Pharmaceutical composition containing sofpironium bromide

Abstract

To provide: means for suppressing a decrease in viscosity during long-term storage in a non-aqueous or low-water-content formulation for external application containing sofpironium bromide as an active ingredient; alternatively, a non-aqueous or low-water-content formulation of sofpironium bromide for external application in which a decrease in viscosity during long-term storage is suppressed, the sense of use for patients remains stable, and the formulation exhibits stable pharmaceutical properties; or alternatively, an external formulation of sofpironium bromide that exerts therapeutic effects on diseases involving acetylcholine (for example, primary focal hyperhidrosis).SOLUTION: A pharmaceutical formulation for external application to the human body surface in which a decrease in viscosity during long-term storage is suppressed contains sofpironium bromide, a water-soluble polymer, and ethanol, has a pH of 5.2 or less, and is a uniformly dispersed non-aqueous formulation or a low-water-content formulation having a water content of 5% or less.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical preparation containing sofpironium bromide as an active ingredient. [Background technology]

[0002] Pharmaceutical preparations must be provided in a physically and chemically stable form, and it is preferable that their properties, pharmaceutical characteristics, content of related substances, and purity of the active ingredient remain within certain ranges over a long period of time. In particular, in the case of topical preparations for external application, it is desirable that the pharmaceutical characteristics be stable over a long period of time from the viewpoints of handling and usability.

[0003] Acetylcholine is known as one of the major neurotransmitters in the body and has a variety of pharmacological actions, including the sweating action caused by the activation of sweat glands. Therefore, anticholinergic agents are useful for the treatment, therapy, or prevention of various acetylcholine-related diseases, such as hyperhidrosis.

[0004] Hyperhidrosis is a condition in which excessive sweating occurs on the palms, soles, armpits, etc. due to heat, mental stress, or other causes. This condition interferes with daily life (e.g., documents and notebooks get torn by sweat, people cannot hold hands with others due to concerns about sweat, underwear needs to be changed multiple times a day, and cell phones get wet and damaged) and significantly reduces quality of life (Non-Patent Document 1). Human sweat glands include eccrine and apocrine sweat glands, and the sweat that causes hyperhidrosis is secreted from the eccrine sweat glands (Non-Patent Document 2). Eccrine sweat glands are regulated by cholinergic nerves, and it is thought that acetylcholine induces sweating by stimulating M3-type muscarinic receptors located on the postsynaptic membrane of eccrine sweat glands (Non-Patent Document 3).

[0005] Hyperhidrosis is classified into generalized hyperhidrosis and focal hyperhidrosis depending on whether it occurs throughout the body or in a specific area of ​​the body, with focal hyperhidrosis often occurring on the palms, soles, and axillae. It is also classified as primary hyperhidrosis, which has no particular etiology, and secondary hyperhidrosis, which occurs in conjunction with other diseases (for example, systemic hyperhidrosis is caused by drugs or cardiovascular disease, while focal hyperhidrosis is caused by peripheral neuropathy, etc.). Therefore, primary axillary hyperhidrosis is a condition in which excessive sweating occurs in the armpits without a specific etiology, interfering with daily life.

[0006] An example of an anticholinergic agent for topical application that is useful for treating hyperhidrosis is soft glycopyrrolate (Patent Document 1). Soft glycopyrrolate is a derivative of the anticholinergic agent glycopyrrolate, and one representative soft glycopyrrolate is sofpironium bromide.

[0007] Sofpironium bromide has the following formula (I): [ka] (hereinafter, may be referred to as "BBI-4000" or "Compound (I)"), which is a quaternary ammonium bromide salt. Various topical formulations for topical application of sofpironium bromide have been reported.

[0008] Patent Document 2 discloses a topical formulation containing BBI-4000, ethanol, dimethiconol blend 20, and Klucel (registered trademark, hydroxypropyl cellulose, hereinafter also referred to as "HPC") (e.g., Table III), and reports that this formulation can be used to treat hyperhidrosis.

[0009] Patent Documents 3 and 4 disclose that in a formulation containing Dimethiconol Blend 20, a small amount of Dimethiconol Blend 20 coalesces as small droplets at the bottom of the container over time, and disclose a formulation containing BBI-4000, ethanol, isopropyl myristate (hereinafter also referred to as "IPM"), and hydroxypropyl cellulose (HPC) as a formulation in which droplets do not form (e.g., TABLE VIII).

[0010] In the design of topical formulations, the viscosity of the formulation is an important physical property because it affects the retention of the active ingredient in the affected area. If the formulation viscosity is not maintained appropriately, the drug cannot be retained in the affected area, resulting in dripping, adhesion to clothing, and other adverse effects on the patient's experience. Therefore, it is necessary to develop stable topical formulations that are both comfortable to use and whose properties, such as viscosity and spreadability, do not change significantly even after long-term storage.

[0011] Generally, water-soluble polymers such as cellulose-based polymers are added to topical preparations to impart viscosity, etc. However, the viscosity of topical preparations imparted by the water-soluble polymers may decrease over time due to decomposition of the polymers by light or heat. In particular, when a cellulose-based polymer is incorporated into a high-water content preparation, the viscosity stability is low, and the viscosity of the preparation may decrease over time. On the other hand, the phenomenon of viscosity decrease over time has not been reported in non-aqueous or low-water content preparations containing water-soluble polymers, and there is no prior knowledge on the circumstances under which viscosity decrease over time can be suppressed.

[0012] The above-mentioned Patent Documents 2, 3, and 4 disclose non-aqueous formulations containing sofpironium bromide and a water-soluble polymer, but do not disclose or suggest means for imparting high stability that enables long-term storage. Furthermore, they do not disclose or suggest highly stable low-water-content formulations containing sofpironium bromide and a water-soluble polymer. Furthermore, no means are known for maintaining the viscosity of non-aqueous or low-water-content formulations containing sofpironium bromide and a water-soluble polymer for a long period of time. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. WO2014 / 144075 [Patent Document 2] International Publication No. WO2015 / 138776 [Patent Document 3] International Publication No. WO2017 / 015485 [Patent Document 4] International Publication No. WO2018 / 017852 [Non-patent literature]

[0014] [Non-Patent Document 1] Journal of the Japanese Dermatological Association. 2015; 125: 1379-1400 [Non-patent document 2] Development and structure of sweat glands. MB Derma. 2014; 220: 9-12. [Non-patent document 3] Hyperhidrosis-Causes and treatment of enhanced sweating. Dtsch Arztebl Int. 2009; 106: 32-7. DISCLOSURE OF THE INVENTION [Problem to be solved by the invention]

[0015] One of the problems to be solved by the present invention is to provide a means for suppressing the decrease in viscosity during long-term storage in a non-aqueous or low-water-content preparation for topical application containing sofpironium bromide as an active ingredient. Another problem to be solved by the present invention is to provide a non-aqueous or low-water-content formulation of sofpironium bromide for topical application that inhibits viscosity loss during long-term storage, does not cause any change in the patient's sensation when used, and has stable formulation properties as a pharmaceutical. A further problem to be solved by the present invention is to provide an external preparation of sofpironium bromide that is effective in treating diseases involving acetylcholine (for example, primary localized hyperhidrosis, etc.). [Means for solving the problem]

[0016] The inventors have investigated long-term stable topical formulations of sofpironium bromide and found that in non-aqueous formulations of sofpironium bromide, the viscosity of the formulation imparted with a water-soluble polymer decreases over time. As mentioned above, there have been no reports of a decrease in viscosity over time in non-aqueous formulations or low-water-content formulations containing a water-soluble polymer, and it was completely unexpected that such a decrease in viscosity over time would occur in a non-aqueous formulation of sofpironium bromide. Since a decrease in formulation viscosity over time affects the patient's experience of use, it is desirable to avoid this problem. Therefore, the present inventors conducted extensive research to solve the above-mentioned problem, which was previously unknown in the art.

[0017] The inventors have investigated the factors that affect the stability of sofpironium bromide formulations and found that in non-aqueous formulations containing sofpironium bromide and a water-soluble polymer, the pH of the formulation has a significant impact on stability, and have demonstrated that the decrease in viscosity over time can be suppressed by maintaining the pH of the formulation at 5.2 or less.

[0018] Next, the present inventors conducted a detailed study on the effect of the water content in the formulation on the stability of sofpironium bromide formulations. Common technical knowledge would predict that increasing the water content would impair the stability of the formulation. However, surprisingly, they found that even in low-water-content formulations with a water content of 5% or less, maintaining the pH of the formulation at 5.2 or less minimizes the increase in related substances and inhibits viscosity loss over time. Furthermore, the present inventors discovered that the inhibitory effect on viscosity loss is independent of the type of additives, such as non-volatile oils and pH adjusters, and that maintaining the pH of the sofpironium bromide formulation at 5.2 or less results in a physically and chemically stable formulation.

[0019] The inventors further conducted their research and found that the above formulation is stable for a long period of time, has excellent properties as a pharmaceutical, and exhibits extremely excellent effects that can be applied clinically, thereby completing the present invention.

[0020] That is, the present invention includes the following inventions.

[01] A pharmaceutical preparation for topical application to a human body surface, comprising: (a) sofpironium bromide, (b) one or more water-soluble polymers; (c) ethanol; a pH of 5.2 or less, a uniformly dispersed non-aqueous formulation or a low-moisture formulation having a water content of 5 w / w% or less, The pH is measured at one or more selected time points within six months of preparation, the pH being determined by measuring the pH of the formulation stored at room temperature, and the pH being the value after immersing a pH electrode for non-aqueous solvents in the formulation for five minutes.

[0021]

[02] The formulation according to

[01] above, wherein the content of sofpironium bromide is 1 w / w% to 20 w / w% based on the total formulation amount.

[03] The formulation according to

[01] or

[02] , wherein the pH is within the range of 2.5 to 5.2.

[04] The preparation according to

[01] or

[02] above, which is a homogeneously dissolved preparation.

[0022]

[05] The formulation according to any one of

[01] to

[04] , wherein the water-soluble polymer is a water-soluble vinyl polymer-based polymer or a water-soluble cellulose-based polymer.

[06] The formulation of any one of

[01] to

[04] , wherein the water-soluble polymer is selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl copolymer, polyvinylpyrrolidone, and copovidone.

[0023]

[07] The formulation according to any one of

[01] to

[04] , wherein the water-soluble polymer is hydroxypropyl cellulose or carboxyvinyl polymer.

[08] The formulation according to any one of

[01] to

[07] , wherein the content of the water-soluble polymer is 0.01 w / w% to 5.0 w / w% of the total formulation amount.

[09] The formulation according to any one of

[01] to

[08] , wherein the ethanol content is 50 w / w% or more and less than 99 w / w% of the total formulation amount.

[0024]

[10] The formulation according to any one of

[01] to

[09] , further comprising a pH adjuster.

[11] The formulation according to

[10] above, wherein the pH adjuster is an acid selected from the group consisting of tartaric acid, acetic acid, and citric acid, or a salt thereof.

[12] The formulation according to

[10] or

[11] , wherein the content of the pH adjuster is 0.015 w / w% to 5 w / w% of the total formulation amount.

[0025]

[13] The formulation according to any one of

[01] to

[12] (excluding formulations containing dimethiconol blend 20), further containing a non-volatile oil.

[14] The formulation according to

[13] , wherein the non-volatile oil is selected from the group consisting of non-volatile esters, non-volatile ethers, non-volatile silicones, and non-volatile alcohols.

[0026]

[15] Non-volatile oils R1COOR2, wherein one of R1 and R2 is an optionally substituted C4-C 40 Straight chain alkyl group or optionally substituted C4-C 40 is a branched chain alkyl group, and The other of R1 and R2 is an optionally substituted C1-C 40 The formulation according to

[13] , wherein the alkyl group is a non-volatile ester selected from the group consisting of monoesters, diesters, and triesters.

[0027]

[16] Non-volatile oils include ethyl myristate, 2-octyldodecyl myristate, butyl stearate, isocetyl stearate, 2-octyldodecyl stearate, hexyl laurate, 2-hexyldecyl laurate, 2-ethylhexyl palmitate, 2-octyldecyl palmitate, cetearyl octanoate, isononyl isononanoate, octyldodecyl neopentanoate, 2-octyldodecyl erucate, and 2-octyl benzoate. Dodecyl, Decanoic Acid Ester, Ricinoleic Acid Ester, Isopropyl Myristate, Diisopropyl Adipate, Medium Chain Triglyceride, Isopropyl Palmitate, Alkyl Ethylhexanoate (C14-C18), Myristyl Myristate, Ethyl Oleate, Oleyl Oleate, Ethylhexyl Palmitate, Cetyl Palmitate, 2-Hexyldecyl Myristate, 2-Hexyldecyl Palmitate, PPG-3 Benzyl Myristate ether, isotridecyl isononanoate, triethylhexyl trimellitate, C12-C15 alkyl benzoate, diethoxyethyl succinate, propylene glycol dicaprate, propylene glycol dicaprylate, caprylic / capric triglyceride, triethylhexanoin, triisostearin, isopropyl isostearate, isostearyl isostearate, polyglyceryl-2 triisostearate, diethylhexyl succinate, PPG-2 myristyl propionate, pentaerythrityl tetraisostearate, diethyl sebacate, PPG-3 benzyl ether ethylhexanoate, glyceryl tribehenate, cetyl 2-ethylhexanoate, diisostearyl malate, 2-ethylhexyl stearate, triethylhexyl citrate, and alkyl lactates such as ethyl lactate.

[0028]

[17] The formulation described in

[13] above, wherein the non-volatile oil is a non-volatile fatty acid ester selected from the group consisting of isopropyl myristate, diisopropyl adipate, and medium-chain fatty acid triglycerides.

[18] The formulation according to

[13] , wherein the non-volatile oil is a non-volatile silicone selected from the group consisting of medical grade silicone oil, methylphenylsilicone, methylhydrogensilicone, decamethylpentacyclosiloxane, octamethyltetracyclosiloxane, cyclomethicone 5-NF, PEG-12 dimethicone, dimethicone 20 cSt, dimethicone 100 cSt, dimethicone 350 cSt, dimethicone 500 cSt, dimethicone 1000 cSt, and dimethicone 12500 cSt.

[0029]

[19] The formulation according to

[13] , wherein the non-volatile oil is a non-volatile silicone selected from the group consisting of cyclomethicone 5-NF, PEG-12 dimethicone, dimethicone 20 cSt, and dimethicone 350 cSt.

[20] The formulation according to any one of

[13] to

[19] , wherein the content of the non-volatile oil is 0.5 w / w% to 10 w / w% of the total formulation amount.

[0030]

[21] The formulation according to any one of

[01] to

[20] , further comprising a polyhydric alcohol.

[22] The formulation according to

[21] above, wherein the polyhydric alcohol is selected from the group consisting of hexylene glycol, propylene glycol, ethylene glycol, glycerol, and butylene glycol.

[23] The formulation according to

[21] or

[22] , wherein the content of the polyhydric alcohol is 1.0 w / w% to 30 w / w% of the total formulation amount.

[0031]

[24] The formulation according to any one of

[01] to

[23] , having a viscosity at 25°C of 10 mPa·s to 2000 mPa·s.

[25] The formulation according to any one of

[01] to

[24] , wherein the viscosity at 25°C is 10 mPa·s to 1000 mPa·s after storage at room temperature for 36 months or at 40°C for 3 months.

[0032]

[26] The formulation according to any one of

[01] to

[25] above, for treating, treating, or preventing a disease selected from the group consisting of hyperhidrosis, overactive bladder, chronic obstructive pulmonary disease, heart disease, sialorrhea, eye disease, and bronchial asthma.

[0033]

[27] After storage at room temperature for 36 months or at 40°C for 3 months, the following formula (II): [ka] The content of compound (II) represented by the formula (II) is 1.5 w / w% or less relative to the content of sofpironium bromide, and the purity of sofpironium bromide is 90 w / w% or more.

[0034]

[28] Any one of the preparations

[01] to

[27] above, which contains sofpironium bromide as an active ingredient and is administered topically to both axillae once a day, for treating, curing, or preventing primary axillary hyperhidrosis in which the total weight of sweat produced in both axillae for 5 minutes before treatment as measured by gravimetric measurement is 100 mg or more.

[29] The formulation described in

[28] above, characterized by being applied topically for a treatment period of at least 6 weeks, for use in treating, curing, or preventing primary axillary hyperhidrosis in which the total weight of sweat produced in both axillae over a 5-minute period before treatment is 400 mg or more as measured by gravimetric measurement. [Effects of the Invention]

[0035] According to the present invention, by maintaining the pH of a non-aqueous or low-water-content formulation containing sofpironium bromide and a water-soluble polymer at 5.2 or less, it is possible to suppress the decrease in viscosity over time during long-term storage, and to provide a topical formulation with excellent properties as a pharmaceutical composition. [Brief explanation of the drawings]

[0036] [Figure 1]Test Example 7: Time course of a confirmatory study of BBI-4000 in patients with primary axillary hyperhidrosis. In the figure, *1 Baseline includes three time points, Baseline 1 to 3, and *2 End of treatment includes three time points, Week 6, 1 to 3. DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention will be described in detail below. The formulation of the present invention is a topical formulation containing sofpironium bromide as an active ingredient. The content of sofpironium bromide in the formulation of the present invention is not particularly limited, but is preferably 1 w / w% to 30 w / w%, more preferably 1 w / w% to 20 w / w%, and even more preferably 5 w / w% to 15 w / w%. In one embodiment of the present invention, the particularly preferred content of sofpironium bromide is 5 w / w% based on the total amount of the formulation. In another embodiment of the present invention, the particularly preferred content of sofpironium bromide is 10 w / w% based on the total amount of the formulation. In another embodiment of the present invention, the particularly preferred content of sofpironium bromide is 15 w / w% based on the total amount of the formulation. In this specification, when a range is stated as "from A to B," "AB," or "A to B," the range also includes the numerical values ​​at the ends unless otherwise specified.

[0038] The formulation of the present invention is not particularly limited as long as it is a pharmaceutical formulation for external application to the surface of the human body, and includes liquids, lotions, ointments, creams, and gels. The formulation of the present invention is preferably a liquid or gel, more preferably a liquid.

[0039] The formulation of the present invention contains sofpironium bromide as an active ingredient, and by topical administration to the surface of the human body, can be used as a medicine for the treatment, therapy, or prevention of various diseases associated with the action of acetylcholine.

[0040] As used herein, "body surface" refers to the surface of human skin, etc. Specifically, it refers to the skin surfaces of the limbs, body, and head, etc., and more specifically refers to the skin surfaces of the palms, head, face, shoulders, chest, buttocks, abdomen, back, pubic area, armpits, etc., as well as hair, nails, etc. According to one embodiment of the present invention, the body surface (application site) suitable for application is not particularly limited, but is preferably, for example, the skin surface, and particularly preferably the skin surface of the armpits, etc.

[0041] As used herein, the terms "topical administration" or "external application" refer to the application of a pharmaceutical preparation to a lesion on the surface of the human body or to the area surrounding the lesion. In one embodiment of the invention, the formulation of the invention is an external solution for applying the drug to the axilla. In another embodiment of the present invention, the formulation of the present invention is an external solution for applying the drug to the palm of the hand. In another embodiment of the present invention, the formulation of the present invention is an external solution for applying the drug to the body. In general, in primary localized hyperhidrosis, excessive sweating occurs symmetrically on the head, face, palms, soles, axillae, etc. Therefore, the preparation of the present invention is preferably an external preparation to be applied to both axillae and palms, but when excessive sweating occurs in one axilla or one palm, the preparation of the present invention can also be applied to that axilla or palm.

[0042] As used herein, the term "uniformly dispersed" refers to a formulation whose composition is uniform, balanced, and stable. Specifically, this term refers to a formulation in which separation of liquid phases, generation of droplets, precipitation of formulation components or other components, etc. does not occur under normal storage conditions (e.g., at room temperature for a storage period of 3 years, etc.), and includes, for example, a formulation in which the formulation is uniformly dissolved. The formulation of the present invention is a formulation in which the components of the formulation are uniformly dispersed, and can be stably stored under normal storage conditions without generating oil droplets or the like. The preparation of the present invention is preferably a homogeneously dissolved preparation, more preferably a homogeneously dissolved and clear preparation. Furthermore, the formulation of the present invention does not undergo discoloration or deterioration over time, a large increase or decrease in the content of the active ingredient, or a large increase in related substances, which would deviate from pharmaceutical formulation standards, and there are no problems with microbiological quality, making it preferable as a pharmaceutical formulation.

[0043] As used herein, the term "water content" refers to the amount of water contained relative to the total amount of the formulation. As used herein, the term "nonaqueous preparation" refers to a preparation in which the water content is 0 w / w% or which is substantially free of water. As used herein, the term "preparation substantially free of water" refers to, for example, a preparation having a water content of 1 w / w % or less. As used herein, the term "low-water content preparation" refers to a preparation having a water content of 20 w / w% or less.

[0044] In one embodiment of the present invention, the water content of the formulation of the present invention is preferably 10 w / w% or less, more preferably 5 w / w% or less, even more preferably 3 w / w% or less, even more preferably 2 w / w% or less, and particularly preferably 1 w / w% or less. In one embodiment of the present invention, the water content of the formulation of the present invention is preferably 0.001 w / w% to 10 w / w%, more preferably 0.001 w / w% to 5 w / w%, and even more preferably 0.001 w / w% to 3 w / w%. In another embodiment of the present invention, the formulation of the present invention is preferably a non-aqueous formulation or a low-moisture formulation with a moisture content of 5 w / w% or less, more preferably a non-aqueous formulation or a low-moisture formulation with a moisture content of 3 w / w% or less, even more preferably a non-aqueous formulation or a low-moisture formulation with a moisture content of 2 w / w% or less, even more preferably a non-aqueous formulation or a low-moisture formulation with a moisture content of 1 w / w% or less, and particularly preferably a non-aqueous formulation.

[0045] In another embodiment of the present invention, the formulation of the present invention is preferably a non-aqueous formulation or a low-moisture formulation having a moisture content of 0.001 w / w% to 5 w / w%, more preferably a non-aqueous formulation or a low-moisture formulation having a moisture content of 0.001 w / w% to 3 w / w%, even more preferably a non-aqueous formulation or a low-moisture formulation having a moisture content of 0.001 w / w% to 2 w / w%, even more preferably a non-aqueous formulation or a low-moisture formulation having a moisture content of 0.001 w / w% to 1 w / w%, with a non-aqueous formulation being particularly preferred. In another embodiment of the present invention, the formulation of the present invention is preferably a low-water content formulation having a water content of 0.001 w / w% to 5 w / w%, more preferably a low-water content formulation having a water content of 0.002 w / w% to 3 w / w%, even more preferably a low-water content formulation having a water content of 0.005 w / w% to 2 w / w%, and even more preferably a low-water content formulation having a water content of 0.01 w / w% to 1 w / w%.

[0046] The water-soluble polymer contained in the preparation of the present invention is not particularly limited as long as it can be used as a pharmaceutical additive and can impart a certain level of viscosity to the preparation. A preferred water-soluble polymer is one that has a viscosity at 25°C in the range of 2.0 mPa·s to 2000 mPa·s in the case of a non-aqueous formulation containing 1.25 w / w% of the water-soluble polymer relative to the total formulation amount. Under the same conditions, the water-soluble polymer is preferably one having a viscosity in the range of 5.0 mPa·s to 1500 mPa·s, more preferably one having a viscosity in the range of 10 mPa·s to 1000 mPa·s, and even more preferably one having a viscosity in the range of 100 mPa·s to 800 mPa·s.

[0047] Specific examples of water-soluble polymers include cellulose-based polymers, vinyl polymer-based polymers, and acrylate polymer-based polymers. Specific examples of cellulose-based polymers include hydroxyalkyl celluloses (e.g., hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxybutyl cellulose), hydroxyalkyl alkyl celluloses (e.g., hydroxyethyl methyl cellulose (HEMC), hydroxypropyl methyl cellulose (HPMC)), alkyl celluloses (e.g., methyl cellulose), carboxymethyl cellulose, and cellulose esters (cellulose acetate).

[0048] Specific examples of vinyl polymer-based macromolecules include carboxyvinyl polymer, polyvinyl alcohol, polyvinyl copolymers (copolymers in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, etc.), polyvinylpyrrolidone (povidone), copovidone, and vinyl acetate resin. Specific examples of acrylate polymers include aminoalkyl methacrylate copolymers (e.g., aminoalkyl methacrylate copolymer RS) and ethyl acrylate-methyl methacrylate copolymers.

[0049] In the present invention, the preferred water-soluble polymer is a cellulose-based polymer. In one embodiment of the present invention, the cellulose-based polymer is preferably HMC, HEC, HPC, HEMC, HPMC, methyl cellulose, ethyl cellulose, or carboxymethyl cellulose, more preferably HEC, HPC, or HPMC, and even more preferably HPC. In another embodiment of the present invention, the cellulosic polymer is preferably a hydroxyalkyl cellulose or a hydroxyalkyl alkyl cellulose, more preferably a hydroxy C2-C4 alkyl cellulose or a hydroxy C2-C4 alkyl C1-C4 alkyl cellulose, and even more preferably a hydroxy C2-C4 alkyl cellulose.

[0050] "Hydroxyalkyl cellulose" refers to cellulose in which the hydroxyl groups of cellulose are substituted with a large number of hydroxyalkyl groups, and is a reaction product of cellulose with an alkylene oxide such as ethylene oxide or propylene oxide. "Hydroxy C2-C4 alkyl cellulose" refers to a hydroxyalkyl cellulose in which the carbon number of the hydroxyalkyl group is 2 to 4. Specific examples include hydroxyethyl cellulose (HEC) and hydroxypropyl cellulose (HPC). "Hydroxyalkyl alkyl cellulose" refers to cellulose in which the hydroxyl groups of cellulose are substituted with multiple alkyl and hydroxyalkyl groups. "Hydroxy C2-C4 alkyl C1-C4 alkyl cellulose" refers to hydroxyalkyl alkyl cellulose in which the hydroxyalkyl group has 2 to 4 carbon atoms and the alkyl group has 1 to 4 carbon atoms. Specific examples of these include hydroxypropyl methylcellulose (HPMC).

[0051] In one embodiment of the present invention, the content of the water-soluble polymer is not particularly limited, but is preferably 0.01 w / w% to 5.0 w / w%, more preferably 0.1 w / w% to 2.5 w / w%, even more preferably 0.5 w / w% to 2.0 w / w%, even more preferably 1.0 w / w% to 1.5 w / w%, and particularly preferably 1.25 w / w% relative to the total formulation amount.

[0052] In one embodiment of the present invention, the water-soluble polymer is preferably 0.01 w / w% to 5.0 w / w% HEC, HPC, or HPMC, more preferably 0.1 w / w% to 2.5 w / w% HEC, HPC, or HPMC, even more preferably 0.5 w / w% to 2.0 w / w% HEC, HPC, or HPMC, still more preferably 1.0 w / w% to 1.5 w / w% HEC, HPC, or HPMC, particularly preferably 1.25 w / w% HEC, HPC, or HPMC, still more preferably 1.0 w / w% to 1.5 w / w% HEC, HPC, or HPMC, particularly preferably 1.25 w / w% HEC, HPC, or HPMC, still more preferably 1.0 w / w% or more to 1.5 w / w% or less HEC, HPC, or HPMC, and particularly preferably 1.25 w / w% HEC, HPC, or HPMC.

[0053] In one embodiment of the invention, the formulation of the invention contains ethanol as a solvent. As used herein, "ethanol" is a term that encompasses various grades of ethanol, including, for example, absolute ethanol and 95% ethanol. In one embodiment of the present invention, the preferred ethanol is 95% ethanol. In another embodiment of the present invention, the preferred ethanol is absolute ethanol. In one embodiment of the present invention, the preferred ethanol content is 30 w / w% to 95 w / w% of the total formulation weight, more preferably 50 w / w% to 90 w / w%, even more preferably 60 w / w% to 85 w / w%, and even more preferably 70 w / w% to 85 w / w%. In another embodiment of the present invention, the preferred content of ethanol is 60 w / w% to 95 w / w%, more preferably 60 w / w% to 90 w / w%, and even more preferably 60 w / w% to 85 w / w% based on the total formulation weight.

[0054] In this specification, pH refers to the value measured after immersing a pH electrode for non-aqueous solvents in the test preparation for 5 minutes. Examples of pH electrodes for non-aqueous solvents include pH electrodes for low electrical conductivity water / non-aqueous solvents (pH electrodes that can be used for both low electrical conductivity water and non-aqueous solvents). In this specification, for example, pH refers to the value measured after immersing a low-electrical conductivity pH electrode for aqueous and non-aqueous solvents, calibrated using a pH standard solution, in 10.0 g of a test preparation for 5 minutes. pH measurement using a low-electrical conductivity pH electrode for aqueous and non-aqueous solvents is explained in the 17th Revised Japanese Pharmacopoeia Commentary (Hirokawa Shoten), and measurements were performed in this test in accordance with the Japanese Pharmacopoeia. Low-electrical conductivity pH electrodes for aqueous and non-aqueous solvents are readily available commercially, for example, from Horiba Advanced Techno Co., Ltd. pH measurements can be performed using the electrode at temperatures ranging from approximately 0 to 60°C, preferably from 1 to 30°C, and more preferably from 20 to 30°C. Here, "immersing the pH electrode" refers to a state in which the liquid junction of the pH electrode is completely immersed in the test preparation so that the pH can be measured accurately.

[0055] In one embodiment of the present invention, the time point at which pH is measured in the present invention is not particularly limited. That is, unless otherwise noted, the time point of measurement may include pH at all time points, such as pH immediately after preparation of the formulation, pH 1 month after preparation, pH 2 months after preparation, pH 3 months after preparation, pH 6 months after preparation, pH 12 months after preparation, pH 24 months after preparation, or pH 36 months after preparation. In one embodiment of the present invention, the formulation of the present invention has a pH of 5.2 or less when prepared, a pH of 5.2 or less 1 month after preparation, a pH of 5.2 or less 2 months after preparation, a pH of 5.2 or less 3 months after preparation, a pH of 5.2 or less 6 months after preparation, a pH of 5.2 or less 12 months after preparation, a pH of 5.2 or less 18 months after preparation, a pH of 5.2 or less 24 months after preparation, or a pH of 5.2 or less 36 months after preparation. In one embodiment of the present invention, the formulation of the present invention has a pH range of 2.5 to 5.2 when prepared, a pH range of 2.5 to 5.2 1 month after preparation, a pH range of 2.5 to 5.2 2 months after preparation, a pH range of 2.5 to 5.2 3 months after preparation, a pH range of 2.5 to 5.2 6 months after preparation, a pH range of 2.5 to 5.2 12 months after preparation, a pH range of 2.5 to 5.2 18 months after preparation, a pH range of 2.5 to 5.2 24 months after preparation, or a pH range of 2.5 to 5.2 36 months after preparation. In one embodiment of the present invention, the formulation of the present invention has a pH in the range of 2.5 to 5.2 when prepared, a pH in the range of 2.5 to 5.2 1 month after preparation, a pH in the range of 2.5 to 5.2 2 months after preparation, a pH in the range of 2.5 to 5.2 3 months after preparation, a pH in the range of 2.5 to 5.2 6 months after preparation, a pH in the range of 2.5 to 5.2 12 months after preparation, a pH in the range of 2.5 to 5.2 18 months after preparation, a pH in the range of 2.5 to 5.2 24 months after preparation, or a pH in the range of 2.5 to 5.2 36 months after preparation when the formulation is stored at room temperature. In each of the above embodiments, it is sufficient that the pH at any one time point satisfies the above condition, but it is preferable that the pH at two or more time points satisfies the condition, and it is particularly preferable that the pH at all time points satisfies the above condition.

[0056] In one embodiment of the invention, the pH of a formulation of the invention is determined by measuring the pH of the formulation at one or more selected time points over a six month period after preparation and stored at room temperature. In one embodiment of the present invention, the pH of the formulation of the present invention is determined by measuring the pH of the formulation at one or more selected time points within six months after preparation and stored at room temperature between preparation and measurement. In one embodiment of the present invention, the pH of the formulation of the present invention is determined by measuring the pH of the formulation at one or more selected time points within one month after preparation and stored at room temperature between preparation and measurement. The pH of the formulation of the present invention is 5.2 or less, preferably 2.5 to 5.2, more preferably 3.0 to 5.2, and even more preferably 3.0 to 5.0. In one embodiment of the present invention, the pH determined by measuring the pH of the formulation stored at room temperature between preparation and measurement at one or more time points selected within six months after preparation is 5.2 or less, preferably 2.5 to 5.2, more preferably 3.0 to 5.2, and even more preferably 3.0 to 5.0. In this specification, room temperature refers to a temperature between 1°C and 30°C.

[0057] The pH of the formulations of the present invention is maintained below 5.2, preferably between 2.5 and 5.2. In one embodiment of the present invention, more preferred formulations of the present invention are maintained at a pH of 2.5 to 5.0, and even more preferred formulations of the present invention are maintained at a pH of 2.5 to 4.5. In another embodiment of the present invention, preferred formulations of the present invention are maintained at a pH of 3.0 to 5.2, more preferred formulations of the present invention are maintained at a pH of 3.0 to 5.0, and even more preferred formulations of the present invention are maintained at a pH of 3.0 to 4.5.

[0058] In one embodiment of the present invention, more typically, the pH of the formulation of the present invention refers to the highest pH value during the storage period of the formulation. For example, when it is described that the pH is "5.2 or less", it means that the highest pH value during the storage period of the formulation is 5.2 or less, in other words, it means that the pH is maintained at 5.2 or less during the storage period. In one embodiment of the present invention, when the formulation of the present invention is prepared and stored at 40°C for 3 months, the pH is maintained within a range of 2.5 to 5.2, preferably 2.5 to 5.0, and more preferably 2.5 to 4.5 for 3 months after preparation. In another embodiment of the present invention, when the formulation of the present invention is prepared and stored at room temperature for 36 months after preparation, the pH is maintained at 5.2 or less, preferably 5.0 or less, and more preferably 4.8 or less for 36 months after preparation. In another embodiment of the present invention, the formulation of the present invention maintains a pH of 2.5 to 5.2, preferably 3.0 to 5.2, and more preferably 3.0 to 5.0, for 36 months after preparation when stored at room temperature for 36 months after preparation. In another embodiment of the present invention, when the formulation of the present invention is prepared and stored at room temperature for 24 months after preparation, the pH is maintained at 5.2 or less, preferably 5.0 or less, and more preferably 4.8 or less for 24 months after preparation. In another embodiment of the present invention, the formulation of the present invention maintains a pH of 2.5 to 5.2, preferably 3.0 to 5.2, and more preferably 3.0 to 5.0, for 24 months after preparation when stored at room temperature for 24 months after preparation. In another embodiment of the present invention, when the formulation of the present invention is prepared and stored at room temperature for 12 months after preparation, the pH is maintained at 5.2 or less, preferably 5.0 or less, and more preferably 4.8 or less for 12 months after preparation. In another embodiment of the present invention, the formulation of the present invention maintains a pH of 2.5 to 5.2, preferably 3.0 to 5.2, and more preferably 3.0 to 5.0, for 12 months after preparation when stored at room temperature for 12 months after preparation. In another embodiment of the present invention, when the formulation of the present invention is prepared and stored at room temperature for 6 months, the pH is maintained at 5.2 or less, preferably 5.0 or less, and more preferably 4.8 or less for 6 months after preparation. In another embodiment of the present invention, the formulation of the present invention maintains a pH of 2.5 to 5.2, preferably 3.0 to 5.2, and more preferably 3.0 to 5.0, for 6 months after preparation when stored at room temperature for 6 months after preparation. In another embodiment of the present invention, the pH of the formulation of the present invention is maintained at 3.0 to 5.2, preferably 3.0 to 5.0, more preferably 3.0 to 4.8, and even more preferably 3.0 to 4.5, for 3 months after preparation when stored at 40°C for 3 months after preparation.

[0059] The formulation of the present invention may further contain a pH adjuster to maintain the pH within the above-mentioned preferred range. The pH adjuster is not particularly limited as long as it can be used as a pharmaceutical additive, and examples thereof include inorganic acids, inorganic acid salts, organic acids, and organic acid salts.

[0060] The inorganic acid refers to, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydroiodic acid, and the like. The inorganic acid salts include, for example, ammonium chloride, potassium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, and the like.

[0061] An organic acid means that the acid has at least one carbon atom in its chemical structure, and typically refers to a monovalent organic acid, a divalent organic acid, or a trivalent organic acid. Specific examples of organic acids include organic carboxylic acids such as acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tannic acid, butyric acid, valeric acid, hybenzic acid, pamoic acid, enanthic acid, tartronic acid, decanoic acid, teoclic acid, salicylic acid, α-hydroxy acids, amino acids, and oxalic acid, and organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0062] Specific examples of α-hydroxy acids include glycolic acid, L-lactic acid, DL-lactic acid, D-lactic acid, malic acid, citric acid, L-tartaric acid, DL-tartaric acid, D-tartaric acid, mandelic acid, arabic acid, and gluconic acid. Specific examples of amino acids include glycine, alanine, glutamic acid, aspartic acid, phenylalanine, β-alanine, isoleucine, leucine, proline, glutamine, serine, threonine, valine, tryptophan, and tyrosine. In this specification, the term "citric acid" includes anhydrous citric acid, citric acid hydrate, and the like.

[0063] The pH adjusting agents listed above include all of their stereoisomers, geometric isomers, hydrates, anhydrates, solvates, and mixtures thereof. In one embodiment of the present invention, a preferred pH adjuster is an organic acid or a salt thereof, a more preferred pH adjuster is an α-hydroxy acid or a salt thereof, an even more preferred pH adjuster is citric acid or tartaric acid or a salt thereof, an even more preferred pH adjuster is anhydrous citric acid or D-tartaric acid or a salt thereof, and an especially preferred pH adjuster is anhydrous citric acid.

[0064] In one embodiment of the present invention, the content of the pH adjuster contained in the formulation is not particularly limited, but is preferably 0.015 w / w% to 5 w / w%, more preferably 0.025 w / w% to 1 w / w%, even more preferably 0.05 w / w% to 0.2 w / w%, and particularly preferably 0.05 w / w% or more to less than 0.1 w / w% of the total formulation amount. In one embodiment of the present invention, the preferred pH adjuster is anhydrous citric acid, preferably 0.015 w / w% to 5 w / w% of the total formulation weight, more preferably 0.015 w / w% to 1.0 w / w% of anhydrous citric acid, even more preferably 0.015 w / w% to 0.2 w / w% of anhydrous citric acid, particularly preferably 0.015 w / w% to 0.075 w / w% of anhydrous citric acid, and even more preferably 0.05 w / w% to 0.075 w / w% of anhydrous citric acid.

[0065] The formulations of the present invention may further contain a non-volatile oil. As used herein, the term "non-volatile oil" refers to a pharmaceutically acceptable non-volatile liquid or gel base, and specifically includes non-volatile esters, non-volatile silicones, non-volatile alcohols, non-volatile fatty acids, non-volatile ethers, and the like. The non-volatile oil is not particularly limited as long as it can be used as a pharmaceutical additive, can be formulated together with ethanol to form a uniformly dispersed or dissolved sofpironium bromide preparation, and does not cause an unpleasant feeling after application. Preferred non-volatile oils of the present invention are non-volatile esters, non-volatile silicones, or non-volatile ethers, more preferably non-volatile esters or non-volatile silicones.

[0066] In one embodiment of the present invention, the preferred non-volatile oils are non-volatile esters. The non-volatile ester refers to an ester oil that has one or more ester groups (—COO—) in one molecule and has no volatility. Preferred nonvolatile esters of the present invention include esters having a linear or branched alkyl group having 4 or more carbon atoms. The nonvolatile esters in the present invention include all of monoesters, diesters, and triesters. The term "monoester" refers to an ester having one ester group in one molecule, a "diester" refers to an ester having two ester groups in one molecule, and a "triester" refers to an ester having three ester groups in one molecule. In this specification, the terms "monoester," "diester," and "triester" refer to non-volatile monoesters, non-volatile diesters, and non-volatile triesters.

[0067] In one embodiment of the present invention, the non-volatile oil is represented by R1COOR2, wherein one of R1 and R2 is an optionally substituted C4-C 40Straight chain alkyl group or optionally substituted C4-C 40 a branched alkyl group, and the other of R1 and R2 is an optionally substituted C1-C 40 a non-volatile ester selected from the group consisting of an alkyl group, a monoester, a diester, or a triester; In another embodiment of the present invention, a preferred non-volatile oil is represented by R1COOR2, where R1 is a C4-C alkyloxycarbonyl group optionally substituted with a hydroxyl group or a C1-C4 alkyloxycarbonyl group. 40 Straight chain alkyl group or C4-C 40 A branched alkyl group, and R2 is a hydroxyl group or a C1-C 40 The non-volatile ester is selected from the group consisting of a monoester, diester, or triester, which is a C1-C4 alkyl group optionally substituted with an alkyloxycarbonyl group.

[0068] In another embodiment of the present invention, preferred non-volatile esters are represented by R1COOR2, where R1 is a C4-C alkyloxycarbonyl group optionally substituted with a C1-C4 alkyloxycarbonyl group. 40 is a straight chain alkyl group and R2 is C1-C 22 The non-volatile ester is selected from the group consisting of a monoester, diester, or triester, which is a C1-C4 alkyl group optionally substituted with an alkylcarbonyloxy group.

[0069] "C4-C 40 The term "straight-chain alkyl group" refers to a straight-chain alkyl group having 4 to 40 carbon atoms, such as a normal butyl group, a normal pentyl group, a normal hexyl group, a normal heptyl group, a normal octyl group, a normal nonyl group, a normal undecyl group, a normal dodecyl group, a normal tridecyl group, a normal tetradecyl group, a normal pentadecyl group, a normal hexadecyl group, a normal heptadecyl group, or a normal octadecyl group. "C4-C 40 "Branched chain alkyl group" refers to a branched chain alkyl group having from 4 to 40 carbon atoms. The term "C1-C4 alkyl group" refers to an alkyl group having 1 to 4 carbon atoms, including straight-chain alkyl groups and branched-chain alkyl groups. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl groups. "C1-C 40 "Alkyl group" refers to an alkyl group having 1 to 40 carbon atoms, including C4-C 40 Straight chain alkyl groups, C4-C 40 Branched chain alkyl groups include C1-C4 alkyl groups.

[0070] The term "optionally substituted" means that any one or more hydrogen atoms may be replaced with a substituent other than hydrogen, such as a hydroxyl group, a C1-C4 alkyloxycarbonyl group, or a C4-C 40 It may be substituted with an alkylcarbonyloxy group.

[0071] The term "C1-C4 alkyloxycarbonyl group" refers to an alkyloxycarbonyl group in which the alkyl portion is the above-mentioned C1-C4 alkyl group, such as a methyloxycarbonyl group, an ethyloxycarbonyl group, or a normal propyloxycarbonyl group. "C1-C 40 The term "alkylcarbonyloxy group" refers to a group in which the alkyl portion is one of the C1-C 40 It means an alkylcarbonyloxy group, which is an alkyl group, such as a normal butylcarbonyloxy group, a normal hexylcarbonyloxy group, a normal heptylcarbonyloxy group, or a normal octylcarbonyloxy group.

[0072] "Optionally substituted C4-C 40 straight-chain alkyl group, optionally substituted C4-C 40 The substituents of the "branched alkyl group" and "optionally substituted C1-C4 alkyl group" are a hydroxyl group, a C1-C4 alkyloxycarbonyl group, or a C4-C 40 These may be substituted one or more times at any position.

[0073] In one embodiment of the present invention, specific examples of preferred monoesters include ethyl myristate, 2-octyldodecyl myristate, butyl stearate, isocetyl stearate, 2-octyldodecyl stearate, hexyl laurate, 2-hexyldecyl laurate, 2-ethylhexyl palmitate, 2-octyldecyl palmitate, cetearyl octanoate, isononyl isononanoate, octyldodecyl neopentanoate, 2-octyldodecyl erucate, 2-octyldodecyl benzoate, decanoic acid esters, ricinoleic acid esters, isopropyl myristate, isopropyl palmitate, alkyl ethylhexanoate (C 14 -C 18 ), myristyl myristate, ethyl oleate, oleyl oleate, ethylhexyl palmitate, cetyl palmitate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, PPG-3 benzyl ether myristate, isotridecyl isononanoate, alkyl benzoate (C 12 -C 15 ), isopropyl isostearate, isostearyl isostearate, PPG-2 myristyl propionate, cetyl 2-ethylhexanoate, 2-ethylhexyl stearate, medium-chain fatty acid monoglycerides, or alkyl lactates such as ethyl lactate. A more preferred monoester of the present invention is isopropyl myristate.

[0074] In one embodiment of the present invention, preferred diesters of the present invention include diisopropyl adipate, di-n-propyl adipate, dioctyl adipate, bis(2-ethylhexyl) adipate, diisostearyl adipate, medium-chain fatty acid diglycerides, or diethyl sebacate. A more preferred diester of the present invention is diisopropyl adipate.

[0075] In one embodiment of the present invention, specific examples of preferred triesters of the present invention include triisostearyl citrate, trioctyldodecyl citrate, trioleyl citrate, glyceryl trioctanoate, triethyl citrate, or medium-chain fatty acid triglycerides. The more preferred triesters of the present invention are medium chain triglycerides.

[0076] As used herein, medium-chain fatty acid triglyceride refers to a non-volatile component in which one molecule of glycerol is ester-bonded with three molecules of fatty acid, and the fatty acid is a saturated fatty acid having 6 to 14 carbon atoms. The fatty acid preferably has 8 to 12 carbon atoms, and examples thereof include caprylic acid, capric acid, and lauric acid. Preferred medium-chain fatty acid triglycerides include caprylic acid triglyceride, capric acid triglyceride, a mixture of triglycerides of caprylic acid and capric acid, a mixture of triglycerides of caprylic acid, capric acid, and lauric acid, and tri(caprylic acid / capric acid)glyceride. For example, Miglyol (registered trademark) 810 and 812 can be used. A preferred medium chain triglyceride of the present invention is caprylic / capric triglyceride.

[0077] In this specification, a medium-chain fatty acid diglyceride is a non-volatile diester in which two molecules of fatty acid are ester-bonded to one molecule of glycerol, and a medium-chain fatty acid monoglyceride is a non-volatile monoester in which one molecule of fatty acid is ester-bonded to one molecule of glycerol.

[0078] In one embodiment of the present invention, the non-volatile oil may be a non-volatile silicone. Specific examples of preferred non-volatile silicones include dimethicone, Silastic®, medical grade silicone oil, methylphenyl silicone, methylhydrogen silicone, decamethylpentacyclosiloxane, octamethyltetracyclosiloxane, dimethylpolysiloxane, methylphenylpolysiloxane, cyclomethicone 5-NF, PEG-12 dimethicone, dimethicone 20 cSt, dimethicone 100 cSt, dimethicone 350 cSt, dimethicone 500 cSt, dimethicone 1000 cSt, and dimethicone 12500 cSt. More preferred non-volatile silicones of the present invention include cyclomethicone 5-NF, PEG-12 dimethicone, dimethicone 20 cSt, or dimethicone 350 cSt.

[0079] In one embodiment of the invention, the formulations of the invention may contain two or more non-volatile oils. When the formulation of the present invention contains two or more non-volatile oils, it is preferred that the formulation contains two or more non-volatile esters selected from the preferred non-volatile esters listed above. For example, a formulation of the present invention may contain two monoesters, a monoester and a diester, a monoester and a triester, two diesters, a diester and a triester, two triesters, a monoester and a non-volatile silicone, a diester and a non-volatile silicone, a triester and a non-volatile silicone, or two non-volatile silicones.

[0080] The non-volatile oil content of the present invention is preferably 0.1 w / w% to 50 w / w% of the total formulation, more preferably 0.2 w / w% to 25 w / w%, even more preferably 0.5 w / w% to 10 w / w%, even more preferably 1.0 w / w% to 5.0 w / w%, and particularly preferably 2.5 w / w%.

[0081] In one embodiment of the present invention, the preferred non-volatile oil is isopropyl myristate, diisopropyl adipate, or medium-chain triglyceride in an amount of 0.1 w / w % to 50 w / w % based on the total formulation weight. In one embodiment of the present invention, more preferred non-volatile oils are isopropyl myristate, diisopropyl adipate, or medium-chain fatty acid triglycerides in an amount of 0.5 w / w% to 10 w / w% based on the total formulation weight. In one embodiment of the present invention, a more preferred non-volatile oil is isopropyl myristate, diisopropyl adipate, or medium-chain triglyceride in an amount of 1.0 w / w% to 5.0 w / w% based on the total formulation weight.

[0082] In one embodiment of the present invention, the formulation of the present invention may further comprise a polyhydric alcohol. In this specification, the term "polyhydric alcohol" refers to a compound in which multiple hydrogen atoms at any position of a hydrocarbon or ether are substituted with hydroxyl groups. The polyhydric alcohol is not particularly limited as long as it can be used as an additive for pharmaceuticals, and examples thereof include hexylene glycol (HG), propylene glycol (PG), ethylene glycol, glycerol, butylene glycol (BG), glycerin, etc.

[0083] In this specification, the term "glycerin" includes concentrated glycerin (cGly) and the like. In one embodiment of the present invention, preferred polyhydric alcohols are C2-C 10 It is a compound in which two or three hydrogen atoms at any position of the hydrocarbon are replaced by hydroxyl groups. In one embodiment of the present invention, preferred polyhydric alcohols are compounds in which two or three hydrogen atoms at any position of a C2-C6 hydrocarbon are substituted with hydroxyl groups. In one embodiment of the present invention, the preferred polyhydric alcohol is hexylene glycol, butylene glycol, or glycerin.

[0084] The content of polyhydric alcohol in the present invention is preferably 0.1 w / w% to 50 w / w% of the total formulation, more preferably 0.5 w / w% to 40 w / w%, even more preferably 1.0 w / w% to 30 w / w%, even more preferably 2.0 w / w% to 20 w / w%, and particularly preferably 10 w / w%.

[0085] In one embodiment of the present invention, the preferred polyhydric alcohol is hexylene glycol, butylene glycol, or glycerin in an amount of 0.1 w / w% to 50 w / w% based on the total formulation weight. In one embodiment of the present invention, the more preferred polyhydric alcohol is hexylene glycol, butylene glycol, or glycerin in an amount of 1.0 w / w% to 30 w / w% based on the total formulation weight. In one embodiment of the present invention, the more preferred polyhydric alcohol is hexylene glycol, butylene glycol, or glycerin in an amount of 2.0 w / w% to 20 w / w% based on the total formulation weight.

[0086] As used herein, "viscosity" is synonymous with consistency and indicates the resistance of a liquid to flow. As used herein, "viscosity of a formulation" refers to the viscosity at 25°C unless otherwise specified. Viscosity can generally be easily measured by the method described in the general testing methods of the Japanese Pharmacopoeia, as well as by testing methods commonly used by those skilled in the art. For example, viscosity can be measured by the viscosity measurement method shown in the following examples. In one embodiment of the present invention, the viscosity of the formulation of the present invention at 25°C is preferably from 10 mPa·s to 2000 mPa·s, more preferably from 100 mPa·s to 1500 mPa·s. In another embodiment of the present invention, the viscosity of the formulation of the present invention is preferably from 10 mPa·s to 1000 mPa·s at 25° C., more preferably from 100 mPa·s to 800 mPa·s. In another embodiment of the present invention, the viscosity of the formulation of the present invention is preferably from 10 mPa·s to 800 mPa·s at 25°C, more preferably from 50 mPa·s to 800 mPa·s.

[0087] As used herein, "at the time of preparation" refers to the time when the formulation is prepared or immediately after. Unless otherwise specified, it is synonymous with the time when the product is prepared. Typically, it refers to within one week after preparation, preferably within five days after preparation, and more preferably within three days after preparation.

[0088] In this specification, the term "decrease in viscosity over time" refers in a broad sense to a phenomenon in which the viscosity of a formulation after storage for any period of time decreases by 30% or more compared to the viscosity at the time of preparation, and more narrowly to a phenomenon in which the viscosity decreases by 20% or more, 10% or more, or 5% or more. In one embodiment of the present invention, the decrease in viscosity over time in this specification refers to a phenomenon in which the viscosity after storage at room temperature for 6 months, 12 months, 24 months, or 36 months after preparation is lower than the viscosity at the time of preparation. Unless otherwise specified, the viscosity refers to the value measured at 25°C. In one embodiment of the present invention, the decrease in viscosity over time in this specification refers to a phenomenon in which the viscosity after storage at 40° C. for one month after preparation, the viscosity after storage at 40° C. for two months, or the viscosity after storage at 40° C. for three months is lower than the viscosity at the time of preparation. Unless otherwise specified, the viscosity refers to the value measured at 25° C.

[0089] In one embodiment of the present invention, the viscosity of the formulation of the present invention, after being prepared and stored at room temperature for 12 months, exhibits a change rate of viscosity within ±30%, preferably within ±20%, more preferably within ±10%, and even more preferably within ±5% of the viscosity at the time of preparation. In one embodiment of the present invention, the viscosity of the formulation of the present invention, after being prepared and stored at room temperature for 24 months, exhibits a change rate of within ±30% of the viscosity at the time of preparation, preferably within ±20%, more preferably within ±10%, and even more preferably within ±5%. In one embodiment of the present invention, the viscosity of the formulation of the present invention, after being prepared and stored at room temperature for 36 months, exhibits a change in viscosity within ±30%, preferably within ±20%, more preferably within ±10%, and even more preferably within ±5% of the viscosity at the time of preparation. In one embodiment of the present invention, the viscosity of the formulation of the present invention, after storage at 40°C for 3 months after preparation, exhibits a change in viscosity within ±30% of the viscosity at the time of preparation, preferably within ±20%, more preferably within ±10%, and even more preferably within ±5%.

[0090] The preparation of the present invention is stable for a long period of time and hardly produces any decomposition products during storage, making it suitable as a pharmaceutical product. In one embodiment of the present invention, the formulation of the present invention has a hydroxybenzoate of formula (II): [ka] The content of compound (II) represented by the formula (II) is 1.5 w / w% or less relative to the content of sofpironium bromide, and the purity of sofpironium bromide is 90 w / w% or more.

[0091] In another embodiment of the present invention, the formulation of the present invention has a compound (II) content of 1.5 w / w% or less relative to the sofpironium bromide content and a purity of 95 w / w% or more after storage at room temperature for 24 months from preparation, after storage at room temperature for 36 months from preparation, or after storage at 40°C for 3 months from preparation.

[0092] In another embodiment of the present invention, the formulation of the present invention has a compound (II) content of 1.5 w / w% or less relative to the sofpironium bromide content and a purity of 98 w / w% or more after storage at room temperature for 24 months from preparation, after storage at room temperature for 36 months from preparation, or after storage at 40°C for 3 months from preparation.

[0093] In another embodiment of the present invention, the formulation of the present invention has a compound (II) content of 0.4 w / w% or less relative to the sofpironium bromide content and a purity of 99.6 w / w% or more after storage at room temperature for 24 months from preparation, after storage at room temperature for 36 months from preparation, or after storage at 40°C for 3 months from preparation.

[0094] In another embodiment of the present invention, the formulation of the present invention, after storage at room temperature for 24 months after preparation, after storage at room temperature for 36 months after preparation, or after storage at 40°C for 3 months after preparation, has a compound (II) content of 1.5 w / w% or less relative to the sofpironium bromide content, a total content of impurities other than compound (II) of 1.0 w / w% or less relative to the sofpironium bromide content, and a purity of sofpironium bromide of 98 w / w% or more.

[0095] In another embodiment of the present invention, the formulation of the present invention, after storage at room temperature for 24 months after preparation, after storage at room temperature for 36 months after preparation, or after storage at 40°C for 3 months after preparation, has a compound (II) content of 1.5 w / w% or less relative to the sofpironium bromide content, a total content of impurities other than compound (II) of 0.5 w / w% or less relative to the sofpironium bromide content, and a purity of sofpironium bromide of 98 w / w% or more.

[0096] In another embodiment of the present invention, the formulation of the present invention, after storage at room temperature for 24 months after preparation, after storage at room temperature for 36 months after preparation, or after storage at 40°C for 3 months after preparation, has a compound (II) content of 0.4 w / w% or less relative to the sofpironium bromide content, a total content of impurities other than compound (II) of 0.4 w / w% or less relative to the sofpironium bromide content, and a purity of sofpironium bromide of 99.6 w / w% or more.

[0097] Next, the uses of the formulation of the present invention and typical examples of its use will be described. The formulation of the present invention can be used for the treatment, therapy, or prevention of diseases for which the anticholinergic effect of the active ingredient sofpironium bromide is expected to be effective, particularly primary hyperhidrosis, overactive bladder, chronic obstructive pulmonary disease, heart disease, sialorrhea, eye diseases, bronchial asthma, etc.

[0098] The preparation of the present invention can be preferably used for the treatment or prevention of hyperhidrosis, and more preferably for the treatment or prevention of localized hyperhidrosis. In one embodiment of the invention, the formulations of the invention can be used to treat, cure or prevent primary axillary hyperhidrosis. In another embodiment of the present invention, the formulations of the present invention can be used to treat, cure, or prevent primary palmar hyperhidrosis.

[0099] In one embodiment of the present invention, the topical application formulation of the present invention is used specifically to treat, cure, or prevent primary axillary hyperhidrosis, and a pharmaceutically acceptable formulation containing 1 w / w% to 15 w / w% sofpironium bromide, preferably 5 w / w% sofpironium bromide, is administered topically to the axilla, preferably both axillae, once daily for a treatment period of at least 6 weeks. [Example]

[0100] The formulations according to the present invention will be described in more detail below as examples along with each test example, although it is not intended that the present invention be limited to these examples.

[0101] [Test Example 1] Accelerated Test (1) of Sofpironium Bromide in Various Non-aqueous Preparations <Solution Preparation Method> The formulation components were stirred and dissolved in absolute ethanol to obtain the formulations with the composition components and concentrations shown in the table. The details of each formulation produced by this method are shown in the table below.

[0102] [Table 1] * IPM: Isopropyl Myristate, HG: Hexylene Glycol, D-TA: D-Tartaric Acid, DIA: Diisopropyl Adipate, MCT: Medium-chain Triglyceride, BG: Butylene Glycol, cGly: Concentrated Glycerin ** q.s. to 100: The balance is composed of absolute ethanol so that the total amount is 100%.

[0103] <Viscosity Measurement Method> The viscometer was set at 25 °C, 5 rpm, and a preheating time of 30 seconds. After rotating approximately 1 mL of this product with a cone rotor: R-H1°34’×R24 for 200 seconds, the value was measured (Japanese Pharmacopoeia Viscosity Measurement Method, Method 2).

[0104] [Table 2]

[0105] <pH Measurement Method> To suppress the variation in the pH value, the amount of the test preparation needs to be within a certain range with respect to the internal solution from the pH electrode. In the pH measurement of this test example, the amount of the test preparation was 10.0 g. For the calibration of the pH electrode, an oxalate pH standard solution, a phthalate pH standard solution, or a phosphate pH standard solution was used. The temperature difference between the pH standard solution used for calibration and the test preparation was ±2 °C, and the temperature of the preparation at the time of pH measurement was in the range of 20 to 30 °C. 10.0 g of the test preparation was weighed into a Maruem (registered trademark) No. 4 bottle, and a low-electrical conductivity pH electrode for aqueous and non-aqueous solvents calibrated using a pH standard solution was immersed in the preparation for 5 minutes and the value was measured.

[0106] [Table 3]

[0107] <Stability test method: 40°C ± 2°C / 75% RH ± 5% RH, protected from light, stored for 3 months> The viscosity change rate (%) after storage at 40°C for three months was calculated relative to the viscosity at the time of preparation, and a change within ±30% was rated as "A," and a change exceeding ±30% was rated as "B." The results are shown in the table below. The pH values ​​in the table below indicate the maximum values ​​during the storage period (i.e., up to three months after preparation).

[0108] [Table 4]

[0109] [Table 5]

[0110] Surprisingly, the pH of the sofpironium bromide composition fluctuated over time, and when the maximum value was 5.4 or higher, the viscosity imparted by the water-soluble polymer decreased over time (Comparative Examples 1 to 3). On the other hand, as shown in Examples 1 to 7, it was revealed that when the pH of the sofpironium bromide formulation was maintained at 5.2 or less, the decrease in viscosity was suppressed.

[0111] [Test Example 2] Accelerated Study of Sofpironium Bromide in Various Non-Aqueous Formulations (2)

[0112] <Liquid preparation method> Compositions of Reference Examples 1 to 5 (preparations not containing sofpironium bromide), Comparative Example 4, and Examples 8 to 12 were prepared in the same manner as in Test Example 1. These preparations were used in viscosity stability tests. In addition, Reference Examples 1 to 5, Comparative Example 4, and Examples 8 to 12 are preparations containing sofpironium bromide, anhydrous citric acid, absolute ethanol, IPM (2.5 w / w%), HG (10 w / w%), and HPC (1.25 w / w%). The contents of sofpironium bromide and anhydrous citric acid are shown in Table 6. The remainder is absolute ethanol, so that the total amount is 100%.

[0113] <Test Method> The pH measurement method was the same as in Test Example 1.

[0114] <Viscosity measurement method> For formulations containing 0% and 5% BBI-4000, the viscometer was set to 25°C, 10 rpm, and a preheat time of 30 seconds. Approximately 1 mL of the viscometer was rotated for 200 seconds with a cone rotor (RH 1°34' x R24) and the viscosity was measured (Viscosity Measurement Method 2). For formulations containing 15% BBI-4000, the viscometer was set to 25°C, 7 rpm, and a preheat time of 30 seconds. Approximately 1 mL of the viscometer was rotated for 200 seconds with a cone rotor (RH 1°34' x R24) and the viscosity was measured (Viscosity Measurement Method 2, Japanese Pharmacopoeia).

[0115] [Table 6]

[0116] <Stability test method: 40°C ± 2°C / 75% RH ± 5% RH, protected from light, stored for 3 months> In the table below, the definition of pH, the measurement method, and the criteria for judgment are the same as those in Test Example 1. [Table 7]

[0117] [Table 8]

[0118] When sofpironium bromide was not contained, even when the pH was significantly high (e.g., Reference Example 1), the rate of increase or decrease in viscosity was slight, and no relationship was observed between the pH and the rate of increase or decrease in viscosity (Reference Examples 1 to 5). These results demonstrate that the decrease in viscosity over time in non-aqueous sofpironium bromide preparations is an extremely unique phenomenon that only becomes apparent when sofpironium bromide is included in the preparation.

[0119] When the maximum pH value was 5.5 up to three months after preparation, the viscosity decreased significantly over time (Comparative Example 4). On the other hand, when the pH was maintained at 5.2 or less up to three months after preparation, the viscosity decrease over time was slight or not observed (Examples 8 to 12). This tendency was also observed when the sofpironium bromide concentration was 15 w / w% (Example 12). When the formulation of Example 10 was stored at 40°C for six months, the viscosity was 322 mPa·s. The viscosity change rate compared to when the formulation was prepared was -13%, and stability was maintained even after six months.

[0120] <Purity test> The results of the purity test (related substances) for the formulation of Example 10 (BBI-4000 gel 5% (citric acid concentration: 0.050%)) in a 3-month stability test at 40°C ± 2°C / 75% RH ± 5% RH, protected from light, are shown in the table below.

[0121] [Table 9] *: All are compound (II). **: Less than the limit of quantification (0.04%) ***: Ethyl cyclopentylmandelate -: Not detected.

[0122] Compound (II) is a compound obtained by hydrolysis of the ethyl ester of sofpironium bromide, and is represented by the following formula: [ka]

[0123] In the purity test, the only related substances detected at concentrations exceeding 0.1% were Compound (II) and ethyl cyclopentylmandelate. Therefore, the non-aqueous formulation of sofpironium bromide according to the present invention was shown to be an extremely stable composition with almost no related substances (including impurities) generated during storage.

[0124] [Test Example 3] Accelerated testing of sofpironium bromide in various low-moisture formulations <Liquid preparation method> The compositions of Examples 13 to 15 were prepared in the same manner as in Test Example 1. The ingredients were stirred and dissolved in absolute ethanol to obtain formulations with the constituent components and concentrations shown in the table. The contents of each formulation produced by this method are shown in the table below.

[0125] [Table 10] ** qs to 100: The remainder is made up of absolute ethanol to make the total volume 100%.

[0126] <Test Method> The pH measurement method was the same as in Test Example 1, and the viscosity measurement method was the same as in Test Example 2.

[0127] <Stability test method: 40°C ± 2°C / 75% RH ± 5% RH, protected from light, stored for 3 months> In the table below, the definition and criteria of pH are the same as those in Test Example 1.

[0128] [Table 11]

[0129] [Table 12]

[0130] As shown in the table above, Examples 13 to 15, which had a water content of 5 w / w% or less, showed only a slight increase or decrease in viscosity. That is, similar to the non-aqueous formulation of sofpironium bromide, it was revealed that even in low-water formulations with a water content of at least 5 w / w% or less, the decrease in viscosity over time was slight when the pH was maintained at 5.2 or less.

[0131] <Purity test> The results of the purity test (related substances) for the preparations of Examples 13 to 15 (BBI-4000 5% gel (citric acid concentration: 0.050%)) in a stability test at 40°C ± 2°C / 75% RH ± 5% RH, protected from light, for 3 months are shown in the table below.

[0132] [Table 13] *: All are compound (II). **: Less than the limit of quantification (0.04%) ***: Ethyl cyclopentylmandelate -: Not detected.

[0133] From the above table, it was confirmed that as the amount of water added increased, the amount of compound (II) produced by hydrolysis increased slightly, but other related substances were hardly produced. As described above, the low-water content formulation of sofpironium bromide according to the present invention was shown to be a stable formulation, producing only very small amounts of related substances, at least when the water content was 5 w / w% or less. From the above results, it was revealed that low-water formulations of sofpironium bromide with a water content of 5 w / w% or less, like non-aqueous formulations, show almost no decrease in viscosity over time and show limited production of related substances, demonstrating an excellent profile as a pharmaceutical formulation.

[0134] [Test Example 4] Accelerated Study of Sofpironium Bromide in Various Non-Aqueous Formulations (3)

[0135] <Liquid preparation method> Examples 16 to 19 were prepared in the same manner as in Test Example 1. The ingredients were stirred and dissolved in absolute ethanol to obtain formulations with the constituent components and concentrations shown in the table. The contents of each formulation produced by this method are shown in the table below.

[0136] [Table 14] *D-TA:D-tartaric acid ** qs to 100: The remainder is made up of absolute ethanol to make the total volume 100%.

[0137] <Test Method> The pH measurement method and the viscosity measurement method were the same as in Test Example 1.

[0138] <Stability test method: 40°C ± 2°C / 75% RH ± 5% RH, protected from light, stored for 3 months> In the table below, the definition and criteria of pH are the same as those in Test Example 1.

[0139] [Table 15]

[0140] [Table 16]

[0141] As shown in Examples 16 to 19, even under non-aqueous conditions without the addition of non-volatile oil or polyhydric alcohol, it was found that viscosity reduction was suppressed when the pH of the sofpironium bromide formulation was maintained at 5.2 or below.

[0142] [Test Example 5] Accelerated Study of Sofpironium Bromide in Various Non-Aqueous Formulations (4)

[0143] <Liquid preparation method> Examples 20 to 23 were prepared in the same manner as in Test Example 1. The ingredients were stirred and dissolved in absolute ethanol to obtain formulations with the constituent components and concentrations shown in the table. The contents of each formulation produced by this method are shown in the table below.

[0144] [Table 17] * IPM: Isopropyl myristate, HG: Hexylene glycol, CVP: Carboxyvinyl polymer, CyM: Cyclomethicone, PD: PEG-12 dimethicone ** qs to 100: The remainder is made up of absolute ethanol to make the total volume 100%.

[0145] <Test Method> The pH measurement method and the viscosity measurement method were the same as in Test Example 1.

[0146] <Stability test method: 40°C ± 2°C / 75% RH ± 5% RH, protected from light, stored for 3 months> In the table below, the definition and criteria of pH are the same as those in Test Example 1.

[0147] [Table 18]

[0148] [Table 19]

[0149] As shown in Examples 20 to 23, regardless of the type of non-volatile oil or water-soluble polymer used, it was found that viscosity reduction was suppressed when the pH of the sofpironium bromide formulation was maintained at 5.2 or less.

[0150] [Test Example 6] Long-term storage test of sofpironium bromide preparations

[0151] <Liquid preparation method> Using the same method as in Test Example 1, the solutions of Examples 24, 25, Comparative Examples 5, and 6 in the table below were prepared and used in various tests. The ingredients were stirred and dissolved in absolute ethanol to obtain formulations with the constituent components and concentrations shown in the table. The contents of each formulation produced by this method are shown in the table below.

[0152] [Table 20] * IPM: Isopropyl myristate, HG: Hexylene glycol, ** qs to 100: The remainder is made up of absolute ethanol to make the total volume 100%.

[0153] <Test Method> The pH measurement method and the viscosity measurement method were the same as in Test Example 1.

[0154] <Stability test method 1: 25°C ± 2°C / 60% RH ± 5% RH, protected from light, stored for 24 months> The formulations of Examples 24 and 25 were used in Stability Test 1. The pH values ​​in the table below indicate the maximum values ​​during the storage period (i.e., up to 24 months after preparation). The criteria in the table are the same as those in Test Example 1. Comparative Example 5 was similarly stored for 6 months.

[0155] <Stability test method 2: 30°C ± 2°C / 60% RH ± 5% RH, protected from light, stored for 12 months> The formulation of Comparative Example 6 was used in Stability Test 2. The pH values ​​in the table below indicate the maximum values ​​during the storage period (i.e., up to 12 months after preparation). The criteria in the table are the same as those in Test Example 1.

[0156] [Table 21]

[0157] [Table 22]

[0158] The formulations of Comparative Examples 5 and 6, which had an anhydrous citric acid concentration of 0.001 w / w%, had a pH of 6.1 to 5.9 when prepared, and when stored at room temperature, the pH fluctuated over time, similar to Comparative Examples 1 to 4 in Test Example 1. The formulation of Comparative Example 6, which had an anhydrous citric acid concentration of 0.001 w / w%, showed a significant decrease in viscosity (-76%) after 12 months of storage at room temperature. On the other hand, the formulations of Examples 24 and 25, which had an anhydrous citric acid concentration of 0.05 w / w%, maintained a pH of 5.2 or less after preparation, and showed little change in viscosity over time. Therefore, a sofpironium bromide formulation that maintains a pH of 5.2 or less after preparation can suppress a decrease in viscosity over time. In particular, this study revealed that formulations that have a pH of 2.5 to 5.2 at any time up to six months after preparation when stored at room temperature are preferred. For example, formulations that have a pH of 2.5 to 5.2 at one month, three months, or six months after preparation when stored at room temperature are preferred.

[0159] <Purity test> In a long-term storage test (25°C ± 2°C / 60% RH ± 5% RH, protected from light) of the formulations of Examples 24 and 25, purity tests (for related substances) were conducted up to 24 months after preparation. In Example 24, a slight HPLC peak for ethyl cyclopentylmandelate was observed at 24 months. In Example 25, no increase in related substances or appearance of new related substances was observed during the storage period after preparation. These results demonstrated that the formulations of Examples 24 and 25 were stable in long-term storage tests.

[0160] As described above, it was revealed that, regardless of test conditions such as storage temperature, sofpironium bromide preparations maintained at a pH of 5.2 or less, as shown in Examples 24 and 25, do not show an increase in impurities over a long period of time and suppress a decrease in viscosity.

[0161] [Test Example 7] A confirmatory study of BBI-4000 in patients with primary axillary hyperhidrosis

[0162] This randomized, double-blind, parallel-group study evaluated the superiority of a topical formulation containing sofpironium bromide (5% sofpironium bromide, 1.25% hydroxypropyl cellulose, 2.5% isopropyl myristate, 0.05% anhydrous citric acid, 10% hexylene glycol, and the remainder, absolute ethanol) applied to the axilla once daily before bedtime for 6 weeks compared with a placebo formulation (0% sofpironium bromide).The primary endpoints were the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of the total axillary sweat weight at the end of treatment to the baseline (measured before treatment) of 0.5 or less.

[0163] In this study, "pre-treatment" refers to the time point before treatment with the administration of a pharmaceutical formulation of sofpironium bromide. In this study, "end of treatment" refers to the visit that served as the reference point for the end of treatment. End of treatment consists of three visits after the specified administration period, and the HDSS score and sweat weight at the end of treatment refer to their median values ​​unless otherwise noted. In this study, "during treatment" refers to the period between the start and end of treatment.

[0164] In this study, "baseline" refers to each measurement value related to the severity of symptoms as a baseline before administration. The baseline is measured at a specified period before administration. In this study, the baseline HDSS score and sweat weight refer to the median values ​​of each measurement on three visits within a nine-day period, defined as baseline 1, baseline 2, and baseline 3. The number of days of administration of sofpironium bromide pharmaceutical preparations is the number of days from Baseline 3 as Day 1, and expressions such as "administration period" and "number of weeks of administration" also follow this standard. Baseline 3 is the day administration of sofpironium bromide pharmaceutical preparations began. The time course of this test is shown in Figure 1.

[0165] <Efficacy analysis> (1) Primary efficacy analysis The proportion of subjects whose HDSS score at the end of treatment was 1 or 2 and whose ratio of the total sweat weight of both axillae at the end of treatment to the baseline was 0.5 or less was analyzed using the chi-square test.

[0166] (2) Secondary analysis of efficacy 1) Sweat weight The median of the total sweat weight of both axillae at baseline 1 to 3 was used as the baseline sweat weight, and the median of the total sweat weight of both axillae at week 6 of administration 1 to 3 was used as the total sweat weight of both axillae at the end of treatment. Basic statistics for the total sweat weight of both axillae were calculated for each administration group at each time point and compared between administration groups. In addition, the following were calculated, confidence intervals were shown for the differences between administration groups, and statistical tests were performed. The proportion of subjects whose ratio of total axillary sweat weight at the end of treatment to baseline was 0.5 or less Change from baseline in total sweat weight in both axillae at the end of treatment 2) HDSS The median HDSS score from baseline 1 to 3 was used as the baseline HDSS score, and the median HDSS score from 1 to 3 at week 6 of treatment was used as the HDSS score at the end of treatment. Data were compiled by treatment group and by time of administration. In addition, the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment was calculated, and confidence intervals for the differences between treatment groups were presented and statistical tests were performed.

[0167] <Efficacy survey items> The following items were investigated and the results were recorded: (1) Sweat weight measurement 1) Measurement conditions · Temperature: 20℃~28℃, Humidity: 20%RH~80%RH 2) Measurement method Pre-weighed filter papers were placed in both armpits of the subjects for 5 minutes. Thereafter, the weight of the filter paper containing the sweat was measured to calculate the sweat weight. The test was conducted for each subject between 8:00 AM and 7:00 PM, with the difference in test duration not exceeding 4 hours.

[0168] (2) HDSS The criteria for determining the HDSS score are as follows: [Table 23]

[0169] <Target patients and main inclusion criteria> Patients with primary axillary hyperhidrosis who are 12 years of age or older at the time of consent and who meet the following diagnostic criteria and conditions: 1. Patients diagnosed with primary axillary hyperhidrosis who meet two or more of the following six criteria during the screening interview (1) The first symptoms appeared at age 25 or younger (2) Sweating occurs symmetrically (3) Sweating stops during sleep (4) Excessive sweating occurs at least once a week (5) Family history (6) Excessive sweating interferes with daily life 2. Patients who meet all of the following conditions: (1) HDSS score of 3 or 4 at each time point from baseline 1 to 3 (2) Sweat weight in each axilla is 50 mg or more at any two of the three time points (baseline 1 to 3).

[0170] <Major exclusion criteria> 1. Patients with secondary hyperhidrosis 2. Patients whose hyperhidrosis symptoms have started or worsened due to menopause 3. Patients who are candidates for thoracic sympathectomy

[0171] <Patients eligible for clinical trials> A total of 281 patients with primary axillary hyperhidrosis were randomly assigned to receive the study drug (140 in the 0% group and 141 in the 5% group), and data analysis was performed on these patient groups.

[0172] <Results of primary efficacy endpoint> The percentage of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of the total sweat weight of both axillae at the end of treatment to baseline of 0.5 or less is shown in the table below.

[0173] [Table 24] The proportion of subjects who demonstrated efficacy was 36.4% (51 / 140) in the 0% group and 53.9% (76 / 141) in the 5% group, which was 17.5% (95% confidence interval: 6.02-28.93) higher in the 5% group than in the 0% group, demonstrating a statistically significant difference between the treatment groups (chi-square test: p = 0.003).

[0174] <Secondary efficacy endpoint results> (1) HDSS The proportion of subjects with an HDSS score of 1 or 2 at the end of treatment was 47.9% (67 / 140) in the 0% group and 60.3% (85 / 141) in the 5% group. The 5% group had a higher HDSS score of 1 or 2 than the 0% group by 12.4% (95% confidence interval: 0.86-23.99), demonstrating a statistically significant difference between the groups (chi-square test: p = 0.036).

[0175] (2) Sweat weight The proportion of subjects whose axillary total sweat weight ratio at the end of treatment was 0.5 or less compared to baseline was 66.4% (93 / 140) in the 0% group and 77.3% (109 / 141) in the 5% group. The 5% group had a higher ratio of 10.9% (95% confidence interval: 0.44-21.32) than the 0% group, with a statistically significant difference between the groups (chi-square test: p = 0.042).

[0176] <Efficacy results in patients with a total axillary sweat weight of 400 mg or more> To examine efficacy in patients with severe baseline axillary total sweating weight, efficacy was examined in a subgroup of patients with baseline axillary total sweating weight of 400 mg or more. The analysis results are shown in the table below.

[0177] [Table 25]

[0178] The primary endpoint, "the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweat weight at the end of treatment to baseline of 0.5 or less," was higher in the 5% group than in the 0% group in all categories. The between-group difference was 15.5% in the 100 mg to less than 400 mg category and 46.2% in the 400 mg or more category. In other words, the between-group difference was greater in the 400 mg or more category.

[0179] The "proportion of subjects with an HDSS score of 1 or 2 at the end of treatment" and the "proportion of subjects with a ratio of total axillary sweat weight to baseline at the end of treatment of 0.5 or less" were higher in the 5% group than in the 0% group in all categories. The mean total axillary sweat weight was smaller in the 5% group than in the 0% group in all categories and at each evaluation point after administration. The mean total axillary sweat weight at the end of treatment was smaller in the 5% group than in the 0% group in all categories. In conclusion, in subjects whose baseline total axillary sweat weight was 400 mg or more, improvements were observed in the 5% group compared to the 0% group in all evaluation items.

[0180] <5% Change in HDSS score before and after treatment in the BBI-4000 group> In a randomized, double-blind, parallel-group comparison of patients with primary axillary hyperhidrosis, 5% BBI-4000 was applied to the axilla once daily for six weeks. Each subject's HDSS score before treatment was subtracted from their HDSS score at the end of treatment, and the difference (ΔHDSS) was calculated. The 140 cases for which both pre- and post-treatment HDSS scores were available were analyzed, and the mean change in ΔHDSS and standard deviation were calculated. As a result, the average ΔHDSS in the 5% BBI-4000 group was 1.14±0.87. [Industrial Applicability]

[0181] According to the present invention, it is possible to provide a stable non-aqueous and low-water formulation of sofpironium bromide in which the decrease in viscosity over time during long-term storage is suppressed. Additionally, the formulations of the present invention can be used to treat, cure, or prevent primary axillary hyperhidrosis.

Claims

1. 1. A pharmaceutical formulation for topical application to a human body surface, comprising: (a) sofpironium bromide; (b) one or more water-soluble polymers; (c) ethanol; a pH of 5.2 or less, a uniformly dispersed non-aqueous formulation or a low-moisture formulation having a water content of 5 w / w% or less, The pH is measured at one or more selected time points within six months of preparation, the pH being determined by measuring the pH of the formulation stored at room temperature, and the pH being the value after immersing a pH electrode for non-aqueous solvents in the formulation for five minutes.

2. 2. The formulation according to claim 1, wherein the content of sofpironium bromide is 1 w / w% to 20 w / w% based on the total formulation weight.

3. 3. The formulation of claim 1 or claim 2, wherein the pH is in the range of 2.5 to 5.

2.

4. 3. The formulation according to claim 1 or claim 2, which is a homogeneously dissolved formulation.

5. The formulation according to any one of claims 1 to 4, wherein the water-soluble polymer is a water-soluble vinyl polymer-based polymer or a water-soluble cellulose-based polymer.

6. 5. The formulation of claim 1, wherein the water-soluble polymer is selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl copolymer, polyvinylpyrrolidone, and copovidone.

7. 5. The formulation according to claim 1, wherein the water-soluble polymer is hydroxypropyl cellulose or a carboxyvinyl polymer.

8. 8. The formulation according to claim 1, wherein the content of the water-soluble polymer is 0.01 w / w% to 5.0 w / w% of the total formulation amount.

9. 9. The formulation according to claim 1, wherein the ethanol content is 50 w / w% or more and less than 99 w / w% of the total formulation amount.

10. The formulation according to any one of claims 1 to 9, further comprising a pH adjuster.

11. 11. The formulation of claim 10, wherein the pH adjuster is an acid selected from the group consisting of tartaric acid, acetic acid, and citric acid, or a salt thereof.

12. 12. The formulation according to claim 10 or 11, wherein the content of the pH adjuster is 0.015 w / w % to 5 w / w % based on the total formulation weight.

13. 13. A formulation according to any one of claims 1 to 12 (excluding formulations containing dimethiconol blend 20) further comprising a non-volatile oil.

14. 14. The formulation of claim 13, wherein the non-volatile oil is selected from the group consisting of non-volatile esters, non-volatile ethers, non-volatile silicones, and non-volatile alcohols.

15. The non-volatile oil R 1 COOR 2 and R 1 and R 2 one of which is optionally substituted C 4 -C 40 A straight chain alkyl group or an optionally substituted C 4 -C 40 is a branched chain alkyl group, and R 1 and R 2 The other is optionally substituted C 1 -C 40 14. The formulation of claim 13, wherein the alkyl group is a non-volatile ester selected from the group consisting of monoesters, diesters, and triesters.

16. Non-volatile oils include ethyl myristate, 2-octyldodecyl myristate, butyl stearate, isocetyl stearate, 2-octyldodecyl stearate, hexyl laurate, 2-hexyldecyl laurate, 2-ethylhexyl palmitate, 2-octyldecyl palmitate, cetearyl octanoate, isononyl isononanoate, octyldodecyl neopentanoate, 2-octyldodecyl erucate, and 2-octyldodecyl benzoate. decanoate, ricinoleate, isopropyl myristate, diisopropyl adipate, medium-chain triglyceride, isopropyl palmitate, alkyl ethylhexanoate (C14-C18), myristyl myristate, ethyl oleate, oleyl oleate, ethylhexyl palmitate, cetyl palmitate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, PPG-3 benzyl ester myristate 14. The formulation of claim 13, wherein the non-volatile fatty acid ester is selected from the group consisting of methyl ether, isotridecyl isononanoate, triethylhexyl trimellitate, alkyl benzoate (C12-C15), diethoxyethyl succinate, propylene glycol dicaprate, propylene glycol dicaprylate, caprylic / capric triglyceride, triethylhexanoin, triisostearin, isopropyl isostearate, isostearyl isostearate, polyglyceryl-2 triisostearate, diethylhexyl succinate, PPG-2 myristyl propionate, pentaerythrityl tetraisostearate, diethyl sebacate, PPG-3 benzyl ether ethylhexanoate, glyceryl tribehenate, cetyl 2-ethylhexanoate, diisostearyl malate, 2-ethylhexyl stearate, triethylhexyl citrate, and alkyl lactates such as ethyl lactate.

17. 14. The formulation of claim 13, wherein the non-volatile oil is a non-volatile fatty acid ester selected from the group consisting of isopropyl myristate, diisopropyl adipate, and medium-chain triglycerides.

18. 14. The formulation of claim 13, wherein the non-volatile oil is a non-volatile silicone selected from the group consisting of medical grade silicone oil, methylphenylsilicone, methylhydrogensilicone, decamethylpentacyclosiloxane, octamethyltetracyclosiloxane, cyclomethicone 5-NF, PEG-12 dimethicone, dimethicone 20 cSt, dimethicone 100 cSt, dimethicone 350 cSt, dimethicone 500 cSt, dimethicone 1000 cSt, and dimethicone 12500 cSt.

19. 14. The formulation of claim 13, wherein the non-volatile oil is a non-volatile silicone selected from the group consisting of cyclomethicone 5-NF, PEG-12 dimethicone, dimethicone 20 cSt, and dimethicone 350 cSt.

20. 20. A formulation according to any one of claims 13 to 19, wherein the content of non-volatile oil is from 0.5 w / w% to 10 w / w% of the total formulation.

21. 21. The formulation according to any one of claims 1 to 20, further comprising a polyhydric alcohol.

22. 22. The formulation of claim 21, wherein the polyhydric alcohol is selected from the group consisting of hexylene glycol, propylene glycol, ethylene glycol, glycerol, and butylene glycol.

23. 23. The formulation according to claim 21 or claim 22, wherein the content of the polyhydric alcohol is 1.0 w / w% to 30 w / w% of the total formulation amount.

24. 24. A formulation according to any one of claims 1 to 23, having a viscosity at 25°C of from 10 mPa·s to 2000 mPa·s.

25. 25. The formulation according to claim 1, wherein the formulation has a viscosity of 10 mPa s to 1000 mPa s at 25°C after storage at room temperature for 36 months or after storage at 40°C for 3 months.

26. 26. The formulation of any one of claims 1 to 25 for treating, treating, or preventing a disease selected from the group consisting of hyperhidrosis, overactive bladder, chronic obstructive pulmonary disease, heart disease, sialorrhea, eye disease, and bronchial asthma.

27. After storage at room temperature for 36 months or at 40°C for 3 months, the following formula (II): 【Chemistry 1】 27. A formulation according to any one of claims 1 to 26, wherein the content of compound (II) represented by the formula: is 1.5 w / w% or less relative to the content of sofpironium bromide, and the purity of sofpironium bromide is 90 w / w% or more.

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