CN117771172A - Aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone - Google Patents
Aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone Download PDFInfo
- Publication number
- CN117771172A CN117771172A CN202311818685.6A CN202311818685A CN117771172A CN 117771172 A CN117771172 A CN 117771172A CN 202311818685 A CN202311818685 A CN 202311818685A CN 117771172 A CN117771172 A CN 117771172A
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- CN
- China
- Prior art keywords
- ophthalmic composition
- eye
- aqueous ophthalmic
- drops
- aqueous
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 306
- 229950003529 diquafosol Drugs 0.000 title claims abstract description 130
- 229920000036 polyvinylpyrrolidone Polymers 0.000 title claims abstract description 107
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 title claims abstract description 107
- 239000001267 polyvinylpyrrolidone Substances 0.000 title claims abstract description 94
- NMLMACJWHPHKGR-NCOIDOBVSA-N P(1),P(4)-bis(uridin-5'-yl) tetraphosphate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O NMLMACJWHPHKGR-NCOIDOBVSA-N 0.000 title claims abstract description 56
- 150000003839 salts Chemical class 0.000 title claims abstract description 48
- 239000003889 eye drop Substances 0.000 claims abstract description 362
- 229940012356 eye drops Drugs 0.000 claims abstract description 177
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 76
- 206010013774 Dry eye Diseases 0.000 claims abstract description 75
- 239000006196 drop Substances 0.000 claims abstract description 64
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims abstract description 60
- 229910001961 silver nitrate Inorganic materials 0.000 claims abstract description 30
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 63
- 229940127557 pharmaceutical product Drugs 0.000 claims description 63
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 22
- 229940023490 ophthalmic product Drugs 0.000 claims description 18
- 239000011734 sodium Substances 0.000 claims description 16
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 13
- 229910052708 sodium Inorganic materials 0.000 claims description 13
- 230000002265 prevention Effects 0.000 claims description 5
- 210000000026 apposition eye Anatomy 0.000 claims 5
- OWTGMPPCCUSXIP-FNXFGIETSA-J tetrasodium;[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O OWTGMPPCCUSXIP-FNXFGIETSA-J 0.000 description 97
- 238000012360 testing method Methods 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 52
- 238000009472 formulation Methods 0.000 description 48
- 239000008213 purified water Substances 0.000 description 47
- 239000000243 solution Substances 0.000 description 29
- 239000011780 sodium chloride Substances 0.000 description 26
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 25
- 230000000694 effects Effects 0.000 description 25
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 24
- 239000003002 pH adjusting agent Substances 0.000 description 24
- 238000004321 preservation Methods 0.000 description 23
- 238000000034 method Methods 0.000 description 20
- 239000003814 drug Substances 0.000 description 17
- 241000894006 Bacteria Species 0.000 description 15
- 238000011049 filling Methods 0.000 description 15
- 238000002156 mixing Methods 0.000 description 15
- 239000002997 ophthalmic solution Substances 0.000 description 15
- 229940054534 ophthalmic solution Drugs 0.000 description 15
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 13
- 238000010998 test method Methods 0.000 description 13
- VLBOGLLDGKZDIR-UHFFFAOYSA-N O.[Na].C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(CN)N Chemical compound O.[Na].C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(CN)N VLBOGLLDGKZDIR-UHFFFAOYSA-N 0.000 description 12
- YQLLDALKLIDLCT-UHFFFAOYSA-N O.C(C)(=O)ON(CCN(OC(C)=O)OC(C)=O)OC(C)=O.[Na] Chemical compound O.C(C)(=O)ON(CCN(OC(C)=O)OC(C)=O)OC(C)=O.[Na] YQLLDALKLIDLCT-UHFFFAOYSA-N 0.000 description 11
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 11
- 239000003755 preservative agent Substances 0.000 description 11
- 229920003082 Povidone K 90 Polymers 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 230000002335 preservative effect Effects 0.000 description 10
- 238000005464 sample preparation method Methods 0.000 description 10
- 229920003081 Povidone K 30 Polymers 0.000 description 9
- 150000003378 silver Chemical class 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 8
- 230000008378 epithelial damage Effects 0.000 description 8
- 210000000744 eyelid Anatomy 0.000 description 8
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 7
- 210000002919 epithelial cell Anatomy 0.000 description 7
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- 241000222122 Candida albicans Species 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 238000004043 dyeing Methods 0.000 description 6
- 210000000981 epithelium Anatomy 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 230000007794 irritation Effects 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 229910001868 water Inorganic materials 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 210000005036 nerve Anatomy 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229910001424 calcium ion Inorganic materials 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 210000004087 cornea Anatomy 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 238000002690 local anesthesia Methods 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- CMHHMUWAYWTMGS-UHFFFAOYSA-N oxybuprocaine Chemical compound CCCCOC1=CC(C(=O)OCCN(CC)CC)=CC=C1N CMHHMUWAYWTMGS-UHFFFAOYSA-N 0.000 description 4
- 210000000578 peripheral nerve Anatomy 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241001331781 Aspergillus brasiliensis Species 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- 229910021607 Silver chloride Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 230000036982 action potential Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229940095731 candida albicans Drugs 0.000 description 3
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- 235000011187 glycerol Nutrition 0.000 description 3
- 208000024908 graft versus host disease Diseases 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 210000004561 lacrimal apparatus Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 229940019931 silver phosphate Drugs 0.000 description 3
- 229910000161 silver phosphate Inorganic materials 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
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- 239000003732 agents acting on the eye Substances 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/0012—Galenical forms characterised by the site of application
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Landscapes
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Abstract
An aqueous ophthalmic composition comprising diquafosol or a salt thereof and polyvinylpyrrolidone. An aqueous ophthalmic composition for preventing or treating dry eye, which contains diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone having a K value of 90, and silver nitrate, and is characterized in that the aqueous ophthalmic composition is used by eye drop administration for 1 to 2 times and for 1 day for 2 to 4 times. An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium, polyvinylpyrrolidone and silver nitrate at a concentration of 3% (w/v), wherein the aqueous ophthalmic composition has a viscosity of 3 to 30mpa·s at 25 ℃, and is characterized by being used in 1 to 2 drops for 1 day for 2 to 4 eye drops.
Description
The present application is a divisional application of chinese patent application No.202080059970.2 (PCT application No. PCT/JP 2020/031917) having a filing date of 25/8 and a title of "aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone".
Technical Field
The present invention relates to an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone.
Background
The diquafos is also known as P 1 ,P 4 Purine receptor agonists of di (uridine-5') tetraphosphoric acid or Up4U with lacrimal secretion promoting effect, sodium quartenase as "DIQUAS (registered trademark) Eye drops 3% "(hereinafter, also referred to as" DIQUAS) (registered trademark) Eye drops ") are used for the treatment of dry eye (Japanese patent publication No. 3652707 (patent document 1), DIQUAS (registered trademark) Eye drops 3% drug instructions (non-patent document 1)). DIQUAS (registered trademark) The dosage of the eye drops is usually 1 drop per 1 day and 6 drops per 1 day (non-patent document 1), but there are serious dry eye patients who cannot obtain a sufficient therapeutic effect even when they are used in the predetermined dosage. In addition, in daily life, there is a situation in which it is difficult to regularly drip eyes on a daily basis, and thus, there is also a patient who cannot obtain a desired effect due to poor eye drip compliance. In addition, although the frequency is low, there is still a factor of DIQUAS (registered trademark) The use of an eye drop complains about side effects such as eye irritation (non-patent document 1).
As an attempt to search for a novel therapeutic agent for dry eye with a higher tear level increasing effect, an example of using diquafosol or a salt thereof in combination with a conventional therapeutic agent for dry eye is known. Japanese patent application laid-open No. 2012-077080 (patent document 2) discloses that the secretion of tears is synergistically promoted by using diquafosol or a salt thereof in combination with hyaluronic acid as a therapeutic agent for dry eye. Japanese patent application laid-open No. 2015-160626 (patent document 3) discloses that the secretion of tears is synergistically promoted by the combination of diquafosol or a salt thereof with rebamipide as a therapeutic agent for dry eye.
Prior art literature
Patent literature
Patent document 1: japanese patent No. 3652707
Patent document 2: japanese patent application laid-open No. 2012-077080
Patent document 3: japanese patent application laid-open No. 2015-160626
Non-patent literature
Non-patent document 1: DIQUAS (registered trademark) 3% eye drop medicine instruction
Disclosure of Invention
Problems to be solved by the invention
It is an interesting object to provide an aqueous ophthalmic composition capable of enhancing the efficacy of diquafosol or a salt thereof and reducing side effects such as ocular irritation.
Means for solving the problems
As a result of intensive studies, the inventors of the present application have found that an aqueous ophthalmic composition (hereinafter, also referred to as "the present composition") containing diquafosol or a salt thereof and polyvinylpyrrolidone exhibits a remarkable improvement in the fluorescein staining score, that is, a remarkable corneal epithelial damage improving effect, and that it is clear that polyvinylpyrrolidone enhances the efficacy of diquafosol or a salt thereof. Furthermore, the inventors of the present application have found that the present composition having a certain viscosity by containing polyvinylpyrrolidone having a certain K value can be used in a smaller amount than the conventional DIQUAS (registered trademark) The number of times of the eye drops is equal to that of the prior DIQUAS (registered trademark) The eye drops have equal or better therapeutic effect. It has also been found that the present compositions exhibit high activityCell activity and high safety to conjunctival epithelium. It has also been found that the present composition does not exhibit nerve irritation and can further improve the comfort of eye drops. It has also been found that the present composition having a silver salt exhibits excellent preservation efficacy even when the silver salt is contained in the present composition.
Namely, the present invention relates to the following aspects.
(1) An aqueous ophthalmic composition comprising diquafosol or a salt thereof, and polyvinylpyrrolidone.
(2) The aqueous ophthalmic composition according to (1), which further contains a silver salt.
(3) The aqueous ophthalmic composition of (2), wherein the silver salt comprises silver nitrate.
(4) The aqueous ophthalmic composition according to any one of (1) to (3), which is used for preventing or treating dry eye.
(5) The aqueous ophthalmic composition according to (4), which contains diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
(6) The aqueous ophthalmic composition according to (4), which contains diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
(7) The aqueous ophthalmic composition according to (4), which contains diquafosol sodium at a concentration of 1 to 5% (w/v), and has a viscosity of 1.5 to 30 mPas at 25 ℃.
(8) The aqueous ophthalmic composition according to (4), which contains diquafosol sodium at a concentration of 3% (w/v), has a viscosity of 1.5 to 30 mPas at 25 ℃.
(9) The aqueous ophthalmic composition according to any one of (5) to (8), wherein the aqueous ophthalmic composition is used by eye-drop administration 2 to 4 times for 1 day.
(10) The aqueous ophthalmic composition according to any one of (5) to (8), wherein the aqueous ophthalmic composition is administered 3 times by eye-drop for 1 day.
(11) The aqueous ophthalmic composition according to (9) or (10), wherein 1 to 2 drops are administered by 1 eye drop.
(12) An ophthalmic pharmaceutical product, which is characterized in that 0.1 to 1mL of the aqueous ophthalmic composition of (1) is filled in a unit dose type eye drop container.
(13) An ophthalmic pharmaceutical product, which is characterized in that a unit dose type eye drop container is filled with 0.3 to 0.5mL of the aqueous ophthalmic composition of (1).
(14) An ophthalmic pharmaceutical product, wherein 1 to 10mL of the aqueous ophthalmic composition according to any one of (1) to (3) is filled in a multi-dose eye drop container.
(15) An ophthalmic pharmaceutical product, wherein 5mL of the aqueous ophthalmic composition according to any one of (1) to (3) is filled in a multi-dose eye drop container.
(16) An ophthalmic pharmaceutical product, characterized in that 1 to 10mL of the aqueous ophthalmic composition of (1) is filled in a PFMD container.
(17) An ophthalmic pharmaceutical product, wherein a PFMD container is filled with 5mL of the aqueous ophthalmic composition of (1).
(18) The ophthalmic pharmaceutical product according to any one of (12) to (17), which is used for preventing or treating dry eye.
(19) The ophthalmic pharmaceutical product according to (18), wherein the aqueous ophthalmic composition comprises diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
(20) The ophthalmic pharmaceutical product according to (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 and 120 or less.
(21) The ophthalmic pharmaceutical product according to (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 mPas at 25 ℃.
(22) The ophthalmic pharmaceutical product according to (18), wherein the aqueous composition contains diquafosol sodium at a concentration of 3% (w/v) and has a viscosity of 1.5 to 30 mPas at 25 ℃.
(23) The ophthalmic pharmaceutical product according to any one of (19) to (22), wherein the ophthalmic pharmaceutical product is administered 2 to 4 times by eye drop for 1 day.
(24) The ophthalmic pharmaceutical product according to any one of (19) to (22), wherein the ophthalmic pharmaceutical product is administered 3 times by eye drop for 1 day.
(25) The ophthalmic pharmaceutical product according to (23) or (24), wherein 1 to 2 drops are administered by 1 eye drop.
(26) The aqueous ophthalmic composition according to any one of (1) to (4), which contains polyvinylpyrrolidone having a K value of 17 or more.
(27) The aqueous ophthalmic composition according to any one of (1) to (4), which comprises polyvinylpyrrolidone having a K value of 17 to 120.
(28) The aqueous ophthalmic composition according to any one of (1) to (4), which comprises polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
(29) The aqueous ophthalmic composition according to any one of (1) to (4), which comprises polyvinylpyrrolidone having a K value of 90.
(30) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the concentration of polyvinylpyrrolidone is 0.001% (w/v) or more.
(31) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the diquafosol or a salt thereof is 0.0001 to 10% (w/v).
(32) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of diquafosol or a salt thereof is 0.01 to 5% (w/v).
(33) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of the diquafosol or a salt thereof is 1 to 5% (w/v).
(34) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the concentration of diquafosol or a salt thereof is 3% (w/v).
(35) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the pH of the aqueous ophthalmic composition is in the range of 6 to 8.
(36) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the pH of the aqueous ophthalmic composition is in the range of 7 to 8.
(37) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the aqueous ophthalmic composition is a sterile aqueous eye drop.
(38) The aqueous ophthalmic composition according to any one of (1) to (11), which can be stored at room temperature.
(39) The aqueous ophthalmic composition according to any one of (1) to (6), wherein the viscosity of the aqueous ophthalmic composition is 1.5 to 30 mPas at 25 ℃.
(40) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the salt of diquafos is diquafos sodium.
(41) An aqueous ophthalmic composition for preventing or treating dry eye, which contains diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone having a K value of 90, and silver nitrate, and is characterized in that the aqueous ophthalmic composition is used by eye drop administration for 1 to 2 times and for 1 day for 2 to 4 times.
(42) An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium, polyvinylpyrrolidone and silver nitrate at a concentration of 3% (w/v), wherein the aqueous ophthalmic composition has a viscosity of 3 to 30mpa·s at 25 ℃, and is characterized by being used in 1 to 2 drops for 1 day for 2 to 4 eye drops.
(43) The aqueous ophthalmic composition according to (41) or (42), which is used by eye-drop administration 3 times for 1 day.
(44) An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 0.1 to 1mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 is filled in a unit dose type eye drop container, and the aqueous ophthalmic composition is used in 1 to 2 drops for 1 day for 2 to 4 eye drop administrations.
(45) An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 0.1 to 1mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone in a concentration of 3% (w/v) is filled in a unit dose type eye drop container, and the aqueous ophthalmic composition has a viscosity of 3 to 30mpa·s at 25 ℃ and is used in 1 to 2 drops for 2 to 4 eye drops for 1 day.
(46) An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 is filled in a multi-dose eye drop container, and the aqueous ophthalmic composition is used by 1 to 2 drops for 1 day for 2 to 4 eye drop administrations.
(47) An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a multi-dose eye drop container, the aqueous ophthalmic composition having a viscosity of 3 to 30mpa·s at 25 ℃ and being used in 1 to 2 drops for 2 to 4 eye drops for administration.
(48) An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 is filled in a PFMD container, and the aqueous ophthalmic composition is used by eye drop administration for 1 to 2 drops for 1 day and 2 to 4 drops.
(49) An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a PFMD container, the aqueous ophthalmic composition having a viscosity of 3 to 30mpa·s at 25 ℃ and being used in 1 to 2 drops for 2 to 4 eye drops for administration for 1 day.
(50) The ophthalmic pharmaceutical product according to any one of (44) to (49), wherein the ophthalmic pharmaceutical product is administered 3 times in 1 day of eye drop.
(51) The ophthalmic pharmaceutical product of any one of (46) or (47), which further contains silver nitrate.
In addition, the invention also relates to the following scheme.
The method for treating dry eye (A-1) comprising the step of instilling an aqueous ophthalmic composition filled in a unit dose type eye-drop container to a patient 1 to 2 drops for 2 to 4 times per 1 day, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and 0.1 to 1mL of the aqueous ophthalmic composition is filled in the unit dose type eye-drop container.
The method for treating dry eye (A-2) comprising the step of instilling an aqueous ophthalmic composition filled in a unit dose type eye-drop container 1 to 2 drops and 1 day 2 to 4 times to a patient, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and has a viscosity of 3 to 30 mPa.s at 25 ℃, and the unit dose type eye-drop container is filled with 0.1 to 1mL of the aqueous ophthalmic composition.
The method for treating dry eye (A-3) comprising the step of instilling an aqueous ophthalmic composition filled in a multi-dose eye-drop container 1 to 2 drops and 1 day 2 to 4 times to a patient, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and 1 to 10mL of the aqueous ophthalmic composition is filled in the multi-dose eye-drop container.
The method for treating dry eye (A-4) comprising the step of instilling an aqueous ophthalmic composition filled in a multi-dose eye-drop container 1 to 2 drops and 1 day 2 to 4 times to a patient, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and has a viscosity of 3 to 30 mPa.s at 25 ℃, and the aqueous ophthalmic composition is filled in the multi-dose eye-drop container 1 to 10mL.
The method for treating dry eye according to (A-5), comprising the step of eye-drop-administering an aqueous ophthalmic composition filled in a PFMD container to a patient 1 to 2 drops for 2 to 4 times per 1 day, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and 1 to 10mL of the aqueous ophthalmic composition is filled in the PFMD container.
The method for treating dry eye according to (A-6), which comprises the step of eye-drop-administering an aqueous ophthalmic composition filled in a PFMD container to a patient 1 to 2 drops for 2 to 4 times per 1 day, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and has a viscosity of 3 to 30 mPa.s at 25 ℃, and the PFMD container is filled with 1 to 10mL of the aqueous ophthalmic composition.
The method for treating dry eye according to any one of (A-1) to (A-6), wherein the method comprises the step of administering the aqueous ophthalmic composition to a patient 1 to 2 drops for 1 day and 3 drops for 1 day.
The ophthalmic pharmaceutical product (B-1) is characterized in that 0.1 to 1mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and a polyvinylpyrrolidone having a K value of 90 are filled in a unit dose type eye drop container for preventing or treating dry eye, and the aqueous ophthalmic composition is used in 1 to 2 drops for 1 day and 2 to 4 eye drop administrations.
The ophthalmic pharmaceutical product (B-2) is characterized in that 0.1 to 1mL of an aqueous ophthalmic composition containing 3% (w/v) of diquafosol sodium and polyvinylpyrrolidone is filled in a unit dose type eye drop container for preventing or treating dry eye, and the aqueous ophthalmic composition has a viscosity of 3 to 30 mPas at 25 ℃ and is used in 1 to 2 drops for 1 day and 2 to 4 eye drops for administration.
The ophthalmic pharmaceutical product (B-3) is characterized in that 1 to 10mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and a polyvinylpyrrolidone having a K value of 90 are filled in a multi-dose eye-drop container for preventing or treating dry eye, and the aqueous ophthalmic composition is used by eye-drop administration for 1 to 2 drops and for 1 to 4 days.
The ophthalmic pharmaceutical product (B-4) is characterized in that 1 to 10mL of an aqueous ophthalmic composition containing 3% (w/v) of diquafosol sodium and polyvinylpyrrolidone is filled in a multi-dose eye-drop container for preventing or treating dry eye, and the aqueous ophthalmic composition has a viscosity of 3 to 30 mPas at 25 ℃ and is used in 1 to 2 drops for 2 to 4 eye-drop administrations for 1 day.
The ophthalmic pharmaceutical product (B-5) is characterized in that 1 to 10mL of an aqueous ophthalmic composition containing 3% (w/v) of diquafosol sodium and a polyvinylpyrrolidone having a K value of 90 are filled in a PFMD container for preventing or treating dry eye, and the aqueous ophthalmic composition is used by eye drop administration for 1 to 2 times and for 1 day for 2 to 4 times.
The ophthalmic pharmaceutical product (B-6) is characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and having a viscosity of 3 to 30 mPas at 25 ℃ is filled in a PFMD container for prevention or treatment of dry eye, and the aqueous ophthalmic composition is used in 1 to 2 drops for 1 day for 2 to 4 eye drops.
The ophthalmic pharmaceutical product according to any one of (B-1) to (B-6), wherein the aqueous ophthalmic composition is used in 1-2 drops and 3 drops for 1 day.
The use of (C-1) an aqueous ophthalmic composition for producing a medicament for preventing or treating dry eye, wherein the aqueous ophthalmic composition comprises diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and 0.1 to 1mL of the aqueous ophthalmic composition is filled in a unit dose type eye drop container and administered in 1 to 2 drops for 1 day and 2 to 4 drops for 1 day.
The use of (C-2) an aqueous ophthalmic composition comprising diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and having a viscosity of 3 to 30 mPas at 25 ℃, wherein 0.1 to 1mL of the aqueous ophthalmic composition is filled in a unit dose type eye drop container and administered 1 to 2 drops for 1 day and 2 to 4 drops for 1 day, for the manufacture of a medicament for preventing or treating dry eye.
The use of (C-3) an aqueous ophthalmic composition for producing a medicament for preventing or treating dry eye, wherein the aqueous ophthalmic composition comprises diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and 1 to 10mL of the aqueous ophthalmic composition is filled in a multi-dose eye-drop container and administered in 1 to 2 drops for 1 day and 2 to 4 drops for 1 day.
The use of (C-4) an aqueous ophthalmic composition comprising diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and having a viscosity of 3 to 30 mPas at 25 ℃, wherein 1 to 10mL of the aqueous ophthalmic composition is filled in a multi-dose eye-drop container and administered in 1 to 2 drops for 1 day and 2 to 4 drops for 1 day, for the manufacture of a medicament for preventing or treating dry eye.
The use of (C-5) an aqueous ophthalmic composition for producing a medicament for preventing or treating dry eye, wherein the aqueous ophthalmic composition comprises diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and 1 to 10mL of the aqueous ophthalmic composition is filled in a PFMD container and administered in 1 to 2 drops for 1 day and 2 to 4 drops for 1 day.
The use of (C-6) an aqueous ophthalmic composition for producing a medicament for preventing or treating dry eye, wherein the aqueous ophthalmic composition comprises diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) and has a viscosity of 3 to 30 mPas at 25 ℃, and 1 to 10mL of the aqueous ophthalmic composition is filled in a PFMD container and administered 1 to 2 drops for 1 day and 2 to 4 drops for 1 day.
The use of the aqueous ophthalmic composition according to any one of (C-7) to (C-6), wherein the aqueous ophthalmic composition is administered in 1-2 drops for 1 day and 3 drops for 1 day.
(D-1) A method for imparting preservation efficacy to an aqueous ophthalmic composition comprising diquafosol or a salt thereof and polyvinylpyrrolidone, which comprises the step of adding a silver salt to the aqueous ophthalmic composition.
(D-2) A method for maintaining the preservation efficacy of an aqueous ophthalmic composition comprising diquafosol or a salt thereof and polyvinylpyrrolidone, which comprises the step of adding a silver salt to the aqueous ophthalmic composition.
The above-described respective configurations of the present invention may be arbitrarily selected from 2 or more kinds and combined.
ADVANTAGEOUS EFFECTS OF INVENTION
The composition has high tear level increasing effect, and can be used for administration of DIQUAS with eye drop (registered trademark) A stronger therapeutic effect on dry eye can be expected than in the case of eye drops. Therefore, it is also expected that the present composition will be better than the conventional DIQUAS (registered trademark) The low concentration of the eye drops exerts the same or better dry eye treatment effect. In addition, the existing DIQUAS (registered trademark) The eye drops require 6 times for 1 day, and there are patients who cannot obtain the desired effect due to poor eye compliance, and the present composition having a certain viscosity by containing polyvinylpyrrolidone having a certain K value can be used as a liquid for the treatment of the eye drops (registered trademark) The small number of times of eye drops shows the same effect as the prior DIQUAS (registered trademark) The eye drops have an equivalent or better therapeutic effect, and thus improvement in eye drop compliance can be expected.
In addition, the present composition exhibits high living cell activity, is highly safe for the conjunctival epithelium, does not exhibit nerve irritation, and is expected to improve the comfort of eye drops.
In addition, even if silver salt is contained in the composition, the silver salt is stable and shows excellent preservation efficacy.
Drawings
FIG. 1 is a graph showing fluorescein staining scores of cornea.
FIG. 2 is a graph showing the results of a corneal epithelial cell-based cytotoxicity test.
FIG. 3 is a graph showing the maximum fluorescence intensity (RFUmax) after adding diquafosol sodium.
Detailed Description
The present invention will be described in further detail.
In the present specification, "(w/v)%" means the mass (g) of the target component contained in 100mL of the aqueous ophthalmic composition of the present invention.
In the present specification, "PVP" means polyvinylpyrrolidone.
In the present specification, "HEC" refers to hydroxyethylcellulose.
In the present specification, "CMC-Na" refers to sodium carboxymethyl cellulose.
In the present specification, "HPMC" refers to hydroxypropyl methylcellulose.
In the present specification, "CVP" means carboxyvinyl polymer.
In the present specification, "diquafosol eye drops" refers to aqueous eye drops containing diquafosol or a salt thereof.
In the present specification, "diquafosol sodium eye drops" refers to aqueous eye drops containing diquafosol sodium.
"Desmox" is a compound represented by the following chemical structural formula.
[ chemical formula 1]
The "salt of diquafosol" is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include metal salts with lithium, sodium, potassium, calcium, magnesium, zinc, and the like; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1, 2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid (pamoic acid), polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, dimethyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, and the like; quaternary ammonium salts with methyl bromide, methyl iodide, and the like; salts with halogen ions such as bromide, chloride, iodide; salts with ammonia; salts with organic amines such as triethylenediamine, 2-aminoethanol, 2-iminodi (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, procaine, N-bis (phenylmethyl) -1, 2-ethylenediamine, and the like; etc.
In the present invention, "diquafos or a salt thereof" also includes a hydrate of diquafos (free form) or a salt thereof and an organic solvate.
In the case where a polymorph or group of polymorphs (a polymorphic system) is present in the diquafos or salt thereof, the above-mentioned polymorph or group of polymorphs (polymorphic system) is also included in the scope of the present invention. The term "polymorph group (polymorph system)" as used herein means each crystal form and the whole process thereof at each stage when the crystal form is changed depending on conditions and states such as preparation, crystallization, and storage of the above crystals.
The "diquafos or a salt thereof" of the present invention is preferably a sodium salt of diquafos, and particularly preferably a tetrasodium salt of diquafos (also referred to simply as "diquafos sodium" in the present specification) represented by the following chemical structural formula.
[ chemical formula 2]
The diquafos or a salt thereof can be produced by a method disclosed in Japanese patent application laid-open No. 2001-510484.
The present composition 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.
In the present invention, the concentration of the diquafosol or a salt thereof is not particularly limited, and for example, is preferably 0.0001 to 10% (w/v), more preferably 0.001 to 5% (w/v), still more preferably 0.01 to 5% (w/v), still more preferably 0.1 to 5% (w/v), still more preferably 1 to 5% (w/v), and particularly preferably 3% (w/v). More specifically, it is preferably 0.001% (w/v), 0.002% (w/v), 0.003% (w/v), 0.004% (w/v), 0.005% (w/v), 0.006% (w/v), 0.007% (w/v), 0.008% (w/v), 0.009% (w/v), 0.01% (w/v), 0.02% (w/v), 0.03% (w/v), 0.04% (w/v), 0.05% (w/v), 0.06% (w/v), 0.07% (w/v), 0.08% (w/v), 0.09% (w/v), 0.1% (w/v), 0.2% (w/v), 0.3% (w/v), 0.4% (w/v), 0.5% (w/v), 0.6% (w/v), 0.7% (w/v), 0.8% (w/v), 0.9% (w/v), 1% (w/v), 1.5% (w/v), 0.08% (w/v), 0.09% (w/v), 0.3% (w/v), 0.1% (w/v), 0.2% (w/v), 4.5% (w/v) or 5% (w/v).
In the present invention, "polyvinylpyrrolidone" means a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone, and is generally used as a thickener. Polyvinylpyrrolidone is also known as povidone. The K value of polyvinylpyrrolidone used in the present invention is preferably 17 or more, more preferably 17 to 120, still more preferably 25 to 120, still more preferably 30 to 120, still more preferably more than 30 and 120 or less, still more preferably 40 to 120, still more preferably 60 to 120, particularly preferably 60 to 90, and even more preferably 90. Examples thereof include 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. The K value of polyvinylpyrrolidone is a viscosity characteristic value related to the molecular weight, and is a value calculated by applying a relative viscosity value (25 ℃) measured by a capillary viscometer to the following Fikentscher formula (1).
[ mathematics 1]
In the formula (1), eta rel For the relative viscosity of the aqueous polyvinylpyrrolidone solution with respect to water, c is the poly (ethylene) in the aqueous polyvinylpyrrolidone solutionVinyl pyrrolidone concentration (%).
Here, according to the description of the K value of the seventeenth revised japanese pharmacopoeia "povidone", the K value is 90 to 108% of the display K value, and thus "K90" means that the viscosity characteristic value (K value) calculated by applying to the above formula (1) is in the range of 81 to 97.2, for example.
In the present invention, one kind of polyvinylpyrrolidone may be used alone, and two or more kinds of polyvinylpyrrolidone having different K values may be used in any combination.
In the present invention, the concentration of polyvinylpyrrolidone is not particularly limited, and may be, for example, 0.001% (w/v) or more, preferably 0.001 to 10% (w/v), more preferably 0.01 to 10% (w/v), still more preferably 0.05 to 10% (w/v), still more preferably 0.1 to 5% (w/v), and particularly preferably 1 to 5% (w/v).
The composition may further contain pharmaceutically acceptable preservatives as required. Examples thereof include silver salts such as silver nitrate, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, boric acid, borax, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, poise Li Lv ammonium, and polyhexamethylene biguanide hydrochloride.
As is clear from the test results described later, the present composition containing a silver salt has excellent preservation efficacy, and therefore, the preferred preservative in the present invention is a silver salt. Examples of the silver salt 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 silver protein, and preferably silver nitrate.
In the present invention, the concentration of the silver salt is not particularly limited, and for example, it is not particularly limited as long as it is in the range of 0.00000001 to 1% (w/v). Specifically, the lower limit value is, for example, preferably 0.00000001% (w/v) or more, 0.0000001% (w/v) or more, 0.000001% (w/v) or more, 0.0000025% (w/v) or more, 0.000004% (w/v) or more, 0.000005% (w/v) or more, 0.000008% (w/v) or more, 0.00001% (w/v) or more, 0.000016% (w/v) or more, 0.000025% (w/v) or more, 0.00004% (w/v) or more, 0.00005% (w/v) or more, 0.00008% (w/v) or more, or 0.0001% (w/v) or more. The upper limit is preferably, 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 0.001% (w/v) or less.
In the present composition, pharmaceutically acceptable additives may be further added as required in addition to the polyvinylpyrrolidone and the preservative. For example, a buffer such as sodium phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid may be selected and added as needed; a isotonic agent such as calcium chloride, sodium chloride, potassium chloride, concentrated glycerol, and the like; stabilizers such as sodium ethylenediamine tetraacetate, sodium ethylenediamine tetraacetate hydrate, citric acid hydrate, sodium citrate hydrate, etc.; surfactants such as polysorbate; antioxidants such as ascorbic acid; thickening agents (also referred to as tackifiers) such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose; and pH adjusting agents such as hydrochloric acid and sodium hydroxide. These additives may be used alone in an amount of 1, or may be used in an amount of 2 or more in any combination. The present composition may not contain a cellulose-based polymer such as hydroxyethyl cellulose or hydroxypropyl methylcellulose as a thickener.
The pH of the present composition is not limited to a specific value as long as it is within a range allowable as a drug. However, the pH of the present composition is preferably 8 or less, more preferably in the range of 4 to 8, still more preferably in the range of 5 to 8, still more preferably in the range of 6 to 8, still more preferably in the range of 7 to 8, and particularly preferably around 7. More specifically, for example, the pH is preferably 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0, more preferably 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.
In the present invention, the term "ophthalmic composition" refers to a composition for use in the prevention and/or treatment of ocular diseases and the like. Examples of the dosage form include eye drops, eye ointments, injections, ointments (for example, which can be applied to eyelid skin), and the like, and eye drops are preferable. The eye drops are the same as or similar to the eye drops, and the definition of eye drops is also intended to include eye drops for contact lenses.
In the present invention, the "aqueous ophthalmic composition" is an aqueous ophthalmic composition containing water as a solvent (base), and more preferably an aqueous eye drop.
The present composition may be a solution type eye drop or a suspension type eye drop depending on the nature and content of the active ingredient and the additive.
The present composition is preferably a sterile aqueous eye drop. Here, the term "aseptic" refers to a state in which microorganisms are killed or removed, and specifically, for example, refers to a state that meets the standard of the preservation efficacy test described in japanese pharmacopoeia of seventeenth revision.
The present composition is preferably capable of being stored at room temperature.
The viscosity of the present composition is not particularly limited as long as it is within a pharmaceutically acceptable range, and is adjusted, for example, so as to be in a range of preferably 1 to 500mpa·s, more preferably in a range of more than 1.4 and 100mpa·s or less, still more preferably in a range of 1.5 to 100mpa·s, still more preferably in a range of 1.5 to 50mpa·s, still more preferably in a range of 1.5 to 30mpa·s, still more preferably in a range of 1.5 to 20mpa·s, still more preferably in a range of 1.5 to 10mpa·s, still more preferably in a range of 2 to 10mpa·s, particularly preferably in a range of 3 to 10mpa·s, still more preferably in a range of 5 to 10mpa·s, and even more preferably in a range of 7 to 10mpa·s. The viscosity of the present composition may be adjusted so as to be in the range of 1.5 to 30mpa·s, preferably in the range of 2 to 30mpa·s, more preferably in the range of 3 to 30mpa·s, still more preferably in the range of 5 to 30mpa·s, and particularly preferably in the range of 7 to 30mpa·s. The lower limit of the viscosity of the present composition is preferably, for example, 1 mPas or more, 1.5 mPas or more, 2 mPas or more, 3 mPas or more, 5 mPas or more, or 7 mPas or more. In addition, as the upper limit value thereof, for example Preferably 500 mPas or less, 100 mPas or less, 50 mPas or less, 30 mPas or less, 20 mPas or less, or 10 mPas or less. In addition, the viscosity of the composition was measured using a rotational viscometer (25 ℃ C.; 50 s) -1 Shear rate) of the polymer is measured.
The osmotic pressure of the present composition is not limited to a specific value as long as it is allowed as a drug. However, the osmotic pressure of the present composition is preferably 2 or less, more preferably in the range of 0.5 to 2, still more preferably in the range of 0.7 to 1.6, still more preferably in the range of 0.8 to 1.4, and particularly preferably in the range of 0.9 to 1.2.
The composition can be stored in an airtight container (specifically, an eye drop container). Examples of the eye-drop container that can be filled with the present composition include "multi-dose eye-drop container" and "unit dose eye-drop container".
In the present invention, the "ophthalmic drug product" refers to an ophthalmic drug product in which the present composition is filled in an eye drop container. The "ophthalmic pharmaceutical product" herein includes, for example, an ophthalmic product. The definition of each term in the "ophthalmic pharmaceutical product" of the present invention is the same as that of each term in the "present composition".
In the present invention, the term "multi-dose type eye drop container" means an eye drop container including a container body and a lid body attachable to the container body, wherein the lid body of the eye drop container can be opened and resealed freely. The multi-dose eye drop container accommodates therein a plurality of times of eye drops which are generally used for a certain period of time. In addition, when the composition does not contain a preservative such as benzalkonium chloride, the composition can be contained in a PFMD (Preservative Free Multi Dose) container. The amount of the composition to be filled in the multi-dose eye drop container or the PFMD container is, for example, preferably 1 to 20mL, more preferably 1 to 15mL, still more preferably 1 to 10mL, still more preferably 2.5 to 10mL, and particularly preferably 5mL.
On the other hand, the term "unit dose type eye-drop container" means an eye-drop container which is pointed out in the following objects: a cap is welded and sealed to the bottle mouth part, and the welded part between the cap and the bottle-shaped main body is broken and opened for use. The unit dose type eye drop container accommodates an amount of eye drop once or several times. The ophthalmic solution contained in the unit dose type eye drop container generally does not contain a preservative such as benzalkonium chloride. The filling amount of the present composition to be filled in the unit dose type eye drop container is, for example, preferably 0.1 to 1mL, more preferably 0.1 to 0.5mL, still more preferably 0.3mL to 0.5mL, and particularly preferably 0.3mL or 0.4mL.
The use of the present composition may be appropriately changed depending on the dosage form, the severity of the symptoms of the patient to be administered, the age, the weight, the judgment of the doctor, etc., and for example, in the case of selecting an eye drop as the dosage form, the eye drop administration may be performed 1 time, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, particularly preferably 1 drop, 1 to 6 times, preferably 1 day 1 to 4 times, more preferably 1 day 2 to 4 times, further preferably 1 day 3 times, and daily to weekly. More specifically, the number of times of eye drops here is, for example, preferably 6 times on 1 day, 5 times on 1 day, 4 times on 1 day, 3 times on 1 day, 2 times on 1 day, or 1 time on 1 day, more preferably 6 times on 1 day, 4 times on 1 day, 3 times on 1 day, or 2 times on 1 day, further preferably 4 times on 1 day, 3 times on 1 day, or 2 times on 1 day, particularly preferably 3 times on 1 day.
In addition, in the case where the concentration of diquafosol or a salt thereof in the present composition is 3% (w/v), the administration for eye drops may be performed in 1-5 drops, preferably 1-3 drops, more preferably 1-2 drops, particularly preferably 1 drop, 1 day 6 times, 1 day 5 times, 1 day 4 times, 1 day 3 times, 1 day 2 times, or 1 day 1 times, preferably 1 day 6 times, 1 day 4 times, 1 day 3 times, or 1 day 2 times, more preferably 1 day 4 times, or 1 day 3 times, particularly preferably 1 day 3 times, in 1 amount of 1 to 5 drops.
Further, 1 drop is preferably 10 to 50. Mu.L, more preferably 20 to 50. Mu.L, and particularly preferably 40 to 50. Mu.L.
The composition is useful for the prevention or treatment of dry eye, and is useful as a prophylactic or therapeutic agent for dry eye. Dry eye is defined as "chronic diseases of tear and keratoconjunctival epithelium due to various factors, and is a disease accompanied by ocular discomfort and visual abnormalities", and keratoconjunctivitis sicca (KCS: keratoconjunctivitis sicca) is included in dry eye. In the present invention, the occurrence of dry eye symptoms due to wearing of soft contact lenses is also included in dry eye.
Among the symptoms of dry eye, subjective symptoms such as dry eye, eye discomfort, eye fatigue, heaviness, photophobia, eye pain, blurred vision (haziness) and the like include objective manifestations such as congestion and corneal conjunctival epithelial damage. In the present invention, "prevention or treatment of dry eye" includes improvement of subjective symptoms and/or objective manifestations described above.
Regarding the cause of dry eye, although there are many points of unclear origin, the following reasons have been reported: sjogren's syndrome; congenital lacrimal gland-free disease; sarcoidosis; graft versus host disease (GVHD: graft Versus Host Disease) caused by bone marrow transplantation; ocular pemphigus (ocular pemphigoid); thefin-prednisone syndrome (Stevens-Johnson syndrome); lacrimal passage obstruction caused by trachoma, etc.; diabetes mellitus; decreased reflex secretion due to corneal refractive correction surgery (LASIK: laser (-assisted) in Situ Keratomileusis), etc.; meibomian gland insufficiency; decreased oil layer due to blepharitis and the like; blink dysfunction or eyelid closure dysfunction due to eye-protrusion, rabbit eyes, etc.; decreased mucin secretion from the embryonic cells; VDT (Visual Display Terminals) operation; etc.
In addition, the present composition is capable of instilling an eye of a dry eye patient wearing a soft contact lens. Here, the term "to drop the eye of a dry eye patient wearing a soft contact lens" means to drop an eye drop in a state where the soft contact lens is worn on the cornea of the dry eye patient.
Examples
The results of pharmacological tests and examples of preparation are shown below, and these examples are for better understanding of the present invention and do not limit the scope of the present invention.
[ test 1]
The change with time of the amount of tears after eye-drop of the present composition was evaluated using normal male white rabbits.
(sample preparation method)
Eye drops 1:
eye drop 1 was prepared according to the formulation table shown in table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), ethylenediamine tetraacetic acid sodium hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterilized purified water to give 50mL of a 6-fold concentrated solution. Further, 10mL of the 6-fold concentrated solution was mixed with 5mL of sterilized purified water, and then a pH adjuster was appropriately added thereto to adjust the pH to 7, and sterilized purified water was added thereto to 20mL to obtain a 3-fold concentrated solution. PVP K90 (4 g) was dissolved in sterilized purified water to a total of 100g, and then autoclaved (121 ℃ C. For 20 minutes) to prepare a 4.00% (w/w) PVP K90 solution. To 6.0g of 4.00% (w/w) PVP K90 solution, 4mL of the 3-fold concentrated solution was added, and after the total amount of the solution was adjusted to 12mL, a pH adjuster was appropriately added to adjust the pH to 7, thereby preparing an eye drop 1.
Eye drops 2:
eye drop 2 was prepared according to the formulation table shown in table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), ethylenediamine tetraacetic acid sodium hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterilized purified water to give 50mL of a 6-fold concentrated solution. Further, 10mL of the 6-fold concentrated solution was mixed with 5mL of sterilized purified water, PVP K30 (1.2 g) was dissolved, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterilized purified water was added to adjust the pH to 20mL, to obtain a 3-fold concentrated solution. To 4mL of the 3-fold concentrate, sterilized purified water was added to adjust the total amount to 12mL, and then a pH adjuster was appropriately added to adjust the pH to 7, thereby preparing eye drop 2.
Eye drops 3:
eye drops 3 were prepared according to the formulation table shown in table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), ethylenediamine tetraacetic acid sodium hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterilized purified water to give 50mL of a 6-fold concentrated solution. Further, 10mL of the 6-fold concentrated solution was mixed with 5mL of sterilized purified water, and then a pH adjuster was appropriately added thereto to adjust the pH to 7, and sterilized purified water was added thereto to 20mL to obtain a 3-fold concentrated solution. Hydroxyethyl cellulose (15 g) was dissolved in 1500mL of sterilized purified water, and the solution was subjected to high-pressure steam sterilization (121 ℃ C. For 20 minutes) to prepare a 1.00% (w/w) hydroxyethyl cellulose solution. To 3.6g of 1.00% (w/w) hydroxyethylcellulose solution, 4mL of the 3-fold concentrated solution was added, and after the total amount was adjusted to 12mL by adding sterilized purified water, a pH adjuster was appropriately added to adjust the pH to 7, thereby preparing eye drop 3.
Eye drops 4:
eye drops 4 were prepared according to the formulation table shown in table 1. Specifically, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), ethylenediamine tetraacetic acid sodium hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterilized purified water to give 50mL of a 6-fold concentrated solution. Further, 10mL of the 6-fold concentrated solution was mixed with 5mL of sterilized purified water, and then a pH adjuster was appropriately added thereto to adjust the pH to 7, and sterilized purified water was added thereto to 20mL to obtain a 3-fold concentrated solution. To 4mL of the 3-fold concentrate, sterilized purified water was added to adjust the total amount to 12mL, and then a pH adjuster was appropriately added to adjust the pH to 7, thereby preparing an eye drop 4.
Eye drops 5:
eye drop 5 was prepared according to the formulation table shown in table 1. Specifically, diquafosol sodium (18 g), sodium hydrogen phosphate hydrate (1.2 g), and ethylenediamine tetraacetic acid sodium hydrate (0.06 g) were dissolved in sterilized purified water to make 100mL, and a 6-fold concentrated solution was obtained. Further, after mixing 2.5mL of the 6-fold concentrated solution with 5mL of sterilized purified water, PVP K60% aqueous solution (0.67 g) and sodium chloride (0.068 g) were dissolved, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterilized purified water was added to 15mL, thereby preparing eye drop 5.
The viscosities of the prepared eye drops 1 to 5 were measured according to the methods described in Japanese pharmacopoeia, 2.53 viscometer, 2 nd rotary viscometer, 2.1.3 cone-plate rotary viscometer (cone-plate viscometer) of the seventeenth revision. Specifically, kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows.
(measurement conditions)
Rotor angle: 1 degree
Rotor diameter: 50mm
Sample amount: 0.57mL
Measuring temperature: 25 DEG C
Shear rate:50s -1
measurement time: the viscosity was measured every 2 seconds, and the average value of 1 minute was used as the viscosity.
(test method and drug administration method)
Benoxil was added dropwise to normal male white rabbits (total 16 32 eyes) (registered trademark) Eye drops 0.4% (manufactured by shentian pharmaceutical Co., ltd.) were used for local anesthesia. After 3 minutes, schirmer test paper (Ayumi Pharmaceutical, inc.) was inserted into the lower eyelid, and after 1 minute of insertion, the wet portion was drawn out and the length (tear amount) of the wet portion was read. This was used as the previous value. Then, each of the eye drops 1 to 5 was subjected to 1 eye drop (a group of 4 eyes of 8, only the eye drop 4 was 12 eyes of 24). Before inserting Schirmer test paper (Ayumi Pharmaceutical Co., ltd.) into the lower eyelid for 3 minutes, benoxil was added dropwise (registered trademark) Eye drops 0.4% (manufactured by shentian pharmaceutical Co., ltd.) were used for local anesthesia. After each eye drop was carried out for 60 minutes, schirmer test paper (Ayumi Pharmaceutical, inc.) was inserted into the lower eyelid, and after 1 minute of insertion, the wet portion was withdrawn and the length (tear amount) of the wet portion was read.
(evaluation method)
The change in the amount of tear before and after the eye drop was calculated as delta tear (mm/min).
(test results)
Delta tear amounts (mm/min) at 60 minutes after eye drop are shown in tables 1 and 2 (each value is an average value of 8 eyes. Of these, only eye drop 4 is an average value of 24 eyes). The tear level increasing effect of the present composition was evaluated according to the following criteria.
+++: delta tear quantity (mm/min) at 60 minutes after eye drop is 4 mm/min or more;
++: delta tear volume (mm/min) at 60 minutes after eye drop is 1 mm/min or more and less than 4 mm/min;
+: delta tear volume (mm/min) at 60 minutes post-eye drop exceeds 0 mm/min and is less than 1 mm/min;
-: the delta tear quantity (mm/min) at 60 minutes after eye drop is 0 mm/min or less.
TABLE 1
(in Table 1, the unit is g/100 mL)
| Eye drops | 1 | 2 | 3 | 4 |
| Diquarfoso sodium | 3 | 3 | 3 | 3 |
| PVP K30 | - | 2 | - | - |
| PVP K90 | 2 | - | - | - |
| HEC | - | - | 0.3 | - |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 | 0.2 | 0.2 |
| Sodium ethylenediamine tetraacetate hydrate | 0.01 | 0.01 | 0.01 | 0.01 |
| Sodium chloride | 0.45 | 0.45 | 0.45 | 0.45 |
| PH regulator | q.s. | q.s. | q.s. | q.s. |
| pH | 7.0 | 7.0 | 7.0 | 7.0 |
| Viscosity (mPa. S) | 7.4 | 1.4 | 26.9 | 1.0 |
| Delta tear volume 60 minutes after eye drop (mm/min) | 4.4 | 0.4 | -0.6 | 0.3 |
| Evaluation | +++ | + | - | + |
As shown in the results of table 1, the eye drop containing PVP K30 (eye drop 2) showed no increase in tear level at 60 minutes after the eye drop, similar to the eye drop containing no PVP K30 (eye drop 4). In addition, HEC is also generally used as a thickener, however, although the eye drop containing HEC (eye drop 3) has a high viscosity, the effect of increasing the tear amount at 60 minutes after the eye drop is not observed as in the eye drop 4. In contrast, the eye drop containing PVP K90 (eye drop 1) showed an extremely high increase in tear level compared to eye drops 2 to 4.
TABLE 2
(in Table 2, the unit is g/100 mL)
| Eye drops | 5 |
| Diquarfoso sodium | 3 |
| PVP K60 | 2 |
| Sodium hydrogen phosphate hydrate | 0.2 |
| Sodium ethylenediamine tetraacetate hydrate | 0.01 |
| Sodium chloride | 0.45 |
| PH regulator | q.s. |
| pH | 7.0 |
| Viscosity (mPa. S) | 3.0 |
| Delta tear volume 60 minutes after eye drop (mm/min) | 4.4 |
| Evaluation | +++ |
As shown in the results of table 2, even when PVP has a K value of 60, the eye drop containing PVP (eye drop 5) has a high tear amount increasing effect.
(consider
The polyvinyl pyrrolidone increases the viscosity of an aqueous composition containing diquafosol or a salt thereof, and enhances the efficacy of the diquafosol or a salt thereof, but particularly when the K value exceeds 30 as in the case of adding polyvinyl pyrrolidone or when the viscosity of the aqueous composition exceeds 1.4 as in the case of adding polyvinyl pyrrolidone, the efficacy of the diquafosol or a salt thereof is significantly enhanced.
[ test 2]
The rat extraorbital lacrimal gland removal model is widely used as a model for evaluating the effect of treatment of corneal epithelial damage due to dry eye, and also as a model for evaluating P2Y 2 Models of the therapeutic effects of receptor agonists were used (invest. Ophtalmol. Mis. Sci.,42 (1), 96-100 (2001)). Using this dry eye model, it was studied whether the effect of improving corneal epithelial damage could be obtained by eye-drop administration of the present composition.
(method for producing Dry eye model)
Using male SD rats, a rat extraorbital lacrimal gland excision model was made following the method of Fujihara et al (invest. Ophthalmol. Mis. Sci.,42 (1), 96-100 (2001)). Specifically, after general anesthesia is performed by administration of sodium pentobarbital, the extraorbital lacrimal gland is removed, and corneal epithelial damage is induced.
(sample preparation method)
Eye drops a:
sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediamine tetraacetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), and diquafosol sodium (3 g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.5.
Eye drops B:
sodium hydrogen phosphate hydrate (0.2 g), sodium ethylenediamine tetraacetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g) and polyvinylpyrrolidone K90 (4 g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.5.
Eye drops X:
as the eye drop X, "DIQUAS" used as a therapeutic agent for dry eye syndrome was used (registered trademark) Eye drops 3% "(manufactured by shentian pharmaceutical co., ltd.). In the eye drop X, 1mL of water contains 30mg of diquafosol sodium as an active ingredient, and potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium ethylenediamine tetraacetate hydrate, and a pH regulator as additives.
The viscosities of the prepared eye drops A, B and X were measured according to the methods described in the seventeenth revised japanese pharmacopoeia, the 2.53 viscometer, the 2 nd rotary viscometer, and the 2.1.3 cone-plate rotary viscometer (cone-plate viscometer). Specifically, kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows.
(measurement conditions)
Rotor angle: 1 degree
Rotor diameter: 50mm
Sample amount: 0.57mL
Measuring temperature: 25 DEG C
Shear rate: 50s -1
Measurement time: the viscosity was measured every 2 seconds, and the average value of 1 minute was taken as the viscosity.
The measured viscosity for each eye drop is as follows.
Eye drops a:7.9 mPas
Eye drops B:28.0 mPa.s
Eye drops X:0.9 mPa.s
(test method and drug administration method)
For rats induced with the above corneal epithelial damage, eye drops a, B, and X were administered in the following manner.
Eye drops a, 3 administration groups 1 day: eye drop a was applied to both eyes for 4 weeks in 3 times over 1 day. (a group of 6 eyes of 12)
Eye drops B, 3 administration groups 1 day: eye drop B was applied to both eyes for 4 weeks in 3 times over 1 day. (a group of 6 eyes of 12)
Eye drops X, 6 administration groups 1 day: eye drops X were applied to both eyes for 4 weeks in 6 times per 1 day. (a group of 6 eyes of 12)
Rats that did not induce the corneal epithelial damage and were not dropped for 4 weeks were used as an eye-drop-free group (a group of 4 8 eyes).
After 4 weeks from the start of the eye drop, the damaged portion of the cornea was stained with fluorescein, and corneal epithelial damage was determined by the method of village et al (New ophthalmology, 21 (1), 87-90 (2004)). That is, the degree of staining with fluorescein was evaluated for each of the upper, middle and lower portions of the cornea based on the following criteria, and the total average of these scores was calculated. Note that 0.5 was set as an intermediate value between the scores of 0, 1, 2, and 3.
(determination criterion)
0: undyed;
1: sparse dyeing, wherein each point-shaped dyeing part is far away;
2: dyeing to a medium degree, wherein a part of the punctiform dyeing parts are adjacent;
3: the dyeing is dense, and the dyeing parts in each dot shape are adjacent.
(results)
The calculated fluorescein staining scores for each group are plotted in fig. 1. The score was the average value of 8 or 12 cases each+standard error.
As can be seen from fig. 1, for the group of 1 day 3 administrations of eye drop a, improvement in the fluorescein staining score was observed from 2 weeks after the start of eye drop B over the 1 day 3 administrations of eye drop B. For the 1 day 6 administration group of eye drop X, an improvement in the fluorescein staining score was observed after four weeks from the start of eye drop, as compared to the 1 day 3 administration of eye drop B. After four weeks of eye-drop, the 1 day 3 administration group of eye-drop a showed the same degree of effect as the 1 day 6 administration group of eye-drop X.
(consider
Eye drop X as "DIQUAS (registered trademark) 3% "for dry eye, the number of eye drops was 6 times per day 1. Regarding the present composition to which polyvinylpyrrolidone K90 was added, it was found that 3 times of eye drops for 1 day had a sufficient therapeutic effect on dry eye, and that exceeding "DIQUAS" was observed especially after 2 weeks from the start of eye drops (registered trademark) 3% "eye drops for 6 times a day. Thus, the present composition is shown to be less than the existing DIQUAS (registered trademark) The number of times of the eye drops is equal to that of the prior DIQUAS (registered trademark) The eye drops have equal or better therapeutic effect. Especially considering the test results of test 1, it was shown that a poly with a K value exceeding 30 was addedThe present composition of vinylpyrrolidone or the present composition having a viscosity exceeding 1.4 by adding polyvinylpyrrolidone can be used for eye-drop for 2 to 4 times per day to exert the same effect as the conventional "DIQUAS (registered trademark) 3% "of eye drops, 6 times of eye drops in 1 day.
[ test 3]
In order to investigate the effect of the present composition on corneal epithelial cells, a test for cytotoxicity against corneal epithelial cells was performed.
(sample preparation method)
Eye drops Y, C and D were prepared according to the formulations shown in table 3.
Eye drops Y:
an eye drop of eye drop Y was prepared according to the formulation shown in table 3. Specifically, sodium hydrogen phosphate hydrate (0.2 g), ethylenediamine tetraacetic acid sodium hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and diquafosol sodium (3 g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.5.
Eye drops C and D:
each of the eye drops C and D was prepared in the same manner as the eye drop Y according to the formulation shown in table 3.
The viscosities of the prepared eye drops Y, C and D were measured according to the methods described in the seventeenth revised japanese pharmacopoeia, the 2.53 viscometer, the 2 nd rotary viscometer, and the 2.1.3 cone-plate rotary viscometer (cone-plate viscometer). Specifically, kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows.
(measurement conditions)
Rotor angle: 1 degree
Rotor diameter: 50mm
Sample amount: 0.57mL
Measuring temperature: 25 DEG C
Shear rate: 50s -1
Measurement time: the viscosity was measured every 2 seconds, and the average value of 1 minute was taken as the viscosity.
TABLE 3
(in Table 3, the unit is g/100 mL)
| Eye drops | Y | C | D |
| Diquarfoso sodium | 3 | 3 | 3 |
| PVP K90 | - | 2 | 4 |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 | 0.2 |
| Sodium ethylenediamine tetraacetate hydrate | 0.01 | 0.01 | 0.01 |
| Silver nitrate | 0.00004 | 0.00004 | 0.00004 |
| Sodium chloride | 0.45 | 0.45 | 0.45 |
| PH regulator | q.s. | q.s. | q.s. |
| pH | 7.5 | 7.5 | 7.5 |
| Viscosity (mPa. S) | 1.0 | 8.1 | 27.2 |
(test method)
SV40 immortalized human corneal epithelial cells (HCE-T: institute of physical and chemical, center of biological origin, cell No.: RCB 2280) were inoculated (1X 10) 4 Cells/well) were cultured in 96-well plates in D-MEM/F12 medium containing 10% FBS for 1 day. The next day, after replacing the culture medium with eye drop Y, eye drop C or eye drop D, the above corneal epithelial cells were cultured for 5, 10 and 15 minutes. The activity of living cells (absorbance at 490 nm) was measured using a cell proliferation assay kit (Cell Proliferation Assay Kit) (Promega Corp., catalog number: G3580).
(results)
The test results are shown in FIG. 2.
As can be seen from fig. 2, in the case of the diquafosol eye drops (eye drops C and D) containing polyvinylpyrrolidone, the immortalized human corneal epithelial cells maintained high survival rate even after 15 minutes of culture. On the other hand, in the case of the diquafosol eye drop (eye drop Y) containing no polyvinylpyrrolidone, the survival rate was reduced with time.
(consider
The cultured immortalized human corneal epithelial cells exhibit high living cell activity in the case of polyvinylpyrrolidone-containing diquafosol eye drops, and are therefore more safe for corneal conjunctival epithelium and useful for diseases in which corneal conjunctival epithelium is unstable such as dry eye.
[ test 4]
The irritation of diquafosol sodium in the presence of PVP to peripheral nerves was studied.
(sample preparation method)
Formula liquid 1:
formulation 1 was prepared according to the formulation table shown in table 4. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterilized purified water, and a pH adjuster was added thereto to adjust the pH to 7.5, and then the total amount was adjusted to 100mL to obtain a 10-fold buffer. PVP K30 (16 g) was dissolved in sterilized purified water, and the total amount was adjusted to 200mL to obtain an 8% PVP K30 aqueous solution. 2mL of 10-fold buffer solution and 5mL of 8% PVP K30 aqueous solution were weighed, the total amount was adjusted to 20mL with sterilized purified water, and the pH was adjusted to 7.5 with a pH adjustor to obtain formulation 1.
Formula liquid 2:
formulation 2 was prepared according to the formulation table shown in table 4. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterilized purified water, and a pH adjuster was added thereto to adjust the pH to 7.5, and then the total amount was adjusted to 100mL to obtain a 10-fold buffer. 10-fold buffer solution (2 mL) and PVP K90 (0.4 g) were dissolved in sterilized purified water, and the pH was adjusted to 7.5 with a pH adjuster to a total of 20mL, to obtain formulation 2.
Formula liquid 3:
formulation 3 was prepared according to the formulation table shown in table 4. Specifically, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterilized purified water, and a pH adjuster was added thereto to adjust the pH to 7.5, and then the total amount was adjusted to 100mL to obtain a 10-fold buffer. 2mL of 10-fold buffer and sodium chondroitin sulfate (0.06 g) were added to sterilized purified water, and the pH was adjusted to 7.5 using a pH adjuster, and after confirming dissolution, the total amount was adjusted to 20mL, to obtain formulation 3.
Formula liquid 4-6:
according to the formulation table shown in Table 4, formulations 4 to 6 were prepared in the same manner as formulation 3.
TABLE 4
(in Table 4, the units are g/100 mL)
| Formula liquid | 1 | 2 | 3 | 4 | 5 | 6 |
| Sodium chloride | 0.85 | 0.85 | 0.85 | 0.85 | 0.80 | 0.85 |
| Sodium hydrogen phosphate hydrate | 0.20 | 0.20 | 0.20 | 0.20 | 0.20 | 0.20 |
| PVP K30 | 2.00 | - | - | - | - | - |
| PVP K90 | - | 2.00 | - | - | - | - |
| Chondroitin sulfate sodium salt | - | - | 0.30 | - | - | - |
| HPMC | - | - | - | 0.30 | - | - |
| CVP | - | - | - | - | 0.30 | - |
| CMC-Na | - | - | - | - | - | 0.30 |
| PH regulator | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. |
| pH | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 |
(test method)
Cultured peripheral nerve cells (rat dorsal root ganglion neurons, purchased from LONZA JAPAN) were incubated in a buffer (FLIPR Calcium 6Assay Kit,Molecular Devices company) containing intracellular Calcium fluorescence indicator pigment. 40% of the total amount of the buffer was replaced with each of the above-described formulations. In the non-stimulated group and the stimulated control group, the buffer was treated in the same manner as the formulation liquid. After standing at room temperature, the measurement of the calcium-indicating pigment by fluorescence over time was started using a fluorescence reader (fluorescence plate reader). The fluorescence intensity was measured continuously by adding diquafosol sodium (final concentration: 0.3%) 60 seconds after the start.
(evaluation method)
The maximum fluorescence intensity (RFUmax) after addition was calculated by setting the fluorescence intensity (RFU) immediately before addition of sodium quartate to 100%.
(test results)
The results are shown in FIG. 3. RFU was increased after addition of diquafosol sodium in the stimulation control group and the formulation solutions 3 to 6, and RFUmax of 103.5% or more was recorded. On the other hand, RFUmax was less than 101% in each of the PVP-containing formulations 1 and 2.
(consider
Peripheral nerve cells that have received some of the stimuli generate an action potential to become excited, and the signals of the stimuli converted to the action potential are then transmitted to the central nervous system. The action potential refers to a change in cell membrane potential caused by the inflow of cations including calcium ions into cells. Therefore, an increase in the concentration of calcium ions in nerve cells has been widely used experimentally as an indicator for indicating the excited state of nerve cells. When diquafosol sodium is exposed to peripheral nerve cells, a rapid increase in fluorescence intensity of intracellular calcium ions is observed, and it is shown that nerve cells receive diquafosol sodium as a stimulus and become excited. In the groups of the polymer formulations 3 to 6 containing no PVP as comparative examples, the same stimulus response was also confirmed, and the polymers of chondroitin sulfate sodium, HPMC, CVP and CMC-Na did not exert any influence on the nerve stimulating properties of diquafosa sodium. In contrast, in the formulations 1 and 2 containing PVP, the increase in the intracellular calcium ion signal after addition of the diquafosol sodium was not shown. That is, it was revealed that diquafosol sodium in the presence of PVP did not exhibit nerve irritation, and that the comfort of diquafosol sodium eye drops was improved by the addition of PVP.
[ test 5]
The effect of the present composition on the stability of the preservative was investigated.
(sample preparation method)
Eye drops 6:
eye drops 6 were prepared according to the formulation shown in table 5. Specifically, diquafosol sodium (3 g), chlorhexidine gluconate (0.0025 g), hydroxyethylcellulose (0.2 g), sodium hydrogen phosphate hydrate (0.2 g), ethylenediamine tetraacetic acid sodium hydrate (0.01 g), and sodium chloride (0.45 g) were dissolved in water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.5.
7-10% of eye drops:
according to the formulations shown in Table 5, eye drops 7 to 10 were prepared in the same manner as in eye drop 6.
TABLE 5
(in Table 5, the units are g/100 mL)
(test method)
The eye drops 6 and 7 were stored at 60℃for four weeks, and the content of chlorhexidine gluconate at this time was quantified by High Performance Liquid Chromatography (HPLC) to calculate the residual rate (%). The eye drops 8 and 9 were stored at 60℃for 2 weeks, and the content of chlorhexidine gluconate at this time was quantified by High Performance Liquid Chromatography (HPLC) to calculate the residual rate (%). The eye drop 10 was stored at 60℃for four weeks, and the silver nitrate content was quantified by high-frequency inductively coupled plasma emission spectrometry (ICP-AES) to calculate the residual percentage (%).
(test results)
The results of the stability test are shown in table 6.
TABLE 6
| Eye drops | 6 | 7 | 8 | 9 | 10 |
| Residual Rate (%) | 90.1 | 20.4 | 26.7 | 8.0 | 100 |
(consider
When chlorhexidine gluconate salt is contained as a preservative in an aqueous ophthalmic composition (the present composition) containing diquafosol or a salt thereof and polyvinylpyrrolidone, the residual rate is significantly reduced (eye drops 7 to 9). On the other hand, when silver nitrate is contained as a silver salt as a preservative, the residual rate thereof is high (eye drop 10). The above demonstrates that the present composition destabilizes chlorhexidine gluconate and, on the other hand, stabilizes silver salts.
[ test 6]
The preservation efficacy of the present compositions containing silver salts was investigated.
(sample preparation method)
Eye drops 11:
eye drop 11 was prepared according to the formulation shown in table 7. Specifically, diquafosol sodium (3 g), silver nitrate (0.00008 g), sodium hydrogen phosphate hydrate (0.2 g), ethylenediamine tetraacetic acid sodium hydrate (0.01 g), polyvinylpyrrolidone K30 (2 g), concentrated glycerin (1.2 g), and hydroxyethylcellulose (0.25 g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.5.
12-15% of eye drops:
each of the eye drops 12 to 15 was prepared in the same manner as the eye drop 11 according to the formulation shown in table 7.
TABLE 7
(in Table 7, the units are g/100 mL)
| Eye drops | 11 | 12 | 13 | 14 | 15 |
| Diquarfoso sodium | 3 | 3 | 3 | 3 | 3 |
| Silver nitrate | 0.00008 | 0.00004 | 0.000016 | 0.000008 | 0.000004 |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
| Sodium ethylenediamine tetraacetate hydrate | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
| PVP K30 | 2 | 2 | 2 | 2 | 2 |
| Sodium chloride | - | 0.45 | 0.45 | 0.45 | 0.45 |
| Concentrated glycerol | 1.2 | - | - | - | - |
| HEC | 0.25 | 0.25 | 0.25 | 0.25 | 0.25 |
| PH regulator | q.s | q.s | q.s | q.s | q.s |
| pH | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 |
(test method)
The preservation efficacy test was conducted in compliance with the preservation efficacy test method of the seventeenth revised japanese pharmacopoeia. In this test, esherichia Coli (E.coli), pseudomonas aeruginosa (P.aeroginosa), staphylococcus aureus (S.aureus), candida albicans (C.albicans) and Aspergillus brasiliensis (A.brilloiensis) were used as test bacteria.
(test results)
The test results are shown in Table 8.
TABLE 8
(Unit: log removal Rate)
The test results in table 8 show how much the number of viable bacteria at the time of the test was reduced from the number of inoculated bacteria, for example, "1", in terms of log removal rate, and the number of viable bacteria at the time of the test was reduced to 10% of the number of inoculated bacteria.
As shown in table 8, the present composition containing silver salt was shown to meet the preservation efficacy test standard of japanese pharmacopoeia.
(consider
From the above results, it was revealed that the present composition containing silver salts has excellent preservation efficacy.
[ test 7]
The composition was evaluated for the change with time of the amount of tear at 90 minutes after eye drop using normal male white rabbits.
(sample preparation method)
Eye drops 16:
as an eye drop 16, sodium hydrogen phosphate hydrate (0.2 g), ethylenediamine tetraacetic acid sodium hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), and diquafosol sodium (3 g) were dissolved in sterilized purified water to make 100mL, and a pH adjustor (q.s.) was added to make the pH 7.5.
Eye drops 17:
as the eye drop 17, "DIQUAS" used as a therapeutic agent for dry eye is used (registered trademark) Eye drops 3% "(manufactured by shentian pharmaceutical co., ltd.). The eye drop 17 contains 30mg of diquafosol sodium as an active ingredient in 1mL of water, and potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium ethylenediamine tetraacetate hydrate, and a pH adjuster as additives.
(test method and drug administration method)
Benoxil was added dropwise to normal male white rabbits (total of 12 24 eyes) (registered trademark) Eye drops 0.4% (manufactured by shentian pharmaceutical Co., ltd.) were used for local anesthesia. After 3 minutes, schirmer test paper (Ayumi Pharmaceutical, inc.) was inserted into the lower eyelid, and after 1 minute of insertion, the wet portion was pulled out to read the length (tear amount). This was used as the previous value. Next, each of the eye drops 16, 17 was dropped 1 time (a group of 6 eyes of 12). Before inserting Schirmer test paper (Ayumi Pharmaceutical Co., ltd.) into the lower eyelid for 3 minutes, benoxil was added dropwise (registered trademark) Eye drops 0.4% (manufactured by shentian pharmaceutical Co., ltd.) were used for local anesthesia. After each eye drop was carried out for 90 minutes, schirmer test paper (Ayumi Pharmaceutical, inc.) was inserted into the lower eyelid, and after 1 minute of insertion, the wet portion was withdrawn, and the length (tear amount) of the wet portion was read.
(evaluation method)
The change in the amount of tear before and after the eye drop was calculated as delta tear (mm/min).
(test results)
The delta tear amount (mm/min) at 90 minutes after eye drop is shown in table 9 (each value is an average value of 12 eyes). The tear level increasing effect of the present composition was evaluated according to the following criteria.
+++: delta tear quantity (mm/min) at 90 min after eye drop is above 4 mm/min
++: delta tear volume (mm/min) at 90 minutes after eye drop is 1 mm/min or more and less than 4 mm/min
+: delta tear volume (mm/min) at 90 minutes after eye drop exceeds 0 mm/min and is less than 1 mm/min
-: delta tear quantity (mm/min) at 90 minutes after eye drop is 0 mm/min or less
TABLE 9
| Eye drops | 16 | 17 |
| Delta tear volume 90 minutes after eye drop (mm/min) | 2.0 | -0.3 |
| Evaluation | ++ | - |
As shown in the results of table 9 above, the present composition also showed a high tear level increasing effect 90 minutes after eye drop.
[ test 8]
The preservation efficacy of the present compositions containing silver salts was investigated.
(sample preparation method)
Eye drops 18:
eye drop 18 was prepared according to the formulation shown in table 10. Specifically, diquafosol sodium (3 g), silver nitrate (0.00003 g), sodium hydrogen phosphate hydrate (0.2 g), ethylenediamine tetraacetic acid sodium hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), and sodium chloride (0.45 g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.0.
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.
TABLE 10
(in Table 10, the units are g/100 mL)
| Eye drops | 18 | 19 |
| Diquarfoso sodium | 3 | 3 |
| Sodium ethylenediamine tetraacetate hydrate | 0.01 | - |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 |
| PVP K90 | 2 | 2 |
| Silver nitrate | 0.00003 | 0.00003 |
| Sodium chloride | 0.45 | 0.45 |
| PH regulator | q.s | q.s |
| pH | 7.0 | 7.0 |
(test method)
The preservation efficacy test was conducted in compliance with the preservation efficacy test method of the seventeenth revised japanese pharmacopoeia. In this test, esherichia Coli (E.coli), pseudomonas aeruginosa (P.aeroginosa), staphylococcus aureus (S.aureus), candida albicans (C.albicans) and Aspergillus brasiliensis (A.brilloiensis) were used as test bacteria.
(test results)
The test results are shown in Table 11.
TABLE 11
(Unit: log removal Rate)
The test results in table 11 show how much the number of viable bacteria at the time of the test was reduced from the number of inoculated bacteria, for example, "1", in terms of log removal rate, and the number of viable bacteria at the time of the test was reduced to 10% of the number of inoculated bacteria.
As shown in table 11, it was revealed that the present composition containing silver salt, regardless of the presence or absence of EDTA, was in accordance with the preservation efficacy test standard of japanese pharmacopoeia.
(consider
According to the above results, the present composition containing silver salts has excellent preservation efficacy.
[ test 9]
The preservation efficacy of the present compositions containing silver salts was investigated.
(sample preparation method)
Eye drops 20:
eye drop 20 was prepared according to the formulation shown in table 12. Specifically, diquafosol sodium (3 g), silver nitrate (0.00004 g), sodium hydrogen phosphate hydrate (0.2 g), ethylenediamine tetraacetic acid sodium hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), and sodium chloride (0.45 g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.5.
Eye drops 21 to 23:
each of the eye drops 21 to 23 was prepared in the same manner as the eye drop 20 according to the formulation shown in table 12.
TABLE 12
(in Table 12, the units are g/100 mL)
| Eye drops | 20 | 21 | 22 | 23 |
| Diquarfoso sodium | 3 | 3 | 3 | 3 |
| Sodium ethylenediamine tetraacetate hydrate | 0.01 | - | 0.01 | 0.01 |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 | 0.2 | 0.2 |
| PVP K90 | 2 | 2 | 2 | 2 |
| Silver nitrate | 0.00004 | 0.00004 | - | - |
| Silver phosphate | - | - | 0.0000328 | - |
| Silver chloride | - | - | - | 0.0000337 |
| Sodium chloride | 0.45 | 0.45 | 0.45 | 0.45 |
| PH regulator | q.s | q.s | q.s | q.s |
| pH | 7.5 | 7.5 | 7.5 | 7.5 |
(test method)
The preservation efficacy test was conducted in compliance with the preservation efficacy test method of the seventeenth revised japanese pharmacopoeia. In this test, esherichia Coli (E.coli), pseudomonas aeruginosa (P.aeroginosa), staphylococcus aureus (S.aureus), candida albicans (C.albicans) and Aspergillus brasiliensis (A.brilloiensis) were used as test bacteria.
(test results)
The test results are shown in Table 13.
TABLE 13
(Unit: log removal Rate)
The test results in table 13 show how much the number of viable bacteria at the time of the test was reduced from the number of inoculated bacteria, for example, "1", in terms of log removal rate, and the number of viable bacteria at the time of the test was reduced to 10% of the number of inoculated bacteria.
As shown in table 13, it was revealed that the present composition containing silver salt, regardless of the presence or absence of EDTA, was in accordance with the preservation efficacy test standard of japanese pharmacopoeia. In addition, it was revealed that an eye drop containing silver phosphate and silver chloride as silver salts in addition to silver nitrate also meets the preservation efficacy test standard of japanese pharmacopoeia.
(consider
According to the above results, the present composition containing silver salts has excellent preservation efficacy.
[ test 10]
The effect of the present composition on the stability of the preservative was investigated.
(sample preparation method)
Eye drops 24:
an eye drop 24 was prepared by dissolving diquafosol sodium (3 g), ethylenediamine tetraacetic acid sodium hydrate (0.01 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.45 g), polyvinylpyrrolidone K90 (2 g), and silver nitrate (0.00004 g) in water to make the solution 100mL, and adding a pH adjuster (q.s.) to make the pH 7.5.
(test method)
The eye drops 24 were stored at 40℃for 6 months, and the silver nitrate content was quantified by high-frequency inductively coupled plasma emission spectrometry (ICP-AES) to calculate the residual rate (%).
(test results)
The results of the stability test are shown in table 14.
TABLE 14
| Residual Rate (%) | |
| 40 ℃ for 6 months | 97.0 |
(consider
When silver nitrate is contained as a silver salt as a preservative, the residual rate is high. This shows that the silver salt is stable in the present composition.
Preparation example
The pharmaceutical agents of the present invention will be described more specifically by way of examples of preparations, but the present invention is not limited to these examples of preparations.
(formulation example 1: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. 1 to 10mL of the above eye drops are filled in a multi-dose eye drop container or a PFMD container, and an ophthalmic pharmaceutical product can be produced. In addition, the ophthalmic product can be produced by filling 0.1 to 1mL of the above-mentioned eye drops into a unit dose type eye drop container. The eye drops can be stored at room temperature.
(formulation example 2: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. 1 to 10mL of the above eye drops are filled in a multi-dose eye drop container or a PFMD container, and an ophthalmic pharmaceutical product can be produced. In addition, the ophthalmic product can be produced by filling 0.1 to 1mL of the above-mentioned eye drops into a unit dose type eye drop container. The eye drops can be stored at room temperature.
(formulation example 3: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. 1 to 10mL of the above eye drops are filled in a multi-dose eye drop container or a PFMD container, and an ophthalmic pharmaceutical product can be produced. In addition, ophthalmic pharmaceutical products can be produced by filling the unit dose type eye drop containers with 0.1 to 1mL of the above eye drops. The eye drops can be stored at room temperature.
(formulation example 4: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. The ophthalmic product can be produced by filling 1 to 10mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic solution container. The eye drops can be stored at room temperature.
(formulation example 5: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. The ophthalmic product can be produced by filling 1 to 10mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic solution container. The eye drops can be stored at room temperature.
(formulation example 6: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. The ophthalmic product can be produced by filling 1 to 10mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic solution container. The eye drops can be stored at room temperature.
(formulation example 7: sterile aqueous eye drops (3% (w/v))
In 100mL
The above eye drops can be prepared by adding diquafosol sodium and the other above components to the sterilized purified solution and mixing them sufficiently. 1 to 10mL of the above eye drops are filled in a multi-dose eye drop container or a PFMD container, and an ophthalmic pharmaceutical product can be produced. In addition, the ophthalmic product can be produced by filling 0.1 to 1mL of the above-mentioned eye drops into a unit dose type eye drop container. The eye drops can be stored at room temperature.
(formulation example 8: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. 1 to 10mL of the above eye drops are filled in a multi-dose eye drop container or a PFMD container, and an ophthalmic pharmaceutical product can be produced. In addition, the ophthalmic product can be produced by filling 0.1 to 1mL of the above-mentioned eye drops into a unit dose type eye drop container. The eye drops can be stored at room temperature.
(formulation example 9: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. 1 to 10mL of the above eye drops are filled in a multi-dose eye drop container or a PFMD container, and an ophthalmic pharmaceutical product can be produced. In addition, the ophthalmic product can be produced by filling 0.1 to 1mL of the above-mentioned eye drops into a unit dose type eye drop container. The eye drops can be stored at room temperature.
(formulation example 10: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. The ophthalmic product can be produced by filling 1 to 10mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic solution container. The eye drops can be stored at room temperature.
(formulation example 11: sterile aqueous eye drops (3% (w/v))
In 100mL
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The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. The ophthalmic product can be produced by filling 1 to 10mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic solution container. The eye drops can be stored at room temperature.
(formulation example 12: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. The ophthalmic product can be produced by filling 1 to 10mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic solution container. The eye drops can be stored at room temperature.
(formulation example 13: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. 1 to 10mL of the above eye drops are filled in a multi-dose eye drop container or a PFMD container, and an ophthalmic pharmaceutical product can be produced. In addition, the ophthalmic product can be produced by filling 0.1 to 1mL of the above-mentioned eye drops into a unit dose type eye drop container. The eye drops can be stored at room temperature.
(formulation example 14: sterile aqueous eye drops (3% (w/v))
In 100mL
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other above-mentioned components to sterilized purified water and mixing them thoroughly. The ophthalmic product can be produced by filling 1 to 10mL of the above-mentioned ophthalmic solution into a multi-dose type ophthalmic solution container. The eye drops can be stored at room temperature.
Industrial applicability
Existing DIQUAS (registered trademark) Eye drops require 6 times for 1 day, but even when used in a given dosage, there are severe dry eye patients who cannot obtain a sufficient therapeutic effect. In addition, there are also patients who cannot obtain a desired effect due to poor eye drop compliance. The composition exhibits a higher level of activity than the prior DIQUAS (registered trademark) The eye drops have a stronger dry eye treatment effect, and further, an improvement in eye compliance is expected due to a decrease in the number of times of eye drops. In addition, the present composition is also expected to be superior to the conventional DIQUAS (registered trademark) The low concentration of the eye drops exerts the same or better dry eye treatment effect.
In addition, the present composition exhibits high living cell activity, is highly safe for the conjunctival epithelium, does not exhibit nerve irritation, and is expected to improve the comfort of eye drops.
In addition, even if silver salt is contained in the composition, the silver salt is stable and shows excellent preservation efficacy.
Claims (51)
1. An aqueous ophthalmic composition comprising diquafosol or a salt thereof, and polyvinylpyrrolidone.
2. The aqueous ophthalmic composition of claim 1 further comprising a silver salt.
3. The aqueous ophthalmic composition of claim 2 wherein the silver salt comprises silver nitrate.
4. An aqueous ophthalmic composition according to any one of claims 1 to 3 for use in the prevention or treatment of dry eye.
5. The aqueous ophthalmic composition according to claim 4, wherein the aqueous ophthalmic composition comprises diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
6. The aqueous ophthalmic composition according to claim 4, wherein the aqueous ophthalmic composition comprises diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
7. The aqueous ophthalmic composition according to claim 4, which 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 ℃.
8. The aqueous ophthalmic composition of claim 4, comprising diquafosa sodium at a concentration of 3% (w/v), the aqueous ophthalmic composition having a viscosity of 1.5 to 30 mPa-s at 25 ℃.
9. The aqueous ophthalmic composition according to any one of claims 5 to 8, which is used by eye-drop administration 2 to 4 times for 1 day.
10. The aqueous ophthalmic composition of any one of claims 5 to 8, wherein the aqueous ophthalmic composition is administered 3 times as 1 day eye drops.
11. Aqueous ophthalmic composition according to claim 9 or 10, characterized in that it is used in 1-2 drops administered in 1 eye drop.
12. An ophthalmic pharmaceutical product comprising a unit dose type eye drop container filled with 0.1 to 1mL of the aqueous ophthalmic composition of claim 1.
13. An ophthalmic pharmaceutical product comprising a unit dose type eye drop container filled with 0.3 to 0.5mL of the aqueous ophthalmic composition of claim 1.
14. An ophthalmic product comprising a multi-dose eye drop container filled with 1 to 10mL of the aqueous ophthalmic composition according to any one of claims 1 to 3.
15. An ophthalmic pharmaceutical product, characterized in that 5mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 is filled in a multi-dose eye-drop container.
16. An ophthalmic pharmaceutical product comprising 1 to 10mL of the aqueous ophthalmic composition of claim 1 filled in a PFMD container.
17. An ophthalmic pharmaceutical product comprising a PFMD container filled with 5mL of the aqueous ophthalmic composition of claim 1.
18. The ophthalmic pharmaceutical product according to any one of claims 12 to 17, for use in preventing or treating dry eye.
19. The ophthalmic pharmaceutical product according to claim 18, wherein the aqueous ophthalmic composition comprises diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
20. 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 and 120 or less.
21. The ophthalmic pharmaceutical product of 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 ℃.
22. The ophthalmic pharmaceutical product of claim 18, wherein the aqueous composition contains diquafosol sodium at a concentration of 3% (w/v) and has a viscosity of 1.5 to 30 mPa-s at 25 ℃.
23. The ophthalmic pharmaceutical product according to any one of claims 19 to 22, wherein it is administered 2 to 4 times in 1 day eye drops.
24. The ophthalmic pharmaceutical product according to any one of claims 19 to 22, wherein it is administered 3 times in 1 day eye drops.
25. Ophthalmic pharmaceutical product according to claim 23 or 24, characterized in that it is used in 1-2 drops administered in 1 eye drop.
26. The aqueous ophthalmic composition according to any one of claims 1 to 4, which comprises polyvinylpyrrolidone having a K value of 17 or more.
27. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 to 120.
28. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of more than 30 and 120 or less.
29. The aqueous ophthalmic composition of any one of claims 1 to 4 comprising polyvinylpyrrolidone having a K value of 90.
30. 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.
31. 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).
32. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of diquafosol or a salt thereof is 0.01 to 5% (w/v).
33. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of diquafosol or a salt thereof is 1 to 5% (w/v).
34. The aqueous ophthalmic composition of any one of claims 1-4, wherein the concentration of diquafosol or a salt thereof is 3% (w/v).
35. The aqueous ophthalmic composition according to any one of claims 1 to 11, having a pH in the range of 6 to 8.
36. The aqueous ophthalmic composition according to any one of claims 1 to 11, having a pH in the range of 7 to 8.
37. The aqueous ophthalmic composition of any one of claims 1-11, which is a sterile aqueous eye drop.
38. The aqueous ophthalmic composition according to any one of claims 1 to 11, which can be stored at room temperature.
39. The aqueous ophthalmic composition according to any one of claims 1 to 6, having a viscosity of 1.5 to 30 mPa-s at 25 ℃.
40. The aqueous ophthalmic composition of any one of claims 1-4, wherein the salt of diquafosol is diquafosol sodium.
41. An aqueous ophthalmic composition for preventing or treating dry eye, which contains diquafosol sodium at a concentration of 3% (w/v), polyvinylpyrrolidone having a K value of 90, and silver nitrate, and is characterized in that the aqueous ophthalmic composition is used by eye drop administration for 1 to 2 times and for 1 day for 2 to 4 times.
42. An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium, polyvinylpyrrolidone and silver nitrate at a concentration of 3% (w/v), wherein the aqueous ophthalmic composition has a viscosity of 3 to 30mpa·s at 25 ℃, and is characterized by being used in 1 to 2 drops for 1 day for 2 to 4 eye drops.
43. The aqueous ophthalmic composition of claim 41 or 42, wherein the aqueous ophthalmic composition is administered 3 times as 1 day eye drops.
44. An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 0.1 to 1mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 is filled in a unit dose type eye drop container, and the aqueous ophthalmic composition is used in 1 to 2 drops for 1 day for 2 to 4 eye drop administrations.
45. An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 0.1 to 1mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone in a concentration of 3% (w/v) is filled in a unit dose type eye drop container, and the aqueous ophthalmic composition has a viscosity of 3 to 30mpa·s at 25 ℃ and is used in 1 to 2 drops for 2 to 4 eye drops for 1 day.
46. An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 is filled in a multi-dose eye drop container, and the aqueous ophthalmic composition is used by 1 to 2 drops for 1 day for 2 to 4 eye drop administrations.
47. An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a multi-dose eye drop container, the aqueous ophthalmic composition having a viscosity of 3 to 30mpa·s at 25 ℃ and being used in 1 to 2 drops for 2 to 4 eye drops for administration.
48. An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 is filled in a PFMD container, and the aqueous ophthalmic composition is used by eye drop administration for 1 to 2 drops for 1 day and 2 to 4 drops.
49. An ophthalmic pharmaceutical product for preventing or treating dry eye, characterized in that 1 to 10mL of an aqueous ophthalmic composition containing diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w/v) is filled in a PFMD container, the aqueous ophthalmic composition having a viscosity of 3 to 30mpa·s at 25 ℃ and being used in 1 to 2 drops for 2 to 4 eye drops for administration for 1 day.
50. The ophthalmic pharmaceutical product of any one of claims 44-49, wherein the ophthalmic product is administered 3 times in 1 day eye drops.
51. The ophthalmic pharmaceutical product of any one of claims 46 or 47, further comprising silver nitrate.
Applications Claiming Priority (4)
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| JP2019154525 | 2019-08-27 | ||
| JP2019-154525 | 2019-08-27 | ||
| PCT/JP2020/031917 WO2021039748A1 (en) | 2019-08-27 | 2020-08-25 | Diquafosol or salt thereof, and aqueous ophthalmic composition containing polyvinylpyrrolidone |
| CN202080059970.2A CN114286670B (en) | 2019-08-27 | 2020-08-25 | Aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone |
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| CN202080059970.2A Division CN114286670B (en) | 2019-08-27 | 2020-08-25 | Aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone |
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| CN202080059970.2A Active CN114286670B (en) | 2019-08-27 | 2020-08-25 | Aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone |
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| JP7175431B1 (en) * | 2021-03-30 | 2022-11-18 | 千寿製薬株式会社 | Suspension containing heterocyclideneacetamide derivative |
| CN114646705A (en) * | 2022-03-22 | 2022-06-21 | 武汉绿合医药科技有限公司 | Method for detecting content of related substances in diquafosol sodium eye drops |
| JP7245383B1 (en) | 2022-09-20 | 2023-03-23 | 参天製薬株式会社 | Method for Suppressing Decrease in pH of Ophthalmic Composition Containing Diquafosol or Its Salt |
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| JPH0365270A (en) | 1989-07-31 | 1991-03-20 | Kanzaki Paper Mfg Co Ltd | Manufacture of coated sheet |
| JPH0365270U (en) | 1989-10-31 | 1991-06-25 | ||
| US5358706A (en) * | 1992-09-30 | 1994-10-25 | Union Carbide Chemicals & Plastics Technology Corporation | Muco-adhesive polymers |
| CA2125060C (en) * | 1993-07-02 | 1999-03-30 | Henry P. Dabrowski | Ophthalmic solution for artificial tears |
| US5422116A (en) * | 1994-02-18 | 1995-06-06 | Ciba-Geigy Corporation | Liquid ophthalmic sustained release delivery system |
| US5900407A (en) * | 1997-02-06 | 1999-05-04 | Inspire Pharmaceuticals, Inc. | Method of treating dry eye disease with uridine triphosphates and related compounds |
| KR100549904B1 (en) * | 1996-03-27 | 2006-05-16 | 더 유니버시티 오브 노쓰 캐롤라이나 엣 채플 힐 | A pharmaceutical composition for treating ciliary dyskinesia, containing uridinde triphosphate and related compounds |
| US6274626B1 (en) * | 1998-12-22 | 2001-08-14 | Bausch & Lomb Incorporated | Pheniramine-containing compositions and method for treating allergic responses |
| EP1245233A4 (en) * | 1999-12-27 | 2006-03-15 | Santen Pharmaceutical Co Ltd | System for stabilizing lacrimal fluid layer |
| KR100832821B1 (en) * | 2000-05-30 | 2008-05-28 | 산텐 세이야꾸 가부시키가이샤 | Ectocornea extension promoters |
| SG177132A1 (en) * | 2005-02-14 | 2012-01-30 | Johnson & Johnson Vision Care | A comfortable ophthalmic device and methods of its production |
| EA026680B1 (en) * | 2010-09-10 | 2017-05-31 | Сантен Фармасьютикал Ко., Лтд. | Agent for treatment of dry eye characterized by combining p2yreceptor agonist with hyaluronic acid or salt thereof, method for treating dry eye, and use of the p2yreceptor agonist and hyaluronic acid or salt thereof |
| SG10201508591UA (en) * | 2010-12-28 | 2015-11-27 | Santen Pharmaceutical Co Ltd | Ophthalmic solution comprising diquafosol, method for producing the same, and method for inhibiting formation of insoluble precipitate |
| KR20120077080A (en) | 2010-12-30 | 2012-07-10 | 동우 화인켐 주식회사 | Optical film and backlight unit using the same |
| US20160213708A1 (en) * | 2012-01-08 | 2016-07-28 | Medicure Technologies Ltd. | Ophthalmic composition |
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| WO2015169728A1 (en) * | 2014-05-07 | 2015-11-12 | Croma-Pharma Gesellschaft M.B.H. | Aqueous ophthalmic solution and method for treating dry eye syndrome |
| SG11201705138QA (en) * | 2014-12-25 | 2017-07-28 | Santen Pharmaceutical Co Ltd | Aqueous ophthalmic solution |
| RU2742032C2 (en) * | 2015-06-05 | 2021-02-01 | Сантен Фармасьютикал Ко., Лтд. | Therapeutic agent for dry eye, characterized by eye application of dry eyes, wearing flexible contact lenses |
| KR20220163519A (en) * | 2018-02-28 | 2022-12-09 | 산텐 세이야꾸 가부시키가이샤 | Ophthalmic composition comprising diquafosol and cationic polymer |
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| TW202122094A (en) | 2021-06-16 |
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| KR20220052971A (en) | 2022-04-28 |
| CN114286670A (en) | 2022-04-05 |
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| JPWO2021039748A1 (en) | 2021-09-30 |
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| KR102656181B1 (en) | 2024-04-08 |
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