Medicine containing softpironium bromide

Abstract

This invention provides a pharmaceutical preparation for long-term preservation of a product with inhibited viscosity reduction when applied topically to the surface of the human body. The preparation contains sofosfoam bromide, a water-soluble polymer, and ethanol, has a pH value of 5.2 or lower, and is a uniformly dispersed non-aqueous preparation or a low-aqueous preparation with a water content of 5% or lower.

Description

[Technical Field]

[0001] This invention relates to a pharmaceutical preparation containing sofpironium bromide as an active ingredient. [Previous Technology]

[0002] Pharmaceutical formulations must be provided in a physicochemically stable form, preferably with their properties, formulation characteristics, content of similar substances, and purity of active ingredients remaining within a certain range over a long period. In particular, in the case of topical application of formulations, from an operational or user experience point of view, it is desirable to have formulations with long-term stable pharmaceutical properties.

[0003] Acetylcholine is known to be one of the main neurotransmitters in living organisms and has a variety of pharmacological effects. For example, sweating caused by the activation of sweat glands is one of them. Therefore, anticholinergic agents are useful for the management, treatment, or prevention of various acetylcholine-related diseases such as hyperhidrosis.

[0004] Hyperhidrosis is a pathological condition characterized by excessive sweating in the palms, soles, and armpits due to heat, mental stress, or other factors, causing inconvenience in daily life (e.g., books or notebooks are damaged by sweat, people are reluctant to hold hands with others because of sweat, need to change underwear several times a day, and mobile phones become wet and damaged by sweat), significantly reducing QOL (Non-Patent Literature 1). Human sweat glands include eccrine sweat glands and apocrine sweat glands, and the sweat that causes hyperhidrosis is secreted by the eccrine sweat glands (Non-Patent Literature 2). It is generally believed that eccrine sweat glands are regulated by cholinergic nerves, and acetylcholine induces sweating by stimulating M3 muscarinic receptors located on the postsynaptic membrane of the eccrine sweat glands (Non-Patent Literature 3).

[0005] Hyperhidrosis is classified into generalized hyperhidrosis and localized hyperhidrosis based on whether it occurs throughout the body or in a part of it. Localized hyperhidrosis mostly occurs in the palms, soles, and armpits. Furthermore, it is classified into primary hyperhidrosis without a specific cause and secondary hyperhidrosis caused by other diseases (e.g., in the case of generalized hyperhidrosis, drug-induced or circulatory organ diseases; in the case of localized hyperhidrosis, peripheral nerve disorders). Therefore, primary axillary hyperhidrosis refers to a condition without a specific cause, characterized by excessive sweating in the armpits that interferes with daily life.

[0006] Soft glycopyrrolate (Patent Document 1) is an example of a topical anticholinergic agent useful for the treatment of hyperhidrosis. Soft glycopyrrolate is a derivative of glycopyrrolate, an anticholinergic agent. One representative example of soft glycopyrrolate is sofosfoam bromide.

[0007] Soferoammonium bromide is an ester compound of the following formula (I) (hereinafter sometimes referred to as "BBI-4000" or "compound (I)"), which is a bromide salt of quaternary ammonium:

[0007] . To date, a variety of topical formulations for the application of sofosfoam bromide have been reported.

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

[0009] Patent documents 3 and 4 have disclosed that in formulations containing polydimethylsiloxane alcohol blend 20, a small amount of polydimethylsiloxane alcohol blend 20 will periodically aggregate at the bottom of the container in the form of small droplets. For formulations that do not produce droplets in the formulation, formulations containing BBI-4000, ethanol, isopropyl myristate (hereinafter also referred to as "IPM") and hydroxypropyl cellulose (HPC) have been disclosed (e.g., TABLE VIII).

[0010] In the design of topical formulations, the viscosity of the formulation affects the retention of the active ingredient on the affected area, and is therefore one of the important physical properties. When the formulation viscosity is not maintained appropriately, the medication cannot be retained on the affected area, and the liquid may drip or adhere to clothing, affecting the user experience. Therefore, it is necessary to develop stable topical formulations that provide excellent user experience and whose viscosity or spreadability does not change significantly even after long-term storage.

[0011] Generally, water-soluble polymers such as cellulose-based polymers are added to topical formulations to impart viscosity. However, the viscosity of topical formulations imparted by water-soluble polymers can decrease over time due to polymer decomposition caused by light or heat. In particular, when cellulose-based polymers are incorporated into high-water-content formulations, viscosity stability is lower, and the viscosity of the formulation decreases over time. On the other hand, in non-aqueous or low-water-content formulations containing water-soluble polymers, the phenomenon of viscosity decrease over time has not been reported to date, and there has been no prior understanding of under what conditions this viscosity decrease can be suppressed.

[0012] Patent documents 2, 3, and 4 disclosed non-aqueous formulations containing sofosfoam bromide and water-soluble polymers, but did not disclose or suggest any means of imparting higher stability for long-term storage. Furthermore, they did not disclose or suggest any low-aqueous formulations containing sofosfoam bromide and water-soluble polymers that exhibit higher stability. Moreover, any means of maintaining the viscosity of a formulation over a long period in non-aqueous or low-aqueous formulations containing sofosfoam bromide and water-soluble polymers are completely unknown.

[0012] [Previous Technical Documents]

[0012] [Patent Documents]

[0013] [Patent Document 1] International Publication No. WO2014 / 144075

[0013] [Patent Document 2] International Publication No. WO2015 / 138776

[0013] [Patent Document 3] International Publication No. WO2017 / 015485

[0013] [Patent Document 4] International Publication No. WO2018 / 017852

[0013] [Non-patent literature]

[0014] [Non-Patent Literature 1] Journal of the Japanese Dermatological Society. 2015; 125: 1379-1400

[0014] [Non-Patent Literature 2] Occurrence and structure of sweat glands. MB Derma. 2014; 220: 9-12.

[0014] [Non-Patent Literature 3] Hyperhidrosis-Causes and treatment of enhanced sweating. Dtsch Arztebl Int. 2009; 106: 32-7.

[0015] One of the problems to be solved by the present invention is to provide a means for inhibiting viscosity reduction during long-term storage in non-aqueous or low-aqueous formulations for coating other than containing sofosfoam as an active ingredient.

[0015] Another problem that the present invention aims to solve is to provide a non-aqueous or low-aqueous preparation for topical application of sofosfoam bromide, which has suppressed the decrease in viscosity during long-term storage, does not change the user experience, and has stable formulation characteristics as a pharmaceutical product.

[0015] Another problem that the present invention aims to solve is to provide a topical preparation of sofosfoam bromide that has shown therapeutic effects on diseases related to acetylcholine (such as primary local hyperhidrosis).

[0016] As a result of long-term review of topical formulations of stable sofosfoam bromide, the inventors have found that in non-aqueous formulations of sofosfoam bromide, the viscosity of the formulation imparted by the water-soluble polymer decreases over time.

[0016] As previously mentioned, there have been no reported instances of viscosity reduction over time in non-aqueous formulations or low-aqueous formulations containing water-soluble polymers. The occurrence of such a viscosity reduction over time in a non-aqueous formulation of sofosfoam bromide is unexpected. This viscosity reduction over time affects the user experience, and therefore, it is desirable to avoid this problem. Consequently, the inventors have undertaken dedicated research to address this previously unknown issue in the field.

[0017] The inventors investigated the factors affecting the stability of sofosfoam bromide formulations and found that in non-aqueous formulations containing sofosfoam bromide and water-soluble polymers, the pH value of the formulation has a significant impact on stability. They also found that by maintaining the pH value of the formulation below 5.2, the viscosity reduction over time can be suppressed.

[0018] Subsequently, the inventors examined in detail the effect of water content in the formulation on the stability of the sofosfoam bromide formulation. From a technical perspective, it is expected that increasing the water content would impair the stability of the formulation. However, surprisingly, it was found that even in low-water-content formulations with a water content of less than 5%, by maintaining the pH value of the formulation below 5.2, the increase in similar substances was minimal, and the time-dependent viscosity reduction could be suppressed. Furthermore, the inventors discovered that the aforementioned inhibition of viscosity reduction was not dependent on the type of additives such as non-volatile oils or pH adjusters; by maintaining the pH value of the sofosfoam bromide formulation below 5.2, a physicochemically stable formulation could be obtained.

[0019] The inventors further reviewed the invention and found that the above-mentioned preparation is long-term stable, has excellent properties as a pharmaceutical product, and can be applied in clinical practice and shows extremely good effects. Therefore, the present invention was completed.

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

[0020]

[01] A pharmaceutical preparation for external application to the surface of the human body, comprising the following (a) to (c),

[0020] (a) Sofospromonium bromide,

[0020] (b) One or more kinds of water-soluble polymers, and

[0020] (c) Ethanol;

[0020] The pharmaceutical preparation has a pH value below 5.2 and is a uniformly dispersed non-aqueous preparation or a low-aqueous preparation with a water content of below 5 w / w%.

[0020] The aforementioned pH value is determined at one or more arbitrary time points selected within 6 months after the preparation of the solution. The aforementioned pH value is determined by measuring the pH value of the aforementioned preparation after storage at room temperature. The aforementioned pH value is the value after immersing the non-aqueous solvent in the aforementioned preparation for 5 minutes using a pH electrode.

[0021]

[02] As described in the aforementioned

[01] pharmaceutical preparation, wherein the content of sofosfoam bromide is 1 w / w% to 20 w / w relative to the total dose.

[0021]

[03] The pharmaceutical preparation described in

[01] or

[02] above, wherein the pH value is in the range of 2.5 to 5.2.

[0021]

[04] The pharmaceutical preparations described in the aforementioned

[01] or

[02] are preparations that have been uniformly dissolved.

[0022]

[05] The preparation described in any one of the above

[01] to

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

[0022]

[06] The pharmaceutical preparation described in any one of the above

[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 polyvinylpyrrolidone (also known as copolyvinylpyrrolidone).

[0023]

[07] The pharmaceutical preparation described in any of the above

[01] to

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

[0023]

[08] The pharmaceutical preparation described in any of the above

[01] to

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

[0023]

[09] The pharmaceutical preparation described in any of the above

[01] to

[08] , wherein the content of ethanol is 50 w / w or more but less than 99 w / w relative to the total dose.

[0024]

[10] The pharmaceutical preparations described in any of the above

[01] to

[09] further contain a pH adjuster.

[0024]

[11] As described in the pharmaceutical preparation described above in

[10] , the pH adjuster is an acid or salt of the group consisting of tartaric acid, acetic acid and citric acid.

[0024]

[12] The pharmaceutical preparation described in

[10] or

[11] above, wherein the content of the pH adjuster is 0.015 w / w% to 5 w / w relative to the total dose.

[0025]

[13] The pharmaceutical preparations described in any of the above

[01] to

[12] contain non-volatile oils, except for pharmaceutical preparations containing polydimethylsiloxane alcohol blend 20.

[0025]

[14] As described in the pharmaceutical preparations described above in

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

[0026]

[15] As described in the pharmaceutical preparation described in

[13] above, the non-volatile oil is a non-volatile ester selected from the group consisting of monoesters, diesters and triesters, the non-volatile ester being represented by R1COOR2, one of R1 and R2 being a substituted C4-C40 straight-chain alkyl group or a substituted C4-C40 branched-chain alkyl group, and

[0026] The other of R1 and R2 is a substituted C1-C40 alkyl group.

[0027]

[16] As described in the pharmaceutical preparations in

[13] above, the non-volatile oil is selected from ethyl myristate, 2-octyl dodecyl myristate, butyl stearate, isocetyl stearate, 2-octyl dodecyl stearate, hexyl laurate, 2-hexyl decyl laurate, 2-ethylhexyl palmitate, 2-octyl decyl palmitate, cetearyl caprylate, isononyl isononanoate, octyl dodecyl neopentanoate, 2-Octyldodecyl erucic acid, 2-Octyldodecyl benzoate, decanoate, ricinoleate, isopropyl myristate, diisopropyl adipate, medium-chain triglycerides, isopropyl palmitate, alkyl (C14-C18) ethylhexanoate, myristyl myristate, ethyl oleate, oleic acid ester, ethylhexyl palmitate, cetyl palmitate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, P myristate Non-volatile fatty acid esters comprising the group consisting of PG-3 benzyl ether, isothietrazolate, triethylhexyl trimellitate, alkyl (C12-C15) benzoate, diethoxyethyl succinate, propylene glycol didecanoate, propylene glycol dioctanoate, tri(octanoic / capric)glycerides, triethylhexanoate, triisostearin, isopropyl isostearate, isostearate, polyglycerol triisostearate-2, diethylhexyl succinate, PPG-2 myristyl propionate, neopentyl tetrastearate, diethyl sebacate, PPG-3 benzyl ether ethylhexanoate, tris(oxalic acid) trimethylolpropionate, cetyl 2-ethylhexanoate, diisostearate malate, 2-ethylhexyl stearate, triethylhexyl citrate, and ethyl lactate.

[0028]

[17] As described in the pharmaceutical preparation described above in

[13] , 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.

[0028]

[18] As described in the pharmaceutical preparation described above in

[13] , the non-volatile oil is a non-volatile polysiloxane selected from the group consisting of medical grade polysiloxane oil, methyl phenyl polysiloxane, methyl hydrogen polysiloxane, decamethylpentane, octamethyltetracyclosiloxane, cyclomethicone 5-NF, PEG-12 dimethicone, 20 cSt, 100 cSt, 350 cSt, 500 cSt, 1000 cSt and 12500 cSt.

[0029]

[19] As described in the pharmaceutical preparation described above in

[13] , the non-volatile oil is a non-volatile polysiloxane selected from the group consisting of cyclodimethylsiloxane 5-NF, PEG-12 polydimethylsiloxane, polydimethylsiloxane 20cSt and polydimethylsiloxane 350cSt.

[0029]

[20] The pharmaceutical preparation described in any of the above

[13] to

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

[0030]

[21] The pharmaceutical preparations described in any of the above

[01] to

[20] further contain polyols.

[0030]

[22] As described in the pharmaceutical preparations described above in

[21] , the polyols are selected from the group consisting of hexanediol, propylene glycol, ethylene glycol, glycerol and butylene glycol.

[0030]

[23] The pharmaceutical preparation described above in

[21] or

[22] , wherein the content of polyol is 1.0 w / w% to 30 w / w relative to the total dose.

[0031]

[24] The pharmaceutical preparation described in any of the above

[01] to

[23] , wherein the viscosity at 25°C is 10 mPa·s to 2000 mPa·s.

[0031]

[25] The pharmaceutical preparation described in any of the above

[01] to

[24] has a viscosity of 10 mPa·s to 1000 mPa·s at 25°C after being stored at room temperature for 36 months after being prepared or after being stored at 40°C for 3 months after being prepared.

[0032]

[26] The pharmaceutical preparation described in any of the above

[01] to

[25] is used to treat, cure or prevent diseases selected from the group consisting of hyperhidrosis, overactive bladder, chronic obstructive pulmonary disease, heart disease, drooling, eye disease and bronchial asthma.

[0033]

[27] A topical coating preparation, after being prepared and stored at room temperature for 36 months or after being prepared and stored at 40°C for 3 months, has a content of compound (II) as shown in formula (II) below of less than 1.5 w / w% relative to the content of sofosfoam bromide, and the purity of sofosfoam bromide is more than 90 w / w%.

[0033]

[0034]

[28] A topical preparation for treating or preventing primary axillary hyperhidrosis, which is a pharmaceutical preparation of any one of the above

[01] to

[27] , and contains sofosfoam bromide as an active ingredient, and is applied topically to both armpits once a day, wherein the primary axillary hyperhidrosis is defined as a total sweat weight of more than 100 mg in both armpits 5 minutes before treatment, as determined by a weight measurement method.

[0034]

[29] The topical preparation described above in

[28] is used to treat, cure or prevent primary axillary hyperhidrosis, and is applied topically for a treatment period of at least 6 weeks, wherein the primary axillary hyperhidrosis is defined as a total sweat weight of 400 mg or more in both armpits in the 5 minutes prior to treatment, as determined by weight measurement.

[0035] According to the present invention, a non-aqueous or low-aqueous preparation comprising sofeelorammonium bromide and a water-soluble polymer can suppress the time-dependent decrease in viscosity during long-term storage by maintaining the pH value below 5.2, thereby providing an external coating preparation with excellent properties as a component of a pharmaceutical product. [Simplified Explanation of the Diagram]

[0036] Figure 1 shows the timeline of the BBI-4000 validation trial in Case 7, using patients with primary axillary hyperhidrosis as subjects. In the figure, *1 includes the three administration time points from baseline 1 to 3, and *2 includes the three administration time points from week 6 1 to 3 at the end of treatment.

Implementation Method

[0037] Hereinafter, the present invention will be described in detail.

[0037] The formulation of the present invention is a topical administration formulation with sofosfoam bromide as the active ingredient.

[0037] The content of sofosfoam bromide contained 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.

[0037] In one embodiment of the present invention, the preferred content of sofosfoam bromide is 5 w / w relative to the total dose.

[0037] In another embodiment of the present invention, the preferred content of sofosfoam bromide is 10 w / w relative to the total dose.

[0037] In another embodiment of the present invention, the preferred content of sofosfoam bromide is 15 w / w relative to the total dose.

[0037] In addition, in this specification, when the ranges such as "A to B", "AB" or "A to (~)B" are described, the values ​​at the end of the ranges are also included unless otherwise specified.

[0038] The formulations of the present invention are not particularly limited as long as they are pharmaceutical preparations for external application to the surface of the human body, and include liquids, lotions, ointments, creams and gels.

[0038] The formulation of the present invention is preferably a liquid or a gel, and more preferably a liquid.

[0039] The formulation of the present invention contains sofosfoam as an active ingredient and can be applied topically to the surface of the human body for use as a medicine to treat, cure or prevent various diseases related to the action of acetylcholine.

[0040] The term "body surface" as used in this specification refers to the surface of human skin, etc. Specifically, it refers to the skin surface of the body, head, etc. More specifically, it means the skin surface of the palms, head, face, shoulders, chest, buttocks, abdomen, back, genitals, armpits, etc.; or hair, nails, etc. According to one embodiment of the present invention, the body surface (applicable area) suitable for application is not particularly limited, but preferably it is, for example, the skin surface, and particularly preferably the skin surface of the armpit, etc.

[0041] The term "topical application" or "external application" in this specification means applying a pharmaceutical preparation to the lesion site or its surrounding area on the surface of the human body.

[0041] In one embodiment of the present invention, the formulation of the present invention is a liquid for applying the medicine to the armpit.

[0041] In another embodiment of the present invention, the formulation of the present invention is an external liquid for applying the medicine to the palm.

[0041] In another embodiment of the present invention, the formulation of the present invention is a topical liquid for applying a medicine to the body.

[0041] Generally, primary localized hyperhidrosis is characterized by excessive sweating symmetrically on the head, face, palms, soles, and armpits. Therefore, the formulation of the present invention is preferably a topical formulation for application to both armpits and both palms. In cases of excessive sweating on one side of the armpit or one side of the palm, the formulation of the present invention can also be applied to that unilateral armpit or unilateral palm.

[0042] In this specification, "uniformly dispersed" means that the composition of the formulation is equal, balanced and stable. Specifically, it means that under normal storage conditions (e.g., at room temperature, shelf life of 3 years, etc.), no liquid phase separation, droplet formation, precipitation of formulation components or other components will occur, including, for example, formulations that have been uniformly dissolved.

[0042] The formulation of the present invention is a formulation in which the components of the formulation are uniformly dispersed, and under normal storage conditions, it will not produce oil droplets or the like, and can be stored stably.

[0042] The formulation of the present invention is preferably a uniformly dissolved formulation, and more preferably a uniformly dissolved and clarified formulation.

[0042] Furthermore, the formulation of the present invention will not deviate from the pharmaceutical formulation specifications due to time-related discoloration, deterioration, significant increase or decrease in the content of active ingredients, or significant increase in similar substances. It also has no problems in terms of microbiological quality, and is therefore superior as a pharmaceutical formulation.

[0043] In this specification, the term "moisture content" means the amount of water relative to the total dose.

[0043] In this specification, the term "non-aqueous preparation" means a preparation in which the water content is 0 w / w%, or a preparation that is substantially free of water.

[0043] In this specification, the term "substantially anhydrous formulation" means, for example, a formulation in which the water content is less than 1 w / w%.

[0043] In this specification, the term "low-water-content formulation" means a formulation in which the water content is less than 20 w / w%.

[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 most preferably 1 w / w% or less.

[0044] 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.

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

[0045] In another embodiment of the present invention, the formulation of the present invention is preferably a low water content formulation with a water content of 0.001 w / w% to 5 w / w%, more preferably a low water content formulation with a water content of 0.002 w / w% to 3 w / w%, even more preferably a low water content formulation with a water content of 0.005 w / w% to 2 w / w%, and even more preferably a low water content formulation with a water content of 0.01 w / w% to 1 w / w%.

[0046] The water-soluble polymer contained in the formulation of the present invention is not particularly limited as long as it can be used as an additive in pharmaceuticals and can impart a certain viscosity to the formulation.

[0046] Preferably, in the case of a non-aqueous formulation containing 1.25 w / w% of a water-soluble polymer relative to the total dosage, the water-soluble polymer has a viscosity in the range of 2.0 mPa·s to 2000 mPa·s at 25°C. Under the same conditions, the water-soluble polymer is preferably a water-soluble polymer with a viscosity in the range of 5.0 mPa·s to 1500 mPa·s, more preferably a water-soluble polymer with a viscosity in the range of 10 mPa·s to 1000 mPa·s, and even more preferably a water-soluble polymer with a viscosity in the range of 100 mPa·s to 800 mPa·s.

[0047] Specific examples of water-soluble polymers include: cellulose polymers, vinyl polymers, and acrylate polymers.

[0047] Specific examples of cellulose-based polymers include: hydroxyalkyl cellulose (e.g., hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxybutyl cellulose), hydroxyalkylalkyl cellulose (e.g., hydroxyethyl methyl cellulose (HEMC), hydroxypropyl methyl cellulose (HPMC)), alkyl cellulose (e.g., methyl cellulose), carboxymethyl cellulose, cellulose esters (cellulose acetate), etc.

[0048] Specific examples of vinyl polymers include: carboxyvinyl polymers, polyvinyl alcohol, polyvinyl copolymers (polymers in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol / acrylic acid / methyl methacrylate copolymers, polyvinyl alcohol / polyethylene glycol / graft copolymers, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, etc.), polyvinylpyrrolidone (polyvinyl ketone), polyvinylpyrrolidone, vinyl acetate resin, etc.

[0048] Specific examples of acrylate polymers include: aminoalkyl methacrylate copolymers (e.g., aminoalkyl methacrylate copolymer RS), ethyl acrylate / methyl methacrylate copolymers, etc.

[0049] In this invention, the preferred water-soluble polymer is a cellulose-based polymer.

[0049] In one embodiment of the present invention, the cellulose polymer is preferably HMC, HEC, HPC, HEMC, HPMC, methylcellulose, ethylcellulose, or carboxymethylcellulose, more preferably HEC, HPC, or HPMC, and even more preferably HPC.

[0049] In another embodiment of the present invention, the cellulose polymer is preferably hydroxyalkyl cellulose or hydroxyalkylalkyl cellulose, more preferably hydroxyC2-C4 alkyl cellulose or hydroxyC2-C4 alkylC1-C4 alkyl cellulose, and even more preferably hydroxyC2-C4 alkyl cellulose.

[0050] The term "hydroxyalkyl cellulose" refers to cellulose in which the hydroxyl groups are replaced by a number of hydroxyalkyl groups, and is a product of the reaction between cellulose and ethylene oxide, propylene oxide and other alkyl oxides.

[0050] "Hydroxy C2-C4 alkyl cellulose" refers to hydroxyalkyl cellulose with 2 to 4 carbon atoms in the hydroxyalkyl group. Specific examples include hydroxyethyl cellulose (HEC) or hydroxypropyl cellulose (HPC).

[0050] The term "hydroxyalkyl cellulose" refers to cellulose in which the hydroxyl groups are replaced by a plurality of alkyl groups and hydroxyalkyl groups. "Hydroxy C2-C4 alkyl C1-C4 alkyl cellulose" refers to hydroxyalkyl 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 such cellulose include hydroxypropyl methylcellulose (HPMC).

[0051] In one embodiment of the present invention, the content of 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 most preferably 1.25 w / w, relative to the total dosage.

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

[0053] In one embodiment of the present invention, the formulation of the present invention contains ethanol as a solvent.

[0053] In this specification, the term "ethanol" is used to refer to various grades of ethanol, including, for example, anhydrous ethanol and 95% ethanol.

[0053] In one embodiment of the present invention, the preferred ethanol is 95% ethanol.

[0053] In another embodiment of the present invention, the preferred ethanol is anhydrous ethanol.

[0053] In one embodiment of the present invention, the preferred content of ethanol relative to the total dosage is 30 w / w% to 95 w / w, 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.

[0053] In another embodiment of the present invention, the preferred content of ethanol relative to the total dosage 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.

[0054] In this specification, pH value refers to the value after immersing a non-aqueous solvent in the test preparation for 5 minutes using a pH electrode.

[0054] pH electrodes for non-aqueous solvents include, for example, pH electrodes for low-conductivity water / non-aqueous solvents (pH electrodes that can be used for both low-conductivity water and non-aqueous solvents).

[0054] In this specification, for example, pH value refers to the value obtained by immersing a low conductivity water / non-aqueous solvent pH electrode, which has been corrected using a pH standard solution, in 10.0 g of the test preparation for 5 minutes.

[0054] The determination of pH value using a pH electrode for water / non-aqueous solvents with low conductivity is explained in the 17th revision of the Japanese Pharmacopoeia (Hirokawa Shoten). This test was conducted according to the Japanese Pharmacopoeia. A commercially available pH electrode for water / non-aqueous solvents with low conductivity can be easily purchased from companies such as Horiba Advanced Techno Co., Ltd. The pH value can be determined using the aforementioned electrode at a temperature range of approximately 0 to 60°C, preferably 1 to 30°C, and even more preferably 20 to 30°C.

[0054] Here, "immersion pH electrode" means that the liquid-contact portion of the pH electrode is completely immersed in the test preparation in a manner that allows for accurate pH measurement.

[0055] In one embodiment of the present invention, the time point for pH value measurement is not particularly limited. That is, unless otherwise specified, the pH value at the moment the preparation solution is completed, the pH value one month after preparation, the pH value two months after preparation, the pH value three months after preparation, the pH value six months after preparation, the pH value twelve months after preparation, the pH value twenty-four months after preparation, or the pH value thirty-six months after preparation, etc., can be included at all time points.

[0055] In one embodiment of the present invention, the pH value of the formulation of the present invention is below 5.2 when the solution is prepared, below 5.2 after 1 month of preparation, below 5.2 after 2 months of preparation, below 5.2 after 3 months of preparation, below 5.2 after 6 months of preparation, below 5.2 after 12 months of preparation, below 5.2 after 18 months of preparation, below 5.2 after 24 months of preparation, or below 5.2 after 36 months of preparation.

[0055] In one embodiment of the present invention, the pH value of the formulation of the present invention is in the range of 2.5 to 5.2 when the solution is prepared, the pH value is in the range of 2.5 to 5.2 after 1 month of preparation, the pH value is in the range of 2.5 to 5.2 after 2 months of preparation, the pH value is in the range of 2.5 to 5.2 after 3 months of preparation, the pH value is in the range of 2.5 to 5.2 after 6 months of preparation, the pH value is in the range of 2.5 to 5.2 after 12 months of preparation, the pH value is in the range of 2.5 to 5.2 after 18 months of preparation, the pH value is in the range of 2.5 to 5.2 after 24 months of preparation, or the pH value is in the range of 2.5 to 5.2 after 36 months of preparation.

[0055] In one embodiment of the present invention, when the formulation of the present invention is stored at room temperature, the pH value at the time of preparation is in the range of 2.5 to 5.2, the pH value after 1 month of preparation is in the range of 2.5 to 5.2, the pH value after 2 months of preparation is in the range of 2.5 to 5.2, the pH value after 3 months of preparation is in the range of 2.5 to 5.2, the pH value after 6 months of preparation is in the range of 2.5 to 5.2, the pH value after 12 months of preparation is in the range of 2.5 to 5.2, the pH value after 18 months of preparation is in the range of 2.5 to 5.2, the pH value after 24 months of preparation is in the range of 2.5 to 5.2, or the pH value after 36 months of preparation is in the range of 2.5 to 5.2.

[0055] In each of the above-mentioned samples, it is acceptable as long as the pH value at any time point meets the above conditions. It is preferable that the pH value at two or more time points meets the conditions, and even more preferable that the pH value at all time points meets the above conditions.

[0056] In one embodiment of the present invention, the pH value of the preparation of the present invention is determined at one or more arbitrary time points selected within 6 months after the preparation is prepared, and the pH value is determined by measuring the pH value of the preparation after storage at room temperature.

[0056] In one embodiment of the present invention, the pH value of the preparation of the present invention is determined at one or more arbitrary time points selected within 6 months after preparation, and the pH value is determined by measuring the pH value of the preparation after storage at room temperature between preparation and measurement.

[0056] In one embodiment of the present invention, the pH value of the preparation of the present invention is determined at one or more arbitrary time points selected within one month after preparation, and the pH value is determined by measuring the pH value of the preparation after storage at room temperature between preparation and measurement.

[0056] The pH value of the formulation of the present invention is below 5.2, preferably 2.5 to 5.2, more preferably 3.0 to 5.2, and even more preferably 3.0 to 5.0.

[0056] In one embodiment of the present invention, the pH value is determined by measuring one or more arbitrary time points selected within 6 months after preparation, and the pH value determined by measuring the pH value of the preparation after storage at room temperature between preparation and measurement 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.

[0056] In addition, in this specification, room temperature refers to 1°C to 30°C.

[0057] The pH value of the formulation of the present invention is maintained below 5.2, preferably between 2.5 and 5.2.

[0057] In one embodiment of the present invention, it is more preferred that the formulation of the present invention is maintained at a pH value of 2.5 to 5.0, and even more preferably that the formulation of the present invention is maintained at a pH value of 2.5 to 4.5.

[0057] In another embodiment of the present invention, the preferred formulation of the present invention is maintained at a pH value of 3.0 to 5.2, more preferably the formulation of the present invention is maintained at a pH value of 3.0 to 5.0, and even more preferably the formulation of the present invention is maintained at a pH value of 3.0 to 4.5.

[0058] In one embodiment of the present invention, more typically, the pH value in the formulation of the present invention refers to the highest pH value during the storage of the formulation. For example, when described as "pH value below 5.2", it means that the highest pH value during the storage of the formulation is below 5.2, in other words, it means that the pH value is maintained below 5.2 during storage.

[0058] In one embodiment of the present invention, when the preparation of the present invention is stored at 40°C for 3 months after preparation, the pH value is maintained at 2.5 to 5.2, preferably at 2.5 to 5.0, and even more preferably at 2.5 to 4.5.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 36 months after preparation, the pH value is maintained below 5.2, preferably below 5.0, and more preferably below 4.8.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 36 months after preparation, the pH value is maintained at 2.5 to 5.2, preferably 3.0 to 5.2, and even more preferably 3.0 to 5.0.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 24 months after preparation, the pH value is maintained below 5.2, preferably below 5.0, and more preferably below 4.8.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 24 months after preparation, the pH value is maintained at 2.5 to 5.2, preferably 3.0 to 5.2, and even more preferably 3.0 to 5.0.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 12 months after preparation, the pH value is maintained below 5.2, preferably below 5.0, and more preferably below 4.8.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 12 months after preparation, the pH value is maintained at 2.5 to 5.2, preferably 3.0 to 5.2, and even more preferably 3.0 to 5.0.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 6 months after preparation, the pH value is maintained below 5.2, preferably below 5.0, and more preferably below 4.8.

[0058] In another embodiment of the present invention, when the preparation of the present invention is stored at room temperature for 6 months after preparation, the pH value is maintained at 2.5 to 5.2, preferably 3.0 to 5.2, and even more preferably 3.0 to 5.0.

[0058] In another embodiment of the present invention, the pH value of the preparation of the present invention is maintained at 3.0 to 5.2 after being prepared and stored at 40°C for 3 months. It is more preferably maintained at 3.0 to 5.0, even more preferably maintained at 3.0 to 4.8, and still more preferably maintained at 3.0 to 4.5.

[0059] In order to maintain the pH value within the above-mentioned preferred range, the formulation of the present invention may further include a pH adjuster. The pH adjuster is not particularly limited in type, as long as it is an additive that can be used in pharmaceuticals, and examples include: inorganic acids, inorganic acid salts, organic acids or organic acid salts, etc.

[0060] The so-called inorganic acids refer to, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydroiodic acid, etc.

[0060] The so-called inorganic acid salts refer to, for example: ammonium hydrochloride, potassium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.

[0061] An organic acid means that the chemical structure of the acid has at least one carbon atom, typically referring to a monovalent organic acid, a divalent organic acid or a trivalent organic acid.

[0061] Specifically, the so-called organic acids can include acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tannic acid, butyric acid, valeric acid, hibenzic acid, papoic acid, heptanoic acid, tartronic acid, decanoic acid, teoclic acid, salicylic acid, α-hydroxy acid, amino acid, oxalic acid and other organic carboxylic acids, as well as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic sulfonic acids.

[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, arabinic acid, and gluconic acid, etc.

[0062] Specific examples of amino acids include: glycine, alanine, glutamic acid, aspartic acid, phenylalanine, β-alanine, isoleucine, leucine, proline, glutamic acid, serine, threonine, valine, tryptophan, and tyrosine, etc.

[0062] In addition, in this specification, when referred to as "citric acid", it includes anhydrous citric acid and citric acid hydrate, etc.

[0063] The pH adjusters listed above include all of their stereoisomers, geometric isomers, hydrates, anhydrous hydrates, solvates and mixtures thereof.

[0063] In one embodiment of the present invention, the preferred pH adjuster is an organic acid or its salt, the more preferred pH adjuster is an α-hydroxy acid or its salt, the even more preferred pH adjuster is citric acid or tartaric acid or its salt, the even more preferred pH adjuster is anhydrous citric acid or D-tartaric acid or its salt, and the most 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 most preferably 0.05 w / w% or more but less than 0.1 w / w, relative to the total dosage.

[0064] In one embodiment of the present invention, the preferred pH adjuster relative to the total dosage is 0.015 w / w% to 5 w / w% anhydrous citric acid, more preferably 0.015 w / w% to 1.0 w / w% anhydrous citric acid, even more preferably 0.015 w / w% to 0.2 w / w% anhydrous citric acid, particularly preferably 0.015 w / w% to 0.075 w / w%, and even more preferably 0.05 w / w% to 0.075 w / w% anhydrous citric acid.

[0065] The formulation of the present invention may also contain more non-volatile oils.

[0065] In this specification, the term "non-volatile oil" refers to pharmaceutically permissible non-volatile liquid or gel bases, specifically including non-volatile esters, non-volatile polysiloxanes, non-volatile alcohols, non-volatile fatty acids, and non-volatile ethers.

[0065] Non-volatile oils are not particularly limited as long as they can be used as additives in pharmaceuticals, can be combined with ethanol to form a uniformly dispersed or dissolved sophoroferomycin bromide preparation, and do not cause an unpleasant user experience after application.

[0065] The preferred non-volatile oil of the present invention is a non-volatile ester, a non-volatile polysiloxane or a non-volatile ether, and more preferably a non-volatile ester or a non-volatile polysiloxane.

[0066] In one embodiment of the present invention, the preferred non-volatile oil is a non-volatile ester.

[0066] The term non-volatile ester refers to an ester oil that has one or more ester groups (-COO-) in one molecule and is not volatile.

[0066] Preferred non-volatile esters of the present invention include esters having 4 or more carbon atoms in the form of straight-chain or branched-chain alkyl groups.

[0066] The non-volatile esters in this invention include all of the following: monoesters, diesters and triesters.

[0066] In addition, the term "monoester" refers to an ester having one ester group in one molecule, the term "diester" refers to an ester having two ester groups in one molecule, and the term "triester" refers to an ester having three ester groups in one molecule.

[0066] In this specification, when referred to only as "monoester", "diesel" and "triester", it means non-volatile monoester, non-volatile dieel and non-volatile triester.

[0067] In one embodiment of the present invention, the non-volatile oil is a non-volatile ester selected from the group consisting of monoesters, diesters or triesters, wherein the monoester, diester or triester is represented by R1COOR2, one of R1 and R2 is a substituted C4-C40 straight-chain alkyl or a substituted C4-C40 branched-chain alkyl, and the other of R1 and R2 is a substituted C1-C40 alkyl.

[0067] In another embodiment of the present invention, the preferred non-volatile oil is a non-volatile ester selected from the group consisting of monoesters, diesters or triesters, wherein the monoester, diester or triester is represented by R1COOR2, where R1 is a C4-C40 straight-chain alkyl or C4-C40 branched-chain alkyl that can be substituted with hydroxyl or C1-C40 alkyloxycarbonyl, and R2 is a C1-C4 alkyl that can be substituted with hydroxyl or C1-C40 alkyloxycarbonyl.

[0068] In another embodiment of the present invention, the preferred nonvolatile ester is a nonvolatile ester selected from the group consisting of monoesters, diesters or triesters, wherein the monoester, diester or triester is represented by R1COOR2, where R1 is a C4-C40 straight-chain alkyl group that can be substituted with a C1-C4 alkyloxycarbonyl group, and R2 is a C1-C4 alkyl group that can be substituted with a C1-C22 alkylcarbonyloxy group.

[0069] The term "C4-C40 straight-chain alkyl" refers to straight-chain alkyl groups with 4 to 40 carbon atoms, including: n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecanyl, n-hexadecyl, n-heptadecyl, n-heptadecyl, n-octadecyl, etc.

[0069] The term "C4-C40 branched alkyl" refers to a branched alkyl group having 4 to 40 carbon atoms.

[0069] The term "C1-C4 alkyl" refers to alkyl groups having 1 to 4 carbon atoms, including straight-chain alkyl groups and branched-chain alkyl groups. Specifically, it refers to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl, terbutyl, etc.

[0069] The term "C1-C40 alkyl" refers to alkyl groups having 1 to 40 carbon atoms, including C4-C40 straight-chain alkyl, C4-C40 branched-chain alkyl, and C1-C4 alkyl.

[0070] The term "substitutable" as used above means that any one or more hydrogen atoms can be replaced by substituents other than hydrogen. For example, they can be substituted by hydroxyl, C1-C4 alkyloxycarbonyl or C4-C40 alkylcarbonyloxy.

[0071] The term "C1-C4 alkyloxycarbonyl" refers to alkyloxycarbonyl groups whose alkyl part is the aforementioned C1-C4 alkyl group, such as methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, etc.

[0071] The term "C1-C40 alkyl carbonyloxy" refers to alkyl carbonyloxy groups whose alkyl part is the aforementioned C1-C40 alkyl group, such as n-butyl carbonyloxy, n-hexyl carbonyloxy, n-heptyl carbonyloxy, n-octyl carbonyloxy, etc.

[0072] The substituents of the terms “substitutable C4-C40 straight-chain alkyl,” “substitutable C4-C40 branched-chain alkyl,” and “substitutable C1-C4 alkyl” can be categorized as hydroxyl, C1-C4 alkyloxycarbonyl, or C4-C40 alkylcarbonyloxy, etc. These can be substituted by one or more at any position.

[0073] In one embodiment of the present invention, preferred examples of monoesters may include: ethyl myristate, 2-octyl dodecyl myristate, butyl stearate, isocetyl stearate, 2-octyl dodecyl stearate, hexyl laurate, 2-hexyl decyl laurate, 2-ethylhexyl palmitate, 2-octyl decyl palmitate, cetearyl caprylate, isononyl isononanoate, octyl dodecyl neopentanoate, 2-octyl dodecyl erucic acid, 2-octyl dodecyl benzoate, decanoate, ricinoleate, isopropyl myristate, and isopropyl palmitate. Alkyl (C14-C18) esters of ethylhexanoate, myristyl ester of myristate, ethyl oleate, oleic acid ester, ethylhexyl palmitate, cetyl palmitate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, PPG-3 benzyl ether of myristate, isothietrate isononanoate, alkyl (C12-C15) esters of benzoic acid, isopropyl isostearate, isostearate isostearate, PPG-2 myristyl propionate, cetyl ester of 2-ethylhexanoate, 2-ethylhexyl stearate, medium-chain fatty acid monoglycerides, or ethyl lactate and other lactic acid alkyl esters.

[0073] A preferred monoester of the present invention is isopropyl myristate.

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

[0074] A 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 may be listed as: triisostearate citrate, trioctyl dodecyl citrate, trioleate citrate, trioctyl glycerol, triethyl citrate, or medium-chain fatty acid triglycerides.

[0075] A more preferred triester of the present invention is a medium-chain fatty acid triglyceride.

[0076] In this specification, the term "medium-chain triglyceride" refers to a non-volatile component formed by the ester bonding of three fatty acid molecules in one molecule of glycerol, specifically a saturated fatty acid with 6 to 14 carbon atoms. The preferred carbon number of the fatty acid is 8 to 12, and options include, for example, caprylic acid, capric acid, and lauric acid. Preferred medium-chain triglycerides include: caprylic acid triglyceride, capric acid triglyceride, a mixture of caprylic and capric acid triglycerides, a mixture of caprylic, capric, and lauric acid triglycerides, and tri(caprylic / capric) glycerides. Examples of products that can be used include Miglyol (registered trademark) 810 and 812.

[0076] The preferred medium-chain fatty acid triglyceride of the present invention is tri(caprylic acid / capric acid) glyceride.

[0077] In this specification, the so-called medium-chain fatty acid diglyceride is a non-volatile diester formed by ester bonding of 2 fatty acid molecules in 1 molecule of glycerol, and the so-called medium-chain fatty acid monoglyceride is a non-volatile monoester formed by ester bonding of 1 fatty acid molecule in 1 molecule of glycerol.

[0078] In one embodiment of the present invention, the non-volatile oil may also be a non-volatile polysiloxane.

[0078] Specific examples of preferred non-volatile polysiloxanes include: polydimethylsiloxane, Sealastic (registered trademark), medical grade polysiloxane oil, methylphenyl polysiloxane, methylhydropolysiloxane, decamethylpentane, octamethyltetracyclosiloxane, dimethyl polysiloxane, methylphenyl polysiloxane, cyclodimethylsiloxane 5-NF, PEG-12 polydimethylsiloxane, polydimethylsiloxane 20cSt, polydimethylsiloxane 100cSt, polydimethylsiloxane 350cSt, polydimethylsiloxane 500cSt, polydimethylsiloxane 1000cSt and polydimethylsiloxane 12500cSt, etc.

[0078] Examples of more preferred non-volatile polysiloxanes of the present invention include: cyclodimethylsiloxane 5-NF, PEG-12 polydimethylsiloxane, polydimethylsiloxane 20cSt or polydimethylsiloxane 350cSt.

[0079] In one embodiment of the present invention, the formulation of the present invention may also contain two or more non-volatile oils.

[0079] In the case where the formulation of the present invention contains two or more non-volatile oils, it is preferable to contain a formulation containing two or more non-volatile esters selected from the above-mentioned preferred non-volatile esters.

[0079] For example, the formulation of the present invention may also contain two monoesters, monoesters and diesters, monoesters and triesters, two diesters, diesters and triesters, two triesters, monoesters and non-volatile polysiloxanes, diesters and non-volatile polysiloxanes, triesters and non-volatile polysiloxanes, or two non-volatile polysiloxanes.

[0080] The preferred content of the non-volatile oil in this invention is 0.1 w / w% to 50 w / w% relative to the total dosage. More preferably, the content of the non-volatile oil is 0.2 w / w% to 25 w / w% relative to the total dosage; even more preferably, the content of the non-volatile oil is 0.5 w / w% to 10 w / w; even more preferably, the content of the non-volatile oil is 1.0 w / w% to 5.0 w / w; and most preferably, the content of the non-volatile oil is 2.5 w / w.

[0081] In one embodiment of the present invention, the preferred non-volatile oil system is 0.1 w / w% to 50 w / w% of isopropyl myristate, diisopropyl adipate, or medium-chain triglycerides.

[0081] In one embodiment of the present invention, the preferred non-volatile oil system is relative to 0.5 w / w% to 10 w / w% of isopropyl myristate, diisopropyl adipate, or medium-chain triglycerides.

[0081] In one embodiment of the present invention, the preferred non-volatile oil system is relative to 1.0 w / w% to 5.0 w / w% of isopropyl myristate, diisopropyl adipate, or medium-chain triglycerides.

[0082] In one embodiment of the present invention, the formulation of the present invention may also contain polyols.

[0082] In this specification, "polyol" refers to a compound in which multiple hydrogen atoms are substituted to form hydroxyl groups at any position in a hydrocarbon or ether.

[0082] There are no particular limitations on polyols as long as they can be used as additives in pharmaceuticals. Examples include: hexanediol (HG), propylene glycol (PG), ethylene glycol, glycerin, butylene glycol (BG), glycerol, etc.

[0083] In addition, in this specification, when it is referred to as "glycerol", it includes concentrated glycerol (cGly) and the like.

[0083] In one embodiment of the present invention, the preferred polyol is a compound in which two or three hydrogen atoms at any position in a C2-C10 hydrocarbon are substituted to form hydroxyl groups.

[0083] In one embodiment of the present invention, the preferred polyol is a compound in which two or three hydrogen atoms at any position in a C2-C6 hydrocarbon are substituted to form hydroxyl groups.

[0083] In one embodiment of the present invention, the preferred polyol is hexanediol, butanediol or glycerol.

[0084] The preferred content of the polyol in this invention is 0.1 w / w% to 50 w / w, relative to the total dosage. More preferably, the polyol content is 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 polyol system is hexanediol, butanediol or glycerol in a total dosage of 0.1 w / w% to 50 w / w%.

[0085] In one embodiment of the present invention, the preferred polyol system is hexanediol, butanediol or glycerol in a total dosage of 1.0 w / w% to 20 w / w%.

[0085] In one embodiment of the present invention, the preferred polyol system is hexanediol, butanediol or glycerol in a total dosage of 2.0 w / w% to 20 w / w%.

[0086] The term “viscosity” as used in this specification is synonymous with viscosity, which refers to the magnitude of resistance to the flow of a liquid.

[0086] Unless otherwise specified, the term "viscosity of the formulation" in this specification refers to viscosity at 25°C. Viscosity can be easily determined by methods not described in the general test methods of the Japanese Pharmacopoeia, but can also be easily determined by test methods commonly used by those skilled in the art. For example, it can be measured by the viscosity measurement method shown in the examples below.

[0086] In one embodiment of the present invention, the viscosity of the formulation of the present invention is preferably 10 mPa·s to 2000 mPa·s at 25°C, and more preferably 100 mPa·s to 1500 mPa·s.

[0086] 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, and more preferably from 100 mPa·s to 800 mPa·s.

[0086] In another embodiment of the present invention, the viscosity of the formulation of the present invention is preferably 10 mPa·s to 800 mPa·s at 25°C, and more preferably 50 mPa·s to 800 mPa·s.

[0087] The term "when preparing the solution" in this specification refers to the time of manufacturing the formulation or immediately after manufacturing. Unless otherwise specified, it is synonymous with the time of manufacturing the product. Typically, it refers to within one week after preparation, preferably within five days after preparation, and even more preferably within three days after preparation.

[0088] The term "viscosity reduction over time" in this specification, broadly speaking, refers to the phenomenon that the viscosity of the preparation decreases by more than 30% after storage for any period of time relative to the viscosity at the time of preparation. More narrowly speaking, it refers to the phenomenon that the viscosity decreases by more than 20%, more than 10%, or more than 5%.

[0088] In one embodiment of the present invention, in this specification, the decrease in viscosity over time refers to the phenomenon that the viscosity after conditioning is lower than the viscosity after 6 months, 12 months, 24 months, or 36 months of storage at room temperature, relative to the viscosity at the time of conditioning. Unless otherwise specified, viscosity refers to the value measured at 25°C.

[0088] In one embodiment of the present invention, in this specification, the decrease in viscosity over time refers to the phenomenon that the viscosity after conditioning, after storage at 40°C for 1 month, 2 months, or 3 months, is lower than the viscosity at the time of conditioning. Unless otherwise specified, 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 relative to the viscosity at the time of preparation, after being stored at room temperature for 12 months, increases or decreases by within ±30%, more preferably within ±20%, more preferably within ±10%, and even more preferably within ±5%.

[0089] In one embodiment of the present invention, the viscosity of the formulation of the present invention relative to the viscosity at the time of preparation, after being stored at room temperature for 24 months, increases or decreases by within ±30%, more preferably within ±20%, more preferably within ±10%, and even more preferably within ±5%.

[0089] In one embodiment of the present invention, the viscosity of the formulation of the present invention relative to the viscosity at the time of preparation, after being stored at room temperature for 36 months, increases or decreases by within ±30%, more preferably within ±20%, more preferably within ±10%, and even more preferably within ±5%.

[0089] In one embodiment of the present invention, the viscosity of the formulation of the present invention relative to the viscosity at the time of preparation, after being stored at 40°C for 3 months, increases or decreases by within ±30%, more preferably within ±20%, more preferably within ±10%, and even more preferably within ±5%.

[0090] The formulation of the present invention is stable over a long period of time and hardly produces decomposition products during storage, thus making it suitable as a pharmaceutical product.

[0090] In one embodiment of the present invention, after the formulation of the present invention is prepared and stored at room temperature for 24 months, 36 months, or 40°C for 3 months, the content of compound (II) shown in formula (II) below is 1.5 w / w% or less relative to the content of sofosfoam bromide, and the purity of sofosfoam bromide is 90 w / w% or more:

[0090]

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

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

[0093] In another embodiment of the present invention, the preparation of the present invention is prepared and stored at room temperature for 24 months, 36 months, or 40°C for 3 months after preparation, and the content of compound (II) is less than 0.4 w / w% relative to the content of sofosfoam bromide, and the purity of sofosfoam bromide is greater than 99.6 w / w%.

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

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

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

[0097] Next, the uses and typical examples of the formulation of the present invention will be described.

[0097] The formulations of the present invention can be used to treat, cure or prevent diseases for which efficacy can be expected through the anticholinergic effect of sofosfoam bromide, which is an active ingredient, specifically primary hyperhidrosis, overactive bladder, chronic obstructive pulmonary disease, heart disease, drooling, eye disease or bronchial asthma, etc.

[0098] The formulation of the present invention is preferably used to treat or prevent hyperhidrosis, and more preferably to treat or prevent localized hyperhidrosis.

[0098] In one embodiment of the present invention, the preparation of the present invention can be used to treat, cure or prevent primary axillary hyperhidrosis.

[0098] In another embodiment of the present invention, the formulation 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 specifically intended for the treatment or prevention of primary axillary hyperhidrosis, wherein a pharmaceutically permissible formulation comprising 1 w / w% to 15 w / w% of sofosbuvir, preferably 5 w / w% of sofosbuvir, is applied topically to the armpits, preferably both armpits, once daily for at least 6 weeks of treatment.

[0099] [Example]

[0100] Hereinafter, according to each test example, the preparation of the present invention will be described in more detail as an example. However, the present invention is not intended to be limited to this example.

[0101] [Test Example 1]

[0101] Accelerated test (1) of solfronium bromide in various non-aqueous preparations

[0101] <Preparation method>

[0101] Mix and dissolve the blending components in absolute ethanol to obtain a preparation so as to achieve the components and concentrations shown in the table below. The content of each preparation manufactured by this method is shown in the following table.

[0102] [Table 1]

[0103] <Viscosity measurement method>

[0103] Set the viscometer at 25 °C and 5 rpm, set the preheating time at 30 seconds, and measure the value after rotating about 1 mL of this product with a conical rotor: R-H1°34’×R24 for 200 seconds (Japanese Pharmacopoeia viscosity measurement method, Method 2).

[0104] [Table 2]

[0105] <pH value measurement method>

[0105] To suppress the deviation of the pH value, the amount of the test preparation must be within a certain range relative to the internal solution from the pH electrode. In the pH value measurement of this test example, the amount of the test preparation is 10.0 g.

[0105] In the calibration of the pH electrode, use oxalate pH standard solution, phthalate pH standard solution or phosphate pH standard solution. The temperature difference between the pH standard solution used for calibration and the test preparation is ±2 °C, and the temperature of the preparation during the pH value measurement is in the range of 20 to 30 °C.

[0105] Weigh 10.0 g of the test preparation in a Maruemu (registered trademark) No. 4 bottle, immerse the low conductivity water / non-aqueous solvent pH electrode calibrated with the pH standard solution in the preparation, and measure the value after 5 minutes.

[0106] [Table 3]

[0107] <Stability test method: 40 °C ± 2 °C / 75% RH ± 5% RH, protected from light, stored for 3 months>

[0107] Calculate the viscosity increase / decrease (%) relative to the viscosity at the time of preparation, after storage at 40°C for 3 months. Classify the case within ±30% as "A" and the case exceeding ±30% as "B". The results are shown in the table below.

[0107] In addition, the pH values ​​in the table below represent the highest values ​​during the storage period (i.e., up to the 3rd month after preparation).

[0108] [Table 4]

[0109] [Table 5]

[0110] Surprisingly, the pH value of the sofemamide bromide composition changed over time, and when its highest value was above 5.4, the viscosity imparted by the water-soluble polymer decreased over time (Comparative Examples 1 to 3).

[0110] On the other hand, as shown in Examples 1 to 7, it was found that when the pH of the sofosfoam bromide formulation was maintained below 5.2, the reduction in viscosity was suppressed.

[0111] [Experimental Example 2]

[0111] Accelerated testing of sofosfoam bromide in various non-aqueous formulations (2)

[0112] <Preparation Method>

[0112] The compositions of Reference Examples 1 to 5 (formulations without sofosfoam bromide), Comparative Example 4, and Examples 8 to 12 were prepared using the same method as in Test Example 1. These formulations were then used for viscosity stability tests.

[0112] In addition, Reference Examples 1 to 5, Comparative Examples 4, and Examples 8 to 12 are formulations containing sofosfoam bromide, anhydrous citric acid, anhydrous ethanol, IPM (2.5 w / w%), HG (10 w / w%), and HPC (1.25 w / w%). The contents of sofosfoam bromide and anhydrous citric acid are shown in Table 6. The residue is composed of anhydrous ethanol, with the total amount being 100%.

[0113] <Test Methods>

[0113] The method for pH value determination is the same as that for Experimental Example 1.

[0114] <Viscosity Measurement Methods>

[0114] For formulations with BBI-4000 content of 0% and 5%, the viscometer was set to 25°C, 10 rpm, and a preheating time of 30 seconds. The value was measured after approximately 1 mL was rotated with a conical rotor (R-H1°34'×R24) for 200 seconds (Viscosity Determination Method 2). For formulations with BBI-4000 content of 15%, the viscometer was set to 25°C, 7 rpm, and a preheating time of 30 seconds. The value was measured after approximately 1 mL was rotated with a conical rotor (R-H1°34'×R24) for 200 seconds (Japanese Pharmacopoeia Viscosity Determination Method 2).

[0115] [Table 6]

[0116] <Stability test method: 40℃±2℃ / 75%RH±5%RH, protected from light, stored for 3 months>

[0116] In the table below, the definition, measurement method and judgment criteria of pH value are the same as those in Experiment Example 1.

[0116]

[0117] [Table 8]

[0118] When sofefenamic acid bromide is not present, even if the pH value becomes significantly higher (see Example 1, etc.), the increase or decrease in viscosity is slight, and no relationship is observed between pH value and viscosity increase or decrease (see Examples 1 to 5). From this result, it can be concluded that the time-dependent viscosity decrease in non-aqueous formulations of sofefenamic acid bromide is a very unique phenomenon that only begins to appear when sofefenamic acid bromide is included in the formulation.

[0119] When the highest pH value reached 5.5 up to the third month after preparation, the viscosity decreased significantly over time (Comparative Example 4). On the other hand, during the period up to three months after preparation, when the pH value remained below 5.2, the viscosity decrease over time was slight or not observed (Examples 8 to 12). Furthermore, this tendency was also the same when the concentration of sofosfoam bromide was 15 w / w% (Example 12). The formulation of Example 10 was 322 mPa·s after being stored at 40°C for 6 months. The viscosity change rate compared to the preparation time was -13%, maintaining stability even after 6 months.

[0120] <Purity Test>

[0120] The results of the purity test (similar substance) of the formulation of Example 10 (BBI-4000 gel 5% (citric acid concentration: 0.050%)) in the stability test at 40℃±2℃ / 75%RH±5%RH, protected from light, for 3 months are shown in the table below.

[0121] [Table 9]

[0122] Compound (II) is the compound obtained by hydrolysis of the ethyl ester of sofospromonium bromide, and is represented by the following formula.

[0122]

[0123] In the above purity test, the only similar substances detected were compound (II) and ethyl cyclopentyl mandelate, which were found to be more than 0.1%. Therefore, it is shown that the non-aqueous formulation of sofosfoam bromide of the present invention produces almost no similar substances (including impurities) during storage and is an extremely stable composition.

[0124] [Experimental Example 3]

[0124] Accelerated testing of sofosfoam bromide in various low-water-content formulations

[0124] <Preparation Method>

[0124] The compositions of Examples 13 to 15 were prepared by means of the same method as in Test Example 1. The blended components were stirred / dissolved in anhydrous ethanol in such a manner as shown in the table to obtain the formulations. The contents of each formulation manufactured by this method are shown in the table below.

[0125] [Table 10]

[0126] <Test Methods>

[0126] The method for determining pH value is the same as that for test example 1, and the method for determining viscosity is the same as that for test example 2.

[0127] <Stability test method: 40℃±2℃ / 75%RH±5%RH, protected from light, stored for 3 months>

[0127] In the table below, the definition and judgment criteria of pH value are the same as those in Experimental Example 1.

[0128] [Table 11]

[0129] [Table 12]

[0130] As shown in the table above, the viscosity increase or decrease rates of Examples 13 to 15 with a water content of 5 w / w% or less are slight. That is, it has been found that, similar to the non-aqueous formulations of sofosfoam bromide, even in low-aqueous formulations with a water content of at least 5 w / w%, the viscosity decrease over time is slight by maintaining the pH value below 5.2.

[0131] <Purity Test>

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

[0132] [Table 13]

[0133] As shown in the table above, it is confirmed that as the amount of water added increases, the amount of compound (II) generated by hydrolysis increases slightly, but almost no other similar substances are produced.

[0133] As shown above, when the water content of the low-water-content formulation of sofosfoam bromide of the present invention is at least 5 w / w%, the formation of similar substances is extremely small and the formulation is stable.

[0133] As can be seen from the above results, the low-aqueous formulation of sofosfoam bromide with a water content of less than 5 w / w% exhibits almost no viscosity reduction over time, similar to the non-aqueous formulation, and the formation of similar substances is also limited, showing excellent performance as a pharmaceutical formulation (Profile).

[0134] [Experimental Example 4]

[0134] Accelerated testing of sofosfoam bromide in various non-aqueous formulations (3)

[0135] <Preparation Method>

[0135] Examples 16 to 19 were prepared using the same method as in Test Example 1. The blended components were stirred / dissolved in anhydrous ethanol in such a manner as shown in the table to obtain the formulations. The contents of each formulation manufactured by this method are shown in the table below.

[0136] [Table 14]

[0137] <Test Methods>

[0137] The pH value measurement method and the viscosity measurement method are the same as those in Test Example 1.

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

[0139] [Table 15]

[0140] [Table 16]

[0141] It was found that even under non-aqueous conditions without the addition of non-volatile oils and polyols, as shown in Examples 16 to 19, the reduction in viscosity was suppressed when the pH of the sofosfoam bromide formulation was maintained below 5.2.

[0142] [Experimental Example 5]

[0142] Accelerated testing of sofosfoam bromide in various non-aqueous formulations (4)

[0143] <Preparation Method>

[0143] Examples 20 to 23 were prepared using the same method as in Test Example 1. The blended components were stirred / dissolved in anhydrous ethanol in such a manner as shown in the table to obtain the formulations. The contents of each formulation manufactured by this method are shown in the table below.

[0144] [Table 17]

[0145] <Test Methods>

[0145] The pH value measurement method and the viscosity measurement method are the same as those in Test Example 1.

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

[0147] [Table 18]

[0148] [Table 19]

[0149] It has been found that, regardless of the type of non-volatile oil or water-soluble polymer used, as shown in Examples 20 to 23, when the pH of the sofosfoam bromide formulation is maintained below 5.2, the reduction in viscosity is suppressed.

[0150] [Experimental Example 6]

[0150] Long-term preservation test of sofosfoam bromide preparations

[0151] <Preparation Method>

[0151] Using the same method as in Test Example 1, the solutions of Examples 24, 25, Comparative Example 5, and Comparative Example 6 in the table below were prepared and used in various tests. The blended components were stirred / dissolved in anhydrous ethanol in such a manner as to achieve the constituent components and concentrations shown in the table to obtain the formulations. The contents of each formulation manufactured by this method are shown in the table below.

[0152] [Table 20]

[0153] <Test Methods>

[0153] The pH value measurement method and the viscosity measurement method are the same as those in Test Example 1.

[0154] <Stability Test Method 1: Store at 25℃±2℃ / 60%RH±5%RH, protected from light, for 24 months>

[0154] The formulations of Examples 24 and 25 were used in stability test 1. The pH values ​​in the table below represent the highest values ​​during the storage period (i.e., up to the 24th month after preparation). The judgment 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℃±2℃ / 60%RH±5%RH, protected from light, stored for 12 months>

[0155] The formulation of Comparative Example 6 was used for stability test 2. The pH values ​​in the table below represent the highest values ​​during the storage period (i.e., up to the 12th month after preparation). The judgment 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, with anhydrous citric acid concentration of 0.001 w / w%, had a pH value of 6.1 to 5.9 when prepared. When stored at room temperature, the pH value changed over time, similar to that of Comparative Examples 1 to 4 of Test Example 1.

[0158] The formulation of Comparative Example 6, with an anhydrous citric acid concentration of 0.001 w / w%, showed a significant decrease in viscosity (-76%) after being stored at room temperature for 12 months. On the other hand, the formulations of Examples 24 and 25, with an anhydrous citric acid concentration of 0.05 w / w%, maintained a pH value below 5.2 after liquid preparation, and showed minimal change in viscosity over time.

[0158] Therefore, the bromide folium preparation with a pH value maintained below 5.2 after conditioning can inhibit the decrease in viscosity over time.

[0158] In particular, this experiment revealed that when storing the formulation at room temperature, it is preferable that the pH value is between 2.5 and 5.2 at any time point up to the 6th month after preparation. For example, when storing the formulation at room temperature, it is preferable that the pH value is within the range of 2.5 to 5.2 at the 1st, 3rd, or 6th month after preparation.

[0159] <Purity Test>

[0159] In the long-term storage test (25℃±2℃ / 60%RH±5%RH, protected from light) of the formulations of Examples 24 and 25, purity tests (for similar substances) were performed up to 24 months after preparation. In Example 24, a very small HPLC peak of cyclopentylmandelate was observed at 24 months. In Example 25, no increase in similar substances or the appearance of new similar substances was observed during the storage period after preparation. These results demonstrate that the formulations of Examples 24 and 25 are stable in the long-term storage test.

[0160] As described above, regardless of the storage temperature and other test conditions, as shown in Examples 24 and 25, the bromide sofemidine preparation with a pH value maintained below 5.2 did not show an increase in impurities over a long period of time, and the decrease in viscosity was suppressed.

[0161] [Experimental Example 7]

[0161] Validation trial of BBI-4000 in patients with primary axillary hyperhidrosis

[0162] This study aimed to verify the efficacy of a topical medication containing sofosfilodium bromide (5 w / w sofosfilodium bromide, 1.25 w / w hydroxypropyl cellulose, 2.5 w / w isopropyl myristate, 0.05 w / w anhydrous citric acid, 10 w / w hexanediol, with the residue consisting of anhydrous ethanol) applied once daily to the armpits before bedtime for 6 weeks, compared with a placebo (0 w / w sofosfilodium bromide). The primary assessment criteria were defined as a HDSS score of 1 or 2 at the end of treatment and a ratio of the combined axillary sweat weight at the end of treatment to baseline (sweat weight measured before treatment) of less than 0.5.

[0163] In this study, "before treatment" refers to a time point prior to the administration of the pharmaceutical preparation containing sofosfoam bromide.

[0163] In this trial, "at the end of treatment" refers to the hospital visit period that serves as the baseline for the end of treatment. The end of treatment consists of three hospital visits following the predetermined administration period, and the HDSS score and sweat weight at the end of treatment, unless otherwise noted, refer to their median values.

[0163] In this study, "during the treatment period" refers to the period between the start and end of treatment.

[0164] In this study, “baseline” refers to the measured values ​​that are related to the pre-administration baseline symptom severity. The baseline is measured within a specified period before administration.

[0164] The baseline HDSS score and sweat weight in this test case refer to the median value of the measurements taken on three hospital visits within 9 days, defined as baseline 1, baseline 2 and baseline 3.

[0164] The number of days for administering the pharmaceutical preparation of sofosfoam bromide is the number of days with baseline 3 as day 1, and the "administration period" or "administration week" is also based on this basis. Baseline 3 is the date on which the administration of the pharmaceutical preparation of sofosfoam bromide begins.

[0164] The timeline of this experiment is shown in Figure 1.

[0165] <Analysis of Validity>

[0165] (1) Main analysis of validity

[0165] The proportion of subjects whose HDSS score at the end of treatment was 1 or 2 and whose ratio of the total weight of sweating in both armpits at the end of treatment to baseline was less than 0.5 was analyzed by chi-square test.

[0166] (2) Secondary analysis of validity

[0166] 1) Weight of sweat

[0166] The median of the total sweat weight of both armpits at baseline 1 to 3 was used as the baseline sweat weight, and the median of the total sweat weight of both armpits at week 6 (1 to 3) was used as the total sweat weight of both armpits at the end of treatment.

[0166] For the total weight of sweat produced in both armpits, basic statistics were calculated for each implementation period according to the treatment group, and comparisons were made between the treatment groups. Furthermore, the following confidence intervals were calculated for the differences between treatment groups, and statistical tests were performed.

[0166] ‧The proportion of subjects whose total axillary sweat weight at the end of treatment was less than 0.5 compared to baseline.

[0166] ‧The change in the total weight of sweat produced in both armpits from baseline at the end of treatment.

[0166] 2)HDSS

[0166] The median HDSS score from baseline 1 to 3 was used as the baseline HDSS score, and the median HDSS score from week 1 to 3 at week 6 was used as the HDSS score at the end of treatment. Totals were calculated for each administration period, depending on the administration group. Furthermore, the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment was calculated, and confidence intervals were established for differences between administration groups, followed by statistical testing.

[0167] <Investigation Items on Validity>

[0167] Investigate the following items and record the results.

[0167] (1) Measurement of sweat weight

[0167] 1) Measurement conditions

[0167] ‧Temperature: 20°C to 28°C, Humidity: 20%RH to 80%RH

[0167] 2) Determination method

[0167] Place pre-weighed filter paper under the subject's armpits for 5 minutes.

[0167] Then, the weight of the filter paper containing sweat was measured and the weight of the sweat was calculated.

[0167] Furthermore, each subject was tested at a time between 8:00 AM and 7:00 PM, with the time difference not exceeding 4 hours.

[0168] (2)HDSS

[0168] The criteria for determining HDSS scores are as follows.

[0168]

[0169] <Target Patients and Main Inclusion Criteria>

[0169] Patients with primary axillary hyperhidrosis who are 12 years of age or older at the time of obtaining consent and meet the following diagnostic criteria and conditions.

[0169] 1. Patients diagnosed with primary axillary hyperhidrosis who meet two or more of the following six criteria during the screening and consultation process.

[0169] (1) The initial symptoms appeared in people under 25 years old.

[0169] (2) Symmetrical sweating can be observed on both sides.

[0169] (3) Sweating stops during sleep

[0169] (4) More than one episode of excessive sweating per week

[0169] (5) Observed family history

[0169] (6) Excessive sweating interferes with daily life.

[0169] 2. Patients who meet all of the following conditions

[0169] (1) HDSS scores of 3 or 4 at each time point from baseline 1 to 3.

[0169] (2) At any two of the three time points from baseline 1 to 3, the weight of sweat produced in each axilla was 50 mg or more.

[0170] <Main Exclusion Criteria>

[0170] 1. Patients with secondary hyperhidrosis

[0170] 2. Patients whose hyperhidrosis symptoms began or worsened due to amenorrhea.

[0170] 3. Patients suitable for thoracic sympathetic nerve block surgery

[0171] <Patients in clinical trials>

[0171] 281 patients with primary axillary hyperhidrosis were randomly assigned to the investigational drug (140 in the 0% group and 141 in the 5% group), and data analysis was performed using these patient groups as subjects.

[0172] <Results of the main evaluation items for effectiveness>

[0172] The proportion of subjects whose HDSS score at the end of treatment was 1 or 2 and whose total axillary sweat weight at the end of treatment was less than 0.5 compared with baseline is shown in the table below.

[0173] [Table 24]

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

[0174] <Results of secondary evaluation items for effectiveness>

[0174] (1)HDSS

[0174] The proportion of participants 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. This was 12.4% higher in the 5% group than in the 0% group (95% confidence interval: 0.86 to 23.99), which was statistically significant between the groups (chi-square test: p=0.036).

[0175] (2) Weight of sweat

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

[0176] <Efficacy results in patients with a combined axillary sweat weight of 400 mg or more>

[0176] In order to examine the effectiveness of the method in patients with severe sweating based on the baseline total axillary sweat weight, the effectiveness was examined in a subset of patients whose baseline total axillary sweat weight was 400 mg or more.

[0176] The analysis results are shown in the table below.

[0177] [Table 25]

[0178] The proportion of subjects whose HDSS score at the end of treatment was 1 or 2, and whose ratio of the total axillary sweat weight at the end of treatment to baseline was less than 0.5, which is a primary assessment item, was higher in the 5% group than in the 0% group across all categories. Furthermore, the inter-group difference was 15.5% in categories with a difference between 100 mg and 400 mg, and 46.2% in categories with a difference between 400 mg and 400 mg. That is, the difference between groups was greater in categories with a difference between 400 mg and 400 mg.

[0179] The percentage of subjects with an HDSS score of 1 or 2 at the end of treatment and the percentage of subjects whose combined axillary sweat weight at the end of treatment was less than 0.5 compared to baseline were both higher in the 5% group and lower in the 0% group across all categories. The average combined axillary sweat weight was lower in the 5% group and lower in the 0% group across all categories and at each assessment time point after treatment. The average combined axillary sweat weight at the end of treatment was lower in the 5% group and lower in the 0% group across all categories.

[0179] In the above, for subjects whose baseline total axillary sweat weight was 400 mg or more, improvement was observed in the 5% group in all assessment items compared to the 0% group.

[0180] <Changes in HDSS scores before and after treatment in the 5% BBI-4000 group>

[0180] In a randomized, double-blind, parallel intergroup comparison of patients with primary axillary hyperhidrosis, 5% of BBI-4000 was applied to the axilla once daily for 6 weeks. The difference (ΔHDSS) was calculated by subtracting the HDSS score at the end of treatment from the HDSS score before treatment for each subject. 140 cases with both pre-treatment and end-treatment HDSS scores were used as the analysis subjects, and the mean change and standard deviation of ΔHDSS were calculated.

[0180] As a result, the mean ΔHDSS of the 5%BBI-4000 group was 1.14±0.87.

[0180] [Industrial Applicability]

[0181] According to the present invention, a stable composition in which the viscosity of non-aqueous and low-aqueous formulations of sofosfoam bromide is suppressed over time during long-term storage can be provided.

[0181] Furthermore, the formulation of the present invention can be used to treat, cure or prevent primary axillary hyperhidrosis.

Claims

1. A pharmaceutical preparation for external application to the surface of the human body, comprising (a) to (c), (a) sofpironium bromide, (b) one or more water-soluble polymers, and (c) ethanol, wherein the pharmaceutical preparation has a pH value of 5.2 or less, and is a uniformly dispersed low-aqueous preparation with a water content of 0.01 w / w% to 5 w / w%. The aforementioned pH value was measured at one or more arbitrary time points within 6 months after preparation. The aforementioned pH value was determined by measuring the pH value of the aforementioned preparation stored at room temperature. The aforementioned pH value was the value after immersing the non-aqueous solvent in the aforementioned preparation for 5 minutes using a pH electrode. The water-soluble polymer is selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, carboxyvinyl polymers, polyvinyl alcohol, polyvinyl copolymers, polyvinylpyrrolidone, and polyvinylpyrrolidone.

2. The pharmaceutical preparation as described in claim 1, wherein, The content of sofosfoam bromide is 1 w / w% to 20 w / w relative to the total dose.

3. The pharmaceutical preparation as described in claim 1 or 2 has a pH value in the range of 2.5 to 5.

2.

4. The pharmaceutical preparation described in claim 1 or 2 is a preparation that has been uniformly dissolved.

5. The pharmaceutical preparation as described in claim 1 or 2, wherein, The water-soluble polymer is hydroxypropyl cellulose or carboxyvinyl polymer.

6. The pharmaceutical preparation as described in claim 1 or 2, wherein, The content of water-soluble polymers is 0.01 w / w% to 5.0 w / w, relative to the total dose.

7. The pharmaceutical preparation as described in claim 1 or 2, wherein, The ethanol content was above 50 w / w but below 99 w / w relative to the total dose.

8. The pharmaceutical preparations described in claim 1 or 2 further contain a pH adjuster.

9. The pharmaceutical preparation as described in claim 8, wherein, pH adjusters are acids or their salts selected from the group consisting of tartaric acid, acetic acid, and citric acid.

10. The pharmaceutical preparation as described in claim 8, wherein, The pH adjuster content is 0.015 w / w% to 5 w / w, relative to the total dose.

11. The pharmaceutical preparations described in claim 1 or 2 further contain non-volatile oils, except for pharmaceutical preparations containing dimethiconol blend 20.

12. The pharmaceutical preparation as described in claim 11, wherein, Non-volatile oils are selected from the group consisting of non-volatile esters, non-volatile ethers, non-volatile polysiloxanes, and non-volatile alcohols.

13. The pharmaceutical preparation as described in claim 11, wherein, Non-volatile oils are non-volatile esters selected from the group consisting of monoesters, diesters and triesters. The aforementioned non-volatile esters are represented by R1COOR2, where one of R1 and R2 is a substituted C4-C40 straight-chain alkyl or a substituted C4-C40 branched-chain alkyl, and the other of R1 and R2 is a substituted C1-C40 alkyl.

14. The pharmaceutical preparation as described in claim 11, wherein, The non-volatile oil is selected from ethyl myristate, 2-octyl dodecyl myristate, butyl stearate, isocetyl stearate, 2-octyl dodecyl stearate, hexyl laurate, 2-hexyl decyl laurate, 2-ethylhexyl palmitate, 2-octyl decyl palmitate, cetearyl caprylate, isononyl isononanoate, octyl dodecyl neopentanoate, 2-octyl dodecyl erucic acid, and 2-octyl dodecyl benzoate. Decanoate, Ricinoleate, Isopropyl Myristate, Diisopropyl Adipate, Medium-Chain Fatty Acid Triglycerides, Isopropyl Palmitate, Alkyl (C14-C18) Ethylhexanoate, Myristyl Myristate, Ethyl Oleate, Oleate Oleate, Ethylhexyl Palmitate, Cetyl Palmitate, 2-Hexyldecyl Myristate, 2-Hexyldecyl Palmitate, PPG-3 Benzyl Ether Myristate, Isotridecyl Isonononanoate Non-volatile fatty acid esters comprising triethylhexyl trimellitate, alkyl (C12-C15) benzoate, diethoxyethyl succinate, propylene glycol didecanoate, propylene glycol dioctanoate, tri(octanoic / decanoic acid) glycerides, triethylhexanoate, triisostearin, isopropyl isostearate, isostearate, polyglycerol triisostearate-2, diethylhexyl succinate, PPG-2 myristyl propionate, neopentyl tetrastearate, diethyl sebacate, PPG-3 benzyl ether ethylhexanoate, tris(2-ethylhexanoate) cetyl ester, diisostearate malate, 2-ethylhexyl stearate, triethylhexyl citrate, and ethyl lactate, etc.

15. The pharmaceutical preparation as described in claim 11, wherein, Non-volatile oils are non-volatile fatty acid esters selected from the group consisting of isopropyl myristate, diisopropyl adipate, and medium-chain triglycerides.

16. The pharmaceutical preparation as described in claim 11, wherein, The non-volatile oil is a non-volatile polysiloxane selected from the group consisting of medical-grade polysiloxane oil, methylphenyl polysiloxane, methylhydropolysiloxane, decamethylpentane, octamethyltetracyclosiloxane, cyclomethicone 5-NF, PEG-12 dimethicone, 20cSt, 100cSt, 350cSt, 500cSt, 1000cSt, and 12500cSt.

17. The pharmaceutical preparation as described in claim 11, wherein, The non-volatile oil is a non-volatile polysiloxane selected from the group consisting of cycloisocyanate polydimethylsiloxane 5-NF, PEG-12 polydimethylsiloxane, polydimethylsiloxane 20cSt and polydimethylsiloxane 350cSt.

18. The pharmaceutical preparation as described in claim 11, wherein, The content of non-volatile oils is 0.5 w / w% to 10 w / w relative to the total dose.

19. The pharmaceutical preparation described in claim 1 or 2 further contains polyols.

20. The pharmaceutical preparation as described in claim 19, wherein, Polyols are selected from the group consisting of hexanediol, propylene glycol, ethylene glycol, glycerol, and butylene glycol.

21. The pharmaceutical preparation as described in claim 19, wherein, The polyol content ranges from 1.0 w / w% to 30 w / w relative to the total dose.

22. The pharmaceutical preparation as described in claim 1 or 2, wherein, The viscosity at 25°C is 10 mPa·s to 2000 mPa·s.

23. The pharmaceutical preparation as described in claim 1 or 2, wherein, After being prepared and stored at room temperature for 36 months, or after being prepared and stored at 40°C for 3 months, the viscosity at 25°C is 10 mPa·s to 1000 mPa·s.

24. The pharmaceutical preparation described in claim 1 or 2 is used to treat, cure or prevent diseases selected from the group consisting of hyperhidrosis, overactive bladder, chronic obstructive pulmonary disease, heart disease, drooling, eye disease and bronchial asthma.

25. The pharmaceutical preparation as described in claim 1 or 2, wherein, After preparation and storage at room temperature for 36 months or after preparation and storage at 40°C for 3 months, the content of compound (II) shown in formula (II) below is less than 1.5 w / w% relative to the content of sofosfoam bromide, and the purity of sofosfoam bromide is greater than 90 w / w%.

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