WO2010150812A1 - 眼科用組成物及び白濁・沈殿抑制方法 - Google Patents
眼科用組成物及び白濁・沈殿抑制方法 Download PDFInfo
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- WO2010150812A1 WO2010150812A1 PCT/JP2010/060633 JP2010060633W WO2010150812A1 WO 2010150812 A1 WO2010150812 A1 WO 2010150812A1 JP 2010060633 W JP2010060633 W JP 2010060633W WO 2010150812 A1 WO2010150812 A1 WO 2010150812A1
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
- A61K47/02—Inorganic compounds
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- 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
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- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- 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
Definitions
- the present invention relates to an ophthalmic composition containing vitamin A, and more specifically, an ophthalmic composition having a stable appearance, which does not cause white turbidity / precipitation due to storage stability and freezing and thawing of vitamin A, and this composition
- the present invention relates to a method for suppressing cloudiness / precipitation caused by freezing and thawing of an object.
- the present invention relates to a dry eye therapeutic agent having an effect of treating corneal / conjunctival damage and containing vitamin A.
- Vitamin A is attracting attention as an effective component for the prevention and treatment of cornea / conjunctiva and keratoses of mucosa.
- the effect of vitamin A on dry eye symptoms such as corneal / conjunctival dryness has been reported.
- vitamin A which is a fat-soluble vitamin, is very sensitive to air, light, heat, acid, metal ions, and the like, and particularly unstable in an aqueous solution, so it is suitable for ophthalmic compositions such as eye drops. It was difficult to mix stably.
- Patent Documents 1 and 2 JP-A-5-331056, Japanese Patent Laid-Open No. 6-40907
- a method of stabilizing with vitamin E which is a hydrophobic antioxidant see Patent Document 3: Japanese Patent Laid-Open No. 6-247853
- stabilization from the container / packaging surface Techniques see Patent Document 4: Japanese Patent Laid-Open No. 2003-113078
- stabilization techniques manufactured by high energy emulsification see Japanese Patent Laid-Open No. 2002-332225
- dry eye refers to a state in which the keratoconjunctiva on the eyeball surface is damaged due to qualitative or quantitative abnormality of tears.
- Tear fluid consists of three layers: an oil layer, an aqueous layer, and a mucin layer. When the qualitative and quantitative balance of this three-layer structure is destroyed, the tear fluid becomes unstable, the cornea is damaged, and dry eye Is triggered. In dry eye treatment, it is important to restore the three-layer structure of the tear oil layer, water layer, and mucin layer, and to treat corneal disorders.
- Vitamin A is known as an essential substance for proliferation and differentiation of epithelial cells, and promotes mucin production (for example, Non-Patent Document 1: Kubo, Y., J Jpn Ophthalmol Sci. 103, 580-583. 1999.), and the action of healing corneal wounds (for example, see Non-Patent Document 2: Ubels, JL, Curr Eye Res. 4, 1049-1057.1985.).
- Vitamin A is expected to be a useful drug for dry eye treatment that is effective in “recovery of mucous layer of tear fluid” and “treatment of keratoconjunctival disorder”. From the above, a dry eye therapeutic agent containing vitamin A having a high dry eye therapeutic effect has been desired.
- the present inventors have studied to obtain a more stable stabilization of vitamin A, in particular, a stable ophthalmic preparation even in a vitamin A high concentration range where it is difficult to ensure stability.
- Oxyethylene polyoxypropylene glycol was selected.
- preparations formulated with polyoxyethylene polyoxypropylene glycol when stored at low temperatures, especially when frozen, cause white turbidity and white precipitation upon thawing, and the appearance deteriorates further due to repeated freezing and thawing. It became clear that there was.
- eye drops can be stored at room temperature or in a refrigerator. In more extreme cases, the eye drops may be frozen, such as being left in a refrigerator at a low temperature or being left in a cold area in winter.
- the present invention has been made in view of the above circumstances, and is an ophthalmic composition containing vitamin A and polyoxyethylene polyoxypropylene glycol, which is excellent in storage stability of vitamin A, and at the time of freezing and thawing.
- the purpose of the present invention is to provide an ophthalmic composition having no appearance of white turbidity / precipitation and having a stable appearance, and a method for suppressing white turbidity / precipitation by freezing and thawing the composition.
- Another object of the present invention is to provide a dry eye therapeutic agent in which the effect of vitamin A on the treatment of corneal / conjunctival damage is improved.
- the present inventors have added (C) to (G) components to an ophthalmic composition containing (A) vitamin A and (B) polyoxyethylene polyoxypropylene glycol. : (C) trometamol, (D) polyhydric alcohol, (E) saccharide, (F) phosphoric acid and its salt, and (G) one or more components selected from monovalent neutral salts, preferably It has been found that by combining two or more types in combination, the storage stability of vitamin A is excellent, and clouding and precipitation in freezing and thawing can be suppressed, and the present invention has been made.
- polyoxyethylene polyoxypropylene glycol has a narrow L1 micelle region of the aqueous solution with respect to its concentration, and it becomes a viscous gel state with slight concentration Prone.
- nonionic surfactants such as polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester have the L1 micelle region spreading to a high concentration side and are not easily affected by the concentration effect. That is, white turbidity / precipitation during freezing and thawing is a problem specific to polyoxyethylene polyoxypropylene glycol.
- the present invention provides the following ophthalmic composition and a method for suppressing cloudiness and precipitation by freezing and thawing the composition.
- A Vitamin A
- B Polyoxyethylene polyoxypropylene glycol
- C Trometamol
- D Polyhydric alcohol
- E Sugar
- F Phosphoric acid and its salt
- G 1
- An ophthalmic composition comprising one or more selected from valent neutral salts.
- the ophthalmic composition according to [1] comprising two or more selected from the components (C) to (G). [3].
- the ophthalmic composition according to any one of [1] to [7] which contains no preservative. [10].
- an ophthalmic composition having a stable appearance, in which vitamin A is stably blended and does not cause white turbidity / precipitation even when frozen and thawed, and a method for suppressing white turbidity / precipitation by freezing and thawing the composition.
- the ophthalmic composition of the present invention comprises (A) vitamin A, (B) polyoxyethylene polyoxypropylene glycol, (C) trometamol, (D) polyhydric alcohol, (E) saccharide, (F) phosphoric acid. And a salt thereof, and (G) one or more selected from monovalent neutral salts.
- vitamin A examples include, in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, and the like. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitate is usually commercially available in the range of 1 million to 1.8 million international units (hereinafter abbreviated as IU). Specifically, retinol palmitate ester (manufactured by DSM Nutrition Japan Co., Ltd.) 1.7 million I.U./g).
- IU international units
- the component (A) can be used alone or in combination of two or more, and the blending amount is preferably 50,000 to 500,000 units / 100 mL based on the total amount of the ophthalmic composition, 000 to 300,000 units / 100 mL is more preferable, and 100,000 to 200,000 units / 100 mL is more preferable.
- W (mass) / V (volume)% (g / 100 mL) it is preferably 0.03 to 0.3 W / V%, depending on the unit of vitamin A to be blended, preferably 0.03 to 0.18 W. / V% is more preferable, and 0.06 to 0.12 W / V% is more preferable.
- Vitamin A has the effect of treating corneal / conjunctival damage, dry eye, and fatigue / hazy eyes, but if it is less than 50,000 units / 100 mL, the effect of treating corneal / conjunctival damage is insufficient. If the amount exceeds 500,000 units / 100 mL, there may be a problem of side effects.
- the polyoxyethylene polyoxypropylene glycol is not particularly limited, and those described in the pharmaceutical additive standards (medicine regulations) can be used.
- the average degree of polymerization of ethylene oxide is preferably 4 to 200, more preferably 20 to 200, and the average degree of polymerization of propylene oxide is preferably 5 to 100, more preferably 20 to 70, and may be a block copolymer or a random polymer.
- Lutrol F127 manufactured by BASF
- Unilube 70DP-950B manufactured by NOF Corporation
- Polyoxyethylene such as glycol (Pluronic F127, also known as Poloxamer 407)
- Pronon # 188P manufactured by NOF Corporation
- Polyoxypropylene (30) glycol (Pluronic F-68, also known as Poloxamer 188), Polyoxyethylene (42) Polyoxypropylene (67) glycol (Pluronic P123, also known as Poloxamer 403)
- Pronon # 235P Polyoxyethylene
- a component can be used individually by 1 type or in combination of 2 or more types.
- the blending amount in the ophthalmic composition is preferably 5 W / V% or less, more preferably 0.4 to 5 W / V%, from the viewpoint of storage stability of vitamin A, corneal / conjunctival damage treatment, and dry eye treatment effect. . If it is less than 0.4 W / V%, solubilization of vitamin A may be difficult. Further, the cloudiness / precipitation at the time of freezing and thawing is less likely to occur as the blending amount of the component (B) is smaller. Therefore, the content of the component (B) is preferably 5 W / V% or less.
- the blending amount of trometamol is, for example, preferably 0.001 to 5 W / V%, more preferably 0.01 to 3 W / V%, and further preferably 0.1 to 2 W / V% in the ophthalmic composition. preferable. By adding 0.001 W / V% or more, white turbidity / precipitation suppression can be further obtained.
- the greater the amount of trometamol the higher the white turbidity / precipitation suppressing effect. However, if it exceeds 5 W / V%, the osmotic pressure may increase too much, and a feeling of irritation may be felt.
- polyhydric alcohol examples include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. Among these, glycerin and propylene glycol are preferable, and glycerin is more preferable.
- the blending amount of the polyhydric alcohol is, for example, preferably 0.001 to 5 W / V% in the ophthalmic composition, more preferably 0.005 to 3 W / V%, and still more preferably 0.01 to 2 W / V%. If it is less than 0.001 W / V%, the antifreezing effect is weak and the cloudiness / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.
- saccharides examples include glucose, cyclodextrin, xylitol, sorbitol, mannitol, trehalose and the like. These may be any of d-form, l-form or dl-form. Among these, xylitol, sorbitol, mannitol and trehalose are preferable, sorbitol, mannitol and trehalose are more preferable, and mannitol and trehalose are further preferable.
- the blending amount of the saccharide is, for example, preferably 0.001 to 5 W / V%, more preferably 0.005 to 3 W / V%, still more preferably 0.01 to 2 W / V% in the ophthalmic composition.
- 05 to 1 W / V% is particularly preferable. If it is less than 0.001 W / V%, the antifreezing effect is weak and the cloudiness / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.
- Phosphoric acid and salts thereof Phosphoric acid, monosodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, dihydrogen phosphate
- Examples include potassium and dipotassium hydrogen phosphate.
- monosodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, and disodium hydrogen phosphate are preferable, and sodium dihydrogen phosphate, sodium hydrogen phosphate, and disodium hydrogen phosphate are more preferable. More preferred is disodium hydrogen phosphate.
- the blending amount of phosphoric acid and its salt is, for example, preferably 0.001 to 5 W / V% in the ophthalmic composition, more preferably 0.005 to 3 W / V%, and further preferably 0.01 to 2 W / V%. 0.05 to 1 W / V% is particularly preferable. If it is less than 0.001 W / V%, the antifreezing effect is weak and the cloudiness / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.
- the monovalent neutral salt examples include sodium chloride and potassium chloride. Of these, sodium chloride is preferred.
- the blending amount of the monovalent neutral salt is preferably 0.001 to 5 W / V% in the ophthalmic composition, more preferably 0.01 to 3 W / V%, still more preferably 0.1 to 2 W / V%, 0.1 to 1 W / V% is particularly preferable. If it is less than 0.001 W / V%, the antifreezing effect is weak, and white turbidity / precipitation may not be suppressed. If it exceeds 5 W / V%, the osmotic pressure may increase excessively.
- (C) trometamol is preferable.
- These cloudiness / precipitation-inhibiting components can be used alone or in combination of two or more, for example, two or more of the same components can be combined, such as using two or more of component (D). Good.
- component (D) Good When two or more kinds are combined, it is more preferable because a synergistic effect is obtained in the freezing suppression effect of bulk water and ethylene oxide chain hydrated water.
- it is particularly preferable to combine (C) trometamol with other components and it is preferable to use two or more of glycerin, trometamol, and trehalose, particularly glycerin and trometamol.
- the ethylene oxide chain hydrated water is preferable from the viewpoint of antifreezing effect.
- trometamol not only prevents freezing of bulk water, but also binds to the ethylene oxide chain of micelles, so that glycerin penetrates into the ethylene oxide chain, thereby disturbing the orientation of the ethylene oxide chain and preventing freezing of the ethylene oxide chain.
- the ophthalmic composition of the present invention preferably contains trometamol from the viewpoint of improving the storage stability of vitamin A. Although this mechanism is not clear, for example, it can be considered as follows.
- Polyoxyethylene polyoxypropylene glycol is a nonionic surfactant having a polyoxyethylene (EO) chain and a polyoxypropylene (PO) chain.
- trometamol Encapsulates vitamin A with the EO chain on the outside and the PO chain on the inside to form micelles.
- the —NH 2 group present in trometamol is directly bonded to the ether bond of the EO chain, thereby strengthening the micelle structure.
- trometamol binds to the EO chain outside the micelle, thereby strengthening the micelle structure and reducing the degree of freedom. As a result, the molecular mobility of the PO chain inside the micelle is reduced. From the above, it is considered that trometamol contributes to the stabilization of micelles formed from vitamin A and polyoxyethylene polyoxypropylene glycol, and consequently contributes to the storage stability of vitamin A.
- the total blending amount of these components (C) to (G) is preferably 0.001 to 5 W / V% in the ophthalmic composition, but particularly when used in combination of two kinds, 0.01 to 5% in the ophthalmic composition.
- 5 W / V% is more preferable, further preferably 0.1 to 4 W / V%, particularly preferably 0.5 to 3 W / V%, and particularly preferably 1 to 3 W / V%.
- 0.01 to 5 W / V% is more preferable, and 0.1 to 4 W / V% is more preferable.
- the total of the components (C) to (G) is preferably 0.02 to 200 parts by mass per 1 part by mass of the component (A). Further, the total of the components (C) to (G) is preferably 0.001 to 20 parts by mass per 1 part by mass of the components (A) + (B).
- various components to be blended in the ophthalmic composition can be blended within a range that does not impair the effects of the present invention.
- these components include surfactants other than the component (B), buffers, thickeners, pH adjusters, preservatives, isotonic agents, stabilizers, cooling agents, drugs, water, and the like. . These can be used individually by 1 type or in combination of 2 or more types, respectively, and can mix
- Surfactant other than component (B) Surfactants other than component (B) include, for example, nonionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and alkyldiaminoethyl. Examples include glycine-type amphoteric surfactants such as glycine. The blending amount thereof is preferably 0.0001 to 10 W / V%, more preferably 0.005 to 5 W / V% in the ophthalmic composition. However, from the viewpoint of the effect of treating corneal / conjunctival damage and dry eye, the amount of these surfactants should be small, preferably 0.5 W / V% or less.
- Preservatives can be blended within a range that does not impair the effects of the present invention.
- the ophthalmic composition of the present invention should not contain any preservatives from the viewpoint of eye irritation. Is preferred.
- the preservative include benzalkonium chloride, benzethonium chloride, sorbic acid or a salt thereof, paraoxybenzoic acid ester (methylparaben, ethylparaben, propylparaben, etc.), chlorhexidine gluconate, thimerosal, phenylethyl alcohol, alkyldiaminoethyl hydrochloride
- Examples include glycine, polyhexanide hydrochloride, and polydronium chloride.
- the blending amount of the preservative with respect to the total amount of the ophthalmic composition is, for example, 0.00001 to 5 W / V%, preferably 0.0001 to 3 W / V%, more preferably 0.001 to 2 W / V%. .
- cationic surfactants such as benzalkonium chloride and benzethonium chloride
- hydrophobic preservatives such as parabens (methylparaben, ethylparaben, propylparaben, etc.) and chlorobutanol
- these compounding amounts are preferably 0.004 W / V% or less in the composition, more preferably 0.003 W / V% or less, and it is more preferable that these are not contained and not included.
- the preservative power may be one or more, preferably two or more, in combination of sodium edetate, boric acid and trometamol. Moreover, when it is set as a unit dose container and a container with a filter, it can be set as preservative-free.
- Buffering agent examples include boric acid or a salt thereof (such as borax), citric acid or a salt thereof (such as sodium citrate), tartaric acid or a salt thereof (such as sodium tartrate), gluconic acid or a salt thereof. (Sodium gluconate, etc.), acetic acid or a salt thereof (sodium acetate, etc.), various amino acids and the like (epsilon-aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate, etc.).
- the trometamol of (C) component can be used also as a buffering agent, and it is preferable from the point of mildness and the antiseptic effect of a composition. Furthermore, when boric acid and borax are used in combination, a particularly high antiseptic effect is obtained. In the present invention, the stability of vitamin A is further improved when boric acid, trometamol, citric acid or a salt thereof is added.
- the blending amount of the buffer is preferably 0.001 to 10 W / V%, more preferably 0.01 to 5 W / V% in the ophthalmic composition.
- (Iv) Thickener examples include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like. By blending these, the retention is increased, and the corneal / conjunctival damage healing effect is further improved.
- the blending amount of the thickener with respect to the total amount of the ophthalmic composition is, for example, 0.001 to 10 W / V%, preferably 0.001 to 5 W / V%, and more preferably 0.01 to 3 W / V%.
- (V) pH adjuster It is preferable to use an inorganic acid or an inorganic alkali agent as the pH adjuster.
- (diluted) hydrochloric acid is mentioned as an inorganic acid.
- the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. Among these, hydrochloric acid and sodium hydroxide are preferable.
- the pH (20 ° C.) of the ophthalmic composition of the present invention is preferably 4.0 to 9.0, more preferably 5.0 to 8.0, and still more preferably 6.0 to 8.0. . In the present invention, pH is measured at 20 ° C. using a pH osmometer (HOSM-1, manufactured by Toa DKK Corporation).
- the blending amount of the pH adjuster with respect to the total amount of the ophthalmic composition is, for example, 0.00001 to 10 W / V%, preferably 0.0001 to 5 W / V%, more preferably 0.001 to 3 W / V%. is there.
- the isotonic agent examples include calcium chloride and magnesium chloride.
- the blending amount of the isotonizing agent with respect to the total amount of the ophthalmic composition is, for example, 0.001 to 5 W / V%, preferably 0.01 to 3 W / V%, more preferably 0.1 to 2 W / V%. It is.
- (Vii) Stabilizer examples include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like.
- the blending amount of the stabilizer with respect to the total amount of the ophthalmic composition is, for example, 0.001 to 5 W / V%, preferably 0.01 to 3 W / V%, more preferably 0.1 to 2 W / V%. is there.
- Cooling agent examples include menthol, camphor, borneol, geraniol, cineol, linalool, and the like.
- the blending amount of the refreshing agent is preferably 0.0001 to 5 W / V%, more preferably 0.001 to 2 W / V%, and more preferably 0.005 to 1 W / V% as a total amount of the compound in the ophthalmic composition. Is more preferable, and 0.007 to 0.8 W / V% is particularly preferable.
- drugs active pharmaceutical ingredient
- drugs pharmaceutical active ingredients
- decongestants eg, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate
- anti-inflammatory / astringents For example, neostigmine methyl sulfate, ⁇ -aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulene sul
- decongestants e
- the blending amount of these components in the ophthalmic composition is appropriately selected according to the type of preparation, the type of drug, etc., and the blending amounts of various components are known in the art. For example, it can be selected from a range of 0.00001 or more, particularly 0.0001 to 30 W / V%, preferably about 0.001 to 10 W / V% with respect to the whole preparation. More specifically, the compounding quantity with respect to the ophthalmic composition whole quantity of each component is as follows, for example.
- a decongestant for example, it is 0.0001 to 0.5 W / V%, preferably 0.0005 to 0.3 W / V%, and more preferably 0.001 to 0.1 W / V%.
- a flame retardant / astringent it is, for example, 0.0001 to 10 W / V%, preferably 0.0001 to 5 W / V%.
- an antihistamine for example, it is 0.0001 to 10 W / V%, preferably 0.001 to 5 W / V%.
- water-soluble vitamins for example, 0.0001 to 1 W / V%, preferably 0.0001 to 0.5 W / V%.
- an amino acid for example, it is 0.0001 to 10 W / V%, preferably 0.001 to 3 W / V%.
- sulfa drugs and fungicides for example, it is 0.00001 to 10 W / V%, preferably 0.0001 to 10 W / V%.
- a local anesthetic it is, for example, 0.001 to 1 W / V%, preferably 0.01 to 1 W / V%.
- the ophthalmic composition of the present invention may be used as it is, or may be prepared as a suspension or gel.
- eye drops for example, general eye drops, contact lens eye drops, etc.
- eye wash generally eye wash, eye wash used after removing contact lens
- contact etc.
- a lens mounting liquid, a contact lens removing liquid, and the like are listed.
- the contact lens user tend to damage the cornea and conjunctiva because of dryness of the eyes due to the use of contact lenses, and often develop dry eye symptoms.
- vitamin A compounded in the ophthalmic composition of the present invention has a dry eye improving effect
- the contact lens user uses the ophthalmic composition of the present invention to produce dry eye.
- the ophthalmic composition of the present invention has an excellent corneal / conjunctival damage treatment effect, it can be used as a dry eye treatment agent.
- the effect of the therapeutic agent for dry eye of the present invention can be further exerted by instilling 30 to 60 ⁇ L at a time, 3 to 6 times a day.
- the ophthalmic composition of the present invention is liquid and its viscosity is preferably 1 to 50 mPa ⁇ s, more preferably 1 to 30 mPa ⁇ s, still more preferably 1 to 20 mPa ⁇ s in the case of eye drops. 5 mPa ⁇ s is more preferable.
- the viscosity is measured at 20 ° C. using an E-type viscometer (VISCONIC ELD-R, Tokyo Keiki Co., Ltd.).
- the preparation method of the ophthalmic composition of the present invention is not particularly limited.
- vitamin A is solubilized in purified water with polyoxyethylene polyoxypropylene glycol, and then each component is added. It can be obtained by adjusting the pH. Thereafter, it can be aseptically filled into a suitable container such as a container made of polyethylene terephthalate.
- the present invention relates to an ophthalmic composition containing (A) vitamin A, (B) polyoxyethylene polyoxypropylene glycol, (C) trometamol (D) polyhydric alcohol, (E) saccharide, (F) phosphoric acid. And a salt thereof, and (G) one or more selected from monovalent neutral salts, a method for inhibiting cloudiness and precipitation by freezing and thawing is provided.
- this white turbidity / precipitation suppression method the components and blending amounts are the same as described above.
- retinol palmitate remaining rate (%) > The content of retinol palmitate in the ophthalmic composition was measured immediately after production and after storage for 6 months at 40 ° C. and 75% RH (severe test). The measurement was performed using a high performance liquid chromatograph method. From the obtained retinol palmitate content, the retinol palmitate residual rate (%) was calculated based on the following formula.
- Retinol palmitic acid residual ratio (%) ⁇ retinol palmitic acid ester content after storage / retinol palmitic acid ester content immediately after production ⁇ ⁇ 100 ⁇ Evaluation> ⁇ : 70% or more ⁇ : 65% or more and less than 70% ⁇ : 60% or more and less than 65% ⁇ : less than 60%
- Vitamin A, polyoxyethylene polyoxypropylene glycol, and antioxidant were preliminarily dissolved at 85 ° C and the preliminarily dissolved product was heated to 85 ° C. Solubilized in sterilized purified water, and after cooling, a water-soluble blending component such as trometamol was added to adjust pH (20 ° C.) to obtain an ophthalmic composition. 15 mL of the obtained ophthalmic composition was filled in an eye drop container with a 15 mL filter (manufactured by polyethylene terephthalate). The ophthalmic compositions of Test Examples 1 to 12 had sufficient antiseptic power. About the obtained ophthalmic composition, the said corneal / conjunctival damage treatment effect was evaluated. The results are also shown in the table.
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Abstract
Description
本発明は、上記事情に鑑みなされたものであって、ビタミンAとポリオキシエチレンポリオキシプロピレングリコールとを含有する眼科用組成物であって、ビタミンAの保存安定性に優れると共に、凍結融解時においても、白濁・沈殿が生じない、外観が安定した眼科用組成物及びこの組成物の凍結融解による白濁・沈殿抑制方法を提供することを目的とする。
また、本発明は、ビタミンAの角膜・結膜損傷治療効果が向上したドライアイ治療剤を提供することを目的とする。
これに対して、上記白濁・沈殿抑制成分を加えることにより、バルク水の凍結を防止したり、ミセルのエチレンオキシド鎖に浸透することにより、エチレンオキシド鎖の配向を乱し、エチレンオキシド鎖の凍結を防止して、ミセルの会合状態を安定化することにより凍結融解時の白濁・沈殿を防止することができると考えることもできる。
[1].(A)ビタミンAと、(B)ポリオキシエチレンポリオキシプロピレングリコールと、(C)トロメタモール、(D)多価アルコール、(E)糖類、(F)リン酸及びその塩、並びに(G)1価中性塩から選ばれる1種又は2種以上とを含有することを特徴とする眼科用組成物。
[2].(C)~(G)成分から選ばれる2種以上を含有する[1]記載の眼科用組成物。
[3].(D)成分がグリセリン、(E)成分がキシリトール、ソルビトール、マンニトール又はトレハロース、(F)成分がリン酸二水素ナトリウム、(G)成分が塩化ナトリウムである[1]又は[2]記載の眼科用組成物。
[4].(C)~(G)成分の合計配合量が、0.001~5W/V%である[1]~[3]のいずれかに記載の眼科用組成物。
[5].(B)成分の配合量が、5W/V%以下である[1]~[4]のいずれかに記載の眼科用組成物。
[6].(A)成分が、レチノールパルミチン酸エステル、レチノール酢酸エステル及びレチノイン酸からなる群から選ばれる1種又は2種以上である[1]~[5]のいずれかに記載の眼科用組成物。
[7].(A)成分の配合量が、50,000~500,000単位/100mLである[1]~[6]のいずれかに記載の眼科用組成物。
[8].カチオン性界面活性剤及び疎水性防腐剤の配合量が0.004W/V%以下であることを特徴とする[1]~[7]のいずれかに記載の眼科用組成物。
[9].防腐剤無配合である[1]~[7]のいずれかに記載の眼科用組成物。
[10].コンタクトレンズ用である[1]~[9]のいずれかに記載の眼科用組成物。
[11].ドライアイ治療剤である[7]~[10]のいずれかに記載の眼科用組成物。
[12].(A)ビタミンA、(B)ポリオキシエチレンポリオキシプロピレングリコールを含有する眼科用組成物に、(C)トロメタモール、(D)多価アルコール、(E)糖類、(F)リン酸及びその塩、並びに(G)1価中性塩から選ばれる1種又は2種以上を配合することを特徴とする凍結融解による白濁・沈殿抑制方法。
ビタミンAとしては、ビタミンAそれ自体の他に、ビタミンA油等のビタミンA含有混合物、ビタミンA脂肪酸エステル等のビタミンA誘導体等が挙げられる。具体的には、レチノールパルミチン酸エステル、レチノール酢酸エステル、レチノール、レチノイン酸、レチノイド等が挙げられる。中でも、レチノールパルミチン酸エステル、レチノール酢酸エステル、レチノイン酸が好ましい。レチノールパルミチン酸エステルは、通常100万~180万国際単位(以下、I.U.と略記する)のものが市販されており、具体的には、DSMニュートリションジャパン(株)製レチノールパルミチン酸エステル(170万I.U./g)等が挙げられる。
ポリオキシエチレンポリオキシプロピレングリコールは特に限定されるものではなく、医薬品添加物規格(薬添規)に記載されたものを用いることができる。エチレンオキシドの平均重合度は4~200が好ましく、20~200がより好ましく、プロピレンオキシドの平均重合度は5~100が好ましく、20~70がより好ましく、ブロック共重合体でもランダム重合体でもよい。
(C)トロメタモール
トロメタモールの配合量は、例えば、眼科用組成物中0.001~5W/V%が好ましく、0.01~3W/V%がより好ましく、0.1~2W/V%がさらに好ましい。0.001W/V%以上配合することで、白濁・沈殿抑制をより得ることができる。トロメタモールの量は多いほど白濁・沈殿抑制効果が高いが、5W/V%を超えると、浸透圧が上昇しすぎることにより、刺激感を感じる場合がある。
(D)多価アルコール
多価アルコールとしては、グリセリン、プロピレングリコール、ブチレングリコール、ポリエチレングリコール等が挙げられる。中でも、グリセリン、プロピレングリコールが好ましく、グリセリンがより好ましい。
糖類としては、グルコース、シクロデキストリン、キシリトール、ソルビトール、マンニトール、トレハロース等が挙げられる。これらは、d体、l体又はdl体のいずれでもよい。中でも、キシリトール、ソルビトール、マンニトール、トレハロースが好ましく、ソルビトール、マンニトール、トレハロースがより好ましく、マンニトール、トレハロースがさらに好ましい。
リン酸及びその塩としては、リン酸、リン酸一ナトリウム、リン酸二水素ナトリウム、リン酸水素ナトリウム、リン酸三ナトリウム、リン酸水素二ナトリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられる。中でも、リン酸一ナトリウム、リン酸二水素ナトリウム、リン酸水素ナトリウム、リン酸三ナトリウム、リン酸水素二ナトリウムが好ましく、リン酸二水素ナトリウム、リン酸水素ナトリウム、リン酸水素二ナトリウムがより好ましく、リン酸水素二ナトリウムがさらに好ましい。リン酸及びその塩の配合量は、例えば、眼科用組成物中0.001~5W/V%が好ましく、0.005~3W/V%がより好ましく、0.01~2W/V%がさらに好ましく、0.05~1W/V%が特に好ましい。0.001W/V%未満だと、凍結防止効果が弱く、白濁・沈殿抑制されない場合があり、5W/V%を超えると、浸透圧が上昇しすぎる場合がある。
1価中性塩としては、例えば、塩化ナトリウム、塩化カリウム等が挙げられる。中でも、塩化ナトリウムが好ましい。1価中性塩の配合量は、眼科用組成物中0.001~5W/V%が好ましく、0.01~3W/V%がより好ましく、0.1~2W/V%がさらに好ましく、0.1~1W/V%が特に好ましい。0.001W/V%未満だと、凍結防止効果が弱く、白濁・沈殿抑制されない場合があり、5W/V%を超えると、浸透圧上昇しすぎる場合がある。
さらに、(A)+(B)成分1質量部あたり、(C)~(G)成分の合計が0.001~20質量部が好ましい。
本発明の眼科用組成物には、前記成分の他、眼科用組成物に配合する各種成分を、本発明の効果を損なわない範囲で配合することができる。これらの成分としては、(B)成分以外の界面活性剤、緩衝剤、粘稠剤、pH調整剤、防腐剤、等張化剤、安定化剤、清涼化剤、薬物、水等が挙げられる。これらは、それぞれ1種単独で又は2種以上を適宜組み合わせて用いることができ、適量を配合することができる。
(B)成分以外の界面活性剤には、例えば、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル等の非イオン界面活性剤、アルキルジアミノエチルグリシンなどのグリシン型両性界面活性剤等が挙げられる。これらの配合量は、眼科用組成物中0.0001~10W/V%が好ましく、より好ましくは0.005~5W/V%である。但し、角膜・結膜損傷治療及びドライアイ治療効果の点から、これらの界面活性剤の量は少ないほうがよく、0.5W/V%以下が好ましい。
防腐剤は本発明の効果を損なわない範囲で配合することもできるが、本発明の眼科用組成物は、眼刺激の点から防腐剤を含有しない防腐剤無配合とすることが好ましい。防腐剤としては、例えば、塩化ベンザルコニウム、塩化ベンゼトニウム、ソルビン酸又はその塩、パラオキシ安息香酸エステル(メチルパラベン、エチルパラベン、プロピルパラベン等)、グルコン酸クロルヘキシジン、チメロサール、フェニルエチルアルコール、塩酸アルキルジアミノエチルグリシン、塩酸ポリヘキサニド、塩化ポリドロニウム等が挙げられる。防腐剤の眼科用組成物全量に対する配合量は、例えば、0.00001~5W/V%であり、好ましくは0.0001~3W/V%、さらに好ましくは0.001~2W/V%である。
緩衝剤としては、例えば、ホウ酸又はその塩(ホウ砂等)、クエン酸又はその塩(クエン酸ナトリウム等)、酒石酸又はその塩(酒石酸ナトリウム等)、グルコン酸又はその塩(グルコン酸ナトリウム等)、酢酸又はその塩(酢酸ナトリウム等)、各種アミノ酸等(イプシロン-アミノカプロン酸、アスパラギン酸カリウム、アミノエチルスルホン酸、グルタミン酸、グルタミン酸ナトリウム等)等が挙げられる。また、(C)成分のトロメタモールは緩衝剤としても使用でき、低刺激、かつ組成物の防腐効果の点から好ましい。さらに、ホウ酸、ホウ砂を併用すると、特に高い防腐効果が得られる。なお、本発明においては、ホウ酸、トロメタモール、クエン酸又はその塩を配合すると、さらにビタミンAの安定性が向上する。緩衝剤の配合量は、眼科用組成物中0.001~10W/V%が好ましく、より好ましくは0.01~5W/V%である。
粘稠剤としては、例えば、ポリビニルピロリドン、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリビニルアルコール、ヒアルロン酸ナトリウム、コンドロイチン硫酸ナトリウム、ポリアクリル酸、カルボキシビニルポリマー等が挙げられる。これらを配合することにより、滞留性が高まり角膜・結膜損傷治癒効果がより向上する。粘稠剤の眼科用組成物全量に対する配合量は、例えば、0.001~10W/V%、好ましくは0.001~5W/V%、さらに好ましくは0.01~3W/V%である。
pH調整剤としては、無機酸又は無機アルカリ剤を使用することが好ましい。例えば、無機酸としては(希)塩酸が挙げられる。無機アルカリ剤としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。これらの中でも、塩酸、水酸化ナトリウムが好ましい。本発明の眼科用組成物のpH(20℃)は、4.0~9.0が好ましく、より好ましくは5.0~8.0であり、さらに好ましくは6.0~8.0である。なお、本発明において、pHの測定は20℃でpH浸透圧計(HOSM-1,東亜ディーケーケー(株)製)を用いて行う。pH調整剤の眼科用組成物全量に対する配合量は、例えば、0.00001~10W/V%であり、好ましくは0.0001~5W/V%、さらに好ましくは0.001~3W/V%である。
等張化剤としては、例えば、塩化カルシウム、塩化マグネシウム等が挙げられる。等張化剤の眼科用組成物全量に対する配合量は、例えば、0.001~5W/V%であり、好ましくは0.01~3W/V%、さらに好ましくは0.1~2W/V%である。
安定化剤としては、例えば、エデト酸ナトリウム、シクロデキストリン、亜硫酸塩、ジブチルヒドロキシトルエン等が挙げられる。なお、本発明においては、安定化剤を配合すると、さらにビタミンAの安定性が向上する。安定化剤の眼科用組成物全量に対する配合量は、例えば、0.001~5W/V%であり、好ましくは0.01~3W/V%、さらに好ましくは0.1~2W/V%である。
清涼化剤としては、例えば、メントール、カンフル、ボルネオール、ゲラニオール、シネオール、リナロール等が挙げられる。清涼化剤の配合量は、眼科用組成物中、化合物の総量として、0.0001~5W/V%が好ましく、0.001~2W/V%がより好ましく、0.005~1W/V%がさらに好ましく、0.007~0.8W/V%が特に好ましい。
薬物(薬学的有効成分)としては、例えば、充血除去剤(例えば、塩酸ナファゾリン、塩酸テトラヒドロゾリン、塩酸フェニレフリン、エピネフリン、塩酸エフェドリン、dl-塩酸メチルエフェドリン、硝酸テトラヒドロゾリン、硝酸ナファゾリン等);消炎・収斂剤(例えば、メチル硫酸ネオスチグミン、ε-アミノカプロン酸、アラントイン、塩化ベルベリン、硫酸亜鉛、乳酸亜鉛、塩化リゾチーム、グリチルリチン酸二カリウム、グリチルリチン酸アンモニウム、グリチルレチン酸、サリチル酸メチル、トラネキサム酸、アズレンスルホン酸ナトリウム等);抗ヒスタミン剤(例えば、塩酸イプロヘプチン、塩酸ジフェンヒドラミン、ジフェンヒドラミン、塩酸イソチペンジル、マレイン酸クロルフェニラミン等);抗アレルギー剤(例えば、クロモグリク酸ナトリウム、フマル酸ケトチフェン等);水溶性ビタミン(活性型ビタミンB2、ビタミンB6、ビタミンB12等);アミノ酸(例えば、L-アスパラギン酸カリウム、L-アスパラギン酸マグネシウム、アミノエチルスルホン酸、コンドロイチン硫酸ナトリウム等、グルタチオン等);サルファ剤、殺菌剤(例えば、イオウ、イソプロピルメチルフェノール、ヒノキチオール等);局所麻酔剤(例えば、リドカイン、塩酸リドカイン、塩酸プロカイン、塩酸ジブカイン等);散瞳剤(例えば、トロピカミド等)を適宜配合することができる。
消炎・収斂剤であれば、例えば、0.0001~10W/V%、好ましくは0.0001~5W/V%である。
抗ヒスタミン剤であれば、例えば、0.0001~10W/V%、好ましくは0.001~5W/V%である。
水溶性ビタミンであれば、例えば、0.0001~1W/V%、好ましくは0.0001~0.5W/V%である。
アミノ酸であれば、例えば、0.0001~10W/V%、好ましくは0.001~3W/V%である。
サルファ剤、殺菌剤であれば、例えば、0.00001~10W/V%、好ましくは0.0001~10W/V%である。
局所麻酔剤であれば、例えば、0.001~1W/V%、好ましくは0.01~1W/V%である。
表1~11に示す組成の眼科用組成物(点眼剤)を調製し、下記評価を行った。結果を表中に併記する。
眼科用組成物(点眼剤)をポリエチレンテレフタレート製の目薬容器に充填(N=3)し、凍結(-20℃)・融解(25℃)の操作を5回繰り返し、以下の基準に従い評価した。
評価基準
5:5回目において、液は澄明であり、白濁・沈殿が生じていない
4:4回目において、液は澄明であり、白濁・沈殿が生じていないが、
5回目において、白濁もしくは沈殿が生じている
3:3回目において、液は澄明であり、白濁・沈殿が生じていないが、
4回目において、白濁もしくは沈殿が生じている
2:2回目において、液は澄明であり、白濁・沈殿が生じていないが、
3回目において、白濁もしくは沈殿が生じている
1:1回目において、白濁もしくは沈殿が生じている
ここで、澄明とは、「濁りがなく、透きとおっていること」をいう。
眼科用組成物中のレチノールパルミチン酸エステル含量を、製造直後及び40℃・75%RHで6ヶ月保存後(過酷試験)に測定した。測定は、高速液体クロマトグラフ法を用いて行った。得られたレチノールパルミチン酸エステル含量から、下記式に基づき、レチノールパルミチン酸エステル残存率(%)を算出した。
レチノールパルミチン酸エステル残存率(%)={保存後のレチノールパルミチン酸エステル含量/製造直後のレチノールパルミチン酸エステル含量}×100
<評価>
◎:70%以上
○:65%以上70%未満
△:60%以上65%未満
×:60%未満
ウサギにヘプタノール処理(ヘプタノール/エタノール=8:2(容量比)混液を片眼200μL滴下)を行い、ウサギの角膜・結膜上皮に障害を与えたモデルを作製した。その後、試料を11日間(6回(100μL/回)/日)連続して点眼した。点眼期間中、定期的にフルオレセイン染色(2%フルオレセイン片眼50μL滴下)を行い、角膜・結膜損傷治療効果を、Lenp判定基準に従い、15点満点(ヘプタノール処理直後のスコアを15点とし、改善に向かうに従いスコアは減少する)で評価した。表1~11に、5日目の評価結果を示した。
表12,13に示す組成の眼科用組成物(点眼剤)を、ビタミンA、ポリオキシエチレンポリオキシプロピレングリコール、抗酸化剤を85℃で予備溶解し、その予備溶解物を85℃に加温した滅菌精製水に可溶化し、冷却後、トロメタモールなどの水溶性配合成分を加え、pH(20℃)を調整して眼科用組成物を得た。得られた眼科用組成物15mLを、15mL用フィルター付き点眼容器(ポリエチエレンテレフタレート製)に充填した。なお、試験例1~12の眼科用組成物は十分な防腐力を有していた。得られた眼科用組成物について、上記角膜・結膜損傷治療効果の評価を行った。結果を表中に併記する。
*2:プロノン#188P、薬添規、日本油脂(株)
*3:プロノン#235P、薬添規、日本油脂(株)
Claims (12)
- (A)ビタミンAと、(B)ポリオキシエチレンポリオキシプロピレングリコールと、(C)トロメタモール、(D)多価アルコール、(E)糖類、(F)リン酸及びその塩、並びに(G)1価中性塩から選ばれる1種又は2種以上とを含有することを特徴とする眼科用組成物。
- (C)~(G)成分から選ばれる2種以上を含有する請求項1記載の眼科用組成物。
- (D)成分がグリセリン、(E)成分がキシリトール、ソルビトール、マンニトール又はトレハロース、(F)成分がリン酸二水素ナトリウム、(G)成分が塩化ナトリウムである請求項1又は2記載の眼科用組成物。
- (C)~(G)成分の合計配合量が、0.001~5W/V%である請求項1~3のいずれか1項記載の眼科用組成物。
- (B)成分の配合量が、5W/V%以下である請求項1~4のいずれか1項記載の眼科用組成物。
- (A)成分が、レチノールパルミチン酸エステル、レチノール酢酸エステル及びレチノイン酸からなる群から選ばれる1種又は2種以上である請求項1~5のいずれか1項記載の眼科用組成物。
- (A)成分の配合量が、50,000~500,000単位/100mLである請求項1~6のいずれか1項記載の眼科用組成物。
- カチオン性界面活性剤及び疎水性防腐剤の配合量が0.004W/V%以下であることを特徴とする請求項1~7のいずれか1項記載の眼科用組成物。
- 防腐剤無配合である請求項1~7のいずれか1項記載の眼科用組成物。
- コンタクトレンズ用である請求項1~9のいずれか1項記載の眼科用組成物。
- ドライアイ治療剤である請求項7~10のいずれか1項記載の眼科用組成物。
- (A)ビタミンA、(B)ポリオキシエチレンポリオキシプロピレングリコールを含有する眼科用組成物に、(C)トロメタモール、(D)多価アルコール、(E)糖類、(F)リン酸及びその塩、並びに(G)1価中性塩から選ばれる1種又は2種以上を配合することを特徴とする凍結融解による白濁・沈殿抑制方法。
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KR1020127001338A KR101690816B1 (ko) | 2009-06-25 | 2010-06-23 | 안과용 조성물 및 백탁·침전 억제 방법 |
US13/380,637 US20120108672A1 (en) | 2009-06-25 | 2010-06-23 | Ophthalmic composition and method for prevention of cloudiness/precipitation |
CN201080037088.4A CN102481268B (zh) | 2009-06-25 | 2010-06-23 | 眼科用组合物和白浊、沉淀的抑制方法 |
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JP2009150874A JP5736635B2 (ja) | 2009-06-25 | 2009-06-25 | ドライアイ治療剤 |
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KR (1) | KR101690816B1 (ja) |
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Cited By (2)
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JP5673531B2 (ja) * | 2009-06-30 | 2015-02-18 | ライオン株式会社 | 眼科用組成物 |
WO2018003796A1 (ja) * | 2016-06-30 | 2018-01-04 | ライオン株式会社 | 眼科用製品及び粘度低下抑制方法 |
Families Citing this family (6)
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US9278991B2 (en) | 2012-01-26 | 2016-03-08 | Inotek Pharmaceuticals Corporation | Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)} methyl nitrate and processes of preparation thereof |
US9522160B2 (en) * | 2013-03-15 | 2016-12-20 | Inotek Pharmaceuticals Corporation | Ophthalmic formulations |
JP2017002035A (ja) | 2015-06-05 | 2017-01-05 | 参天製薬株式会社 | ソフトコンタクトレンズが装用されたドライアイ患者の眼に点眼されるように用いられることを特徴とするドライアイ治療剤 |
CA3080016A1 (en) * | 2017-11-22 | 2019-05-31 | Bausch & Lomb Incorporated | Ophthalmic viscoelastic compositions |
KR102658489B1 (ko) * | 2017-12-28 | 2024-04-18 | 라이온 가부시키가이샤 | 안과용 제품 및 마스킹 방법 |
JP7217364B2 (ja) * | 2019-11-29 | 2023-02-02 | 千寿製薬株式会社 | 医薬組成物 |
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- 2010-06-23 CN CN201080037088.4A patent/CN102481268B/zh active Active
- 2010-06-23 WO PCT/JP2010/060633 patent/WO2010150812A1/ja active Application Filing
- 2010-06-23 US US13/380,637 patent/US20120108672A1/en not_active Abandoned
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JP7040440B2 (ja) | 2016-06-30 | 2022-03-23 | ライオン株式会社 | 眼科用製品及び粘度低下抑制方法 |
JP7314986B2 (ja) | 2016-06-30 | 2023-07-26 | ライオン株式会社 | 眼科用製品及び粘度低下抑制方法 |
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TWI501764B (zh) | 2015-10-01 |
KR20120112352A (ko) | 2012-10-11 |
CN102481268A (zh) | 2012-05-30 |
CN102481268B (zh) | 2014-04-02 |
US20120108672A1 (en) | 2012-05-03 |
KR101690816B1 (ko) | 2016-12-28 |
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