WO2021039748A1 - Diquafosol or salt thereof, and aqueous ophthalmic composition containing polyvinylpyrrolidone - Google Patents
Diquafosol or salt thereof, and aqueous ophthalmic composition containing polyvinylpyrrolidone Download PDFInfo
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- WO2021039748A1 WO2021039748A1 PCT/JP2020/031917 JP2020031917W WO2021039748A1 WO 2021039748 A1 WO2021039748 A1 WO 2021039748A1 JP 2020031917 W JP2020031917 W JP 2020031917W WO 2021039748 A1 WO2021039748 A1 WO 2021039748A1
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- aqueous ophthalmic
- ophthalmic composition
- diquafosol
- polyvinylpyrrolidone
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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
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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
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
- A61P27/04—Artificial tears; Irrigation solutions
Definitions
- the present invention relates to an aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone.
- (B-1) An ophthalmic pharmaceutical product in which 0.1 to 1 mL of an aqueous ophthalmic composition used for prevention or treatment of dry eye is filled in a unit dose type eye drop container, and the aqueous ophthalmic composition is It contains 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone having a K value of 90, and is characterized by being used so as to be instilled 1 to 2 drops at a time and 2 to 4 times a day. Ophthalmic pharmaceutical products.
- the use of the substance is characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled in a PFMD container and used so as to be instilled 1 to 2 drops at a time and 2 to 4 times a day.
- (C-7) Any of (C-1) to (C-6), wherein the aqueous ophthalmic composition is used by instilling 1 to 2 drops at a time, 3 times a day. Use of the aqueous ophthalmic composition according to 1.
- this composition Since this composition has a high tear volume increasing effect, a stronger dry eye therapeutic effect is expected as compared with the case of instillation of existing Diquas (registered trademark) ophthalmic solution. Therefore, it is also expected that this composition exerts a dry eye therapeutic effect comparable to or higher than that of the existing Diquas (registered trademark) ophthalmic solution at a lower concentration.
- the existing Diquas (registered trademark) ophthalmic solution needs to be instilled 6 times a day, and although there are some patients who do not obtain the expected effect due to poor eye drop adherence, polyvinylpyrrolidone having a certain K value.
- the silver salt is stable and exhibits excellent preservative effect.
- CMC-Na sodium carboxymethyl cellulose
- HPMC hydroxypropylmethyl cellulose
- CVP carboxyvinyl polymer
- diquafosol ophthalmic solution means an aqueous ophthalmic solution containing diquafosol or a salt thereof.
- the “salt of diquafosol” is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a metal salt with lithium, sodium, potassium, calcium, magnesium, zinc, etc .; hydrochloric acid, hydrobromic acid, hydroiodide.
- diquafosol or a salt thereof also includes a hydrate and an organic solvate of diquafosol (free form) or a salt thereof.
- diquafosol or salt thereof is preferably a sodium salt of diquafosol, and a diquafosol tetrasodium salt represented by the following chemical structural formula (also simply referred to as "diquafosol sodium" in the present specification) is particularly preferable. preferable.
- polyvinylpyrrolidone K17 polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, polyvinylpyrrolidone K120 and the like can be mentioned.
- ⁇ rel is the relative viscosity of the polyvinylpyrrolidone aqueous solution with respect to water
- c is the polyvinylpyrrolidone concentration (%) in the polyvinylpyrrolidone aqueous solution.
- K90 is the above formula.
- the viscosity characteristic value (K value) calculated by applying to (1) is in the range of 81 to 97.2.
- one kind of polyvinylpyrrolidone may be used alone, or two or more kinds of polyvinylpyrrolidones having different K values may be used in any combination.
- the concentration of polyvinylpyrrolidone is not particularly limited, but is, for example, 0.001% (w / v) or more, preferably 0.001 to 10% (w / v), more preferably 0. 0.01 to 10% (w / v), more preferably 0.05 to 10% (w / v), even more preferably 0.1 to 10% (w / v), and even more preferably 0.1 to 5 % (W / v), particularly preferably 1-5% (w / v).
- composition can be further supplemented with pharmaceutically acceptable preservatives as needed.
- pharmaceutically acceptable preservatives such as silver nitrate, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, boric acid, borax, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, Examples thereof include chlorobutanol, polydronium chloride, and polyhexanide hydrochloride.
- a preferable preservative in the present invention is a silver salt.
- silver salts include silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, and protein silver.
- silver nitrate is preferable.
- the concentration of the silver salt is not particularly limited, and is not particularly limited as long as it is in the range of 0.00000001 to 1% (w / v), for example.
- the lower limit values are, for example, 0.00000001% (w / v) or more, 0.000000001% (w / v) or more, 0.000001% (w / v) or more, 0.0000025%.
- the upper limit is, for example, 1% (w / v) or less, 0.5% (w / v) or less, 0.1% (w / v) or less, 0.05% (w / v) or less.
- 0.01% (w / v) or less, 0.005% (w / v) or less, or 0.001% (w / v) or less is preferable.
- pharmaceutically acceptable additives can be further added to the composition, if necessary.
- buffering agents such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, epsilon-aminocaproic acid; calcium chloride, sodium chloride, potassium chloride, concentrated glycerin, etc.
- Isotonic agents such as sodium edetate, sodium edetate hydrate, citrate hydrate, sodium citrate hydrate; surfactants such as polysorbate; antioxidants such as ascorbic acid;
- a thickening agent also referred to as a thickener
- hydroxyethyl cellulose or hydroxypropyl methyl cellulose such as hydroxyethyl cellulose or hydroxypropyl methyl cellulose
- a pH adjusting agent such as hydrochloric acid or sodium hydroxide can be selected and added as necessary.
- the composition does not have to contain a cellulosic polymer which is a thickening agent such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose.
- the "ophthalmic composition” refers to a composition for use in the prevention and / or treatment of eye diseases and the like.
- the dosage form include eye drops, eye ointments, injections, ointments (for example, which can be administered to the skin of the eyelids), and the like, and eye drops are preferable.
- eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.
- the present composition may be a soluble eye drop or a suspension eye drop depending on the properties and contents of the active ingredient and the additive.
- the composition can be stored in an airtight container, specifically, an eye drop container.
- an eye drop container filled with the present composition
- examples of the eye drop container filled with the present composition include a "multi-dose type eye drop container” and a "unit-dose type eye drop container”.
- the "ophthalmic pharmaceutical product” refers to a product for ophthalmic pharmaceuticals in which the present composition is filled in an eye drop container.
- examples of the "ophthalmic pharmaceutical product” include eye drop products.
- the definition of each term in the “ophthalmic pharmaceutical product” of the present invention is the same as the definition of each term in the "composition”.
- the "multi-dose type eye drop container” is an eye drop container provided with a container body and a cap that can be attached to the container body, and the cap can be freely opened and resealed.
- the multi-dose type eye drop container usually contains a plurality of doses of eye drops for use for a certain period of time.
- the composition may be contained in a PFMD (Preservative Free Multi Dose) container.
- Dry eye symptoms include subjective symptoms such as dry eyes, discomfort, eye fatigue, dullness, photophobia, eye pain, and blurred vision (blurred vision), as well as other symptoms such as congestion and keratoconjunctival epithelial disorders. Findings are also included.
- "prevention or treatment of dry eye” also includes improvement of the above-mentioned subjective symptoms and / or objective findings.
- Eye drops B Sterilized purified water containing sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and polyvinylpyrrolidone K90 (4 g). The pH was adjusted to 100 mL, and a pH regulator (q.s.) was added to adjust the pH to 7.5.
- Eye drops X As the eye drop X, "Diquas (registered trademark) eye drop 3%" (manufactured by Santen Pharmaceutical Co., Ltd.), which is used as a therapeutic agent for dry eye, was used.
- Ophthalmic solution X contains 30 mg of sodium diquafosol as an active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, and sodium edetate hydrate as additives. , Contains a pH regulator.
- Eye drops Y An ophthalmic solution of ophthalmic solution Y was prepared according to the formulation shown in Table 3. Specifically, sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), sodium diquafosol ( 3 g) was dissolved in sterilized purified water to make 100 mL, and a pH adjuster (q.s.) was added to make pH 7.5.
- Table 3 sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), sodium diquafosol ( 3 g) was dissolved in sterilized purified water to make 100 mL, and a pH adjuster (q.s.) was added to make pH 7.5.
- Eye drops C and D Each eye drop C and D was prepared in the same manner as the eye drop Y according to the formulation shown in Table 3.
Abstract
Description
(1)ジクアホソルまたはその塩、およびポリビニルピロリドンを含有する水性眼科用組成物。 That is, the present invention relates to the following.
(1) An aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone.
(3)銀塩が、硝酸銀を含む、(2)に記載の水性眼科用組成物。 (2) The aqueous ophthalmic composition according to (1), which further contains a silver salt.
(3) The aqueous ophthalmic composition according to (2), wherein the silver salt contains silver nitrate.
(A-1)ユニットドーズ型点眼容器に充填された水性眼科用組成物を患者に1回1~2滴、1日2~4回点眼投与することを含むドライアイの治療方法であって、前記水性眼科用組成物は3%(w/v)の濃度のジクアホソルナトリウムおよびK値が90のポリビニルピロリドンを含有し、前記ユニットドーズ型点眼容器には前記水性眼科用組成物0.1~1mLが充填されている、ドライアイの治療方法。 The present invention also relates to the following.
(A-1) A method for treating dry eye, which comprises administering 1 to 2 drops of an aqueous ophthalmic composition filled in a unit dose type eye drop container to a patient at a time, 2 to 4 times a day. The aqueous ophthalmic composition contains 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone having a K value of 90, and the unit dose type eye drop container contains the aqueous ophthalmic composition 0.1. A method for treating dry eye, which is filled with ~ 1 mL.
本明細書において、「(w/v)%」は、本発明の水性眼科用組成物100mL中に含まれる対象成分の質量(g)を意味する。 The present invention will be described in more detail.
In the present specification, "(w / v)%" means the mass (g) of the target component contained in 100 mL of the aqueous ophthalmic composition of the present invention.
本明細書において、「HEC」は、ヒドロキシエチルセルロースを意味する。 As used herein, "PVP" means polyvinylpyrrolidone.
As used herein, "HEC" means hydroxyethyl cellulose.
本明細書において、「ジクアホソル点眼液」は、ジクアホソルまたはその塩を含有する水性点眼液を意味する。 As used herein, "CVP" means a carboxyvinyl polymer.
As used herein, "diquafosol ophthalmic solution" means an aqueous ophthalmic solution containing diquafosol or a salt thereof.
本組成物の粘度は、医薬として許容される範囲であれば特に限定されるものではないが、例えば、好ましくは1~500mPa・sの範囲内、より好ましくは1.4超ないし100mPa・s以下の範囲内、さらに好ましくは1.5~100mPa・sの範囲内、よりさらに好ましくは1.5~50mPa・sの範囲内、もっと好ましくは1.5~30mPa・sの範囲内、よりもっと好ましくは1.5~20mPa・sの範囲内、ことさら好ましくは1.5~10mPa・sの範囲内、よりことさら好ましくは2~10mPa・sの範囲内、特に好ましくは3~10mPa・sの範囲内、より特に好ましくは5~10mPa・sの範囲内、さらに特に好ましくは7~10mPa・sの範囲内になるように調整される。また、本組成の粘度は、1.5~30mPa・sの範囲内、好ましくは2~30mPa・sの範囲内、より好ましくは3~30mPa・sの範囲内、さらに好ましくは5~30mPa・sの範囲内、特に好ましくは7~30mPa・sの範囲内になるように調整することもできる。本組成物の粘度の下限値としては、例えば、1mPa・s以上、1.5mPa・s以上、2mPa・s以上、3mPa・s以上、5mPa・s以上、または7mPa・s以上が好ましい。また、その上限値としては、例えば、500mPa・s以下、100mPa・s以下、50mPa・s以下、30mPa・s以下、20mPa・s以下、または10mPa・s以下が好ましい。また、本組成物の粘度は、回転粘度計(25℃;50s-1のせん断速度)で測定される。 The composition is preferably storable at room temperature.
The viscosity of the present composition is not particularly limited as long as it is within a pharmaceutically acceptable range, but for example, it is preferably in the range of 1 to 500 mPa · s, more preferably more than 1.4 to 100 mPa · s or less. Within the range of, more preferably within the range of 1.5 to 100 mPa · s, even more preferably within the range of 1.5 to 50 mPa · s, even more preferably within the range of 1.5 to 30 mPa · s, even more preferably. Is in the range of 1.5 to 20 mPa · s, particularly preferably in the range of 1.5 to 10 mPa · s, more preferably in the range of 2 to 10 mPa · s, particularly preferably in the range of 3 to 10 mPa · s. , More particularly preferably within the range of 5 to 10 mPa · s, and even more particularly preferably within the range of 7 to 10 mPa · s. The viscosity of the present composition is in the range of 1.5 to 30 mPa · s, preferably in the range of 2 to 30 mPa · s, more preferably in the range of 3 to 30 mPa · s, and further preferably in the range of 5 to 30 mPa · s. It can also be adjusted so as to be within the range of, particularly preferably within the range of 7 to 30 mPa · s. As the lower limit of the viscosity of the composition, for example, 1 mPa · s or more, 1.5 mPa · s or more, 2 mPa · s or more, 3 mPa · s or more, 5 mPa · s or more, or 7 mPa · s or more is preferable. Further, as the upper limit value, for example, 500 mPa · s or less, 100 mPa · s or less, 50 mPa · s or less, 30 mPa · s or less, 20 mPa · s or less, or 10 mPa · s or less is preferable. The viscosity of the composition is measured with a rotational viscometer (25 ° C; 50s- 1 shear rate).
正常雄性白色ウサギを用いて、本組成物の点眼後における涙液量の経時変化を評価した。 [Test 1]
Using normal male white rabbits, the time course of tear volume after instillation of this composition was evaluated.
点眼液1:
表1に示す処方表に従い、点眼液1を調製した。すなわち、ジクアホソルナトリウム(9g)、リン酸水素ナトリウム水和物(0.6g)、エデト酸ナトリウム水和物(0.03g)および塩化ナトリウム(1.35g)を滅菌精製水に溶解して50mLとして6倍濃厚液を得た。また、6倍濃厚液10mLと滅菌精製水5mLを混合後、pH調節剤を適宜添加してpHを7に調整し、滅菌精製水を加えて20mLとし、3倍濃厚液を得た。PVP K90(4g)を滅菌精製水に溶解し、全量を100gとした後に高圧蒸気滅菌(121℃20分)し、4.00%(w/w)PVP K90溶液とした。4.00%(w/w)PVP K90溶液6.0gに3倍濃厚液4mLを添加し、滅菌精製水を加え全量12mLに調整後、pH調節剤を適宜添加してpHを7に調整することにより、点眼液1を調製した。 (Sample preparation method)
Eye drops 1:
Ophthalmic solution 1 was prepared according to the prescription table shown in Table 1. That is, sodium diquafosol (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterile purified water. A 6-fold concentrated solution was obtained with 50 mL. Further, after mixing 10 mL of the 6-fold concentrated solution and 5 mL of sterilized purified water, a pH adjuster was appropriately added to adjust the pH to 7, and sterilized purified water was added to make 20 mL, and a 3-fold concentrated solution was obtained. PVP K90 (4 g) was dissolved in sterilized purified water to make the total amount 100 g, and then high-pressure steam sterilization (121 ° C. for 20 minutes) to obtain a 4.00% (w / w) PVP K90 solution. Add 4 mL of 3-fold concentrated solution to 6.0 g of 4.00% (w / w) PVP K90 solution, add sterile purified water to adjust the total volume to 12 mL, and then add a pH adjuster as appropriate to adjust the pH to 7. Therefore, ophthalmic solution 1 was prepared.
表1に示す処方表に従い、点眼液2を調製した。すなわち、ジクアホソルナトリウム(9g)、リン酸水素ナトリウム水和物(0.6g)、エデト酸ナトリウム水和物(0.03g)および塩化ナトリウム(1.35g)を滅菌精製水に溶解して50mLとして6倍濃厚液を得た。また、6倍濃厚液10mLと滅菌精製水5mLを混合後、PVP K30(1.2g)を溶解後、pH調節剤を適宜添加してpHを7に調整し、滅菌精製水を加えて20mLとし、3倍濃厚液を得た。3倍濃厚液4mLに、滅菌精製水を加え全量12mLに調整後、pH調節剤を適宜添加してpHを7に調整することにより、点眼液2を調製した。 Eye drops 2:
Eye drops 2 were prepared according to the prescription table shown in Table 1. That is, sodium diquafosol (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterile purified water. A 6-fold concentrated solution was obtained with 50 mL. In addition, after mixing 10 mL of 6-fold concentrated solution and 5 mL of sterile purified water, dissolve PVP K30 (1.2 g), adjust the pH to 7 by appropriately adding a pH adjuster, and add sterile purified water to make 20 mL. A 3-fold concentrated solution was obtained.
表1に示す処方表に従い、点眼液3を調製した。すなわち、ジクアホソルナトリウム(9g)、リン酸水素ナトリウム水和物(0.6g)、エデト酸ナトリウム水和物(0.03g)および塩化ナトリウム(1.35g)を滅菌精製水に溶解して50mLとして6倍濃厚液を得た。また、6倍濃厚液10mLと滅菌精製水5mLを混合後、pH調節剤を適宜添加してpHを7に調整し、滅菌精製水を加えて20mLとし、3倍濃厚液を得た。ヒドロキシエチルセルロース(15g)を滅菌精製水1500mLに溶解し、高圧蒸気滅菌(121℃20分)し、1.00%(w/w)ヒドロキシエチルセルロース溶液とした。1.00%(w/w)ヒドロキシエチルセルロース溶液3.6gに3倍濃厚液4mLを添加し、滅菌精製水を加え全量12mLに調整後、pH調節剤を適宜添加してpHを7に調整することにより、点眼液3を調製した。 Eye drops 3:
Eye drops 3 were prepared according to the prescription table shown in Table 1. That is, sodium diquafosol (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterile purified water. A 6-fold concentrated solution was obtained with 50 mL. Further, after mixing 10 mL of the 6-fold concentrated solution and 5 mL of sterilized purified water, a pH adjuster was appropriately added to adjust the pH to 7, and sterilized purified water was added to make 20 mL, and a 3-fold concentrated solution was obtained. Hydroxyethyl cellulose (15 g) was dissolved in 1500 mL of sterilized purified water and sterilized by high pressure steam (121 ° C. for 20 minutes) to obtain a 1.00% (w / w) hydroxyethyl cellulose solution. Add 4 mL of 3-fold concentrated solution to 3.6 g of 1.00% (w / w) hydroxyethyl cellulose solution, add sterile purified water to adjust the total volume to 12 mL, and then add a pH adjuster as appropriate to adjust the pH to 7. As a result, eye drops 3 were prepared.
表1に示す処方表に従い、点眼液4を調製した。すなわち、ジクアホソルナトリウム(9g)、リン酸水素ナトリウム水和物(0.6g)、エデト酸ナトリウム水和物(0.03g)および塩化ナトリウム(1.35g)を滅菌精製水に溶解して50mLとして6倍濃厚液を得た。また、6倍濃厚液10mLと滅菌精製水5mLを混合後、pH調節剤を適宜添加してpHを7に調整し、滅菌精製水を加えて20mLとし、3倍濃厚液を得た。3倍濃厚液4mLに、滅菌精製水を加え全量12mLに調整後、pH調節剤を適宜添加してpHを7に調整することにより、点眼液4を調製した。 Eye drops 4:
表1に示す処方表に従い、点眼液5を調製した。すなわち、ジクアホソルナトリウム(18g)、リン酸水素ナトリウム水和物(1.2g)、エデト酸ナトリウム水和物(0.06g)を滅菌精製水に溶解して100mLとして6倍濃厚液を得た。また、6倍濃厚液2.5mLと滅菌精製水5mLを混合後、PVP K60 45%水溶液(0.67g)と塩化ナトリウム(0.068g)を溶解後、pH調節剤を適宜添加してpHを7に調整し、滅菌精製水を加えて15mLとすることにより、点眼液5を調製した。 Eye drops 5:
Eye drops 5 were prepared according to the prescription table shown in Table 1. That is, sodium diquafosol (18 g), sodium hydrogen phosphate hydrate (1.2 g), and sodium edetate hydrate (0.06 g) were dissolved in sterile purified water to obtain a 6-fold concentrated solution as 100 mL. It was. In addition, after mixing 2.5 mL of 6-fold concentrated solution and 5 mL of sterilized purified water, dissolve PVP K60 45% aqueous solution (0.67 g) and sodium chloride (0.068 g), and then add a pH adjuster as appropriate to adjust the pH.
ローター角度:1°
ローター直径:50mm
試料量:0.57mL
測定温度:25℃
せん断速度:50s-1
測定時間:2秒毎に粘度を測定し、1分間の平均値を粘度とした。 The viscosities of the prepared ophthalmic solutions 1 to 5 are the 17th revised Japanese Pharmacy, 2.53 viscosity measurement method, the second rotational viscometer method, 2.1.3 conical-plate type rotational viscometer (cone). The measurement was performed according to the method described in (Plate type viscometer). Specifically, Kinexus pro + (manufactured by Malvern) was used, and the measurement conditions were set as follows. (Measurement condition)
Rotor angle: 1 °
Rotor diameter: 50 mm
Sample volume: 0.57 mL
Measurement temperature: 25 ° C
Shear velocity: 50s -1
Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was taken as the viscosity.
正常雄性白色ウサギ(計16匹32眼)にベノキシール(登録商標)点眼液0.4%(参天製薬株式会社製)を点眼し、局所麻酔を施した。3分後に下眼瞼にシルメル試験紙(あゆみ製薬株式会社製)を挿入し、挿入1分後に抜き取り、濡れた部分の長さ(涙液量)を読み取った。これを前値とした。次に、各点眼液1~5を1回点眼した(一群4匹8眼、点眼液4のみ12匹24眼)。下眼瞼にシルメル試験紙(あゆみ製薬株式会社製)を挿入する3分前に、ベノキシール(登録商標)点眼液0.4%(参天製薬株式会社製)を点眼し、局所麻酔を施した。各点眼液点眼60分後に、下眼瞼にシルメル試験紙(あゆみ製薬株式会社製)を挿入し、挿入1分後に抜き取り、濡れた部分の長さ(涙液量)を読み取った。 (Test method and drug administration method)
Normal male white rabbits (16 animals, 32 eyes in total) were instilled with Benokiseal (registered trademark) ophthalmic solution 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) and subjected to local anesthesia. After 3 minutes, a Sylmel test paper (manufactured by AYUMI Pharmaceutical Corporation) was inserted into the lower eyelid, and 1 minute after the insertion, the paper was removed and the length of the wet portion (tear volume) was read. This was used as the previous value. Next, each eye drop 1 to 5 was instilled once (4 animals in a group, 8 eyes,
点眼液点眼前後の涙液量の変化をΔ涙液量(mm/分)として算出した。 (Evaluation methods)
Ophthalmic solution The change in tear volume before and after instillation was calculated as Δ tear volume (mm / min).
点眼後60分におけるΔ涙液量(mm/分)を表1、2に示す(各値は8眼の平均値。但し、点眼液4のみ24眼の平均値)。また、本組成物の涙液量増加作用を以下の基準に従って評価した。
+++:点眼後60分におけるΔ涙液量(mm/分)が4mm/分以上
++:点眼後60分におけるΔ涙液量(mm/分)が1mm/分以上、4mm/分未満
+:点眼後60分におけるΔ涙液量(mm/分)が0mm/分超乃至1mm/分未満
-:点眼後60分におけるΔ涙液量(mm/分)が0mm/分以下 (Test results)
The amount of Δtear fluid (mm / min) 60 minutes after instillation is shown in Tables 1 and 2 (each value is an average value of 8 eyes. However, only
+++: Delta tear volume (mm / min) 60 minutes after instillation is 4 mm / min or more
++: Delta tear volume (mm / min) 60 minutes after instillation is 1 mm / min or more and less than 4 mm / min
+: Delta tear volume (mm / min) 60 minutes after instillation is more than 0 mm / min to less than 1 mm / min
-: Delta tear volume (mm / min) 60 minutes after instillation is 0 mm / min or less
ポリビニルピロリドンはジクアホソルまたはその塩を含有する水性組成物の粘度を上昇させ、ジクアホソルまたはその塩の薬効を増強させたが、特に、K値が30超のポリビニルピロリドンを添加する場合、またはポリビニルピロリドン添加により水性組成物の粘度が1.4超となる場合に、ジクアホソルまたはその塩の薬効が顕著に増強されることが示された。 (Discussion)
Polyvinylpyrrolidone increased the viscosity of an aqueous composition containing diquafosol or a salt thereof and enhanced the medicinal effect of diquafosol or a salt thereof, but especially when polyvinylpyrrolidone having a K value of more than 30 was added or polyvinylpyrrolidone was added. It was shown that the medicinal effect of diquafosol or a salt thereof is remarkably enhanced when the viscosity of the aqueous composition exceeds 1.4.
ラット眼窩外涙腺摘出モデルは、ドライアイを原因とする角膜上皮障害の治療効果を評価するモデルとして汎用されており、また、P2Y2受容体作動薬の治療効果を評価するモデルとしても利用されている(Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001))。当該ドライアイモデルを用いて、本組成物を点眼投与することで角膜上皮障害の改善効果が得られるか否かを検討した。 [Test 2]
Rat exorbital lacrimal gland extraction model is widely used as a model for evaluating the therapeutic effect of corneal epithelial disorders caused by dry eye, also, it is also utilized as a model for evaluating the therapeutic effect of P2Y 2 receptor agonist (Invest. Orbitol. Vis. Sci., 42 (1), 96-100 (2001)). Using the dry eye model, it was examined whether or not the improvement effect of corneal epithelial damage could be obtained by instillation of this composition.
雄性SDラットを用い、Fujiharaらの方法(Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001))に準じてラット眼窩外涙腺摘出モデルを作製した。すなわち、ソムノペンチルを投与して全身麻酔を施した後、眼窩外涙腺を摘出し、角膜上皮障害を誘発した。 (How to make a dry eye model)
Using male SD rats, a rat extraorbital lacrimal gland resection model was prepared according to the method of Fujihara et al. (Invest. Ofphthalmol. Vis. Sci., 42 (1), 96-100 (2001)). That is, after general anesthesia was administered by administering somnopentil, the extraorbital lacrimal gland was removed to induce corneal epithelial damage.
点眼液A:
リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、塩化ナトリウム(0.45g)、硝酸銀(0.00004g)、ポリビニルピロリドンK90(2g)、ジクアホソルナトリウム(3g)を滅菌精製水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とした。 (Sample preparation method)
Eye drops A:
Sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), diquafosol Sodium (3 g) was dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs.) Was added to make pH 7.5.
リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、塩化ナトリウム(0.45g)、硝酸銀(0.00004g)、ポリビニルピロリドンK90(4g)を滅菌精製水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とした。 Eye drops B:
Sterilized purified water containing sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and polyvinylpyrrolidone K90 (4 g). The pH was adjusted to 100 mL, and a pH regulator (q.s.) was added to adjust the pH to 7.5.
点眼液Xとして、ドライアイ治療薬として使用されている「ジクアス(登録商標)点眼液3%」(参天製薬株式会社製)を使用した。点眼液Xは、水1mL中、有効成分としてジクアホソルナトリウムを30mg含有し、添加物として塩化カリウム、塩化ナトリウム、クロルヘキシジングルコン酸塩液、リン酸水素ナトリウム水和物、エデト酸ナトリウム水和物、pH調節剤を含有する。 Eye drops X:
As the eye drop X, "Diquas (registered trademark) eye drop 3%" (manufactured by Santen Pharmaceutical Co., Ltd.), which is used as a therapeutic agent for dry eye, was used. Ophthalmic solution X contains 30 mg of sodium diquafosol as an active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, and sodium edetate hydrate as additives. , Contains a pH regulator.
(測定条件)
ローター角度:1°
ローター直径:50mm
試料量:0.57mL
測定温度:25℃
せん断速度:50s-1
測定時間:2秒毎に粘度を測定し、1分間の平均値を粘度とした。 The viscosities of the prepared ophthalmic solutions A, B and X are the 17th revised Japanese Pharmacy, 2.53 viscosity measurement method, the second rotational viscometer method, 2.1.3 conical-plate type rotational viscometer. The measurement was performed according to the method described in (Cone plate type viscometer). Specifically, Kinexus pro + (manufactured by Malvern) was used, and the measurement conditions were set as follows.
(Measurement condition)
Rotor angle: 1 °
Rotor diameter: 50 mm
Sample volume: 0.57 mL
Measurement temperature: 25 ° C
Shear velocity: 50s -1
Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was taken as the viscosity.
点眼液A:7.9mPa・s
点眼液B:28.0mPa・s
点眼液X:0.9mPa・s
(試験方法および薬物投与方法)
前記角膜上皮障害を誘発されたラットに対して、点眼液A、点眼液B、点眼液Xを以下のように投与した。
・点眼液A、1日3回投与群:点眼液Aを両眼に1日3回、4週間点眼した。(一群6匹12眼)
・点眼液B、1日3回投与群:点眼液Bを両眼に1日3回、4週間点眼した。(一群6匹12眼)
・点眼液X、1日6回投与群:点眼液Xを両眼に1日6回、4週間点眼した。(一群6匹12眼)
なお、前記角膜上皮障害を誘発していないラットで、4週間無点眼であったもの無点眼群とした(一群4匹8眼)。 The measured viscosities of each eye drop were as follows.
Eye drops A: 7.9 mPa · s
Eye drops B: 28.0 mPa · s
Eye drops X: 0.9 mPa · s
(Test method and drug administration method)
Eye drops A, eye drops B, and eye drops X were administered to the rats in which the corneal epithelial disorder was induced as follows.
-Eye drop A, 3 times a day administration group: Eye drops A were instilled into both eyes 3 times a day for 4 weeks. (6 animals in a group, 12 eyes)
-Eye drop B, 3 times a day administration group: Eye drops B were instilled in both eyes 3 times a day for 4 weeks. (6 animals in a group, 12 eyes)
-Eye drop X, 6 times a day administration group: Eye drops X were instilled into both eyes 6 times a day for 4 weeks. (6 animals in a group, 12 eyes)
Rats that did not induce the corneal epithelial disorder and had no eye drops for 4 weeks were included in the non-eye drop group (4 animals in a group, 8 eyes).
0:染色されていない、
1:染色が疎であり、各点状の染色部分は離れている、
2:染色が中程度であり、点状の染色部分の一部が隣接している、
3:染色が密であり、各点状の染色部分は隣接している。 (Criteria)
0: Undyed,
1: Staining is sparse, and each dot-shaped dyed part is separated.
2: The staining is moderate, and a part of the punctate stained part is adjacent.
3: Dyeing is dense, and each dot-shaped dyed part is adjacent.
算出された各群のフルオレセイン染色スコアをグラフ化したものを図1に示す。なお、スコアは各8または12例の平均値+標準誤差である。 (result)
FIG. 1 shows a graph of the calculated fluorescein staining scores of each group. The score is the average value + standard error of each of 8 or 12 cases.
点眼液Xは「ジクアス(登録商標)点眼液3%」としてドライアイの治療に使用され、その点眼回数は1日6回である。ポリビニルピロリドンK90が添加された本組成物については、ドライアイに対して1日3回点眼で十分な治療効果を有することが明らかとなり、特に点眼開始2週間後においては「ジクアス(登録商標)点眼液3%」の1日6回点眼を凌ぐ治療効果が認められた。したがって、本組成物が既存のジクアス(登録商標)点眼液よりも少ない点眼回数で既存のジクアス(登録商標)点眼液と同等またはそれ以上の治療効果を奏することが示された。特に、試験1の試験結果を勘案すれば、K値が30超のポリビニルピロリドンが添加された本組成物、またはポリビニルピロリドン添加により粘度が1.4超となった本組成物の1日2~4回点眼が、既存の「ジクアス(登録商標)点眼液3%」の1日6回点眼と同等またはそれ以上の治療効果を奏することが示唆された。 (Discussion)
Ophthalmic solution X is used as "Diquas (registered trademark) ophthalmic solution 3%" for the treatment of dry eye, and the number of instillations is 6 times a day. It was clarified that this composition to which polyvinylpyrrolidone K90 was added had a sufficient therapeutic effect on dry eye by instilling it three times a day, and especially two weeks after the start of instillation, "Diquas (registered trademark) instillation was performed. The therapeutic effect of "3% solution" was observed to surpass that of instillation 6 times a day. Accordingly, the composition has been shown to exhibit the existing Jikuasu ® ophthalmic solution equal to or more therapeutic effects in a small eye number than the existing Jikuasu ® ophthalmic solution. In particular, considering the test results of Test 1, the present composition to which polyvinylpyrrolidone having a K value of more than 30 is added, or the present composition having a viscosity of more than 1.4 due to the addition of polyvinylpyrrolidone, 2 to 1 day It was suggested that the 4th instillation had a therapeutic effect equal to or higher than that of the existing "Diquas (registered trademark) ophthalmic solution 3%" 6 times a day.
本組成物が角膜上皮細胞に及ぼす影響を検討するため、角膜上皮細胞の細胞障害性に対する試験を行った。 [Test 3]
In order to investigate the effect of this composition on corneal epithelial cells, a test was conducted on the cytotoxicity of corneal epithelial cells.
表3に示す処方に従って、点眼液Y、CおよびDを調製した。 (Sample preparation method)
Eye drops Y, C and D were prepared according to the formulations shown in Table 3.
表3に示す処方に従って、点眼液Yの点眼液を調製した。具体的には、リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、塩化ナトリウム(0.45g)、硝酸銀(0.00004g)、ジクアホソルナトリウム(3g)を滅菌精製水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とした。 Eye drops Y:
An ophthalmic solution of ophthalmic solution Y was prepared according to the formulation shown in Table 3. Specifically, sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), sodium diquafosol ( 3 g) was dissolved in sterilized purified water to make 100 mL, and a pH adjuster (q.s.) was added to make pH 7.5.
表3に示す処方に従って、点眼液Yと同様に点眼液CおよびDの各点眼液を調製した。 Eye drops C and D:
Each eye drop C and D was prepared in the same manner as the eye drop Y according to the formulation shown in Table 3.
(測定条件)
ローター角度:1°
ローター直径:50mm
試料量:0.57mL
測定温度:25℃
せん断速度:50s-1
測定時間:2秒毎に粘度を測定し、1分間の平均値を粘度とした。 The viscosities of the prepared ophthalmic solutions Y, C and D are the 17th revised Japanese Pharmacy, 2.53 viscosity measurement method, the second rotational viscometer method, 2.1.3 conical-plate type rotational viscometer. The measurement was performed according to the method described in (Cone plate type viscometer). Specifically, Kinexus pro + (manufactured by Malvern) was used, and the measurement conditions were set as follows.
(Measurement condition)
Rotor angle: 1 °
Rotor diameter: 50 mm
Sample volume: 0.57 mL
Measurement temperature: 25 ° C
Shear velocity: 50s -1
Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was taken as the viscosity.
SV40不死化ヒト角膜上皮細胞(HCE-T:理化学研究所、バイオリソースセンター、Cell No.:RCB2280)を96ウエルプレートに播種(1×104細胞/ウエル)し、10%FBS含有D-MEM/F12培地で1日培養した。翌日、培地を点眼液Y、点眼液Cまたは点眼液Dに交換した後、前記角膜上皮細胞を5、10および15分間培養した。Cell Proliferation Assay Kit(Promega社製、カタログ番号:G3580)を用いて、生細胞活性(490nmの吸光度に相当する)を測定した。 (Test method)
SV40 immortalized human corneal epithelial cells (HCE-T: RIKEN, Bioresource Center, Cell No .: RCB2280) were seeded in 96-well plates (1 × 10 4 cells / well) and D-MEM containing 10% FBS / The cells were cultured in F12 medium for 1 day. The next day, after exchanging the medium with eye drops Y, eye drops C or eye drops D, the corneal epithelial cells were cultured for 5, 10 and 15 minutes. Living cell activity (corresponding to absorbance at 490 nm) was measured using the Cell Proflation Assay Kit (manufactured by Promega, Catalog No .: G3580).
試験結果を図2に示す。 (result)
The test results are shown in FIG.
ポリビニルピロリドンを含有させたジクアホソル点眼液は、培養した不死化ヒト角膜上皮細胞において高い生細胞活性を示すことから、角結膜上皮に対する安全性がより高く、ドライアイのような角結膜上皮が不安定な疾患に用いるのに有用である。 (Discussion)
Diquafosol ophthalmic solution containing polyvinylpyrrolidone shows high viable cell activity in cultured immortalized human corneal epithelial cells, so that it is safer for corneal conjunctival epithelium and unstable corneal epithelium such as dry eye. It is useful for use in various diseases.
PVP共存下でのジクアホソルナトリウムの末梢神経に対する刺激性を検討した。 [Test 4]
The irritation of diquafosol sodium to peripheral nerves in the presence of PVP was investigated.
処方液1:
表4に示す処方表に従い、処方液1を調製した。すなわち、塩化ナトリウム(8.5g)、リン酸水素ナトリウム水和物(2g)を滅菌精製水に溶解してpH調節剤を添加し、pHを7.5に調整後、全量を100mLに調整し、10倍緩衝液を得た。PVP K30(16g)を滅菌精製水に溶解し、全量を200mLに調整し、8%PVP K30水溶液を得た。10倍緩衝液2mL、8%PVP K30水溶液5mLを量り取り、滅菌精製水で全量を20mLに調整し、pH調整剤を用いてpHを7.5に調整し、処方液1を得た。 (Sample preparation method)
Prescription solution 1:
The prescription solution 1 was prepared according to the prescription table shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL. A 10-fold buffer was obtained. PVP K30 (16 g) was dissolved in sterile purified water to adjust the total volume to 200 mL to obtain an 8% aqueous solution of PVP K30. 2 mL of a 10-fold buffer solution and 5 mL of an 8% PVP K30 aqueous solution were weighed, the total volume was adjusted to 20 mL with sterile purified water, and the pH was adjusted to 7.5 using a pH adjuster to obtain a prescription solution 1.
表4に示す処方表に従い、処方液2を調製した。すなわち、塩化ナトリウム(8.5g)、リン酸水素ナトリウム水和物(2g)を滅菌精製水に溶解してpH調節剤を添加し、pHを7.5に調整後、全量を100mLに調整し、10倍緩衝液を得た。10倍緩衝液2mL、PVP K90(0.4g)を滅菌精製水に溶解し、pH調整剤を用いてpHを7.5に調整し、全量を20mLとして処方液2を得た。 Prescription solution 2:
The
表4に示す処方表に従い、処方液3を調製した。すなわち、塩化ナトリウム(8.5g)、リン酸水素ナトリウム水和物(2g)を滅菌精製水に溶解してpH調節剤を添加し、pHを7.5に調整後、全量を100mLに調整し、10倍緩衝液を得た。10倍緩衝液2mL、コンドロイチン硫酸ナトリウム(0.06g)を滅菌精製水に添加し、pH調整剤を用いてpHを7.5に調整し、溶解を確認して全量を20mLに調整し処方液3を得た。 Prescription solution 3:
The prescription solution 3 was prepared according to the prescription table shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL. A 10-fold buffer was obtained. Add 2 mL of 10-fold buffer and sodium chondroitin sulfate (0.06 g) to sterile purified water, adjust the pH to 7.5 using a pH adjuster, confirm dissolution, and adjust the total volume to 20 mL. I got 3.
表4に示す処方表に従い、処方液3と同様に処方液4~6を調製した。 Prescription solution 4-6:
According to the prescription table shown in Table 4,
培養した末梢神経細胞(ラット後根神経節ニューロン、ロンザジャパンより購入)を、細胞内カルシウム指示蛍光色素を含む緩衝液(FLIPR Calcium 6 Assay Kit、Molecular Devices社)中でインキュベーションした。緩衝液全量の40%を上記の各処方液に置換した。なお、無刺激群および刺激対照群には処方液に代えて緩衝液を同様に処置した。室温下で静置した後、蛍光プレートリーダーを用いてカルシウム指示色素の経時的蛍光測定を開始した。開始から60秒後にジクアホソルナトリウム(終濃度:0.3%)を添加し、蛍光強度の測定を継続した。 (Test method)
Cultured peripheral nerve cells (rat dorsal root ganglion neurons, purchased from Ronza Japan) were incubated in a buffer containing an intracellular calcium-indicating fluorescent dye (FLIPR Calcium 6 Assay Kit, Molecular Devices). 40% of the total amount of buffer was replaced with each of the above formulations. The non-stimulation group and the stimulation control group were similarly treated with a buffer solution instead of the prescription solution. After allowing to stand at room temperature, the fluorescence measurement of the calcium indicator dye over time was started using a fluorescent plate reader. Sodium diquafosol (final concentration: 0.3%) was added 60 seconds after the start, and the measurement of fluorescence intensity was continued.
ジクアホソルナトリウム添加直前の蛍光強度(RFU)を100%として、添加後の最大蛍光強度(RFUmax)を算出した。 (Evaluation methods)
The maximum fluorescence intensity (RFUmax) after the addition was calculated with the fluorescence intensity (RFU) immediately before the addition of diquafosol sodium as 100%.
結果を図3に示す。刺激対照群および処方液3~6では、ジクアホソルナトリウム添加後にRFUが上昇し、103.5%以上のRFUmaxを記録した。一方、PVPを含有する処方液1および2の各群ではRFUmaxはすべて101%未満であった。 (Test results)
The results are shown in FIG. In the stimulation control group and the prescription solutions 3 to 6, RFU increased after the addition of diquafosol sodium, and RFUmax of 103.5% or more was recorded. On the other hand, RFUmax was less than 101% in each group of
何らかの刺激を受容した末梢神経細胞は活動電位を発生して興奮状態となり、活動電位に変換された刺激の信号はその後、中枢神経系へと伝達される。活動電位とはカルシウムイオンを含む陽イオンの細胞内流入によって生じた細胞膜電位変化である。そのため、神経細胞内カルシウムイオン濃度の上昇は、神経細胞の興奮状態を表す指標として実験的に広く用いられている。末梢神経細胞にジクアホソルナトリウムを曝露すると速やかに細胞内カルシウムイオンの蛍光強度に上昇がみられ、神経細胞がジクアホソルナトリウムを刺激として受容し、興奮状態になったことが示された。比較例としたPVPを含まないポリマー処方液3~6の各群においても同様の刺激応答が認められ、コンドロイチン硫酸ナトリウム、HPMC、CVPおよびCMC-Naの各ポリマーは、ジクアホソルナトリウムの神経刺激性に対してなんら影響を及ぼさなかった。これに対して、PVPを含む処方液1および2の下では、ジクアホソルナトリウム添加後の神経細胞内カルシウムイオンシグナルの上昇は示されなかった。すなわち、PVPと共存下にあるジクアホソルナトリウムは神経刺激性を示さず、PVPの添加によってジクアホソルナトリウム点眼液の差し心地感が改善されることが示唆された。 (Discussion)
Peripheral nerve cells that receive some stimulus generate action potentials and become excited, and the stimulus signals converted into action potentials are then transmitted to the central nervous system. The action potential is a change in cell membrane potential caused by the intracellular influx of cations including calcium ions. Therefore, the increase in the intracellular calcium ion concentration is widely used experimentally as an index showing the excitable state of nerve cells. When peripheral nerve cells were exposed to diquafosol sodium, the fluorescence intensity of intracellular calcium ions was rapidly increased, indicating that the nerve cells received diquafosol sodium as a stimulus and became excited. Similar stimulus responses were observed in each group of polymer formulations 3 to 6 containing no PVP as a comparative example, and each polymer of chondroitin sodium sulfate, HPMC, CVP and CMC-Na was neurostimulated with diquafosol sodium. It had no effect on sex. In contrast, under
本組成物が防腐剤の安定性に及ぼす影響を検討した。 [Test 5]
The effect of this composition on the stability of preservatives was investigated.
点眼液6:
表5に示す処方に従って、点眼液6を調製した。具体的には、ジクアホソルナトリウム(3g)、クロルヘキシジングルコン酸塩(0.0025g)、ヒドロキシエチルセルロース(0.2g)、リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、塩化ナトリウム(0.45g)を水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とした。 (Sample preparation method)
Eye drops 6:
Ophthalmic solution 6 was prepared according to the formulation shown in Table 5. Specifically, sodium diquafosol (3 g), chlorhexidine sulconate (0.0025 g), hydroxyethyl cellulose (0.2 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate. (0.01 g) and sodium chloride (0.45 g) were dissolved in water to make 100 mL, and a pH regulator (q.s.) was added to make pH 7.5.
表5に示す処方に従って、点眼液6と同様に点眼液7~10を調製した。 Eye drops 7-10:
According to the prescription shown in Table 5, eye drops 7 to 10 were prepared in the same manner as in eye drops 6.
点眼液6および7を60℃で、それぞれ4週まで保存したときの、クロルヘキシジングルコン酸塩の含有量を高速液体クロマトグラフィー(HPLC)を用いて定量し、その残存率(%)を算出した。点眼液8および9を60℃で、それぞれ2週まで保存したときの、クロルヘキシジングルコン酸塩の含有量を、高速液体クロマトグラフィー(HPLC)を用いて定量し、その残存率(%)を算出した。点眼液10を60℃で4週まで保存したときの、硝酸銀の含有量を高周波誘導結合プラズマ発光分光分析法(ICP-AES)を用いて定量し、その残存率(%)を算出した。 (Test method)
The content of chlorhexidine gluconate when the eye drops 6 and 7 were stored at 60 ° C. for up to 4 weeks was quantified by using high performance liquid chromatography (HPLC), and the residual rate (%) was calculated. The content of chlorhexidine gluconate when the eye drops 8 and 9 were stored at 60 ° C. for up to 2 weeks was quantified by using high performance liquid chromatography (HPLC), and the residual rate (%) was calculated. .. The silver nitrate content when the
安定性試験の結果を表6に示す。 (Test results)
The results of the stability test are shown in Table 6.
ジクアホソルまたはその塩、およびポリビニルピロリドンを含有する水性眼科用組成物(本組成物)において、防腐剤としてクロルヘキシジングルコン酸塩を含有させた場合、その残存率は著しく低下した(点眼液7~9)。一方、防腐剤として銀塩である硝酸銀を含有させた場合、その残存率は高かった(点眼液10)。以上より、本組成物は、クロルヘキシジングルコン酸塩を不安定化させる一方で、銀塩を安定化させることが示された。 (Discussion)
In an aqueous ophthalmic composition (the present composition) containing diquafosol or a salt thereof and polyvinylpyrrolidone, when chlorhexidine gluconate was contained as a preservative, the residual rate was significantly reduced (eye drops 7 to 9). .. On the other hand, when silver nitrate, which is a silver salt, was contained as a preservative, the residual rate was high (eye drops 10). From the above, it was shown that this composition stabilizes the silver salt while destabilizing the chlorhexidine gluconate.
銀塩を含有する本組成物の保存効力について検討した。 [Test 6]
The preservative effect of this composition containing a silver salt was examined.
点眼液11:
表7に示す処方に従って、点眼液11を調製した。具体的には、ジクアホソルナトリウム(3g)、硝酸銀(0.00008g)、リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、ポリビニルピロリドンK30(2g)、濃グリセリン(1.2g)、ヒドロキシエチルセルロース(0.25g)を滅菌精製水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とした。 (Sample preparation method)
Eye drops 11:
Ophthalmic solution 11 was prepared according to the formulation shown in Table 7. Specifically, sodium diquafosol (3 g), silver nitrate (0.00008 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K30 (2 g). ), Concentrated glycerin (1.2 g) and hydroxyethyl cellulose (0.25 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs.) Was added to make pH 7.5.
表7に示す処方に従って、点眼液11と同様に点眼液12~15の各点眼液を調製した。 Eye drops 12 to 15:
According to the prescription shown in Table 7, each eye drop of 12 to 15 was prepared in the same manner as the eye drop 11.
保存効力試験は、第十七改正日本薬局方の保存効力試験法に準拠して行なった。本試験では、試験菌として、Esherichia Coli(E.coli)、Pseudomonas aeruginosa(P.aeruginosa)、Staphylococcus aureus(S.aureus)、Candida albicans(C.albicans)およびAspergillus brasiliensis(A.brasiliensis)を用いた。 (Test method)
The storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..
試験結果を表8に示す。 (Test results)
The test results are shown in Table 8.
上記の結果から、銀塩を含有する本組成物は優れた保存効力を有することが示された。 (Discussion)
From the above results, it was shown that the present composition containing a silver salt has an excellent preservative effect.
正常雄性白色ウサギを用いて、本組成物の点眼後90分における涙液量の経時変化を評価した。 [Test 7]
Using normal male white rabbits, the time course of tear volume was evaluated 90 minutes after instillation of this composition.
点眼液16:
点眼液16として、リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、塩化ナトリウム(0.45g)、硝酸銀(0.00004g)、ポリビニルピロリドンK90(2g)、ジクアホソルナトリウム(3g)を滅菌精製水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とした。 (Sample preparation method)
Eye drops 16:
As the ophthalmic solution 16, sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g). ), Sodium diquafosol (3 g) was dissolved in sterile purified water to make 100 mL, and a pH adjuster (q.s.) was added to make pH 7.5.
点眼液17として、ドライアイ治療薬として使用されている「ジクアス(登録商標)点眼液3%」(参天製薬株式会社製)を使用した。点眼液17は、水1mL中、有効成分としてジクアホソルナトリウムを30mg含有し、添加物として塩化カリウム、塩化ナトリウム、クロルヘキシジングルコン酸塩液、リン酸水素ナトリウム水和物、エデト酸ナトリウム水和物、pH調節剤を含有する。 Eye drops 17:
As the eye drop 17, "Diquas (registered trademark) eye drop 3%" (manufactured by Santen Pharmaceutical Co., Ltd.), which is used as a therapeutic agent for dry eye, was used. The ophthalmic solution 17 contains 30 mg of sodium diquafosol as an active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, and sodium edetate hydrate as additives. , Contains a pH regulator.
正常雄性白色ウサギ(計12匹24眼)にベノキシール(登録商標)点眼液0.4%(参天製薬株式会社製)を点眼し、局所麻酔を施した。3分後に下眼瞼にシルメル試験紙(あゆみ製薬株式会社製)を挿入し、挿入1分後に抜き取り、濡れた部分の長さ(涙液量)を読み取った。これを前値とした。次に、各点眼液16,17を1回点眼した(一群6匹12眼)。下眼瞼にシルメル試験紙(あゆみ製薬株式会社製)を挿入する3分前に、ベノキシール(登録商標)点眼液0.4%(参天製薬株式会社製)を点眼し、局所麻酔を施した。各点眼液点眼90分後に、下眼瞼にシルメル試験紙(あゆみ製薬株式会社製)を挿入し、挿入1分後に抜き取り、濡れた部分の長さ(涙液量)を読み取った。 (Test method and drug administration method)
Normal male white rabbits (12 animals, 24 eyes in total) were instilled with Benokiseal (registered trademark) ophthalmic solution 0.4% (manufactured by Santen Pharmaceutical Co., Ltd.) and subjected to local anesthesia. After 3 minutes, a Sylmel test paper (manufactured by AYUMI Pharmaceutical Corporation) was inserted into the lower eyelid, and 1 minute after the insertion, the paper was removed and the length of the wet portion (tear volume) was read. This was used as the previous value. Next, each eye drop 16 and 17 was instilled once (6 animals in a group, 12 eyes). Three minutes before inserting the Sylmel test paper (manufactured by AYUMI Pharmaceutical Corporation) into the lower eyelid, 0.4% of Benokiseal (registered trademark) ophthalmic solution (manufactured by Santen Pharmaceutical Corporation) was instilled and local anesthesia was applied. 90 minutes after each ophthalmic solution was instilled, a Sylmel test paper (manufactured by AYUMI Pharmaceutical Corporation) was inserted into the lower eyelid, and 1 minute after the insertion, it was withdrawn and the length of the wet portion (tear volume) was read.
点眼液点眼前後の涙液量の変化をΔ涙液量(mm/分)として算出した。 (Evaluation methods)
Ophthalmic solution The change in tear volume before and after instillation was calculated as Δ tear volume (mm / min).
点眼後90分におけるΔ涙液量(mm/分)を表9に示す(各値は12眼の平均値)。また、本組成物の涙液量増加作用を以下の基準に従って評価した。
+++:点眼後90分におけるΔ涙液量(mm/分)が4mm/分以上
++:点眼後90分におけるΔ涙液量(mm/分)が1mm/分以上、4mm/分未満
+:点眼後90分におけるΔ涙液量(mm/分)が0mm/分超乃至1mm/分未満
-:点眼後90分におけるΔ涙液量(mm/分)が0mm/分以下 (Test results)
Table 9 shows the amount of Δtear fluid (mm / min) 90 minutes after instillation (each value is the average value of 12 eyes). In addition, the tear volume increasing effect of this composition was evaluated according to the following criteria.
+++: Delta tear volume (mm / min) 90 minutes after instillation is 4 mm / min or more
++: Delta tear volume (mm / min) 90 minutes after instillation is 1 mm / min or more and less than 4 mm / min
+: Delta tear volume (mm / min) 90 minutes after instillation is more than 0 mm / min to less than 1 mm / min
-: Delta tear volume (mm / min) 90 minutes after instillation is 0 mm / min or less
銀塩を含有する本組成物の保存効力について検討した。 [Test 8]
The preservative effect of this composition containing a silver salt was examined.
点眼液18:
表10に示す処方に従って、点眼液18を調製した。具体的には、ジクアホソルナトリウム(3g)、硝酸銀(0.00003g)、リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、ポリビニルピロリドンK90(2g)、塩化ナトリウム(0.45g)を滅菌精製水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.0とした。 (Sample preparation method)
Eye drops 18:
Ophthalmic solution 18 was prepared according to the formulation shown in Table 10. Specifically, sodium diquafosol (3 g), silver nitrate (0.00003 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g). ), Sodium chloride (0.45 g) was dissolved in sterilized purified water to make 100 mL, and a pH adjuster (qs.) Was added to make the pH 7.0.
表10に示す処方に従って、点眼液18と同様に点眼液19を調製した。 Eye drops 19:
An eye drop 19 was prepared in the same manner as the eye drop 18 according to the formulation shown in Table 10.
保存効力試験は、第十七改正日本薬局方の保存効力試験法に準拠して行った。本試験では、試験菌として、Esherichia Coli(E.coli)、Pseudomonas aeruginosa(P.aeruginosa)、Staphylococcus aureus(S.aureus)、Candida albicans(C.albicans)およびAspergillus brasiliensis(A.brasiliensis)を用いた。 (Test method)
The storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..
試験結果を表11に示す。 (Test results)
The test results are shown in Table 11.
上記の結果から、銀塩を含有する本組成物は優れた保存効力を有することが示された。 (Discussion)
From the above results, it was shown that the present composition containing a silver salt has an excellent preservative effect.
銀塩を含有する本組成物の保存効力について検討した。 [Test 9]
The preservative effect of this composition containing a silver salt was examined.
点眼液20:
表12に示す処方に従って、点眼液20を調製した。具体的には、ジクアホソルナトリウム(3g)、硝酸銀(0.00004g)、リン酸水素ナトリウム水和物(0.2g)、エデト酸ナトリウム水和物(0.01g)、ポリビニルピロリドンK90(2g)、塩化ナトリウム(0.45g)を滅菌精製水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とした。 (Sample preparation method)
Eye drops 20:
表12に示す処方に従って、点眼液20と同様に点眼液21~23の各点眼液を調製した。 Eye drops 21-23:
According to the prescription shown in Table 12, each eye drop of the eye drops 21 to 23 was prepared in the same manner as the
保存効力試験は、第十七改正日本薬局方の保存効力試験法に準拠して行った。本試験では、試験菌として、Esherichia Coli(E.coli)、Pseudomonas aeruginosa(P.aeruginosa)、Staphylococcus aureus(S.aureus)、Candida albicans(C.albicans)およびAspergillus brasiliensis(A.brasiliensis)を用いた。 (Test method)
The storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..
試験結果を表13に示す。 (Test results)
The test results are shown in Table 13.
上記の結果から、銀塩を含有する本組成物は優れた保存効力を有することが示された。 (Discussion)
From the above results, it was shown that the present composition containing a silver salt has an excellent preservative effect.
本組成物が防腐剤の安定性に及ぼす影響を検討した。 [Test 10]
The effect of this composition on the stability of preservatives was investigated.
点眼液24:
ジクアホソルナトリウム(3g)、エデト酸ナトリウム水和物(0.01g)、リン酸水素ナトリウム水和物(0.2g)、塩化ナトリウム(0.45g)、ポリビニルピロリドンK90(2g)、硝酸銀(0.00004g)を水に溶解して100mLとし、pH調節剤(q.s.)を添加して、pH7.5とし、点眼液24を調製した。 (Sample preparation method)
Eye drops 24:
Sodium diquafosol (3 g), sodium edetate hydrate (0.01 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.45 g), polyvinylpyrrolidone K90 (2 g), silver nitrate ( 0.00004 g) was dissolved in water to make 100 mL, and a pH adjuster (q.s.) was added to make the pH 7.5, and an ophthalmic solution 24 was prepared.
点眼液24を40℃で6か月まで保存したときの硝酸銀の含有量を高周波誘導結合プラズマ発光分光分析法(ICP-AES)を用いて定量し、その残存率(%)を算出した。 (Test method)
The content of silver nitrate when the ophthalmic solution 24 was stored at 40 ° C. for up to 6 months was quantified using high frequency inductively coupled plasma emission spectroscopy (ICP-AES), and the residual rate (%) was calculated.
安定性試験の結果を表14に示す。 (Test results)
The results of the stability test are shown in Table 14.
防腐剤として銀塩である硝酸銀を含有させた場合、その残存率は高かった。以上より、本組成物において、銀塩は安定であることが示された。 (Discussion)
When silver nitrate, which is a silver salt, was contained as a preservative, the residual rate was high. From the above, it was shown that the silver salt is stable in this composition.
製剤例を挙げて本発明の薬剤をさらに具体的に説明するが、本発明はこれらの製剤例にのみ限定されるものではない。 [Formulation example]
The agent of the present invention will be described in more detail with reference to formulation examples, but the present invention is not limited to these formulation examples.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
エデト酸ナトリウム水和物 0.0001~0.1g
ポリビニルピロリドン K90 0.0001~10g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器またはPFMD容器に充填し、眼科医薬用製品を製造することができる。また、上記点眼液0.1~1mLをユニットドーズ型点眼容器に充填し、眼科医薬用製品を製造することもできる。なお、上記点眼液は室温で保存することができる。 (Prescription Example 1: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1g
Polyvinylpyrrolidone K90 0.0001-10g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container or PFMD container. Further, 0.1 to 1 mL of the above ophthalmic solution can be filled in a unit dose type eye drop container to produce an ophthalmic pharmaceutical product. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
エデト酸ナトリウム水和物 0.0001~0.1g
ポリビニルピロリドン K60 0.0001~10g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器またはPFMD容器に充填し、眼科医薬用製品を製造することができる。また、上記点眼液0.1~1mLをユニットドーズ型点眼容器に充填し、眼科医薬用製品を製造することもできる。なお、上記点眼液は室温で保存することができる。 (Prescription example 2: sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1g
Polyvinylpyrrolidone K60 0.0001-10g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container or PFMD container. Further, 0.1 to 1 mL of the above ophthalmic solution can be filled in a unit dose type eye drop container to produce an ophthalmic pharmaceutical product. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
エデト酸ナトリウム水和物 0.0001~0.1g
ポリビニルピロリドン K40 0.0001~10g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器またはPFMD容器に充填し、眼科医薬用製品を製造することができる。また、上記点眼液0.1~1mLをユニットドーズ型点眼容器に充填し、眼科医薬品製品を製造することもできる。なお、上記点眼液は室温で保存することができる。 (Prescription Example 3: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1g
Polyvinylpyrrolidone K40 0.0001-10g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container or PFMD container. Further, 0.1 to 1 mL of the above ophthalmic solution can be filled in a unit dose type eye drop container to produce an ophthalmic pharmaceutical product. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
エデト酸ナトリウム水和物 0.0001~0.1g
ポリビニルピロリドン K90 0.0001~10g
硝酸銀 0.00000001~1g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器に充填し、眼科医薬用製品を製造することができる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 4: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1g
Polyvinylpyrrolidone K90 0.0001-10g
Silver nitrate 0.00000001 ~ 1g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
エデト酸ナトリウム水和物 0.0001~0.1g
ポリビニルピロリドン K60 0.0001~10g
硝酸銀 0.00000001~1g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器に充填し、眼科医薬用製品を製造することができる。なお、上記点眼液は室温で保存することができる。 (Prescription Example 5: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1g
Polyvinylpyrrolidone K60 0.0001-10g
Silver nitrate 0.00000001 ~ 1g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
エデト酸ナトリウム水和物 0.0001~0.1g
ポリビニルピロリドン K40 0.0001~10g
硝酸銀 0.00000001~1g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器に充填し、眼科医薬用製品を製造することができる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 6: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Sodium edetate hydrate 0.0001-0.1g
Polyvinylpyrrolidone K40 0.0001-10g
Silver nitrate 0.00000001 ~ 1g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
ポリビニルピロリドン K90 0.0001~10g
pH調節剤 適量
滅菌精製液にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼剤を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器またはPFMD容器に充填し、眼科医薬用製品を製造することができる。また、上記点眼液0.1~1mLをユニットドーズ型点眼容器に充填し、眼科医薬用製品を製造することもできる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 7: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K90 0.0001-10g
pH adjuster Appropriate amount Diquafosol sodium and other above-mentioned components are added to a sterilized purified solution, and these are sufficiently mixed to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container or PFMD container. Further, 0.1 to 1 mL of the above ophthalmic solution can be filled in a unit dose type eye drop container to produce an ophthalmic pharmaceutical product. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
ポリビニルピロリドン K60 0.0001~10g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器またはPFMD容器に充填し、眼科医薬用製品を製造することができる。また、上記点眼液0.1~1mLをユニットドーズ型点眼容器に充填し、眼科医薬用製品を製造することもできる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 8: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K60 0.0001-10g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container or PFMD container. Further, 0.1 to 1 mL of the above ophthalmic solution can be filled in a unit dose type eye drop container to produce an ophthalmic pharmaceutical product. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
ポリビニルピロリドン K40 0.0001~10g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器またはPFMD容器に充填し、眼科医薬用製品を製造することができる。また、上記点眼液0.1~1mLをユニットドーズ型点眼容器に充填し、眼科医薬用製品を製造することもできる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 9: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K40 0.0001-10g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container or PFMD container. Further, 0.1 to 1 mL of the above ophthalmic solution can be filled in a unit dose type eye drop container to produce an ophthalmic pharmaceutical product. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
ポリビニルピロリドン K90 0.0001~10g
硝酸銀 0.00000001~1g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器に充填し、眼科医薬用製品を製造することができる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 10: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K90 0.0001-10g
Silver nitrate 0.00000001 ~ 1g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
ポリビニルピロリドン K60 0.0001~10g
硝酸銀 0.00000001~1g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器に充填し、眼科医薬用製品を製造することができる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 11: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K60 0.0001-10g
Silver nitrate 0.00000001 ~ 1g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
ポリビニルピロリドン K40 0.0001~10g
硝酸銀 0.00000001~1g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器に充填し、眼科医薬用製品を製造することができる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 12: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Polyvinylpyrrolidone K40 0.0001-10g
Silver nitrate 0.00000001 ~ 1g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
クエン酸水和物 0.0001~0.1g
ポリビニルピロリドン K90 0.0001~10g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器またはPFMD容器に充填し、眼科医薬用製品を製造することができる。また、上記点眼液0.1~1mLをユニットドーズ型点眼容器に充填し、眼科医薬用製品を製造することもできる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 13: Sterile aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Citric acid hydrate 0.0001-0.1g
Polyvinylpyrrolidone K90 0.0001-10g
pH regulator Appropriate amount Add diquafosol sodium and other above-mentioned components to sterilized purified water and mix them well to prepare the above-mentioned eye drops. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container or PFMD container. Further, 0.1 to 1 mL of the above ophthalmic solution can be filled in a unit dose type eye drop container to produce an ophthalmic pharmaceutical product. The above eye drops can be stored at room temperature.
100mL中
ジクアホソルナトリウム 3g
リン酸水素ナトリウム水和物 0.01~0.5g
塩化ナトリウム 0.01~1g
クエン酸水和物 0.0001~0.1g
ポリビニルピロリドン K90 0.0001~10g
硝酸銀 0.00000001~1g
pH調節剤 適量
滅菌精製水にジクアホソルナトリウムおよびそれ以外の上記成分を加え、これらを十分に混合することで上記点眼液を調製できる。上記点眼液1~10mLをマルチドーズ型点眼容器に充填し、眼科医薬用製品を製造することができる。なお、上記点眼剤は室温で保存することができる。 (Prescription Example 14: Aseptic aqueous ophthalmic solution (3% (w / v)))
Diquafosol sodium 3g in 100mL
Sodium hydrogen phosphate hydrate 0.01-0.5 g
Sodium chloride 0.01-1g
Citric acid hydrate 0.0001-0.1g
Polyvinylpyrrolidone K90 0.0001-10g
Silver nitrate 0.00000001 ~ 1g
pH adjuster Appropriate amount Diquafosol sodium and other above-mentioned components are added to sterilized purified water, and these are sufficiently mixed to prepare the above-mentioned ophthalmic solution. An ophthalmic pharmaceutical product can be produced by filling 1 to 10 mL of the above ophthalmic solution in a multi-dose type eye drop container. The above eye drops can be stored at room temperature.
Claims (51)
- ジクアホソルまたはその塩、およびポリビニルピロリドンを含有する水性眼科用組成物。 An aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone.
- さらに、銀塩を含有する、請求項1に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 1, further containing a silver salt.
- 銀塩が、硝酸銀を含む、請求項2に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 2, wherein the silver salt contains silver nitrate.
- ドライアイの予防または治療のための、請求項1~3のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 3, for the prevention or treatment of dry eye.
- 1~5%(w/v)の濃度のジクアホソルナトリウムおよびK値が30超ないし120以下のポリビニルピロリドンを含有する、請求項4に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 4, which contains sodium diquafosol at a concentration of 1 to 5% (w / v) and polyvinylpyrrolidone having a K value of more than 30 to 120 or less.
- 3%(w/v)の濃度のジクアホソルナトリウムおよびK値が30超ないし120以下のポリビニルピロリドンを含有する、請求項4に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 4, which contains sodium diquafosol at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of more than 30 to 120 or less.
- 1~5%(w/v)の濃度のジクアホソルナトリウムを含有し、粘度が25℃において1.5~30mPa・sである、請求項4に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 4, which contains sodium diquafosol at a concentration of 1 to 5% (w / v) and has a viscosity of 1.5 to 30 mPa · s at 25 ° C.
- 3%(w/v)の濃度のジクアホソルナトリウムを含有し、粘度が25℃において1.5~30mPa・sである、請求項4に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 4, which contains diquafosol sodium at a concentration of 3% (w / v) and has a viscosity of 1.5 to 30 mPa · s at 25 ° C.
- 1日2~4回点眼投与されるように用いられることを特徴とする、請求項5~8のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 5 to 8, wherein the composition is used so as to be instilled 2 to 4 times a day.
- 1日3回点眼投与されるように用いられることを特徴とする、請求項5~8のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 5 to 8, which is used so as to be administered by eye drops three times a day.
- 1回1~2滴、点眼投与されるように用いられることを特徴とする、請求項9または10に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 9 or 10, characterized in that it is used so as to be administered by instillation in 1 to 2 drops at a time.
- 請求項1に記載の水性眼科用組成物0.1~1mLがユニットドーズ型点眼容器に充填されていることを特徴とする眼科医薬用製品。 An ophthalmic pharmaceutical product, characterized in that 0.1 to 1 mL of the aqueous ophthalmic composition according to claim 1 is filled in a unit dose type eye drop container.
- 請求項1に記載の水性眼科用組成物0.3~0.5mLがユニットドーズ型点眼容器に充填されていることを特徴とする眼科医薬用製品。 An ophthalmic pharmaceutical product, wherein 0.3 to 0.5 mL of the aqueous ophthalmic composition according to claim 1 is filled in a unit dose type eye drop container.
- 請求項1~3のいずれか1項に記載の水性眼科用組成物1~10mLがマルチドーズ型点眼容器に充填されていることを特徴とする眼科医薬用製品。 An ophthalmic pharmaceutical product characterized in that 1 to 10 mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 is filled in a multi-dose type eye drop container.
- 請求項1~3のいずれか1項に記載の水性眼科用組成物5mLがマルチドーズ型点眼容器に充填されていることを特徴とする、眼科医薬用製品。 An ophthalmic pharmaceutical product, characterized in that 5 mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 is filled in a multi-dose type eye drop container.
- 請求項1に記載の水性眼科用組成物1~10mLがPFMD容器に充填されていることを特徴とする眼科医薬用製品。 An ophthalmic pharmaceutical product, wherein 1 to 10 mL of the aqueous ophthalmic composition according to claim 1 is filled in a PFMD container.
- 請求項1に記載の水性眼科用組成物5mLがPFMD容器に充填されていることを特徴とする眼科医薬用製品。 An ophthalmic pharmaceutical product, wherein 5 mL of the aqueous ophthalmic composition according to claim 1 is filled in a PFMD container.
- ドライアイの予防または治療のための、請求項12~17のいずれか1項に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to any one of claims 12 to 17, for the prevention or treatment of dry eye.
- 水性眼科用組成物が1~5%(w/v)の濃度のジクアホソルナトリウムおよびK値が30超ないし120以下のポリビニルピロリドンを含有する、請求項18に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 1 to 5% (w / v) and polyvinylpyrrolidone having a K value of more than 30 to 120 or less.
- 水性眼科用組成物が3%(w/v)の濃度のジクアホソルナトリウムおよびK値が30超ないし120以下のポリビニルピロリドンを含有する、請求項18に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of more than 30 to 120 or less.
- 水性組成物が1~5%(w/v)の濃度のジクアホソルナトリウムを含有し、25℃において1.5~30mPa・sの粘度を有する、請求項18に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous composition contains diquafosol sodium at a concentration of 1 to 5% (w / v) and has a viscosity of 1.5 to 30 mPa · s at 25 ° C.
- 水性組成物が3%(w/v)の濃度のジクアホソルナトリウムを含有し、25℃において1.5~30mPa・sの粘度を有する、請求項18に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous composition contains sodium diquafosol at a concentration of 3% (w / v) and has a viscosity of 1.5 to 30 mPa · s at 25 ° C.
- 1日2~4回点眼投与されるように用いられることを特徴とする、請求項19~22のいずれか1項に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to any one of claims 19 to 22, which is used so as to be administered by eye drops 2 to 4 times a day.
- 1日3回点眼投与されるように用いられることを特徴とする、請求項19~22のいずれか1項に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to any one of claims 19 to 22, which is used so as to be administered by eye drops three times a day.
- 1回1~2滴、点眼投与されるように用いられることを特徴とする、請求項23または24に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to claim 23 or 24, which is used so as to be administered by eye drops in an amount of 1 to 2 drops at a time.
- K値が17以上のポリビニルピロリドンを含む、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, which contains polyvinylpyrrolidone having a K value of 17 or more.
- K値が17~120のポリビニルピロリドンを含む、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, which comprises polyvinylpyrrolidone having a K value of 17 to 120.
- K値が30超ないし120以下のポリビニルピロリドンを含む、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, which comprises polyvinylpyrrolidone having a K value of more than 30 to 120 or less.
- K値が90のポリビニルピロリドンを含む、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, which comprises polyvinylpyrrolidone having a K value of 90.
- 前記ポリビニルピロリドンの濃度が、0.001%(w/v)以上である、請求項1~11のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the concentration of polyvinylpyrrolidone is 0.001% (w / v) or more.
- 前記ジクアホソルまたはその塩の濃度が、0.0001~10%(w/v)である、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 0.0001 to 10% (w / v).
- 前記ジクアホソルまたはその塩の濃度が、0.01~5%(w/v)である、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 0.01 to 5% (w / v).
- 前記ジクアホソルまたはその塩の濃度が、1~5%(w/v)である、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 1 to 5% (w / v).
- 前記ジクアホソルまたはその塩の濃度が、3%(w/v)である、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or a salt thereof is 3% (w / v).
- 前記水性眼科用組成物のpHが、6~8の範囲である、請求項1~11のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the pH of the aqueous ophthalmic composition is in the range of 6 to 8.
- 前記水性眼科用組成物のpHが、7~8の範囲である、請求項1~11のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the pH of the aqueous ophthalmic composition is in the range of 7 to 8.
- 前記水性眼科用組成物が無菌水性点眼液である、請求項1~11のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the aqueous ophthalmic composition is a sterile aqueous ophthalmic solution.
- 室温で保存可能である、請求項1~11のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 11, which can be stored at room temperature.
- 前記水性眼科用組成物の粘度が25℃において1.5~30mPa・sである、請求項1~6のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 6, wherein the viscosity of the aqueous ophthalmic composition is 1.5 to 30 mPa · s at 25 ° C.
- 前記ジクアホソルの塩が、ジクアホソルナトリウムである、請求項1~4のいずれか1項に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the salt of the diquafosol is diquafosol sodium.
- 1回1~2滴、1日2~4回点眼投与されるように用いられることを特徴とする、3%(w/v)の濃度のジクアホソルナトリウム、K値が90のポリビニルピロリドンおよび硝酸銀を含有する、ドライアイの予防または治療のための水性眼科用組成物。 Diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone with a K value of 90 and, characterized in that it is used to be administered by instillation 1 to 2 drops at a time, 2 to 4 times a day. An aqueous ophthalmic composition containing silver nitrate for the prevention or treatment of dry eye.
- 1回1~2滴、1日2~4回点眼投与されるように用いられることを特徴とする、3%(w/v)の濃度のジクアホソルナトリウム、ポリビニルピロリドンおよび硝酸銀を含有する、ドライアイの予防または治療のための水性眼科用組成物であって、粘度が25℃において3~30mPa・sである、水性眼科用組成物。 It contains 3% (w / v) concentration of diquafosol sodium, polyvinylpyrrolidone and silver nitrate, characterized in that it is used to be administered by instillation 1 to 2 drops at a time, 2 to 4 times a day. An aqueous ophthalmic composition for the prevention or treatment of dry eye, the aqueous ophthalmic composition having a viscosity of 3 to 30 mPa · s at 25 ° C.
- 1日3回点眼投与されるように用いられることを特徴とする、請求項41または42に記載の水性眼科用組成物。 The aqueous ophthalmic composition according to claim 41 or 42, which is used so as to be administered by eye drops three times a day.
- 3%(w/v)の濃度のジクアホソルナトリウムおよびK値が90のポリビニルピロリドンを含有する水性眼科用組成物0.1~1mLがユニットドーズ型点眼容器に充填された、ドライアイの予防または治療のための眼科医薬用製品であって、1回1~2滴、1日2~4回、前記水性眼科用組成物が点眼投与されるように用いられることを特徴とする、眼科医薬用製品。 Prevention of dry eye, 0.1-1 mL of an aqueous ophthalmic composition containing 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90 was filled in a unit dose type eye drop container. Alternatively, it is an ophthalmic pharmaceutical product for treatment, characterized in that the aqueous ophthalmic composition is used by instillation 1 to 2 drops at a time, 2 to 4 times a day. Product for.
- 3%(w/v)の濃度のジクアホソルナトリウムおよびポリビニルピロリドンを含有する水性眼科用組成物0.1~1mLがユニットドーズ型点眼容器に充填された、ドライアイの予防または治療のための眼科医薬用製品であって、前記水性眼科用組成物が25℃において3~30mPa・sの粘度を有し、且つ1回1~2滴、1日2~4回、点眼投与されるように用いられることを特徴とする、眼科医薬用製品。 0.1-1 mL of an aqueous ophthalmic composition containing 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone was filled in a unit dose type eye drop container for the prevention or treatment of dry eye. An ophthalmic pharmaceutical product such that the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa · s at 25 ° C. and is instilled in 1 to 2 drops at a time, 2 to 4 times a day. An ophthalmic pharmaceutical product characterized by being used.
- 3%(w/v)の濃度のジクアホソルナトリウムおよびK値が90のポリビニルピロリドンを含有する水性眼科用組成物1~10mLがマルチドーズ型点眼容器に充填された、ドライアイの予防または治療のための眼科医薬用製品であって、1回1~2滴、1日2~4回、前記水性眼科用組成物が点眼投与されるように用いられることを特徴とする、眼科医薬用製品。 Prevention or treatment of dry eye in which 1-10 mL of an aqueous ophthalmic composition containing 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone having a K value of 90 was filled in a multidose eye drop container. A product for ophthalmic medicine, characterized in that the aqueous ophthalmic composition is used by instillation 1 to 2 drops at a time, 2 to 4 times a day. ..
- 3%(w/v)の濃度のジクアホソルナトリウムおよびポリビニルピロリドンを含有する水性眼科用組成物1~10mLがマルチドーズ型点眼容器に充填された、ドライアイの予防または治療のための眼科医薬用製品であって、前記水性眼科用組成物が25℃において3~30mPa・sの粘度を有し、且つ1回1~2滴、1日2~4回、点眼投与されるように用いられることを特徴とする、眼科医薬用製品。 An ophthalmic drug for the prevention or treatment of dry eye, in which 1 to 10 mL of an aqueous ophthalmic composition containing 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone is filled in a multidose eye drop container. The aqueous ophthalmic composition is used so as to have a viscosity of 3 to 30 mPa · s at 25 ° C. and to be instilled 1 to 2 drops at a time, 2 to 4 times a day. An ophthalmic pharmaceutical product characterized by this.
- 3%(w/v)の濃度のジクアホソルナトリウムおよびK値が90のポリビニルピロリドンを含有する水性眼科用組成物1~10mLがPFMD容器に充填された、ドライアイの予防または治療のための眼科医薬用製品であって、1回1~2滴、1日2~4回、前記水性眼科用組成物が点眼投与されるように用いられることを特徴とする、眼科医薬用製品。 1-10 mL of an aqueous ophthalmic composition containing 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone with a K value of 90 was filled in a PFMD container for the prevention or treatment of dry eye. An ophthalmic pharmaceutical product, wherein the aqueous ophthalmic composition is used by instillation 1 to 2 drops at a time, 2 to 4 times a day.
- 3%(w/v)の濃度のジクアホソルナトリウムおよびポリビニルピロリドンを含有する水性眼科用組成物1~10mLがPFMD容器に充填された、ドライアイの予防または治療のための眼科医薬用製品であって、前記水性眼科用組成物が25℃において3~30mPa・sの粘度を有し、且つ1回1~2滴、1日2~4回、点眼投与されるように用いられることを特徴とする、眼科医薬用製品。 An ophthalmic pharmaceutical product for the prevention or treatment of dry eye, in which 1-10 mL of an aqueous ophthalmic composition containing 3% (w / v) concentration of diquafosol sodium and polyvinylpyrrolidone is filled in a PFMD container. The aqueous ophthalmic composition has a viscosity of 3 to 30 mPa · s at 25 ° C., and is characterized in that it is used so as to be instilled 1 to 2 drops at a time and 2 to 4 times a day. Ophthalmic pharmaceutical products.
- 1日3回点眼投与されるように用いられることを特徴とする、請求項44~49のいずれか1項に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to any one of claims 44 to 49, which is used so as to be administered by eye drops three times a day.
- さらに、硝酸銀を含有する、請求項46または47のいずれか1項に記載の眼科医薬用製品。 The ophthalmic pharmaceutical product according to any one of claims 46 or 47, further containing silver nitrate.
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