WO2013146649A1 - ジクアホソル含有点眼液 - Google Patents
ジクアホソル含有点眼液 Download PDFInfo
- Publication number
- WO2013146649A1 WO2013146649A1 PCT/JP2013/058519 JP2013058519W WO2013146649A1 WO 2013146649 A1 WO2013146649 A1 WO 2013146649A1 JP 2013058519 W JP2013058519 W JP 2013058519W WO 2013146649 A1 WO2013146649 A1 WO 2013146649A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ophthalmic solution
- diquafosol
- chelating agent
- acid
- concentration
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
Definitions
- the present invention relates to an aqueous ophthalmic solution containing diquafosol or a salt thereof in a concentration of 0.1 to 10% (w / v) and a chelating agent in a concentration of 0.0001 to 1% (w / v), and a method for producing the same About. Further, the present invention relates to an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v) (hereinafter, also simply referred to as “diquafosol ophthalmic solution”) in a range of 0.0001 to 1%.
- a method for suppressing the generation of insoluble precipitates in the aqueous ophthalmic solution by adding a chelating agent having a concentration of (w / v), a method for reducing eye irritation of the aqueous ophthalmic solution, and the aqueous ophthalmic solution It also relates to a method for improving the storage efficacy.
- Diquafosol is a purine receptor agonist also called P 1 , P 4 -di (uridine-5 ′) tetraphosphate or Up 4 U, and as disclosed in Japanese Patent No. 36552707 (Patent Document 1), It is known to have a fluid secretion promoting action. Cornea, 23 (8), 784-792 (2004) (Non-patent Document 1) improved the corneal epithelial disorder in dry eye patients by administering ophthalmic solution containing diquafosol tetrasodium salt. It is described.
- an ophthalmic solution containing diquafosol tetrasodium salt at a concentration of 3% (w / v) is used as a dry eye treatment (product name: Diquas (registered trademark) ophthalmic solution 3%).
- ophthalmic solutions need to have stable physicochemical properties in the manufacturing and distribution processes and also in the preservation process by patients.
- an ophthalmic solution in which a precipitate is produced during distribution or storage by a patient is not preferable as an ophthalmic solution because the precipitate cannot be removed afterwards.
- precipitates when precipitates are produced in the manufacturing process, it is possible to remove the precipitates in the process of filtering and sterilizing the ophthalmic solution, but the filtration filter becomes clogged during filtration, so the efficiency of filter sterilization becomes worse. There arises a problem that the manufacturing cost increases.
- Patent Document 2 JP 2007-182438 A discloses a method of adding glycerin to eye drops, which is also described in the same document. As described above, the properties and states of the precipitates are different depending on the types of active ingredients and additives, and naturally, the method for suppressing the generation of the precipitates is different for each ophthalmic solution.
- the present inventors have found that insoluble precipitates are formed over time during storage of diquafosol ophthalmic solution, and a chelating agent having a concentration of 0.0001 to 1% (w / v) is added.
- the inventors have found that the generation of the insoluble precipitates can be suppressed, and have reached the present invention.
- the present inventors added a chelating agent at a concentration of 0.0001 to 1% (w / v) to diquafosol ophthalmic solution, thereby reducing the eye irritation of the ophthalmic solution and increasing its storage efficacy. I also found it to improve.
- the present invention relates to an aqueous ophthalmic solution (hereinafter referred to as the following) containing diquafosol or a salt thereof in a concentration of 0.1 to 10% (w / v) and a chelating agent in a concentration of 0.0001 to 1% (w / v). It is simply referred to as “this ophthalmic solution”).
- the chelating agent in the present ophthalmic solution is preferably at least one selected from the group consisting of edetic acid, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid, and salts thereof, More preferred is at least one selected from the group consisting of edetic acid, citric acid, metaphosphoric acid, polyphosphoric acid and salts thereof, and particularly preferred is a salt of edetic acid.
- the concentration of the chelating agent in the ophthalmic solution is preferably 0.0005 to 0.5% (w / v), and 0.001 to 0.1% (w / v). It is particularly preferred.
- the concentration of diquafosol or a salt thereof is preferably 1 to 10% (w / v), particularly preferably 3% (w / v).
- the ophthalmic solution is also a salt of edetic acid as the chelating agent, the concentration of the chelating agent in the ophthalmic solution is 0.001 to 0.1% (w / v), and diquafosol or a salt thereof in the ophthalmic solution The concentration of is preferably 3% (w / v).
- the ophthalmic solution preferably further contains a preservative.
- the present invention also relates to a method for producing an aqueous ophthalmic solution containing diquafosol or a salt thereof in a concentration of 0.1 to 10% (w / v), comprising diquafosol or a salt thereof and a chelating agent in the aqueous ophthalmic solution
- a production method (hereinafter simply referred to as “the present production method”) comprising a step of obtaining an aqueous solution in which the generation of insoluble precipitates is suppressed by mixing an amount of a chelating agent in an amount of 0.0001-1% (w / v) Is also provided).
- the production method preferably includes a step of filtering the obtained aqueous solution with a filter sterilization filter having a pore size of 0.1 to 0.5 ⁇ m.
- the present invention further includes adding a chelating agent at a concentration of 0.0001 to 1% (w / v) to an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v). Is also provided for suppressing the generation of insoluble precipitates in the aqueous ophthalmic solution.
- the present invention further includes adding a chelating agent at a concentration of 0.0001 to 1% (w / v) to an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v). Is also provided for reducing the eye irritation of the aqueous ophthalmic solution.
- the present invention further includes adding a chelating agent at a concentration of 0.0001 to 1% (w / v) to an aqueous ophthalmic solution containing diquafosol or a salt thereof at a concentration of 0.1 to 10% (w / v). Is also provided for improving the storage efficacy of the aqueous ophthalmic solution.
- this ophthalmic solution As is apparent from the results of the storage stability test and filtration performance test described below, in this ophthalmic solution, the generation of insoluble precipitates during storage observed in diquafosol ophthalmic solution containing no chelating agent and the production process (filter sterilization process) ) was prevented from lowering filterability. In addition, as shown in the results of the eye irritation evaluation test and the storage efficacy test described later, this ophthalmic solution also reduces eye irritation and enhances the storage efficacy compared to diquafosol ophthalmic solution containing no chelating agent. confirmed. Therefore, the present ophthalmic solution has stable physicochemical properties even during the production and distribution process and the preservation process by the patient, and also has an excellent preservation effect while reducing eye irritation. In particular, since the ophthalmic solution is suppressed from being deteriorated in filterability during the production process (filtration sterilization process), efficient filtration sterilization is possible in the production process, which contributes to the reduction of production costs.
- Diquafosol is a compound represented by the following structural formula.
- “Diquafosol salt” is not particularly limited as long as it is a pharmaceutically acceptable salt; metal salt with lithium, sodium, potassium, calcium, magnesium, zinc, etc .; hydrochloric acid, hydrobromic acid, hydroiodic acid , Salts with inorganic acids such as nitric acid, sulfuric acid, phosphoric acid; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
- diquafosol or a salt thereof includes diquafosol (free form) or a hydrate and an organic solvate thereof.
- crystal polymorph groups When diquafosol or a salt thereof has crystal polymorphs and crystal polymorph groups (crystal polymorph systems), those crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the scope of the present invention. It is.
- the crystal polymorph group (crystal polymorph system) is an individual crystal form and its process in each stage when the crystal form changes depending on conditions and states such as production, crystallization, and storage of those crystals. Means the whole.
- diquafosol or a salt thereof of the present invention is a sodium salt of diquafosol, and a diquafosol tetrasodium salt represented by the following structural formula (hereinafter also simply referred to as “diquafosol sodium”) is particularly preferred.
- Diquafosol or a salt thereof can be produced by a method disclosed in JP-T-2001-510484.
- the ophthalmic solution may contain an active ingredient other than diquafosol or a salt thereof, but preferably contains diquafosol or a salt thereof as the only active ingredient.
- the concentration of diquafosol or a salt thereof in this ophthalmic solution is 0.1 to 10% (w / v), preferably 1 to 10% (w / v), and 3% (w / v). It is particularly preferred.
- the amount of diquafosol or a salt thereof used in the present production method is such that the final concentration of diquafosol or a salt thereof in the aqueous ophthalmic solution obtained by the present production method is 0.1 to 10% (w / v). It is preferable that the concentration is 1 to 10% (w / v), and it is particularly preferable that the concentration is 3% (w / v).
- the “aqueous eye drop” means an eye drop using water as a solvent.
- the “chelating agent” is not particularly limited as long as it is a compound that chelates metal ions.
- edetic acid ethylenediaminetetraacetic acid
- monosodium edetate, disodium edetate, trisodium edetate Edetic acid or its salts such as sodium, tetrasodium edetate, dipotassium edetate, tripotassium edetate, tetrapotassium edetate
- citric acid monosodium citrate, disodium citrate, trisodium citrate, monocitrate
- Citric acid or salts thereof such as potassium, dipotassium citrate, tripotassium citrate
- metaphosphoric acid or salts thereof such as metaphosphoric acid, sodium metaphosphate, potassium metaphosphate
- pyrophosphoric acid tetrasodium pyrophosphate, t
- Pyrophosphoric acid or its salt Pyrophosphoric acid or its salt; polyphosphoric acid, polyphosphoric acid Polyphosphoric acid or its salt such as sodium or potassium polyphosphate; Malic acid or its salt such as monosodium malate, disodium malate, monopotassium malate, dipotassium malate; sodium tartrate, potassium tartrate, sodium potassium tartrate, etc. And tartaric acid or salts thereof; phytic acid or salts thereof such as sodium phytate and potassium phytate; and the like.
- “edetic acid, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid and salts thereof” include the free forms or hydrates of those salts and Organic solvates are also included.
- preferred chelating agents are edetic acid, edetic acid salt (edetate), citric acid, citric acid salt (citrate), metaphosphoric acid, metaphosphoric acid salt (metaphosphate), polyphosphoric acid, It is a salt of polyphosphoric acid (polyphosphate), including sodium salt of edetic acid (including hydrates such as disodium edetate hydrate), citric acid (hydrates such as citric acid monohydrate) ), Sodium salt of metaphosphoric acid (sodium metaphosphate), and sodium salt of polyphosphoric acid (sodium polyphosphate) are particularly preferred.
- disodium edetate hydrate (hereinafter also simply referred to as “sodium edetate hydrate”) is the most preferable as edetate.
- the concentration of the chelating agent in this ophthalmic solution is 0.0001 to 1% (w / v), preferably 0.0005 to 0.5% (w / v), 0.001 to 0.1% ( w / v) is particularly preferred.
- the amount of the chelating agent used in this production method is such that the final concentration of the chelating agent in the aqueous ophthalmic solution obtained by this production method is 0.0001 to 1% (w / v).
- the final concentration of is preferably 0.0005 to 0.5% (w / v), and the final concentration of the chelating agent is 0.001 to 0.1% (w / v). It is particularly preferred that
- This ophthalmic solution can further contain a preservative.
- preservative examples include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, paraben, sorbic acid, chlorobutanol, boric acid, chlorite, and the like. Benzalkonium chloride is particularly preferred.
- benzalkonium chloride added to the ophthalmic solution is the general formula: [C 6 H 5 CH 2 N (CH 3 ) 2 R] Cl, wherein the alkyl group R has 12 carbon atoms.
- a certain benzalkonium chloride hereinafter, also simply referred to as “BAK-C 12 ”).
- the preservative when the diquafosol or a salt thereof and a chelating agent are mixed, the preservative can be further added.
- the concentration of the preservative is not particularly limited as long as the preservative has a predetermined storage effect, but when the preservative is benzalkonium chloride, 0.0001 to 0 0.1% (w / v) is preferable, 0.0005 to 0.01% (w / v) is more preferable, and 0.001 to 0.005% (w / v) is particularly preferable.
- the amount of the preservative used is not particularly limited as long as the preservative is effective, but when the preservative is benzalkonium chloride, the present production method It is preferable that the final concentration of the preservative in the aqueous ophthalmic solution obtained by the above is 0.0001 to 0.1% (w / v), and the concentration is 0.0005 to 0.01% ( It is more preferable that the amount is w / v), and it is particularly preferable that the concentration is 0.001 to 0.005% (w / v).
- the ophthalmic solution can be added with a pharmaceutically acceptable additive as necessary using a widely used technique, for example, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate.
- Buffering agents such as sodium acetate, epsilon-aminocaproic acid; isotonic agents such as sodium chloride, potassium chloride, concentrated glycerin; interfaces such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil
- An activator or the like can be selected and added as necessary.
- the pH of the present ophthalmic solution may be within the range acceptable for ophthalmic preparations, but is usually preferably within the range of 4-8.
- the additive when the diquafosol and the chelating agent are mixed, the additive can be further added.
- the ophthalmic solution can be sterilized by filtration or other sterilization, and these sterilized ophthalmic solutions are also included in the scope of the present invention.
- an aqueous solution obtained by mixing diquafosol or a salt thereof and a chelating agent can be further sterilized.
- the sterilization method is not particularly limited as long as the obtained aqueous solution can be sterilized, but filtration sterilization is preferable.
- filter sterilization is not particularly limited as long as it is a method capable of filter sterilizing an aqueous solution, but it is preferably filtered using a filter sterilization filter having a pore size of 0.1 to 0.5 ⁇ m.
- insoluble precipitate means a foreign substance that does not re-dissolve during the manufacturing, distribution, and / or storage process of the present ophthalmic solution.
- occurrence of insoluble precipitates means (a) that a visually observable foreign material is produced in the ophthalmic solution, and (b) that no visible foreign material is produced in the ophthalmic solution, but during filtration sterilization. It shall mean both and / or any decrease in filterability.
- the generation of insoluble precipitates is suppressed means that an ophthalmic solution containing the same concentration of diquafosol or a salt thereof and an ophthalmic solution containing the same concentration of diquafosol or a salt thereof and not containing a chelating agent Compared with (a) the occurrence frequency and / or amount of foreign substances in the eye drops that are visible immediately after production or during storage are reduced (including cases where no visible foreign substances are observed). ) And / or (b) the decrease in filterability during filtration sterilization is suppressed (including the case where no decrease in filterability occurs).
- the present invention further provides the generation of insoluble precipitates in the aqueous ophthalmic solution by adding a chelating agent at a concentration of 0.0001 to 1% (w / v) to the aqueous ophthalmic solution containing diquafosol or a salt thereof.
- a method of suppression is also provided.
- “suppressing the generation of insoluble precipitates” is synonymous with the above “suppressing the generation of insoluble precipitates”.
- the definition of each term in the method for suppressing the generation of insoluble precipitates is as described above, and the preferred embodiment is the same as described above.
- the present invention further provides a method for reducing eye irritation of an aqueous ophthalmic solution by adding a chelating agent at a concentration of 0.0001 to 1% (w / v) to an aqueous ophthalmic solution containing diquafosol or a salt thereof.
- reducing eye irritation means an expression frequency (expression rate) of eye irritation as a side effect when an eye drop containing a predetermined concentration of diquafosol or a salt thereof is instilled into a dry eye patient. It is meant to be reduced compared to eye drops containing the same concentration of diquafosol or a salt thereof and no chelating agent.
- the definitions of other terms in the method for reducing eye irritation are as described above, and preferred aspects are also the same as described above.
- the present invention further relates to a method for improving the storage efficacy of an aqueous ophthalmic solution by adding a chelating agent at a concentration of 0.0001 to 1% (w / v) to an aqueous ophthalmic solution containing diquafosol or a salt thereof.
- “Improving preservation efficacy” in the present invention means that an ophthalmic solution containing a predetermined concentration of diquafosol or a salt thereof is compared with an ophthalmic solution containing the same concentration of diquafosol or a salt thereof and containing no chelating agent. , Which means that the amount of preservative that needs to be added to pass the storage efficacy test is reduced.
- the definitions of other terms in the method for improving the storage efficacy are as described above, and preferred embodiments are also the same as described above.
- Example preparation Diquafosol sodium 3g, sodium hydrogenphosphate hydrate 0.2g, sodium chloride 0.41g, potassium chloride 0.15g and benzalkonium chloride 0.0075g dissolved in water to 100mL And a pH regulator was added to adjust the pH to 7.5 and the osmotic pressure ratio to 1.0.
- edetate-containing formulation diquafosol sodium 3 g, sodium hydrogenphosphate hydrate 0.2 g, sodium chloride 0.41 g, potassium chloride 0.15 g, edetic acid 0.001 g or 0.1 g of sodium hydrate and 0.002 g of benzalkonium chloride were dissolved in water to make 100 mL, and a pH regulator was added to adjust the pH to 7.5 and the osmotic pressure ratio to 1.0.
- Test results The test results are shown in Table 1.
- 0.001% (w / v) edetate-containing formulation Diquafosol sodium 30 g, sodium hydrogenphosphate hydrate 2 g, sodium chloride 4.1 g, potassium chloride 1.5 g, sodium edetate hydrate 01 g and 0.075 g of benzalkonium chloride were dissolved in water to 1000 mL, and a pH regulator was added to adjust the pH to 7.5 and the osmotic pressure ratio to 1.0.
- FIG. 1 is a graph showing the results of filtration performance tests with diquafosol ophthalmic solutions for edetate-containing formulations and chelating agent-free formulations, where the vertical axis is the filtration amount (g) and the horizontal axis is the filtration time (minutes). It is.
- g the filtration amount
- minutes the filtration time
- Diquafosol ophthalmic solution containing a chelating agent is completely sterilized by filtration compared to diquafosol ophthalmic solution that does not contain a chelating agent because the decrease in filtration rate during the manufacturing process (filter sterilization process) is completely suppressed. It was suggested that it can be done. In addition, it is thought that the fall of the filtration rate recognized in the diquafosol ophthalmic solution which does not contain a chelating agent is due to clogging of insoluble precipitates (including those that cannot be visually observed).
- edetate-containing formulation 30 g diquafosol sodium, 2 g sodium hydrogen phosphate hydrate, 4.1 g sodium chloride, 1.5 g potassium chloride, sodium edetate hydrate 1 g and 0.075 g of benzalkonium chloride were dissolved in water to 1000 mL, and a pH regulator was added to adjust the pH to 7.5 and the osmotic pressure ratio to 1.0.
- 0.075 g of benzalkonium chloride was dissolved in water to 1000 mL, and a pH regulator was added to adjust the pH to 7.5 and the osmotic pressure ratio to 1.0.
- metaphosphate-containing formulation diquafosol sodium 30 g, sodium hydrogenphosphate hydrate 2 g, sodium chloride 4.1 g, potassium chloride 1.5 g, sodium metaphosphate 0.1 g and benza 0.075 g of ruthenium chloride was dissolved in water to 1000 mL, and a pH regulator was added to adjust the pH to 7.5 and the osmotic pressure ratio to 1.0.
- FIG. 2 is a graph showing the results of a filtration performance test with a diquafosol ophthalmic solution of a formulation containing no chelating agent, or a formulation containing edetate, citric acid, metaphosphate or polyphosphate, and the vertical axis is effective
- the filtration amount per filtration area (g / cm 2 ), and the horizontal axis represents the filtration time (minutes).
- a decrease in filtration rate (decrease in filtration rate) was observed during filter sterilization, whereas for formulations containing citric acid, metaphosphate or polyphosphate, As with the salt-containing formulation, it was shown that the decrease in filtration rate was completely suppressed.
- Diquafosol ophthalmic solution containing a chelating agent is completely sterilized by filtration compared to diquafosol ophthalmic solution that does not contain a chelating agent because the decrease in filtration rate during the manufacturing process (filter sterilization process) is completely suppressed. It was suggested that it can be done.
- Example preparation 3% (w / v) diquafosol sodium-containing / chelate-free formulation diquafosol sodium 3 g, sodium hydrogenphosphate hydrate 0.2 g, sodium chloride 0.41 g, potassium chloride 0.15 g and benzalco 0.0075 g of nium chloride was dissolved in water to make 100 mL, and a pH regulator was added to adjust the pH to 7.2 to 7.8 and the osmotic pressure ratio to 1.0 to 1.1.
- diquafosol sodium-containing / edetate-containing formulation diquafosol sodium 3g, sodium hydrogenphosphate hydrate 0.2g, sodium chloride 0.41g, potassium chloride 0.15g, edetic acid 0.01 g of sodium hydrate and 0.002 g of benzalkonium chloride are dissolved in water to make 100 mL, and a pH regulator is added to adjust the pH to 7.2 to 7.8 and the osmotic pressure ratio to 1.0 to 1.1. It was.
- diquafosol sodium-containing / edetate-containing formulation diquafosol sodium 8g, sodium hydrogenphosphate hydrate 0.2g, sodium edetate hydrate 0.01g and benzalkonium chloride 0.002 g of the product was dissolved in water to 100 mL, and a pH regulator was added to adjust the pH to 7.2 to 7.8 and the osmotic pressure ratio to 1.0 to 1.1.
- Test results The test results are shown in Tables 2 and 3.
- 0.01% (w / v) edetate-containing formulation diquafosol sodium 3 g, sodium hydrogenphosphate hydrate 0.2 g, sodium chloride 0.41 g, potassium chloride 0.15 g, edetate sodium hydrate 0.01 g and 0.0024 g of benzalkonium chloride were dissolved in water to make 100 mL, and a pH regulator was added to adjust the pH to 7.2 to 7.8 and the osmotic pressure ratio to 1.0 to 1.1.
- the preservation efficacy test was performed in accordance with the preservation efficacy test method of the 15th revision Japanese Pharmacopoeia.
- Escherichia Coli E. coli
- Pseudomonas aeruginosa P. aeruginosa
- Staphylococcus aureus S. aureus
- Candida albicans C. albicans
- Candida albicans C. albicans
- Test results The test results are shown in Table 4.
- test results in Table 4 show how much the number of viable bacteria at the time of inspection decreased compared to the number of inoculated bacteria by log reduction. For example, in the case of “1”, the number of viable bacteria at the time of testing Indicates a decrease to 10% of the number of inoculated bacteria.
- the preservative efficacy of the Japanese Pharmacopoeia even when the concentration of the preservative benzalkonium chloride is 0.0036% (w / v).
- the test criteria (category IA) were not met.
- the edetate-containing formulation was shown to meet the above criteria even when the benzalkonium chloride concentration was 0.0024% (w / v).
- the edetate-containing formulation was shown to have a greatly enhanced storage efficacy compared to the chelator-free formulation.
- formulation example The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.
- diquafosol ophthalmic solution containing a chelating agent at a concentration of 0.0001 to 1% (w / v) generation of insoluble precipitates during storage observed in diquafosol ophthalmic solution and filterability in the manufacturing process (filter sterilization process) was suppressed.
- diquafosol ophthalmic solution containing a chelating agent was confirmed to have reduced eye irritation and enhanced preservation efficacy compared to diquafosol ophthalmic solution not containing a chelating agent. Therefore, the present invention has stable physicochemical properties in the production and distribution process and the preservation process by the patient, and also has an excellent preservation effect while reducing eye irritation.
- diquafosol ophthalmic solution containing a chelating agent is suppressed in filterability during the manufacturing process (filter sterilization process), so efficient filtration sterilization is possible in the manufacturing process, contributing to a reduction in manufacturing costs. To do.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Ophthalmology & Optometry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
また、本発明は、0.1~10%(w/v)の濃度のジクアホソルまたはその塩を含有する水性点眼液の製造方法であって、ジクアホソルまたはその塩および該水性点眼液中のキレート剤の最終濃度が0.0001~1%(w/v)となる量のキレート剤を混合して不溶性析出物の発生が抑制された水溶液を得るステップを含む製造方法(以下、単に「本製造方法」ともいう)についても提供する。
本発明において、「キレート剤」とは、金属イオンをキレート化する化合物であれば特に制限はされないが、例えば、エデト酸(エチレンジアミン四酢酸)、エデト酸一ナトリウム、エデト酸二ナトリウム、エデト酸三ナトリウム、エデト酸四ナトリウム、エデト酸二カリウム、エデト酸三カリウム、エデト酸四カリウムなどのエデト酸またはその塩;クエン酸、クエン酸一ナトリウム、クエン酸二ナトリウム、クエン酸三ナトリウム、クエン酸一カリウム、クエン酸二カリウム、クエン酸三カリウムなどのクエン酸またはその塩;メタリン酸、メタリン酸ナトリウム、メタリン酸カリウムなどのメタリン酸またはその塩;ピロリン酸、ピロリン酸四ナトリウム、ピロリン酸四カリウムなどのピロリン酸またはその塩;ポリリン酸、ポリリン酸ナトリウム、ポリリン酸カリウムなどのポリリン酸またはその塩;リンゴ酸一ナトリウム、リンゴ酸二ナトリウム、リンゴ酸一カリウム、リンゴ酸二カリウムなどのリンゴ酸またはその塩;酒石酸ナトリウム、酒石酸カリウム、酒石酸カリウムナトリウムなどの酒石酸またはその塩;フィチン酸ナトリウム、フィチン酸カリウムなどのフィチン酸またはその塩、などを挙げることができる。なお、本発明において、「エデト酸、クエン酸、メタリン酸、ピロリン酸、ポリリン酸、リンゴ酸、酒石酸、フィチン酸およびそれらの塩」には、それぞれのフリー体またはそれらの塩の水和物および有機溶媒和物も含まれるものとする。
ジクアホソル点眼液の保存中の性状変化の有無を目視で確認するとともに、キレート剤であるエデト酸塩が該性状変化に及ぼす影響を検討した。
・キレート剤非含有処方
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0.2g、塩化ナトリウム0.41g、塩化カリウム0.15gおよびベンザルコニウム塩化物0.0075gを水に溶解して100mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
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0.2g、塩化ナトリウム0.41g、塩化カリウム0.15g、エデト酸ナトリウム水和物0.001gまたは0.1gおよびベンザルコニウム塩化物0.002gを水に溶解して100mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
上記キレート剤非含有処方および0.001または0.1%(w/v)エデト酸塩含有処方をガラス容器中で、25℃で3ヶ月間保存した後、目視によりその性状の変化の有無を確認した。
試験結果を表1に示す。
キレート剤を含有するジクアホソル点眼液については、流通過程および患者による保存過程においても、不溶性析出物が発生しないか、または該析出物の発生頻度および量が低減されることが示唆された。
ジクアホソル点眼液のろ過滅菌時のろ過性能の経時的変化を確認するとともに、キレート剤であるエデト酸塩が該変化に及ぼす影響を検討した。
・キレート剤非含有処方
ジクアホソルナトリウム30g、リン酸水素ナトリウム水和物2g、塩化ナトリウム4.1g、塩化カリウム1.5gおよびベンザルコニウム塩化物0.075gを水に溶解して1000mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
ジクアホソルナトリウム30g、リン酸水素ナトリウム水和物2g、塩化ナトリウム4.1g、塩化カリウム1.5g、エデト酸ナトリウム水和物0.01gおよびベンザルコニウム塩化物0.075gを水に溶解して1000mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
各調製物を、ろ過フィルターとして親水性PVDFメンブレンフィルター(日本ポール社製、フロロダインIIディスクフィルターφ47mm、ポアサイズ0.2μm(型式FTKDFL)を2段使用し、ろ過圧力200kPa、室温でろ過を行なった。そのときのろ過時間とろ過量を測定し、その関係をプロットした。
図1は、エデト酸塩含有処方、キレート剤非含有処方それぞれのジクアホソル点眼液でのろ過性能試験の結果を示すグラフであり、縦軸はろ過量(g)、横軸はろ過時間(分)である。図1から明らかなように、キレート剤非含有処方については、ろ過滅菌中にろ過量の低下(ろ過率の低下)が認められる一方、エデト酸塩含有処方では、ろ過率の低下が完全に抑制されることが示された。
キレート剤を含有するジクアホソル点眼液については、製造過程(ろ過滅菌過程)におけるろ過率の低下が完全に抑制されることから、キレート剤を含有しないジクアホソル点眼液と比較して、効率的にろ過滅菌できることが示唆された。なお、キレート剤を含有しないジクアホソル点眼液において認められたろ過率の低下は、不溶性析出物(目視できないものも含まれる)の目詰まりが原因であるものと考えられる。
エデト酸塩およびエデト酸塩以外のキレート剤が、ジクアホソル点眼液のろ過滅菌時のろ過性能の経時的変化に及ぼす影響を比較検討した。
・キレート剤非含有処方
ジクアホソルナトリウム30g、リン酸水素ナトリウム水和物2g、塩化ナトリウム4.1g、塩化カリウム1.5gおよびベンザルコニウム塩化物0.075gを水に溶解して1000mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
ジクアホソルナトリウム30g、リン酸水素ナトリウム水和物2g、塩化ナトリウム4.1g、塩化カリウム1.5g、エデト酸ナトリウム水和物0.1gおよびベンザルコニウム塩化物0.075gを水に溶解して1000mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
ジクアホソルナトリウム30g、リン酸水素ナトリウム水和物2g、塩化ナトリウム4.1g、塩化カリウム1.5g、クエン酸一水和物0.1gおよびベンザルコニウム塩化物0.075gを水に溶解して1000mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
ジクアホソルナトリウム30g、リン酸水素ナトリウム水和物2g、塩化ナトリウム4.1g、塩化カリウム1.5g、メタリン酸ナトリウム0.1gおよびベンザルコニウム塩化物0.075gを水に溶解して1000mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
ジクアホソルナトリウム30g、リン酸水素ナトリウム水和物2g、塩化ナトリウム4.1g、塩化カリウム1.5g、ポリリン酸ナトリウム0.1gおよびベンザルコニウム塩化物0.075gを水に溶解して1000mLとし、pH調節剤を添加して、pH7.5、浸透圧比1.0とした。
各調製物を、ろ過フィルターとして親水性PVDFメンブレンフィルター(日本ポール社製、フロロダインIIディスクフィルターφ25mm、ポアサイズ0.2μm(型式FTKDFL)を2段使用し、ろ過圧力200kPa、室温でろ過を行なった。そのときのろ過時間と有効ろ過面積あたりのろ過量を測定し、その関係をプロットした。
図2は、キレート剤非含有処方、またはエデト酸塩、クエン酸、メタリン酸塩もしくはポリリン酸塩含有処方のそれぞれのジクアホソル点眼液でのろ過性能試験の結果を示すグラフであり、縦軸は有効ろ過面積あたりのろ過量(g/cm2)、横軸はろ過時間(分)を示す。図2から明らかなように、キレート剤非含有処方については、ろ過滅菌中にろ過量の低下(ろ過率の低下)が認められる一方、クエン酸、メタリン酸塩またはポリリン酸塩含有処方では、エデト酸塩含有処方同様に、ろ過率の低下が完全に抑制されることが示された。
キレート剤を含有するジクアホソル点眼液については、製造過程(ろ過滅菌過程)におけるろ過率の低下が完全に抑制されることから、キレート剤を含有しないジクアホソル点眼液と比較して、効率的にろ過滅菌できることが示唆された。
キレート剤を含有しないジクアホソル点眼液である「ジクアス(登録商標)点眼液3%」の添付文書には、同点眼液を使用したドライアイ患者の6.7%で副作用として眼刺激感が認められたことが記載されている。そこで、ドライアイ患者同様に角膜上皮が障害されたn-ヘプタノール角膜上皮剥離モデルを用いて、キレート剤の添加がジクアホソル点眼液の眼刺激性にどのような影響を及ぼすか否かを検討した。
・3%(w/v)ジクアホソルナトリウム含有/キレート剤非含有処方
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0.2g、塩化ナトリウム0.41g、塩化カリウム0.15gおよびベンザルコニウム塩化物0.0075gを水に溶解して100mLとし、pH調節剤を添加して、pH7.2~7.8、浸透圧比1.0~1.1とした。
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0.2g、塩化ナトリウム0.41g、塩化カリウム0.15g、エデト酸ナトリウム水和物0.01gおよびベンザルコニウム塩化物0.002gを水に溶解して100mLとし、pH調節剤を添加して、pH7.2~7.8、浸透圧比1.0~1.1とした。
ジクアホソルナトリウム8g、リン酸水素ナトリウム水和物0.2gおよびベンザルコニウム塩化物0.0075gを水に溶解して100mLとし、pH調節剤を添加して、pH7.2~7.8、浸透圧比1.0~1.1とした。
ジクアホソルナトリウム8g、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およびベンザルコニウム塩化物0.002gを水に溶解して100mLとし、pH調節剤を添加して、pH7.2~7.8、浸透圧比1.0~1.1とした。
リン酸水素ナトリウム水和物0.2g、塩化ナトリウム0.75g、塩化カリウム0.15gおよびベンザルコニウム塩化物0.0075gを水に溶解して100mLとし、pH調節剤を添加して、pH7.2~7.8、浸透圧比1.0~1.1とした。
ウサギの左眼の角膜にn-ヘプタノール処置(1分間)を行なった後、角膜上皮を剥離し、その16~18時間後に、基剤、3%(w/v)ジクアホソルナトリウム含有/キレート剤非含有処方、または3%(w/v)ジクアホソルナトリウム含有/エデト酸塩含有処方を1回点眼し(50μL/眼)、点眼後1分間の瞬目回数の測定および点眼時の痛みに関連する症状の観察を行なった。その後続けて、点眼5分後までの閉目および半眼などの痛みに関する徴候を観察した(1群4例)。
試験結果を表2および表3に示す。
以上のように、ジクアホソル点眼液は、ドライアイ患者同様に角膜上皮が障害されたn-ヘプタノール角膜上皮剥離モデルにおいて、痛みに関する徴候である半眼・閉目を高頻度で引き起こす一方、該点眼液にキレート剤を添加することで、これらの事象の発現頻度は基剤レベルまで軽減されることが示唆された。すなわち、キレート剤を含有しないジクアホソル点眼液をドライアイ患者に点眼した場合に一定頻度で認められる副作用としての眼刺激は、キレート剤の添加により軽減されるものと思われる。
キレート剤がジクアホソル点眼液の保存効力に与える影響を確認するため、保存効力試験を行った。
・キレート剤非含有処方
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0.2g、塩化ナトリウム0.41g、塩化カリウム0.15gおよびベンザルコニウム塩化物0.0036gを水に溶解して100mLとし、pH調節剤を添加して、pH7.2~7.8、浸透圧比1.0~1.1とした。
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0.2g、塩化ナトリウム0.41g、塩化カリウム0.15g、エデト酸ナトリウム水和物0.01gおよびベンザルコニウム塩化物0.0024gを水に溶解して100mLとし、pH調節剤を添加して、pH7.2~7.8、浸透圧比1.0~1.1とした。
保存効力試験は、第十五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。
試験結果を表4に示す。
上記の結果から、ジクアホソル点眼液にキレート剤を添加することで、その保存効力が顕著に向上することが示唆された。すなわち、本点眼液については、キレート剤を含有しないジクアホソル点眼液と比して、点眼液中の防腐剤濃度を低下させ得るものと考えられる。
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。
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 0.1~0.5g
塩化ナトリウム 0.01~1g
塩化カリウム 0.01~1g
エデト酸ナトリウム水和物 0.0001~0.1g
滅菌精製水 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剤を調製できる。
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 0.1~0.5g
塩化ナトリウム 0.01~1g
塩化カリウム 0.01~1g
BAK-C12 0.1~10g
エデト酸ナトリウム水和物 0.0001~0.1g
滅菌精製水 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剤を調製できる。
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 0.1~0.5g
塩化ナトリウム 0.01~1g
塩化カリウム 0.01~1g
BAK-C12 0.1~10g
クエン酸一水和物 0.0001~0.1g
滅菌精製水 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剤を調製できる。
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 0.1~0.5g
塩化ナトリウム 0.01~1g
塩化カリウム 0.01~1g
BAK-C12 0.1~10g
メタリン酸ナトリウム 0.0001~0.1g
滅菌精製水 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剤を調製できる。
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 0.1~0.5g
塩化ナトリウム 0.01~1g
塩化カリウム 0.01~1g
BAK-C12 0.1~10g
ポリリン酸ナトリウム 0.0001~0.1g
滅菌精製水 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剤を調製できる。
Claims (15)
- 0.1~10%(w/v)の濃度のジクアホソルまたはその塩および0.0001~1%(w/v)の濃度のキレート剤を含有する水性点眼液。
- キレート剤が、エデト酸、クエン酸、メタリン酸、ピロリン酸、ポリリン酸、リンゴ酸、酒石酸、フィチン酸およびそれらの塩からなる群より選択される少なくとも1種である、請求項1に記載の点眼液。
- キレート剤が、エデト酸、クエン酸、メタリン酸、ポリリン酸およびそれらの塩からなる群より選択される少なくとも1種である、請求項1に記載の点眼液。
- キレート剤が、エデト酸の塩である、請求項1に記載の点眼液。
- 点眼液中の該キレート剤の濃度が0.0005~0.5%(w/v)である、請求項1~4のいずれかに記載の点眼液。
- 点眼液中の該キレート剤の濃度が0.001~0.1%(w/v)である、請求項1~4のいずれかに記載の点眼液。
- 点眼液中のジクアホソルまたはその塩の濃度が1~10%(w/v)である、請求項1~4のいずれかに記載の点眼液。
- 点眼液中の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のいずれかに記載の点眼液。
- キレート剤がエデト酸の塩であり、点眼液中の該キレート剤の濃度が0.001~0.1%(w/v)であり、点眼液中の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に記載の点眼液。
- さらに防腐剤を含有する、請求項1に記載の点眼液。
- 0.1~10%(w/v)の濃度のジクアホソルまたはその塩を含有する水性点眼液の製造方法であって、ジクアホソルまたはその塩および該水性点眼液中のキレート剤の最終濃度が0.0001~1%(w/v)となる量のキレート剤を混合して不溶性析出物の発生が抑制された水溶液を得るステップを含む、製造方法。
- さらに、得られた水溶液をポアサイズ0.1~0.5μmのろ過滅菌フィルターでろ過するステップを含む、請求項11に記載の方法。
- 0.1~10%(w/v)の濃度のジクアホソルまたはその塩を含有する水性点眼液に、0.0001~1%(w/v)の濃度のキレート剤を加えることによる、該水性点眼液中の不溶性析出物の発生を抑制する方法。
- 0.1~10%(w/v)の濃度のジクアホソルまたはその塩を含有する水性点眼液に、0.0001~1%(w/v)の濃度のキレート剤を加えることによる、該水性点眼液の眼刺激性を軽減する方法。
- 0.1~10%(w/v)の濃度のジクアホソルまたはその塩を含有する水性点眼液に、0.0001~1%(w/v)の濃度のキレート剤を加えることによる、該水性点眼液の保存効力を向上させる方法。
Priority Applications (28)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020147028142A KR101536885B1 (ko) | 2012-03-26 | 2013-03-25 | 디쿠아포솔 함유 점안액 |
MX2014011468A MX353874B (es) | 2012-03-26 | 2013-03-25 | Gotas para los ojos que contienen diquafosol. |
KR1020187018799A KR101935484B1 (ko) | 2012-03-26 | 2013-03-25 | 디쿠아포솔 함유 점안액 |
KR1020157004372A KR101875845B1 (ko) | 2012-03-26 | 2013-03-25 | 디쿠아포솔 함유 점안액 |
IN8632DEN2014 IN2014DN08632A (ja) | 2012-03-26 | 2013-03-25 | |
PL13770386T PL2832359T3 (pl) | 2012-03-26 | 2013-03-25 | Krople do oczu zawierające diquafosol |
EP13770386.4A EP2832359B1 (en) | 2012-03-26 | 2013-03-25 | Diquafosol-containing eye drop |
US14/386,169 US9486529B2 (en) | 2012-03-26 | 2013-03-25 | Ophthalmic solution comprising diquafosol |
KR1020187037979A KR20190002751A (ko) | 2012-03-26 | 2013-03-25 | 디쿠아포솔 함유 점안액 |
BR112014023402-7A BR112014023402B1 (pt) | 2012-03-26 | 2013-03-25 | Solução oftálmica compreendendo diquafosol e métodos para produção da mesma, para inibição da formação dos precipitados insolúveis na mesma, para redução da irritação ocular causada pela mesma e para aumentar a eficácia de conservação da mesma |
SG11201405799TA SG11201405799TA (en) | 2012-03-26 | 2013-03-25 | Ophthalmic solution comprising diquafosol |
ES13770386T ES2702575T3 (es) | 2012-03-26 | 2013-03-25 | Solución oftálmica que comprende diquafosol |
CN201380016616.1A CN104203254A (zh) | 2012-03-26 | 2013-03-25 | 含有地夸磷索的滴眼液 |
AU2013241507A AU2013241507A1 (en) | 2012-03-26 | 2013-03-25 | Ophthalmic solution comprising diquafosol |
EP18193430.8A EP3431092A1 (en) | 2012-03-26 | 2013-03-25 | Ophthalmic solution comprising diquafosol |
CA2868390A CA2868390C (en) | 2012-03-26 | 2013-03-25 | Ophthalmic solution comprising diquafosol |
UAA201411576A UA113981C2 (xx) | 2012-03-26 | 2013-03-25 | Офтальмологічний розчин, що містить диквафасол |
NZ631041A NZ631041A (en) | 2012-03-26 | 2013-03-25 | Opthalmic solution comprising diquafosol |
EA201491771A EA028848B1 (ru) | 2012-03-26 | 2013-03-25 | Офтальмологический раствор, содержащий диквафасол |
KR1020207022714A KR20200096708A (ko) | 2012-03-26 | 2013-03-25 | 디쿠아포솔 함유 점안액 |
DK13770386.4T DK2832359T3 (en) | 2012-03-26 | 2013-03-25 | Eye drop containing diquafosol |
PH12014501955A PH12014501955B1 (en) | 2012-03-26 | 2014-09-01 | Diquafosol-containing eye drop |
HK15105452.3A HK1204922A1 (en) | 2012-03-26 | 2015-06-08 | Diquafosol-containing eye drop |
HK15107460.9A HK1206648A1 (en) | 2012-03-26 | 2015-08-04 | Diquafosol-containing eye drop |
AU2016201110A AU2016201110B2 (en) | 2012-03-26 | 2016-02-23 | Ophthalmic solution comprising diquafosol |
US15/289,273 US10071113B2 (en) | 2012-03-26 | 2016-10-10 | Ophthalmic solution comprising diquafosol |
US16/103,328 US10632139B2 (en) | 2012-03-26 | 2018-08-14 | Ophthalmic solution comprising diquafosol |
US16/819,974 US11166974B2 (en) | 2012-03-26 | 2020-03-16 | Ophthalmic solution comprising Diquafosol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012-069157 | 2012-03-26 | ||
JP2012069157 | 2012-03-26 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/386,169 A-371-Of-International US9486529B2 (en) | 2012-03-26 | 2013-03-25 | Ophthalmic solution comprising diquafosol |
US15/289,273 Continuation US10071113B2 (en) | 2012-03-26 | 2016-10-10 | Ophthalmic solution comprising diquafosol |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013146649A1 true WO2013146649A1 (ja) | 2013-10-03 |
Family
ID=49259901
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2013/058519 WO2013146649A1 (ja) | 2012-03-26 | 2013-03-25 | ジクアホソル含有点眼液 |
Country Status (26)
Country | Link |
---|---|
US (4) | US9486529B2 (ja) |
EP (2) | EP3431092A1 (ja) |
JP (6) | JP5625081B2 (ja) |
KR (5) | KR101875845B1 (ja) |
CN (2) | CN104203254A (ja) |
AU (3) | AU2013241507A1 (ja) |
BR (1) | BR112014023402B1 (ja) |
CA (1) | CA2868390C (ja) |
DK (1) | DK2832359T3 (ja) |
EA (1) | EA028848B1 (ja) |
ES (1) | ES2702575T3 (ja) |
GE (1) | GEP20166470B (ja) |
HK (2) | HK1204922A1 (ja) |
HU (1) | HUE041671T2 (ja) |
IN (1) | IN2014DN08632A (ja) |
MX (1) | MX353874B (ja) |
MY (1) | MY169816A (ja) |
NZ (1) | NZ631041A (ja) |
PH (1) | PH12014501955B1 (ja) |
PL (1) | PL2832359T3 (ja) |
PT (1) | PT2832359T (ja) |
SG (2) | SG11201405799TA (ja) |
TR (1) | TR201820073T4 (ja) |
TW (4) | TWI757799B (ja) |
UA (1) | UA113981C2 (ja) |
WO (1) | WO2013146649A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015105135A1 (ja) * | 2014-01-10 | 2015-07-16 | 参天製薬株式会社 | ピリジルアミノ酢酸化合物含有医薬組成物 |
WO2016104704A1 (ja) * | 2014-12-25 | 2016-06-30 | 参天製薬株式会社 | 水性点眼液 |
WO2017002827A1 (ja) * | 2015-06-29 | 2017-01-05 | ヤマサ醤油株式会社 | P1,p4-ビス(5'-ウリジル)テトラホスフェート結晶の保管方法 |
US20180147230A1 (en) * | 2015-06-05 | 2018-05-31 | Santen Pharmaceutical Co., Ltd. | Therapeutic agent for dry eye characterized by being applied to eye of dry eye patient wearing soft contact lens |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA113981C2 (xx) | 2012-03-26 | 2017-04-10 | Офтальмологічний розчин, що містить диквафасол | |
TWI743858B (zh) * | 2015-06-05 | 2021-10-21 | 日商參天製藥股份有限公司 | 使水性點眼液中之洛赫西定類安定化之方法 |
JP6688057B2 (ja) * | 2015-12-01 | 2020-04-28 | 日水製薬株式会社 | グラム染色用後染色試液及びグラム染色方法 |
MX2020008925A (es) * | 2018-02-28 | 2020-10-01 | Santen Pharmaceutical Co Ltd | Composicion oftalmica que comprende dicuafosol y polimero cationico. |
CN108403625A (zh) * | 2018-04-11 | 2018-08-17 | 东莞解石医药科技有限公司 | 一种含有螯合剂的地夸磷索四钠滴眼液 |
WO2021039748A1 (ja) * | 2019-08-27 | 2021-03-04 | 参天製薬株式会社 | 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 |
CN113720924A (zh) * | 2020-05-25 | 2021-11-30 | 南京帝昌医药科技有限公司 | 一种地夸磷索四钠的含量及有关物质检测方法 |
JPWO2022107790A1 (ja) * | 2020-11-18 | 2022-05-27 | ||
WO2022107791A1 (ja) * | 2020-11-18 | 2022-05-27 | 参天製薬株式会社 | ポリヘキサメチレンビグアナイドまたはその塩を含有する水性点眼液 |
KR102548710B1 (ko) | 2020-12-24 | 2023-06-28 | 주식회사 종근당 | 디쿠아포솔 또는 이의 약제학적으로 허용가능한 염과 토코페롤을 함유하는 건성안 예방 또는 치료용 약제학적 조성물 |
CN112933040A (zh) * | 2021-02-04 | 2021-06-11 | 合肥博思科创医药科技有限公司 | 一种舒更葡糖钠注射液的制备方法 |
WO2023195718A1 (ko) * | 2022-04-04 | 2023-10-12 | 서울대학교산학협력단 | 감미 억제용 조성물 및 식품의 감미 억제 방법 |
CN117838628A (zh) * | 2024-03-01 | 2024-04-09 | 广州市桐晖药业有限公司 | 一种地夸磷索钠滴眼液及其制备方法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001510484A (ja) | 1997-07-25 | 2001-07-31 | インスパイアー ファーマシューティカルズ,インコーポレイティド | ジ(ウリジン5’)−テトラホスフェート及びその塩の大規模生産のための方法 |
JP2002053492A (ja) * | 2000-05-30 | 2002-02-19 | Santen Pharmaceut Co Ltd | 角膜上皮伸展促進剤 |
JP2003160491A (ja) * | 2001-09-11 | 2003-06-03 | Santen Pharmaceut Co Ltd | ジウリジンリン酸含有点眼液 |
JP3652707B2 (ja) | 1997-02-06 | 2005-05-25 | インスパイアー ファーマシューティカルズ,インコーポレイティド | プリン受容体アゴニストによるドライアイ疾患の治療法 |
JP2007182438A (ja) | 2005-12-08 | 2007-07-19 | Kowa Co | 点眼用組成物 |
WO2012090994A1 (ja) * | 2010-12-28 | 2012-07-05 | 参天製薬株式会社 | ジクアホソル含有点眼液およびその製造方法、不溶性析出物発生の抑制方法 |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH075456B2 (ja) * | 1988-10-01 | 1995-01-25 | 参天製薬株式会社 | 点眼液 |
JP2530491B2 (ja) | 1988-12-20 | 1996-09-04 | 参天製薬株式会社 | ヒアルロン酸点眼液 |
TW200402B (ja) | 1990-08-13 | 1993-02-21 | Senju Pharma Co | |
US5504113A (en) | 1994-03-02 | 1996-04-02 | Allergan, Inc. | Enhancement of benzalkonium chloride preservative activity in formulations containing an incompatible drug |
DK0981534T3 (da) | 1997-02-06 | 2006-09-04 | Inspire Pharmaceuticals Inc | Dinukleotider og deres anvendelser |
KR19990074047A (ko) | 1998-03-03 | 1999-10-05 | 김수복 | 콘택트렌즈용 세척, 소독 및 보존제 조성물 |
ES2264266T3 (es) | 1998-08-21 | 2006-12-16 | Senju Pharmaceutical Co., Ltd. | Preparaciones liquidas acuosas. |
JP4880808B2 (ja) | 1999-11-15 | 2012-02-22 | 久光製薬株式会社 | 人工涙液型点眼剤組成物 |
CA2413928C (en) | 2000-05-30 | 2011-01-25 | Santen Pharmaceutical Co., Ltd. | Corneal epithelial migration promoter |
US6555675B2 (en) | 2000-08-21 | 2003-04-29 | Inspire Pharmaceuticals, Inc. | Dinucleoside polyphosphate compositions and their therapuetic use as purinergic receptor agonists |
US6583181B1 (en) | 2000-11-22 | 2003-06-24 | Lonza Inc. | Antimicrobial quaternary ammonium compositions with reduced ocular irritation |
CN1228053C (zh) * | 2001-09-11 | 2005-11-23 | 参天制药株式会社 | 含有二尿苷磷酸的滴眼液 |
US20030109488A1 (en) | 2001-10-11 | 2003-06-12 | Alcon, Inc. | Methods for treating dry eye |
DE602004010862T2 (de) | 2003-04-14 | 2009-01-02 | Wyeth Holdings Corp. | Zusammensetzungen enthaltend Piperacillin und Tazobactam zur Injektion |
JP4806956B2 (ja) | 2004-04-20 | 2011-11-02 | 大正製薬株式会社 | 点眼用液剤 |
US20060073172A1 (en) | 2004-10-01 | 2006-04-06 | Schneider L W | Stabilized ophthalmic solution for the treatment of glaucoma and lowering intraocular pressure |
RU2397768C2 (ru) | 2004-12-02 | 2010-08-27 | Венус Ремедиз Лимитед | Композиции для преодоления опосредованной бета-лактамазой резистентности к антибиотикам с использованием ингибитора бета-лактамазы, предназначенные для инъекции |
KR100870104B1 (ko) * | 2005-11-28 | 2008-11-26 | 주식회사 머젠스 | 안구건조증 치료 및 예방용 조성물 |
JP2008247828A (ja) | 2007-03-30 | 2008-10-16 | Wakamoto Pharmaceut Co Ltd | ラタノプロストを含有する水性医薬組成物。 |
JP2009040727A (ja) * | 2007-08-09 | 2009-02-26 | Towa Yakuhin Kk | ラタノプロストを有効成分とする安定な点眼液剤 |
CN100534423C (zh) * | 2007-11-30 | 2009-09-02 | 张咏梅 | 一种保质期长的氯霉素滴眼液及其制备方法 |
US8119112B2 (en) | 2008-01-31 | 2012-02-21 | Bausch & Lomb Incorporated | Ophthalmic compositions with an amphoteric surfactant and hyaluronic acid |
CN101461778A (zh) * | 2009-01-06 | 2009-06-24 | 河北科技大学 | 不含抑菌剂的盐酸环丙沙星滴眼液及其制备方法 |
EP2393355A4 (en) * | 2009-01-23 | 2012-07-25 | Inspire Pharmaceuticals Inc | METHOD FOR TREATING A DRY EYE WITH AZITHROMYCIN |
CN102100693A (zh) * | 2009-12-16 | 2011-06-22 | 沈阳兴齐制药有限公司 | 一种含有肌肽的人工泪液及其制备方法 |
KR20110104367A (ko) | 2010-03-16 | 2011-09-22 | 삼천당제약주식회사 | 무보존제 안과용 조성물 |
MY173215A (en) | 2010-07-21 | 2020-01-06 | Cumberland Pharmaceuticals Inc | Acetylcysteine compositions and methods of use thereof |
CN106729718A (zh) | 2010-09-10 | 2017-05-31 | 参天制药株式会社 | 以组合p2y2受体激动剂和透明质酸或其盐为特征的干眼症治疗剂 |
WO2012141334A1 (en) * | 2011-04-12 | 2012-10-18 | R-Tech Ueno, Ltd. | Aqueous ophthalmic composition |
UA113981C2 (xx) * | 2012-03-26 | 2017-04-10 | Офтальмологічний розчин, що містить диквафасол | |
MY185108A (en) | 2012-03-26 | 2021-04-30 | Dilafor Ab | Method for treatment of labor arrest |
-
2013
- 2013-03-25 UA UAA201411576A patent/UA113981C2/uk unknown
- 2013-03-25 CN CN201380016616.1A patent/CN104203254A/zh active Pending
- 2013-03-25 GE GEAP201313609A patent/GEP20166470B/en unknown
- 2013-03-25 MY MYPI2014002576A patent/MY169816A/en unknown
- 2013-03-25 TW TW109124203A patent/TWI757799B/zh active
- 2013-03-25 BR BR112014023402-7A patent/BR112014023402B1/pt not_active IP Right Cessation
- 2013-03-25 IN IN8632DEN2014 patent/IN2014DN08632A/en unknown
- 2013-03-25 US US14/386,169 patent/US9486529B2/en active Active
- 2013-03-25 SG SG11201405799TA patent/SG11201405799TA/en unknown
- 2013-03-25 PL PL13770386T patent/PL2832359T3/pl unknown
- 2013-03-25 MX MX2014011468A patent/MX353874B/es active IP Right Grant
- 2013-03-25 KR KR1020157004372A patent/KR101875845B1/ko active IP Right Review Request
- 2013-03-25 CN CN202110358504.0A patent/CN113018259A/zh active Pending
- 2013-03-25 SG SG10201607872PA patent/SG10201607872PA/en unknown
- 2013-03-25 AU AU2013241507A patent/AU2013241507A1/en not_active Abandoned
- 2013-03-25 KR KR1020187018799A patent/KR101935484B1/ko active IP Right Review Request
- 2013-03-25 KR KR1020207022714A patent/KR20200096708A/ko not_active Application Discontinuation
- 2013-03-25 EP EP18193430.8A patent/EP3431092A1/en not_active Withdrawn
- 2013-03-25 HU HUE13770386A patent/HUE041671T2/hu unknown
- 2013-03-25 TW TW102110422A patent/TWI625135B/zh active
- 2013-03-25 EA EA201491771A patent/EA028848B1/ru unknown
- 2013-03-25 CA CA2868390A patent/CA2868390C/en active Active
- 2013-03-25 KR KR1020187037979A patent/KR20190002751A/ko active Application Filing
- 2013-03-25 EP EP13770386.4A patent/EP2832359B1/en active Active
- 2013-03-25 TR TR2018/20073T patent/TR201820073T4/tr unknown
- 2013-03-25 ES ES13770386T patent/ES2702575T3/es active Active
- 2013-03-25 TW TW109100132A patent/TWI723722B/zh active
- 2013-03-25 PT PT13770386T patent/PT2832359T/pt unknown
- 2013-03-25 NZ NZ631041A patent/NZ631041A/en not_active IP Right Cessation
- 2013-03-25 WO PCT/JP2013/058519 patent/WO2013146649A1/ja active Application Filing
- 2013-03-25 KR KR1020147028142A patent/KR101536885B1/ko active IP Right Review Request
- 2013-03-25 TW TW106124911A patent/TWI692364B/zh active
- 2013-03-25 DK DK13770386.4T patent/DK2832359T3/en active
- 2013-03-25 JP JP2013062270A patent/JP5625081B2/ja active Active
-
2014
- 2014-04-14 JP JP2014082821A patent/JP6126041B2/ja active Active
- 2014-09-01 PH PH12014501955A patent/PH12014501955B1/en unknown
-
2015
- 2015-06-08 HK HK15105452.3A patent/HK1204922A1/xx unknown
- 2015-08-04 HK HK15107460.9A patent/HK1206648A1/xx unknown
-
2016
- 2016-02-23 AU AU2016201111A patent/AU2016201111A1/en not_active Withdrawn
- 2016-02-23 AU AU2016201110A patent/AU2016201110B2/en not_active Ceased
- 2016-10-10 US US15/289,273 patent/US10071113B2/en active Active
-
2017
- 2017-04-05 JP JP2017075167A patent/JP6389544B2/ja active Active
-
2018
- 2018-02-07 JP JP2018020154A patent/JP6483299B2/ja active Active
- 2018-08-14 US US16/103,328 patent/US10632139B2/en active Active
-
2019
- 2019-02-12 JP JP2019022692A patent/JP7042762B2/ja active Active
-
2020
- 2020-03-16 US US16/819,974 patent/US11166974B2/en active Active
-
2022
- 2022-03-14 JP JP2022039183A patent/JP7447176B2/ja active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3652707B2 (ja) | 1997-02-06 | 2005-05-25 | インスパイアー ファーマシューティカルズ,インコーポレイティド | プリン受容体アゴニストによるドライアイ疾患の治療法 |
JP2001510484A (ja) | 1997-07-25 | 2001-07-31 | インスパイアー ファーマシューティカルズ,インコーポレイティド | ジ(ウリジン5’)−テトラホスフェート及びその塩の大規模生産のための方法 |
JP2002053492A (ja) * | 2000-05-30 | 2002-02-19 | Santen Pharmaceut Co Ltd | 角膜上皮伸展促進剤 |
JP2003160491A (ja) * | 2001-09-11 | 2003-06-03 | Santen Pharmaceut Co Ltd | ジウリジンリン酸含有点眼液 |
JP2007182438A (ja) | 2005-12-08 | 2007-07-19 | Kowa Co | 点眼用組成物 |
WO2012090994A1 (ja) * | 2010-12-28 | 2012-07-05 | 参天製薬株式会社 | ジクアホソル含有点眼液およびその製造方法、不溶性析出物発生の抑制方法 |
Non-Patent Citations (2)
Title |
---|
"Japanese Pharmacopoeia" |
CORNEA, vol. 23, no. 8, 2004, pages 784 - 792 |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA031813B1 (ru) * | 2014-01-10 | 2019-02-28 | Сантэн Фармасьютикал Ко., Лтд. | Фармацевтическая композиция, содержащая соединение пиридиламиноуксусной кислоты |
US10765750B2 (en) | 2014-01-10 | 2020-09-08 | Santen Pharmaceutical Co., Ltd. | Pharmaceutical composition containing pyridylaminoacetic acid compound |
WO2015105135A1 (ja) * | 2014-01-10 | 2015-07-16 | 参天製薬株式会社 | ピリジルアミノ酢酸化合物含有医薬組成物 |
US10485872B2 (en) | 2014-01-10 | 2019-11-26 | Santen Pharmaceutical Co., Ltd. | Pharmaceutical composition containing pyridylaminoacetic acid compound |
US10149908B2 (en) | 2014-01-10 | 2018-12-11 | Santen Pharmaceutical Co., Ltd. | Pharmaceutical composition containing pyridylaminoacetic acid compound |
EA034517B1 (ru) * | 2014-12-25 | 2020-02-17 | Сантен Фармасьютикал Ко., Лтд. | Водный офтальмологический раствор |
US10278985B2 (en) | 2014-12-25 | 2019-05-07 | Santen Pharmaceutical Co., Ltd. | Aqueous ophthalmic solution |
WO2016104704A1 (ja) * | 2014-12-25 | 2016-06-30 | 参天製薬株式会社 | 水性点眼液 |
US10786526B2 (en) | 2014-12-25 | 2020-09-29 | Santen Pharmaceutical Co., Ltd. | Aqueous ophthalmic solution |
US20180147230A1 (en) * | 2015-06-05 | 2018-05-31 | Santen Pharmaceutical Co., Ltd. | Therapeutic agent for dry eye characterized by being applied to eye of dry eye patient wearing soft contact lens |
RU2742032C2 (ru) * | 2015-06-05 | 2021-02-01 | Сантен Фармасьютикал Ко., Лтд. | Терапевтическое средство против сухости глаз, характеризуемое нанесением на глаза пациентов с сухостью глаз, носящих гибкие контактные линзы |
US10493091B2 (en) | 2015-06-29 | 2019-12-03 | Yamasa Corporation | Method for storing P1, P4-bis(5′-uridyl)teraphosphate crystals |
WO2017002827A1 (ja) * | 2015-06-29 | 2017-01-05 | ヤマサ醤油株式会社 | P1,p4-ビス(5'-ウリジル)テトラホスフェート結晶の保管方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6483299B2 (ja) | ジクアホソル含有点眼液 | |
WO2012090994A1 (ja) | ジクアホソル含有点眼液およびその製造方法、不溶性析出物発生の抑制方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13770386 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013770386 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14386169 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: IDP00201405697 Country of ref document: ID |
|
ENP | Entry into the national phase |
Ref document number: 2868390 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2014/011468 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 20147028142 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2013241507 Country of ref document: AU Date of ref document: 20130325 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112014023402 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 13609 Country of ref document: GE Kind code of ref document: P |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201491771 Country of ref document: EA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 112014023402 Country of ref document: BR Kind code of ref document: A2 Effective date: 20140922 |