] Dyskeratosis refers to the individual keratinization of keratinocytes in the stratum spinosum of the skin, resulting in dyskeratotic cells. In the case of HHD, granular bodies or acantholytic cells with condensed nuclei can be observed. Dyskeratosis can be observed, for example, by collecting diseased skin from a patient and observing it using methods known to those skilled in the art.

[0040] The pharmaceutical composition for HHD according to the present invention, for example, can improve a patient's IGA (Investigator's Global Assessment) score. Here, the IGA score is not particularly limited. IGA scores are generally classified into multiple stages, with higher scores indicating more severe symptoms.

[0041] The pharmaceutical composition for HHD of the present invention can, for example, inhibit or improve the clinical symptoms of the body caused by the aforementioned HHD. Specifically, for example, it can inhibit or improve at least one of the group consisting of the lesion area of ​​the skin, itching, pain, and odor of the aforementioned HHD. According to the pharmaceutical composition for HHD of the present invention, for example, by inhibiting or improving the aforementioned pathological symptoms, the clinical symptoms of the body exemplified herein can be inhibited or improved.

[0042] The affected skin area refers to the area covered by, for example, erythema formed by the aggregation of small blisters. This erythema becomes erosive after the blisters rupture, and may be accompanied by crusts, pustules, pigmentation, or secondary infection, presenting a form similar to impetigo (floaters). The pharmaceutical composition for HHD of the present invention can suppress or improve the affected skin area to, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less compared to before administration.

[0043] Itching can be assessed, for example, using a numerical rating scale for itch, based on the itching experienced by the subject. A numerical rating scale, for example, uses 0 to represent no itching and 10 to represent the most severe itching the subject can imagine. The subject uses this scale to assess itching. The HHD pharmaceutical composition of this invention can reduce the value of the numerical rating scale for itch by, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more compared to the value before administration.

[0044] Pain can be assessed, for example, using a numerical rating scale (NRS) to evaluate the pain experienced by the subject. A numerical rating scale, for example, uses 0 to represent no skin pain and 10 to represent the most severe skin pain the subject can imagine. The subject uses this scale to assess skin pain. The HHD pharmaceutical composition of this invention can reduce the value after administration of a pain-related numerical rating scale by, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more.

[0045] The odor can be assessed, for example, using a numerical rating scale for odor, based on the odor perceived by the test subject. A numerical rating scale, for example, uses 0 to represent no odor and 10 to represent the worst odor the test subject can imagine. The test subject uses this scale to assess the odor. The HHD pharmaceutical composition of this invention can reduce the value after administration of the odor-related numerical rating scale by, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more compared to the value before administration.

[0046] The pharmaceutical composition system for HHD of the present invention can, for example, improve at least one of the aforementioned HHDs selected from the group consisting of PGIS (Patient Global Impression of Severity), PGIC (Patient Global Impression of Change), CGIS (Clinician Global Impression of Severity), CGIC (Clinician Global Impression of Change), DLQI (Dermatology Life Quality Index), and Skindex-29.

[0047] (1) PGIS is a single questionnaire that assesses the overall impression of the severity of the subject's illness using a scoring system. The HHD pharmaceutical composition of this invention can improve PGIS and improve the score. (2) PGIC is a single questionnaire that assesses the overall improvement of the subject's health status using a scoring system. The HHD pharmaceutical composition of this invention can improve PGIC and improve the score. (3) CGIS is a single questionnaire that assesses the physician's overall impression of the severity of the subject's illness using a scoring system. The HHD pharmaceutical composition of this invention can improve CGIS and improve the score. (4) CGIC is a single questionnaire that assesses the physician's overall improvement of the subject's health status using a scoring system. The HHD pharmaceutical composition of this invention can improve CGIC and improve the score. (5) DLQI is a questionnaire that assesses the subject's various QOL-related issues using a scoring system. The HHD pharmaceutical composition of this invention can improve DLQI and improve the score. (6) Skindex-29 is a questionnaire that assesses the subject's various QOL-related issues using a scoring system. The pharmaceutical composition for HHD of the present invention can improve Skindex-29 and improve the score.

[0048] The method of administering the pharmaceutical composition for HHD of the present invention is not particularly limited and may be administered orally or non-orally. Examples of non-oral administration include: percutaneous, subcutaneous, intravenous, intra-arterial, intra-abdominal, intranasal, and intraintestinal administration.

[0049] The dosage form of the pharmaceutical composition for HHD of the present invention is not particularly limited, and can be suitably determined according to the method of administration. Dosage forms include, for example, liquids, gels, creams, and solids. Oral dosage forms include, for example, granules, fine granules, powders, tablets, capsules (e.g., hard capsules, soft capsules), syrups, emulsions, suspensions, liquids, and gels. Furthermore, non-oral dosage forms include, for example, injections, suppositories, and transdermal preparations.

[0050] The pharmaceutical composition for HHD of the present invention only needs to contain the aforementioned MPBS class, and there are no particular limitations on other components. For example, the pharmaceutical composition for HHD of the present invention may contain only the aforementioned MPBS class as an active ingredient, and in addition to the aforementioned MPBS class, it may further contain other active ingredients for HHD.

[0051] The pharmaceutical composition system for HHD of the present invention may contain only the aforementioned active ingredient, or may contain additives in addition to the aforementioned active ingredient. The aforementioned additives are preferably pharmaceutically permissible substances, for example. The types of the aforementioned additives are not particularly limited, and may be appropriately selected according to the intended form. Examples of the aforementioned additives include: carriers, excipients, stabilizers, lubricants, sweeteners, preservatives, suspending agents, dispersants, thickeners, pH adjusters, defoamers, and fragrances. Examples of the aforementioned carriers include: liquids, solids, gels, and creams.

[0052] The recipient of the pharmaceutical composition for HHD of the present invention is not particularly limited, such as humans or non-human animals, preferably humans. Non-human animals include, for example, non-human mammals such as mice, rats, rabbits, and horses.

[0053] The administration conditions of the pharmaceutical composition for HHD of the present invention are not particularly limited, and can be appropriately determined according to the administration method and patient information. The aforementioned patient information may include, for example: age, sex, weight, presence or absence of HHD and its symptoms, severity of HHD and its symptoms, and past medical history.

[0054] Examples of oral administration of the HHD pharmaceutical composition of the present invention can be illustrated by the following conditions. The following examples are for infants, young children, children, adults, or the elderly, and can be appropriately adjusted according to their patient information. The dosage of the aforementioned MPBS class can be expressed, for example, by converting the aforementioned MPBS class into the dosage of the aforementioned anhydrous MPBS. The dosages illustrated below are the dosages of the aforementioned MPBS class converted into the dosage of the aforementioned anhydrous MPBS. As a specific example, the dosage of the aforementioned MPBS monohydrate is converted into the dosage of the aforementioned anhydrous MPBS.

[0055] ・Daily dosage of the aforementioned MPBS (converted to the amount of anhydrous MPBS): Lower limit: e.g., 1 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 100 mg, 150 mg, 200 mg, or 300 mg Upper limit: e.g., 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg Range: For example, 1 to 1000 mg, 10 to 1000 mg, 20 to 1000 mg, 25 to 1000 mg, 30 to 1000 mg, 50 to 1000 mg, 60 to 1000 mg, 100 to 1000 mg, 1 to 600 mg, 10 to 600 mg, 25 to 600 mg, 30 to 600 mg, 50 to 600 mg, 100 to 600 mg, 10 to 500 mg, 20 to 500 mg, 25 to 500 mg. 30 to 500 mg, 50 to 500 mg, 60 to 500 mg, 100 to 500 mg, 200 to 500 mg, 10 to 400 mg, 20 to 400 mg, 25 to 400 mg, 30 to 400 mg, 50 to 400 mg, 60 to 400 mg, 100 to 400 mg, 200 to 400 mg, 10 to 300 mg, 20 to 300 mg, 25 to 300 mg, 30 to 300 mg, 50 to 300 mg g, 60 to 300 mg, 100 to 300 mg, 200 to 300 mg, 10 to 200 mg, 20 to 200 mg, 25 to 200 mg, 30 to 200 mg, 50 to 200 mg, 60 to 200 mg, 100 to 200 mg, 10 to 100 mg, 20 to 100 mg, 25 to 100 mg, 30 to 100 mg, 50 to 100 mg, 60 to 100 mg, 300 to 400 mg, 300 to 500mg, 300-600mg, 300-800mg, 300-1000mg, 300-1200mg, 400-600mg, 400-800mg, 400-1000mg, 400-1200mg, 500-600mg, 500-800mg, 500-1000mg, 500-1200mg, 600-800mg, 600-1000mg, or 600-1200mg Examples of specific dosages: e.g., 1mg, 10mg, 20mg, 25mg, 30mg, 40mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 800mg, 900mg, 1000mg, or 1200mg. Frequency of administration per day: e.g., 1 to 3 times, preferably 1 or 2 times.Ideally, the frequency (interval) should be twice: for example, daily.

[0056] The oral administration of the HHD pharmaceutical composition of the present invention can be freely set to a time point such as before meals, during meals, immediately after meals, after meals, between meals, upon waking, or upon going to bed, with a preference for administration between meals. The administration of the HHD pharmaceutical composition of the present invention between meals refers, for example, to administration at least one hour after the start of food intake, preferably at least two hours after the start of food intake, and / or, for example, to administration at least one hour, two hours, three hours, four hours, or 4.5 hours after the start of the next food intake, preferably one hour after the next food intake. That is, the HHD pharmaceutical composition of the present invention is administered, for example, one or two hours after the start of food intake, to one hour, two hours, three hours, four hours, or 4.5 hours before the next food intake.

[0057] The pharmaceutical composition for HHD of the present invention, as described above, can be used for the treatment or prevention of HHD symptoms, where HHD is, as described above, a disease that causes acantholysis. Therefore, the present invention can also be, for example, a pharmaceutical composition for treating or preventing acantholysis. Furthermore, the present invention can also be, for example, a pharmaceutical composition for simultaneously treating or preventing acantholysis and keratosis.

[0058] [Method for Treatment or Prevention of HHD] The method for treatment or prevention of HHD of the present invention comprises the step of administering 5-methyl-2-(1-piperyl)benzenesulfonic acid to a subject. As mentioned above, 5-methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is not limited in its form and may be any of the aforementioned MPBS types, that is, any one of the aforementioned anhydrous MPBS, the aforementioned MPBS salt, the aforementioned MPBS hydrate, and / or the aforementioned MPBS solvate. Unless otherwise specified, the method for treatment or prevention of HHD of the present invention is referred to below as the method for treatment / prevention of HHD of the present invention. The method for treatment / prevention of the present invention is characterized by administering the aforementioned MPBS types; other conditions and steps are not particularly limited.

[0059] In the treatment / prevention method of the present invention, the aforementioned patient in the test system may be a patient with comorbid HHD or a patient without comorbid HHD.

[0060] In the treatment / prevention method of the present invention, the administration of the aforementioned MPBS is, for example, the administration of the aforementioned pharmaceutical composition for HHD of the present invention. In the present invention, the aforementioned MPBS, its composition, and administration method are as described in the aforementioned pharmaceutical composition for HHD of the present invention.

[0061] [Use of MPBS Classes] This invention relates to 5-methyl-2-(1-piperyl)benzenesulfonic acid for use in the treatment or prevention of HHD. As mentioned above, 5-methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is not limited in its form and can be any of the aforementioned MPBS classes, namely, the aforementioned anhydrous MPBS, the aforementioned MPBS salt, the aforementioned MPBS hydrate, and / or the aforementioned MPBS solvate. In this invention, the aforementioned MPBS classes, their compositions, and methods of use are as described in the aforementioned pharmaceutical compositions for HHD of this invention.

[0062] Furthermore, this invention relates to the use of 5-methyl-2-(1-piperyl)benzenesulfonic acid in the manufacture of pharmaceutical compositions for HHD. 5-Methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is as described above, and its form is not limited; it can be any of the aforementioned MPBS types, namely, any one of the aforementioned anhydrous MPBS, the aforementioned MPBS salt, the aforementioned MPBS hydrate, and / or the aforementioned MPBS solvate. In this invention, the aforementioned MPBS types, their compositions, and methods of use are as described in the aforementioned pharmaceutical compositions for HHD of this invention.

[0063] [Pharmaceutical Composition for Acantholysis and Its Use] The pharmaceutical composition for acantholysis of the present invention comprises 5-methyl-2-(1-piperyl)benzenesulfonic acid. As mentioned above, 5-methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is not limited in its form and may be any of the aforementioned MPBS class, that is, any one of the aforementioned anhydrous MPBS, the aforementioned MPBS salt, the aforementioned MPBS hydrate, and / or the aforementioned MPBS solvate. The pharmaceutical composition for acantholysis of the present invention may, for example, contain only one type as the aforementioned MPBS class, or may contain any two or more types as the aforementioned MPBS class. The aforementioned MPBS class can be used for the treatment or prevention of acantholysis. The pharmaceutical composition for acantholysis of the present invention is characterized by containing the aforementioned MPBS class, and other conditions are not particularly limited. The pharmaceutical composition for acantholysis of the present invention preferably contains the aforementioned MPBS class as an active ingredient. Furthermore, when using the pharmaceutical composition for acantholysis of the present invention for the treatment or prevention of acantholysis, the types of diseases that cause acantholysis as a pathological symptom are not particularly limited.

[0064] According to the pharmaceutical composition for acantholysis of the present invention, as described above, acantholysis can be treated or prevented. The pharmaceutical composition for acantholysis of the present invention can be used, for example, for therapeutic purposes, for preventative purposes, or for both therapeutic and preventative purposes. Hereinafter, the term "treatment / prevention" may be interpreted as treatment, prevention, or any of the meanings of treatment and prevention. The pharmaceutical composition for acantholysis of the present invention can, for example, provide safe treatment / prevention with few side effects. Diseases that cause acantholysis include, for example, familial benign chronic pemphigus.

[0065] In the pharmaceutical composition for acantholysis of the present invention, the aforementioned MPBS class, its composition, and method of use are not particularly limited. For example, the description in the pharmaceutical composition for HHD of the present invention can be used. When used, "HHD" and "symptoms of HHD" can be read as "acantholysis".

[0066] The treatment or prevention method for acantholysis of the present invention includes the step of administering 5-methyl-2-(1-piperyl)benzenesulfonic acid to the subject. As mentioned above, 5-methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is not limited in its form and may be any of the aforementioned MPBS types, that is, any one of the aforementioned anhydrous MPBS, the aforementioned MPBS salt, the aforementioned MPBS hydrate, and / or the aforementioned MPBS solvate. Unless otherwise specified, the treatment or prevention method for acantholysis of the present invention is referred to below as the treatment / prevention method for acantholysis of the present invention. The treatment / prevention method of the present invention is characterized by administering the aforementioned MPBS types; other conditions and steps are not particularly limited. Furthermore, the subject system to which the present invention is applied, such as a patient with acantholysis as a pathological symptom, or a patient with the potential for acantholysis, is not particularly limited in the type of disease causing acantholysis as a pathological symptom.

[0067] In this invention, the aforementioned MPBS class, its components, and its administration methods are not particularly limited, and the descriptions in the aforementioned HHD pharmaceutical components of this invention can be used. When used, "HHD" and "symptoms of HHD" can be read as "acantholysis".

[0068] This invention relates to 5-methyl-2-(1-piperyl)benzenesulfonic acid for use in the treatment or prevention of acantholysis. As mentioned above, 5-methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is not limited in its form and can be any of the aforementioned MPBS types, namely, any of the aforementioned anhydrous MPBS, the aforementioned MPBS salts, the aforementioned MPBS hydrates, and / or the aforementioned MPBS solvates. In this invention, the aforementioned MPBS types, their compositions, and methods of use are as described in the aforementioned pharmaceutical compositions for HHD of this invention. When referred to, "HHD" and "symptoms of HHD" can be read as "acantholysis".

[0069] Furthermore, this invention relates to the use of 5-methyl-2-(1-piperyl)benzenesulfonic acid in the manufacture of pharmaceutical compositions for acantholysis. As mentioned above, 5-methyl-2-(1-piperyl)benzenesulfonic acid (MPBS) is not limited in its form and can be any of the aforementioned MPBS types, namely, any one of the aforementioned anhydrous MPBS, the aforementioned MPBS salt, the aforementioned MPBS hydrate, and / or the aforementioned MPBS solvate. In this invention, the aforementioned MPBS types, their compositions, and methods of use are as described in the aforementioned pharmaceutical compositions for HHD of this invention. When referenced, "HHD" and "symptoms of HHD" can be read as "acantholysis". [Example]

[0070] In the following examples, 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate (hereinafter, in the examples, it is described as compound A) was used as the aforementioned MPBS type.

[0071] [Example 1] Inhibition of Differentiation Abnormalities in an In Vitro HHD Three-Dimensional Cultured Epidermal Model The inhibitory effect of compound A on differentiation abnormalities in an in vitro HHD three-dimensional cultured epidermal model was evaluated. In skin lesions of HHD patients, abnormal differentiation of keratinocytes is known to cause acantholysis. In this model, the effect of compound A on changes in the gene expression of differentiation markers was examined.

[0072] <Experimental Cells and Experimental Design> Since HHD is known to be associated with mutations in the ATP2C1 gene, an in vitro three-dimensional culture epidermal model of HHD induced by ATP2C1 siRNA was created using the following method. The cells and culture medium used were from the LabCyte EPI-KIT (Japan Tissue Engineering Co., Ltd., 401810), a human epidermal model preparation kit. The siRNA was transfected into primary human keratinocytes from the aforementioned human epidermal model preparation kit. For transfection, the transfection reagent used was Lipofectamine RNAiMAX (Thermo Fisher Scientific, 13778), a cationic lipid preparation, and the culture medium used was Opti-MEM (Thermo Fisher Scientific, 31985-062), a reduced serum medium. For the aforementioned siRNA, in this example, ATP2C1 siRNA (Thermo Fisher Scientific, J-006119-05-0005) was used, and for the control, a non-targeting control siRNA (Thermo Fisher Scientific, D-001810-01-05) was used. The final concentration of the aforementioned siRNA was set at 100 nmol / L. Furthermore, in this specification, the term "final concentration" related to each test substance solution and reagent refers to the concentration in the culture medium at the final stage after adding all test substance solutions and reagents.

[0073] Transfected cells containing the aforementioned siRNA were introduced and cultured three-dimensionally using a gas-liquid interface insert and a 24-well plate (Day 0). In vivo epidermal tissue was prepared over 8 days of culture (Day 0 to Day 8). The culture environment was maintained at 37°C and 5% CO2. From the start of the three-dimensional culture (Day 0), an aqueous solution of compound A (solvent: phosphate-buffered saline) was added to the culture medium for the aforementioned epidermal tissue to achieve a final concentration of 10 μmol / L. The culture medium was exchanged daily, and the aqueous solution of compound A was added during each exchange. Eight days after the start of the three-dimensional culture (Day 8), samples of the aforementioned epidermal tissue were taken for evaluation. The population composition was set as follows: a control siRNA treatment group, an ATP2C1 siRNA treatment group, and an ATP2C1 siRNA + compound A treatment group (belonging to the example group). The number of samples was set to 9 epidermal tissues per group.

[0074] <Evaluation Method> RNA was extracted from the sampled epidermal tissue using an RNeasy (trademarked) Mini QIAcube kit (QIAGEN, 74116). The concentration of the RNA was determined using a micro-spectrophotometer (DropSense 96 (trademarked) (Trinean) or LUNATIC (Unchained Labs)), and cDNA was reverse transcribed. In the reverse transcription reaction, SuperScript IV VILO Master Mix (Thermo Fisher Scientific, 11756050) or a High-capacity RNA to cDNA kit (Thermo Fisher Scientific, 4387406) was used. Using the cDNA as a template, RT-qPCR analysis was performed using a QuantStudio 6 Flex Real-Time PCR System (Applied Biosystems). In the RT-qPCR reaction, the master mix used was either TaqMan Fast Advanced Master Mix (Thermo Fisher Scientific, 4444557) or TaqMan Fast Universal PCR Master Mix (Thermo Fisher Scientific, 4352042). The TaqMan probes (Thermo Fisher Scientific) used were those listed in Table 1. Differentiation markers were KRT5 and KRT14 (basal layer markers) and IVL (granular layer marker).

[0075] [Table 1] Gene symbol Gene name Measurement number RPLP0 Ribosomal protein stalk subunit P0 Hs99999902_m1 HPRT1 Inosine phosphoribosyltransferase 1 Hs02800695_m1 KRT5 Keratin 5 Hs00361185_m1 KRT14 Keratin 14 Hs00265033_m1 IVL Envelope protein Hs00846307_s1

[0076] In the aforementioned RT-qPCR analysis, RPLP0 or HPRT1 was used as the internal standard gene. Furthermore, the ΔΔCt method was used to calculate the relative gene expression level, based on the average gene expression level in Day 0 keratinocytes, and the mean and standard error of these values. The inhibition rate was calculated as follows: Inhibition rate (%) = 100 × (AB) / (AC) A: Average relative gene expression level of the ATP2C1 siRNA treatment group; B: Relative gene expression level of the ATP2C1 siRNA + compound A treatment group; C: Average relative gene expression level of the control siRNA treatment group.

[0077] <Statistical Analysis> Statistical analysis was performed using SAS, with the significance level set at 5% on both sides. The successful induction of the in vitro HHD three-dimensional culture epidermal model was determined by comparing the aforementioned control siRNA treatment group and the aforementioned ATP2C1 siRNA treatment group. The pharmacological effect of compound A was determined by comparing the aforementioned ATP2C1 siRNA treatment group and the aforementioned example group (ATP2C1 siRNA + compound A treatment group). All assays used the Student's t-test.

[0078] Figures 1A and 1B are graphs showing the results of gene expression analysis. Specifically, they show the relationship between the administration of MPBS monohydrate and the expression of differentiation marker molecules in an in vitro HHD three-dimensional culture epidermal model. The vertical axis of Figure 1A represents the relative gene expression level based on the gene expression level of keratinocytes at Day 0, and the vertical axis of Figure 1B represents the inhibition rate of the increase in gene expression of differentiation markers induced by ATP2C1 siRNA treatment.

[0079] In the aforementioned ATP2C1 siRNA treatment group, compared with the aforementioned control siRNA treatment group, statistically significant increases were observed in the expression of KRT5 and KRT14, which belong to the basal layer markers, and IVL, which belongs to the granular layer markers that have been reported to exhibit abnormal expression in HHD patients. In contrast, the aforementioned example group, by adding the aforementioned compound A, inhibited the increase in the expression of these differentiation markers, and the abnormal expression of these marker genes was improved.

[0080] [Example 2] Improvement of Intercellular Adhesion Impairment in an In Vitro Epidermal Intercellular Adhesion Impairment Model The improvement effect of compound A on intercellular adhesion in an epidermal intercellular adhesion impairment model was evaluated. It is known that impaired intercellular adhesion results in acantholysis. The impairment of intercellular adhesion was assessed using a Real-Time Cell Analyzer by measuring changes in cell index resistance.

[0081] <Experimental Cells and Experimental Design> An in vivo model of intercellular adhesion damage to epidermal cells was established using 2,2'-methylenebis(6-tert-butyl-4-cresol) (hereinafter referred to as bisphenol) according to the following method. Bisphenol has been reported to selectively inhibit the ATPase activity of SPCA1, a responsible molecule for HHD. Primary human keratinocytes derived from Caucasian women (KURABO, KK-4109) were used as cells. HuMedia-KG2 medium (KURABO, KK-2150S) was used for the culture of the aforementioned primary human keratinocytes. A xCELLigence real-time cell analyzer (Agilent Technologies) was used, set in an incubator at 37°C and 5% CO2.

[0082] First, HuMedia-KG2 culture medium was added to an E-Plate VIEW 96 PET (Agilent Technologies) plate at a rate of 50 μl / well. The plate was placed in the aforementioned real-time cell analyzer, and the background value of the electrical resistance was measured. Next, the plate was removed, and the aforementioned primary human keratinocytes were seeded in the plate at a rate of 100 μl / well to achieve a density of 25,000 cells / well. The plate was then placed back in the aforementioned real-time cell analyzer. Then, the electrical resistance was measured simultaneously with the setup, and the values ​​were recorded at 15-minute intervals (Day 0).

[0083] On Day 1, the aforementioned plate was removed. After removing 50 μl of culture supernatant per well from the wells of the aforementioned plate, calcium solution was added at 100 μl per well to achieve a final calcium concentration of 1.2 mmol / L. The aforementioned plate was placed back into the aforementioned real-time cell analyzer, and the resistance measurement was started again. Then, on Day 2, the aforementioned plate was removed. After removing 100 μl of culture supernatant per well from the wells of the aforementioned plate, compound A was added at 50 μl per well. The aforementioned plate was placed back into the aforementioned real-time cell analyzer, and the resistance measurement was started again. Then, 3 hours after the addition of compound A, the aforementioned plate was removed, and bisphenol solution was added to the aforementioned plate at 50 μl per well. The aforementioned plate was placed back into the aforementioned real-time cell analyzer, and the resistance measurement was started again.

[0084] The group composition is set as three groups: the group without added bisphenol, the group with added bisphenol (compound A not added), and the group with added bisphenol / compound A belonging to the example group. At the time point when the aforementioned bisphenol is added, the final concentration of the aforementioned compound A in the well is set to 0 μmol / L (compound A not added), 0.01 μmol / L, 0.1 μmol / L, or 1 μmol / L, and the final concentration of the aforementioned bisphenol is set to 0 μmol / L (bisphenol not added) or 4 μmol / L.

[0085] Then, the normalized cell index (nCi) 60 hours after the addition of the aforementioned bisphenol was used as an indicator of the inhibition of epidermal cell adhesion damage. nCi was normalized in such a way that the cell index (the resistance value before the addition of the aforementioned bisphenol) was 1.

[0086] <Statistical Analysis> The statistical analysis was performed using SAS (Statistical Analysis System). In the comparison between the aforementioned bisphenol-free group and the aforementioned bisphenol-added group, the Student's t-test was used. Furthermore, the determination of the pharmacological effect of compound A was performed by comparing the aforementioned bisphenol-added group with the aforementioned bisphenol-added / compound A-added group, and the test method used was the Williams multiple comparison test.

[0087] Compound A was evaluated in a bisphenol-induced model of intercellular adhesion damage in the body epidermis. The aforementioned experiment was performed four times, and the mean and standard error of nCi over a 60-hour period following bisphenol addition were calculated and analyzed statistically. The results are shown in Figure 2.

[0088] Figure 2 shows the relationship between the administration of MPBS monohydrate and intercellular adhesion in an in vivo epidermal cell adhesion damage model. The vertical axis represents the standardized electrical resistance value. As shown in Figure 2, the addition of bisphenol to the aforementioned bisphenol-added group of cultured primary human keratinocytes at a final calcium concentration of 1.2 mmol / L significantly reduced nCi compared to the aforementioned bisphenol-free group (p < 0.01). Furthermore, it can be seen that, compared to the aforementioned bisphenol-added group, the aforementioned bisphenol-added / compound A-added group can recover the nCi reduction caused by the addition of bisphenol by pretreatment with compound A. Specifically, by setting the concentration of compound A to 0.1 to 1 μmol / L for pretreatment, the nCi reduction caused by the addition of bisphenol was statistically significantly recovered (p < 0.005). In summary, this suggests the ameliorative effect of compound A on bisphenol-induced epidermal cell adhesion damage.

[0089] [Example 3] Transcriptome analysis of an in vivo epidermal cell adhesion damage model: For the aforementioned compound A, a comprehensive evaluation of the transcriptome of the aforementioned epidermal cell adhesion damage model was conducted, specifically assessing the expression changes of gene transcription products. Gene expression changes were evaluated using a NextSeq500 / 550 sequencer by measuring changes in RNA counts or changes in RNA expression levels after normalization of RNA counts.

[0090] <Experimental Design and Data Analysis Method> Except as shown below, the cells were cultured under the same conditions as in Example 2 above to create the aforementioned epidermal cell adhesion damage model.

[0091] The following shows the experimental groups (1) to (3) of this embodiment. (1) Group 1 (control group): Calcium was added to the wells on Day 1 and cultured for 75 hours in the presence of a final calcium concentration of 1.2 mmol / L. This experimental group did not undergo bisphenol addition treatment and simulated keratinocytes in the presence of calcium. (2) Group 2 (bisphenol addition group): Calcium was added to the wells on Day 1 and cultured for 24 hours in the presence of a final calcium concentration of 1.2 mmol / L, followed by the addition of DMSO solution. After 3 hours of culture from the start of DMSO addition, bisphenol (final concentration 4 μmol / L) was added and cultured for 48 hours. This experimental group was designed to be exposed to bisphenol to simulate the conditions for the production of HHD. (3) Group 3 (compound A addition group): Calcium was added to the wells on Day 1 and cultured for 24 hours in the presence of a final calcium concentration of 1.2 mmol / L, followed by the addition of compound A (final concentration 1 μmol / L). Three hours after the addition of compound A, bisphenol (final concentration 4 μmol / L) was added, and the mixture was incubated for another 48 hours. This experimental group was designed to simulate the conditions under which compound A was introduced into a subject that produces HHD.

[0092] After the culture was completed, cells were collected from each experimental group described in (1) to (3) above, and whole RNA was extracted using Rneasy (registered trademark) Mini QIAcube column (Qiagen) according to the product operation instructions. All extracted RNA samples were DNase treated. Subsequently, using NanoDrop (Thermo Fisher Scientific) and Bioanalizer RNA6000 nanometer wafer (Agilent), the extracted RNA samples all showed a RIN value of 9.4 or higher and a total RNA amount of 1.3 μg or higher, confirming high quality.

[0093] Using the extracted whole RNA (10 ng) as a template, a cDNA library was created using NEBNext (registered trademark) Ultra II Directional RNA Library prep for Illumina (NEB Corporation), NEBNext (registered trademark) Poly(A) mRNA Magnetic Isolation Module (NEB Corporation), and NEBNext (registered trademark) Multiplex Oligos for Illumina (96 Unique Dual Index Primer Pairs, NEB Corporation) according to the operating instructions of each product.

[0094] Next, using the NextSeq 500 / 550 system (Illumina), the sequences of the aforementioned cDNA database were determined according to the product handling guidelines. Quality control was performed using FASTQC (version 0.12.1) and Trimmomatic-0.39, converting the data into FASTQ files.

[0095] Next, using StrandNGS software (version 4.0, Strand Life Science) and Star (version 2.7.10b), and referring to the human genome assembly and transcript annotations (version 101) obtained from the Ensembl database, the types of genes were identified from the 150-base sequence information contained in the aforementioned FASTQ files. Then, the expression levels of these transcripts were calculated. The expression levels of the transcripts were calculated using read counts and normalized TPM values.

[0096] The expression variation analysis used the DESeq2 (inter-group comparison suite) in the statistical analysis software R (version 4.3.2) to calculate the log2 ratio of RNA expression levels and to perform a significance test. The significance test was performed based on the p-value, which was calculated using the Wald test with multiple test correction according to the Benjamini-Hochberg method (BH method). In this analysis, genes with an absolute log2 ratio of 0.585 or higher (expression variation ratio of 1.5-fold or higher) or 0.263 or higher (expression variation ratio of 1.2-fold or higher), and whose p-value obtained from the Wald test between any two groups did not reach 0.1, were specifically defined as "expression variation genes" (expression variation genes; DEG). DEG includes both expression-increasing genes and expression-decreasing genes.

[0097] For the enrichment analysis of gene ontology, the ontological terms defined in the Gene Ontology database, the gene information associated with the ontological terms, and the DEG are compared. Then, based on the Fisher precision test with multiple validation correction using the BH method, ontological terms with p-values ​​less than 0.05 are considered significant, and the DEG is annotated. In this way, ontological terms related to biological functions associated with the DEG are identified.

[0098] The expression levels of transcripts in each experimental group were compared. As a result, in the comparison between the aforementioned group 1 and the aforementioned group 2, 4827 genes (log2 ratio ≥ 0.585; 2025 genes were added and 2802 genes were decreased in the aforementioned group 2, which is considered a pathological group) were identified as DEGs. Furthermore, in the comparison between the aforementioned group 2 and the aforementioned group 3, 1515 genes (log2 ratio ≥ 0.263; 538 genes were added and 977 genes were decreased in the group 3, which is considered a drug-added group) were identified as DEGs.

[0099] The results of enrichment analysis are shown in Tables 2 and 3. Table 2 shows the biological functional ontological terms that increase with bisphenol and decrease with compound A, and Table 3 shows the biological functional ontological terms that decrease with bisphenol and increase with compound A. Among the biological functional ontological terms associated with the obtained DEG, six ontological terms associated with DEG that decrease in the compound A addition group (group 3) compared to those that increase in the bisphenol addition group (group 2; pathological group) are identified (Table 2). Furthermore, ten ontological terms associated with DEG that increase in the compound A addition group (group 3) compared to those that decrease in the bisphenol addition group (group 2; pathological group) are identified (Table 3). These results suggest that the addition of bisphenol leads to activation of small endothelial (ER) stress and changes in Gorgistii function, and that compound A has an inhibitory effect on these changes. Furthermore, it suggests that the addition of bisphenol leads to inhibition of epidermal differentiation and fragility of intercellular adhesions, while compound A can normalize these changes. In summary, this suggests that compound A has a mitigating effect on bisphenol-induced damage to epidermal intercellular adhesions.

[0100] [Table 2] Ontological terms associated with DEG Bisphenol variation Comparison between Group 1 and Group 2 Compound A changes Comparison between Group 2 and Group 3 Direction of change Correction P value Direction of change Correction P value Response to endoplasmic reticulum pressure UP 3.708E-07 DOWN 3.576E-08 Response to topologically incorrect proteins UP 1.311E-04 DOWN 1.617E-05 Gaugid body vesicle transport UP 1.164E-03 DOWN 6.740E-04 Regulation of endoplasmic reticulum pressure response UP 1.604E-03 DOWN 7.435E-03 Intrinsic apoptosis signaling pathway in endoplasmic reticulum stress response UP 2.497E-03 DOWN 7.253E-03 Cellular response to topologically incorrect proteins UP 9.209E-03 DOWN 1.544E-02

[0101] [Table 3] Ontological terms associated with DEG Bisphenol variation Comparison between Group 1 and Group 2 Compound A changes Comparison between Group 2 and Group 3 Direction of change Correction P value Direction of change Correction P value Alcohol metabolism process DOWN 9.393E-12 UP 1.749E-05 Skin development DOWN 2.379E-08 UP 2.729E-32 Sterol biosynthesis process DOWN 1.873E-07 UP 6.905E-04 Epidermal development DOWN 1.783E-06 UP 1.825E-32 Keratinocyte differentiation DOWN 2.876E-05 UP 2.557E-32 Skin epidermal development DOWN 1.894E-04 UP 9.388E-04 Olefin metabolism DOWN 9.998E-04 UP 1.427E-03 Peptide crosslinking DOWN 1.525E-03 UP 1.331E-08 Regulation of peptidase activity DOWN 1.462E-02 UP 2.016E-04 Establishment of the skin barrier DOWN 4.822E-02 UP 2.016E-04

[0102] The present invention has been described above with reference to the embodiments and examples, but the present invention is not limited to the above embodiments and examples. Various modifications that are understandable to those skilled in the art can be made within the scope of the present invention in the structure and details thereof.

[0103] This application asserts priority based on Japanese Special Application No. 2024-104617, filed on June 28, 2024, and its entire disclosure is incorporated herein. [Industrial Applicability]

[0104] The pharmaceutical composition of the present invention, by comprising 5-methyl-2-(1-piperyl)benzenesulfonic acid, can be used for the treatment or prevention of familial benign chronic pemphigus. [Simplified Explanation of the Diagram]

[0012] Figure 1A shows the relationship between the administration of 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate in Example 1 and the expression of differentiation marker molecules in an in vitro HHD three-dimensional culture epidermal model. The vertical axis represents the relative gene expression level based on the gene expression level of keratinocytes at Day 0. Figure 1B shows the relationship between the administration of 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate in Example 1 and the expression of differentiation marker molecules in an in vitro HHD three-dimensional culture epidermal model. The vertical axis represents the inhibition rate of the increase in gene expression of differentiation markers induced by ATP2C1 siRNA treatment. Figure 2 shows the relationship between the administration of 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate in Example 2 and intercellular adhesion in an in vitro epidermal cell adhesion damage model.

Claims

1. Use of a 5-methyl-2-(1-piperyl)benzenesulfonic acid in the manufacture of pharmaceutical compositions for familial benign chronic pemphigus.

2. The use as described in claim 1, which is for inhibiting acantholysis in the aforementioned familial benign chronic pemphigus.

3. The use as described in claim 1 or 2, wherein, The aforementioned pharmaceutical composition is manufactured in such a manner that the dosage of the aforementioned 5-methyl-2-(1-piperyl)benzenesulfonic acid is 1 to 1000 mg / day.

4. The use as described in claim 1 or 2, wherein, 5-Methyl-2-(1-piperyl)benzenesulfonic acid is a monohydrate of 5-methyl-2-(1-piperyl)benzenesulfonic acid.

5. The use as described in claim 4, wherein, The dosage of 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate, converted to anhydrous 5-methyl-2-(1-piperyl)benzenesulfonic acid, is 1 to 1000 mg / day.

6. The use as described in claim 5, wherein, The dosage of 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate, converted to anhydrous 5-methyl-2-(1-piperyl)benzenesulfonic acid, is 50 to 600 mg / day.

7. The use as described in claim 6, wherein, The dosage of 5-methyl-2-(1-piperyl)benzenesulfonic acid monohydrate, converted to anhydrous 5-methyl-2-(1-piperyl)benzenesulfonic acid, is 100 to 400 mg / day.

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