WO2016195073A1 - 水性点眼液 - Google Patents

水性点眼液 Download PDF

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Publication number
WO2016195073A1
WO2016195073A1 PCT/JP2016/066591 JP2016066591W WO2016195073A1 WO 2016195073 A1 WO2016195073 A1 WO 2016195073A1 JP 2016066591 W JP2016066591 W JP 2016066591W WO 2016195073 A1 WO2016195073 A1 WO 2016195073A1
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WIPO (PCT)
Prior art keywords
ophthalmic solution
chlorhexidine
concentration
aqueous ophthalmic
contact lens
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PCT/JP2016/066591
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English (en)
French (fr)
Japanese (ja)
Inventor
孝司 稲垣
直樹 松本
敏弘 小川
祐喜久 若林
明日香 神村
善弘 大下
仁志 中澤
功 松岡
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参天製薬株式会社
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Publication of WO2016195073A1 publication Critical patent/WO2016195073A1/ja

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • 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

Definitions

  • the present invention relates to an aqueous ophthalmic solution (hereinafter, also referred to as diquafosol ophthalmic solution) containing diquafosol or a salt thereof in a concentration of 0.1 to 10% (w / v), wherein 0.0001 to 0.1% (
  • the present invention relates to an aqueous ophthalmic solution containing chlorhexidine at a concentration of w / v).
  • multi-dose type ophthalmic solution there are two types of ophthalmic solutions (multi-dose type ophthalmic solution) that are used many times over a certain period after opening and single-use type (unit dose type ophthalmic solution).
  • the multi-dose type ophthalmic solution generally contains a preservative to prevent the product from being spoiled due to microbial contamination during use and to ensure the storage stability of the ophthalmic solution.
  • BAK benzalkonium chloride
  • the use of BAK at a high concentration is known to cause corneal damage. It has also been pointed out that when a user instills ophthalmic solution containing BAK while wearing a soft contact lens, the BAK contacts the contact lens and deforms the soft contact lens itself. Therefore, it is usually prohibited to instill an ophthalmic solution containing BAK while wearing a soft contact lens.
  • diquafosol is a purine receptor agonist also called P 1 , P 4 -di (uridine-5 ′) tetraphosphate, Up 4 U, etc.
  • diquafosol has a concentration of 3% (w / v).
  • ophthalmic solution containing sol sodium product name: Diquas (registered trademark) ophthalmic solution 3%
  • the Diquas (registered trademark) ophthalmic solution 3% contains BAK for the above reasons.
  • Patent Document 1 discloses an aqueous ophthalmic solution containing diquafosol or a salt thereof in a concentration of 0.1 to 10% (w / v) and a chelating agent in a concentration of 0.0001 to 1% (w / v). It is disclosed.
  • An object of the present invention is to provide a diquafosol ophthalmic solution that does not contain BAK and has higher safety. Furthermore, the subject of this invention is providing the diquafosol ophthalmic solution containing a preservative which is physicochemically stable at the time of preparation of an ophthalmic solution and long-term storage.
  • the present inventors have found that diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v), and 0.0001 to 0.1% (w / v)
  • the present inventors have found that an aqueous ophthalmic solution containing chlorhexidine having a concentration of v) (hereinafter also referred to as the present ophthalmic solution) has an excellent storage effect, and has led to the present invention. Furthermore, the present inventors have found that this ophthalmic solution suppresses deformation of the soft contact lens.
  • the present inventors also found that the ophthalmic solution had higher living cell activity in cultured immortalized human corneal epithelial cells than the ophthalmic solution containing BAK and the ophthalmic solution containing chlorhexidine containing no diquafosol or a salt thereof. It was found to show. In addition, the present inventors have shown that this ophthalmic solution significantly increases NIBUT (non-invasive tear film destruction time) in soft contact lens wearing eyes, that is, in the soft contact lens wearing eye, the tear film is stabilized. I found out. On the other hand, such effects were not observed with artificial tears. Occurrence / deterioration of dry eye symptoms due to wearing soft contact lenses is due to a decrease in tear film stability.
  • NIBUT non-invasive tear film destruction time
  • the ophthalmic solution is also useful for the prevention and / or treatment of dryness and / or eye discomfort in soft contact lens wearing eyes.
  • diquafosol ophthalmic solution containing chlorhexidine in a specific concentration range that is, a concentration of 0.001 to 0.005% (w / v)
  • the present invention provides the following aqueous ophthalmic solution.
  • this invention provides the method of suppressing a deformation
  • the present invention also relates to the following.
  • (14) Prevention of dry eye comprising diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidine at a concentration of 0.0001 to 0.1% (w / v) and An aqueous ophthalmic solution for treatment.
  • Dry eye of aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidine at a concentration of 0.0001 to 0.1% (w / v) Use in the prevention and / or treatment of
  • An aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) and chlorhexidine at a concentration of 0.0001 to 0.1% (w / v) is administered.
  • a method for preventing and / or treating dry eye is administered.
  • the present invention also provides the following aqueous ophthalmic solution.
  • the aqueous ophthalmic solution according to any one of (1) to (12) for preventing or treating dryness or discomfort in the eye wearing a soft contact lens.
  • the present invention also provides the following methods. (21) In the preparation of an aqueous ophthalmic solution containing diquafosol or a salt thereof in a concentration of 0.1 to 10% (w / v) and chlorhexidine, a concentration of 0.0001 to 0.005% (w / v) The method of suppressing the fall of the residual rate of the chlorhexidine in this aqueous
  • this ophthalmic solution has an excellent storage effect. Furthermore, since the present ophthalmic solution suppresses deformation of the soft contact lens, it can be used for a soft contact lens. In addition, this ophthalmic solution shows higher living cell activity in cultured immortalized human corneal epithelial cells than ophthalmic solutions containing BAK and ophthalmic solutions containing chlorhexidine containing no diquafosol or a salt thereof. Therefore, the present ophthalmic solution is more safe for living organisms, particularly the keratoconjunctival epithelium, and is useful for use in diseases where the keratoconjunctival epithelium is unstable such as dry eye.
  • this ophthalmic solution remarkably raises NIBUT in the soft contact lens wearing eye.
  • this ophthalmic solution stabilizes the tear film in the soft contact lens wearing eye. Occurrence / deterioration of dry eye symptoms due to wearing soft contact lenses is due to a decrease in tear film stability.
  • the ophthalmic solution is also useful for the prevention and / or treatment of dryness and / or eye discomfort in soft contact lens wearing eyes.
  • diquafosol ophthalmic solution containing chlorhexidine in a specific concentration range that is, a concentration of 0.001 to 0.005% (w / v) maintains a high residual ratio of chlorhexidine at the time of ophthalmic solution preparation, and Chlorhexidines in eye drops have excellent long-term stability.
  • FIG. 1 is a diagram showing the results of a cytotoxicity test using corneal epithelial cells in Test Example 3.
  • FIG. 2 is a diagram showing the results of Evaluation Test 1 for NIBUT raising effect in Test Example 4.
  • FIG. 3 is a diagram showing the results of Evaluation Test 2 for NIBUT raising action in Test Example 5.
  • Diquafosol is a compound represented by the following chemical structural formula.
  • “Diquafosol salt” is not particularly limited as long as it is a pharmaceutically acceptable salt; metal salt with lithium, sodium, potassium, calcium, magnesium, zinc, etc .; hydrochloric acid, hydrobromic acid, hydroiodic acid , Salts with inorganic acids such as nitric acid, sulfuric acid, phosphoric acid; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
  • diquafosol or a salt thereof includes diquafosol (free form) or a hydrate and an organic solvate thereof.
  • crystal polymorph groups When diquafosol or a salt thereof has crystal polymorphs and crystal polymorph groups (crystal polymorph systems), those crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the scope of the present invention. It is.
  • the crystal polymorph group (crystal polymorph system) is an individual crystal form and its process in each stage when the crystal form changes depending on conditions and states such as production, crystallization, and storage of those crystals. Means the whole.
  • diquafosol or a salt thereof of the present invention is a sodium salt of diquafosol, and diquafosol tetrasodium salt represented by the following chemical structural formula (hereinafter, also simply referred to as “diquafosol sodium”) is particularly preferable.
  • Diquafosol or a salt thereof can be produced by a method disclosed in JP-T-2001-510484.
  • the ophthalmic solution may contain an active ingredient other than diquafosol or a salt thereof, but preferably contains diquafosol or a salt thereof as the only active ingredient.
  • the concentration of diquafosol or a salt thereof in the ophthalmic solution is 0.1 to 10% (w / v), preferably 1 to 10% (w / v), and 3% (w / v) It is particularly preferred that
  • aqueous ophthalmic solution means an ophthalmic solution containing water as a solvent (base).
  • chlorhexidine includes chlorhexidine and salts thereof.
  • Chlorhexidine is a compound represented by the following chemical structural formula, and is also referred to as 1,1′-hexamethylenebis [5- (4-chlorophenyl) biguanide].
  • the “chlorhexidine salt” is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • an organic acid salt for example, a monocarboxylate (acetate salt) , Trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxycarboxylate (gluconic acid) Salt, lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (eg hydrochloride, sulfate, nitrate) , Hydrobromides, phosphates, etc.), salts with organic bases (eg methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, Salt
  • organic bases eg methylamine, triethy
  • Etc. are mentioned.
  • these salts preferably an organic acid salt and / or an inorganic acid salt, more preferably an oxycarboxylate salt, a monocarboxylate salt and / or an inorganic acid salt, still more preferably a gluconate salt, an acetate salt and / or hydrochloric acid. Salts, particularly preferably gluconates are mentioned.
  • These chlorhexidine salts may be used alone or in any combination of two or more.
  • Chlorhexidine and its salt may be synthesized by a known method or can be obtained as a commercial product.
  • the concentration of chlorhexidine in this ophthalmic solution is 0.0001 to 0.1%, preferably 0.0005 to 0.05% (w / v), 0.001 to 0.005% (W / v) or more than 0.001% (w / v) to 0.005% (w / v) or less, preferably 0.0015 to 0.005% (w / v), 0 It is more preferably 0.002 to 0.005% (w / v).
  • the “chelating agent” is not particularly limited as long as it is a compound that chelates metal ions.
  • edetic acid ethylenediaminetetraacetic acid
  • monosodium edetate disodium edetate, trisodium edetate
  • Edetic acid or its salts such as sodium, tetrasodium edetate, dipotassium edetate, tripotassium edetate, tetrapotassium edetate
  • citric acid monosodium citrate, disodium citrate, trisodium citrate, monocitrate
  • Citric acid or salts thereof such as potassium, dipotassium citrate, tripotassium citrate
  • metaphosphoric acid or salts thereof such as metaphosphoric acid, sodium metaphosphate, potassium metaphosphate
  • pyrophosphoric acid tetrasodium pyrophosphate, tetrapotassium pyrophosphate, etc.
  • Pyrophosphoric acid or a salt thereof polyphosphoric acid, polyphosphoric acid Polyphosphoric acid or its salt such as sodium phosphate, potassium polyphosphate; Malic acid or its salt such as monosodium malate, disodium malate, monopotassium malate, dipotassium malate; sodium tartrate, potassium tartrate, sodium potassium tartrate And tartaric acid or salts thereof; phytic acid or salts thereof such as sodium phytate and potassium phytate; and the like.
  • “edetic acid, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid and salts thereof” include the free forms or hydrates of those salts and Organic solvates are also included.
  • the chelating agent includes edetic acid, edetic acid salt (edetate), citric acid, citric acid salt (citrate), metaphosphoric acid, metaphosphoric acid salt (metaphosphate), polyphosphoric acid, Salts of polyphosphoric acid (polyphosphates) are preferred, including sodium salts of edetic acid (including hydrates such as disodium edetate hydrate), citric acids (hydrates such as citric acid monohydrate) ), Sodium salt of metaphosphoric acid (sodium metaphosphate), and sodium salt of polyphosphoric acid (sodium polyphosphate) are particularly preferred.
  • disodium edetate hydrate (hereinafter also simply referred to as “sodium edetate hydrate”) is the most preferable as edetate.
  • these chelating agents may be used alone or in any combination of two or more.
  • the concentration of the chelating agent in the ophthalmic solution is, for example, 0.0001 to 1% (w / v), preferably 0.0005 to 0.5% (w / v), and 0.001 to 0.1. % (W / v) is particularly preferred.
  • a nonionic surfactant can be blended as necessary.
  • the nonionic surfactant is not particularly limited as long as it is within a pharmaceutically acceptable range.
  • polyoxyethylene fatty acid ester polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene fatty acid ester
  • examples thereof include oxyethylene polyoxypropylene glycol and sucrose fatty acid ester.
  • polyoxyethylene fatty acid ester examples include polyoxyl stearate 40
  • polyoxyethylene sorbitan fatty acid ester examples include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, Polysorbate 65 and the like
  • polyoxyethylene castor oil derivatives include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyl 5 Castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like.
  • Xylpropylene glycol includes polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene Examples include ethylene (196) polyoxypropylene (67) glycol and polyoxyethylene (20) polyoxypropylene (20) glycol.
  • nonionic surfactant examples include polyoxyethylene sorbitan fatty acid ester, preferably polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate. 65 and the like, particularly preferably polysorbate 80.
  • nonionic surfactants may be used alone or in any combination of two or more.
  • the concentration of the nonionic surfactant in the ophthalmic solution is, for example, 0.0001 to 10% (w / v), preferably 0.0005 to 1% (w / v), and 0.0005 to 0%. 1% (w / v) is particularly preferred.
  • the ophthalmic solution can be added with a pharmaceutically acceptable additive as necessary using a widely used technique, for example, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate.
  • Buffering agents such as sodium acetate and epsilon-aminocaproic acid; isotonic agents such as sodium chloride, potassium chloride and concentrated glycerin can be selected and added as necessary.
  • the pH of the ophthalmic solution may be within the range that is acceptable for ophthalmic preparations, but is usually preferably within the range of 4-8.
  • a pH adjusting agent such as hydrochloric acid or sodium hydroxide can be appropriately added to the ophthalmic solution.
  • This ophthalmic solution can be used for soft contact lenses, even when wearing soft contact lenses.
  • the soft contact lens include a contact lens mainly composed of hydroxyethyl methacrylate or a silicone hydrogel contact lens.
  • the type of soft contact lens to which this ophthalmic solution is applied is not particularly limited, and may be ionic or nonionic, hydrated or non-hydrated.
  • the present invention can be applied to all soft contact lenses that are commercially available in the future, such as daily disposable lenses, one week disposable lenses, and two week disposable lenses.
  • the ophthalmic solution and the usage of the ophthalmic solution can be appropriately changed according to the dosage form, the severity of the symptoms of the patient to be administered, age, weight, doctor's judgment, etc. When selected, it can be administered to the eye topically in 1 to 10 times a day, preferably 2 to 8 times a day, more preferably 4 to 6 times a day.
  • Dry eye is defined as “a chronic disease of tears and keratoconjunctival epithelium due to various factors and a disease accompanied by eye discomfort and visual abnormality”, and dry keratoconjunctivitis (KCS) is included in dry eye.
  • KCS dry keratoconjunctivitis
  • occurrence of dry eye symptoms caused by wearing soft contact lenses is also included in dry eye.
  • Dry eye symptoms include dryness, eye discomfort, eye fatigue, dullness, dullness, eye pain, foggy vision (blurred eyes), and other symptoms such as hyperemia and keratoconjunctival epithelial disorder. Findings are also included.
  • This ophthalmic solution can be used for “prevention and / or treatment of dry eye”.
  • prevention and / or treatment of dry eye is defined as preventing and / or treating or ameliorating pathological symptoms and / or findings associated with dry eye. Not only means prevention, treatment and / or improvement of subjective symptoms such as eye discomfort, eye fatigue, dullness, drowsiness, eye pain, foggy vision (blurred eyes), redness associated with dry eyes, horns Also included is prevention and / or treatment or amelioration of conjunctival epithelial disorders. “Prevention and / or treatment of dry eye” also includes prevention and / or treatment or amelioration of dry eye symptoms by improving the stability of the tear film in the eye wearing a soft contact lens. The prevention and / or treatment or improvement of dry eye symptoms can be achieved by the prevention and / or treatment or improvement of dry eye symptoms that have become worse when dry eye patients wear soft contact lenses. It also means prevention and / or treatment or amelioration of dry eye symptoms that have occurred.
  • the improvement of tear film stability means that tears are improved quantitatively or qualitatively.
  • the stability of the tear film can be confirmed by measuring BUT (tear film destruction time).
  • BUTs head film destruction time
  • NIBUT non-invasive tear film destruction time
  • prevention or treatment of dry eye or discomfort in soft contact lens wearing eyes means prevention of dry eye or discomfort associated with destabilization of the tear film caused by wearing soft contact lenses. Or it means prevention or treatment of dry eye or discomfort caused by keratoconjunctival epithelial disorder caused by treatment or destabilization.
  • the present invention relates to chlorhexidine having a concentration of 0.005% (w / v) or less in the preparation of an aqueous ophthalmic solution containing diquafosol or a salt thereof and chlorhexidine at a concentration of 0.1 to 10% (w / v).
  • a method for suppressing a decrease in the residual rate of chlorhexidine in the aqueous ophthalmic solution is provided.
  • the concentration of chlorhexidine used is preferably 0.005% (w / v) or less, or 0.0001 to 0.005% (w / v).
  • the present invention provides a method for stabilizing chlorhexidine in aqueous ophthalmic solution containing diquafosol or a salt thereof in a concentration of 0.1 to 10% (w / v) and chlorhexidine.
  • concentration of the chlorhexidine is preferably more than 0.001% (w / v), or more than 0.001% (w / v) to 0.1% (w / v) or less.
  • the following is a storage efficacy test, a soft contact lens deformation inhibition test, a corneal epithelial cell cytotoxicity test, a NIBUT increase action evaluation test, a NIBUT increase action comparison test, a chlorhexidine gluconate residual rate measurement test, and a chlorhexidine
  • CL is an abbreviation for a contact lens
  • SCL is an abbreviation for a soft contact lens.
  • Test Example 1 Preservative Efficacy Test
  • Preservative efficacy tests were conducted on eye drops 1 to 6 having the formulations shown in Table 1.
  • Ophthalmic solution 1 An ophthalmic solution 1 was prepared according to the formulation shown in Table 1. Specifically, diquafosol sodium (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.39 g), potassium chloride (0.15 g), edetate sodium hydrate (0 0.01 g), polysorbate 80 (0.0005 g) and chlorhexidine gluconate (0.002 g) were dissolved in water to 100 mL, and a pH adjuster was added to pH 7.2.
  • Table 1 An ophthalmic solution 1 was prepared according to the formulation shown in Table 1. Specifically, diquafosol sodium (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.39 g), potassium chloride (0.15 g), edetate sodium hydrate (0 0.01 g), polysorbate 80 (0.0005 g) and chlorhexidine gluconate (0.002 g) were dissolved in water to 100 mL, and a pH adjuster was added to pH 7.2.
  • Ophthalmic solutions 2-6 According to the formulation shown in Table 1, eye drops 2 to 6 were prepared in the same manner as eye drops 1.
  • the preservation efficacy test was conducted in accordance with the 16th revised Japanese Pharmacopoeia preservation efficacy test method.
  • Escherichia Coli E. coli
  • Pseudomonas aeruginosa P. aeruginosa
  • Staphylococcus aureus S. aureus
  • Candida albicans C. albicans
  • Candida albicans C. albicans
  • Test results The test results are shown in Table 2.
  • test results in Table 2 indicate how much the number of viable bacteria at the time of inspection decreased compared to the number of inoculated bacteria by log reduction. For example, in the case of “1”, the number of viable bacteria at the time of inspection Indicates a decrease to 10% of the number of inoculated bacteria.
  • Test Example 2 Deformation suppression evaluation test of soft contact lens Using ophthalmic solution 4, the effect on soft contact lens was examined.
  • the contact lens after being immersed for a long time satisfied the criterion. Therefore, it was shown that the ophthalmic solution 4 suppresses deformation of the soft contact lens.
  • the present ophthalmic solution can be used as a soft contact lens because it suppresses deformation of the soft contact lens.
  • SV40 immortalized human corneal epithelial cells (HCE-T: RIKEN, BioResource Center, Cell No .: RCB2280) were seeded in a 96-well plate (1 ⁇ 10 4 cells / well), and 10% FBS-containing D-MEM / Cultured for 1 day in F12 medium. On the next day, after the medium was replaced with eye drops 7, eye drops 8, eye drops 9, or eye drops 10, the corneal epithelial cells were cultured for 15 minutes. Live cell activity (corresponding to absorbance at 490 nm) was measured using Cell Proliferation Assay Kit (Promega, catalog number: G3580).
  • diquafosol ophthalmic solution containing o chlorhexidine gluconate is an ophthalmic solution containing BAK (ophthalmic solution 9, ophthalmic solution 10) and chlorhexidine containing no diquafosol or a salt thereof.
  • BAK ophthalmic solution 9, ophthalmic solution 10
  • chlorhexidine containing no diquafosol or a salt thereof.
  • This ophthalmic solution Since this ophthalmic solution exhibits high living cell activity in cultured immortalized human corneal epithelial cells, it is more safe for living organisms, especially the keratoconjunctival epithelium, and for diseases where the keratoconjunctival epithelium is unstable such as dry eye. Useful for use.
  • Test Example 4 NIBUT elevating action evaluation test 1
  • NIBUT of diquafosol ophthalmic solution in eyes whose stability of the tear film was reduced by wearing soft contact lenses.
  • the present ophthalmic solution improves the decrease in tear film stability caused by wearing a soft contact lens. Such an effect of the present ophthalmic solution was remarkable even when compared with artificial tears generally used for dry eye treatment. Therefore, the present ophthalmic solution is useful for the prevention and / or treatment of dry eye in the soft contact lens wearing eye. The ophthalmic solution is also useful for the prevention and / or treatment of dryness and / or eye discomfort in soft contact lens wearing eyes.
  • NIBUT elevating action evaluation test 2 We investigated NIBUT of diquafosol ophthalmic solution in eyes whose stability of the tear film was reduced by wearing soft contact lenses.
  • the present ophthalmic solution improves the decrease in tear film stability caused by wearing a soft contact lens.
  • Such effects of the present ophthalmic solution were remarkable even when compared with artificial tears and sodium hyaluronate ophthalmic solutions generally used for dry eye treatment. Therefore, the present ophthalmic solution is useful for the prevention and / or treatment of dry eye in the soft contact lens wearing eye.
  • the ophthalmic solution is also useful for the prevention and / or treatment of dryness and / or eye discomfort in soft contact lens wearing eyes.
  • Test Example 6 Comparison test of NIBUT elevation effect Comparison of NIBUT of this eye drop and BAK-containing eye drops (eye drops containing diquafosol sodium and BAK) in eyes whose tear film stability has been reduced by wearing soft contact lenses did.
  • ophthalmic solution 11 containing BAK instead of chlorhexidine gluconate of ophthalmic solution 4 was prepared. Specifically, diquafosol sodium (3 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.41 g), potassium chloride (0.15 g) and BAK (0.0075 g) were added to water. To 100 mL, and a pH adjuster was added to adjust the pH to 7.5.
  • the ophthalmic solution 4 and the ophthalmic solution 11 are both ophthalmic solutions containing an active ingredient (diquafosol sodium) having the same concentration.
  • the ophthalmic solution 4 and the ophthalmic solution 11 are both ophthalmic solutions that conform to the preservation efficacy test standards of the Japanese Pharmacopoeia and have equivalent preservation efficacy.
  • Test Example 7 Chlorhexidine gluconate residual rate measurement test The effect of chlorhexidine gluconate concentration on the residual rate of chlorhexidine gluconate after diquafosol ophthalmic solution preparation was examined.
  • Eye drops 12 An ophthalmic solution 12 was prepared according to the formulation shown in Table 8. Specifically, it was prepared as follows. 1) A 0.5% (w / v) chlorhexidine gluconate solution was prepared. 2) 0.4% (w / v) sodium hydrogen phosphate hydrate, 0.78% (w / v) sodium chloride, 0.3% (w / v) potassium chloride and 0.02% (w / v) An aqueous solution (double concentrated solution) containing sodium edetate hydrate was prepared. 3) The solution prepared in 1) was added to water, and the solution prepared in 2) was further added.
  • Test Example 8 Long-term stability test of chlorhexidine gluconate The long-term stability of chlorhexidine gluconate in diquafosol ophthalmic solution was examined.
  • diquafosol ophthalmic solutions containing chlorhexidine having a specific concentration range that is, a concentration of 0.001 to 0.005% (w / v) are high in chlorhexidines at the time of preparation of the ophthalmic solution. It was shown that chlorhexidine in the ophthalmic solution has excellent long-term stability. Therefore, as shown in Test Example 1, the ophthalmic solution is also expected to have excellent storage efficacy for a long period of time.
  • formulation example The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.
  • This ophthalmic solution has an excellent preservation effect. Furthermore, since the present ophthalmic solution suppresses deformation of the soft contact lens, it can be used for a soft contact lens. In addition, this ophthalmic solution shows higher living cell activity in cultured immortalized human corneal epithelial cells than ophthalmic solutions containing BAK and ophthalmic solutions containing chlorhexidine containing no diquafosol or a salt thereof. Therefore, the present ophthalmic solution is more safe for living organisms, particularly the keratoconjunctival epithelium, and is useful for use in diseases where the keratoconjunctival epithelium is unstable such as dry eye.
  • this ophthalmic solution significantly increases the NIBUT in the soft contact lens wearing eye.
  • such an effect is not recognized in artificial tears. That is, the present ophthalmic solution stabilizes the tear film in the soft contact lens wearing eye. Occurrence / deterioration of dry eye symptoms due to wearing soft contact lenses is due to a decrease in tear film stability.
  • the ophthalmic solution is also useful for the prevention and / or treatment of dryness and / or eye discomfort in soft contact lens wearing eyes.
  • diquafosol ophthalmic solution containing chlorhexidine in a specific concentration range that is, a concentration of 0.001 to 0.005% (w / v) maintains a high residual ratio of chlorhexidine at the time of ophthalmic solution preparation, and Chlorhexidines in eye drops have excellent long-term stability.

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US20230145529A1 (en) 2020-03-31 2023-05-11 Santen Pharmaceutical Co., Ltd. Silver salt-containing ophthalmic aqueous composition filled in resin container
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