JP2019104727A - Aqueous solution containing water-soluble polymer - Google Patents

Abstract

To provide a preparation technique which can prevent a temporal decrease in viscosity of an aqueous solution containing a water-soluble polymer.SOLUTION: The present invention provides an aqueous solution containing a water-soluble polymer, in which there coexist at least one or both of brimonidine and/or a salt thereof and chlorhexidine gluconate.SELECTED DRAWING: None

Description

  The present invention relates to a water-soluble polymer, brimonidine and / or a salt thereof, an aqueous solution containing chlorhexidine gluconate, and the like.

  Brimonidine is a selective adrenergic alpha 2 receptor agonist, which suppresses the formation of aqueous humor and promotes the outflow of aqueous humor through the uveoscleral outflow tract, thereby reducing the intraocular pressure Show. For this reason, brimonidine and its salts are used for the treatment of glaucoma.

  In order to enhance the bioavailability of the pharmacological component contained in the aqueous solution, improving retention of the component on the ocular mucosa has been performed. For example, it is known that the retention of the pharmacological component contained in the aqueous solution can be improved by incorporating a water-soluble polymer into the aqueous solution as a thickener or thickener.

  However, when a water-soluble polymer is blended in an aqueous solution, there is a problem that the viscosity stability is low and the viscosity of the solution decreases with time. Such a decrease in viscosity impairs the feeling of use and prevents the desired drug effect from being developed, so the formulation design and quality assurance of aqueous solutions (particularly eye drops) containing these water-soluble polymers are impaired. Therefore, it is important to suppress the viscosity decrease with time. In particular, in the case of eye drops, the viscosity of the eye drop is set to the same level as that of tear fluid, thereby maintaining the wettability of the keratoconjunctiva, preventing dryness, imparting an action as a lubricating oil between the eyelid and eye in eye movement and the like. And adjustments are made to eliminate discomfort when instilled. Therefore, it is especially important to improve the viscosity stability of the eye drop, as the drop in the viscosity of the eye drop will lead to the attenuation of these functions.

  Heretofore, there has been reported about a formulation technology that suppresses a decrease in viscosity with time in an aqueous solution containing a water-soluble polymer. For example, there is known a mucosal application composition in which aspartic acid or a salt thereof is added to a composition containing carboxymethylcellulose (hereinafter also referred to as "CMC"), which is one of water-soluble polymers, and viscosity reduction is suppressed. (Patent Document 1). There is known an ophthalmic aqueous liquid preparation in which gluconic acid or a metal salt thereof is blended with a composition containing hyaluronic acid to enhance the stability of viscosity (Patent Document 2). However, no formulation technology has been described which can suppress the decrease in viscosity using brimonidine or chlorhexidine gluconate.

Japanese Patent Application Publication No. 2006-104114 WO2008-050776

  An object of the present invention is to provide a formulation technology capable of suppressing a decrease in viscosity with time in an aqueous solution containing a water-soluble polymer.

  As a result of intensive research on the component for suppressing the viscosity decrease of the aqueous solution containing CMC, which is one of water-soluble polymers, the present inventor surprisingly found that brimonidine itself, which is an intraocular pressure-lowering agent, It has been found that such a viscosity reduction suppressing action is exhibited. The inventors have also found that the preservative or preservative chlorhexidine gluconate suppresses the viscosity reduction of the aqueous solution containing CMC. Furthermore, the present inventors have found that by using brimonidine and chlorhexidine gluconate in combination, an excellent viscosity reduction suppressing action is exhibited, and the present invention has been completed.

  The inventor further noted that the combination of brimonidine and / or a salt thereof with chlorhexidine gluconate contains polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), which is one of water-soluble polymers, or hyaluronic acid. The present invention has been accomplished by finding that the aqueous liquid preparation of the present invention exhibits an excellent viscosity drop suppressing action.

  The inventor of the present invention has made it an aqueous solution comprising chlorhexidine gluconate containing brimonidine and / or a salt thereof and CMC, PVA, HPMC or hyaluronic acid which is one of water-soluble polymers, wherein the brimonidine in the aqueous solution is The inventors have found that the present invention exhibits an excellent action to suppress the reduction in the content of the salt thereof and / or the present invention.

  The inventors have found that the combination of brimonidine and / or a salt thereof with chlorhexidine gluconate stabilizes the pH of an aqueous solution containing polyvinyl pyrrolidone (PVP), which is one of water-soluble polymers. It has been found that the present invention is complete.

  That is, the present invention relates to the following aqueous solution, a method for suppressing a viscosity decrease, and a viscosity decrease inhibitor.

[Item 1]
An aqueous solution comprising brimonidine and / or a salt thereof, a water-soluble polymer, and chlorhexidine gluconate.
[Section 2]
The content of brimonidine and / or a salt thereof is 0.05 w / v% to 0.2 w / v%, and the content of water-soluble polymer is 0.05 w / v% to 3 w / v%, and chlorhexidine gluconate The aqueous liquid preparation according to item 1, wherein the content of the acid salt is 0.001 w / v% to 0.01 w / v%.
[Section 3]
The aqueous solution according to Item 1 or 2, wherein a weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and a chlorhexidine gluconate is 1: 1 to 15: 0.01 to 0.1.
[Section 4]
The water-soluble polymer is at least one selected from the group consisting of carboxymethyl cellulose and / or a salt thereof, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, and hyaluronic acid and / or a salt thereof The aqueous solution according to any one of the preceding claims.
[Section 5]
The content of brimonidine and / or its salt is 0.1 w / v%, the content of carboxymethyl cellulose and / or its salt is 0.5 w / v%, the content of chlorhexidine gluconate is 0.0025 w The aqueous | water-based liquid preparation as described in any one of claim | item 1-4 which is / v%-0.005 w / v%.
[Section 6]
The viscosity stability calculated by dividing the viscosity of the aqueous solution after storing the aqueous solution at 60 ° C. for 4 weeks by the viscosity of the aqueous solution before storing for 4 weeks is 90% or more. The aqueous liquid preparation as described in any one of claim | item 5 paragraph.
[Section 7]
The aqueous solution according to any one of claims 1 to 6, wherein the aqueous solution is for ophthalmic use.
[Section 8]
The aqueous solution according to claim 7, wherein the ophthalmic aqueous solution is an eye drop.
[Section 9]
Item 9. The aqueous solution according to any one of Items 1 to 8, for treating glaucoma.
[Section 10]
A method of suppressing viscosity reduction of an aqueous liquid preparation, comprising the step of coexistence of either one or both of brimonidine and / or a salt thereof and chlorhexidine gluconate in an aqueous liquid preparation.
[Item 11]
11. The method according to item 10, comprising the step of coexistence of both brimonidine and / or a salt thereof and chlorhexidine gluconate in an aqueous solution.
[Section 12]
The content of brimonidine and / or a salt thereof is 0.05 w / v% to 0.2 w / v%, and the content of water-soluble polymer is 0.05 w / v% to 3 w / v%, and chlorhexidine gluconate Item 12. The method according to Item 10 or 11, wherein the content of the acid salt is 0.001 w / v% to 0.01 w / v%.
[Section 13]
The weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and a chlorhexidine gluconate is any one of items 10 to 12, wherein the weight ratio is 1: 1 to 15: 0.01 to 0.1. Method described.
[Section 14]
The water-soluble polymer is at least one selected from the group consisting of carboxymethylcellulose and / or a salt thereof, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hyaluronic acid and / or a salt thereof, according to item 10 to item 13, The method according to any one of the preceding claims.
[Section 15]
A viscosity decrease inhibitor containing brimonidine and / or a salt thereof and / or chlorhexidine gluconate for suppressing a viscosity decrease of an aqueous solution containing a water-soluble polymer.
[Section 16]
Item 19. The viscosity decrease inhibitor according to Item 15, which contains both brimonidine and / or a salt thereof and chlorhexidine gluconate.
[Section 17]
The content of brimonidine and / or its salt is 0.05 w / v% to 0.2 w / v%, and the content of chlorhexidine gluconate is 0.001 w / v% to 0.01 w / v% Item 18. The viscosity decrease inhibitor according to item 15 or 16 which is compounded into
[Section 18]
Item 18. The compound according to Item 15 to 17, wherein the weight ratio of brimonidine and / or a salt thereof, the water-soluble polymer, and the chlorhexidine gluconate is 1: 1 to 15: 0.01 to 0.1. The viscosity decrease inhibitor according to any one of the preceding claims.
[Item 19]
The water-soluble polymer is at least one selected from the group consisting of carboxymethylcellulose and / or a salt thereof, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hyaluronic acid and / or a salt thereof, according to item 15 to item 18, The viscosity decrease inhibitor according to any one of the preceding claims.
[Section 20]
A method for suppressing the decrease in the content of brimonidine and / or a salt thereof in an aqueous solution, comprising the step of coexistence of a water-soluble polymer and chlorhexidinegluconate in an aqueous solution containing brimonidine and / or a salt thereof , How to suppress the content reduction.
[Section 21]
A method for stabilizing pH in an aqueous solution containing a water-soluble polymer, comprising the step of coexistence of brimonidine and / or a salt thereof with chlorhexidine gluconate in an aqueous solution containing the water-soluble polymer How to stabilize the
[Section 22]
A method of treating glaucoma, comprising administering an aqueous solution containing brimonidine and / or a salt thereof, a water-soluble polymer, and chlorhexidine gluconate to the eye of a subject in need thereof.

  The aqueous liquid preparation of the present invention can suppress the decrease in viscosity with time while containing a water-soluble polymer, so it is possible to use a water-soluble polymer such as improvement of feeling in use, improvement of retention of drug, enhancement of medicinal effect, etc. The effect to be given can be maintained for a long time.

  It is to be understood that the terms used herein are used in the sense commonly used in the art unless otherwise stated. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

(Definition)
As used herein, "brimonidine" is a selective adrenergic alpha 2 receptor agonist and is formulated as an active ingredient in general aqueous solutions, particularly eye drops. Brimonidine and its salts are commercially available. The salts of brimonidine include, but are not limited to tartrate, hydrochloride or acetate. In the present specification, references to the content or concentration of brimonidine and / or a salt thereof mean the content or concentration converted to brimonidine tartrate, unless otherwise specified.

  As used herein, "water-soluble polymer" refers to a water-soluble polymer. The "water-soluble polymer" is, but not limited to, one used as a thickener or a thickener to impart desired viscosity to an aqueous solution. The "water-soluble polymer" is not particularly limited as long as it is generally used in aqueous solutions as a thickener or a thickener, and polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer (crosslinked polyacrylic acid polymer) Etc .; etc .; cellulose based polymer compounds such as carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose etc .; and natural polymers such as xanthan gum, sodium chondroitin sulfate, sodium hyaluronate etc. .

  In the present specification, "carboxymethyl cellulose (CMC)" is one kind of cellulose-based polymer compound. "Carboxymethylcellulose (CMC)" is commercially available and is generally used as a thickener or thickener to impart the desired viscosity to an aqueous solution. Specifically, for example, NS-300 (manufactured by Gotoku Pharmaceutical Co., Ltd.) or the like is used. Salts of CMC include, but are not limited to, sodium salts, and specifically, for example, T. et al. P. T (manufactured by Gotoku Pharmaceutical Co., Ltd.), Cellogen series (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.), Sun Rose (manufactured by Nippon Paper Chemicals Co., Ltd.), etc. are used. As used herein, references to the content or concentration of CMC and / or its salt refer to the content or concentration converted to sodium carboxymethylcellulose unless otherwise specified.

  In the present specification, “polyvinyl alcohol (PVA)” is one of polyvinyl synthetic resins. PVA is commercially available and is generally used as a thickener or thickener to impart the desired viscosity to the aqueous solution. Specifically, for example, Gohsenol (manufactured by Japan Synthetic Chemical Industry Co., Ltd.) or the like is used.

  In the present specification, “polyvinyl pyrrolidone (PVP)” is one of polyvinyl synthetic resins. PVP is commercially available and is generally used as a thickener or thickener to impart the desired viscosity to an aqueous solution. Specifically, for example, Kollidon 30 (manufactured by BASF Japan Ltd.) and the like are used.

  In the present specification, "hydroxypropyl methylcellulose (HPMC)" is one type of cellulose-based polymer. HPMC is commercially available and is generally used as a thickener or thickener to impart the desired viscosity to an aqueous solution. Specifically, for example, METOLOSE / hypromellose 2906 (manufactured by Shin-Etsu Chemical Co., Ltd.) and the like are used.

  As used herein, "hyaluronic acid" is a type of natural macromolecule. Hyaluronic acid is commercially available and is generally used as a thickener or thickener to impart the desired viscosity to the aqueous solution. Specifically, for example, purified sodium hyaluronate (manufactured by Seikagaku Corporation) is used. Salts of hyaluronic acid include, but are not limited to, sodium salts. In the present specification, references to the content or concentration of hyaluronic acid and / or a salt thereof mean the content or concentration converted to sodium hyaluronate unless otherwise specified.

  As used herein, “chlorhexidine gluconate” is a gluconate of chlorhexidine (C22H30Cl2N10) and is formulated as a preservative or preservative in a common aqueous solution. Chlorhexidine gluconate is commercially available.

  As used herein, "aqueous solution" is an aqueous liquid drug. An aqueous solution can be prepared according to a conventional method. The "aqueous liquid preparation" in the present specification includes, but is not limited to, topical administration preparations for various uses such as ophthalmic use, dental use, otolaryngology and dermatology. The aqueous liquid preparation is prepared by dissolving a water-soluble polymer in purified water to obtain an aqueous solution, and dissolving the aqueous solution in the purified water together with other solid components and optionally liquid components, but is not limited thereto. it can. The pH of the prepared aqueous solution may be adjusted using hydrochloric acid or sodium hydroxide, as appropriate. The aqueous solution may be sterilized in a conventional manner and then filled into a product container. The sterilization method is not particularly limited as long as it is a generally used method, and filter sterilization, filter sterilization, dry heat sterilization, electron beam sterilization, gamma ray sterilization and the like can be mentioned. In one embodiment, the sterilization process is filter filtration.

  In the present specification, the "viscosity" of the aqueous liquid preparation is measured according to the rotational viscometer method as defined in the General Test Method of the 17th Amended Japanese Pharmacopoeia, as described in the Examples. ° C, rotational speed 50 rpm, conical-plate type rotational viscometer, cone rotor used: 0.8 ° × R24 (rotor code: 00)). The viscosity of the aqueous liquid preparation is appropriately set according to the purpose of use.

  In the present specification, "viscosity stability" means that after an aqueous solution is filled in a glass ampoule as described in the examples, it is stored for 4 weeks in a thermostat at 60 ° C. It means the degree to which the viscosity is maintained. In addition, the degree of “viscosity stability” can be expressed by a value calculated by dividing the viscosity of the aqueous solution after storage by the viscosity of the aqueous solution before storage (= viscosity of the aqueous solution after storage [ mPa · s] / viscosity of aqueous solution before storage [mPa · s] × 100).

  In the present specification, “viscosity drop suppression” refers to viscosity stability when an aqueous liquid preparation containing a water-soluble polymer contains either brimonidine and / or a salt thereof and chlorhexidine gluconate, or both. It means that it is higher than the viscosity stability when neither brimonidine and / or its salt nor chlorhexidine gluconate is blended. Further, in the present specification, the “viscosity decrease inhibitor” is an aqueous solution containing a water-soluble polymer, by blending either brimonidine and / or a salt thereof and chlorhexidine gluconate, or both. , An agent for suppressing the decrease in viscosity with time.

  In the present specification, the "content" of brimonidine and / or a salt thereof is measured by liquid chromatography as described in the examples (detector: ultraviolet spectrophotometer (measurement wavelength: 230 nm)). In the present specification, the content of brimonidine and / or its salt in the aqueous solution means the percentage (w / v%) of the weight (g) per volume (ml) of the aqueous solution.

  In the present specification, "suppression of content reduction" of brimonidine and / or a salt thereof refers to brimonidine and / or a salt thereof in an aqueous solution after storage for 2 weeks at 60.degree. C. as described in the examples. It means that the content is higher when chlorhexidine gluconate is blended in an aqueous solution containing brimonidine and / or a salt thereof and a water-soluble polymer than when chlorhexidine gluconate is not blended.

  In the present specification, "suppression of the decrease in the content of brimonidine and / or a salt thereof in an aqueous liquid preparation" can be reworded as "improvement of residual rate" or "stabilization" of brimonidine and / or a salt thereof in an aqueous liquid preparation, etc. it can. In the present specification, the "residuality" of brimonidine and / or its salt in an aqueous solution is, as described in the examples, brimonidine and / or its salt in an aqueous solution after storage for 2 weeks at 60 ° C. Mean the value obtained by dividing the content of B by the content of brimonidine and / or its salt in the aqueous solution before storage. As used herein, the "stabilization" of brimonidine and / or its salt in the aqueous solution is such that the content of brimonidine and / or its salt in the aqueous solution is stable before and after storage for 2 weeks at 60 ° C. Mean that the difference in content is small.

  In the present specification, the “content reduction inhibitor” or the “stabilizer” is the aqueous liquid preparation containing brimonidine and / or a salt thereof by causing a water-soluble polymer and chlorhexidine gluconate to coexist in the aqueous liquid preparation. Means an agent for suppressing the decrease in the content of brimonidine and / or a salt thereof over time.

  The "pH" of the aqueous solution herein is measured with a pH meter using a glass electrode as described in the examples. The pH of the aqueous solution is appropriately set according to the purpose of use.

  In the present specification, “pH stabilization” means, as described in the Examples, that the difference between the pH of the aqueous solution after storage for 2 weeks at 60 ° C. and the pH of the aqueous solution before storage is an aqueous solution Liquid containing a hydrophobic polymer containing brimonidine and / or a salt thereof and chlorhexidine gluconate, which is smaller than when brimonidine and / or a salt or chlorhexidine gluconate is not blended either .

  In the present specification, the “pH stabilizer” stabilizes the pH of the aqueous solution by blending brimonidine and / or a salt thereof with chlorhexidine gluconate in an aqueous solution containing a water-soluble polymer. Means an agent to

  As used herein, "treatment" means alleviation of symptoms, palliation or reduction in the rate of progression. Furthermore, as used herein, “glaucoma” refers to functional structural abnormalities of the eye that have characteristic changes in the optic nerve and visual field, and can usually improve or suppress optic nerve damage by sufficiently lowering the intraocular pressure. It means a disease characterized by: primary open angle glaucoma, normal tension glaucoma, aqueous humor hyperglaucoma, hypertensive hypertension, acute closure angle glaucoma, chronic closure angle glaucoma, mixed glaucoma, steroid glaucoma, amyloid It includes glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma of the lens, plateau iris syndrome and the like.

  As used herein, "subject" means an animal in need of alleviation of symptoms, palliation or reduction in the rate of progression. The animals include, but are not limited to, mammals including humans. In one embodiment, the animal is a human. In another embodiment, the animal is a determined human patient in need of treatment.

  Each component mentioned in the present specification, for example, the concentration of the water soluble polymer (for example, CMC and / or its salt), the concentration of the chlorhexidine gluconate and brimonidine in the aqueous solution, the viscosity of the aqueous solution, viscosity stability, optional The features relating to the additive components of the present invention, the pH in the aqueous liquid preparation, the osmotic pressure and the like apply to each of the elements relating to the first to seventh aspects. The numerical range described in the present specification indicates the range including the upper limit value and the lower limit value except when it is specified as “exceed” or “less than”.

Description of the Preferred Embodiment
While the description of the preferred embodiments is set forth below, it should be understood that this embodiment is an illustration of the present invention and that the scope of the present invention is not limited to such preferred embodiments. It is to be understood that those skilled in the art can easily make modifications, changes and the like within the scope of the present invention with reference to the following preferred embodiments. Those skilled in the art can appropriately combine any of these embodiments.

1. Aqueous Solution The first aspect of the present invention relates to an aqueous solution comprising brimonidine and / or a salt thereof, a water-soluble polymer and chlorhexidine gluconate.

[Brimonidine]
In the aqueous liquid preparation of the present invention, brimonidine and / or a salt thereof is not limited, but is a viscosity reduction inhibitor for suppressing a decrease in viscosity imparted by a water-soluble polymer blended in the aqueous liquid preparation. It is mixed with an aqueous solution as one component.

  The salts of brimonidine include, but are not limited to, pharmaceutically acceptable but limited salts such as tartrate, hydrochloride or acetate. Brimonidine or one of its salts may be used alone or in combination. Among brimonidine and salts thereof, preferred is brimonidine tartrate.

  In the aqueous liquid preparation of the present invention, the concentration of brimonidine and / or a salt thereof is not limited, but may be appropriately set according to the degree of symptoms of the patient to be applied, the amount applied per application, etc. For example, 0.05 w / v% to 0.2 w / v%, preferably 0.07 w / v% to 0.15 w / v%, more preferably 0.09 w / v% to 0.12 w / v%, More preferably, 0.1 w / v% is mentioned.

[Chlorohexidine gluconate]
In the aqueous liquid preparation of the present invention, the chlorhexidine gluconate is not limited, but it is one of the viscosity reduction inhibitors for suppressing the reduction of the viscosity imparted by the water-soluble polymer blended in the aqueous liquid preparation. It is formulated into an aqueous solution as a component. The concentration of chlorhexidine gluconate is not limited, but, for example, 0.001 w / v% to 0.01 w / v%, preferably 0.002 w / v% to 0.007 w / v%, more preferably It is 0.002 w / v% to 0.005 w / v%.

[Water-soluble polymer]
In the aqueous solution of the present invention, the water-soluble polymer is used as, but not limited to, a thickener or a thickener for imparting a desired viscosity to the aqueous solution. The water-soluble polymer is not particularly limited as long as it is generally used in aqueous solutions as a thickener or thickener, and polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer (crosslinked polyacrylic acid polymer etc.) And polyvinyl celluloses such as carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose etc .; and natural polymers such as xanthan gum, sodium chondroitin sulfate and sodium hyaluronate. The aqueous liquid preparation of the present invention may contain the above-described water-soluble polymers singly or in combination of two or more.

  The concentration of the water-soluble polymer is not limited, but is, for example, 0.05 w / v% to 3 w / v%, preferably 0.1 w / v% to 1.5 w / v%, more preferably Is 0.2 w / v% to 1.0 w / v%, more preferably 0.3 w / v% to 0.7 w / v%.

  In one embodiment, the aqueous solution of the present invention comprises a polyvinyl-based polymer, a cellulose-based polymer, or a natural polymer. In another embodiment, the water-soluble polymer is preferably a cellulose-based polymer compound or a natural polymer, more preferably a cellulose-based polymer compound. In another embodiment, the aqueous liquid preparation of the present invention contains at least two water-soluble polymers selected from polyvinyl polymers, cellulose polymers and natural polymers.

  In one embodiment, the polyvinyl-based polymer compound is polyvinyl pyrrolidone, polyvinyl alcohol or carboxyvinyl polymer (crosslinked polyacrylic acid polymer etc.), preferably polyvinyl alcohol from the viewpoint of more effectively suppressing the decrease in viscosity. Or a carboxyvinyl polymer (such as a crosslinked polyacrylic acid polymer), more preferably polyvinyl alcohol. One of these polyvinyl-based polymer compounds may be used alone, or two or more thereof may be used in combination.

  In one embodiment, the cellulose-based polymer compound may be carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose, and in view of more effectively suppressing the decrease in viscosity, preferably It is carboxymethylcellulose or hydroxypropyl methylcellulose, more preferably carboxymethylcellulose. These cellulose polymer compounds may be used alone or in combination of two or more.

  In one embodiment, the salt of CMC is sodium carboxymethylcellulose. Either CMC or a salt thereof may be used alone or in combination.

  In one embodiment, the concentration of CMC and / or its salt is, for example, 0.1 w / v% to 1.5 w / v%, preferably 0.2 w / v% to 1.0 w / v%. And more preferably 0.3 w / v% to 0.7 w / v%.

  In one embodiment, the cellulosic polymeric compound is hydroxypropyl methylcellulose (HPMC). The concentration of HPMC is, for example, 0.01 w / v% to 1.5 w / v%, preferably 0.05 w / v% to 1.0 w / v%, more preferably 0.1 w / v% It is -0.5 w / v%.

  In one embodiment, the natural polymer may be xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, preferably xanthan gum or sodium hyaluronate from the viewpoint of more effectively suppressing the decrease in viscosity. More preferably, it is sodium hyaluronate. These natural polymers may be used alone or in combination of two or more.

  In one embodiment, the natural macromolecule is sodium hyaluronate. The concentration of sodium hyaluronate is, for example, 0.01 w / v% to 1.5 w / v%, preferably 0.01 w / v% to 0.5 w / v%, more preferably 0.01 w / v It is v%-0.1 w / v%.

  In another embodiment, the aqueous solution of the present invention comprises at least one polyvinyl-based polymer, cellulose-based polymer or natural polymer as a thickener or thickener, substantially other thickeners. The composition contains no thickener, contains a combination of brimonidine and / or a salt thereof and chlorhexidine gluconate as a viscosity reduction inhibitor, and is substantially free of other components that suppress the viscosity reduction. As another component which suppresses a viscosity fall, hyaluronic acid, chondroitin sulfate etc. are mentioned, for example.

  In one embodiment, the polyvinyl-based polymer is polyvinyl alcohol (PVA). The concentration of PVA is, for example, 0.01 w / v% to 1.5 w / v%, preferably 0.1 w / v% to 1.5 w / v%, more preferably 0.5 w / v% It is -1.5 w / v%.

  In one embodiment, the aqueous solution of the present invention comprises 0.05 w / v% to 0.2 w / v% of brimonidine and / or a salt thereof, a water-soluble polymer (for example, a cellulose-based polymer, for example, CMC and / or Or 0.1 w / v% to 1.5 w / v% of the salt thereof and 0.001 w / v% to 0.01 w / v% of the chlorhexidine gluconate. In another embodiment, the aqueous solution of the present invention comprises 0.07 to 500 w / v% (preferably 0.09 w / v to 0.12 w / v%) of brimonidine tartrate, more preferably 0.1 w / v%), 0.2 w / v% to 1 w / v% (preferably 0.3 w / v% to 0.7 w / v%), more preferably 0.5 w / v% of a water-soluble polymer And chlorhexidine gluconate is preferably 0.002 w / v% to 0.007 w / v% (preferably 0.002 w / v% to 0.005 w / v%, more preferably 0.0025 w / v% to 0. 5). Contains 005 w / v%).

  In one embodiment, the aqueous solution of the present invention comprises 0.05 to 0.2 w / v% of brimonidine and / or a salt thereof, a water-soluble polymer (for example, a cellulose-based polymer, for example, HPMC as an example; natural) Polymer, for example hyaluronic acid as an example; or polyvinyl-based polymer, as an example, PVA) 0.01 w / v% to 1.5 w / v%, and chlorhexidine gluconate 0.001 w / v% to 0.01 w / Contains v%. In another embodiment, the aqueous solution of the present invention comprises 0.07 to 500 w / v% (preferably 0.09 w / v to 0.12 w / v%) of brimonidine tartrate, more preferably 0.1 w / v%), 0.03 w / v% to 1.3 w / v% (preferably 0.05 w / v% to 1.0 w / v%) of a water-soluble polymer, and chlorhexidine gluconate It contains 0.002 w / v% to 0.007 w / v% (preferably 0.002 w / v% to 0.005 w / v%, more preferably 0.0025 w / v% to 0.005 w / v%) .

[Weight ratio]
In one embodiment, the weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and chlorhexidine gluconate in the aqueous solution of the present invention is 1: 1 to 15: 0.01 to 0.1. Preferably it is 1: 2-10: 0.02-0.07, More preferably, it is 1: 3-7: 0.02-0.05. In this example, the aqueous solution further comprises boric acid and borax (osmotic ratio: 0.9 to 1.1, pH: 6.7 to 7.5).

  In another embodiment, the weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and chlorhexidine gluconate in the aqueous solution of the present invention is 1: 0.1-15: 0.01-0. It is preferably from 1: 0.2 to 12: 0.02 to 0.07, more preferably from 1: 0.5 to 10: 0.02 to 0.05. In this example, the aqueous solution further comprises boric acid and borax (osmotic ratio: 0.9 to 1.1, pH: 6.7 to 7.5).

  In another embodiment, the weight ratio of brimonidine and / or a salt thereof to chlorhexidine gluconate in the aqueous solution of the present invention is 1: 0.01 to 0.1, preferably 1: 0.02 to 0. More preferably, it is 1: 0.02-0.05.

  In another embodiment, the weight ratio of brimonidine and / or a salt thereof to a water-soluble polymer in the aqueous solution of the present invention is 1: 1 to 15, preferably 1: 2 to 10, more preferably It is 1: 3-7.

  In another embodiment, the weight ratio of brimonidine and / or a salt thereof to a water-soluble polymer in the aqueous solution of the present invention is 1: 0.1-15, preferably 1: 0.2-12. And more preferably 1: 0.5-10.

  In another embodiment, the weight ratio of chlorhexidine gluconate to the water-soluble polymer in the aqueous solution of the present invention is 1:30 to 500, preferably 1:60 to 330, more preferably 1: 90-230.

  In another embodiment, the weight ratio of chlorhexidine gluconate to water-soluble polymer in the aqueous solution of the present invention is 1: 10-500.

[viscosity]
The viscosity of the aqueous solution of the present invention is imparted by, but not limited to, the incorporated water soluble polymer. In one embodiment, the viscosity of the aqueous solution of the present invention is adjusted by the incorporation of at least one water soluble polymer. In one embodiment, the viscosity of the aqueous solution of the present invention is adjusted by the formulation of CMC and / or its salt. In another embodiment, the viscosity of the aqueous solution of the present invention is adjusted by formulation of the combination of CMC and / or its salt with other water soluble polymers described herein.

  The viscosity of the aqueous liquid preparation of the present invention is, but not limited to, 1.0 mPa · s or more and less than 30 mPa · s at 25 ° C. and a rotation speed of 50 rpm. In one embodiment, the viscosity of the prepared aqueous solution at 25 ° C. and a rotation speed of 50 rpm is 1.0 mPa · s or more and less than 15 mPa · s. In one embodiment, the viscosity at 25 ° C. of the prepared aqueous solution is 1.5 mPa · s or more and less than 10 mPa · s, and 2.0 mPa · s or more and less than 8.0 mPa · s.

[Viscosity stability]
The degree of viscosity stability of the aqueous solution of the present invention is calculated by dividing the viscosity of the aqueous solution after storage for 4 weeks at 60 ° C. by the viscosity of the aqueous solution before storage for 4 weeks. . In one embodiment, the viscosity stability calculated by dividing the viscosity of the aqueous solution after storage for 4 weeks at 60 ° C. by the viscosity of the aqueous solution before storage for 4 weeks is 80% or more It is. The viscosity stability is preferably 83% or more, more preferably 85% or more, still more preferably 90% or more, and most preferably 92% or more.

[Degree of viscosity reduction suppression]
In one embodiment, the degree of suppression of viscosity reduction is viscosity stability for a water-soluble polymer-containing aqueous solution formulated with both brimonidine and / or a salt thereof and chlorhexidine gluconate, brimonidine and / or It is represented by the difference from the viscosity stability of an aqueous solution containing the same water-soluble polymer except that neither a salt nor chlorhexidine gluconate is blended. It is preferable that the extent of the said viscosity fall suppression is 10% or more, 12% or more, 15% or more, or 20% or more.

  In another embodiment, the degree of suppression of viscosity reduction is viscosity stability of a water-soluble polymer-containing aqueous solution prepared by blending either brimonidine and / or a salt thereof and chlorhexidine gluconate, brimonidine and / or It is represented by the difference from the viscosity stability of the aqueous solution containing the same water-soluble polymer except that neither the salt nor the chlorhexidine gluconate is blended. The degree of suppression of the viscosity reduction is preferably 8% or more, 10% or more, 12% or more, or 14% or more.

[Formulation form]
The formulation form of the aqueous liquid preparation of the present invention includes, but is not limited to, topical administration preparations for various uses such as ophthalmic use, dental use, otolaryngology and dermatology. In one embodiment, the aqueous solution of the present invention is for ophthalmic use, dental use, otolaryngology, dermatology, preferably for ophthalmic use.

  The ophthalmic aqueous solution of the present invention includes, but is not limited to, eye drops, eye washes, contact lens preparations, injections and the like. The aqueous solution of the present invention is particularly preferably eye drops. Further, the form of the eye drop of the present invention is not limited, and may be an aqueous solution, a suspension, an emulsion and the like, preferably an aqueous solution.

[Use]
In one embodiment, the aqueous solution of the present invention is for treating glaucoma.

[Other additives]
The aqueous liquid preparation of the present invention may optionally contain, in addition to the above-mentioned components, if necessary, a preservative or preservative (other than chlorhexidine gluconate), a buffer, a chelating agent, a refreshing agent, an isotonicity agent, etc. It may further contain an agent.

  Preservatives or preservatives include, but are not limited to, sorbic acid or salts thereof, benzoic acid or salts thereof, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, benzalkonium chloride, Chlorhexidine hydrochloride, chlorhexidine acetate, dehydroacetic acid or a salt thereof, benzethonium chloride, benzyl alcohol, zinc chloride, parachlorometaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, dibutyl hydroxytoluene. These additional preservatives or preservatives may be used alone or in combination of two or more.

  In another embodiment, the aqueous solution comprises chlorhexidine gluconate as a preservative or preservative and is substantially free of other preservatives or preservatives.

  Buffers include, but are not limited to, phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, Tris buffers, amino acids. These buffers may be used alone or in combination of two or more. In one embodiment, the buffer is a borate buffer, preferably a combination of boric acid and sodium borate.

  The buffer is formulated, but not limited to, in an amount generally used to impart sufficient buffer capacity to the aqueous solution, and in one embodiment, the content of the buffer is, for example, 0. The content is from 01 to 5 w / v%, preferably from 0.05 to 1 w / v%, and more preferably from 0.1 to 0.5 w / v%.

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

  Refreshing agents include, but are not limited to, l-menthol, borneol, camphor, eucalyptus oil. These cooling agents may be used alone or in combination of two or more.

  Tonicity agents include, but are not limited to, magnesium chloride, sodium chloride, potassium chloride, calcium chloride and their hydrates. These cooling agents may be used alone or in combination of two or more.

[Other pharmacological ingredients]
In one embodiment, the aqueous solution may contain, in addition to brimonidine and / or a salt thereof, other pharmacological components having a therapeutic effect on glaucoma, as long as the effects of the present invention are not impaired. Such other pharmacological ingredients include, for example, prostaglandins such as tafluprost, latanoprost, isopropyl unoprostone; parasympathomimetics such as pilocarpine hydrochloride; anticholinesterase drugs such as distigmine bromide; dipibafrin hydrochloride and the like Sympathomimetic agents; β-blockers such as timolol maleate; β1 blockers such as betaxolol hydrochloride; α1 · β-blockers such as nipradilol, levobnolol hydrochloride; α1 blockers such as bunazosin hydrochloride. These pharmacological components may be used alone or in combination of two or more.

  In another embodiment, the aqueous solution comprises brimonidine and / or a salt thereof as a direct active ingredient against glaucoma and is substantially free of other active ingredients.

[PH]
The pH of the aqueous solution of the present invention is not particularly limited as long as it is applicable to the intended use. For example, when applied to the ocular mucosa, the pH is 6.7 to 7.5, but from the viewpoint of further improving the viscosity stability, preferably pH 6.7 to 7.3, more preferably pH 6.9. It is -7.1, More preferably, it is pH 7.0.

[Osmotic pressure / osmotic pressure ratio]
The osmotic pressure of the aqueous liquid preparation of the present invention is not particularly limited as long as it is applicable to the intended use. For example, when applied to the ocular mucosa, the osmotic pressure is 250 to 350 mOsmol. In addition, the osmotic pressure ratio of the aqueous liquid preparation of the present invention is not particularly limited as long as it is applicable to the intended application. For example, when applied to the mucous membrane of the eye, the osmotic pressure ratio is 0.85 to 1.15. From the viewpoint of further improving the viscosity stability, the osmotic pressure ratio is preferably 0.9 to 1.1, and more preferably 1.0. Osmotic pressure is adjusted according to a conventional method. In one embodiment, the osmotic pressure is adjusted by blending the aqueous solution with a pharmaceutically acceptable salt as an isotonicity agent.

[The number of eye drops]
The eye drops are, but not limited to, one drop, and may be instilled one or more times a day. In one embodiment, the eye drops are instilled one drop twice a day. In the eye drop, the concentration of each component to be blended according to the usage and dose is appropriately set.

2. Method for suppressing viscosity reduction of aqueous solution A second aspect of the present invention relates to brimonidine and / or a salt thereof and chlorhexidine gluconate in an aqueous solution containing a water-soluble polymer (for example, CMC and / or a salt thereof) And a step of coexistence of one or both of the above, and a method of suppressing the viscosity decrease of the aqueous solution.

  In one embodiment, the present invention relates to a method for suppressing the decrease in viscosity of an aqueous solution, which comprises coexistence of both brimonidine and / or a salt thereof and chlorhexidine gluconate in an aqueous solution containing a water-soluble polymer.

  The method is carried out, for example, by incorporating brimonidine and / or a salt thereof and / or a salt thereof with chlorhexidine gluconate in the aqueous solution, while the brimonidine and / or a salt thereof, and chlorhexidine gluconate The order of addition of the respective components of the salt is not particularly limited. Each component at the time of blending is, but is not limited to, a solid or a liquid.

  In the method for suppressing the decrease in viscosity of the aqueous liquid preparation of the present invention, the kind, concentration, weight ratio, viscosity, viscosity stability, viscosity of brimonidine and / or salt thereof, water-soluble polymer and chlorhexidine gluconate used The degree of suppression of reduction, formulation form, use, etc. may be employed singly or in combination as described in the section of “1. Aqueous solution”. Further, in the method for suppressing the decrease in viscosity of the aqueous liquid preparation of the present invention, the other additives and pharmacological components which can be added to the aqueous liquid preparation, pH, osmotic pressure, osmotic pressure ratio, number of eye drops etc. Those described in the column of “can be adopted alone or in combination.

3. Viscosity decrease inhibitor According to a third aspect of the present invention, there is provided a brimonidine and / or a salt thereof, and / or a chlorhexidine gluconate salt for suppressing the viscosity decrease of an aqueous solution containing a water-soluble polymer. The present invention relates to a viscosity decrease inhibitor containing

  In one embodiment, the viscosity decrease inhibitor contains both brimonidine and / or a salt thereof and chlorhexidine gluconate in an aqueous solution containing a water-soluble polymer.

  The viscosity loss inhibitor may be in the form of, but not limited to, liquid or solid (e.g. powder or tablet). The powder or tablet can be manufactured by a conventional method.

  In the viscosity decrease inhibitor of the present invention, with regard to brimonidine and / or a salt thereof, a water-soluble polymer and a chlorhexidine gluconate used, their kind, concentration, weight ratio, viscosity, viscosity stability, degree of viscosity decrease suppression, With regard to the formulation form, use and the like, those described in the section of “1. Aqueous solution” may be adopted alone or in combination. Further, in the viscosity decrease inhibitor of the present invention, other additives and pharmacological components that can be added to the aqueous liquid, pH, osmotic pressure, osmotic pressure ratio, number of eye drops, etc. are also described in the above "1. Those may be employed alone or in combination.

4. Method of Producing an Aqueous Liquid A fourth aspect of the present invention is the production of an aqueous liquid comprising the steps of mixing brimonidine and / or a salt thereof, a water-soluble polymer and a chlorhexidine diconate into a pharmaceutically acceptable aqueous medium. On the way. "Pharmaceutically acceptable aqueous medium" means an aqueous medium that can be used for topical application to the eye, which may be, but is not limited to, purified water. In one embodiment, the blending step may blend a water-soluble polymer (eg, CMC) and purified water, and then blend brimonidine and / or a salt thereof, and chlorhexidine gluconate. The manufacturing method may further include, but is not limited to, adding additional additive components. The manufacturing method may further include, but is not limited to, a sterilization process. In one embodiment, the sterilization process is filter filtration.

  In the method for producing an aqueous liquid preparation of the present invention, the type, concentration, weight ratio, viscosity, viscosity stability, degree of viscosity reduction suppression for brimonidine and / or a salt thereof, water-soluble polymer and chlorhexidine gluconate used The formulation form, use and the like may be employed singly or in combination of those described in the section “1. Aqueous solution”. In addition, in the method for producing an aqueous liquid preparation of the present invention, other additives and pharmacological components that can be added to the aqueous liquid preparation, pH, osmotic pressure, osmotic pressure ratio, number of eye drops, etc. Those described may be employed alone or in combination.

5. Method for suppressing reduction in content of brimonidine and / or salt thereof According to a fifth aspect of the present invention, a water-soluble polymer and chlorhexidine gluconate coexist in an aqueous solution containing brimonidine and / or a salt thereof The present invention relates to a method for suppressing the reduction in the content of brimonidine and / or its salt in an aqueous liquid preparation, which comprises the steps

[Blending order]
In one embodiment, a method for suppressing the reduction in the content of brimonidine and / or a salt thereof in an aqueous solution comprises adding chlorhexidine gluconate to an aqueous solution containing brimonidine and / or a salt thereof and a water-soluble polymer. And coexistence of brimonidine and / or a salt thereof, a water-soluble polymer and chlorhexidine gluconate in an aqueous solution.

  The method for suppressing the content reduction is carried out by causing brimonidine and / or a salt thereof, a water-soluble polymer and a chlorhexidine gluconate to coexist in an aqueous solution, and in the method, brimonidine and / or a salt thereof, The order in which the water-soluble polymer and the chlorhexidine gluconate are incorporated into the aqueous solution is not particularly limited. Each component at the time of blending is, but is not limited to, a solid or a liquid.

[Level of suppression of content reduction]
In one embodiment, the degree of suppression of content reduction is obtained by dividing the content of brimonidine and / or its salt in the aqueous solution after storage by the content of brimonidine and / or its salt in the aqueous solution before storage. ([Content of brimonidine and / or its salt in aqueous solution after storage] / [Content of brimonidine and / or its salt in aqueous solution before storage] × 100). The content reduction suppression degree is 98% or more, preferably 98.5% or more, and more preferably 99% or more.

[Content reduction inhibitor] or [Stabilizer]
In one embodiment of the fifth aspect, the "content reduction inhibitor" or "stabilizer" of brimonidine and / or a salt thereof in an aqueous liquid preparation, comprising a water-soluble polymer, chlorhexidine gluconate, The content reduction inhibitor or the stabilizer containing any one or both of the above is provided. The content reduction inhibitor or stabilizer may be in the form of, but not limited to, liquid or solid (eg powder or tablet). The powder or tablet can be manufactured by a conventional method. In one embodiment, the content reduction inhibitor or stabilizer contains both a water soluble polymer and chlorhexidine gluconate.

  Brimonidine and / or a salt thereof, water solubility, used in the "method for suppressing the decrease in the content of brimonidine and / or the salt thereof in the aqueous liquid preparation according to the present invention", the "content reduction inhibitor" or the "stabilizer" With regard to polymers and chlorhexidine gluconates, their types, concentrations, weight ratios, viscosities, viscosity stability, degree of suppression of viscosity reduction, formulation forms, applications, etc. are those described in the column of “1. aqueous solution” alone. Or it can be adopted in combination. Further, in the method of suppressing the content reduction of the present invention, the other additives and pharmacological components that can be added to the aqueous liquid, pH, osmotic pressure, osmotic pressure ratio, number of eye drops, etc. Those described in the column may be employed alone or in combination.

6. pH Stabilization Method A sixth aspect of the present invention comprises a water-soluble polymer comprising the step of causing brimonidine and / or a salt thereof to coexist with chlorhexidine gluconate in an aqueous solution containing a water-soluble polymer. Provided is a method of stabilizing pH in an aqueous solution.

[Blending order]
In one embodiment, a method of stabilizing pH in an aqueous solution comprising a water soluble polymer is:
In an aqueous solution containing a water-soluble polymer, brimonidine and / or a salt thereof and chlorhexidine gluconate are mixed, and brimonidine and / or a salt thereof, a water-soluble polymer and chlorhexidine gluconate in an aqueous solution Including coexistence with

  The pH stabilization method is carried out by coexistence of brimonidine and / or a salt thereof, a water-soluble polymer, and a chlorhexidine gluconate in an aqueous solution, in which brimonidine and / or a salt thereof, water-soluble The order in which the polymer and chlorhexidine gluconate are incorporated into the aqueous solution is not particularly limited. Each component at the time of blending is, but is not limited to, a solid or a liquid.

[Water-soluble polymer]
In the pH stabilization method of the present invention, the concentration of the water-soluble polymer is not limited, but is, for example, 0.1 w / v% to 5 w / v%, preferably 1 w / v% to 5 w / v %, More preferably 2 w / v% to 4 w / v%.

  In one embodiment, the water soluble polymer is preferably a polyvinyl-based polymer compound. The polyvinyl-based polymer compound is not limited, but is polyvinyl pyrrolidone, polyvinyl alcohol or carboxyvinyl polymer (crosslinked polyacrylic acid polymer etc.), preferably polyvinyl pyrrolidone (PVP) from the viewpoint of pH stabilization of the aqueous solution. )is there. One of these polyvinyl-based polymer compounds may be used alone, or two or more thereof may be used in combination. In one embodiment, the polyvinyl-based polymer is PVP.

  In one embodiment, the concentration of PVA is, for example, 0.1 w / v% to 5 w / v%, preferably 1 w / v% to 5 w / v%, more preferably 2 w / v% to 4 w It is / v%, more preferably 3 w / v%.

[Weight ratio]
In one embodiment, the weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and a chlorhexidine gluconate in the aqueous solution of the present invention is 1: 1 to 50: 0.01 to 0.1. Preferably it is 1: 10-50: 0.02-0.07, More preferably, it is 1: 20-40: 0.02-0.05. In this example, the aqueous solution further comprises boric acid and borax (osmotic ratio: 0.9 to 1.1, pH: 6.7 to 7.5).

[Level of pH stabilization]
In one embodiment, the degree of pH stabilization can be expressed as the difference between the pH of the aqueous solution after storage for 2 weeks at 60 ° C. and the pH of the aqueous solution before storage. The degree of pH stabilization is such that the pH difference is within 1.0, preferably within 0.5, and more preferably within 0.3.

[PH stabilizer]
In one embodiment of the sixth aspect, a "pH stabilizer" for an aqueous solution containing a water-soluble polymer, which comprises one or both of brimonidine and / or a salt thereof and chlorhexidine gluconate. There is provided a pH stabilizer containing The pH stabilization may be, but is not limited to, in the form of a liquid or a solid (eg, a powder or a tablet). The powder or tablet can be manufactured by a conventional method. In one embodiment, the pH stabilizing agent contains both brimonidine and / or a salt thereof and chlorhexidine gluconate.

  Kinds and concentrations of brimonidine and / or a salt thereof, a water-soluble polymer and a chlorhexidine gluconate to be used in the “pH stabilization method” or “pH stabilizer” according to the present invention , Weight ratio, viscosity, viscosity stability, degree of suppression of viscosity decrease, formulation form, use, etc., except for those specified as the sixth aspect, those described in the column of “1. aqueous solution” alone or in combination Can be adopted. In the pH stabilization method of the present invention or the pH stabilizer, the sixth additive may be added to the aqueous liquid preparation and pharmacological components, pH, osmotic pressure, osmotic pressure ratio, number of eye drops, etc. Except for those specified as the embodiments, those described in the above-mentioned "1. aqueous solution" may be adopted alone or in combination.

7. Method of treating glaucoma A seventh aspect of the present invention comprises administering an aqueous solution comprising brimonidine and / or a salt thereof, a water-soluble polymer, and chlorhexidine gluconate to the eye of a subject in need thereof. Provide a method for treating glaucoma.

[Method of administration]
In one embodiment, the aqueous solution comprising brimonidine and / or a salt thereof, a water soluble polymer, and chlorhexidine gluconate is administered by eye drops to the eye of a subject in need thereof.

  In the method for treating glaucoma according to the present invention, the type, concentration, weight ratio, viscosity, viscosity stability, degree of viscosity drop suppression of brimonidine and / or a salt thereof, water-soluble polymer and chlorhexidine gluconate used The formulation form, use and the like may be employed singly or in combination as described in the section "1. Aqueous solution". In the glaucoma treatment method of the present invention, other additives and pharmacological components that can be added to the aqueous solution, pH, osmotic pressure, osmotic pressure ratio, number of eye drops, etc. are also described in the above "1. Aqueous solution" column. These may be employed alone or in combination.

  The present invention has been described above with the preferred embodiments shown for ease of understanding. EXAMPLES The present invention will be described below based on examples, but the above description and the following examples are provided for the purpose of illustration only and are not provided for the purpose of limiting the present invention. Accordingly, the scope of the present invention is not limited to the embodiments or examples specifically described herein, but only by the claims.

Test Example 1 Viscosity stability test (1)
[Preparation of aqueous solution]
An aqueous solution was prepared according to the formulation shown in Table 1. Each aqueous solution was made isotonic by adding an appropriate amount of sodium chloride, and adjusted to pH 7.0 with hydrochloric acid or sodium hydroxide.
CMC (Carboxymethyl cellulose sodium): Daiichi Kogyo Seiyaku Co., Ltd. chlorhexidine gluconate made by: Dai Nippon Sumitomo Pharma Co., Ltd.

[Accelerated deterioration test]
5 mL of a 0.22 μm-filtered aqueous solution was filled into a 5 mL colorless glass ampoule. Each glass ampoule was placed in a table-top constant temperature and humidity chamber (NST-80, Nagano Science Co., Ltd.), and stored at 60 ° C. for 4 weeks under light-shielded conditions.

[Viscosity measurement]
Viscosity [mPa · s] of the aqueous liquid agent is the viscosity measurement method defined in the Japan General Test Method Method 2 Rotational viscometer method (TVE-25 viscometer (corn plate), TVE-25L, Toki Sangyo Co., Ltd.) According to 2.), it measured at 25 degreeC, and 50 rpm of rotational speeds. As the cone rotor, 0.8 ° × R24 (rotor code: 00) was used. The viscosity measurement was performed before and after the accelerated deterioration test. The viscosity stability (%) of the aqueous solution was calculated according to the following formula.
[Equation 1]
Viscosity stability [%] = viscosity of aqueous solution after storage [mPa · s] / viscosity of aqueous solution before storage [mPa · s] × 100

[Test results]
The obtained viscosity stability results are shown in Table 1. The viscosity of the aqueous liquid agent containing the CMC (01 formulation) was 5.681 [mPa · s] before the accelerated deterioration test, and was 3.956 [mPa · s] after the accelerated deterioration test. The viscosity stability of the 01 formulation was 69.6% (= 3.956 mPa · s / 5.681 mPa · s × 100) and was less than 70%.

  The viscosity stability of 02 formulation which mixed brimonidine tartrate with 01 formulation is 87.4% (= 4.79 [mPa · s] /5.698 [mPa · s] × 100), and the viscosity stability of 01 formulation is An improvement in viscosity stability was observed as compared to the viscosity. This result indicates that brimonidine tartrate stabilizes the viscosity of the aqueous solution containing the water-soluble polymer.

  The viscosity stability of the 03 formulation and the 05 formulation in which 0.0025 w / v% and 0.005 w / v% of chlorhexidine gluconate were blended in 01 formulation was 80.7% (= 4.677 [mPa · s] / 5, respectively. .793 [mPa · s] × 100) and 83.6% (= 4.803 [mPa · s] /5.746 [mPa · s] × 100), compared with the viscosity stability of the 01 formulation, An improvement in viscosity stability was observed. These results show that chlorhexidine gluconate stabilizes the viscosity of an aqueous solution containing a water-soluble polymer.

  Formulations in which only one of brimonidine tartrate and chlorhexidine gluconate was incorporated into the 01 formulation (02 formulation, 03 formulation and 05 formulation) showed no viscosity stability exceeding 90%. Further, from the results of the 01 formulation, the 03 formulation and the 05 formulation, the improvement in viscosity stability decreased as the compounding amount of chlorhexidine gluconate increased. However, the viscosity stability of the 06 formulation in which the brimonidine is added to the 05 formulation is improved by 9% as compared to the 05 formulation, and the viscosity stability is 92.6% (= 5.303 [mPa · s] /5.726 It became [mPa · s] × 100) and exceeded 90%. Similar results were obtained with the 04 formulation in which brimonidine was added to the 03 formulation. That is, the viscosity stability of the 04 formulation is improved by 10.9% as compared with the 03 formulation, and the viscosity stability is 91.6% (= 5.249 [mPa · s] /5.728 [mPa · s] × 100), exceeding 90%.

  These results show that the combined use of brimonidine tartrate and chlorhexidine gluconate imparts excellent viscosity stability to an aqueous solution containing a water-soluble polymer, as well as an aqueous solution containing a water-soluble polymer It is shown that blending both components into a solution provides an aqueous solution having excellent viscosity stability.

Production Example Specific examples of the aqueous liquid preparation of the present invention include aqueous liquid preparations having the compositions shown in Tables 2 to 5. In Tables 2 to 5, the unit of the content of each component is "g".

Test Example 2 Viscosity stability test (2)
[Preparation of aqueous solution]
An aqueous solution was prepared according to the formulation shown in Table 6. Each aqueous solution was made isotonic by adding an appropriate amount of sodium chloride, and adjusted to pH 7.0 with hydrochloric acid or sodium hydroxide.
PVA (polyvinyl alcohol): Nippon Synthetic Chemical Industry Co., Ltd. HPMC (hydroxypropyl methyl cellulose): Shin-Etsu Chemical Co., Ltd. chlorhexidine gluconate: Dainippon Sumitomo Pharma Co., Ltd.

[Accelerated deterioration test and viscosity measurement]
The same operation as in Test Example 1 was performed.

[Test results]
The obtained viscosity stability results are shown in Table 6. The viscosity stability of the 07 formulation, which is an aqueous solution containing HPMC, was 84.3% (= 3.769 [mPa · s] /4.473 [mPa · s] × 100). On the other hand, the viscosity stability of the 08 formulation and 09 formulation, which is an aqueous solution containing brimonidine tartrate and chlorhexidine gluconic acid in addition to the aqueous solution containing HPMC, is 91.7% (= 3.898 [mPa · s]). It was /4.251 [mPa * s] * 100) and 91.6% (= 3.792 [mPa * s] /4.141 [mPa * s] * 100). The viscosity stability of the 08 and 09 formulations exceeded 90%. These results show that blending the brimonidine tartrate and chlorhexidine gluconate in an aqueous solution containing HPMC imparts excellent viscosity stability.

  In addition, the viscosity stability of the 10 formulation which is an aqueous solution containing PVA, brimonidine tartrate and chlorhexidine gluconic acid is 100.0% (= 2.449 [mPa · s] /2.448 [mPa · s] × 100) It is shown that this aqueous solution has excellent viscosity stability.

Test Example 3 Viscosity stability test (3)
An aqueous solution was prepared according to the formulation shown in Table 7. Each aqueous solution was made isotonic by adding an appropriate amount of sodium chloride, and adjusted to pH 7.0 with hydrochloric acid or sodium hydroxide.
HA (sodium hyaluronate): manufactured by Seika Kagaku Kogyo Co., Ltd. Chlorhexidine gluconate: Dainippon Sumitomo Pharma Co., Ltd.

[Accelerated deterioration test]
5 mL of the prepared aqueous solution was filled into a 5 mL colorless glass ampoule. Each glass ampoule was placed in a table-top thermostatic chamber (NST-80, Nagano Science Co., Ltd.) and stored at 60 ° C. for 2 weeks under light-shielded conditions.

[Viscosity measurement]
The same operation as in Test Example 1 was performed.

[Test results]
The obtained viscosity stability results are shown in Table 7. The viscosity stability of formulation 11 which is an aqueous solution containing HA was 75.4% (= 1.518 [mPa · s] /2.14 [mPa · s] × 100). On the other hand, the viscosity stability of 12 formulations, which is an aqueous solution containing brimonidine tartrate and chlorhexidine gluconic acid in addition to an aqueous solution containing HA, is 93.0% (= 1.905 [mPa · s] /2.049 It was [mPa · s] × 100). These results show that blending the brimonidine tartrate and the chlorhexidine gluconate in an aqueous solution containing HA imparts excellent viscosity stability.

Test Example 4 Stability Test for Brimonidine Content An aqueous solution was prepared according to the formulation shown in Table 8. Each aqueous solution was made isotonic by adding an appropriate amount of sodium chloride, and adjusted to pH 7.0 with hydrochloric acid or sodium hydroxide.
CMC (carboxymethylcellulose sodium): Daiichi Kogyo Seiyaku Co., Ltd. HPMC (hydroxypropyl methylcellulose): Shin-Etsu Chemical Co., Ltd. PVA (polyvinyl alcohol): Nippon Synthetic Chemical Industry Co., Ltd. HA (sodium hyaluronate): Raw Chemical Industry Co., Ltd. chlorhexidine gluconate: Dainippon Sumitomo Pharma Co., Ltd.

[Accelerated deterioration test]
5 mL of each aqueous solution was filled in a 5 mL polyethylene container, sealed, and stored at 60 ° C. for 2 weeks in the dark.

[Content test]
The aqueous solution after storage was subjected to HPLC under the following conditions to analyze the content of brimonidine.

<Conditions of HPLC>
Preparation of sample solution: Accurately measure 2 mL of each aqueous solution, add purified water to make exactly 20 mL, and use this as the sample solution.
Preparation of standard solution Weigh accurately 10 mg of brimonidine tartrate standard, add purified water to make exactly 100 mL, and use this as the standard solution.
Measurement by Liquid Chromatography The measurement was carried out by liquid chromatography under the following conditions for 25 μL of the sample solution and standard solution.

(Measurement condition)
Detector: Ultraviolet absorptiometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 3.5 μm, 4.6 4.6 mm × 150 mm, Waters Corporation column temperature: 40 ° C.
Area measurement time: 60 minutes Mobile phase A: Mixed solution of 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84/8/8) Mobile phase B: 4.3 mM aqueous phosphoric acid solution / methanol / acetonitrile (volume ratio: 40/30/30) Transfer of mixed liquid mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 9, and linear concentration gradient control is performed.
Washing solution: Acetonitrile / water (volume ratio: 1/1) mixture injection amount: 25 μL
Flow rate: 1.0 mL

[Test results]
The obtained results are shown in Table 10. Formulations containing brimonidine tartrate and water soluble polymers CMC, HPMC, PVA or HA (13 formulations, 15 formulations, 17 formulations, 19 formulations) and these with chlorhexidine gluconate added (14 formulations In comparison with 16 formulations, 18 formulations and 20 formulations, the formulation with chlorhexidine gluconate has a higher survival rate [%] (= [containing brimonidine and / or its salt in aqueous solution after storage Amount] / [content of brimonidine and / or its salt before storage] × 100) is shown. These results show that the incorporation of chlorhexidine gluconate into an aqueous solution containing brimonidine tartrate and a water-soluble polymer suppresses the degradation of brimonidine and exhibits excellent stability by using brimonidine and / or a salt thereof. It shows that the contained aqueous solution can be provided.

Test Example 5 Stability Test to pH An aqueous solution was prepared according to the formulation shown in Table 10. Each aqueous solution was made isotonic by adding an appropriate amount of sodium chloride, and adjusted to pH 7.0 with hydrochloric acid or sodium hydroxide.
PVP (polyvinyl pyrrolidone): manufactured by BASF Japan Ltd.

[Accelerated deterioration test]
The same operation as in Test Example 3 was performed.

[PH measurement]
The pH of the aqueous solution was measured by a pH meter using a glass electrode.

[Test results]
The obtained results are shown in Table 10. In the 21 formulation which is an aqueous solution containing PVP, a drop in pH was observed by storage at 60 ° C. for 2 weeks. On the contrary, in the case of the formulation 22 which is an aqueous liquid preparation in which brimonidine tartrate and chlorhexidine gluconic acid are further added to the aqueous liquid preparation containing PVP, the decrease in pH was suppressed. These results indicate that the addition of brimonidine tartrate and chlorhexidinegluconate to an aqueous solution containing a water-soluble polymer can provide an aqueous solution having excellent pH stability.

Claims (20)

  An aqueous solution comprising brimonidine and / or a salt thereof, a water-soluble polymer, and chlorhexidine gluconate.   The content of brimonidine and / or a salt thereof is 0.05 w / v% to 0.2 w / v%, and the content of water-soluble polymer is 0.05 w / v% to 3 w / v%, and chlorhexidine gluconate The aqueous solution according to claim 1, wherein the content of the acid salt is 0.001 w / v% to 0.01 w / v%.   The aqueous liquid preparation according to claim 1 or 2, wherein a weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and a chlorhexidine gluconate is 1: 1 to 15: 0.01 to 0.1.   The water-soluble polymer is at least one selected from the group consisting of carboxymethylcellulose and / or a salt thereof, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hyaluronic acid and / or a salt thereof. The aqueous solution according to any one of the preceding claims. The content of brimonidine and / or its salt is 0.1 w / v%, the content of carboxymethyl cellulose and / or its salt is 0.5 w / v%, the content of chlorhexidine gluconate is 0.0025 w The aqueous solution according to any one of claims 1 to 4, wherein the ratio is from / v% to 0.005 w / v%.   The viscosity stability calculated by dividing the viscosity of the aqueous solution after storage for 4 weeks at 60 ° C. by the viscosity of the aqueous solution before storage for 4 weeks is 90% or more. Aqueous liquid preparation as described in any one of -5.   The aqueous solution according to any one of claims 1 to 6, wherein the aqueous solution is for ophthalmic use.   The aqueous solution according to claim 7, wherein the ophthalmic aqueous solution is an eye drop.   The aqueous solution according to any one of claims 1 to 8 for treating glaucoma.   A method for suppressing the decrease in viscosity of an aqueous solution, comprising the step of coexistence of either one or both of brimonidine and / or a salt thereof and chlorhexidine gluconate in an aqueous solution containing a water-soluble polymer. Method to suppress viscosity reduction.   The method according to claim 10, comprising the step of coexistence of both brimonidine and / or a salt thereof and chlorhexidine gluconate in an aqueous solution.   The content of brimonidine and / or a salt thereof is 0.05 w / v% to 0.2 w / v%, and the content of water-soluble polymer is 0.05 w / v% to 3 w / v%, and chlorhexidine gluconate The method according to claim 10 or 11, wherein the content of the acid salt is 0.001 w / v% to 0.01 w / v%.   The weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and a chlorhexidine gluconate is 1: 1 to 15: 0.01 to 0.1, according to any one of claims 10 to 12. Method described.   The water-soluble polymer is at least one selected from the group consisting of carboxymethylcellulose and / or a salt thereof, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hyaluronic acid and / or a salt thereof. The method according to any one of the preceding claims.   A viscosity decrease inhibitor containing brimonidine and / or a salt thereof and / or chlorhexidine gluconate for suppressing a viscosity decrease of an aqueous solution containing a water-soluble polymer.   The viscosity decrease inhibitor according to claim 15, which contains both brimonidine and / or a salt thereof and chlorhexidine gluconate.   The content of brimonidine and / or its salt is 0.05 w / v% to 0.2 w / v%, and the content of chlorhexidine gluconate is 0.001 w / v% to 0.01 w / v% The viscosity decrease inhibitor according to claim 15 or 16, which is compounded in   18. The method according to claim 15, wherein the weight ratio of brimonidine and / or the salt thereof, the water-soluble polymer, and the chlorhexidine gluconate is 1: 1 to 15: 0.01 to 0.1. The viscosity decrease inhibitor according to any one of the preceding claims.   The viscosity decrease inhibitor according to any one of claims 15 to 18, wherein the water-soluble polymer comprises carboxymethylcellulose and / or a salt thereof.   A method for suppressing the decrease in the content of brimonidine and / or a salt thereof in an aqueous solution, comprising the step of coexistence of a water-soluble polymer and chlorhexidinegluconate in an aqueous solution containing brimonidine and / or a salt thereof , How to suppress the content reduction.