CN114286670A - Aqueous ophthalmic composition containing diquafosol or salt thereof and polyvinylpyrrolidone - Google Patents
Aqueous ophthalmic composition containing diquafosol or salt thereof and polyvinylpyrrolidone Download PDFInfo
- Publication number
- CN114286670A CN114286670A CN202080059970.2A CN202080059970A CN114286670A CN 114286670 A CN114286670 A CN 114286670A CN 202080059970 A CN202080059970 A CN 202080059970A CN 114286670 A CN114286670 A CN 114286670A
- Authority
- CN
- China
- Prior art keywords
- ophthalmic composition
- aqueous ophthalmic
- drops
- eye
- polyvinylpyrrolidone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 291
- 229950003529 diquafosol Drugs 0.000 title claims abstract description 150
- 229920000036 polyvinylpyrrolidone Polymers 0.000 title claims abstract description 108
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 title claims abstract description 108
- 239000001267 polyvinylpyrrolidone Substances 0.000 title claims abstract description 95
- 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 68
- 150000003839 salts Chemical class 0.000 title claims abstract description 47
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 73
- 206010013774 Dry eye Diseases 0.000 claims abstract description 73
- 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
- 239000011734 sodium Substances 0.000 claims abstract description 10
- 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 abstract description 7
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 7
- 239000003889 eye drop Substances 0.000 claims description 352
- 229940012356 eye drops Drugs 0.000 claims description 210
- 239000006196 drop Substances 0.000 claims description 84
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 78
- 229940127557 pharmaceutical product Drugs 0.000 claims description 73
- 239000000243 solution Substances 0.000 claims description 45
- 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 29
- 230000002265 prevention Effects 0.000 claims description 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 107
- 238000012360 testing method Methods 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 52
- 238000009472 formulation Methods 0.000 description 50
- 239000008213 purified water Substances 0.000 description 46
- 238000000034 method Methods 0.000 description 34
- 230000000694 effects Effects 0.000 description 29
- 210000001508 eye Anatomy 0.000 description 28
- 239000003002 pH adjusting agent Substances 0.000 description 27
- 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
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 23
- 239000003814 drug Substances 0.000 description 18
- 238000004321 preservation Methods 0.000 description 18
- 241000894006 Bacteria Species 0.000 description 15
- 238000002156 mixing Methods 0.000 description 14
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 13
- 238000010998 test method Methods 0.000 description 13
- GXFFSKMBMYHTAE-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydrate Chemical compound O.[Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O GXFFSKMBMYHTAE-UHFFFAOYSA-J 0.000 description 13
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 11
- 229920003082 Povidone K 90 Polymers 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 239000003755 preservative agent Substances 0.000 description 10
- 230000002335 preservative effect Effects 0.000 description 10
- 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 9
- 229920003081 Povidone K 30 Polymers 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 229940037001 sodium edetate Drugs 0.000 description 9
- 239000004354 Hydroxyethyl cellulose 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
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 210000002919 epithelial cell Anatomy 0.000 description 7
- 210000000744 eyelid 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
- 238000004519 manufacturing process Methods 0.000 description 7
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- 241001331781 Aspergillus brasiliensis Species 0.000 description 6
- 241000222122 Candida albicans Species 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 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
- 239000007788 liquid Substances 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 238000003860 storage 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
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- 238000004043 dyeing Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 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
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 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
- 230000006378 damage Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000008378 epithelial damage Effects 0.000 description 4
- 208000014674 injury Diseases 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
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- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- 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
- 229940095731 candida albicans Drugs 0.000 description 3
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 3
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- 235000011187 glycerol Nutrition 0.000 description 3
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- 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
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- 239000001103 potassium chloride Substances 0.000 description 3
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- 238000002360 preparation method Methods 0.000 description 3
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- 229910052727 yttrium 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
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Abstract
An aqueous ophthalmic composition containing 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 which is characterized by being used in such a manner that 1 to 2 drops are applied 1 time and 2 to 4 drops are applied 1 day. An aqueous ophthalmic composition for preventing or treating dry eye, which contains sodium diquafosol at a concentration of 3% (w/v), polyvinylpyrrolidone, and silver nitrate, and which has a viscosity of 3 to 30 mPas at 25 ℃, wherein the aqueous ophthalmic composition is used by 1-2 drops at 1 time and 2-4 drops at 1 day.
Description
Technical Field
The present invention relates to an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone.
Background
Diquafosol is also known as P1,P4-bis (uridine-5') tetraphosphate or purine receptor agonist of Up4U having lacrimal secretion promoting effect, and its salt diquafosol sodium as "DIQUAS(registered trademark)Eye drops 3% "(hereinafter, also referred to as" DIQUAS ")(registered trademark)Eye drops ") and are used for the treatment of dry eye (japanese patent No. 3652707 (patent document 1) and DIQUAS)(registered trademark)Eye drops 3% drug specification (non-patent document 1)). DIQUAS(registered trademark)The dosage of the eye drops is usually 1 time and 1 drop, and 6 times a day (non-patent document 1), but there are also severe dry eye patients who cannot obtain sufficient therapeutic effects even if they are used in a given dosage. In addition, in daily life, it is difficult to frequently apply eye drops daily, and there are also patients who cannot obtain the desired effect due to poor eye drop compliance. In addition, althoughAlthough the frequency is low, the frequency still exists because of DIQUAS(registered trademark)Patients suffering from side effects such as eye irritation are complained of using eye drops (non-patent document 1).
As an attempt to search for a novel dry eye therapeutic agent having a higher tear fluid volume increasing action, an example is known in which diquafosol or a salt thereof is used in combination with a conventional dry eye therapeutic agent. Japanese patent laid-open No. 2012-077080 (patent document 2) discloses that tear secretion is synergistically promoted by using diquafosol or a salt thereof in combination with hyaluronic acid as a therapeutic agent for dry eye. Jp 2015-160826 a (patent document 3) discloses that tear secretion is synergistically promoted by using diquafosol or a salt thereof in combination with rebamipide (rebamipide), which is a therapeutic agent for dry eye.
Documents of the prior art
Patent document
Patent document 1: japanese patent No. 3652707
Patent document 2: japanese laid-open patent publication No. 2012-077080
Patent document 3: japanese patent laid-open publication No. 2015-160826
Non-patent document
Non-patent document 1: DIQUAS (registered trademark) eye drops 3% instruction manual
Disclosure of Invention
Problems to be solved by the invention
It is an interesting object to provide an aqueous ophthalmic composition which can enhance the pharmacological effect of diquafosol or a salt thereof and reduce side effects such as eye 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 containing diquafosol or a salt thereof and polyvinylpyrrolidone (hereinafter, also referred to as "the present composition") exhibits a significant improvement in fluorescein staining score, that is, a significant effect of improving corneal epithelial damage, and it has been clarified that polyvinylpyrrolidone enhances the drug efficacy of diquafosol or a salt thereof. Furthermore, the inventors of the present application have found that by containing polyethylene having a certain K valueThe present compositions of pyrrolidones with certain viscosities can be used in less than the existing DIQUAS(registered trademark)The eye drop has the same eye drop frequency as that of the existing DIQUAS(registered trademark)The eye drops have equal or better treatment effect. In addition, it was found that the present composition exhibits high activity of living cells and is highly safe for corneal conjunctival epithelium. It has also been found that the present composition does not exhibit nerve stimulation and can further improve the comfort of eye drops. It has also been found that even if a silver salt is contained in the present composition, the silver salt is stable, and the present composition having the silver salt exhibits excellent preservation efficacy.
That is, 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 according to (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 comprises diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120.
(6) The aqueous ophthalmic composition according to (4), which comprises diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120.
(7) The aqueous ophthalmic composition according to (4), which contains diquafosol sodium at a concentration of 1 to 5% (w/v), and which 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), and which has a viscosity of 1.5 to 30 mPas at 25 ℃.
(9) The aqueous ophthalmic composition according to any one of (5) to (8), which is used in a form of eye drops to be applied 2 to 4 times in 1 day.
(10) The aqueous ophthalmic composition according to any one of (5) to (8), which is used in a form of eye drops administered 3 times in 1 day.
(11) The aqueous ophthalmic composition according to (9) or (10), which is used in such a manner that 1 to 2 drops are applied to 1 eye drop.
(12) An ophthalmic pharmaceutical product characterized in that a unit dose type eye drop container is filled with 0.1 to 1mL of the aqueous ophthalmic composition of (1).
(13) An ophthalmic pharmaceutical product 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 comprising a multi-dose eye drop container filled with 1 to 10mL of the aqueous ophthalmic composition according to any one of (1) to (3).
(15) An ophthalmic pharmaceutical product comprising a multi-dose eye drop container filled with 5mL of the aqueous ophthalmic composition according to any one of (1) to (3).
(16) An ophthalmic pharmaceutical product characterized in that a PFMD container is filled with 1 to 10mL of the aqueous ophthalmic composition of (1).
(17) An ophthalmic pharmaceutical preparation characterized in that a PFMD container is filled with 5mL of the aqueous ophthalmic composition of (1).
(18) An 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 contains diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120.
(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 not more than 120.
(21) The ophthalmic pharmaceutical preparation 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 preparation 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) An ophthalmic pharmaceutical product according to any one of (19) to (22), wherein the ophthalmic pharmaceutical product is administered in eye drops 2 to 4 times in 1 day.
(24) An ophthalmic pharmaceutical product according to any one of (19) to (22), wherein the ophthalmic pharmaceutical product is administered in eye drops 3 times in 1 day.
(25) An ophthalmic pharmaceutical product according to (23) or (24), wherein 1 to 2 drops are administered to the eye in 1 drop.
(26) The aqueous ophthalmic composition according to any one of (1) to (4), which comprises 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 the 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 the 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 the diquafosol or the 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 the 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 the diquafosol or the 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 solution.
(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 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 which is characterized by being used in such a manner that 1 to 2 drops are applied 1 time and 2 to 4 drops are applied 1 day.
(42) An aqueous ophthalmic composition for preventing or treating dry eye, which contains sodium diquafosol at a concentration of 3% (w/v), polyvinylpyrrolidone, and silver nitrate, and which has a viscosity of 3 to 30 mPas at 25 ℃, wherein the aqueous ophthalmic composition is used by 1-2 drops at 1 time and 2-4 drops at 1 day.
(43) The aqueous ophthalmic composition according to (41) or (42), which is used in such a manner that it is administered 3 times in 1 day in eye drops.
(44) An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a unit dose type eye drop container is filled with 0.1-1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the aqueous ophthalmic composition is used by 1-2 drops in 1 time and 2-4 drops in 1 day.
(45) An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a unit dose type eye drop container is filled with 0.1-1 mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone, the aqueous ophthalmic composition having a viscosity of 3-30 mPas at 25 ℃ and being used in a manner of 1-2 drops by 1 time and 2-4 drops by 1 day.
(46) An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a multi-dose type eye drop container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the aqueous ophthalmic composition is used in 1-2 drops by 1 time and 2-4 drops by 1 day.
(47) An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a multi-dose type eye drop container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone, the aqueous ophthalmic composition having a viscosity of 3-30 mPas at 25 ℃ and being used in a manner of 1-2 drops by 1 time and 2-4 drops by 1 day.
(48) An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a PFMD container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the aqueous ophthalmic composition is used by 1-2 drops at 1 time and 2-4 drops at 1 day.
(49) An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a PFMD container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone, the aqueous ophthalmic composition having a viscosity of 3-30 mPas at 25 ℃ and being used in a manner of 1-2 drops at 1 time and 2-4 drops at 1 day.
(50) An ophthalmic pharmaceutical product according to any one of (44) to (49), which is administered in eye drops 3 times in 1 day.
(51) An ophthalmic pharmaceutical product according to any one of (46) or (47), further comprising silver nitrate.
The present invention also relates to the following aspects.
(A-1) A method for treating dry eye, comprising the step of administering an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 to a patient in a unit dose type eye drop container filled with 0.1 to 1mL of the aqueous ophthalmic composition in the form of 1 dose of 1 to 2 drops and 2 to 4 times a day.
(A-2) A method for treating dry eye, comprising the step of administering an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone, having a viscosity of 3 to 30 mPas at 25 ℃, in a unit dose type eye drop container filled with 0.1 to 1mL of the aqueous ophthalmic composition, to a patient in an eye drop manner of 1 time 1 to 2 drops and 1 day 2 to 4 times.
(A-3) A method for treating dry eye, comprising the step of administering an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 in a form of 1-2 drops 1 time and 2-4 times a day, which is filled in a multi-dose type eye drop container filled with 1-10 mL of the aqueous ophthalmic composition, to a patient in an eye drop manner.
(A-4) A method for treating dry eye, comprising the step of applying an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone, having a viscosity of 3 to 30 mPas at 25 ℃, in a form of 1 to 2 drops 1 time and 2 to 4 times a day, in a multi-dose eye drop container filled with 1 to 10mL of the aqueous ophthalmic composition, to a patient by eye drop.
(A-5) A method for treating dry eye, comprising the step of administering an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90 in an eye drop manner to a patient 1 time by 1 to 2 drops and 1 day by 2 to 4 times by 1 day, the aqueous ophthalmic composition being filled in a PFMD container, wherein the PFMD container is filled with 1 to 10mL of the aqueous ophthalmic composition.
(A-6) A method for treating dry eye, comprising the step of administering an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone in an eye-drop manner 1 time by 1 to 2 drops and 2 to 4 times by 1 day to a patient, wherein the aqueous ophthalmic composition is filled in a PFMD container and 1 to 10mL of the aqueous ophthalmic composition, and has a viscosity of 3 to 30 mPas at 25 ℃.
(A-7) the method for treating dry eye according to any one of (A-1) to (A-6), which comprises the step of administering an aqueous ophthalmic composition to a patient in the form of 1 to 2 drops 1 time and 3 times a day 1.
(B-1) an ophthalmic pharmaceutical product for preventing or treating dry eye, wherein 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 product is used by 1 to 2 drops in 1 dose and 2 to 4 drops in 1 day.
(B-2) an ophthalmic pharmaceutical product for preventing or treating dry eye, wherein 0.1 to 1mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone in a unit dose type eye drop container is filled, has a viscosity of 3 to 30 mPas at 25 ℃, and is used by applying 1 to 2 drops of the aqueous ophthalmic pharmaceutical product to 1 eye drop 1 time and 2 to 4 drops of the aqueous ophthalmic composition to 1 day.
(B-3) an ophthalmic pharmaceutical product for preventing or treating dry eye, wherein 1 to 10mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone having a K value of 90 is filled in a multi-dose type eye drop container, and the product is used by 1 to 2 drops for 1 time and 2 to 4 drops for 1 day.
(B-4) an ophthalmic pharmaceutical product for preventing or treating dry eye, wherein a multi-dose eye drop container is filled with 1 to 10mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone, having a viscosity of 3 to 30 mPas at 25 ℃, and used in a manner of 1-2 drops by 1 time and 2-4 drops by 1 day.
(B-5) an ophthalmic pharmaceutical product for preventing or treating dry eye, wherein 1 to 10mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone having a K value of 90 is filled in a PFMD container, and the aqueous ophthalmic composition is used by 1 to 2 drops at 1 time and 2 to 4 drops at 1 day.
(B-6) an ophthalmic pharmaceutical product for preventing or treating dry eye, wherein 1 to 10mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone in a concentration of 3% and having a viscosity of 3 to 30 mPas at 25 ℃ is filled in a PFMD container, and the product is used by 1 to 2 drops at 1 time and 2 to 4 drops at 1 day.
(B-7) the ophthalmic pharmaceutical product according to any one of (B-1) to (B-6), wherein the aqueous ophthalmic composition is used in a form of 1 to 2 drops per 1 time and 3 drops per 1 day.
(C-1) use of an aqueous ophthalmic composition for the manufacture of 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 wherein 0.1 to 1mL of the aqueous ophthalmic composition is filled in a unit-dose type eye drop container and used in such a manner that 1 to 2 drops are applied in 1 dose and 2 to 4 drops are applied in 1 day.
(C-2) use of an aqueous ophthalmic composition for the manufacture of a medicament for preventing or treating dry eye, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone in a concentration of 3% (w/v), and has a viscosity of 3 to 30mPa · s at 25 ℃, and 0.1 to 1mL of the aqueous ophthalmic composition is filled in a unit dose type eye drop container and used in such a manner that 1 to 2 drops are applied by 1 time and 2 to 4 drops are applied by 1 day.
(C-3) use of an aqueous ophthalmic composition for the manufacture of 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 used in a manner of 1 to 2 drops by 1 time and 2 to 4 drops by 1 day.
(C-4) use of an aqueous ophthalmic composition for the manufacture of 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, and has a viscosity of 3 to 30mPa · s at 25 ℃, and 1 to 10mL of the aqueous ophthalmic composition is filled in a multi-dose eye drop container and used in such a manner that 1 to 2 drops are applied by 1 time and 2 to 4 drops are applied by 1 day.
(C-5) use of an aqueous ophthalmic composition for the manufacture of 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 used in a manner of 1 to 2 drops by 1 time and 2 to 4 drops by 1 day.
(C-6) use of an aqueous ophthalmic composition for the manufacture of a medicament for preventing or treating dry eye, wherein the aqueous ophthalmic composition comprises diquafosol sodium and polyvinylpyrrolidone in a concentration of 3% (w/v), and has a viscosity of 3 to 30mPa · s at 25 ℃, and 1 to 10mL of the aqueous ophthalmic composition is filled in a PFMD container and used in such a manner that 1 to 2 drops are applied 1 time and 2 to 4 drops are applied 1 day.
(C-7) the use of the aqueous ophthalmic composition according to any one of (C-1)) to (C-6), wherein the aqueous ophthalmic composition is used in a form of 1 to 2 drops per time and 3 drops per 1 day.
(D-1) A method for imparting a storage activity to an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone, which comprises a step of adding a silver salt to the aqueous ophthalmic composition.
(D-2) a method for maintaining the storage stability of an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone, which comprises a step of adding a silver salt to the aqueous ophthalmic composition.
The respective configurations of the present invention may be combined by arbitrarily selecting 2 or more.
ADVANTAGEOUS EFFECTS OF INVENTION
The composition has high tear volume increasing effect, and can be administered in combination with eye drops to conventional DIQUAS(registered trademark)In the case of eye drops, a stronger therapeutic effect on dry eye can be expected than in the case of eye drops. Therefore, the present composition can be expected to be used in comparison with the conventional DIQUAS(registered trademark)The low concentration of the eye drops exerts the same or better dry eye treatment effect. Additionally, existing DIQUAS(registered trademark)The eye drops need to be dropped 6 times in 1 day, and there are patients who cannot obtain desired effects due to poor eye drop compliance, but the present composition having a certain viscosity by containing polyvinylpyrrolidone having a certain K value can be used in comparison with the conventional DIQUAS(registered trademark)The eye drops have the same frequency as the existing DIQUAS(registered trademark)Since eye drops have equal or better therapeutic effects, improvement in eye drop compliance is expected.
In addition, the present composition exhibits high living cell activity, is highly safe for corneal conjunctival epithelium, does not exhibit nerve stimulation, and is expected to improve the comfort of eye drops.
In addition, the silver salt is stable even if the composition contains a silver salt, and exhibits excellent storage efficiency.
Drawings
Fig. 1 is a graph showing fluorescein staining scores of corneas.
FIG. 2 is a graph showing the results of a cytotoxicity test based on corneal epithelial cells.
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 hydroxyethyl cellulose.
In the present specification, "CMC-Na" means sodium carboxymethylcellulose.
In the present specification, "HPMC" refers to hydroxypropylmethylcellulose.
In the present specification, "CVP" means a carboxyvinyl polymer.
In the present specification, the term "diquafosol eye drops" refers to aqueous eye drops containing diquafosol or a salt thereof.
In the present specification, the "diquafosol sodium eye drops" refers to aqueous eye drops containing diquafosol sodium.
"diquafosol" 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 includes metal salts formed 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, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide, methyl iodide, etc.; salts with halogen ions such as bromide ion, chloride ion, and iodide ion; salts with ammonia; salts with organic amines such as triethylenediamine, 2-aminoethanol, 2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, procaine, and N, N-bis (phenylmethyl) -1, 2-ethylenediamine; and so on.
In the present invention, "diquafosol or a salt thereof" also includes a hydrate and an organic solvate of diquafosol (free form) or a salt thereof.
When a polymorph or a polymorph group (polymorph system) exists in diquafosol or a salt thereof, the polymorph or the polymorph group (polymorph system) is also included in the scope of the present invention. The "polymorph group (polymorph system)" herein means each crystal form and the whole process thereof in each stage when the crystal form changes according to the conditions and states of the above-mentioned crystals such as preparation, crystallization and storage.
The "diquafosol or a salt thereof" in the present invention is preferably a sodium salt of diquafosol, and particularly preferably a diquafosol tetrasodium salt (also referred to simply as "diquafosol sodium" in the present specification) represented by the following chemical formula.
[ chemical formula 2]
The diquafosol or a salt thereof can be produced by the method disclosed in Japanese patent application laid-open No. 2001-510484.
The 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 diquafosol or a salt thereof is not particularly limited, and is, for example, preferably 0.0001 to 10% (w/v), more preferably 0.001 to 5% (w/v), still more preferably 0.01 to 5% (w/v), yet more preferably 0.1 to 5% (w/v), yet 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), 2% (w/v), 2.5% (w/v), 3% (w/v), 3.5% (w/v), 4% (w/v), 4.5% (w/v), or 5% (w/v).
In the present invention, "polyvinylpyrrolidone" refers to 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 the polyvinylpyrrolidone used in the present invention is preferably 17 or more, more preferably 17 to 120, further preferably 25 to 120, further preferably 30 to 120, further preferably more than 30 and 120 or less, further preferably 40 to 120, further more preferably 60 to 120, particularly preferably 60 to 90, and particularly 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, and polyvinylpyrrolidone K120. The K value of polyvinylpyrrolidone is a viscosity characteristic value relating to molecular weight, and is a value calculated by applying a relative viscosity value (25 ℃) measured by a capillary viscometer to the following formula (1) of Fikentscher.
[ mathematical formula 1]
In the formula (1), etarelC is the polyvinylpyrrolidone concentration (%) in the aqueous polyvinylpyrrolidone solution, which is the relative viscosity of the aqueous polyvinylpyrrolidone solution with respect to water.
Here, since the K value is 90 to 108% of the K value according to the description on the K value of the seventeenth revised japanese pharmacopoeia "povidone", for example, "K90" means that the viscosity characteristic value (K value) calculated by applying the formula (1) is in the range of 81 to 97.2.
In the present invention, one kind of polyvinylpyrrolidone may be used alone, or two or more kinds of polyvinylpyrrolidone having different K values may be used in combination as desired.
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), yet still more preferably 0.1 to 5% (w/v), and particularly preferably 1 to 5% (w/v).
The composition may further contain a pharmaceutically acceptable preservative 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, methylparaben, propylparaben, chlorobutanol, polonium chloride, and polyhexamethylene biguanide hydrochloride.
As is clear from the test results described below, the present composition containing a silver salt has excellent storage efficiency, and therefore, the preservative in the present invention is preferably 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 proteinate, and silver nitrate is preferable.
In the present invention, the concentration of the silver salt is not particularly limited, and is not particularly limited as long as it is in the range of 0.00000001 to 1% (w/v), for example. 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 value 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 less, or 0.001% (w/v) or less.
In the present composition, pharmaceutically acceptable additives may be further added as necessary in addition to the aforementioned polyvinylpyrrolidone and preservative. For example, a buffer such as sodium phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; calcium chloride, sodium chloride, potassium chloride, concentrated glycerin, and the like; stabilizers such as sodium ethylene diamine tetracetate, sodium ethylene diamine tetracetate hydrate, citric acid hydrate, sodium citrate hydrate and the like; surfactants such as polysorbates; antioxidants such as ascorbic acid; thickeners (also referred to as viscosity enhancers) such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose; hydrochloric acid, sodium hydroxide, and other pH adjusting agents. These additives may be used alone in 1 kind, and may be used in combination of 2 or more kinds as desired. The composition may not contain a cellulose polymer as a thickener such as hydroxyethyl cellulose or hydroxypropyl methylcellulose.
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, and 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 "ophthalmic composition" refers to a composition for use in the prevention and/or treatment of an ocular disease or the like. Examples of the dosage form include eye drops, eye ointment, injection, ointment (for example, it can be applied to eyelid skin), and the like, and eye drops are preferable. Here, the term "eye drops" is used as the same meaning as eye drops or eye drops, and the definition of eye drops is also included in eye drops for contact lenses.
In the present invention, the "aqueous ophthalmic composition" is an aqueous ophthalmic composition using water as a solvent (base), and more preferably an aqueous eye drop.
The present composition may be a soluble eye drop or a suspension eye drop depending on the nature, content, and the like of the active ingredient and the additive.
The present composition is preferably a sterile aqueous eye drop. Here, the term "sterile" refers to a state in which microorganisms are killed or removed, and specifically, for example, refers to a state in which the state meets the standards of the preservation efficacy test described in the seventeenth revised japanese pharmacopoeia.
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 within a range of preferably 1 to 500mPa · s, more preferably more than 1.4 and 100mPa · s or less, further preferably within a range of 1.5 to 100mPa · s, further preferably within a range of 1.5 to 50mPa · s, further preferably within a range of 1.5 to 30mPa · s, further preferably within a range of 1.5 to 20mPa · s, further more preferably within a range of 1.5 to 10mPa · s, further more preferably within a range of 2 to 10mPa · s, particularly preferably within a range of 3 to 10mPa · s, particularly preferably within a range of 5 to 10mPa · s, and further particularly preferably within a range of 7 to 10mPa · s. The viscosity of the present composition may be set to be in the range of 1.5 to 30 mPas, preferably 2 to 30 mPas, more preferably 3 to 30 mPas, and still more preferably 5 to 30 mPasThe range is particularly preferably 7 to 30 mPas. The lower limit of the viscosity of the present composition is, for example, preferably 1mPa · s or more, 1.5mPa · s or more, 2mPa · s or more, 3mPa · s or more, 5mPa · s or more, or 7mPa · s or more. The upper limit value is preferably 500mPa · s or less, 100mPa · s or less, 50mPa · s or less, 30mPa · s or less, 20mPa · s or less, or 10mPa · s or less, for example. The viscosity of the composition was measured using a rotational viscometer (25 ℃ C.; 50 s)-1Shear rate of (d) was measured.
The osmotic pressure 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 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 by filling it in an airtight container (specifically, an eyedrop container). Examples of the eye drop container in which the present composition can be filled include a "multi-dose type eye drop container" and a "unit-dose type eye drop container".
In the present invention, the "ophthalmic pharmaceutical product" refers to an ophthalmic pharmaceutical product filled with the present composition in an eye drop container. Here, the "ophthalmic pharmaceutical product" includes, for example, an eye drop product. It should be noted that the definition of each term in the "ophthalmic pharmaceutical preparation" 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" refers to an eye drop container comprising a container body and a lid body attachable to the container body, wherein the lid body of the eye drop container can be freely opened and resealed. In this multi-dose type eye drop container, a plurality of doses of eye drops are stored, which are generally used for a certain period of time. In addition, when the present composition does not contain a preservative such as benzalkonium chloride, the present composition may be contained in a pfmd (regenerative Free Multi dose) container. The amount of the present composition filled in a multi-dose eye drop container or a PFMD container is, for example, preferably 1 to 20mL, more preferably 1 to 15mL, still more preferably 1 to 10mL, yet more preferably 2.5 to 10mL, and particularly preferably 5 mL.
On the other hand, the "unit dose type eye drop container" means an eye drop container for the following purposes: the cap is welded and sealed to the bottle mouth portion, and the welded portion between the cap and the bottle-shaped body is broken and opened for use. The unit dose type eye drop container contains a single dose or a plurality of doses of eye drops. The eye drops contained in the unit dose type eye drop container usually do not contain a preservative such as benzalkonium chloride. The amount of the present composition filled in a unit dose type eye drop container is, for example, preferably 0.1 to 1mL, more preferably 0.1 to 0.5mL, still more preferably 0.3 to 0.5mL, and particularly preferably 0.3mL or 0.4 mL.
The method of use of the present composition may be appropriately changed depending on the dosage form, the weight, age, body weight, judgment of a doctor, and the like of a patient to be administered, and for example, when eye drops are selected as the dosage form, the administration of eye drops may be performed 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, particularly preferably 1 drop, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 2 times a day, further preferably 1 to 3 times a day, and every day to every week. More specifically, the number of eye drops is, for example, preferably 1 day 6, 1 day 5, 1 day 4, 1 day 3, 1 day 2 or 1 day 1, more preferably 1 day 6, 1 day 4, 1 day 3 or 1 day 2, still more preferably 1 day 4, 1 day 3 or 1 day 2, and particularly preferably 1 day 3.
In addition, when the concentration of diquafosol or a salt thereof in the present composition is 3% (w/v), the administration by eye may be performed in such a manner that 1 dose is 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 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 time, 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 addition, 1 drop is preferably 10 to 50 μ L, more preferably 20 to 50 μ L, and particularly preferably 40 to 50 μ L.
The composition is useful for the prevention or treatment of dry eye, and is effective as a preventive or therapeutic agent for dry eye. Dry eye is defined as "chronic diseases of tears and keratoconjunctival epithelium due to various factors, and is a disease accompanied by eye discomfort and abnormal vision", and keratoconjunctivitis sicca (KCS) is included in dry eye. In the present invention, the generation of dry eye symptoms due to the wearing of soft contact lenses is also included in dry eye.
The symptoms of dry eye include subjective symptoms such as dry eye, eye discomfort, eye fatigue, heaviness, photophobia, ophthalmalgia, and blurred vision (cloudiness), as well as objective manifestations such as hyperemia and corneal/conjunctival epithelial injury. In the present invention, the "prevention or treatment of dry eye" also includes the improvement of the subjective symptoms and/or objective manifestations described above.
As for the causes of dry eye, although there are many unclear points, the following causes have been reported: huggeren's syndrome (Sjogren's syndrome); congenital lacrimal disorder; sarcoidosis; graft Versus Host Disease (GVHD: Graft Versus Host Disease) due to bone marrow transplantation; ocular pemphigus (ocular pemphigoid); duffins-Johnson syndrome (Stevens-Johnson syndrome); lacrimal obstruction due to trachoma and the like; diabetes mellitus; a decrease in reflex secretion caused by corneal refractive correction surgery (LASIK: Laser (-assisted) in Situ Keratiomarieuss) or the like; meibomian gland dysfunction; reduction of oil layer due to blepharitis, etc.; blink dysfunction or eyelid closure dysfunction due to eyeball protrusion, rabbit eye, and the like; decreased mucin secretion from embryonic cells; VDT (visual Display terminals) operations; and so on.
The composition can be applied to the eyes of a patient with dry eye who wears soft contact lenses. Here, the term "eye-dropping the eye of a dry eye patient wearing a soft contact lens" means that an eye drop is dropped 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 preparation examples are shown below, which are intended to better understand the present invention and do not limit the scope of the present invention.
[ test 1]
The change with time of tear fluid volume after eye drop of the present composition was evaluated using normal male white rabbits.
(method of preparing sample)
Eye drops 1:
eye drops 1 were prepared according to the formulation table shown in table 1. Specifically, 50mL of diquafosol sodium (9g), sodium hydrogen phosphate hydrate (0.6g), sodium ethylenediaminetetraacetate hydrate (0.03g), and sodium chloride (1.35g) were dissolved in sterilized purified water to obtain 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 to adjust the pH to 7, and 20mL of sterilized purified water was added to obtain a 3-fold concentrated solution. PVP K90(4g) was dissolved in sterilized purified water to make a total amount of 100g, and then autoclaved (121 ℃ 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 3-fold concentrated solution was added, sterilized purified water was added to adjust the total amount to 12mL, and then a pH adjuster was added to adjust the pH to 7, thereby preparing eye drops 1.
Eye drops 2:
eye drops 2 were prepared according to the formulation table shown in table 1. Specifically, 50mL of diquafosol sodium (9g), sodium hydrogen phosphate hydrate (0.6g), sodium ethylenediaminetetraacetate hydrate (0.03g), and sodium chloride (1.35g) were dissolved in sterilized purified water to obtain a 6-fold concentrated solution. Further, after 10mL of the 6-fold concentrated solution was mixed with 5mL of sterilized purified water, PVP K30(1.2g) was dissolved, and then a pH adjuster was added as appropriate to adjust the pH to 7, and sterilized purified water was added to make the volume to 20mL, thereby obtaining a 3-fold concentrated solution. To 4mL of the 3-fold concentrated solution was added sterile purified water to adjust the total volume to 12mL, and then a pH adjuster was added to adjust the pH to 7, thereby preparing eye drops 2.
Eye drops 3:
eye drops 3 were prepared according to the formulation table shown in table 1. Specifically, 50mL of diquafosol sodium (9g), sodium hydrogen phosphate hydrate (0.6g), sodium ethylenediaminetetraacetate hydrate (0.03g), and sodium chloride (1.35g) were dissolved in sterilized purified water to obtain 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 to adjust the pH to 7, and 20mL of sterilized purified water was added to obtain a 3-fold concentrated solution. Hydroxyethyl cellulose (15g) was dissolved in 1500mL of sterilized purified water, and autoclaved (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 was added 4mL of 3-fold concentrated solution, sterilized purified water was added to adjust the total amount to 12mL, and then a pH adjuster was added as appropriate to adjust the pH to 7, thereby preparing eye drops 3.
Eye drops 4:
eye drops 4 were prepared according to the formulation table shown in table 1. Specifically, 50mL of diquafosol sodium (9g), sodium hydrogen phosphate hydrate (0.6g), sodium ethylenediaminetetraacetate hydrate (0.03g), and sodium chloride (1.35g) were dissolved in sterilized purified water to obtain 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 to adjust the pH to 7, and 20mL of sterilized purified water was added to obtain a 3-fold concentrated solution. An eye drop solution 4 was prepared by adding sterilized purified water to 4mL of a 3-fold concentrated solution to adjust the total volume to 12mL, and then appropriately adding a pH adjuster to adjust the pH to 7.
Eye drops 5:
eye drops 5 were prepared according to the formulation table shown in table 1. Specifically, diquafosol sodium (18g), sodium hydrogen phosphate hydrate (1.2g), and sodium ethylenediaminetetraacetate hydrate (0.06g) were dissolved in sterilized purified water to make 100mL, to obtain a 6-fold concentrated solution. Further, 2.5mL of the 6-fold concentrated solution was mixed with 5mL of sterilized purified water, and after dissolving a PVP K6045% aqueous solution (0.67g) and sodium chloride (0.068g), pH was adjusted to 7 by adding a pH adjuster as appropriate, and 15mL of sterilized purified water was added to prepare eye drops 5.
The viscosities of the eye drops 1 to 5 thus prepared were measured by the methods described in the seventeenth revised japanese pharmacopoeia, 2.53 viscometry, 2 nd method rotational viscometer method, and 2.1.3 cone-plate rotational 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
Diameter of the rotor: 50mm
Sample amount: 0.57mL
Measuring temperature: 25 deg.C
Shearing speed: 50s-1
Measuring time: the viscosity was measured every 2 seconds, and the average value of 1 minute was taken as the viscosity.
(test method and drug administration method)
Adding Benoxil dropwise to normal male white rabbit (16 eyes in total)(registered trademark)0.4% of the eye drops (manufactured by Shentian pharmaceutical Co., Ltd.) was subjected to local anesthesia. After 3 minutes, Schirmer test paper (available from Ayumi Pharmaceutical co., ltd.) was inserted into the lower eyelid, and after 1 minute of insertion, the paper was pulled out, and the length of the wetted portion (tear volume) was read. This is taken as the previous value. Then, each of the eye drops 1 to 5 was applied with eye drops 1 time (4 eyes in one set, 8 eyes, and 12 eyes in only eye drop 4). Benoxil was added dropwise 3 minutes before inserting Schirmer test paper (Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid(registered trademark)0.4% of the eye drops (manufactured by Shentian pharmaceutical Co., Ltd.) was subjected to local anesthesia. After each eye drop was dropped for 60 minutes, Schirmer test paper (available from Ayumi Pharmaceutical co., ltd.) was inserted into the lower eyelid, and after insertion for 1 minute, the length of the wetted portion (tear volume) was read.
(evaluation method)
The change in tear volume before and after eye drops were dropped was calculated as Δ tear volume (mm/min).
(test results)
The delta tear volumes (mm/min) at 60 minutes after eye dropping are shown in tables 1 and 2 (each value is an average value for 8 eyes, and only the eye drop 4 is an average value for 24 eyes). The tear volume increasing effect of the present composition was evaluated according to the following criteria.
+++: delta tear volume (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 after eye drop is more than 0 mm/min and less than 1 mm/min;
-: the delta tear volume (mm/min) at 60 minutes after eye drop was 0 mm/min or less.
[ Table 1]
(in Table 1, the unit is g/100mL)
| Eye drops | 1 | 2 | 3 | 4 |
| Diquafosol 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 edetate 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 (mm/min) at 60 minutes after eye drop | 4.4 | 0.4 | -0.6 | 0.3 |
| Evaluation of | +++ | + | - | + |
As shown in the results of table 1, the eye drop containing PVP K30 (eye drop 2) did not exhibit an effect of increasing the tear volume at 60 minutes after eye drop formation, as in the eye drop not containing PVP K30 (eye drop 4). Further, HEC is also generally used as a thickener, but eye drops containing HEC (eye drops 3) have a high viscosity, but the effect of increasing the amount of tear liquid at 60 minutes after eye drop was not observed as in eye drops 4. On the other hand, the eye drops (eye drops 1) containing PVP K90 showed a very high lacrimal fluid volume increasing action as compared with eye drops 2 to 4.
[ Table 2]
(in Table 2, the unit is g/100mL)
| Eye drops | 5 |
| Diquafosol sodium | 3 |
| |
2 |
| Sodium hydrogen phosphate hydrate | 0.2 |
| Sodium edetate hydrate | 0.01 |
| Sodium chloride | 0.45 |
| pH regulator | q.s. |
| pH | 7.0 |
| Viscosity (mPa. s) | 3.0 |
| Delta tear volume (mm/min) at 60 minutes after eye drop | 4.4 |
| Evaluation of | +++ |
As shown in the results of Table 2, even when the K value of PVP was 60, the PVP-containing ophthalmic solution (ophthalmic solution 5) had a high tear fluid volume increasing effect.
(examination)
The polyvinylpyrrolidone increases the viscosity of the aqueous composition containing diquafosol or a salt thereof to enhance the drug effect of the diquafosol or the salt thereof, but particularly when the polyvinylpyrrolidone having a K value of more than 30 is added or when the viscosity of the aqueous composition exceeds 1.4 by adding the polyvinylpyrrolidone, the drug effect of the diquafosol or the 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 P2Y2A model of the therapeutic effect of receptor agonists is used (invest. ophthalmol. mis. sci., 42(1), 96-100 (2001)). Using this dry eye model, it was investigated whether or not the effect of improving corneal epithelial damage could be obtained by administering the present composition in eye drops.
(method for producing xerophthalmia model)
A rat extraorbital lacrimal gland excision model was made using male SD rats according to the method of Fujihara et al (invest. ophthalmol. mis. sci., 42(1), 96-100 (2001)). That is, after general anesthesia with pentobarbital sodium, extraorbital lacrimal glands were removed to induce corneal epithelial injury.
(method of preparing sample)
Eye drops A:
sodium hydrogen phosphate hydrate (0.2g), sodium ethylenediaminetetraacetate hydrate (0.01g), sodium chloride (0.45g), silver nitrate (0.00004g), polyvinylpyrrolidone K90(2g), and diquafosol sodium (3g) 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 (0.2g), sodium ethylenediaminetetraacetate hydrate (0.01g), sodium chloride (0.45g), silver nitrate (0.00004g) and polyvinylpyrrolidone K90(4g) were dissolved in sterilized purified water to give 100mL, and a pH adjuster (q.s.) was added to adjust the pH to 7.5.
Eye drops X:
as eye drops X, "DIQUAS" used as a therapeutic agent for dry eye is used(registered trademark)Eye drops 3% "(Shentian pharmaceutical plant type)Manufactured by society). The eye drops X contain 30mg of diquafosol sodium as an active ingredient in 1mL of water, and potassium chloride, sodium chloride, chlorhexidine gluconate, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and a pH adjuster as additives.
The viscosities of the eye drops A, B and X thus prepared were measured by the methods described in the seventeenth revised japanese pharmacopoeia, 2.53 viscometry, 2 nd rotary viscometer method, and 2.1.3 cone-plate rotary viscometer (cone-plate viscometer). Specifically, using Kinexus pro + (manufactured by Malvern), the measurement conditions were set as follows.
(measurement conditions)
Rotor angle: 1 degree
Diameter of the rotor: 50mm
Sample amount: 0.57mL
Measuring temperature: 25 deg.C
Shearing speed: 50s-1
Measuring time: the viscosity was measured every 2 seconds, and the average value of 1 minute was taken as the viscosity.
The viscosity measured for each eye drop was as follows.
Eye drops A: 7.9 mPas
Eye drops B: 28.0 mPas
Eye drops X: 0.9 mPas
(test method and drug administration method)
Eye drops a, B and X were administered to rats in which the corneal epithelial injury was induced in the following manner.
Eye drops a, 3 administration groups 1 day: the eye drops A were applied to both eyes 1 day 3 times for 4 weeks. (group of 6 eyes 12)
Eye drops B, 3 administration groups 1 day: the eye drops B were applied to both eyes 1 day 3 times for 4 weeks. (group of 6 eyes 12)
Eye drops X, 6 administration groups 1 day: the eye drops X were dropped into both eyes 1 day 6 times for 4 weeks. (group of 6 eyes 12)
The rats that did not induce the corneal epithelial injury and were not dropped with eye for 4 weeks were regarded as the non-dropped group (4 rats with 8 eyes in one group).
After 4 weeks from the start of eye-dropping, the damaged portion of the cornea was stained with fluorescein, and the corneal epithelial damage was judged by the method of village et al (New ophthalmology, 21(1), 87-90 (2004)). That is, scores are determined for each of the upper part, the intermediate part, and the lower part of the cornea based on the degree of staining with fluorescein according to the following criteria, and the total average value of these scores is calculated. Note that 0.5 is set as an intermediate value between the scores of 0, 1,2, and 3.
(criteria for determination)
0: is not dyed;
1: dyeing is sparse, and dyeing parts of various shapes are far away;
2: dyeing is medium, with a portion of the spotted dyed portions adjacent;
3: the dyeing is dense, and the dyeing parts of each dot are adjacent.
(results)
The calculated fluorescein staining scores for each group are plotted in FIG. 1. Note that the score is the average of 8 or 12 cases + standard error.
As can be seen from fig. 1, in the group to which 1 day 3 administrations of eye drop a were given, improvement in fluorescein staining score was observed compared to 1 day 3 administrations of eye drop B from 2 weeks after the start of eye drop. For the group of 6 administrations on 1 day of eye drop X, an improvement in fluorescein staining score was observed four weeks after the start of eye drop, compared to 3 administrations on 1 day of eye drop B. After four weeks of eye drop application, the 1 day 3 administration group of eye drop a showed the same level of effect as the 1 day 6 administration group of eye drop X.
(examination)
Eye drops X as "DIQUAS(registered trademark)3% of eye drops are used for treating xerophthalmia, and the frequency of eye drops is 1 day and 6 times. The present composition containing polyvinylpyrrolidone K90 showed sufficient therapeutic effect on dry eye by 3 eye drops 1 day, and was observed to surpass "DIQUAS" 2 weeks after the start of eye drop(registered trademark)Therapeutic effect of 3% "of eye drops for 1 day and 6 times of eye dropsAnd (5) fruit. Thus, the present compositions are shown to be less aggressive than the existing DIQUAS(registered trademark)The eye drop has the same eye drop frequency as that of the existing DIQUAS(registered trademark)The eye drops have equal or better treatment effect. Particularly, considering the test results of test 1, it was found that the present composition containing polyvinylpyrrolidone having a K value of more than 30 or the present composition containing polyvinylpyrrolidone having a viscosity of more than 1.4 by adding polyvinylpyrrolidone can exhibit "DIQUAS" comparable to the conventional one in 1 day by 2 to 4 times of eye drops(registered trademark)3% "of the eye drops, and 6 times of eye drops in 1 day have equal or better treatment effect.
[ test 3]
In order to examine the effect of the present composition on corneal epithelial cells, a cytotoxicity test was performed on corneal epithelial cells.
(method of preparing sample)
Eye drops Y, C and D were prepared according to the formulation shown in Table 3.
Eye drops Y:
eye drops Y were prepared according to the formulation shown in table 3. Specifically, sodium hydrogen phosphate hydrate (0.2g), sodium ethylenediaminetetraacetate hydrate (0.01g), sodium chloride (0.45g), silver nitrate (0.00004g), and diquafosol sodium (3g) were dissolved in sterilized purified water to give 100mL, and a pH adjuster (q.s.) was added to adjust the pH to 7.5.
Eye drops C and D:
each of eye drops C and D was prepared in the same manner as eye drop Y according to the formulation shown in table 3.
The viscosities of the eye drops Y, C and D thus prepared were measured by the methods described in the seventeenth revised japanese pharmacopoeia, 2.53 viscometry, 2 nd rotary viscometer method, and 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
Diameter of the rotor: 50mm
Sample amount: 0.57mL
Measuring temperature: 25 deg.C
Shearing speed: 50s-1
Measuring 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/100mL)
| Eye drops | Y | C | D |
| Diquafosol sodium | 3 | 3 | 3 |
| PVP K90 | - | 2 | 4 |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 | 0.2 |
| Sodium edetate 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 physico-chemical engineering, center of biological origin, Cell No.: RCB2280) were inoculated (1X 10)4Cells/well) were cultured in a 96-well plate in D-MEM/F12 medium containing 10% FBS for 1 day. The next day, after replacing the medium with eye drops Y, C or D, the 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 (Promega corporation, catalog number: G3580).
(results)
The test results are shown in fig. 2.
As can be seen from fig. 2, regarding 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, regarding diquafosol eye drops (eye drops Y) containing no polyvinylpyrrolidone, the survival rate decreases with time.
(examination)
In the case of diquafosol eye drops containing polyvinylpyrrolidone, cultured immortalized human corneal epithelial cells exhibit high living cell activity, and therefore, are highly safe for the keratoconjunctival epithelium and useful for diseases in which the keratoconjunctival epithelium is unstable such as dry eye.
[ test 4]
The irritation of diquafosol sodium to peripheral nerves in the presence of PVP was investigated.
(method of preparing sample)
Formula liquid 1:
formulation 1 was prepared according to the formulation table shown in table 4. Specifically, sodium chloride (8.5g) and sodium hydrogen phosphate hydrate (2g) were dissolved in sterilized purified water, a pH adjuster was added to adjust the pH to 7.5, and then the total amount was adjusted to 100mL to obtain a 10-fold buffer. PVP K30(16g) was dissolved in sterile purified water, and the total amount was adjusted to 200mL to give an 8% aqueous PVP K30 solution. 2mL of 10-fold buffer and 5mL of 8% PVP K30 aqueous solution were measured, the total amount was adjusted to 20mL with sterilized purified water, and the pH was adjusted to 7.5 with a pH adjuster to obtain formulation 1.
Formula liquid 2:
Formula liquid 3:
formulation 3 was prepared according to the formulation table shown in table 4. Specifically, sodium chloride (8.5g) and sodium hydrogen phosphate hydrate (2g) were dissolved in sterilized purified water, a pH adjuster was added 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 0.06g of sodium chondroitin sulfate were added to sterilized purified water, and after confirming dissolution, the total amount was adjusted to 20mL by adjusting the pH to 7.5 using a pH adjuster, to obtain formulation 3.
4-6 of a formula liquid:
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 unit is g/100mL)
| 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 containing an intracellular Calcium fluorescent indicator dye (FLIPR Calcium 6Assay Kit, Molecular Devices). 40% of the total buffer amount was replaced with each of the above formulations. In the non-stimulated group and the stimulated control group, the buffer solution was similarly treated in place of the formulation solution. After standing at room temperature, the fluorescence measurement of the calcium indicator dye with time was started using a fluorescence plate reader. 60 seconds after the start, sodium diquafosol (final concentration: 0.3%) was added, and the fluorescence intensity measurement was continued.
(evaluation method)
The fluorescence intensity (RFU) immediately before the addition of diquafosol sodium was set to 100%, and the maximum fluorescence intensity (RFUmax) after the addition was calculated.
(test results)
The results are shown in FIG. 3. In the stimulation control group and the formulation solutions 3 to 6, RFU increased after the addition of diquafosol sodium, and RFUmax of 103.5% or more was recorded. On the other hand, RFUmax was less than 101% in each of the groups of PVP-containing formulations 1 and 2.
(examination)
Peripheral nerve cells that have received some stimulation generate an activity potential to become excited, and the signal of the stimulation converted into the activity potential is then transmitted to the central nervous system. The action potential refers to a change in cell membrane potential caused by the influx of cations containing calcium ions into the cell. Therefore, the increase in the concentration of calcium ions in nerve cells is widely used experimentally as an index representing the excitation state of nerve cells. When the diquafosol sodium is exposed to peripheral nerve cells, a rapid increase in the fluorescence intensity of intracellular calcium ions is observed, indicating that the nerve cells become excited upon receiving the diquafosol sodium as a stimulus. The same stimulus response was also confirmed in each group of comparative example polymer formulations 3 to 6 containing no PVP, and the polymers of sodium chondroitin sulfate, HPMC, CVP, and CMC-Na did not affect the nerve stimulating property of sodium diquafosol. On the other hand, formulations 1 and 2 containing PVP showed no increase in the intracellular calcium ion signal after the addition of diquafosol sodium. That is, it was found that diquafosol sodium in the presence of PVP did not exhibit nerve irritation, and the addition of PVP improved the comfort of the diquafosol sodium eye drops.
[ test 5]
The effect of the present composition on the stability of the preservative was investigated.
(method of preparing sample)
Eye drops 6:
eye drops 6 were prepared according to the formulation shown in Table 5. Specifically, diquafosol sodium (3g), chlorhexidine gluconate salt (0.0025g), hydroxyethyl cellulose (0.2g), sodium hydrogen phosphate hydrate (0.2g), sodium edetate hydrate (0.01g), and sodium chloride (0.45g) were dissolved in water to make 100mL, and a pH adjuster (q.s.) was added to make the pH 7.5.
7-10 parts of eye drops:
eye drops 7 to 10 were prepared according to the formulation shown in table 5 in the same manner as eye drop 6.
[ Table 5]
(in Table 5, the unit is g/100mL)
(test method)
The eye drops 6 and 7 were stored at 60 ℃ for four weeks, and the content of chlorhexidine gluconate salt at that time was quantified by High Performance Liquid Chromatography (HPLC), and the residual ratio (%) was calculated. The eye drops 8 and 9 were stored at 60 ℃ for 2 weeks, and the content of chlorhexidine gluconate salt at that time was quantified by High Performance Liquid Chromatography (HPLC), and the residual ratio (%) was calculated. The eye drops 10 were stored at 60 ℃ for four weeks, and the content of silver nitrate at that time was quantified by high-frequency inductively coupled plasma emission spectrometry (ICP-AES), and the residual rate (%) was calculated.
(test results)
The results of the stability test are shown in table 6.
[ Table 6]
| Eye drops | 6 | 7 | 8 | 9 | 10 |
| Residual ratio (%) | 90.1 | 20.4 | 26.7 | 8.0 | 100 |
(examination)
When chlorhexidine gluconate salt is contained as a preservative in an aqueous ophthalmic composition (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 as a silver salt is contained as a preservative, the residual rate is high (eye drops 10). The above results show that the present composition destabilizes chlorhexidine gluconate salts, while stabilizing silver salts.
[ test 6]
The preservation efficacy of the present composition containing silver salt was investigated.
(method of preparing sample)
Eye drops 11:
eye drops 11 were prepared according to the formulation shown in Table 7. Specifically, diquafosol sodium (3g), silver nitrate (0.00008g), sodium hydrogen phosphate hydrate (0.2g), sodium ethylenediaminetetraacetate hydrate (0.01g), polyvinylpyrrolidone K30(2g), concentrated glycerin (1.2g), and hydroxyethyl cellulose (0.25g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make the pH 7.5.
12-15 parts of eye drops:
in the same manner as the eye drop 11, each of the eye drops 12 to 15 was prepared according to the formulation shown in table 7.
[ Table 7]
(in Table 7, the unit is g/100mL)
| Eye drops | 11 | 12 | 13 | 14 | 15 |
| Diquafosol 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 edetate hydrate | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
| |
2 | 2 | 2 | 2 | 2 |
| Sodium chloride | - | 0.45 | 0.45 | 0.45 | 0.45 |
| Concentrated glycerin | 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 carried out in conformity with the preservation efficacy test method of the seventeenth revised Japanese pharmacopoeia. In this test, as test bacteria, escherichia Coli (e.coli), Pseudomonas aeruginosa (p.aeruginosa), Staphylococcus aureus (s.aureus), Candida albicans (c.albicans), and Aspergillus brasiliensis (a.brasiliensis) were used.
(test results)
The test results are shown in table 8.
[ Table 8]
(Unit: logarithmic removal rate)
The test results in table 8 show how much the number of viable bacteria in the test was reduced from the number of inoculated bacteria by a logarithmic removal rate, and for example, in the case of "1", the test results show that the number of viable bacteria in the test was reduced to 10% of the number of inoculated bacteria.
As shown in table 8, the present composition containing a silver salt was shown to conform to the criterion of preservation efficacy test of the japanese pharmacopoeia.
(examination)
The above results show that the present composition containing a silver salt has excellent preservation efficiency.
[ test 7]
The change with time of tear volume at 90 minutes after the eye drop of the present composition was evaluated using normal male white rabbits.
(method of preparing sample)
Eye drops 16:
as the eye drops 16, 100mL of sodium hydrogen phosphate hydrate (0.2g), sodium ethylenediaminetetraacetate hydrate (0.01g), sodium chloride (0.45g), silver nitrate (0.00004g), polyvinylpyrrolidone K90(2g), and diquafosol sodium (3g) were dissolved in sterilized purified water, and a pH adjuster (q.s.) was added to adjust the pH to 7.5.
Eye drops 17:
as eye drops 17, "DIQUAS" used as a therapeutic agent for dry eye is used(registered trademark)Eye drops of 3% "(manufactured by Shentian pharmaceutical Co., Ltd.). The eye drops 17 contained 30mg of diquafosol sodium as an active ingredient in 1mL of water, and potassium chloride, sodium chloride, chlorhexidine gluconate, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and a pH adjuster as additives.
(test method and drug administration method)
Adding Benoxil dropwise into normal male white rabbit (12 eyes in total)(registered trademark)0.4% of the eye drops (manufactured by Shentian pharmaceutical Co., Ltd.) was subjected to local anesthesia. After 3 minutes, Schirmer test paper (Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelidSystem), the sample was inserted for 1 minute and then extracted, and the length of the wetted portion (tear volume) was read. This is taken as the previous value. Subsequently, each of the eye drops 16 and 17 was dropped 1 time (6 eyes in one group and 12 eyes). Benoxil was added dropwise 3 minutes before inserting Schirmer test paper (Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid(registered trademark)0.4% of the eye drops (manufactured by Shentian pharmaceutical Co., Ltd.) was subjected to local anesthesia. After 90 minutes from the dropping of each eye drop, Schirmer test paper (available from Ayumi Pharmaceutical co., ltd.) was inserted into the lower eyelid, and after 1 minute of insertion, the paper was removed, and the length (tear volume) of the wetted portion was read.
(evaluation method)
The change in tear volume before and after eye drops were dropped was calculated as Δ tear volume (mm/min).
(test results)
The Δ tear volumes (mm/min) at 90 minutes after eye dropping are shown in table 9 (each value is an average value of 12 eyes). The tear volume increasing effect of the present composition was evaluated according to the following criteria.
+++: delta tear volume (mm/min) at 90 minutes after eye drop of 4 mm/min or more
++: delta tear volume (mm/min) at 90 minutes after eye drop of 1 mm/min or more and less than 4 mm/min
+: delta tear volume (mm/min) at 90 minutes after eye drop of more than 0 mm/min and less than 1 mm/min
-: delta tear volume (mm/min) at 90 minutes after eye drop is 0 mm/min or less
[ Table 9]
| Eye drops | 16 | 17 |
| 90 minutes after droppingDelta tear fluid amount (mm/min) | 2.0 | -0.3 |
| Evaluation of | ++ | - |
As shown by the results in table 9 above, the present composition also exhibited a high tear amount increasing effect 90 minutes after eye drop.
[ test 8]
The preservation efficacy of the present composition containing silver salt was investigated.
(method of preparing sample)
Eye drops 18:
eye drops 18 were prepared according to the formulation shown in table 10. Specifically, diquafosol sodium (3g), silver nitrate (0.00003g), sodium hydrogen phosphate hydrate (0.2g), sodium ethylenediaminetetraacetate hydrate (0.01g), polyvinylpyrrolidone K90(2g), and sodium chloride (0.45g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make the pH 7.0.
Eye drops 19:
eye drops 19 were prepared in the same manner as eye drops 18 according to the formulation shown in table 10.
[ Table 10]
(in Table 10, the unit is g/100mL)
| Eye drops | 18 | 19 |
| Diquafosol sodium | 3 | 3 |
| Sodium edetate hydrate | 0.01 | - |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 |
| |
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 carried out in conformity with the preservation efficacy test method of the seventeenth revised Japanese pharmacopoeia. In this test, as test bacteria, escherichia Coli (e.coli), Pseudomonas aeruginosa (p.aeruginosa), Staphylococcus aureus (s.aureus), Candida albicans (c.albicans), and Aspergillus brasiliensis (a.brasiliensis) were used.
(test results)
The test results are shown in table 11.
[ Table 11]
(Unit: logarithmic removal rate)
The test results in table 11 show how much the number of viable bacteria in the test was reduced from the number of inoculated bacteria by a logarithmic removal rate, and for example, in the case of "1", the test results show that the number of viable bacteria in 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 a silver salt conformed to the standards of the preservation efficacy test of the japanese pharmacopoeia regardless of the presence or absence of EDTA.
(examination)
The above results show that the present composition containing a silver salt has excellent preservation efficiency.
[ test 9]
The preservation efficacy of the present composition containing silver salt was investigated.
(method of preparing sample)
Eye drops 20:
eye drops 20 were prepared according to the formulation shown in table 12. Specifically, diquafosol sodium (3g), silver nitrate (0.00004g), sodium hydrogen phosphate hydrate (0.2g), sodium ethylenediaminetetraacetate hydrate (0.01g), polyvinylpyrrolidone K90(2g), and sodium chloride (0.45g) were dissolved in sterilized purified water to make 100mL, and a pH adjuster (q.s.) was added to make the pH 7.5.
Eye drops 21-23:
each of eye drops 21 to 23 was prepared in the same manner as eye drop 20 according to the formulation shown in table 12.
[ Table 12]
(in Table 12, the unit is g/100mL)
| Eye drops | 20 | 21 | 22 | 23 |
| Diquafosol sodium | 3 | 3 | 3 | 3 |
| Sodium edetate hydrate | 0.01 | - | 0.01 | 0.01 |
| Sodium hydrogen phosphate hydrate | 0.2 | 0.2 | 0.2 | 0.2 |
| |
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 carried out in conformity with the preservation efficacy test method of the seventeenth revised Japanese pharmacopoeia. In this test, as test bacteria, escherichia Coli (e.coli), Pseudomonas aeruginosa (p.aeruginosa), Staphylococcus aureus (s.aureus), Candida albicans (c.albicans), and Aspergillus brasiliensis (a.brasiliensis) were used.
(test results)
The test results are shown in table 13.
[ Table 13]
(Unit: logarithmic removal rate)
The test results in table 13 show how much the number of viable bacteria in the test was reduced from the number of inoculated bacteria by a logarithmic removal rate, and for example, in the case of "1", the test results show that the number of viable bacteria in 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 a silver salt conformed to the standards of the preservation efficacy test of the japanese pharmacopoeia regardless of the presence or absence of EDTA. Further, it was revealed that the eye drops containing silver phosphate and silver chloride as silver salts in addition to silver nitrate also meet the standards of the preservation efficacy test of the japanese pharmacopoeia.
(examination)
The above results show that the present composition containing a silver salt has excellent preservation efficiency.
[ test 10]
The effect of the present composition on the stability of the preservative was investigated.
(method of preparing sample)
Eye drops 24:
diquafosol sodium (3g), sodium ethylenediaminetetraacetate hydrate (0.01g), sodium hydrogen phosphate hydrate (0.2g), sodium chloride (0.45g), polyvinylpyrrolidone K90(2g), and silver nitrate (0.00004g) were dissolved in water to make 100mL, and a pH adjuster (q.s.) was added to make pH 7.5, thereby preparing eye drops 24.
(test method)
The eye drops 24 were stored at 40 ℃ for 6 months, and the content of silver nitrate was quantified by high-frequency inductively coupled plasma emission spectrometry (ICP-AES), and the residual rate (%) was calculated.
(test results)
The results of the stability test are shown in table 14.
[ Table 14]
| Residual ratio (%) | |
| 6 months at 40 DEG C | 97.0 |
(examination)
When silver nitrate, which is a silver salt, is contained as a preservative, the residual rate is high. This shows that the silver salt is stable in the present composition.
[ preparation examples ]
The medicament of the present invention will be described more specifically by way of formulation examples, but the present invention is not limited to these formulation examples.
(formulation example 1 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drop solution into a multi-dose type eye drop container or a PFMD container. Further, the ophthalmic pharmaceutical product can be produced by filling 0.1 to 1mL of the above-mentioned eye drop solution into a unit dose type eye drop container. The above-mentioned eye drops can be stored at room temperature.
(formulation example 2 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drop solution into a multi-dose type eye drop container or a PFMD container. Further, the ophthalmic pharmaceutical product can be produced by filling 0.1 to 1mL of the above-mentioned eye drop solution into a unit dose type eye drop container. The above-mentioned eye drops can be stored at room temperature.
(formulation example 3 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drop solution into a multi-dose type eye drop container or a PFMD container. Further, the ophthalmic drug product can be produced by filling 0.1 to 1mL of the above-mentioned eye drop solution into a unit dose type eye drop container. The above-mentioned eye drops can be stored at room temperature.
(formulation example 4: sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drops into a multi-dose eye drop container. The eye drops can be stored at room temperature.
(formulation example 5 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drops into a multi-dose eye drop container. The above-mentioned eye drops can be stored at room temperature.
(formulation example 6 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drops into a multi-dose eye drop container. The eye drops can be stored at room temperature.
(formulation example 7 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to a sterilized and purified solution and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drop solution into a multi-dose type eye drop container or a PFMD container. Further, the ophthalmic pharmaceutical product can be produced by filling 0.1 to 1mL of the above-mentioned eye drop solution 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))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drop solution into a multi-dose type eye drop container or a PFMD container. Further, the ophthalmic pharmaceutical product can be produced by filling 0.1 to 1mL of the above-mentioned eye drop solution 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))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drop solution into a multi-dose type eye drop container or a PFMD container. Further, the ophthalmic pharmaceutical product can be produced by filling 0.1 to 1mL of the above-mentioned eye drop solution 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))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drops into a multi-dose eye drop container. The eye drops can be stored at room temperature.
(formulation example 11 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drops into a multi-dose eye drop container. The eye drops can be stored at room temperature.
(formulation example 12 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drops into a multi-dose eye drop container. The eye drops can be stored at room temperature.
(formulation example 13 sterile aqueous eye drops (3% (w/v))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drop solution into a multi-dose type eye drop container or a PFMD container. Further, the ophthalmic pharmaceutical product can be produced by filling 0.1 to 1mL of the above-mentioned eye drop solution 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))
The above-mentioned eye drops can be prepared by adding diquafosol sodium and the other components described above to sterilized purified water and sufficiently mixing them. The ophthalmic pharmaceutical product can be produced by filling 1 to 10mL of the above-mentioned eye drops into a multi-dose eye drop container. The eye drops can be stored at room temperature.
Industrial applicability
Existing DIQUAS(registered trademark)Eye drops require 6 drops for 1 day, but even if they are used in a predetermined amount for a given application, there are severe dry eye patients who cannot obtain a sufficient therapeutic effect. In addition, there are also patients who cannot obtain the desired effect due to poor eye-drop compliance. The composition exerts a better effect than the existing DIQUAS(registered trademark)Eye drops have a stronger therapeutic effect on dry eye, and also improvement in eye drop compliance is expected due to a decrease in the number of times of eye drops. In addition, the present compositions are also expected to be more convenient 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 present composition exhibits high living cell activity, is highly safe for corneal conjunctival epithelium, does not exhibit nerve stimulation, and is expected to improve the comfort of eye drops.
In addition, the silver salt is stable even if the composition contains a silver salt, and exhibits excellent storage efficiency.
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, which comprises diquafosol sodium at a concentration of 1 to 5% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120.
6. The aqueous ophthalmic composition according to claim 4, which comprises diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of more than 30 and not more than 120.
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 mPas at 25 ℃.
8. The aqueous ophthalmic composition according to claim 4, which contains diquafosol sodium at a concentration of 3% (w/v), and has a viscosity of 1.5 to 30 mPas at 25 ℃.
9. An aqueous ophthalmic composition according to any one of claims 5 to 8, characterized in that it is administered in eye drops for 2 to 4 times in 1 day.
10. An aqueous ophthalmic composition according to any one of claims 5 to 8, characterized in that it is used in a manner of being applied in eye drops for 3 times in 1 day.
11. The aqueous ophthalmic composition according to claim 9 or 10, wherein 1 to 2 drops are administered to 1 eye drop.
12. An ophthalmic pharmaceutical product characterized in that a unit dose type eye drop container is filled with 0.1 to 1mL of the aqueous ophthalmic composition according to claim 1.
13. An ophthalmic pharmaceutical product characterized in that a unit dose type eye drop container is filled with 0.3 to 0.5mL of the aqueous ophthalmic composition according to claim 1.
14. An ophthalmic pharmaceutical product comprising 1 to 10mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 in a multi-dose type eye drop container.
15. An ophthalmic pharmaceutical product characterized in that a multidose type eye drop container is filled with 5mL of the aqueous ophthalmic composition according to any one of claims 1 to 3.
16. An ophthalmic pharmaceutical product characterized in that a PFMD container is filled with 1 to 10mL of the aqueous ophthalmic composition according to claim 1.
17. An ophthalmic pharmaceutical preparation, characterized in that a PFMD container is filled with 5mL of the aqueous ophthalmic composition of claim 1.
18. An ophthalmic pharmaceutical product according to any one of claims 12 to 17 for use in the prevention or treatment of dry eye.
19. An 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 not more than 120.
20. An ophthalmic pharmaceutical product according to claim 18, 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.
21. An ophthalmic pharmaceutical product according to claim 18, wherein the aqueous composition contains diquafosol sodium in a concentration of 1 to 5% (w/v) and has a viscosity of 1.5 to 30 mPa-s at 25 ℃.
22. An ophthalmic pharmaceutical product according to 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. An ophthalmic pharmaceutical product according to any one of claims 19 to 22, wherein the product is administered in eye drops for 2 to 4 times in 1 day.
24. An ophthalmic pharmaceutical product according to any one of claims 19 to 22, wherein the product is administered in eye drops for 3 times in 1 day.
25. An ophthalmic pharmaceutical product according to claim 23 or 24, which is used in a manner of administering 1 to 2 drops per 1 drop.
26. An aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 or more.
27. An aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 to 120.
28. An 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. An aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K-value of 90.
30. An 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 the 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 the diquafosol or the 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 the diquafosol or the salt thereof is 1 to 5% (w/v).
34. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of the diquafosol or the salt thereof is 3% (w/v).
35. An aqueous ophthalmic composition according to any one of claims 1 to 11, having a pH in the range of 6 to 8.
36. An aqueous ophthalmic composition according to any one of claims 1 to 11, having a pH in the range of 7 to 8.
37. An aqueous ophthalmic composition according to any one of claims 1 to 11, which is a sterile aqueous eye drop solution.
38. An aqueous ophthalmic composition according to any one of claims 1 to 11, which is capable of being stored at room temperature.
39. The aqueous ophthalmic composition according to any one of claims 1 to 6, which has a viscosity of 1.5 to 30 mPa-s at 25 ℃.
40. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the salt of diquafosol is sodium diquafosol.
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 which is characterized by being used in such a manner that 1 to 2 drops are applied 1 time and 2 to 4 drops are applied 1 day.
42. An aqueous ophthalmic composition for preventing or treating dry eye, which contains sodium diquafosol at a concentration of 3% (w/v), polyvinylpyrrolidone, and silver nitrate, and which has a viscosity of 3 to 30 mPas at 25 ℃, wherein the aqueous ophthalmic composition is used by 1-2 drops at 1 time and 2-4 drops at 1 day.
43. An aqueous ophthalmic composition according to claim 41 or 42, characterized in that it is used in a manner of being administered 3 times in eye drops for 1 day.
44. An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a unit dose type eye drop container is filled with 0.1-1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the aqueous ophthalmic composition is used by 1-2 drops in 1 time and 2-4 drops in 1 day.
45. An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a unit dose type eye drop container is filled with 0.1-1 mL of an aqueous ophthalmic composition containing 3% (w/v) diquafosol sodium and polyvinylpyrrolidone, the aqueous ophthalmic composition having a viscosity of 3-30 mPas at 25 ℃ and being used in a manner of 1-2 drops by 1 time and 2-4 drops by 1 day.
46. An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a multi-dose type eye drop container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the aqueous ophthalmic composition is used in 1-2 drops by 1 time and 2-4 drops by 1 day.
47. An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a multi-dose type eye drop container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone, the aqueous ophthalmic composition having a viscosity of 3-30 mPas at 25 ℃ and being used in a manner of 1-2 drops by 1 time and 2-4 drops by 1 day.
48. An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a PFMD container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone having a K value of 90, and the aqueous ophthalmic composition is used by 1-2 drops at 1 time and 2-4 drops at 1 day.
49. An ophthalmic pharmaceutical product for preventing or treating dry eye is characterized in that a PFMD container is filled with 1-10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w/v) and polyvinylpyrrolidone, the aqueous ophthalmic composition having a viscosity of 3-30 mPas at 25 ℃ and being used in a manner of 1-2 drops at 1 time and 2-4 drops at 1 day.
50. An ophthalmic pharmaceutical product according to any one of claims 44 to 49, wherein the product is administered in eye drops for 3 times in 1 day.
51. An ophthalmic pharmaceutical product according to any one of claims 46 or 47 further comprising silver nitrate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311818685.6A CN117771172A (en) | 2019-08-27 | 2020-08-25 | Aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone |
Applications Claiming Priority (3)
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|---|---|---|---|
| JP2019-154525 | 2019-08-27 | ||
| JP2019154525 | 2019-08-27 | ||
| PCT/JP2020/031917 WO2021039748A1 (en) | 2019-08-27 | 2020-08-25 | Diquafosol or salt thereof, and aqueous ophthalmic composition containing polyvinylpyrrolidone |
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| CN202311818685.6A Division CN117771172A (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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| KR (2) | KR20240049646A (en) |
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| EP4316485A1 (en) * | 2021-03-30 | 2024-02-07 | Senju Pharmaceutical Co., Ltd. | Suspension containing heterocyclidene acetamide 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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| CN114286670B (en) | 2024-01-16 |
| KR102656181B1 (en) | 2024-04-08 |
| KR20220052971A (en) | 2022-04-28 |
| TW202122094A (en) | 2021-06-16 |
| WO2021039748A1 (en) | 2021-03-04 |
| JP6966667B2 (en) | 2021-11-17 |
| JPWO2021039748A1 (en) | 2021-09-30 |
| CN117771172A (en) | 2024-03-29 |
| JP2022003099A (en) | 2022-01-11 |
| KR20240049646A (en) | 2024-04-16 |
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