Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics

Definitions

• 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.
• 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.
• 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.
• a formulation technology that suppresses a decrease in viscosity with time in an aqueous solution containing a water-soluble polymer.
• 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.
• CMC carboxymethylcellulose
• 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 no formulation technology has been described which can suppress the decrease in viscosity using brimonidine or chlorhexidine gluconate.
• Patent document 1 JP-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.
• 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.
• 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.
• 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.
• PVA polyvinyl alcohol
• HPMC hydroxypropyl methylcellulose
• 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.
• PVP polyvinyl pyrrolidone
• the present invention relates to the following aqueous solution, a method for suppressing a viscosity decrease, and a viscosity decrease inhibitor.
• 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 item 1, wherein the content of the acid salt is 0.001 w / v% to 0.01 w / v%.
• aqueous liquid preparation 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.
• 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 item 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 item 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 any one of items 10 to 12, wherein the weight ratio is 1: 1 to 15: 0.01 to 0.1. Method described.
• 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 methyl cellulose, 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 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 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 methyl cellulose, and hyaluronic acid and / or a salt thereof.
• [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.
• 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.
• 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. .
• Carboxymethyl cellulose 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.
• 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.
• polyvinyl alcohol 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.
• Gohsenol manufactured by Japan Synthetic Chemical Industry Co., Ltd.
• Gohsenol manufactured by Japan Synthetic Chemical Industry Co., Ltd.
• Gohsenol manufactured by Japan Synthetic Chemical Industry Co., Ltd.
• polyvinyl pyrrolidone 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.
• Kollidon 30 manufactured by BASF Japan Ltd.
• the like are used.
• HPMC 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.
• METOLOSE / hypromellose 2906 manufactured by Shin-Etsu Chemical Co., Ltd.
• hypromellose 2906 manufactured by Shin-Etsu Chemical Co., Ltd.
• 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.
• purified sodium hyaluronate manufactured by Seikagaku Corporation
• Salts of hyaluronic acid include, but are not limited to, sodium salts.
• 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.
• 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.
• 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.
• the sterilization process is filter filtration.
• 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.
• 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.
• 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.
• 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.
• 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)).
• 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.
• 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.
• “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.
• 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.
• 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.
• 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.
• 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.
• 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 .
• 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.
• treatment means alleviation of symptoms, palliation or reduction in the rate of progression.
• 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.
• glaucoma 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.
• 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.
• the animal is a human.
• 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
• concentration of the water soluble polymer for example, CMC and / or its salt
• concentration of the chlorhexidine gluconate and brimonidine in the aqueous solution for example, 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 the respective elements in 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
• 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 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.
• 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.
• brimonidine and salts thereof preferred is brimonidine tartrate.
• 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. Is, 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.
• 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%.
• 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%.
• the aqueous solution of the present invention comprises a polyvinyl-based polymer, a cellulose-based polymer, or a natural polymer.
• the water-soluble polymer is preferably a cellulose-based polymer compound or a natural polymer, more preferably a cellulose-based polymer compound.
• the aqueous liquid preparation of the present invention contains at least two water-soluble polymers selected from polyvinyl polymers, cellulose polymers and natural polymers.
• 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.
• a carboxyvinyl polymer such as a crosslinked polyacrylic acid polymer
• One of these polyvinyl-based polymer compounds may be used alone, or two or more thereof may be used in combination.
• 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.
• the salt of CMC is sodium carboxymethylcellulose. Either CMC or a salt thereof may be used alone or in combination.
• 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%.
• the cellulosic polymeric compound is hydroxypropyl methylcellulose (HPMC).
• HPMC hydroxypropyl methylcellulose
• 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%.
• 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.
• the natural macromolecule is sodium hyaluronate.
• 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% to 0.1 w / v%.
• 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.
• hyaluronic acid, chondroitin sulfate etc. are mentioned, for example.
• the polyvinyl-based polymer is polyvinyl alcohol (PVA).
• 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%.
• the aqueous solution of the present invention contains 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% thereof and 0.001 w / v% to 0.01 w / v% of chlorhexidine gluconate.
• 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% thereof and 0.001 w / v% to 0.01 w / v% of chlorhexidine gluconate.
• the aqueous solution of the present invention comprises 0.07 w / v% to 0.15 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. Contains 005 w / v%).
• 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 / v Contains v%.
• 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
• polyvinyl-based polymer as an example, PVA
• the aqueous solution of the present invention comprises 0.07 w / v% to 0.15 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%) .
• 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 to 10: 0.02 to 0.07, more preferably 1: 3 to 7: 0.02 to 0.05.
• the aqueous solution further comprises boric acid and borax (osmolarity ratio: 0.9 to 1.1, pH: 6.7 to 7.5).
• the weight ratio of brimonidine and / or a salt thereof, a water-soluble polymer, and a chlorhexidine gluconate salt in the aqueous solution of the present invention is 1: 0.1-15: 0.01-0. And preferably 1: 0.2 to 12: 0.02 to 0.07, more preferably 1: 0.5 to 10: 0.02 to 0.05.
• the aqueous solution further comprises boric acid and borax (osmolarity ratio: 0.9 to 1.1, pH: 6.7 to 7.5).
• 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. And more preferably 1: 0.02 to 0.05.
• 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, and more preferably It is 1: 3-7.
• 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.
• 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.
• the weight ratio of chlorhexidine gluconate to water soluble polymer in the aqueous solution of the present invention is 1:10 to 500.
• 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.
• 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.
• 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.
• 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. .
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the aqueous solution of the present invention is for treating glaucoma.
• 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 and the like. 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.
• 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.
• 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%, 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.
• 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; ⁇ -blockers such as timolol maleate; ⁇ 1 blockers such as betaxolol hydrochloride; ⁇ 1 ⁇ ⁇ -blockers such as nipradilol, levobnolol hydrochloride; ⁇ 1 blockers such as bunazosin hydrochloride.
• prostaglandins such as tafluprost, latanoprost, isopropyl unoprostone
• parasympathomimetics such as pilocarpine hydrochloride
• anticholinesterase drugs such as distigmine
• 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.
• the pH of the aqueous solution of the present invention is not particularly limited as long as it is applicable to the intended use.
• the pH 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. To 7.1, more preferably pH 7.0.
• 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.
• the osmotic pressure when applied to the ocular mucosa, the osmotic pressure is 250 to 350 mOsmol.
• 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.
• the osmotic pressure ratio is 0.85 to 1.15.
• 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 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.
• 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.
• a water-soluble polymer for example, CMC and / or a salt thereof
• 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.
• 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”.
• 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.
• 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
• 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.
• 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.
• 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.
• “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.
• 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.
• 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 used 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.
• 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 a salt thereof in an aqueous liquid preparation, comprising the steps.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• a method of stabilizing pH in an aqueous solution is provided.
• 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
• 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.
• 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%.
• 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.
• PVP polyvinyl pyrrolidone
• One of these polyvinyl-based polymer compounds may be used alone, or two or more thereof may be used in combination.
• the polyvinyl-based polymer is PVP.
• 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%.
• 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 to 50: 0.02 to 0.07, more preferably 1:20 to 40: 0.02 to 0.05.
• the aqueous solution further comprises boric acid and borax (osmolarity ratio: 0.9 to 1.1, pH: 6.7 to 7.5).
• 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.
• 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.
• the pH stabilizing agent contains both brimonidine and / or a salt thereof and chlorhexidine gluconate.
• aqueous solution alone or in combination
• 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.
• 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.
• 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.
• 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.
• 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
• CMC Carboxymethyl cellulose sodium
• 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.
• aqueous liquid preparation of the present invention include aqueous liquid preparations having the compositions shown in Tables 2 to 5.
• 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
• HPMC hydroxypropyl methyl cellulose
• chlorhexidine gluconate Dainippon Sumitomo Pharma Co., Ltd.
• 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
• chlorhexidine gluconate manufactured by Dainippon Sumitomo Pharma Co., Ltd.
• 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
• HPMC hydroxypropyl methylcellulose
• PVA polyvinyl alcohol
• HA sodium hyaluronate
• Raw Chemical Industry Co., Ltd. chlorhexidine gluconate Dainippon Sumitomo Pharma Co., Ltd.
• 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.
• 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 ⁇ L of the sample solution and standard solution.
• PVP polyvinyl pyrrolidone

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