Ophthalmic solution containing water-soluble polymer

Abstract

To provide a new ophthalmic solution containing brimonidine.SOLUTION: Wherein the content of the brimonidine and / or salts thereof is 0. 05w / v% to 0. 2w / v%, the content of the water-soluble polymer is 0. 1w / v% to 1. 5w / v%, the content of the benzalkonium chloride is 0. 001w / v% to 0. 01w / v%, and the weight ratio of the brimonidine and / or salts thereof to the benzalkonium chloride is 1:0.01 to 0.1.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to eye drops and the like containing a water-soluble polymer, brimonidine and / or a salt thereof, and benzalkonium chloride (hereinafter also referred to as "BAK"). [Background technology]

[0002] Brimonidine is a selective adrenergic α2 receptor agonist that suppresses aqueous humor production and promotes aqueous humor outflow via the uveoscleral outflow pathway, thereby lowering intraocular pressure. For this reason, brimonidine and its salts are used to treat glaucoma.

[0003] In order to enhance the bioavailability of pharmacological ingredients contained in eye drops, attempts have been made to improve the retention of the ingredients in the ocular mucosa. For example, it is known that the retention of the pharmacological ingredients contained in eye drops can be improved by incorporating a water-soluble polymer as a thickener or thickener into the eye drops.

[0004] Cellulose-based polymers, a type of water-soluble polymer, are partially decomposed by heat. As a result, the viscosity of a composition containing a cellulose-based polymer may decrease over time. An eye drop formulation is known in which aspartic acid or a salt thereof is blended with a composition containing carboxymethylcellulose (hereinafter also referred to as "CMC") to inhibit viscosity decrease (Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2006-104114 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to provide a novel eye drop containing brimonidine.The present invention also aims to provide a novel eye drop containing a water-soluble polymer that is inhibited from decreasing in viscosity.Furthermore, the present invention also aims to provide a method for inhibiting a decrease in viscosity of an eye drop containing a water-soluble polymer, or an agent for inhibiting a decrease in viscosity. [Means for solving the problem]

[0007] The present inventors have conducted extensive research into components for inhibiting the decrease in viscosity of eye drops containing CMC, and have surprisingly found that brimonidine, an intraocular pressure-lowering agent, itself exhibits such an inhibitory effect on viscosity decrease, and that when used in combination with BAK, it exhibits a synergistically enhanced inhibitory effect on viscosity decrease, thereby completing the present invention.

[0008] That is, the present invention relates to the following eye drops, a method for inhibiting viscosity decrease, and an agent for inhibiting viscosity decrease.

[0009] [Item 1] An eye drop containing brimonidine and / or a salt thereof, a water-soluble polymer, and benzalkonium chloride, wherein the content of brimonidine and / or a salt thereof is 0.05 w / v% to 0.2 w / v%, the content of the water-soluble polymer is 0.1 w / v% to 1.5 w / v%, the content of benzalkonium chloride is 0.001 w / v% to 0.01 w / v%, and the weight ratio of brimonidine and / or a salt thereof to benzalkonium chloride is 1:0.01 to 0.1. [Item 2] The eye drop preparation according to Item 1, wherein the weight ratio of brimonidine and / or a salt thereof, the water-soluble polymer, and the benzalkonium chloride is 1:1 to 15:0.01 to 0.1. [Item 3] The eye drop preparation according to Item 1 or 2, wherein the water-soluble polymer is carboxymethylcellulose and / or a salt thereof. [Item 4] The eye drop preparation according to any one of Items 1 to 3, wherein the viscosity stability calculated by dividing the viscosity of the eye drop preparation after storage at 60°C for 4 weeks by the viscosity of the eye drop preparation before storage for said 4 weeks is 90% or more. [Item 5] The eye drop preparation according to any one of Items 1 to 4, which has a pH of 6.7 to 7.5. [Item 6] The eye drop preparation according to any one of Items 1 to 5, which is used to treat glaucoma. [Item 7] A method for suppressing a decrease in viscosity of an eye drop containing a water-soluble polymer, the method comprising the step of allowing either brimonidine and / or a salt thereof and / or benzalkonium chloride to coexist in the eye drop, wherein the brimonidine and / or salt thereof content is 0.05 w / v% to 0.2 w / v%, the water-soluble polymer content is 0.1 w / v% to 1.5 w / v%, and the benzalkonium chloride content is 0.001 w / v% to 0.01 w / v%. [Item 8] The method according to Item 7, the method comprising the step of allowing both brimonidine and / or a salt thereof and benzalkonium chloride to coexist in the eye drop, and wherein the weight ratio of brimonidine and / or a salt thereof to benzalkonium chloride is 1:0.01 to 0.1. [Item 9] The method according to Item 8, wherein the weight ratio of brimonidine and / or a salt thereof, the water-soluble polymer, and the benzalkonium chloride is 1:1 to 15:0.01 to 0.1. [Item 10] The method according to any one of Items 7 to 9, wherein the eye drops have a pH of 6.7 to 7.5. [Item 11] The method according to any one of Items 7 to 10, wherein the water-soluble polymer is carboxymethyl cellulose and / or a salt thereof. [Item 12] A viscosity decrease inhibitor for inhibiting a decrease in viscosity of an eye drop containing a water-soluble polymer, the viscosity decrease inhibitor comprising brimonidine and / or a salt thereof and benzalkonium chloride in a weight ratio of 1:0.01 to 0.1. [Item 13] The viscosity decrease inhibitor according to Item 12, wherein the weight ratio of brimonidine and / or a salt thereof, the water-soluble polymer, and the benzalkonium chloride is 1:1 to 15:0.01 to 0.1. [Item 14] The viscosity reduction inhibitor according to Item 12 or 13, wherein the water-soluble polymer is carboxymethyl cellulose and / or a salt thereof. [Section 15] An eye drop comprising brimonidine and / or a salt thereof, carboxymethylcellulose, and benzalkonium chloride, The content of brimonidine and / or a salt thereof is 0.1 w / v%, the content of carboxymethylcellulose is 0.1 w / v% to 1.5 w / v%, and the content of benzalkonium chloride is 0.001 w / v% to 0.01 w / v%, The eye drops have a pH of 6.7 to 7.5, and An eye drop having a viscosity stability of 90% or more, calculated by dividing the viscosity of the eye drop after storing the eye drop at 60°C for 4 weeks by the viscosity of the eye drop before storing the eye drop for said 4 weeks. [Section 16] A method for suppressing a decrease in viscosity of an eye drop containing carboxymethylcellulose, the method comprising the step of allowing both brimonidine and / or a salt thereof and benzalkonium chloride to coexist in the eye drop, wherein: The content of brimonidine and / or its salt is 0.1 w / v%, The content of carboxymethyl cellulose is 0.1 w / v% to 1.5 w / v%, The benzalkonium chloride content is 0.001 w / v% to 0.01 w / v%, The eye drops have a pH of 6.7 to 7.5, and The method, wherein the viscosity stability calculated by dividing the viscosity of the eye drop preparation after storing the eye drop preparation at 60°C for 4 weeks by the viscosity of the eye drop preparation before said 4-week storage is 90% or more. [Effects of the Invention]

[0010] According to the present invention, there is provided an eye drop containing a water-soluble polymer and having a viscosity decrease suppressed. According to the present invention, there is provided a method for suppressing a viscosity decrease of an eye drop containing a water-soluble polymer or an agent for suppressing a viscosity decrease. DETAILED DESCRIPTION OF THE INVENTION

[0011] In the present invention, "glaucoma" means a disease characterized by functional and structural abnormalities of the eye, which have characteristic changes in the optic nerve and visual field, and in which optic nerve damage can usually be improved or suppressed by sufficiently lowering the intraocular pressure, and includes primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous humor production glaucoma, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, mixed glaucoma, steroid-induced glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, lenticular capsular glaucoma, plateau iris syndrome, and the like.

[0012] The "water-soluble polymer" is not particularly limited as long as it is one commonly used as a thickener or viscosifier in eye drops, and examples thereof include carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymers (such as cross-linked polyacrylic acid polymers), xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. In the eye drops of the present invention, preferred water-soluble polymers are cellulose-based polymers and / or salts thereof. Examples of cellulose-based polymers and / or salts thereof include carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and salts thereof. In the eye drops of the present invention, particularly preferred water-soluble polymers are carboxymethylcellulose and / or salts thereof. These water-soluble polymers may be used alone or in combination of two or more.

[0013] "Carboxymethylcellulose (CMC) and / or its salts" are commercially available, and specific examples include NS-300, ECG-505 (Godo Pharmaceutical Co., Ltd.), Sunrose (Nippon Paper Chemicals Co., Ltd.), Cellogen Series (Dai-ichi Kogyo Seiyaku Co., Ltd.), Ac-Di-Sol (Asahi Kasei Chemicals Corporation), and Kiccolate ND-2HS (Nichirin Chemical Industry Co., Ltd.). Examples of CMC salts include, but are not limited to, sodium salts. In one embodiment, the CMC salt is sodium carboxymethylcellulose. CMC and its salts may be used alone or in combination. In this specification, references to the content or concentration of CMC and / or its salts refer to the content or concentration converted into sodium carboxymethylcellulose, unless otherwise specified.

[0014] Water-soluble polymers are used, but are not limited to, as thickeners or viscosifiers to impart a desired viscosity to the eye drops. In one embodiment, a water-soluble polymer (e.g., CMC and / or a salt thereof) is blended into the eye drops in an amount that gives the eye drops a viscosity of 1.0 mPa·s or more but less than 30 mPa·s at 25°C and a rotation speed of 60 rpm. The water-soluble polymer is preferably blended in an amount that gives the eye drops a viscosity of 1.0 mPa·s or more but less than 15 mPa·s, 1.5 mPa·s or more but less than 5.0 mPa·s, or 1.5 mPa·s or more but less than 3.0 mPa·s at 25°C and a rotation speed of 60 rpm.

[0015] In one embodiment, the concentration of the water-soluble polymer (for example, CMC and / or a salt thereof) is 0.1 w / v% to 1.5 w / v%, and preferably 0.3 w / v% to 0.7 w / v%, per volume of the eye drops.

[0016] In other embodiments, the eye drops comprise CMC and / or salts thereof as a thickening or thickening agent and are substantially free of other thickening or thickening agents.

[0017] "Brimonidine" is a selective adrenergic α2 receptor agonist and is incorporated as an active ingredient in the eye drops of the present invention. Brimonidine and its salts are commercially available. Brimonidine salts include, but are not limited to, tartrate, hydrochloride, or acetate. In one embodiment, the brimonidine salt is brimonidine tartrate. References herein to the content or concentration of brimonidine and / or its salts refer to the content or concentration converted into brimonidine tartrate, unless otherwise specified.

[0018] In one embodiment, brimonidine and / or a salt thereof is incorporated as one component of a viscosity decrease inhibitor to inhibit the viscosity decrease of the eye drop solution caused by thermal decomposition or denaturation of a water-soluble polymer (e.g., a cellulose-based polymer, e.g., CMC) incorporated in the eye drop solution. The concentration of brimonidine and / or a salt thereof per volume of the eye drop solution is 0.05 w / v% to 0.2 w / v%, preferably 0.07 w / v% to 0.15 w / v%, and more preferably 0.09 w / v% to 0.12 w / v%.

[0019] In one embodiment, the eye drops may contain, in addition to brimonidine and / or a salt thereof, other pharmacological ingredients that exhibit a therapeutic effect against glaucoma, provided that the effects of the present invention are not impaired. Examples of such other pharmacological ingredients include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetics such as pilocarpine hydrochloride; anticholinesterase agents such as distigmine bromide; sympathomimetics such as dipivefrine hydrochloride; β-blockers such as timolol maleate; β-blockers such as betaxolol hydrochloride; α-β-blockers such as nipradilol and levobunolol hydrochloride; and α-blockers such as bunazosin hydrochloride.

[0020] In one embodiment, the eye drops contain brimonidine and / or a salt thereof as a direct active ingredient for glaucoma, and are substantially free of other active ingredients.

[0021] "Benzalkonium chloride (BAK)" is a quaternary ammonium compound and is incorporated as a preservative in the eye drops of the present invention. BAK is commercially available. In one embodiment, BAK is incorporated as one component of a viscosity decrease inhibitor to inhibit the thermal decomposition or denaturation of a water-soluble polymer (e.g., a cellulose-based polymer, e.g., CMC) incorporated in the eye drops, resulting in a decrease in the viscosity of the eye drops. In one embodiment, the concentration of BAK is 0.001 w / v% to 0.01 w / v%, preferably 0.002 w / v% to 0.007 w / v%, and more preferably 0.002 w / v% to 0.005 w / v%, per volume of the eye drops.

[0022] In one embodiment, the eye drops may further contain, in addition to BAK, a preservative or antiseptic commonly used in eye drops, provided that the effects of the present invention are not impaired. Examples of such preservatives or antiseptics include, but are not limited to, sorbic acid or its salts, benzoic acid or its salts, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate, boric acid or its salts, dehydroacetic acid or its salts, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polidronium chloride, thimerosal, and dibutylhydroxytoluene. These additional preservatives or antiseptics may be used alone or in combination.

[0023] In one embodiment, the eye drops contain BAK as a preservative or antiseptic and are substantially free of other preservatives or antiseptics.

[0024] In one embodiment, the weight ratio of brimonidine and / or a salt thereof to BAK is 1:0.01-0.1, preferably 1:0.02-0.07, and more preferably 1:0.02-0.05.

[0025] In one embodiment, the weight ratio of brimonidine and / or a salt thereof, water-soluble polymer (e.g., CMC and / or a salt thereof), and BAK is 1:1-15:0.01-0.1, preferably 1:2-10:0.02-0.07, and more preferably 1:3-7:0.02-0.05.

[0026] In one embodiment, the eye drops optionally contain a buffering agent to provide a buffering effect. Examples of buffering agents include, but are not limited to, phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, Tris buffers, and amino acids. These buffering agents may be used alone or in combination of two or more. In one embodiment, the buffering agent is a borate buffer, preferably a combination of boric acid and sodium borate.

[0027] The buffering agent is blended in an amount generally used to impart sufficient buffering capacity to the eye drop, but is not limited thereto. In one embodiment, the buffering agent is boric acid, and the content thereof is, for example, 0.01 to 5 w / v%, preferably 0.05 to 1 w / v%, and more preferably 0.1 to 0.5 w / v%.

[0028] In addition to the above-mentioned components, the eye drops may further contain optional additives such as a chelating agent and a cooling agent, if necessary.

[0029] Examples of chelating agents include, but are not limited to, edetate, citric acid, and salts thereof. These chelating agents may be used alone or in combination of two or more.

[0030] Cooling agents include, but are not limited to, l-menthol, borneol, camphor, These cooling agents may be used alone or in combination of two or more.

[0031] In the present invention, "eye drops" refers to an aqueous composition. Eye drops can be prepared according to conventional methods. Eye drops can be prepared, but are not limited to, by dissolving a water-soluble polymer in purified water and dissolving the resulting aqueous solution together with solid components in purified water. The pH of the prepared aqueous solution may be adjusted using hydrochloric acid or sodium hydroxide, as appropriate. Eye drops may be sterilized according to conventional methods and then filled into product containers. In one embodiment, the sterilization is performed by filtration.

[0032] In one embodiment, the eye drops have a pH of 6.7 to 7.5 and an osmolality of 250 to 350 mOsm. In another embodiment, the eye drops have a pH of 6.7 to 7.3 and an osmolality ratio of 0.85 to 1.15. In another embodiment, the eye drops preferably have a pH of 7.1 and an osmolality ratio of approximately 1.0. The term "approximately" in relation to an osmolality ratio means ±0.1, and an osmolality ratio of approximately 1.0 indicates 0.9 to 1.1. The osmolality is adjusted according to a conventional method. In one embodiment, the osmolality is adjusted by incorporating a pharmaceutically acceptable salt into the eye drops as an isotonic agent. Pharmaceutically acceptable salts include, but are not limited to, magnesium chloride, sodium chloride, potassium chloride, calcium chloride, and hydrates thereof.

[0033] As used herein, the "viscosity" of an eye drop is measured according to Method 2, Rotational Viscosity Method, as defined in the Japanese Pharmacopoeia General Testing Methods, as described in the Examples. The viscosity of the prepared eye drop is appropriately set depending on the intended use. The viscosity of the eye drop is, but is not limited to, 1.0 mPa·s or more but less than 30 mPa·s at 25°C and a rotational speed of 60 rpm. In one embodiment, the viscosity of the prepared eye drop at 25°C and a rotational speed of 60 rpm is 1.0 mPa·s or more but less than 15 mPa·s. In one embodiment, the viscosity of the prepared eye drop at 25°C is 1.5 mPa·s or more but less than 5.0 mPa·s, or 1.5 mPa·s or more but less than 3.0 mPa·s.

[0034] The viscosity of the eye drop solution is imparted by, but not limited to, the water-soluble polymer added. In one embodiment, the viscosity of the eye drop solution is adjusted by the amount of water-soluble polymer (e.g., cellulose-based polymer) added, or by the amount of CMC and / or a salt thereof added substantially alone. In another embodiment, the viscosity of the eye drop solution is adjusted by combining CMC and / or a salt thereof with another water-soluble polymer described herein.

[0035] As used herein, "viscosity stability" refers to the stability of an eye drop filled into a glass ampoule, stored in an incubator at 60°C for 4 weeks, and calculated by dividing the viscosity of the aqueous solution after storage by the viscosity of the aqueous solution before storage (=viscosity of aqueous solution after storage [mPa s] / viscosity of aqueous solution before storage [mPa s] × 100), as described in the Examples. In one embodiment, the viscosity stability is 90% or more, preferably 92% or more, and more preferably 94% or more.

[0036] As used herein, "suppression of viscosity decrease" means that the viscosity stability of an eye drop containing a water-soluble polymer when either or both of brimonidine and / or a salt thereof and BAK are blended is higher than the viscosity stability when neither brimonidine and / or a salt thereof nor BAK is blended. In one embodiment, the degree of viscosity decrease suppression is such that the difference between the viscosity stability of an eye drop containing a water-soluble polymer (e.g., CMC) blended with brimonidine and / or a salt thereof and BAK and the viscosity stability of an identical eye drop containing a water-soluble polymer except that brimonidine and / or a salt thereof and BAK are not blended is 4% or more, 5% or more, 6% or more, or 7% or more.

[0037] In one embodiment, the eye drops are for treating glaucoma. As used herein, "treatment" refers to the alleviation, amelioration, or slowing of the progression of symptoms. In one embodiment, the eye drops contain brimonidine and / or a salt thereof in an amount effective for treating glaucoma, and do not contain any other pharmacological ingredients.

[0038] The eye drops are administered, but not limited to, in a single dose of several drops, once or multiple times a day. In one embodiment, the eye drops are administered in a single dose, twice a day. The concentrations of the components of the eye drops are appropriately determined depending on the dosage and administration method.

[0039] A first aspect of the present invention relates to an eye drop preparation containing a water-soluble polymer, brimonidine and / or a salt thereof, and BAK. In one embodiment, the eye drop preparation contains 0.05 w / v % to 0.2 w / v % of brimonidine and / or a salt thereof, 0.1 w / v % to 1.5 w / v % of a water-soluble polymer (e.g., a cellulose-based polymer, e.g., CMC and / or a salt thereof), and 0.001 w / v % to 0.01 w / v % of BAK, with a weight ratio of brimonidine and / or a salt thereof to BAK of 1:0.01 to 0.1.

[0040] In another embodiment, the eye drops contain brimonidine tartrate at 0.07 w / v% to 0.15 w / v% (preferably 0.09 w / v% to 0.12 w / v%, more preferably 0.1 w / v%), CMC at 0.3 w / v% to 0.7 w / v% (preferably 0.5 w / v%), and BAK at 0.001 w / v% to 0.01 w / v% (preferably 0.002 w / v% to 0.007 w / v%). w / v%, more preferably 0.002 w / v% to 0.005 w / v%, the weight ratio of brimonidine tartrate to benzalkonium chloride is 1:0.01 to 0.1 (preferably 1:0.02 to 0.07, more preferably 1:0.02 to 0.05), and further contains boric acid and borax (osmotic pressure ratio: 0.9 to 1.1 (i.e., about 1.0), pH: 6.7 to 7.5).

[0041] In other embodiments, the eye drops contain at least one cellulosic polymer and / or a salt thereof (e.g., CMC and / or a salt thereof) as a thickening or viscosifying agent, and are substantially free of other thickening or viscosifying agents, and contain a combination of brimonidine and / or a salt thereof and BAK as a viscosity loss inhibitor, and are substantially free of other viscosity loss inhibitors.

[0042] A second aspect of the present invention relates to a method for suppressing a decrease in viscosity of an eye drop, comprising the step of allowing either or both of brimonidine and / or a salt thereof and BAK to coexist in an eye drop containing a water-soluble polymer (e.g., CMC and / or a salt thereof). More preferably, it relates to a method for suppressing a decrease in viscosity of an eye drop, comprising allowing both brimonidine and / or a salt thereof and BAK to coexist in an eye drop containing a water-soluble polymer (e.g., CMC and / or a salt thereof). This method is not particularly limited, and can be carried out, for example, by blending brimonidine and / or a salt thereof and BAK into the eye drop, with no particular limitation being imposed on the order in which the water-soluble polymer, brimonidine and / or a salt thereof, and BAK are added. The components to be blended may be, but are not limited to, solids or liquids.

[0043] In one embodiment, the weight ratio of brimonidine and / or a salt thereof to BAK is 1:0.01-0.1, preferably 1:0.02-0.07, and more preferably 1:0.02-0.05. In one embodiment, the weight ratio of brimonidine and / or a salt thereof to CMC and / or a salt thereof to BAK is 1:1-15:0.01-0.1, preferably 1:2-10:0.02-0.07, and more preferably 1:3-7:0.02-0.05.

[0044] In one embodiment, the eye drops containing brimonidine and / or a salt thereof, a water-soluble polymer, and BAK coexist contain 0.05 w / v% to 0.2 w / v% of brimonidine and / or a salt thereof per volume of the eye drops, 0.1 w / v% to 1.5 w / v% of CMC and / or a salt thereof per volume of the eye drops, and 0.001 w / v% to 0.01 w / v% of BAK per volume of the eye drops.

[0045] A third aspect of the present invention relates to a viscosity decrease inhibitor for inhibiting viscosity decrease of an eye drop containing a water-soluble polymer, which contains brimonidine and / or a salt thereof and BAK in a weight ratio of 1:0.01 to 0.1. In one embodiment, the weight ratio of brimonidine and / or a salt thereof and BAK contained in the viscosity decrease inhibitor is 1:0.02 to 0.07, preferably 1:0.02 to 0.05.

[0046] In one embodiment, the weight ratio of brimonidine and / or its salt, water-soluble polymer, and BAK in the eye drops after blending with the viscosity decrease inhibitor is 1:1 to 15:0.01 to 0.1, preferably 1:2 to 10:0.02 to 0.07, and more preferably 1:3 to 7:0.02 to 0.05, based on the content of the water-soluble polymer (e.g., CMC and / or its salt) in the eye drops blended with the viscosity decrease inhibitor. The viscosity decrease inhibitor may be in the form of, but is not limited to, a liquid or solid (e.g., a powder or tablet). The powder or tablet can be prepared by a conventional method.

[0047] A fourth aspect of the present invention relates to a method for producing an eye drop, comprising the step of mixing 0.05 w / v% to 0.2 w / v% brimonidine and / or a salt thereof, 0.1 w / v% to 1.5 w / v% water-soluble polymer, and 0.001 w / v% to 0.01 w / v% BAK in a pharmaceutically acceptable aqueous medium. The term "pharmaceutically acceptable aqueous medium" refers to an aqueous medium that can be used for topical application to the eye, and may be, but is not limited to, purified water. In one embodiment, the blending step may involve blending a water-soluble polymer (e.g., CMC) with purified water, followed by blending brimonidine and / or a salt thereof and BAK. The manufacturing method may further include, but is not limited to, blending additional additive components. The manufacturing method may further include, but is not limited to, a sterilization step. In one embodiment, the sterilization step is filtration.

[0048] The characteristics of each element mentioned in this specification, such as the concentrations of the water-soluble polymer (e.g., CMC and / or a salt thereof), BAK, and brimonidine in the eye drop solution, the viscosity and viscosity stability of the eye drop solution, any additional components, the pH of the eye drop solution, and the osmotic pressure, apply to each element related to the first to fourth aspects. Numerical ranges described in this specification include the upper and lower limit values, unless explicitly stated as "greater than" or "less than." [Example]

[0049] [Preparation of eye drops] Aqueous liquid preparations were prepared according to the formulations shown in Table 1. Each aqueous liquid preparation was made isotonic by adding appropriate amounts of sodium chloride, potassium chloride, calcium chloride hydrate, and magnesium chloride, and adjusted to pH 7.0 with hydrochloric acid or sodium hydroxide.

[0050] [Table 1]

[0051] [Accelerated aging test] Five mL of the aqueous solution was filtered through a 0.22 μm filter and filled into a 5 mL colorless glass ampoule. Each glass ampoule was placed in an incubator (CH-M20-01, Nagano Science Co., Ltd.) and stored at 60°C for 4 weeks under light-shielded conditions.

[0052] [Viscosity measurement] The viscosity [mPa s] of the aqueous liquid formulation was measured at 25°C and a rotational speed of 60 rpm according to the Japanese Pharmacopoeia General Testing Method, Method 2, Rotational Viscosity Method (cone-plate type rotational viscometer (cone-plate type viscometer, TVE-20L, Toki Sangyo Co., Ltd.)). Viscosity measurements were carried out before and after the accelerated aging test. The viscosity stability (%) of the aqueous liquid formulation was calculated according to the following formula. (Number 1) Viscosity stability [%] = Viscosity of aqueous liquid after storage [mPa·s] / Viscosity of aqueous liquid before storage [mPa ·s]×100

[0053] [Test Results] The viscosity of the aqueous solution of Formulation 1 was 2.513 mPa·s before the accelerated aging test and 2.370 mPa·s after the accelerated aging test. The viscosity stability was 94.3%. Similarly, the viscosity stability of formulations 2, 3 and 4 was calculated. Prescription 2: 90.8[%] (=2.399[mPa·s] / 2.641[mPa·s]×100); Formulation 3: 87.4% (= 2.213 mPa·s / 2.531 mPa·s × 100), and Prescription 4: 86.5% (= 2.173 mPa·s / 2.513 mPa·s × 100).

[0054] Table 2 summarizes the test results and ingredient combinations for Formulations 1 to 4. [Table 2]

[0055] An aqueous solution containing 0.5 w / v% sodium carboxymethylcellulose exhibited viscosity stability of less than 90% after storage at 60°C for 4 weeks (Formulation 3). An aqueous solution containing 0.005 w / v% BAK in addition to the aqueous solution components of Formulation 3 also exhibited viscosity stability of less than 90% (Formulation 4). This suggests that the addition of BAK has little effect on the viscosity stability of aqueous solutions containing sodium carboxymethylcellulose (Formulations 3 and 4).

[0056] An aqueous solution containing 0.1 w / v% brimonidine tartrate in addition to the aqueous solution components of Formulation 3 exhibited viscosity stability exceeding 90% (Formulation 2), suggesting that the addition of brimonidine tartrate can improve the viscosity stability of aqueous solutions containing sodium carboxymethylcellulose (Formulations 2 and 3).

[0057] An aqueous solution containing 0.1 w / v% brimonidine tartrate and 0.005 w / v% BAK in addition to the aqueous solution components of Formulation 3 exhibited a viscosity stability of approximately 95% (Formulation 1). The improvement in viscosity stability of the aqueous solutions containing both brimonidine tartrate and BAK (Formulations 1 and 3) exceeded the sum of the improvement in viscosity stability of the aqueous solutions containing either of the above two components (Formulations 2 to 4). These results suggest that the combination of brimonidine tartrate and benzalkonium chloride synergistically improved the viscosity stability of aqueous solutions containing sodium carboxymethylcellulose.

Claims

1. An eye drop comprising brimonidine and / or a salt thereof, a water-soluble polymer, and benzalkonium chloride, wherein the content of brimonidine and / or a salt thereof is 0.05 w / v % to 0.2 w / v %, the content of the water-soluble polymer is 0.1 w / v % to 1.5 w / v %, the content of benzalkonium chloride is 0.001 w / v % to 0.01 w / v %, the weight ratio of brimonidine and / or a salt thereof to benzalkonium chloride is 1:0.01 to 0.1, and the pH is 6.7 to 7.0, with the proviso that the eye drop does not contain timolol.

2. The eye drop according to claim 1, wherein the water-soluble polymer is a cellulose-based polymer and / or a salt thereof.

3. 3. The eye drop preparation according to claim 1, wherein the weight ratio of brimonidine and / or a salt thereof, the water-soluble polymer, and benzalkonium chloride is 1:1-15:0.01-0.

1.

4. The eye drop preparation according to any one of claims 1 to 3, which has a pH of 6.

7.

5. 5. The eye drop preparation according to claim 1, wherein the viscosity stability calculated by dividing the viscosity of the eye drop preparation after storage at 60°C for 4 weeks by the viscosity of the eye drop preparation before the storage for 4 weeks is 90% or more.

6. The eye drop preparation according to any one of claims 1 to 5, which is for treating glaucoma.

7. A method for suppressing a decrease in viscosity of an eye drop containing a water-soluble polymer, the method comprising a step of causing both brimonidine and / or a salt thereof and benzalkonium chloride to coexist in the eye drop, wherein the content of brimonidine and / or a salt thereof is 0.05 w / v % to 0.2 w / v %, the content of the water-soluble polymer is 0.1 w / v % to 1.5 w / v %, the content of benzalkonium chloride is 0.001 w / v % to 0.01 w / v %, and the pH is 6.7 to 7.0, with the proviso that the eye drop does not contain timolol.

8. The method according to claim 7 , wherein the water-soluble polymer is a cellulose-based polymer and / or a salt thereof.

9. 9. The method according to claim 7 or 8, wherein the weight ratio of brimonidine and / or a salt thereof to benzalkonium chloride is 1:0.01-0.

1.

10. The method according to any one of claims 7 to 9, wherein the weight ratio of brimonidine and / or a salt thereof, the water-soluble polymer, and the benzalkonium chloride is 1:1-15:0.01-0.

1.

11. The method according to any one of claims 7 to 10, wherein the pH is 6.7.

Images