US20140315836A1 - Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder - Google Patents

Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder Download PDF

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Publication number
US20140315836A1
US20140315836A1 US14/360,070 US201214360070A US2014315836A1 US 20140315836 A1 US20140315836 A1 US 20140315836A1 US 201214360070 A US201214360070 A US 201214360070A US 2014315836 A1 US2014315836 A1 US 2014315836A1
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Prior art keywords
keratoconjunctiva
agent
acid
keratoconjunctival disorder
glucosylglycerol
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Inventor
Kyo Aizawa
Yoshihisa Iida
Takashi Shimoida
Yasuhiro Kotani
Koushi Iwaia
Kazuhisa Doi
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Toyo Sugar Refining Co Ltd
Otsuka Pharmaceutical Factory Inc
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Toyo Sugar Refining Co Ltd
Otsuka Pharmaceutical Factory Inc
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Application filed by Toyo Sugar Refining Co Ltd, Otsuka Pharmaceutical Factory Inc filed Critical Toyo Sugar Refining Co Ltd
Assigned to TOYO SUGAR REFINING CO., LTD., OTSUKA PHARMACEUTICAL FACTORY, INC. reassignment TOYO SUGAR REFINING CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AIZAWA, KYO, DOI, KAZUHISA, IIDA, YOSHIHISA, IWATA, KOUSHI, KOTANI, YASUHIRO, SHIMOIDA, TAKASHI
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    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates to a protective agent for the keratoconjunctiva or a suppressive agent for a keratoconjunctival disorder, and more particularly relates to a protective agent for the keratoconjunctiva or a suppressive agent for a keratoconjunctival disorder, which suppresses a keratoconjunctival disorder caused by drying or the like and protects the keratoconjunctiva.
  • the lacrimal fluid is spread across the surface of the eye made up of the cornea and the conjunctiva (keratoconjunctiva) so as to keep the eye wet and prevent drying of the surface of the eye. Further, the lacrimal fluid serves as a lubricant for protecting the keratoconjunctiva from stimulation by blinking and contributes to the maintenance of smoothness of the surface of the keratoconjunctiva. In addition, the lacrimal fluid has a bacteriostatic effect so as to prevent infection with bacteria, fungi, viruses. etc., and also provides the keratoconjunctiva with oxygen and various nutrients and removes. carbon dioxide and metabolites.
  • keratoconjunctival xerosis keratoconjunctival xerosis
  • the cause of this dry eye is considered to be a decrease in the amount of secreted lacrimal fluid.
  • a disorder is caused in the keratoconjunctiva to cause discomfort in the eye such as dryness, pain, or red eye, infection in the eye such as conjunctivitis, or the like.
  • the keratoconjunctiva may be damaged to reduce visual acuity in some cases.
  • an artificial lacrimal fluid containing a viscoelastic substance such as hyaluronic acid, and a protein such as sericin is mainly performed, and for example, a protective agent for the keratoconjunctiva or an improving agent for a keratoconjunctival disorder containing a silk protein, sericin, as an active ingredient is known (see, for example, Patent Document 1).
  • glucosylglycerol is a component contained in a brewed product such as refined sake (Japanese rice wine), and has sweetness, thermal stability, low reactivity in the Mallard reaction, water-retaining properties, non-cariogenic properties, indigestible properties, etc., and also has a promoting effect on the proliferation of vascular endothelial cells, a suppressive effect on an increase in blood glucose level, an antimicrobial effect, etc., and has been used in foods, cosmetics, pharmaceuticals, and so on.
  • a whitening agent containing ⁇ -D-glucopyranosyl glycerol ( ⁇ -glucosylglycerol) as an active ingredient see, for example, Patent Document 2
  • an agent for accelerating the production of dermal matrix containing ⁇ -D-glucopyranosyl glycerol ( ⁇ -glucosylglycerol) as an active ingredient see, for example, Patent Document 3
  • Patent Document 2 a whitening agent containing ⁇ -D-glucopyranosyl glycerol ( ⁇ -glucosylglycerol) as an active ingredient
  • ⁇ -glucosylglycerol has various effects, and therefore is applied in various ways, however, the compound is used mainly as an external preparation for the skin, and the effect thereof on the keratoconjunctiva of the eye has not been known so far.
  • Patent Document 1 JP-A-2010-83829
  • Patent Document 2 JP-A-2004-331581
  • Patent Document 3 JP-A-2004-331579
  • an object of the invention is to provide a protective agent for the keratoconjunctiva or a suppressive agent for a keratoconjunctival disorder, which has an excellent effect of suppressing a keratoconjunctival disorder caused by drying or the like and protecting the keratoconjunctiva.
  • the present inventors made intensive studies for achieving a protective agent for the keratoconjunctiva which exhibits a suppressive effect on a keratoconjunctival disorder, and as a result, they found that glyceryl glucoside exhibits an excellent suppressive effect on a keratoconjunctival disorder, and thus completed the invention.
  • the invention provides the following (1) to (6).
  • a protective agent for a keratoconjunctiva or a suppressive agent for a keratoconjunctival disorder comprising glucosylglycerol as an active ingredient.
  • the protection of the keratoconjunctiva or the suppression of the a keratoconjunctival disorder is protection of the keratoconjunctiva against an endogenous disease of Sjogren's syndrome, Stevens-Johnson syndrome, or dry eye syndrome (dry eye) or an exogenous disease due to postsurgery, a drug, an injury, or the wearing of a contact lens or the suppression. of the keratoconjunctival disorder due to said diseases.
  • a method of protecting a keratoconjunctiva or suppressing a keratoconjunctival disorder comprising administering glucosylglycerol.
  • a protective agent for the keratoconjunctiva and a suppressive agent for a keratoconjunctival disorder which have an excellent suppressive effect on a keratoconjunctival disorder can be provided.
  • FIG. 1 is a graph showing the measurement results of absorbance measured in Examples of the invention.
  • the “protection of the keratoconjunctiva” refers to the protection of keratoconjunctival tissue from a keratoconjunctival disorder which can he caused by any of various factors. Specifically, the “protection of the keratoconjunctiva” can he roughly divided into the protection from a keratoconjunctival disorder caused by an exogenous factor and the protection. from a keratoconjunctival disorder caused by an endogenous factor. Examples of the exogenous factor include an injury, a burn injury, a chemical substance, a drug, UV light, the wearing of a contact is lens, a foreign substance, an eyelash, outside air drying, and infection.
  • keratorefractive surgery or cataract surgery
  • cataract surgery is also included in the exogenous factor
  • examples of the endogenous factor include Sjogren's syndrome, dry eye syndrome (dry eye), and diabetic keratopathy.
  • the “keratoconjunctiva” refers to the cornea and the conjunctiva, and the cornea is made up of five layers including a corneal epithelial layer, a Bowman's membrane, a corneal stromal layer, a Descemet's membrane, and a corneal endothelial layer, and the conjunctiva is made up of a conjunctival epithelial layer and a lamina intestinal layer.
  • the conical epithelial layer and the conjunctival epithelial layer are located on the outermost surfaces of the cornea and the conjunctiva, respectively, and each comprises a set of epithelial cell layers in which the cells migrate one another, and is likely to be damaged by an effect from the outside. Therefore, according to a preferred embodiment of the invention, the keratoconjunctiva in the “protection of the keratoconjunctiva” refers to the keratoconjunctival epithelium the corneal epithelium and the conjunctival epithelium).
  • the “suppression of a keratoconjunctival disorder” refers to the inclusion of improvement of a keratoconjunctival disorder caused by any of the above-described factors, alleviation of the symptoms, reduction of the symptoms, mitigation of the symptoms, and also treatment, healing, acceleration of healing, and so on.
  • the protective agent for the keratoconjunctiva and the suppressive agent for a ketatoconjunctival disorder (hereinafter sometimes referred to collectively as pharmaceutical agents) of the invention comprises glucosylglycerol as an active ingredient.
  • glucosylglycerol to be used as the active ingredient 1- ⁇ -glyceryl glucoside (Formula 1), 2- ⁇ -glyceryl glucoside (Formula 2), 1- ⁇ -glyceryl glucoside (Formula 3), and 2- ⁇ -glyceryl glucoside (Formula 4), which are represented by the following formulae (1) to (4), are known, and among these compounds, one type can be used alone or a plurality of types can be used in combination.
  • the method of obtaining such glucosylglycerol is not particularly limited, and for example, a method of allowing glycerine derived from palm to act on a substrate of a saccharide derived from corn, a method of allowing fungal ⁇ -glucosidase, cyclodextrin glucanotransferase, or sucrose phosphorylase to act on a substrate of a carbohydrate in a glycerol solution, a method of performing extraction and purification from a brewed product such as refined sake (Japanese rice wine), miso (fermented soybean paste), or mirin (sweet sake for seasoning), a method of treating isomaltose, maltitol, or the like with lead tetraacetate or a periodate to split glycol, followed by reduction, a method of subjecting ⁇ -glucoside synthesized by Koening-Knorr reaction to anomerization, followed by hydrolysis of ⁇ -glucoside with ⁇ -glu
  • a method of allowing glycerine derived from palm to act on a substrate of a carbohydrate derived from corn a method of allowing cyclodextrin glucanotransferase to act on a substrate of a carbohydrate in a glycerol solution (see, for example, JP-A-2004-099472), or a method of allowing sucrose phosphorylase to act on a substrate of a carbohydrate in a glycerol solution (see, for example, WO 2008/034158) is particularly preferred from the viewpoint of cost and safety.
  • the glucosylglycerol can be used as such, but may be used after being diluted with water or a polar solvent, or after being subjected to a purification treatment of decoloring and deodorization within a range which does not cause denaturation or decomposition, or after being subjected to a fractionation treatment using column chromatography or the like. Further, the glucosylglycerol can be used after being encapsulated in a vesicle such as a liposome, a microcapsule, or the like.
  • the amount of the glucosylglycerol to be added to the protective agent for the keratoconjunctiva Or the suppressive agent for a keratoconjunctival disorder in the invention varies depending on the dosage form or type of the pharmaceutical agent, the severity of the keratoconjunctival disorder, etc., and cannot be uniformly specified, however, for example, the glucosylglycerol is preferably contained in the pharmaceutical agent in an amount of preferably from 0.01 to 80% by mass, more preferably from 0.05 to 50% by mass, further more preferably from 0.01 to 10% by mass.
  • the glucosylglycerol is contained in the pharmaceutical agent in an amount of 0.01% by mass or more, the desired effect of the invention of this application is sufficiently obtained, and therefore, such an amount is preferred, and if the amount thereof is 80% by mass or less, an increase in viscosity of the pharmaceutical agent due to the glucosylglycerol falls within a desired range, and therefore, such an amount is preferred.
  • the pH and osmotic pressure thereof are not particularly limited as long as they fall within a range that is acceptable as a pharmaceutical preparation for ophthalmic topical administration.
  • the pH thereof is preferably from 5 to 9.5, more preferably from 6 to 9, further more preferably from 7 to 9,
  • the ratio of the osmotic pressure of the pharmaceutical preparation (except for an ophthalmic ointment) to that of physiological saline is, for example, from 0.3 to 4.3, preferably from 0.3 to 2.2, particularly preferably from about 0.5 to 1.5.
  • the pH and osmotic pressure thereof can be adjusted by a method known in this technical field using a pH adjusting agent, an isotonizing agent, a salt, or the like.
  • the protective agent for the keratoconjunctiva and the suppressive agent for a keratoconjunctival disorder of the invention are formulated into pharmaceutical preparations, various components (including a pharmacologically active component and a biologically active component) to be used in a pharmaceutical preparation for ophthalmic topical administration can be added as needed within a range that does not inhibit the effect of the invention.
  • a decongestant component is not particularly limited, and for example, a decongestant component, an ocular accommodation agent component, an anti-inflammatory agent component or an astringent component, an antihistamine agent component or an anti-allergic agent component, a vitamin, an amino acid, an antimicrobial agent component, a microbicidal agent component, a saccharide, a polysaccharide or a derivative thereof, cellulose or a derivative thereof or a salt thereof, a water-soluble polymer other than the above-described components, a local anesthetic component, asteroid component, a therapeutic component for glaucoma, a therapeutic component for cataract, etc. can be exemplified.
  • one component may be used alone or two or more components may be used in combination.
  • Examples of the decongestant component include ⁇ -adrenergic agonists, imidazoline derivatives (such as naphazoline and tetrahydrozoline), ⁇ -phenylethylamine derivatives (such as phenylephrine, epinephrine, ephedrine, and methylephedrine), and pharmaceutically or physiologically acceptable salts thereof (for example, inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, and methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate, etc.).
  • imidazoline derivatives such as naphazoline and tetrahydrozoline
  • ocular muscle accommodation agent component examples include cholinesterase inhibitors having an active center similar to acetylcholine and quaternary ammonium compounds and salts thereof such as neostigmine methylsulfate.
  • anti-inflammatory agent component or astringent component examples include celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesil, acemetacin, ibuprofen, tiaprofenic acid, loxoprofen sodium, tiaramide hydrochloride, epsilon-aminocaproic acid, berberine and pharmacologically acceptable salts thereof (such as berberine chloride and berberine sulfate), azulene sulfonic acid and pharmacologically acceptable salts thereof (such as azulene sulfonate sodium), zinc salts (such as zinc sulfate and zinc lactate), lysozyme, lysozyme chloride, methyl salicylate, allantoin, and glycyrr,
  • antihistamine agent component or anti-allergic agent component examples include chlorpheniramine diphenhydramine, iproheptine, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycic acid, tranilast, amlexanox mequitazine, loratadine, fexofenadine, cetirizine, ibudilast, suplatast, pemirolast, repirinast, tazanolast, oxatomide, terfenadine, epinastine, astemizole, ebastine, and salts thereof (such as chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptine hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine
  • the vitamin examples include A vitamins [such as retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, and pharmacologically acceptable salts thereof (such as retinol acetate and retinol palmitate)], B vitamins [such as thiamine, dicethiamine, thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl nitrate ester salts, dicethiamine hydrochloride, fursulthiamine hydrochloride, octothiamine, cycothiamine, bisibuthiamine, bisbenthiamine, fursultiamine, prosulthiamine, benfothiamine, riboflavin, flavin adenine dinucleotide flavin adenine dinucleotide sodium, riboflavin, riboflavin sodium phosphate, riboflavin butyrate,
  • amino acids examples include leucine, isoleucine, valine, methionine threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine glycylglycine, aminoethylsulfonic acid (taurine), and salts thereof (such as potassium aspartate, magnesium aspartate, and cysteine hydrochloride).
  • antimicrobial agent component or microbicidal agent component examples include sulfonamides (such as sulfamethoxazole sulfisoxasol sulfisomidine, and pharmacologically acceptable salts thereof (such as sodium sulfamethaxazole and sodium sulfisomidine)), acrinol, quaternary ammonium compounds (such as benzalkonium, benzethonium cetylpyridinium, and pharmacologically acceptable salts thereof (such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, and cetylpyridinium bromide), alkylpolyaminoethylglycine, newquinolone agents (such as lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin and ciprofloxacin chloride), berberine and salts
  • saccharide examples include monosaccharides (such as glucose), disaccharides (such as trehalose, lactose, and fructose), oligosaccharides (such as lactulose, raffinose, and pullulan), and sugar alcohols (such as mannitol, xylitol, and sorbitol).
  • monosaccharides such as glucose
  • disaccharides such as trehalose, lactose, and fructose
  • oligosaccharides such as lactulose, raffinose, and pullulan
  • sugar alcohols such as mannitol, xylitol, and sorbitol.
  • polysaccharide or derivative thereof examples include gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac resin, quince seed, Dammar gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid (alginic acid), chitin and derivatives thereof, chitosan and derivatives thereof, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, and salts thereof (such as sodium alginate, sodium hyaluronate, and sodium chondroitin sulfate).
  • gum arabic karaya gum
  • xanthan gum carob gum
  • guar gum
  • Examples of the cellulose or derivative thereof or salt thereof include cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, and nitro cellulose.
  • water-soluble polymer other than the above-described components examples include polyvinyl alcohols (completely or partially saponified compounds) and polyvinylpyrrolidone.
  • Examples of the local anesthetic component include lidocaine, oxybuprocaine, dibucaine, procaine, ethyl aminobenzoate, meprylcaine, mepivacaine, bupivacaine, cocaine, and salts thereof (such as lidocaine hydrochloride and oxybuprocaine hydrochloride).
  • steroid component examples include hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, paramethasone, betamethasone, and salts thereof.
  • Examples of the therapeutic component for glaucoma include timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, unoprostone, dipivefrin hydrochloride, epinephrine, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide, methazolamide, and salts thereof.
  • Examples of the therapeutic component for cataract include pirenoxine, glutathione, salivary glands hormone, tiopronin, dihydroazapentacene disulfonate, and salts thereof (such as sodium 5,12-dihydroazapentacene disulfonate).
  • various components or additives are appropriately selected in a conventional manner according to the intended use or form thereof within a range that does not impair the effect of the invention, and one or more components or additives may be added in combination.
  • various additives which are generally used for the preparation of a pharmaceutical preparation for ophthalmic topical administration, a semi-solid preparation, a liquid preparation, etc,, such as a carrier (such as water, an aqueous solvent, or an aqueous or oily base), a thickening agent, a surfactant, a preservative, an microbicidal agent or an antimicrobial agent, a pH adjusting agent, an isotonizing agent, a flavor or a refreshing agent, a chelating agent, and a buffer can be exemplified.
  • a carrier such as water, an aqueous solvent, or an aqueous or oily base
  • a thickening agent such as water, an aqueous solvent, or an aqueous or oily base
  • a surfactant such as water, an aqueous solvent, or an aqueous or oily base
  • a surfactant such as water, an aqueous solvent, or an aqueous or oily base
  • thickening agent examples include polysaccharides and derivatives thereof (such as gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac resin, quince seed, Dammar gum, tragacanth gum, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin.
  • polysaccharides and derivatives thereof such as gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac resin, quince seed, Dammar gum, tragacanth gum, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin.
  • surfactant examples include non-ionic surfactants such as polyoxyethylene (POE)-polyoxypropylene (POP) block copolymers, (such as poloxamer 407, poloxamer 235, and poloxamer 188), polyoxyethylene-polyoxypropylene block copolymer adducts of ethylene diamine (such as poloxamine), POE sorbitan fatty acid esters such as POE (20) sorbitan monolaurates (polysorbate 20), POE (20) sorbitan monooleates (polysorbate 80), and polysorbate 60, POE hydrogenated castor oils such as POE (60) hydrogenated castor oil, POE alkyl ethers such as POE (9) lauryl ether, POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether, POE alkylphenyl ethers such as POE (10) nonylphenyl ether, and POE alkylpheny
  • Examples of the preservative, microbicidal agent or antimicrobial agent include sorbic acid and salts thereof (such as sorbic acid, potassium sorbate, sodium sorbate, and triclocarban sorbate), p-hydroxybenzoate esters (such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and butyl p-hydroxybenzoate), acrinol, methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine and salts thereof, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, silver-loaded zirconium phosphate, mercurochrome,
  • Examples of the pH adjusting agent include inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, and boric acid), organic acids (such as lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, and aminoethylsulfonic acid), gluconolactone, ammonium acetate, inorganic bases (such as sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, and magnesium hydroxide), organic bases (such as monoethanolamine, triethanolamine diisopropanolamine, triisopropanolamine, and lysine), borax, and pharmacologically acceptable salts thereof.
  • inorganic acids such as hydrochloric acid, sulfuric acid
  • the isotonizing agent examples include inorganic salts (such as sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, &sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulphate, and sodium acetate), polyhydric alcohols (such as glycerin, propylene glycol, ethylene glycol, and 1,3-butylene glycol), and saccharides (such as glucose, mannitol, and sorbitol).
  • inorganic salts such as sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, &sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulphate, and sodium acetate
  • polyhydric alcohols such as glycerin, propylene glycol, ethylene glycol, and 1,3-butylene glycol
  • flavor or refreshing agent examples include terpenes (such as menthol, camphor, borneol, geraniol, cineole, anethole, limonene, and eugenol, which may be in any form of d-,l- and dl-forms), essential oils (such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, mentha oil cinnamon oil, and rose oil).
  • terpenes such as menthol, camphor, borneol, geraniol, cineole, anethole, limonene, and eugenol, which may be in any form of d-,l- and dl-forms
  • essential oils such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, mentha oil cinnamon oil, and rose oil.
  • chelating agent examples include edetic acid, citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, and pharmacologically acceptable salts thereof.
  • the buffer examples include borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers, epsilon-aminocaproic acid, and aspartate salts.
  • Specific examples thereof include boric acid and salts thereof (such as sodium borate, potassium tetraborate, and potassium metaborate), phosphoric acid and salts thereof (such as sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate), carbonic acid and salts thereof (such as sodium hydrogen carbonate and sodium carbonate), and citric acid and salts thereof (such as sodium citrate and potassium citrate).
  • the production can be appropriately performed by a known method, and for example, in the case where the agent is formulated into an eye drop, an eyewash, a solution for use in wearing contact lenses, or an agent for contact lenses, glucosylglycerol and arbitrary additive components are mixed in an appropriate diluent such as distilled water or purified water, the osmotic pressure and pH of the resulting mixture is adjusted to the above-described values, and then, the mixture is subjected to an autoclaving treatment or a filtration sterilization treatment in an aseptic environment.
  • an appropriate diluent such as distilled water or purified water
  • the resulting mixture is aseptically filled into a container having been washed and sterilized, whereby the production can be achieved.
  • the agent is formulated into an ophthalmic ointment
  • a conventionally used ophthalmic ointment base ⁇ -glucosylglycerol and arbitrary additive components are mixed, and the preparation can be aseptically performed according to a common procedure.
  • the protective agent for the keratoconjunctiva and the suppressive agent for a keratoconjunctival disorder of the invention can be applied for the purpose of preventing a keratoconjunctival disorder caused by a factor, for example, an endogenous disease of Sjogren's syndrome, Stevens-Johnson syndrome, or dry eye syndrome (dry eye), an exogenous disease due to postsurgery, a drug, an injury, or the wearing of a contact lens, or the like, alleviating such a keratoconjunctival disorder, mitigating or halting the progression of such a keratoconjunctival disorder, accelerating the healing of such a keratoconjunctival disorder, etc.
  • a factor for example, an endogenous disease of Sjogren's syndrome, Stevens-Johnson syndrome, or dry eye syndrome (dry eye), an exogenous disease due to postsurgery, a drug, an injury, or the wearing of a contact lens, or the like,
  • a method of applying the protective agent for the keratoconjunctiva or the suppressive agent for a keratoconjunctival disorder of the invention is not particularly limited, and can he applied on a daily basis, or the suppressive agent for a keratoconjunctival disorder may be applied with arbitrary frequency after a keratoconjunctival disorder occurs. Further, the application amount may be appropriately adjusted according to the symptoms, etc., and the agent is generally instilled about 1 to 6 times a day at a dose of about 1 to 3 drops per instillation.
  • glucosylglycerol is a composition (trade name: COSARTE-2G, manufactured. by Toyo Sugar Refining Co., Ltd.) containing 65.2% of glyceryl glucoside ( ⁇ -form: 65%, ⁇ -form: 35%), 8.1% of glyceryl maltoside, 0.7% of glyceryl maltotrioside, 6.0% of glycerin, and 20.0% of water.
  • Example 1 Glucosylglycerol (*1) 3 10 — Physiological saline 97 90 — Aqueous solution of 0.1% sodium — — 100 hyaluronate (*2) (*1): COSARTE-2G (trade name, manufactured by Toyo Sugar Refining Co., Ltd.) (*2): 0.1% Hyalein ophthalmic solution (trade name, manufactured by Santen Pharmaceutical Co., Ltd.)
  • FIG. 1 shows an absorbance at a wavelength of 660 nm, and a higher value indicates a higher severity of the keratoconjunctival disorder.
  • the ophthalmic solutions of Examples 1 to 2 can alleviate the keratoconjunctival disorder, and further, as compared with the ophthalmic solution of Example 1, the ophthalmic solution of Example 2 has a higher effect of alleviating a keratoconjunctival disorder, and therefore, it was found that as the concentration of glucosylglycerol is increased, a higher effect can be obtained.
  • the protective agent for the keratoconjunctiva a and the suppressive agent for a keratoconjunctival disorder of the invention have at excellent effect of alleviating a keratoconjunctival disorder, and therefore are useful as a protective agent for the keratoconjunctiva and a suppressive agent for a keratoconjunctival disorder for suppressing a keratoconjunctival disorder caused by drying or the like and protecting the keratoconjunctiva.

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AU2012341425B2 (en) 2017-03-02
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ES2751248T3 (es) 2020-03-30
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