Anti-acanthamoeba liquid

Abstract

The purpose of the present invention is to provide an anti-acanthamoeba liquid which has an anti-acanthamoeba effect, has little impact on ocular tissue, is safe, and has versatility that can be applied to most contact lenses. The purpose is achieved by a solution for resisting acanthamoeba, which comprises a sodium dihydrogen phosphate dihydrate, a basic isoosmotic adjusting agent, and polydiallyldimethylammonium chloride having an average molecular weight of 10,000 to 1100,000, and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to a liquid agent having a disinfecting effect on acanthamoeba. BACKGROUND

[0002] Acanthamoeba keratitis is an infectious disease of the cornea caused by infection of the cornea with microorganisms of the genus Acanthamoeba (hereinafter also referred to simply as acanthamoeba). Patients with acanthamoeba keratitis not only have strong pain in the eye, but also have the possibility of losing sight due to corneal perforation if the disease becomes severe. The number of cases of acanthamoeba keratitis has been increasing in recent years.

[0003] Acanthamoeba is a protozoan that is widely present in soil and fresh water and the like, and also lives in tap water. Generally, the possibility of infection by acanthamoeba is low for a healthy cornea. However, in the case where a wound is present in the cornea, infection can occur due to invasion and attachment of acanthamoeba from the wound. In addition, contact lenses of contact lens wearers can be contaminated with acanthamoeba brought by tap water and the like, and acanthamoeba keratitis can occur due to wearing of the contact lenses.

[0004] Treatment of acanthamoeba keratitis is generally performed by corneal scraping and administration of an antifungal drug. However, acanthamoeba keratitis is a refractory infectious disease, and problems such as early detection difficulty, recurrence of inflammation, prolonged treatment time, and corneal scarring remain, which impose a heavy burden on patients. Contact lens wearers can prevent or treat corneal infection by using a liquid agent containing an agent having an anti-acanthamoeba effect, which prevents contamination by acanthamoeba.

[0005] As such a liquid agent, there are known: an anti-acanthamoeba disinfecting and preserving agent for contact lenses containing an effective amount of polylysine (for example, see Patent Literature 1); an anti-acanthamoeba composition containing lactoferrin as a glycoprotein or a peptide as an enzymatic hydrolysate thereof as an effective ingredient (for example, see Patent Literature 2); and an anti-parasitic composition containing caspofungin, which is an echinocandin agent, and a biguanide compound as effective ingredients (for example, see Patent Literature 3).

[0006] On the other hand, in recent years, a multi-purpose solution (MPS) that can perform cleaning, rinsing, disinfecting, and preserving of contact lenses by one liquid agent has been widely popularized because of the ease of handling. As a disinfecting ingredient added to the MPS, an organic nitrogen-based disinfectant is generally used. There is known a preventive and therapeutic agent for acanthamoeba keratitis containing both an organic nitrogen-based disinfectant and a diallyldialkylammonium polymer as effective ingredients, which can be applied to the MPS (for example, see Patent Literature 4). In addition, there is known a method of improving the bactericidal activity against acanthamoeba by simultaneously adding a polyol and boric acid to an alexidine (for example, see Patent Literature 5).

[0007] Prior Art Documents Patent Documents Patent Document 1: Japanese Patent Application Laid-Open (JP-A) No. 2002-143277 Patent Document 2: Japanese Patent Application Laid-Open (JP-A) No. 2011-246458 Patent Document 3: Japanese Patent Application Laid-Open (JP-A) No. 2013-234176 Patent Document 4: Japanese Patent Application Laid-Open (JP-A) No. 2014-218461 Patent Document 5: Japanese Patent Application Laid-Open (JP-A) No. 2018-035151 SUMMARY

[0008] Problems to be Solved by the Invention However, the agents, compositions, and methods described in Patent Documents 1 to 5 each have a problem.

[0009] The Acanthamoeba disinfectant preservative described in Patent Document 1 has a problem of insufficient versatility because the effective component, polylysine, cannot be applied to soft contact lenses of Class IV (high ionicity and high water content).

[0010] The anti-Acanthamoeba composition described in Patent Document 2 has a problem of low safety because the peptide of the glycoprotein or its decomposition product as the effective component is deposited in the ocular tissue, resulting in visual impairment and ocular impairment.

[0011] The antiparasitic composition described in Patent Document 3 has a problem of low safety because the effective component, caspofungin, inhibits the activity of 1,3-beta glucan synthase, which is a major component of the cell wall, thereby exerting antifungal activity, but caspofungin can cause adverse effects such as an allergic reaction, liver dysfunction, and ocular pruritus.

[0012] The prophylactic and therapeutic agent for Acanthamoeba keratitis described in Patent Document 4 contains a high concentration of a diallyldialkylammonium polymer as the effective component, and has a problem that the polymer can cause adverse effects such as an allergic reaction, liver dysfunction, and ocular pruritus.

[0013] The method described in Patent Document 5 is characterized by simultaneously adding a polyol and boric acid to alametidine. Among them, boric acid has been widely used in ophthalmic solutions because of its preservative effect. However, in recent years, it has been reported that boric acid damages the cornea, and as a result, causes ocular impairment and the like, and therefore the addition of boric acid to ophthalmic solutions has started to be restricted.

[0014] Thus, the agents, compositions, and methods described in Patent Documents 1 to 5 have problems of safety to the ocular tissue and versatility of the contact lenses as the applicable object, even if the effective components exhibit a disinfecting effect on Acanthamoeba.

[0015] Therefore, an object of the present application is to provide an anti- Acanthamoeba liquid agent which has an anti- Acanthamoeba effect, has a small effect on ocular tissues, has safety, and has versatility applicable to most contact lenses.

[0016] Means for solving the problem The present inventors have repeatedly and intensively studied liquid agents which have a small effect on ocular tissues but exhibit a disinfecting effect on Acanthamoeba. Among them, when a component which has been confirmed to be safe for ocular tissues, i.e., sodium phosphate monobasic, and an alkaline isotonicity adjusting agent are used in combination, a disinfecting effect on fungi is confirmed, but no disinfecting effect on Acanthamoeba is confirmed.

[0017] Therefore, the present inventors have further repeatedly and intensively studied, and finally focused on polydiallyldimethylammonium chloride which has also been confirmed to be safe for ocular tissues, and found that, when a prescribed polydiallyldimethylammonium chloride is used in combination with sodium phosphate monobasic and an alkaline isotonicity adjusting agent, an excellent disinfecting effect on Acanthamoeba is exhibited.

[0018] Surprisingly, a liquid agent containing sodium phosphate monobasic, an alkaline isotonicity adjusting agent, and a prescribed polydiallyldimethylammonium chloride is applicable to a wide variety of contact lenses.

[0019] Based on this insight, as a liquid agent capable of solving the problem of the present application, the present inventors have finally succeeded in producing a liquid agent containing sodium phosphate monobasic, an alkaline isotonicity adjusting agent, and a prescribed polydiallyldimethylammonium chloride. The present application is an application completed based on this insight and the first successful example discovered for the first time by the present inventors.

[0020] Therefore, according to the present application, each of the following anti- Acanthamoeba liquid agents can be provided.

[0021] [1] An anti- Acanthamoeba liquid agent containing sodium phosphate monobasic, an alkaline isotonicity adjusting agent, and polydiallyldimethylammonium chloride having an average molecular weight of 10,000 to 1,100,000.

[0022] [2] The anti- Acanthamoeba liquid agent according to item [1], wherein the ratio of the content of the alkaline isotonicity adjusting agent to the content of the sodium phosphate monobasic ([alkaline isotonicity adjusting agent] / [sodium phosphate monobasic]) is 0.01 to 2, and the pH is 6.5 to 8.5.

[0023] [3] The anti- Acanthamoeba liquid agent according to item [1] or [2], wherein the ratio of the content of the polydiallyldimethylammonium chloride to the content of the sodium phosphate monobasic ([polydiallyldimethylammonium chloride] / [sodium phosphate monobasic]) is 0.00005 to 0.01.

[0024] [4] The liquid preparation against Acanthamoeba according to any one of items [1] to [3], wherein the ratio of the content of the polydiallyldimethylammonium chloride relative to the total content of the content of the sodium dihydrogen phosphate and the content of the basic isotonicity adjusting agent is 0.000001 to 1 ([polydiallyldimethylammonium chloride] / ([sodium dihydrogen phosphate] + [basic isotonicity adjusting agent]).

[0025] [5] The liquid preparation against Acanthamoeba according to any one of items [1] to [4], wherein the basic isotonicity adjusting agent is one or more kinds of basic isotonicity adjusting agents selected from the group consisting of 2-amino-2-hydroxymethyl-l,3-propanediol, 2-amino-2-ethyl-l,3-propanediol, and arginine, and salts thereof.

[0026] [6] The liquid preparation against Acanthamoeba according to any one of items [1] to [5], wherein the polydiallyldimethylammonium chloride is polydiallyldimethylammonium chloride having an average molecular weight of 100,000 to 1,000,000.

[0027] [7] The liquid preparation against Acanthamoeba according to any one of items [1] to [6], further comprising an isotonicity adjusting agent different from the basic isotonicity adjusting agent.

[0028] [8] The liquid preparation against Acanthamoeba according to item [7], wherein the isotonicity adjusting agent is one or more kinds of isotonicity adjusting agents selected from the group consisting of sodium chloride, potassium chloride, 1,2-propanediol, 1,3-propanediol, mannitol, and sorbitol.

[0029] [9] The liquid preparation against Acanthamoeba according to any one of items [1] to [8], further comprising one or more kinds of quaternary ammonium salts selected from the group consisting of polyhexamethylene biguanide hydrochloride, alexidine, myristamidopropyl dimethylamine, benzalkonium chloride, benzethonium chloride, and polyquaternium-1.

[0030] Effects of the Invention According to the present application, Acanthamoeba can be killed by a combination of components that have been proven to be safe in ophthalmic liquid preparations. Furthermore, according to the present application, various contact lenses can be disinfected with Acanthamoeba as the target without causing deformation or the like. Thus, the liquid preparation against Acanthamoeba of one embodiment of the present application is not only highly safe for ocular tissues, but also has versatility that can be applied to most contact lenses, and also has an excellent disinfecting effect on Acanthamoeba.

[0031] Furthermore, the liquid preparation against Acanthamoeba of one embodiment of the present application can be used for cleaning, rinsing, disinfecting, and storing of contact lenses, and thus can be used daily as an MPS. According to the present application, a contact lens wearer can reduce or avoid the risk of contracting an Acanthamoeba keratitis caused by Acanthamoeba. DETAILED DESCRIPTION

[0032] The following describes the details of each mode of the present application, but the present application can take various modes as long as the object of the present application is achieved.

[0033] Unless otherwise specified, the terms in the present specification are used in the meanings commonly used by those skilled in the art of chemistry for handling ophthalmic lenses such as contact lenses, and should not be interpreted as having an undue limiting meaning. Furthermore, since the speculations and theories made in the present specification are made based on the insights and experiences of the present inventor up to now, the present application is not limited only to these speculations and theories.

[0034] The "content" is synonymous with concentration and usage amount (addition amount), and refers to the proportion of the amount of a component with respect to the total amount of the final product. The total amount of the content of the component is not more than 100%. In the present specification, unless otherwise specified, the unit of the content refers to "mass / volume percentage (w / v%)". In addition, in the case of using a commercial product, the content of the component is preferably the amount of the component contained in the commercial product, but can also be the amount of the commercial product itself.

[0035] The term "and / or" means any one of the listed related items or any combination or all of the combinations of two or more of them.

[0036] "Comprise" means that an element other than the explicitly stated element can be added (synonymous with "at least contain"), and includes "consist of" and "essentially consist of". That is, "comprise" can mean to contain the explicitly stated element and any one or two or more elements, and can mean to consist of the explicitly stated element or essentially consist of the explicitly stated element. The elements can include components, procedures, conditions, parameters, and the like.

[0037] The "-" of the numerical range is a range including the values before and after it, and a range excluding one of the boundary values contained therein is also included. For example, "0 w / v% - 100 w / v%" can be any one of 0 w / v% or more, 100 w / v% or less, and 0 w / v% or more and 100 w / v% or less.

[0038] The number of digits of an integer value and the number of digits of a significant figure are the same. For example, the significant figure of 1 is 1 digit, and the significant figure of 10 is 2 digits. In addition, the number of digits after the decimal point of a decimal value and the number of digits of a significant figure are the same. For example, the significant figure of 0.1 is 1 digit, and the significant figure of 0.10 is 2 digits.

[0039] [Effects of the liquid preparation for anti- Acanthamoeba] The liquid agent for anti-acanthamoeba according to one embodiment of the present application has an anti-acanthamoeba effect against Acanthamoeba microorganisms. The degree of the anti-acanthamoeba effect can be confirmed using Acanthamoeba castellanii ATCC 50370 as an index. The anti-acanthamoeba effect possessed by the liquid agent for anti-acanthamoeba according to one embodiment of the present application is, for example, a degree in which the sterilization effect is confirmed against Acanthamoeba castellanii ATCC 50370, and is preferably a degree in which the death rate of ameba is 80% or more, more preferably 90% or more, according to the method described in the Examples described later, and / or is preferably a degree in which the logarithmic reduction value is evaluated to be 0.5 or more, more preferably 1.0 or more, further preferably 1.5 or more, more further preferably 2.0 or more, according to the evaluation method 2 of the acanthamoeba sterilization effect.

[0040] The liquid agent for anti-acanthamoeba according to one embodiment of the present application has an anti-acanthamoeba effect against Acanthamoeba microorganisms. The degree of the anti-acanthamoeba effect can be confirmed using Acanthamoeba castellanii ATCC 50370 as an index. The anti-acanthamoeba effect possessed by the liquid agent for anti-acanthamoeba according to one embodiment of the present application is, for example, a degree in which the sterilization effect is confirmed against Acanthamoeba castellanii ATCC 50370, and is preferably a degree in which the death rate of ameba is 80% or more, more preferably 90% or more, according to the method described in the Examples described later, and / or is preferably a degree in which the logarithmic reduction value is evaluated to be 0.5 or more, more preferably 1.0 or more, further preferably 1.5 or more, more further preferably 2.0 or more, according to the evaluation method 2 of the acanthamoeba sterilization effect.

[0041] The liquid agent for anti-acanthamoeba according to one embodiment of the present application has a high safety to ocular tissues. The safety is, for example, a degree in which no particular negative influence is exerted on ocular tissues, and is preferably a degree in which the relative colony formation rate is 75% or more when the concentration is adjusted to 2.5 v / v%, more preferably a degree in which the relative colony formation rate is 75% or more when the concentration is adjusted to 5 v / v%, further preferably a degree in which the relative colony formation rate is 75% or more when the concentration is adjusted to 10 v / v% or more, and more further preferably a degree in which the relative colony formation rate is 75% or more when the concentration is adjusted to 20 v / v%, when evaluated according to the evaluation method of the safety described in the Examples described later.

[0042] The liquid agent for anti-acanthamoeba according to the present application has a contact lens compatibility in which the degree, base curve, diameter, and the like of most types of contact lenses are not changed. The contact lens compatibility is, for example, a degree in which no particular change in shape is caused in the contact lens to be used, and is preferably a degree in which the change in the power is ±0.25 D or less, and / or is preferably a degree in which the change in the base curve (BC) is ±0.2 mm or less, and / or is preferably a degree in which the change in the diameter (DIA) is ±0.2 mm or less, when evaluated according to the contact lens compatibility evaluation described in the Examples described later.

[0043] [Effective ingredient] The liquid formulation for anti- Acanthamoeba according to an embodiment of the present application contains sodium dihydrogen phosphate, an alkaline isotonicity adjusting agent, and polydiallyldimethylammonium chloride having a prescribed average molecular weight (hereinafter, also referred to simply as polydiallyldimethylammonium chloride) as an effective ingredient for exerting an anti- Acanthamoeba effect.

[0044] The sodium dihydrogen phosphate can be any one of inorganic phosphoric acid compounds represented by the chemical formula NaH2PO4, and can be anhydrous, a hydrate such as monohydrate, dihydrate, or the like, but a general sodium dihydrogen phosphate dihydrate is preferred. In addition, the liquid formulation for anti- Acanthamoeba according to an embodiment of the present application can contain other inorganic phosphoric acid compounds in addition to the sodium dihydrogen phosphate. As such inorganic phosphoric acid compounds, sodium phosphate dibasic, sodium phosphate tribasic, potassium dihydrogen phosphate, potassium phosphate dibasic, potassium phosphate tribasic, calcium dihydrogen phosphate, calcium phosphate dibasic, and the like can be exemplified, and they can be anhydrous or a hydrate. The other inorganic phosphoric acid compounds can be used alone as any one of the above or in combination of two or more.

[0045] The content of the sodium dihydrogen phosphate can be appropriately set as an amount that exhibits an anti- Acanthamoeba effect in combination with the alkaline isotonicity adjusting agent and the polydiallyldimethylammonium chloride, and is preferably, for example, 0.001 w / v% to 5 w / v%, more preferably 0.01 w / v% to 3 w / v%, further preferably 0.05 w / v% to 2 w / v%, and more further preferably 0.1 w / v% to 1 w / v%. The total amount of the content of the sodium dihydrogen phosphate and the content of the other inorganic phosphoric acid compounds can be appropriately set, and is preferably, for example, 0.01 w / v% to 5 w / v%, more preferably 0.05 w / v% to 3 w / v%, and further preferably 0.1 w / v% to 2 w / v%.

[0046] The basic isotonicity adjusting agent is an agent having a basic group and used to adjust the osmotic pressure of the liquid agent for anti-acanthamoeba of one embodiment of the present application to a desired range (e.g., the same degree as that of tear). The basic isotonicity adjusting agent can be exemplified by, for example, ammonia, monoethanolamine, diethanolamine, triethanolamine, 2-amino-2-methyl-l-propanol, 2-amino-2-methyl-l,3-propanediol, 2-amino-2-hydroxymethyl-l,3-propanediol, 2-amino-2-ethyl-l,3-propanediol, arginine, and salts thereof, and the like, and from the viewpoint that the effect on the ocular tissue is small and that the pH in the vicinity of neutral exhibits a buffering action, an organic buffer having an amino group is preferred, and 2-amino-2-hydroxymethyl-l,3-propanediol, 2-amino-2-ethyl-l,3-propanediol, and arginine are more preferred. The basic isotonicity adjusting agent can be used alone any one of them or in combination of two or more. From the viewpoint that the pH in the vicinity of neutral exhibits a strong buffering action, the basic isotonicity adjusting agent is preferably 2-amino-2-hydroxymethyl-l,3-propanediol or a combination of 2-amino-2-hydroxymethyl-l,3-propanediol and another basic isotonicity adjusting agent.

[0047] The content of the basic isotonicity adjusting agent is an amount exhibiting an anti-acanthamoeba effect by combining sodium phosphate monobasic and polydiallyldimethylammonium chloride, and can be appropriately set in consideration of the irritation to the ocular tissue and the osmotic pressure, and is preferably 0.001 w / v% to 20 w / v%, more preferably 0.005 w / v% to 10 w / v%, and further preferably 0.008 w / v% to 5 w / v%.

[0048] From the viewpoint of the anti-acanthamoeba effect, the ratio of the content of sodium phosphate monobasic to the content of the basic isotonicity adjusting agent is preferably within a prescribed range. The ratio of the content of the basic isotonicity adjusting agent to the content of sodium phosphate monobasic ([basic isotonicity adjusting agent] / [sodium phosphate monobasic]) is preferably 0.001 to 10, more preferably 0.005 to 5, further preferably 0.01 to 3, and more further preferably 0.04 to 2. The total content of sodium phosphate monobasic and the basic isotonicity adjusting agent can be appropriately set in consideration of the irritation to the ocular tissue and the osmotic pressure of the liquid agent for anti-acanthamoeba of one embodiment of the present application.

[0049] Polydiallyldimethylammonium chloride is a cationic polymer having a prescribed average molecular weight and having a diallyldimethylammonium chloride unit represented by the following general formula (I) in the molecule. Polydiallyldimethylammonium chloride is also referred to as polyquaternium-6.

[0050] [Chemical Formula 1]

[0051] [In the formula, n represents an integer in which the average molecular weight of the polymer is set within the range specified above.] The polydiallyldimethylammonium chloride is specified for the average molecular weight, specifically 10,000 to 11,000,000, but if the safety to the ocular tissue is considered while showing the anti-Entamoeba action, for example, the polydiallyldimethylammonium chloride in which the average molecular weight is preferably in the range of 100,000 to 1,000,000, more preferably 120,000 to 800,000, further preferably 150,000 to 500,000 is preferable. The average molecular weight indicates the weight average molecular weight.

[0052] The method for producing the polydiallyldimethylammonium chloride is not particularly limited, and for example, a method in which a water-soluble monomer of diallyldimethylammonium chloride is used as a raw material, and cyclization polymerization is performed by a radical polymerization initiator such as peroxide, light irradiation to obtain a linear homopolymer, and the like can be exemplified.

[0053] The polydiallyldimethylammonium chloride can also use a commercially available product. As the commercially available product, for example, "MERQUAT 100" (molecular weight: 150,000) of Lubrizol Corporation, "ME Polymer H-40W" (molecular weight: 240,000) of DKS Co., Ltd., "COSMUAT VG" (molecular weight: 200,000) of SENKA Corporation, "Unisense FPA1002L" (molecular weight: 500,000) of SENKA Corporation, "Unisense FPA7000E" (molecular weight: 1,200,000) of SENKA Corporation, "Flocare C106MV" (molecular weight: 150,000) of SNF Corporation, "Genamin PDAC" (molecular weight: 230,000) of Clariant International Ltd., and the like (the polymer names show registered trademarks or trade names, respectively. Hereinafter, the same applies to the polymer) can be exemplified. Furthermore, the polydiallyldimethylammonium chloride can also use the medical product, the medical product outside product raw material specification 2021 (outside raw rule) polydimethyl methylene pyrrolidinium chloride liquid.

[0054] The content of the polydiallyldimethylammonium chloride can be appropriately set as long as it is an amount that shows the anti-Entamoeba action by combining sodium dihydrogen phosphate and an alkaline isotonicity adjusting agent, and for example, in view of the fact that the polydiallyldimethylammonium chloride has a great influence on the sterilization effect, 0.00001 w / v% to 10 w / v% is preferable, 0.00005 w / v% to 1 w / v% is more preferable, and 0.00008 w / v% to 0.05 w / v% is further preferable.

[0055] In order to make the combination of sodium phosphate monobasic, an alkaline isotonic adjusting agent, and polydiallyldimethylammonium chloride function as an effective ingredient, the total amount of the contents thereof is preferably within a prescribed range. The total amount is, for example, preferably 0.01 w / v% to 10 w / v%, more preferably 0.05 w / v% to 5 w / v%, and further preferably 0.1 w / v% to 3 w / v%.

[0056] From the viewpoint of the effect against Acanthamoeba, the ratio of the content of polydiallyldimethylammonium chloride to the content of sodium phosphate monobasic, or the ratio of the content of polydiallyldimethylammonium chloride to the total amount of the content of sodium phosphate monobasic and the content of an alkaline isotonic adjusting agent is preferably within a prescribed range.

[0057] The ratio of the content of polydiallyldimethylammonium chloride to the content of sodium phosphate monobasic ([polydiallyldimethylammonium chloride] / [sodium phosphate monobasic]) is preferably 0.00001 to 1, more preferably 0.00005 to 0.5, and further preferably 0.0001 to 0.1.

[0058] The ratio of the content of polydiallyldimethylammonium chloride to the total amount of the content of sodium phosphate monobasic and the content of an alkaline isotonic adjusting agent ([polydiallyldimethylammonium chloride] / ([sodium phosphate monobasic]+[alkaline isotonic adjusting agent])) is, for example, preferably 0.000001 to 1, more preferably 0.00001 to 0.5, and further preferably 0.00003 to 0.1.

[0059] By making the ratio of the content of polydiallyldimethylammonium chloride to the content of sodium phosphate monobasic, or the ratio of the content of polydiallyldimethylammonium chloride to the total amount of the content of sodium phosphate monobasic and the content of an alkaline isotonic adjusting agent be within the above range, the liquid preparation for Acanthamoeba of one embodiment of the present application not only exerts a sterilizing effect on Acanthamoeba, but also can have safety to ocular tissues.

[0060] [Other components] The liquid preparation for Acanthamoeba of one embodiment of the present application contains sodium phosphate monobasic, an alkaline isotonic adjusting agent, and polydiallyldimethylammonium chloride, and can contain other components in addition thereto. As the other components, an isotonic adjusting agent other than the alkaline isotonic adjusting agent can be exemplified. In the present specification, in the case where only an isotonic adjusting agent is referred to, it means an isotonic adjusting agent other than the alkaline isotonic adjusting agent, that is, an isotonic adjusting agent having no alkaline group.

[0061] The isotonic adjusting agent can be exemplified by, for example, sodium chloride, potassium chloride, propylene glycol (PG), 1,2-propanediol, 1,3-propanediol, mannitol, sorbitol, sodium carbonate, sodium bicarbonate, glycerol, and the like, and any one of them can be used alone or two or more of them can be used in combination.

[0062] The content of the isotonicity adjusting agent can be appropriately set as an amount that imparts an appropriate osmotic pressure to the anti- Acanthamoeba solution of one embodiment of the present application on ocular tissues, and is preferably, for example, 0 w / v% to 10 w / v%, more preferably 0.001 w / v% to 5 w / v%, further preferably 0.01 w / v% to 3 w / v%, more further preferably 0.05 w / v% to 2 w / v%, or 0.1 w / v% to 1.8 w / v%.

[0063] The other components are not particularly limited as long as the problem to be solved by the present application is not hindered, and examples include additives and the like that are contained in general contact lenses. As the additives, for example, disinfectants, surfactants, chelating agents, thickening agents, wetting agents, isotonicity adjusting agents, enzymes such as proteolytic enzymes and lipolytic enzymes, and the like can be given. Only a part of the other components is given below, but they are merely examples and are not limiting.

[0064] As specific examples of the disinfectants, for example, biguanide disinfectants such as polyhexamethylene biguanide (PHMB), polyaminopropyl biguanide, alexidine, chlorhexidine gluconate (GCH), and the like; quaternary ammonium disinfectants such as myristylamidopropyl dimethylamine, benzalkonium chloride, benzethonium chloride, polyquaternium-1, and the like; iodine disinfectants such as chlorhexidine gluconate, povidone iodine, and the like; hydrogen peroxide disinfectants, and the like can be given, and an organic nitrogen disinfectant is preferred, and polyhexamethylene biguanide (PHMB) is more preferred. The content of the disinfectant can be appropriately set, and is preferably, for example, 0 w / v% to 1.0 w / v% in consideration of irritation to ocular tissues and safety.

[0065] As preferred specific examples of the surfactants, if the influence on the contact lenses is taken into consideration, nonionic surfactants can be given. As specific examples of the nonionic surfactants, polyoxyethylene polyoxypropylene glycol, ethylenediamine tetrapolyoxypropylene condensate, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ester, polyoxyethylene sorbitan alkyl ester, and the like can be given, but polyoxyethylene polyoxypropylene glycol, ethylenediamine tetrapolyoxypropylene condensate, and polyoxyethylene hydrogenated castor oil are preferred.

[0066] As specific examples of the polyoxyethylene polyoxypropylene glycol, there can be mentioned polyoxyethylene (50) polyoxypropylene (40) glycol, polyoxyethylene (300) polyoxypropylene (55) glycol, polyoxyethylene (200) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (200) polyoxypropylene (70) glycol, and the like, which are commercially available as Kolliphor P188, Kolliphor P407 (manufactured by BASF Corporation), Pluronic (registered trademark) F-68, F-88, F-108, F-77, F-127, L-64, P-84, P-84 (manufactured by Ajinomoto Co., Inc.), and the like.

[0067] As specific examples of the ethylenediaminetetrapolyoxypropylene condensate, there can be mentioned tetrafunctional block copolymers of a polyoxyethylene polyoxypropylene copolymer and ethylenediamine, and the like, which are commercially available as Tetoronic 904, 908, 1104, 1107, 1304, 1504 (manufactured by BASF Corporation), Synperonic T304, 707, 908 (manufactured by Croda), Pluronic (registered trademark) TR-704, TR-913R (manufactured by Ajinomoto Co., Inc.), and the like.

[0068] As specific examples of the polyoxyethylene hydrogenated castor oil, there can be mentioned polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, and the like, which are commercially available as Kolliphor RH-40 (manufactured by BASF Corporation), HCO-40, HCO-50, HCO-60 (manufactured by Nikko Chemicals Co., Ltd.), and the like.

[0069] The surfactant can be used alone with any one of the above-mentioned substances or in combination with two or more of them. The content of the surfactant can be appropriately set, and, for example, in consideration of the safety to the ocular tissue and the compatibility with the contact lens, it is preferably 0 w / v% to 5 w / v%, more preferably 0 w / v% to 2.5 w / v%, further preferably 0 w / v% to 1 w / v%, and still further preferably 0 w / v% to 0.5 w / v%.

[0070] As specific examples of the chelating agent, there can be mentioned chelating agents generally used in ophthalmic solutions, specifically, there can be mentioned ethylenediaminetetraacetic acid, citric acid, tartaric acid, and the like, polybasic carboxylic acids and salts thereof, and the like, and one of them can be used alone or two or more of them can be used in combination. The content of the chelating agent can be appropriately set as an amount generally used in ophthalmic solutions, and, for example, in consideration of the safety to the ocular tissue, it is preferably 0 w / v% to 10 w / v%, more preferably 0.001 w / v% to 5 w / v%, and further preferably 0.01 w / v% to 1 w / v%.

[0071] Specific examples of thickeners include those commonly used in ophthalmic solutions, such as cellulose compounds like hydroxyethyl cellulose, hydroxypropyl methylcellulose (TC-5R, etc.), and sodium carboxymethyl cellulose, and vinyl compounds like polyvinyl alcohol and carboxyvinyl polymers. The content of the thickener can be set appropriately, as long as it is the amount commonly used in ophthalmic solutions. For example, considering safety for ocular tissues, it is preferably 0w / v%-5w / v%, more preferably 0.001w / v%-2w / v, and even more preferably 0.01w / v%-1w / v.

[0072] Specific examples of wetting agents include those commonly used in ophthalmic solutions, such as hyaluronic acid and its salts, amino acids and their salts, polyvinyl alcohol, and 2-methacryloyloxyethylphosphorylcholine polymers.

[0073] One embodiment of the anti-Acanthamoeba liquid of the present invention is prepared by dissolving the various components in a solvent such as water. The solvent is preferably purified water, ion-exchanged water, or water commonly used in ophthalmic solutions. The water content is preferably, for example, 90 w / v%-99.9 w / v, more preferably 95 w / v%-99.5 w / v.

[0074] [Anti-Acanthamoeba Liquid] As long as it does not hinder the solution of the problem of the present invention, the anti-Acanthamoeba liquid of one aspect of the present invention can have various properties. For example, preferably, when the anti-Acanthamoeba liquid of one aspect of the present invention is used in contact with eye tissue and contact lenses, it has the property of not having a negative effect on eye tissue and contact lenses.

[0075] In this case, in order to reduce irritation to eye tissues and to allow the alkaline isotonic adjuster to function as an isotonic adjuster, in one embodiment of the anti-Acanthamoeba liquid of the present invention, for example, the pH is preferably 5.5-9.5, more preferably 6.0-9.0, and even more preferably 6.5-8.5; the osmotic pressure is preferably 200 mOsm / L-400 mOsm / L, more preferably 220 mOsm / L-350 mOsm / L.

[0076] The anti- Acanthamoeba liquid agent of one embodiment of the present application can be manufactured according to a method for manufacturing a liquid agent known to those skilled in the art for use in the field of ophthalmology. For example, the anti- Acanthamoeba liquid agent of one embodiment of the present application can be manufactured by simultaneously or sequentially adding, to purified water, a mixture of sodium dihydrogen phosphate, an alkaline isotonizing agent, and polydiallyldimethylammonium chloride, and any other components. The anti- Acanthamoeba liquid agent of one embodiment of the present application can be subjected to filtration treatment or the like for the purpose of removing insoluble components, or can be subjected to sterilization treatment or the like for the purpose of preventing the introduction of microorganisms. The anti- Acanthamoeba liquid agent of one embodiment of the present application is preferably a filtered liquid agent, and / or is preferably a sterilized liquid agent. Specific examples of the method for manufacturing the anti- Acanthamoeba liquid agent of one embodiment of the present application can be found in the methods described in the Examples below.

[0077] The anti- Acanthamoeba liquid agent of one embodiment of the present application can be used as a liquid composition, as a pharmaceutical product or a quasi-pharmaceutical product formulation. As a pharmaceutical product or a quasi-pharmaceutical product formulation, there can be mentioned eye drops, artificial tears, eye washes, contact lens storage solutions, cleaning agents, and disinfectants.

[0078] From the viewpoint of safety to ocular tissues and compatibility with most contact lenses, the anti- Acanthamoeba liquid agent of one embodiment of the present application is preferably a contact lens care solution. In the case where the anti- Acanthamoeba liquid agent of one embodiment of the present application is a contact lens care solution, the anti- Acanthamoeba liquid agent of one embodiment of the present application can be used for cleaning, rinsing, and disinfecting a contact lens, and the anti- Acanthamoeba liquid agent of one embodiment of the present application and a contact lens can be stored in a storage container, and the like.

[0079] Hereinafter, the present application will be described in more detail by way of Examples, but the present application is not limited to these Examples, and can take various forms as long as the problems of the present application can be solved.

[0080] Examples [1. Preparation of Test Solutions] The test solutions of the Examples and Comparative Examples were prepared according to the formulations shown in Tables 1A to 1C. Note that the units of the amounts of the components in the tables are "w / v%".

[0081] Specifically, each component described in Tables 1A to 1C was weighed so as to be in the amount described in Tables 1A to 1C. Next, a liquid in which each component was dissolved by being added to purified water was made to a total amount of 100 mL, and further stirred sufficiently until uniform. Each test solution was prepared by filtering and sterilizing the obtained solution using a PES membrane filter having a pore size of 0.2 pm.

[0082] [2. Evaluation Method 1 for Acanthamoeba Disinfecting Effect] Acanthamoeba castellaii (ATCC50370) was used as the test strain.

[0083] After centrifuging the Acanthopanax senticosus culture broth cultured at 28°C in liquid medium, 1 / 4 Ringer's solution was added to suspend the precipitated cells, and the Acanthopanax senticosus concentration was adjusted to 1×10⁻⁶. 7 cells / mL-10 8 Cells / mL were used to obtain a Chlamydia acicularis suspension. In each of the 10 mL test solutions used in the examples and comparative examples, 0.1 mL of the Chlamydia acicularis suspension was inoculated. The inoculated test solutions were then incubated at 25°C for 4 hours for sterilization.

[0084] Dilute and mix 0.4 w / v% trypan blue solution into the disinfected test solution. For the diluted test solution, measure the total cell count, viable cell count, and dead cell count using a hemocytometer and an optical microscope. Based on the measured values, calculate the dead cell rate according to the proportion of dead cells to total cells. Test solutions with a calculated dead cell rate of 80% or higher are considered to have disinfection effect.

[0085] [3. Evaluation method for the disinfection effect of Acanthamoeba 2] In addition to changing the concentration of Acanthamoeba to 5×10 6 Except for cells / mL, prepare Acanthamoeba suspension in the same manner as described in [2. Evaluation method 1 for Acanthamoeba disinfection effect] and perform disinfection treatment.

[0086] Add 9 mL of inactivating agent (a 1 / 4 Ringer's solution containing 3.5% lecithin and 1.5% polysorbate) to 1 mL of the disinfected test solution. Then, continuously prepare a 10-fold dilution series using the 1 / 4 Ringer's solution to obtain 10... -1 -10 -6 The diluted treatment solution.

[0087] 2 mL of 1.5% agar solution was added to each 12-well cell culture plate beforehand, and a suspension of Escherichia coli (E. coli (ATCC8739)) (approximately 1 × 10⁻⁶) was seeded onto the agar. 10 0.1 mL of the diluted treatment solution (cells / mL) was added to the culture plate at each concentration point. -1 -10 -6 1 mL was dispensed into 4 wells. The culture plates were then incubated at 28°C for 14 days.

[0088] By performing the above culture, if the acanthamoeba is alive, it preys on the E. coli, and the acanthamoeba proliferates. On the other hand, if the acanthamoeba dies, the E. coli proliferates. The number of positive wells and the number of negative wells of each dilution series were counted by the Reed-Muench method using the acanthamoeba suspension added to the 1 / 4 Linger solution as a control, and the LD 50 was calculated from the total number of wells.

[0089] [4. Evaluation method of disinfection effect of fungi] In the evaluation of the disinfection effect of fungi, Candida albicans (ATCC 10231) was used as a test strain.

[0090] Candida albicans cultured on the slope of the agar medium at 35°C for 18 hours was suspended by adding a Dulbecco's phosphate buffer, and the recovered suspension was used as a bacterial stock solution. The bacterial stock solution was diluted with a Dulbecco's phosphate buffer to adjust the concentration to 10 5 -10 6 cfu / mL, and a bacterial suspension was obtained.

[0091] In 10 mL of each test solution of the examples and comparative examples, 0.1 mL of the bacterial suspension was inoculated. The inoculated test solution was cultured at 25°C for 4 hours and 6 hours, and subjected to disinfection treatment.

[0092] After 1 mL of the test solution subjected to disinfection treatment was added to 9 mL of a neutralizing broth, a 10-fold dilution series was prepared with a Dulbecco's phosphate buffer, and a diluted test solution subjected to disinfection treatment was obtained. 1 mL of the solution at three concentration points of an appropriate dilution rate was dispensed into a disposable petri dish, and then a Sabouraud dextrose agar medium was injected into the petri dish to perform dilution mixing. The petri dish after dilution mixing was cultured at 35°C for 48 hours, and the number of viable bacteria was determined from the number of colonies obtained.

[0093] A 10-fold dilution series was prepared with a Dulbecco's phosphate buffer, and the number of bacteria of the bacterial suspension, i.e., the initial number of bacteria, was determined by the agar medium plating method as described above.

[0094] From the initial number of bacteria obtained and the number of viable bacteria obtained using the diluted test solution subjected to disinfection treatment, the log reduction value (Log Reduction) of each test solution subjected to disinfection treatment was determined from the following formula.

[0095] Log Reduction value = initial number of bacteria - number of viable bacteria of the test sample The judgment of the disinfecting effect was made according to the primary standard of ISO test, and the test solution having a logarithmic reduction value of the prescribed disinfecting time of 1.0 or more was judged to have a disinfecting effect (Reference: ISO 14729).

[0096] [5. Evaluation method of safety] After trypsin treatment and recovery of Chinese hamster lung-derived cells V79 cells pre-cultured in a CO2 incubator set at 37°C, the cells were suspended in Eagle's minimum essential medium containing fetal bovine serum as a cell culture medium to obtain a cell suspension.

[0097] The test solutions of Examples and Comparative Examples were dispensed into the wells of a cell culture plate so that the solution concentration was 20%, 10%, 5%, and 2.5% (v / v%), and then the cell suspension was added so that the cell number was 100, and Eagle's minimum essential medium containing fetal bovine serum was added so that the volume of each well was 2000 μL. For example, in the case of a solution concentration of 20%, a medium of 1500 μL, a cell suspension (1000 cells / mL) of 100 μL, and a test solution of 400 μL were mixed to prepare. The plate was incubated in a CO2 incubator set at 37°C for 7 days. As a comparative control, a preparation was prepared by culturing in a cell culture medium without adding a test solution. The relative colony formation rate of each test solution at each concentration point was calculated according to the following formula.

[0098] Relative colony formation rate (%) = (number of colonies at each concentration point / number of colonies of comparative control) x 100 The relative colony formation rate was directly used as the safety to the ocular tissue, and the safety of each test solution was evaluated by comparing the relative colony formation rate at the same concentration as follows.

[0099] ++: Relative colony formation rate of 75% or more ±: Relative colony formation rate of more than 50% and less than 75% -: Relative colony formation rate of 50% or less [6. Evaluation of contact lens compatibility] As a test lens, "SEED 2 week Fine UV Plus" (Group 1), "SEED 2 week Pure" (Group 4), "J&J ACUVUE OASYS" (Group VC), "Alcon AIR OPTIX HydraGlyde" (Group VC), and "CooperVision Biofinity" (Group VC) were used.

[0100] Each test lens was taken out from the blister pack and the surface moisture was removed. The test lens after the removal of the moisture was immersed in a D-PBS and the parameters (Power, BC, and DIA) before the treatment with the test solution were measured.

[0101] Next, each test lens was rubbed 30 times with a finger using the test solution of the examples and comparative examples (cyclic treatment). The test lens after the cyclic treatment was immersed in a phosphate buffer and the above parameters were measured.

[0102] The compatibility of each test solution to the contact lens was evaluated based on the amount of change before and after the cyclic treatment according to the following contact lens approval criteria shown below.

[0103] +: the amount of change in Power was within ±0.25 D, the amount of change in BC was within ±0.2 mm, and the amount of change in DIA was within ±0.2 mm.

[0104] -: the amount of change in Power exceeded ±0.25 D, the amount of change in BC exceeded ±0.2 mm, or the amount of change in DIA exceeded ±0.2 mm.

[0105] [7. Evaluation method of physical properties of test solution] The pH of the test solution of the examples and comparative examples was measured at room temperature using a pH meter "Main body: Seven Compact S220, Electrode: InLab MicroPro-Ism" (manufactured by Mettler-Toledo, Inc.); and the osmotic pressure was measured using an osmometer "AD-3250" (manufactured by Advanced Instruments, Inc.).

[0106] [8. Evaluation results] The results of the measurement of the pH and the osmotic pressure (mOsm) of the test solution are shown in Tables 1A-C. The pH of the test solution of Examples 1-22 was 6.55-8.52 and the osmotic pressure was 230-339. Therefore, it was found that these test solutions were suitable as a contact lens solution.

[0107] The test solutions of Examples 1 to 11 and Comparative Examples 1 to 6 were evaluated for their disinfecting effects on Acanthamoeba by the Acanthamoeba disinfecting effect evaluation method 1. The results are shown in Table 1A and Table 1C. As shown in the tables, the test solutions of Examples 1 to 11, which were combinations of sodium phosphate dibasic dihydrate, an alkaline isotonicity adjusting agent, and polydiallyldimethylammonium chloride having an average molecular weight of 10,000 to 1,100,000, had a death rate of Acanthamoeba of 80% or more, and were found to have sufficient disinfecting effects on Acanthamoeba. In contrast, the test solutions of Comparative Examples 1 to 6, which were combinations of sodium phosphate dibasic dihydrate and an alkaline isotonicity adjusting agent, and which contained polydiallyldimethylammonium chloride having an average molecular weight of 8,500 or 1,200,000, or which did not contain polydiallyldimethylammonium chloride, had a death rate of Acanthamoeba of 70% or less, and were found to have no disinfecting effects on Acanthamoeba.

[0108] Further, the test solutions of Examples 1 to 11, which were confirmed to have Acanthamoeba disinfecting effects, had a ratio of the content of the alkaline isotonicity adjusting agent to the content of sodium phosphate dibasic dihydrate ([alkaline isotonicity adjusting agent] / [sodium phosphate dibasic]) in the range of 0.01 to 2, and the test solutions of Comparative Examples 3 to 6, which were not found to have Acanthamoeba disinfecting effects, had a ratio of the content of the alkaline isotonicity adjusting agent to the content of sodium phosphate dibasic dihydrate not in the above range.

[0109] The test solutions of Examples 12 to 22 and Comparative Examples 7 to 8 were evaluated for their disinfecting effects on Acanthamoeba by the Acanthamoeba disinfecting effect evaluation method 2. The results are shown in Table 1B and Table 1C. As shown in the tables, the test solutions of Examples 12 to 22, which were combinations of sodium phosphate dibasic dihydrate, an alkaline isotonicity adjusting agent, and polydiallyldimethylammonium chloride having an average molecular weight of 10,000 to 1,100,000, had a log reduction value of 2.00 to 2.33, and were found to have sufficient disinfecting effects on Acanthamoeba. In contrast, the test solutions of Comparative Examples 7 to 8, which were combinations of sodium phosphate dibasic dihydrate and an alkaline isotonicity adjusting agent, and which contained polydiallyldimethylammonium chloride having an average molecular weight of 8,500, or which did not contain polydiallyldimethylammonium chloride, had a log reduction value of 0.25, and were found to have no disinfecting effects on Acanthamoeba.

[0110] Thus, according to the Acanthamoeba disinfecting effect evaluation method performed this time, it was found that the test solutions, which were combinations of sodium phosphate dibasic dihydrate, an alkaline isotonicity adjusting agent, and polydiallyldimethylammonium chloride having an average molecular weight of 10,000 to 1,100,000, had excellent disinfecting effects on Acanthamoeba.

[0111] The disinfection efficacy of the test solutions in Examples 12-15, 17-22, and Comparative Examples 7-8 against fungi was evaluated using methods for evaluating fungal disinfection. The results are shown in Tables 1B and 1C. As shown in the tables, even considering the length of disinfection time, the logarithmic reduction values ​​were sometimes greater than 1.0 and sometimes less than 1.0, indicating that the test solutions in the examples cannot be definitively said to have a disinfection effect on fungi. In contrast, the test solution in Comparative Example 8, which contained polydiallyl dimethylammonium with an average molecular weight of 8500, did not have a disinfection effect on fungi. However, the test solution in Comparative Example 7, which contained sodium dihydrogen phosphate dihydrate and an alkaline isotonic adjuster but did not contain polydiallyl dimethylammonium chloride, showed a logarithmic reduction value of 1.0 or greater for all disinfection times, demonstrating a disinfection effect on fungi.

[0112] Based on the above results, it is surprising that, compared with the case without polydiallyl dimethylammonium chloride, the liquid containing sodium dihydrogen phosphate dihydrate and alkaline isotonic regulator, and containing polydiallyl dimethylammonium chloride with an average molecular weight of 10,000-1,100,000, has a specific disinfection effect on Acanthamoeba, despite having a lower disinfection effect on fungi.

[0113] When evaluating the safety and contact lens compatibility of the test solutions in Examples 12-22, all test solutions were rated "+" at all evaluated concentrations, and the contact lens compatibility of all tested contact lenses was rated "+". Based on the combined evaluation results of safety and contact lens compatibility, pH value, and osmotic pressure, it can be concluded that the solution containing sodium dihydrogen phosphate dihydrate, an alkaline isotonic adjuster, and polydiallyl dimethyl ammonium chloride with an average molecular weight of 10,000-1,100,000 is a solution with excellent disinfection effect against Acanthamoeba and suitable for contact lenses.

[0114] [Table 1A]

[0115] [Table 1B]

[0116] [Table 1C]

[0117] Industrial availability The anti-Acanthamoeba liquid of one aspect of the present invention has high safety for ocular tissues, wide applicability to contact lenses, and excellent disinfection effect against Acanthamoeba. Therefore, by using it as a contact lens care solution such as MPS, it can reduce or avoid the risk of wearers developing keratitis caused by Acanthamoeba, thus contributing to the health and well-being of contact lens wearers. Cross-reference to related applications

[0118] This application claims priority to Japanese Patent Application No. 2023-123521, filed July 28, 2023, the entire contents of which are incorporated herein by reference. Furthermore, the entire contents of all documents referenced in the detailed description of the invention in this application, including Patent Documents 1-5, are incorporated herein by reference.

Claims

1. An anti-Entamoeba histolytica liquid agent comprising sodium phosphate monobasic, an alkaline isotonizing agent, and polydiallyldimethylammonium chloride having an average molecular weight of 10,000 to 1,000,000.

2. The anti-Entamoeba histolytica liquid agent according to claim 1, wherein the ratio of the content of the alkaline isotonizing agent to the content of the sodium phosphate monobasic ([alkaline isotonizing agent] / [sodium phosphate monobasic]) is 0.01 to 2, and the pH is 6.5 to 8.

5.

3. The anti-Entamoeba histolytica liquid agent according to claim 1, wherein the ratio of the content of the polydiallyldimethylammonium chloride to the content of the sodium phosphate monobasic ([polydiallyldimethylammonium chloride] / [sodium phosphate monobasic]) is 0.00005 to 0.

01.

4. The anti-Entamoeba histolytica liquid agent according to claim 1, wherein the ratio of the content of the polydiallyldimethylammonium chloride to the total content of the content of the sodium phosphate monobasic and the content of the alkaline isotonizing agent ([polydiallyldimethylammonium chloride] / ([sodium phosphate monobasic]+[alkaline isotonizing agent])) is 0.000001 to 1.

5. The anti-Entamoeba histolytica liquid agent according to claim 1, wherein the alkaline isotonizing agent is one or more alkaline isotonizing agents selected from the group consisting of 2-amino-2-hydroxymethyl-l,3-propanediol, 2-amino-2-ethyl-l,3-propanediol, and arginine, and salts thereof.

6. The anti-Entamoeba histolytica liquid agent according to claim 1, wherein the polydiallyldimethylammonium chloride is polydiallyldimethylammonium chloride having an average molecular weight of 100,000 to 1,000,000.

7. The anti-Entamoeba histolytica liquid agent according to claim 1, further comprising an isotonizing agent different from the alkaline isotonizing agent.

8. The anti-Entamoeba histolytica liquid agent according to claim 7, wherein the isotonizing agent is one or more isotonizing agents selected from the group consisting of sodium chloride, potassium chloride, 1,2-propanediol, 1,3-propanediol, mannitol, and sorbitol.

9. The anti-Entamoeba histolytica liquid agent according to claim 1, further comprising one or more quaternary ammonium salts selected from the group consisting of polyhexamethylene biguanide hydrochloride, alexidine, myristamidopropyl dimethylamine, benzalkonium chloride, benzethonium chloride, and polyquaternium-1.

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