JP2006117656A - Composition applicable to mucosa and containing hyaluronic acid or its salt - Google Patents
Composition applicable to mucosa and containing hyaluronic acid or its salt Download PDFInfo
- Publication number
- JP2006117656A JP2006117656A JP2005280056A JP2005280056A JP2006117656A JP 2006117656 A JP2006117656 A JP 2006117656A JP 2005280056 A JP2005280056 A JP 2005280056A JP 2005280056 A JP2005280056 A JP 2005280056A JP 2006117656 A JP2006117656 A JP 2006117656A
- Authority
- JP
- Japan
- Prior art keywords
- oil
- composition
- salt
- viscosity
- mucosa
- 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 104
- 150000003839 salts Chemical class 0.000 title claims abstract description 74
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 58
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 58
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 58
- 210000004877 mucosa Anatomy 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 55
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 39
- 239000008158 vegetable oil Substances 0.000 claims abstract description 39
- 239000004359 castor oil Substances 0.000 claims abstract description 34
- 235000019438 castor oil Nutrition 0.000 claims abstract description 31
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 31
- 239000008159 sesame oil Substances 0.000 claims abstract description 26
- 235000011803 sesame oil Nutrition 0.000 claims abstract description 26
- 239000002736 nonionic surfactant Substances 0.000 claims abstract description 20
- 235000019483 Peanut oil Nutrition 0.000 claims abstract description 19
- 239000004006 olive oil Substances 0.000 claims abstract description 19
- 235000008390 olive oil Nutrition 0.000 claims abstract description 19
- 239000000312 peanut oil Substances 0.000 claims abstract description 19
- 235000012424 soybean oil Nutrition 0.000 claims abstract description 19
- 239000003549 soybean oil Substances 0.000 claims abstract description 19
- 235000019484 Rapeseed oil Nutrition 0.000 claims abstract description 15
- 239000010495 camellia oil Substances 0.000 claims abstract description 15
- 235000005687 corn oil Nutrition 0.000 claims abstract description 15
- 239000002285 corn oil Substances 0.000 claims abstract description 15
- 235000019489 Almond oil Nutrition 0.000 claims abstract description 14
- 235000019486 Sunflower oil Nutrition 0.000 claims abstract description 14
- 239000008168 almond oil Substances 0.000 claims abstract description 14
- 235000012343 cottonseed oil Nutrition 0.000 claims abstract description 14
- 239000002385 cottonseed oil Substances 0.000 claims abstract description 14
- 239000002600 sunflower oil Substances 0.000 claims abstract description 14
- 239000010497 wheat germ oil Substances 0.000 claims abstract description 14
- 239000003240 coconut oil Substances 0.000 claims abstract description 11
- 235000019864 coconut oil Nutrition 0.000 claims abstract description 11
- -1 fatty acid esters Chemical class 0.000 claims description 23
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 21
- 230000000087 stabilizing effect Effects 0.000 claims description 11
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 229920001400 block copolymer Polymers 0.000 claims description 5
- 230000005722 itchiness Effects 0.000 claims description 5
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 210000004400 mucous membrane Anatomy 0.000 claims description 4
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 4
- 210000002850 nasal mucosa Anatomy 0.000 claims description 3
- 230000007423 decrease Effects 0.000 abstract description 10
- 238000013329 compounding Methods 0.000 abstract description 3
- 235000002639 sodium chloride Nutrition 0.000 description 70
- 239000003889 eye drop Substances 0.000 description 32
- 229940012356 eye drops Drugs 0.000 description 25
- 238000012360 testing method Methods 0.000 description 25
- 239000000872 buffer Substances 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 238000000746 purification Methods 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 241000196324 Embryophyta Species 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 229920002385 Sodium hyaluronate Polymers 0.000 description 9
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 9
- 235000010338 boric acid Nutrition 0.000 description 9
- 239000004327 boric acid Substances 0.000 description 9
- 229940010747 sodium hyaluronate Drugs 0.000 description 9
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 208000003251 Pruritus Diseases 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 229960001484 edetic acid Drugs 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001720 carbohydrates Chemical class 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 5
- 206010013774 Dry eye Diseases 0.000 description 5
- 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 description 5
- 239000002253 acid Substances 0.000 description 5
- 229910021538 borax Inorganic materials 0.000 description 5
- 235000015165 citric acid Nutrition 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000000691 measurement method Methods 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 5
- 229940068968 polysorbate 80 Drugs 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229940083542 sodium Drugs 0.000 description 5
- 235000010339 sodium tetraborate Nutrition 0.000 description 5
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 5
- 239000002562 thickening agent Substances 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 230000003204 osmotic effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- 239000004328 sodium tetraborate Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 235000019482 Palm oil Nutrition 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229960002684 aminocaproic acid Drugs 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003899 bactericide agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000006172 buffering agent Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 3
- 239000007979 citrate buffer Substances 0.000 description 3
- 239000000850 decongestant Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000007803 itching Effects 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 239000002997 ophthalmic solution Substances 0.000 description 3
- 229940054534 ophthalmic solution Drugs 0.000 description 3
- 239000002540 palm oil Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 150000004804 polysaccharides Chemical class 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 2
- 241000219193 Brassicaceae Species 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 244000060011 Cocos nucifera Species 0.000 description 2
- 235000013162 Cocos nucifera Nutrition 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 241000221017 Euphorbiaceae Species 0.000 description 2
- 241000220485 Fabaceae Species 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 235000003222 Helianthus annuus Nutrition 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 2
- 241000207834 Oleaceae Species 0.000 description 2
- 241000209504 Poaceae Species 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 235000004789 Rosa xanthina Nutrition 0.000 description 2
- 241000220222 Rosaceae Species 0.000 description 2
- 244000000231 Sesamum indicum Species 0.000 description 2
- 235000003434 Sesamum indicum Nutrition 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000000607 artificial tear Substances 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- OJVABJMSSDUECT-UHFFFAOYSA-L berberin sulfate Chemical compound [O-]S([O-])(=O)=O.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 OJVABJMSSDUECT-UHFFFAOYSA-L 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229920003064 carboxyethyl cellulose Polymers 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- IFQUWYZCAGRUJN-UHFFFAOYSA-N ethylenediaminediacetic acid Chemical compound OC(=O)CNCCNCC(O)=O IFQUWYZCAGRUJN-UHFFFAOYSA-N 0.000 description 2
- 239000003885 eye ointment Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000012812 general test Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 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 2
- 230000001771 impaired effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229940091250 magnesium supplement Drugs 0.000 description 2
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- 235000019477 peppermint oil Nutrition 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 229940037001 sodium edetate Drugs 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- YLXIPWWIOISBDD-NDAAPVSOSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;4-[(1r)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CNC[C@H](O)C1=CC=C(O)C(O)=C1 YLXIPWWIOISBDD-NDAAPVSOSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- BFUUJUGQJUTPAF-UHFFFAOYSA-N 2-(3-amino-4-propoxybenzoyl)oxyethyl-diethylazanium;chloride Chemical compound [Cl-].CCCOC1=CC=C(C(=O)OCC[NH+](CC)CC)C=C1N BFUUJUGQJUTPAF-UHFFFAOYSA-N 0.000 description 1
- URDCARMUOSMFFI-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetic acid Chemical compound OCCN(CC(O)=O)CCN(CC(O)=O)CC(O)=O URDCARMUOSMFFI-UHFFFAOYSA-N 0.000 description 1
- BDOYKFSQFYNPKF-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;sodium Chemical compound [Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O BDOYKFSQFYNPKF-UHFFFAOYSA-N 0.000 description 1
- FXKZPKBFTQUJBA-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;sodium;dihydrate Chemical compound O.O.[Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O FXKZPKBFTQUJBA-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- HMFKFHLTUCJZJO-UHFFFAOYSA-N 2-{2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy}ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCC(OCCO)C1OCC(OCCO)C1OCCO HMFKFHLTUCJZJO-UHFFFAOYSA-N 0.000 description 1
- ZXSGQNYQJIUMQN-UHFFFAOYSA-N 3-(2-methylpiperidin-1-ium-1-yl)propyl benzoate;chloride Chemical compound Cl.CC1CCCCN1CCCOC(=O)C1=CC=CC=C1 ZXSGQNYQJIUMQN-UHFFFAOYSA-N 0.000 description 1
- TWQWRHIQRAZHPR-XNXCGYEVSA-N 3-[2-[(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]carbonylbenzenesulfonic acid Chemical compound O=C([C@]1(O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)COC(=O)C1=CC=CC(S(O)(=O)=O)=C1 TWQWRHIQRAZHPR-XNXCGYEVSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 241000233788 Arecaceae Species 0.000 description 1
- 241000208838 Asteraceae Species 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000011331 Brassica Nutrition 0.000 description 1
- 235000005637 Brassica campestris Nutrition 0.000 description 1
- 241001301148 Brassica rapa subsp. oleifera Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 240000001548 Camellia japonica Species 0.000 description 1
- 235000006467 Camellia japonica Nutrition 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BALXUFOVQVENIU-GNAZCLTHSA-N Ephedrine hydrochloride Chemical compound Cl.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GNAZCLTHSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- XLRHXNIVIZZOON-WFUPGROFSA-L Flavin adenine dinucleotide disodium Chemical compound [Na+].[Na+].C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1COP([O-])(=O)OP([O-])(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 XLRHXNIVIZZOON-WFUPGROFSA-L 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 239000005792 Geraniol Substances 0.000 description 1
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- 241000219146 Gossypium Species 0.000 description 1
- 235000009438 Gossypium Nutrition 0.000 description 1
- 235000009432 Gossypium hirsutum Nutrition 0.000 description 1
- 244000299507 Gossypium hirsutum Species 0.000 description 1
- YHGJHDJZIOYZIR-URPSFYETSA-N Helenien Chemical compound CC1(C)C[C@H](OC(=O)CCCCCCCCCCCCCCC)CC(C)=C1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@@H]1C(C)(C)C[C@@H](OC(=O)CCCCCCCCCCCCCCC)C=C1C YHGJHDJZIOYZIR-URPSFYETSA-N 0.000 description 1
- YHGJHDJZIOYZIR-KFTCWRDFSA-N Helenien Natural products O=C(O[C@H]1C=C(C)[C@H](/C=C/C(=C\C=C\C(=C/C=C/C=C(\C=C\C=C(/C=C/C=2C(C)(C)C[C@H](OC(=O)CCCCCCCCCCCCCCC)CC=2C)\C)/C)\C)/C)C(C)(C)C1)CCCCCCCCCCCCCCC YHGJHDJZIOYZIR-KFTCWRDFSA-N 0.000 description 1
- 241000208818 Helianthus Species 0.000 description 1
- 244000020551 Helianthus annuus Species 0.000 description 1
- ZJVFLBOZORBYFE-UHFFFAOYSA-N Ibudilast Chemical compound C1=CC=CC2=C(C(=O)C(C)C)C(C(C)C)=NN21 ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 240000000982 Malva neglecta Species 0.000 description 1
- 235000000060 Malva neglecta Nutrition 0.000 description 1
- 241000219071 Malvaceae Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- GZENKSODFLBBHQ-ILSZZQPISA-N Medrysone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C(C)=O)CC[C@H]21 GZENKSODFLBBHQ-ILSZZQPISA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 235000002725 Olea europaea Nutrition 0.000 description 1
- YYVFXSYQSOZCOQ-UHFFFAOYSA-N Oxyquinoline sulfate Chemical compound [O-]S([O-])(=O)=O.C1=C[NH+]=C2C(O)=CC=CC2=C1.C1=C[NH+]=C2C(O)=CC=CC2=C1 YYVFXSYQSOZCOQ-UHFFFAOYSA-N 0.000 description 1
- 241000282373 Panthera pardus Species 0.000 description 1
- 241000207960 Pedaliaceae Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002413 Polyhexanide Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 240000000528 Ricinus communis Species 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- WDTODOXBYLKKKB-UHFFFAOYSA-N Sulfamethoxazole sodium Chemical compound [Na+].CC1=CON=C1[N-]S(=O)(=O)C1=CC=C(N)C=C1 WDTODOXBYLKKKB-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- PPWHTZKZQNXVAE-UHFFFAOYSA-N Tetracaine hydrochloride Chemical compound Cl.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 PPWHTZKZQNXVAE-UHFFFAOYSA-N 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- 238000005147 X-ray Weissenberg Methods 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000007244 Zea mays Nutrition 0.000 description 1
- CANRESZKMUPMAE-UHFFFAOYSA-L Zinc lactate Chemical compound [Zn+2].CC(O)C([O-])=O.CC(O)C([O-])=O CANRESZKMUPMAE-UHFFFAOYSA-L 0.000 description 1
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 description 1
- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 description 1
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 1
- DNSAKUGJOSFARZ-FOMYWIRZSA-N [2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] hexanoate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CCCCC)(O)[C@@]1(C)C[C@@H]2O DNSAKUGJOSFARZ-FOMYWIRZSA-N 0.000 description 1
- SIVHMKRQTQHNIO-UHFFFAOYSA-N [3-(dimethylamino)-2-hydroxypropyl] 4-(propylamino)benzoate Chemical compound CCCNC1=CC=C(C(=O)OCC(O)CN(C)C)C=C1 SIVHMKRQTQHNIO-UHFFFAOYSA-N 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- FZQSLXQPHPOTHG-UHFFFAOYSA-N [K+].[K+].O1B([O-])OB2OB([O-])OB1O2 Chemical compound [K+].[K+].O1B([O-])OB2OB([O-])OB1O2 FZQSLXQPHPOTHG-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- VWQZJJZGISNFOE-UHFFFAOYSA-N acitazanolast Chemical compound OC(=O)C(=O)NC1=CC=CC(C2=NNN=N2)=C1 VWQZJJZGISNFOE-UHFFFAOYSA-N 0.000 description 1
- 229950001122 acitazanolast Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- YHGJHDJZIOYZIR-UHFFFAOYSA-N all-trans-lutein dipalmitate Natural products CC1(C)CC(OC(=O)CCCCCCCCCCCCCCC)CC(C)=C1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCC)C=C1C YHGJHDJZIOYZIR-UHFFFAOYSA-N 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- SGRYPYWGNKJSDL-UHFFFAOYSA-N amlexanox Chemical compound NC1=C(C(O)=O)C=C2C(=O)C3=CC(C(C)C)=CC=C3OC2=N1 SGRYPYWGNKJSDL-UHFFFAOYSA-N 0.000 description 1
- 229960003731 amlexanox Drugs 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960002028 atropine sulfate Drugs 0.000 description 1
- 229960005354 betamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-LWCNAHDDSA-L betamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-LWCNAHDDSA-L 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 1
- 229940116229 borneol Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 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 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- IVHBBMHQKZBJEU-UHFFFAOYSA-N cinchocaine hydrochloride Chemical compound [Cl-].C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCC[NH+](CC)CC)=C21 IVHBBMHQKZBJEU-UHFFFAOYSA-N 0.000 description 1
- 239000001926 citrus aurantium l. subsp. bergamia wright et arn. oil Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- PIQVDUKEQYOJNR-VZXSFKIWSA-N ***e hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@H]2CC[C@@H]([NH+]2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 PIQVDUKEQYOJNR-VZXSFKIWSA-N 0.000 description 1
- 229960003771 ***e hydrochloride Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000004332 deodorization Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- RPBJOYICBFNIMN-RDWMNNCQSA-M dexamethasone sodium m-sulfobenzoate Chemical compound [Na+].O=C([C@]1(O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)COC(=O)C1=CC=CC(S([O-])(=O)=O)=C1 RPBJOYICBFNIMN-RDWMNNCQSA-M 0.000 description 1
- 229960002344 dexamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 description 1
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 description 1
- 229940045574 dibucaine hydrochloride Drugs 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960002534 ephedrine hydrochloride Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960003072 epinephrine hydrochloride Drugs 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- OUDSFQBUEBFSPS-UHFFFAOYSA-N ethylenediaminetriacetic acid Chemical compound OC(=O)CNCCN(CC(O)=O)CC(O)=O OUDSFQBUEBFSPS-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000010643 fennel seed oil Substances 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 229960001048 fluorometholone Drugs 0.000 description 1
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229940113087 geraniol Drugs 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- XZSVYVIYKBHVMV-FOMYWIRZSA-N hydrocortisone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CCCCC)(O)[C@@]1(C)C[C@@H]2O XZSVYVIYKBHVMV-FOMYWIRZSA-N 0.000 description 1
- 229960002491 ibudilast Drugs 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960003630 ketotifen fumarate Drugs 0.000 description 1
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229960001828 levocabastine hydrochloride Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229960001983 magnesium aspartate Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- CRSJYWPXKKSOCQ-CBAPHJFVSA-L magnesium;(2s)-2-aminobutanedioate;hydron;tetrahydrate Chemical compound O.O.O.O.[Mg+2].[O-]C(=O)[C@@H](N)CC(O)=O.[O-]C(=O)[C@@H](N)CC(O)=O CRSJYWPXKKSOCQ-CBAPHJFVSA-L 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001011 medrysone Drugs 0.000 description 1
- 239000001683 mentha spicata herb oil Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229940051020 methylephedrine hydrochloride Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 229960004760 naphazoline hydrochloride Drugs 0.000 description 1
- 229960004186 naphazoline nitrate Drugs 0.000 description 1
- OSZNNLWOYWAHSS-UHFFFAOYSA-M neostigmine methyl sulfate Chemical compound COS([O-])(=O)=O.CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 OSZNNLWOYWAHSS-UHFFFAOYSA-M 0.000 description 1
- 229960002253 neostigmine methylsulfate Drugs 0.000 description 1
- GSGDTSDELPUTKU-UHFFFAOYSA-N nonoxybenzene Chemical compound CCCCCCCCCOC1=CC=CC=C1 GSGDTSDELPUTKU-UHFFFAOYSA-N 0.000 description 1
- WGVIBWRLLMUUAJ-UHFFFAOYSA-N o-[2-(diethylamino)ethyl] 4-amino-2-hexoxybenzenecarbothioate Chemical compound CCCCCCOC1=CC(N)=CC=C1C(=S)OCCN(CC)CC WGVIBWRLLMUUAJ-UHFFFAOYSA-N 0.000 description 1
- PRGUDWLMFLCODA-UHFFFAOYSA-N oxybuprocaine hydrochloride Chemical compound [Cl-].CCCCOC1=CC(C(=O)OCC[NH+](CC)CC)=CC=C1N PRGUDWLMFLCODA-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- BEEDODBODQVSIM-UHFFFAOYSA-N oxymetazoline hydrochloride Chemical compound Cl.CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 BEEDODBODQVSIM-UHFFFAOYSA-N 0.000 description 1
- 229960005162 oxymetazoline hydrochloride Drugs 0.000 description 1
- 229960001257 oxyquinoline sulfate Drugs 0.000 description 1
- 229940101267 panthenol Drugs 0.000 description 1
- 235000020957 pantothenol Nutrition 0.000 description 1
- 239000011619 pantothenol Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960004811 pemirolast potassium Drugs 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 1
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229920001987 poloxamine Polymers 0.000 description 1
- 229920005646 polycarboxylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229940068988 potassium aspartate Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 1
- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960002800 prednisolone acetate Drugs 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 229960001371 proparacaine hydrochloride Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- 229960001327 pyridoxal phosphate Drugs 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 235000019719 rose oil Nutrition 0.000 description 1
- 239000010666 rose oil Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940068459 sodium pantothenate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- XTXYCJOBMKKQOW-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(2,6-dimethylpyrimidin-4-yl)azanide Chemical compound [Na+].CC1=NC(C)=CC([N-]S(=O)(=O)C=2C=CC(N)=CC=2)=N1 XTXYCJOBMKKQOW-UHFFFAOYSA-N 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 235000011078 sorbitan tristearate Nutrition 0.000 description 1
- 239000001589 sorbitan tristearate Substances 0.000 description 1
- 229960004129 sorbitan tristearate Drugs 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 229960002494 tetracaine hydrochloride Drugs 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
本発明は、ヒアルロン酸又はその塩を含有する組成物において、ヒアルロン酸又はその塩を安定に保持し、組成物の粘度低下が防止された粘膜適用組成物に関する。また、本発明は、組成物中においてヒアルロン酸又はその塩を安定に保持する方法、及びヒアルロン酸又はその塩を含有する組成物の粘度を安定に保持する方法に関する。 The present invention relates to a composition for applying to mucous membranes, in which hyaluronic acid or a salt thereof is stably retained in a composition containing hyaluronic acid or a salt thereof, and a decrease in the viscosity of the composition is prevented. The present invention also relates to a method for stably maintaining hyaluronic acid or a salt thereof in the composition and a method for stably maintaining the viscosity of a composition containing hyaluronic acid or a salt thereof.
眼粘膜や鼻粘膜、口腔内粘膜等に適用される粘膜適用組成物においては、各成分の生物学的利用能を高めるために、粘膜への組成物の滞留性を向上する必要がある。そこで、ヒアルロン酸又はその塩といった粘性を付与しうる化合物を組成物に配合して、滞留性を向上させる製剤設計が行われている。 In a composition for mucosa applied to the ocular mucosa, nasal mucosa, intraoral mucosa, etc., it is necessary to improve the retention of the composition in the mucosa in order to increase the bioavailability of each component. Therefore, a formulation design has been performed in which a compound capable of imparting viscosity, such as hyaluronic acid or a salt thereof, is blended in the composition to improve the retention.
また、眼組織においては、ドライアイ、言い換えると、涙液の質的または量的な異常により引き起こされた角結膜上皮障害に対して、人工涙液を投与することで症状を緩和する簡便な治療方法がある。ドライアイの治療に用いられる人工涙液型点眼薬には、ヒアルロン酸又はその塩を配合することによって、人工涙液を結膜嚢内に滞留させて角膜表面が乾燥するのを防ぐことで角膜細胞を保護してドライアイ治療効果を期待することができる。さらに、ヒアルロン酸又はその塩には、単に細胞を保護するのみならず積極的に角膜上皮細胞障害を治療する効果があることもわかっている。 In eye tissue, a simple treatment to relieve symptoms by administering artificial tears to dry eye, in other words, keratoconjunctival epithelial disorder caused by qualitative or quantitative abnormalities of tears There is a way. By adding hyaluronic acid or its salt to the artificial tears-type eye drops used for the treatment of dry eye, the artificial tears are retained in the conjunctival sac to prevent the corneal cells from drying out. Can protect and expect dry eye treatment effect. Furthermore, it has been found that hyaluronic acid or a salt thereof not only protects cells but also positively treats corneal epithelial cell disorders.
粘膜滞留性の改善効果やドライアイ症状の緩和効果、角膜上皮細胞障害治療効果といった有用な効果は、ヒアルロン酸又はその塩の適度な分子量及び、ヒアルロン酸を含有することによって組成物に付与される粘性に起因している。そこで、粘膜適用組成物においては、適度な粘度を設定すること並びに所望の設定粘度を長期的に安定に保持することが重要である。しかし、ヒアルロン酸又はその塩は、水溶液中において、pHの変動、フリーラジカルや金属の存在によって安定性が損なわれるという問題があり、粘性の低下とともに分子量の低下が起こってしまう問題があった。 Useful effects such as improving mucosal retention, alleviating dry eye symptoms, and treating corneal epithelial cell damage are imparted to the composition by containing hyaluronic acid or a suitable molecular weight thereof and hyaluronic acid. This is due to viscosity. Therefore, in the composition for applying to mucosa, it is important to set an appropriate viscosity and to maintain a desired set viscosity stably for a long period of time. However, hyaluronic acid or a salt thereof has a problem that stability is impaired due to a change in pH and the presence of free radicals and metals in an aqueous solution, and there is a problem that a molecular weight is lowered with a decrease in viscosity.
さらに、点眼薬や洗眼薬等の粘膜適用組成物には、薬効成分の安定性や溶解性を高めたり使用感(官能性)を高めるために、界面活性剤が配合されることがあるが、ヒアルロン酸又はその塩を含有した組成物の粘度は、非イオン界面活性剤の存在下において、低下が促進されることがわかった。 Furthermore, in order to increase the stability and solubility of medicinal ingredients and the feeling of use (functionality), a surfactant may be added to the composition applied to mucous membranes such as eye drops and eye wash. It has been found that the viscosity of a composition containing hyaluronic acid or a salt thereof is accelerated to decrease in the presence of a nonionic surfactant.
これまでに、生物粘着剤又は粘度増強剤であるポリマー、例えばポリアクリル酸類、アクリル酸塩コポリマー類、架橋されたポリアクリル酸類、セルロース,セルロース誘導体,デキストラン,ヒアルロン酸のような多糖類の分解が、溶液やスラリー中の金属イオンによって促進されるが、EDTAよりも遊離イオンと錯体化する能力が大きいキレート化剤であるホスホン酸又はホスホン酸エステルを使用することによって、遊離の金属イオンを減少させポリマーの組成物の粘度を崩壊、分解又は他の不活性化の速度を減少できることがわかっている(特許文献1)。 To date, polymers that are bioadhesives or viscosity enhancing agents, such as polyacrylic acids, acrylate copolymers, cross-linked polyacrylic acids, cellulose, cellulose derivatives, dextran, hyaluronic acid have been degraded. Reduced free metal ions by using phosphonic acids or phosphonates, chelating agents that are promoted by metal ions in solutions and slurries but have a greater ability to complex with free ions than EDTA. It has been found that the viscosity of polymer compositions can be disrupted, reducing the rate of degradation, degradation or other inactivation (US Pat.
また、ヒアルロン酸ナトリウム水溶液にヨウ素含有の還元剤又は硫黄含有の還元剤を添加することで安定化する方法(特許文献2)、ヒアルロン酸又はその塩と、ポリオール(グリセリン、エチレングリコール等),ポリカルボン酸(クエン酸、カルボキシビニルポリマー等),ポリカルボン酸塩(エデト酸二ナトリウム、クエン酸のアルカリ金属塩等)及び糖質(ソルビトール、トレハロース、カルボキシメチルセルロース等)よりなる群から選択される少なくとも1種の化合物を動粘度安定化剤として含有する眼手術用角膜乾燥防止点眼剤の粘度を安定化する方法(特許文献3)、ヒアルロン酸又はその塩と、ポリオール,ポリカルボン酸,ポリカルボン酸塩,糖質及びアミノ酸よりなる群から選択される少なくとも1種の化合物を動粘度安定化剤として含有してなり、37℃における粘度が2000センチポアズ以上20000センチポアズ未満である眼手術用補助剤を安定化する方法(特許文献4)、ヒアルロン酸又はその塩と、ポリオール,ポリカルボン酸,ポリカルボン酸塩及び糖質よりなる群から選択される少なくとも1種の化合物を含有してなり、粘度が2〜2000mm2/sである点眼水溶液の粘度を安定化する方法(特許文献5)、ヒアルロン酸又はその塩と、クエン酸又はその塩を含有する注射用組成物を安定化する方法(特許文献6)、ヒアルロン酸又はその塩と、酒石酸、コハク酸、酢酸、グルタミン酸、グリシン、リンゴ酸及び乳酸から選ばれる1又は2以上の物質を含有する組成物を安定化する方法(特許文献7)等が知られている。 In addition, a method of stabilizing by adding an iodine-containing reducing agent or sulfur-containing reducing agent to a sodium hyaluronate aqueous solution (Patent Document 2), hyaluronic acid or a salt thereof, a polyol (glycerin, ethylene glycol, etc.), poly At least selected from the group consisting of carboxylic acids (citric acid, carboxyvinyl polymers, etc.), polycarboxylates (disodium edetate, alkali metal salts of citric acid, etc.) and carbohydrates (sorbitol, trehalose, carboxymethyl cellulose, etc.) A method for stabilizing the viscosity of an ophthalmic surgical corneal desiccation ophthalmic solution containing one compound as a kinematic viscosity stabilizer (Patent Document 3), hyaluronic acid or a salt thereof, polyol, polycarboxylic acid, polycarboxylic acid Stable kinematic viscosity of at least one compound selected from the group consisting of salts, carbohydrates and amino acids A method for stabilizing an ophthalmic surgery adjuvant having a viscosity at 37 ° C. of 2000 centipoise or more and less than 20000 centipoise (Patent Document 4), hyaluronic acid or a salt thereof, polyol, polycarboxylic acid, poly A method for stabilizing the viscosity of an ophthalmic aqueous solution containing at least one compound selected from the group consisting of a carboxylate and a saccharide and having a viscosity of 2 to 2000 mm 2 / s (Patent Document 5), hyaluron A method for stabilizing an injectable composition containing an acid or a salt thereof and citric acid or a salt thereof (Patent Document 6), hyaluronic acid or a salt thereof, tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid and A method of stabilizing a composition containing one or more substances selected from lactic acid (Patent Document 7) is known.
しかしながら、いずれの技術も十分ではなく粘膜適用組成物の実用化にいたる技術として十分ではなかった。 However, none of these techniques is sufficient, and it is not sufficient as a technique for practical use of the composition applied to mucosa.
そこで、ヒアルロン酸又はその塩を安定に保持するとともに、組成物の粘性を長期的に保持する方法、特に非イオン性界面活性剤の存在下においても保持する方法が求められていた。 Therefore, there has been a demand for a method for stably maintaining hyaluronic acid or a salt thereof and maintaining the viscosity of the composition for a long period of time, particularly a method for maintaining it even in the presence of a nonionic surfactant.
本発明者らは、前記目的を達成するために鋭意検討の結果、ヒアルロン酸又はその塩を含有した組成物において、ヒマシ油、ゴマ油、オリブ油、ダイズ油またはラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油、ヤシ油から選ばれる少なくとも1種の植物油を含有することによって、ヒアルロン酸又はその塩を安定に保持することができ、また、粘膜適用組成物の粘度を所定の粘度に安定に保持することができることを見出した。さらには、非イオン性界面活性剤を配合した組成物においても、ヒアルロン酸又はその塩を安定に保持することができ、また、粘膜適用組成物の粘度を所定の粘度に安定に保持することができることを見出して、本発明を完成するに至った。 As a result of intensive studies to achieve the above object, the present inventors have found that in a composition containing hyaluronic acid or a salt thereof, castor oil, sesame oil, olive oil, soybean oil or peanut oil, almond oil, wheat germ oil , Camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, coconut oil, can contain hyaluronic acid or a salt thereof stably by containing at least one vegetable oil. It has been found that the viscosity of a product can be stably maintained at a predetermined viscosity. Furthermore, even in a composition containing a nonionic surfactant, hyaluronic acid or a salt thereof can be stably maintained, and the viscosity of the composition applied to mucosa can be stably maintained at a predetermined viscosity. The present invention was completed by finding out what can be done.
本発明はかかる知見に基づいて開発されたものである。
すなわち本発明は、下記(1)〜(8)に掲げる組成物である:
(1)i)ヒアルロン酸またはその塩と、ii)ヒマシ油、ゴマ油、オリブ油、ダイズ油,ラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油又はヤシ油から選ばれる少なくとも1種の植物油を含有する粘膜適用組成物、
(2)i)ヒアルロン酸またはその塩と、ii)非イオン性界面活性剤、及びiii)ヒマシ油、ゴマ油、オリブ油、ダイズ油,ラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油又はヤシ油から選ばれる少なくとも1種の植物油を含有する粘膜適用組成物、
(3)20℃での粘度が2mPa・s以上10万mPa・s以下である(1)又は(2)に記載の粘膜適用組成物、
(4) 20℃での粘度が1.2mPa・s以上100mPa・s以下である(1)又は(2)に記載の粘膜適用組成物、
(5) 非イオン性界面活性剤が、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー、ポリオキシエチレンソルビタン脂肪酸エステル類またはポリオキシエチレン硬化ヒマシ油類から選択される非イオン性界面活性剤である(1)乃至(4)のいずれかに記載の粘膜適用組成物、
(6) 眼粘膜適用組成物又は鼻粘膜適用組成物である(1)乃至(5)のいずれかに記載の粘膜適用組成物、
(7) 眼適用時における痒みが抑制された(6)に記載の眼粘膜適用組成物、
(8) pHが4.0〜10.0である(1)乃至(7)のいずれかに記載の粘膜適用組成物、
さらに、本発明は、下記(9)又は(10)に掲げる方法である:
(9)ヒアルロン酸又はその塩と、ヒマシ油、ゴマ油、オリブ油、ダイズ油、ラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油またはヤシ油から選ばれる少なくとも1種の植物油を組成物中で共存することにより、ヒアルロン酸又はその塩を安定化する方法。
(10)ヒアルロン酸又はその塩と、ヒマシ油、ゴマ油、オリブ油、ダイズ油、ラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油またはヤシ油から選ばれる少なくとも1種の植物油を組成物中に共に配合することにより、組成物の粘度を安定化する方法。
なお、本明細書中、特に言及しない限り、%はw/v%を意味するものとする。また、本明細書中でコンタクトレンズとは、ハード、酸素透過性ハード、ソフト、カラー等のあらゆるタイプのコンタクトレンズを包含する意味とする。
The present invention has been developed based on such findings.
That is, the present invention is a composition listed in the following (1) to (8):
(1) i) hyaluronic acid or a salt thereof; and ii) castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or palm A mucosa-applied composition containing at least one vegetable oil selected from oils;
(2) i) hyaluronic acid or a salt thereof, ii) nonionic surfactant, and iii) castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil A composition for applying to mucosa comprising at least one vegetable oil selected from rapeseed oil, sunflower oil, cottonseed oil or coconut oil,
(3) The composition for applying to mucosa according to (1) or (2), wherein the viscosity at 20 ° C. is 2 mPa · s or more and 100,000 mPa · s or less,
(4) The composition for applying to mucosa according to (1) or (2), wherein the viscosity at 20 ° C. is 1.2 mPa · s or more and 100 mPa · s or less,
(5) The nonionic surfactant is a nonionic surfactant selected from a polyoxyethylene-polyoxypropylene block copolymer, a polyoxyethylene sorbitan fatty acid ester or a polyoxyethylene hydrogenated castor oil (1 ) To (4), a composition for applying to mucosa,
(6) The composition for application to mucosa according to any one of (1) to (5), which is a composition for application to an ocular mucosa or a composition for application to a nasal mucosa.
(7) The composition for application to the ocular mucosa according to (6), wherein itchiness at the time of ocular application is suppressed
(8) The composition for applying to mucosa according to any one of (1) to (7), wherein the pH is 4.0 to 10.0.
Furthermore, the present invention is the method described in the following (9) or (10):
(9) Hyaluronic acid or a salt thereof and castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or coconut oil A method of stabilizing hyaluronic acid or a salt thereof by coexisting at least one vegetable oil in a composition.
(10) Hyaluronic acid or a salt thereof and castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or coconut oil A method of stabilizing the viscosity of a composition by incorporating at least one vegetable oil together in the composition.
In the present specification, unless otherwise specified,% means w / v%. Further, in the present specification, the contact lens is meant to include all types of contact lenses such as hard, oxygen permeable hard, soft, and color.
本発明では、ヒアルロン酸又はその塩を含有する組成物に特定の植物油を含有することによって、ヒアルロン酸又はその塩の安定性を高め、組成物の粘度の低下を防止することができる。さらに、本発明では、ヒアルロン酸又はその塩とともに非イオン性界面活性剤を含有する組成物であっても特定の植物油を含有することによって、ヒアルロン酸又はその塩の安定性を高め、組成物の粘度の低下を防止することができる。このような効果を有する本発明の粘膜適用組成物は、点眼剤、洗眼剤、眼軟膏剤、コンタクトレンズ装着液、コンタクトレンズ用剤(洗浄液、保存液、殺菌液、マルチパーパスソリューションなど)、点鼻剤などの眼科用組成物、耳鼻科用組成物として有用である。
また、本発明の粘膜適用組成物が、点眼剤、洗眼剤、コンタクトレンズ装着液などの眼粘膜適用組成物である場合においては、ヒアルロン酸又はその塩を含有する組成物を眼に適用した際に生じる痒みを抑制することができ、使用感にも優れている。
In this invention, the stability of hyaluronic acid or its salt can be improved by containing a specific vegetable oil in the composition containing hyaluronic acid or its salt, and the fall of the viscosity of a composition can be prevented. Furthermore, in the present invention, even if the composition contains a nonionic surfactant together with hyaluronic acid or a salt thereof, the stability of hyaluronic acid or a salt thereof can be improved by containing a specific vegetable oil. A decrease in viscosity can be prevented. The mucous membrane composition of the present invention having such effects includes eye drops, eye washes, eye ointments, contact lens mounting liquids, contact lens preparations (cleaning liquids, storage liquids, bactericidal liquids, multipurpose solutions, etc.) It is useful as an ophthalmic composition such as a nasal agent and an otolaryngological composition.
In addition, when the composition for mucosa of the present invention is an ophthalmic mucosa application composition such as eye drops, eye wash, contact lens mounting liquid, etc., when a composition containing hyaluronic acid or a salt thereof is applied to the eye It is possible to suppress the stagnation that occurs in the skin, and the feeling of use is excellent.
本発明におけるヒアルロン酸又はその塩は、鶏冠から得られたものであっても、微生物由来のものであっても、いずれでもよく市販のものを利用することができる。ここで、ヒアルロン酸の塩としては、ナトリウム、カリウムなどのアルカリ金属、カルシウム、マグネシウムなどのアルカリ土類金属、アルミニウムなどの金属との塩などが例示できるが、ナトリウム塩、カリウム塩が好適に用いられる。また、ヒアルロン酸に比較して、塩の状態のヒアルロン酸を用いる方がより安定であることから好ましい。 The hyaluronic acid or a salt thereof in the present invention may be obtained from a chicken crown or a microorganism, and any commercially available product can be used. Here, examples of the salt of hyaluronic acid include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with metals such as aluminum. Sodium salts and potassium salts are preferably used. It is done. Moreover, it is preferable to use hyaluronic acid in a salt state as compared with hyaluronic acid because it is more stable.
また、本発明に用いるヒアルロン酸又はその塩は、平均分子量が50〜500万の範囲にあるものが好ましく、50〜400万の範囲にあることがより好ましく、60万〜250万が特に好ましく、80万〜200万の範囲にあることがよりさらに好ましい。本発明に用いるヒアルロン酸又はその塩は、市販のものを用いることができる。かかる市販品として代表的には、商品名「バイオヒアルロン酸ナトリウム」(資生堂株式会社製)平均分子量110〜160万、商品名「ヒアルロンサンHA−QA」(キューピー株式会社製)平均分子量60〜120万、商品名「ヒアルロンサンHA−AM」(キューピー株式会社製)平均分子量60〜120万等の市販品が例示できる。 The hyaluronic acid or a salt thereof used in the present invention preferably has an average molecular weight in the range of 500 to 5,000,000, more preferably in the range of 50,000 to 4,000,000, particularly preferably 600,000 to 2,500,000, More preferably, it is in the range of 800,000 to 2,000,000. A commercially available thing can be used for the hyaluronic acid or its salt used for this invention. Typical examples of such commercially available products are “Bio Sodium Hyaluronate” (manufactured by Shiseido Co., Ltd.), average molecular weight of 110 to 1.6 million, and trade name “Hyaluron Sun HA-QA” (manufactured by Kewpie Co., Ltd.), average molecular weight of 60 to 1,200,000. , And commercial name “Hyaluron Sun HA-AM” (manufactured by Kewpie Co., Ltd.) with an average molecular weight of 60 to 1,200,000.
ここで、本明細書において平均分子量とは、粘度平均分子量を意味する。粘度平均分子量は公知の測定方法により求めることができる。具体的には、ヒアルロン酸ナトリウム(乾燥物)を0.2M塩化ナトリウム溶液に溶解し、30℃における極限粘度(η)を求めLaurentの式(η(極限粘度)=0.00036×Mv(粘度平均分子量)0.78)より粘度平均分子量が求められる。極限粘度(η)の測定は、例えば、第14改正日本薬局方の一般試験法、粘度測定法(毛細管粘度計法)によることができる。 Here, the average molecular weight in this specification means a viscosity average molecular weight. The viscosity average molecular weight can be determined by a known measurement method. Specifically, sodium hyaluronate (dried product) was dissolved in a 0.2 M sodium chloride solution, and the intrinsic viscosity (η) at 30 ° C. was obtained to calculate the Laurent equation (η (intrinsic viscosity) = 0.00036 × Mv (viscosity). Average molecular weight) 0.78 ), the viscosity average molecular weight is determined. The intrinsic viscosity (η) can be measured, for example, by a general test method or a viscosity measurement method (capillary viscometer method) according to the 14th revised Japanese Pharmacopoeia.
ヒアルロン酸又はその塩の粘膜適用組成物に対する使用量は、組成物に付与する所望の粘度に応じて適宜設定することができ分子量や種類などによって異なるので一概に規定できないが、通常、ヒアルロン酸又はその塩の組成物中の濃度として、0.001〜10%、好ましくは0.005〜5%、さらに好ましくは0.01〜2%、特に好ましくは0.01〜1%程度で用いることができる。また、ヒアルロン酸又はその塩の植物油に対する割合としては、通常、ヒアルロン酸又はその塩の1重量部に対して植物油を0.01〜500重量部、好ましくは0.1〜250重量部、より好ましくは0.1〜150重量部、特に好ましくは0.1〜100重量部程度で用いることができる。 The amount of hyaluronic acid or a salt thereof used for the composition applied to the mucosa can be appropriately set according to the desired viscosity to be applied to the composition, and varies depending on the molecular weight or type, but cannot generally be defined. The concentration of the salt in the composition is 0.001 to 10%, preferably 0.005 to 5%, more preferably 0.01 to 2%, particularly preferably about 0.01 to 1%. it can. Moreover, as a ratio with respect to vegetable oil of hyaluronic acid or its salt, normally, 0.01-500 weight part of vegetable oil is preferable with respect to 1 weight part of hyaluronic acid or its salt, Preferably it is 0.1-250 weight part, More preferably Can be used in an amount of about 0.1 to 150 parts by weight, particularly preferably about 0.1 to 100 parts by weight.
本発明における非イオン性界面活性剤は、ヒアルロン酸又はその塩と配合することによって粘膜適用組成物の粘度を低下させるが、特定の植物油とともに配合することによって粘膜適用組成物の粘度低下を抑制できる。かかる非イオン性界面活性剤としては、通常当業者が粘膜適用組成物に利用しうるものを用いることができ、例えば、非イオン性界面活性剤であるポリオキシエチレン(以下、POEともいう。)−ポリオキシプロピレン(以下、POPともいう。)ブロックコポリマー (例えば、ポロクサマー407 、ポロクサマー235 、ポロクサマー188 など) ;ポロキサミンなどのエチレンジアミンのPOE-POPブロックコポリマー付加物;モノラウリル酸POE(20)ソルビタン(ポリソルベート20) ,モノオレイン酸POE(20)ソルビタン (ポリソルベート80) ,POEソルビタンモノステアレート(ポリソルベート60),POEソルビタントリステアレート(ポリソルベート65) などのPOEソルビタン脂肪酸エステル類;POE硬化ヒマシ油5 ,POE硬化ヒマシ油10 ,POE硬化ヒマシ油20 ,POE硬化ヒマシ油40 ,POE硬化ヒマシ油50、POE硬化ヒマシ油60 ,POE硬化ヒマシ油100などのPOE硬化ヒマシ油類;POE(9) ラウリルエーテルなどのPOEアルキルエーテル類;POE(20)POP(4) セチルエーテルなどのPOE・POPアルキルエーテル類;POE(10)ノニルフェニルエーテルなどのPOEアルキルフェニルエーテル類などが挙げられる。なお、括弧内の数字は付加モル数を示す。なかでも好ましくは、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー、POEソルビタン脂肪酸エステル類又はPOE硬化ヒマシ油類から選ばれる非イオン性界面活性剤であり、特に好ましくは、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油60である。 The nonionic surfactant in the present invention decreases the viscosity of the composition applied to mucosa by blending with hyaluronic acid or a salt thereof, but can suppress the decrease in viscosity of the composition applied to mucosa by blending with a specific vegetable oil. . As such a nonionic surfactant, those which can be usually used by those skilled in the art for a composition applied to mucosa can be used. For example, polyoxyethylene (hereinafter also referred to as POE) which is a nonionic surfactant. -Polyoxypropylene (hereinafter also referred to as POP) block copolymer (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.); POE-POP block copolymer adduct of ethylenediamine such as poloxamine; POE (20) sorbitan monolaurate ( POE sorbitan fatty acid esters such as polysorbate 20), monooleic acid POE (20) sorbitan (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65); POE hydrogenated castor oil 5, POE cured chick POE hardened castor oils such as Pear oil 10, POE hardened castor oil 20, POE hardened castor oil 50, POE hardened castor oil 50, POE hardened castor oil 60, POE hardened castor oil 100; POE such as POE (9) lauryl ether POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether. The numbers in parentheses indicate the number of added moles. Among them, nonionic surfactants selected from polyoxyethylene-polyoxypropylene block copolymers, POE sorbitan fatty acid esters or POE hydrogenated castor oils are preferable, and polyoxyethylene-polyoxypropylene blocks are particularly preferable. Copolymer, polysorbate 80, polyoxyethylene hydrogenated castor oil 60.
非イオン性界面活性剤の粘膜適用組成物中における使用量は、界面活性剤の種類などによって異なるので一概に規定できないが、通常、0.0001〜5%、好ましくは0.001〜1%、さらに好ましくは0.005〜1%、特に好ましくは0.01〜0.5%程度で用いられる。 The amount of the nonionic surfactant used in the composition applied to the mucosa varies depending on the type of the surfactant and the like, and thus cannot be generally defined, but is usually 0.0001 to 5%, preferably 0.001 to 1%. More preferably, it is used at about 0.005 to 1%, particularly preferably about 0.01 to 0.5%.
本発明の組成物では、特定の植物油、すなわち、ヒマシ油、ゴマ油、オリブ油、ダイズ油またはラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油又はヤシ油から選ばれる少なくとも1種の植物油を必須成分として含有する。 In the composition of the present invention, certain vegetable oils, i.e. castor oil, sesame oil, olive oil, soybean or peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or coconut oil It contains at least one vegetable oil selected from as an essential component.
本発明におけるヒマシ油とは、トウダイグサ科トウゴマ属の植物(Ricinus communis Linne(Euphorbiaceae)等)の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば日本薬局方に収載されたヒマシ油は(第14改正 日本薬局方解説書D-972〜973参照)、圧搾後に油滓を遠心分離後、活性白土による脱色を行い、次いで、高温下(200〜220℃)、高真空で水蒸気蒸留を行い、脱酸・脱臭することによって得ることができる。また、通常当業者が粘膜適用組成物に利用しうるものを用いることができ、市販のものを用いることもできる。
ゴマ油とは、ゴマ科ゴマ属の植物(Sesamum indicum Linne(Pedaliaceae)等)の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば日本薬局方に収載されたゴマ油は(第14改正 日本薬局方解説書D-389〜390参照)、冷圧法で採取した油を炒らずに精製して得ることできる。
The castor oil in the present invention refers to a vegetable oil obtained from the seed of a plant belonging to the genus Euphorbiaceae (Ricinus communis Linne (Euphorbiaceae), etc.). It can be obtained from seeds using known extraction methods and known purification methods. For example, castor oil listed in the Japanese Pharmacopoeia (see 14th revision Japanese Pharmacopoeia Description D-972 to 973) After the oil cake is centrifuged, it can be obtained by decolorization with activated clay, followed by steam distillation at high temperature (200 to 220 ° C.) and high vacuum, and deoxidation and deodorization. In addition, those that can be used by those skilled in the art for the composition applied to mucosa can be used, and commercially available products can also be used.
Sesame oil refers to a vegetable oil obtained from the seeds of a plant belonging to the genus Sesame, such as Sesamum indicum Linne (Pedaliaceae). It can be obtained from seeds using known exploitation methods and known purification methods. For example, sesame oil listed in the Japanese Pharmacopoeia (see 14th revision Japanese Pharmacopoeia Description D-389-390) It can be obtained by refining the collected oil without frying.
オリブ油とは、モクセイ科オリーブ属の植物(Olea europaea Linne(Oleaceae)等)の果実から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて果実から得ることができるが、例えば日本薬局方に収載されたオリブ油は(第14改正 日本薬局方解説書D-174〜177参照)、成熟果実を直ちに冷圧(加熱せずに搾油する)法により搾油し、その後物理的なろ過や遠心分離で処理し、通常の精製工程に掛けて得ることができる。 Olive oil refers to a vegetable oil obtained from the fruit of a plant belonging to the genus Oleaceae (Olea europaea Linne (Oleaceae), etc.). It can be obtained from fruits using known exploitation methods and known purification methods. For example, olive oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-174-177) is a mature fruit The oil can be immediately extracted by a cold pressure (squeezing without heating) method, then processed by physical filtration or centrifugation, and subjected to a normal purification step.
ダイズ油とは、マメ科ダイズ属(Glycine max Merrill(Leguminosae)等)の植物の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば日本薬局方に収載されたダイズ油は(第14改正 日本薬局方解説書D-700〜701参照)、ダイズを破砕・圧扁後(冷圧又は温圧しても精油できる)、溶剤(ヘキサン)による抽出法で採油することができる。 Soybean oil refers to a vegetable oil obtained from the seed of a plant of the leguminous soybean genus (Glycine max Merrill (Leguminosae, etc.)). It can be obtained from seeds using known exploitation methods and known purification methods. For example, soybean oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-700-701) After crushing and crushing (essential oil can be obtained by cold pressure or hot pressure), oil can be collected by extraction with a solvent (hexane).
ラッカセイ油とは、マメ科ラッカセイ属(Arachis hypogaea Linne(Leguminosae)等)の植物の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば、日本薬局方に収載されたラッカセイ油は(第14改正 日本薬局方解説書D-1194〜1196参照)、種子をロールで粉砕し、加熱し、圧搾し、得られた油をろ過し精製して得ることができる。 Peanut oil refers to a vegetable oil obtained from seeds of a plant belonging to the genus Arachis hypogaea Linne (Leguminosae). It can be obtained from seeds using known exploitation methods and known purification methods. For example, peanut oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia Description D-1194-1196), seed Can be obtained by crushing with a roll, heating, pressing, and filtering and purifying the oil obtained.
アルモンド油とは、バラ科サクラ属(Prunus amygdalus Batsch(Rosaceae)等)の核仁から得られる植物油をいう。公知の搾取方法・公知の精製方法を用いて核仁から得ることができる(医薬品添加物規格1998 P97等参照)。 Almond oil refers to a vegetable oil obtained from the nuclear seeds of the Rosaceae family, such as Prunus amygdalus Batsch (Rosaceae). It can be obtained from nuclei using a known exploitation method or a known purification method (see Pharmaceutical Additive Standard 1998, P97, etc.).
小麦胚芽油とは、イネ科コムギ属(Triticum aestivum Linne(Gramdneae)等)の植物の胚芽から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて胚芽から得ることができる(医薬品添加物規格1998 P318等参照)。 Wheat germ oil refers to a vegetable oil obtained from the germ of a plant of the genus Wheat (Triticum aestivum Linne (Gramdneae), etc.). It can be obtained from embryos using a known exploitation method or a known purification method (see Pharmaceutical Additive Standard 1998 P318 etc.).
ツバキ油とは、ツバキ科ツバキ属(Camellia japonica Linne(Theaceae)等)の植物の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば、日本薬局方に収載されたツバキ油は(第14改正 日本薬局方解説書D-778〜779参照)、天日又は人工乾燥し種皮を除いた種子を粉砕して蒸煮し圧搾し、その後ろ過して精製して得られる。 Camellia oil refers to a vegetable oil obtained from the seeds of plants belonging to the genus Camellia japonica Linne (Theaceae). It can be obtained from seeds using known exploitation methods and known purification methods. For example, camellia oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia Description D-778-779) It is obtained by pulverizing, steaming and pressing seeds that have been sun-dried or artificially dried and then seeded, and then purified by filtration.
トウモロコシ油とは、イネ科トウモロコシ属(Zea mays Linne(Gramineae)等)の胚芽から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて胚芽から得ることができるが、例えば、日本薬局方に収載されたトウモロコシ油は(第14改正 日本薬局方解説書D-816〜817参照)、胚芽を穀粒から取り分け、急熱乾燥後圧搾し、圧搾かすをヘキサンで抽出して採油することができる。 Corn oil refers to a vegetable oil obtained from the germ of a genus Gramineae (Zea mays Linne (Gramineae), etc.). It can be obtained from embryos using known exploitation methods and known purification methods. For example, corn oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-816-817) Can be separated from the grain, pressed after rapid drying, extracted with hexane and oiled.
ナタネ油とは、アブラナ科アブラナ属(Brassica campestris Linne subsp. napus Hooker fil.et Anderson var. nippo-oleifera Makino(Cruciferae)等)の植物の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば、日本薬局方に収載されたナタネ油は(第14改正 日本薬局方解説書D-839参照)、種子を加熱し圧搾した後、そのかすを溶剤抽出し、圧搾油と合わせ原油とするのが一般的である。得られた原油を精製して用いる。 Rapeseed oil refers to a vegetable oil obtained from the seeds of plants of the Brassicaceae genus Brassica (Brassica campestris Linne subsp. Napus Hooker fil. Et Anderson var. Nippo-oleifera Makino (Cruciferae), etc.). It can be obtained from seeds using known exploitation methods or known purification methods. For example, rapeseed oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-839) heats the seeds. After squeezing, the residue is generally solvent extracted and combined with the squeezed oil to obtain crude oil. The crude oil obtained is refined and used.
ヒマワリ油とは、キク科ヒマワリ属(Helianthus annuus Linne(Compositae))の植物の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができる(医薬品添加物規格1998 P518等参照)。 Sunflower oil refers to a vegetable oil obtained from the seeds of plants of the genus Sunflower (Helianthus annuus Linne (Compositae)). It can be obtained from seeds using a known exploitation method or a known purification method (see Pharmaceutical Additive Standard 1998 P518, etc.).
綿実油とは、アオイ科ワタ属(Gossypium hirsutum Linne(Gossypium)又はその同属植物(Malvaceae)等)の植物の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば、種子から圧搾法又は抽出法により得た不揮発性の脂肪油を精製して得ることができる(医薬品添加物規格1998 P719 or 第14改正 日本薬局方解説書B-936等参照)。 Cottonseed oil refers to a vegetable oil obtained from the seeds of a plant of the family Mallow (Gossypium hirsutum Linne (Gossypium) or its genus plant (Malvaceae), etc.). It can be obtained from seeds using a known extraction method or a known purification method. For example, it can be obtained by purifying non-volatile fatty oil obtained from a seed by a pressing method or extraction method (standard for pharmaceutical additives) 1998 P719 or 14th revision Japanese Pharmacopoeia Manual B-936 etc.).
ヤシ油とは、ヤシ科ココヤシ属(Cocos nucifera Linne(Palmae)等)の植物の種子から得た植物油をいう。公知の搾取方法・公知の精製方法を用いて種子から得ることができるが、例えば、日本薬局方に収載されたヤシ油は(第14改正 日本薬局方解説書D-1160〜1161参照)、コプラを粉砕して蒸煮して圧搾し、浮遊物を除いて精製して得られる。 Palm oil refers to a vegetable oil obtained from the seeds of a plant of the genus Cocos nucifera Linne (Palmae). It can be obtained from seeds using known exploitation methods or known purification methods. For example, palm oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia Description D-1160 to 1161), Copra It is obtained by crushing, steaming and squeezing, removing the suspended solids and purifying.
これらの特定油は1種又は2種以上を組み合わせて用いることができる。また、なかでも好ましくは、ヒマシ油、ゴマ油、オリブ油、ダイズ油、ラッカセイ油であり、特に好ましくはヒマシ油、ゴマ油である。なお、これらの特定の植物油は、通常当業者が粘膜適用組成物に利用しうるものを用いることができ、市販のものを用いることもできる。 These specific oils can be used alone or in combination of two or more. Of these, castor oil, sesame oil, olive oil, soybean oil, and peanut oil are preferable, and castor oil and sesame oil are particularly preferable. In addition, as these specific vegetable oils, those that can be used for a composition applied to mucosa by those skilled in the art can be used, and commercially available ones can also be used.
本発明の特定の植物油の粘膜適用組成物中における使用量は、植物油の種類などによって異なるので一概に規定できないが、通常、0.0001〜60%、好ましくは0.001〜30%、より好ましくは0.001〜10%、特に好ましくは0.001〜5%、より特に好ましくは0.001〜1%程度である。眼科用組成物の場合には、0.001〜5%が好ましく、0.001〜1%がより好ましく、0.001〜0.5%程度がさらに好ましい。 The amount of the specific vegetable oil of the present invention used in the composition applied to the mucosa varies depending on the type of the vegetable oil and cannot be defined unconditionally, but is usually 0.0001 to 60%, preferably 0.001 to 30%, more preferably. Is 0.001 to 10%, particularly preferably 0.001 to 5%, and particularly preferably about 0.001 to 1%. In the case of an ophthalmic composition, 0.001 to 5% is preferable, 0.001 to 1% is more preferable, and about 0.001 to 0.5% is more preferable.
本発明の特定の植物油による粘度低下抑制効果や使用感改善効果は、粘膜適用組成物中にエデト酸またはその薬理学的に許容される塩を配合した場合に、更に顕著となる。さらに、本発明では、ヒアルロン酸又はその塩と非イオン性界面活性剤とを含有しても特定の植物油をともに含有することによって粘度が安定に保持されているが、さらに、エデト酸もしくはその塩を含有することによって、粘度安定性がさらに顕著に改善された粘膜適用組成物が得られる。 The effect of suppressing the decrease in viscosity and the effect of improving the feeling of use due to the specific vegetable oil of the present invention become more prominent when edetic acid or a pharmacologically acceptable salt thereof is blended in the mucosa-applied composition. Furthermore, in the present invention, even if hyaluronic acid or a salt thereof and a nonionic surfactant are contained, the viscosity is stably maintained by containing both the specific vegetable oil, but further, edetic acid or a salt thereof By containing the composition, a composition for applying to mucosa having a significantly improved viscosity stability can be obtained.
かかるエデト酸またはその薬理学的に許容される塩としては、例えば、エデト酸(エチレンジアミン四酢酸,EDTA)、エチレンジアミン二酢酸(EDDA)、ジエチレントリアミン五酢酸(DTPA)、N−(2−ヒドロキシエチル)エチレンジアミン三酢酸(HEDTA)などが例示できる。これらは、1種又は2種以上配合でき、薬理学的に又は生理学的に許容される塩(例えば、エチレンジアミン四酢酸ナトリウム等)として使用してもよい。なかでも好ましくは、エチレンジアミン四酢酸またはその塩であり、例えばエチレンジアミン四酢酸二ナトリウム、エチレンジアミン四酢酸二ナトリウム・二水和物(以下、エデト酸ナトリウムともいう。)である。 Examples of such edetic acid or a pharmacologically acceptable salt thereof include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), and N- (2-hydroxyethyl). Examples thereof include ethylenediaminetriacetic acid (HEDTA). These may be used alone or in combination, and may be used as a pharmacologically or physiologically acceptable salt (for example, sodium ethylenediaminetetraacetate). Among them, ethylenediaminetetraacetic acid or a salt thereof is preferable, for example, ethylenediaminetetraacetic acid disodium, ethylenediaminetetraacetic acid disodium dihydrate (hereinafter also referred to as sodium edetate).
エデト酸またはその塩の眼科用組成物での使用量は、分子量や種類などによって異なるので一概に規定できないが、その組成物中の濃度として、0.0001〜1%、好ましくは0.001〜0.5%、特に好ましくは、0.005〜0.3%程度の使用量である。 The amount of edetic acid or a salt thereof used in an ophthalmic composition varies depending on the molecular weight, type, etc., and thus cannot be specified unconditionally, but the concentration in the composition is 0.0001 to 1%, preferably 0.001 to The amount used is 0.5%, particularly preferably about 0.005 to 0.3%.
本発明において、ヒアルロン酸又はその塩を含有した粘膜適用組成物は、所望の効果を得るために適切な粘度に初期設定して設定粘度を長期的に安定に保持することができる。眼科用組成物の粘度は、眼粘膜に適用した時の差し心地(使用感)や薬物滞留能、ドライアイなどの疾患の治療等に多大な影響を与えることから、適切な粘度を設計し、設計した粘度が長期的に安定に保持されることが重要となる。適切な粘度を設定する場合において、例えば眼科用組成物では通常、20℃における粘度が1.2mPa・s以上に設計し、2mPa・s以上に保持して設計することが好ましく、通常2〜300mPa・s、好ましくは、5〜200mPa・s、特に好ましくは15〜100mPa・s、更に好ましくは20〜80mPa・s程度に設計することができる。本発明においては粘度が安定に保持されるので、低粘度域でも効果を発揮することができ、例えば、1.2〜100mPa・s、好ましくは1.2〜80mPa・s、より好ましくは2〜80mPa・s、さらに好ましくは3〜70mPa・sにおいても有用である。
鼻科用組成物では通常、20℃における粘度が1.2mPa・s以上に設計し、2〜10万mPa・s以上に保持して設計することが好ましく、通常2〜10万mPa・s、好ましくは、50〜1万mPa・s、特に好ましくは100〜5000mPa・s程度に設計することができる。本発明においては粘度が安定に保持されるので、低粘度域でも効果を発揮することができ、例えば、1.2〜100mPa・s、好ましくは1.2〜80mPa・s、より好ましくは2〜80mPa・s、さらに好ましくは3〜70mPa・sにおいても有用である。
なお、本発明の粘膜適用組成物は、ヒアルロン酸またはその塩に加えてセルロース系増粘剤やビニル系増粘剤などを用いて粘度を調整することができる。
In the present invention, the composition for applying to mucosa containing hyaluronic acid or a salt thereof can be initially set to an appropriate viscosity to obtain a desired effect, and the set viscosity can be stably maintained for a long time. The viscosity of the ophthalmic composition has a great effect on the comfort (use feeling), drug retention, and treatment of diseases such as dry eye when applied to the ocular mucosa. It is important that the designed viscosity is kept stable over the long term. In the case of setting an appropriate viscosity, for example, in an ophthalmic composition, the viscosity at 20 ° C. is usually designed to be 1.2 mPa · s or more, and preferably 2 mPa · s or more, and usually 2 to 300 mPa. · S, preferably 5 to 200 mPa · s, particularly preferably 15 to 100 mPa · s, more preferably about 20 to 80 mPa · s. In the present invention, since the viscosity is stably maintained, the effect can be exhibited even in a low viscosity region, for example, 1.2 to 100 mPa · s, preferably 1.2 to 80 mPa · s, more preferably 2 to 2 mPa · s. It is also useful at 80 mPa · s, more preferably 3 to 70 mPa · s.
In a nasal composition, the viscosity at 20 ° C. is usually designed to be 1.2 mPa · s or more, preferably 2 to 100,000 mPa · s or more, and usually 2 to 100,000 mPa · s. Preferably, it can be designed to be 50 to 10,000 mPa · s, particularly preferably about 100 to 5000 mPa · s. In the present invention, since the viscosity is stably maintained, the effect can be exhibited even in a low viscosity region, for example, 1.2 to 100 mPa · s, preferably 1.2 to 80 mPa · s, more preferably 2 to 2 mPa · s. It is also useful at 80 mPa · s, more preferably 3 to 70 mPa · s.
The mucosa-applied composition of the present invention can be adjusted in viscosity using a cellulose-based thickener, a vinyl-based thickener, or the like in addition to hyaluronic acid or a salt thereof.
本発明の粘膜適用組成物は、発明の効果を利用するものであればその使用用途は特定されず、医薬品、医薬部外品、雑品等の各種分野において利用することができる。例えば、点眼剤(ハードまたはソフトコンタクトレンズを装用中にも使用することができる点眼剤を含む、また、点眼薬ともいう。)、洗眼剤(ハードまたはソフトコンタクトレンズを装用中にも使用することができる洗眼剤を含む。)、眼軟膏剤、コンタクトレンズ装着液、コンタクトレンズ用剤(洗浄液、保存液、殺菌液、マルチパーパスソリューションなど)、点鼻剤などが挙げられる。なかでも、点眼剤、洗眼剤、コンタクトレンズ装着液、点鼻剤に有用である。 The use application of the mucosa of the present invention is not specified as long as it uses the effects of the invention, and can be used in various fields such as pharmaceuticals, quasi drugs, and miscellaneous goods. For example, eye drops (including eye drops that can be used while wearing hard or soft contact lenses, also referred to as eye drops), eye wash (hard or soft contact lenses should also be used while wearing Eye ointment, contact lens mounting solution, contact lens preparation (cleaning solution, preservative solution, bactericidal solution, multi-purpose solution, etc.), nasal drops and the like. Among these, it is useful for eye drops, eye wash, contact lens mounting liquid, and nasal drops.
本発明の粘膜適用組成物には、本発明の効果を妨げない限り、種々の成分(薬理活性成分や生理活性成分を含む)を組み合わせて含有してもよい。このような成分の種類は特に制限されず、例えば、充血除去成分、眼調節薬成分、抗炎症薬成分または収斂薬成分、抗ヒスタミン薬成分又は抗アレルギー薬成分、ビタミン類、アミノ酸類、抗菌薬成分、殺菌薬成分、糖類、多糖類またはその誘導体、セルロース又はその誘導体又はそれらの塩、前述以外の水溶性高分子、局所麻酔薬成分、ステロイド成分、緑内障治療薬などが例示できる。本発明において好適な成分としては、例えば、次のような成分が挙げられる。
充血除去成分:例えば、α−アドレナリン作動薬、具体的にはエピネフリン、塩酸エピネフリン、塩酸エフェドリン、塩酸オキシメタゾリン、塩酸テトラヒドロゾリン、塩酸ナファゾリン、塩酸フェニレフリン、塩酸メチルエフェドリン、酒石酸水素エピネフリン、硝酸ナファゾリンなど。これらはd体、l体又はdl体のいずれでもよい。
眼筋調節薬成分:例えば、アセチルコリンと類似した活性中心を有するコリンエステラーゼ阻害剤、具体的にはメチル硫酸ネオスチグミン、トロピカミド、ヘレニエン硫酸アトロピンなど。
抗炎症薬成分または収斂薬成分:例えば、硫酸亜鉛、乳酸亜鉛、アラントイン、イプシロン−アミノカプロン酸、インドメタシン、塩化リゾチーム、硝酸銀、プラノプロフェン、アズレンスルホン酸ナトリウム、グリチルリチン酸二カリウム、ジクロフェナクナトリウム、ブロムフェナクナトリウム、塩化ベルベリン、硫酸ベルベリンなど。
抗ヒスタミン薬成分又は抗アレルギー薬成分:例えば、アシタザノラスト、アンレキサノクス、イブジラスト、トラニラスト、塩酸ジフェンヒドラミン、塩酸レボカバスチン、フマル酸ケトチフェン、クロモグリク酸ナトリウム、ペミロラストカリウム、マレイン酸クロルフェニラミンなど。
ビタミン類:例えば、酢酸レチノール、パルミチン酸レチノール、塩酸ピリドキシン、フラビンアデニンジヌクレオチドナトリウム、リン酸ピリドキサール、シアノコバラミン、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム、アスコルビン酸、酢酸トコフェロールなど。
アミノ酸類:例えば、アミノエチルスルホン酸(タウリン)、グルタミン酸、クレアチニン、アスパラギン酸カリウム、アスパラギン酸マグネシウム、アスパラギン酸マグネシウム・カリウム混合物、グルタミン酸ナトリウム、コンドロイチン硫酸ナトリウムなど。これらはd体、l体又はdl体のいずれでもよい。
抗菌薬成分または殺菌薬成分:例えば、アルキルポリアミノエチルグリシン、スルファメトキサゾール、スルフイソキサゾール、スルファメトキサゾールナトリウム、スルフイソミジンナトリウム、硫酸ベルベリン、塩化ベルベリン、ホウ酸など。
糖類:例えば単糖類、二糖類、具体的にはグルコース、トレハロースなど。
多糖類又はその誘導体:例えば、コンドロイチン硫酸ナトリウムなど。
セルロース又はその誘導体又はそれらの塩:例えば、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシエチルセルロースまたはこれらの薬理学的に許容される塩など。
前述以外の水溶性高分子:ポリビニルアルコール(完全又は部分ケン化物)、ポリビニルピロリドン、ポリエチレングリコール、デキストランなど。
局所麻酔薬成分:例えば、塩酸オキシブプロカイン、塩酸コカイン、塩酸コルネカイン、塩酸ジブカイン、塩酸テトラカイン、塩酸パラブチルアミノ安息香酸ジエチルアミノエチル、塩酸ピペロカイン、塩酸プロカイン、塩酸プロパラカイン、塩酸ヘキソチオカイン、塩酸リドカインなど。
ステロイド成分:例えば、デキサメタゾン、ヒドロコルチゾン、フルオロメトロン、プレドニゾロン、メチルプレドニゾロン、ヒドロキシメステロン(hydroxymesterone)、カプロン酸ヒドロコルチゾン、カプロン酸プレドニゾロン、酢酸コルチゾン、酢酸ヒドロコルチゾン、酢酸プレドニゾロン、デキサメタゾンメタスルホベンゾエートナトリウム、デキサメタゾン硫酸ナトリウム、デキサメタゾンリン酸ナトリウム、トリアムシノロンアセトニド、ベタメタゾンリン酸ナトリウム、メタスルホ安息香酸デキサメタゾンナトリウム、メチルプレドニゾロンなど。
The mucosa-applied composition of the present invention may contain various components (including pharmacologically active components and physiologically active components) in combination as long as the effects of the present invention are not hindered. The type of such components is not particularly limited, and examples thereof include, for example, a decongestant component, an eye regulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial agents Examples include components, bactericidal components, saccharides, polysaccharides or derivatives thereof, cellulose or derivatives or salts thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, and glaucoma therapeutic agents. Examples of suitable components in the present invention include the following components.
Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.
Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.
Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diclofenac sodium, bromfena Sodium chloride, berberine chloride, berberine sulfate, etc.
Antihistamine component or antiallergic agent component: for example, acitazanolast, amlexanox, ibudilast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium, chlorpheniramine maleate and the like.
Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, etc.
Amino acids: For example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, potassium aspartate, magnesium aspartate, magnesium / aspartate mixture, sodium glutamate, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.
Antibacterial component or bactericidal component: For example, alkylpolyaminoethylglycine, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisomidine sodium, berberine sulfate, berberine chloride, boric acid and the like.
Sugars: for example, monosaccharides, disaccharides, specifically glucose, trehalose and the like.
Polysaccharides or derivatives thereof: for example, sodium chondroitin sulfate.
Cellulose or a derivative thereof or a salt thereof: For example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose or a pharmacologically acceptable salt thereof.
Water-soluble polymers other than those mentioned above: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, polyethylene glycol, dextran, etc.
Local anesthetic components: for example, oxybuprocaine hydrochloride, ***e hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride.
Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.
粘膜適用組成物中のこれらの成分の配合量は製剤の種類、活性成分の種類などに応じて適宜選択され、各種成分の配合量は当該技術分野で既知である。例えば、製剤全体に対して0.0001〜30%、好ましくは、0.001〜10%程度の範囲から選択できる。より具体的には、各成分の含有量は、例えば眼科用組成物について以下の通りである。 The compounding amounts of these components in the mucosa-applied composition are appropriately selected according to the type of preparation, the type of active ingredient, and the like, and the compounding amounts of various components are known in the art. For example, it can be selected from the range of about 0.0001 to 30%, preferably about 0.001 to 10% with respect to the whole preparation. More specifically, the content of each component is, for example, as follows for the ophthalmic composition.
充血除去成分(血管収縮薬又は交感神経興奮薬):例えば、0.0001〜0.5%、好ましくは、0.0005〜0.3%、さらに好ましくは0.001〜0.1%。
眼筋調節薬成分:例えば、0.0001〜0.5%、好ましくは、0.0005〜0.1%、さらに好ましくは0.0005〜0.01%。
抗炎症薬成分または収斂薬成分:例えば、0.0001〜10%、好ましくは0.0001〜5%。
抗ヒスタミン薬成分または抗アレルギー薬成分:例えば、0.0001〜10%、好ましくは0.001〜5%。
ビタミン類:例えば、0.0001〜1%、好ましくは、0.0001〜0.5%。
アミノ酸類:例えば、0.0001〜10%、好ましくは0.001〜3%。
抗菌薬成分または殺菌薬成分:例えば、0.00001〜10%、好ましくは、0.0001〜10%。
糖類:例えば、0.0001〜5%、好ましくは0.001〜5%、さらに好ましくは0.01〜2%。
多糖類又はその誘導体:例えば、0.0001〜2%、好ましくは0.01〜2%、さらに好ましくは0.01〜1%。
セルロース又はその誘導体又はそれらの塩:例えば、0.001〜5%、好ましくは0.01〜1%。
前述以外の水溶性高分子:例えば、0.001〜10%、好ましくは0.001〜5%、さらに好ましくは0.01〜3%。
局所麻酔薬成分:例えば、0.001〜1%、好ましくは0.01〜1%。
ステロイド成分:例えば、0.001〜1%、好ましくは0.01〜1%。
Decongestant component (vasoconstrictor or sympathomimetic drug): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.001 to 0.1%.
Eye muscle modulator component: For example, 0.0001 to 0.5%, preferably 0.0005 to 0.1%, more preferably 0.0005 to 0.01%.
Anti-inflammatory component or astringent component: for example, 0.0001-10%, preferably 0.0001-5%.
Antihistamine component or antiallergic agent component: for example, 0.0001 to 10%, preferably 0.001 to 5%.
Vitamins: For example, 0.0001 to 1%, preferably 0.0001 to 0.5%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.
Antibacterial component or bactericidal component: For example, 0.00001 to 10%, preferably 0.0001 to 10%.
Saccharides: For example, 0.0001 to 5%, preferably 0.001 to 5%, more preferably 0.01 to 2%.
Polysaccharide or derivative thereof: for example, 0.0001 to 2%, preferably 0.01 to 2%, more preferably 0.01 to 1%.
Cellulose or a derivative thereof or a salt thereof: For example, 0.001 to 5%, preferably 0.01 to 1%.
Water-soluble polymers other than those described above: For example, 0.001 to 10%, preferably 0.001 to 5%, more preferably 0.01 to 3%.
Local anesthetic component: For example, 0.001-1%, preferably 0.01-1%.
Steroid component: For example, 0.001 to 1%, preferably 0.01 to 1%.
また、本発明の粘膜適用組成物には、発明の効果を損なわない範囲であれば、その用途や形態に応じて、常法に従い、様々な成分や添加物を適宜選択し、一種またはそれ以上を併用して含有させてもよい。それらの成分または添加物として、例えば、半固形剤や液剤などの調製に一般的に使用される担体(水、水性溶媒、水性または油性基剤など)、増粘剤、糖類、界面活性剤、防腐剤、殺菌剤又は抗菌剤、pH調節剤、等張化剤、香料または清涼化剤、緩衝剤、などの各種添加剤を挙げることができる。 Further, in the composition for applying to mucosa of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired. May be used in combination. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, surfactants, Various additives such as preservatives, bactericides or antibacterial agents, pH regulators, tonicity agents, fragrances or refreshing agents, and buffering agents can be mentioned.
以下に本発明の粘膜適用組成物に使用される代表的な成分を例示するが、これらに限定されない。
増粘剤:例えば、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシエチルセルロースまたはこれらの薬理学的に許容される塩などのセルロース誘導体、カルボキシビニルポリマー、アルギン酸、ポリビニルアルコール(完全、又は部分ケン化物)、ポリビニルピロリドン、マクロゴール、コンドロイチン硫酸ナトリウムなど。
糖類:例えば、グルコース、シクロデキストリンなど。
糖アルコール類:例えば、キシリトール、ソルビトール、マンニトールなど。
これらはd体、l体又はdl体のいずれでもよい。
界面活性剤:例えば、アルキルジアミノエチルグリシンなどのグリシン型両性界面活性剤;アルキル4級アンモニウム塩(具体的には、塩化ベンザルコニウム、塩化ベンゼトニウムなどの陽イオン界面活性剤など。なお、括弧内の数字は付加モル数を示す。
防腐剤、殺菌剤又は抗菌剤:例えば、塩酸アルキルジアミノエチルグリシン、安息香酸ナトリウム、エタノール、塩化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、クロロブタノール、ソルビン酸、ソルビン酸カリウム、デヒドロ酢酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、硫酸オキシキノリン、フェネチルアルコール、ベンジルアルコール、ビグアニド化合物(具体的には、ポリヘキサメチレンビグアニドなど)、グローキル(ローディア社製 商品名)など。
pH調整剤:例えば、塩酸、ホウ酸、アミノエチルスルホン酸、イプシロン−アミノカプロン酸、酢酸、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、ホウ砂、トリエタノールアミン、モノエタノールアミンなど。
等張化剤:例えば、亜硫酸水素ナトリウム、亜硫酸ナトリウム、塩化カリウム、塩化カルシウム、塩化ナトリウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、チオ硫酸ナトリウム、硫酸マグネシウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、グリセリン、プロピレングリコールなど。
香料又は清涼化剤:例えば、カンフル、ゲラニオール、ボルネオール、メントール、リュウノウ、ウイキョウ油、クールミント油、スペアミント油、ハッカ水、ハッカ油、ペパーミント油、ベルガモット油、ユーカリ油、ローズ油など。これらはd体、l体又はdl体のいずれでもよい。
緩衝剤:アミノエチルスルホン酸、イプシロン−アミノカプロン酸、クエン酸緩衝剤、酢酸緩衝剤、炭酸緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤など。具体的には、クエン酸、クエン酸ナトリウム、酢酸、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、ホウ酸、ホウ砂 、リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウムなど。
安定剤:ジブチルヒドロキシトルエン、トロメタモール、ナトリウムホルムアルデヒドスルホキシレート(ロンガリット)、トコフェロール、ピロ亜硫酸ナトリウム、モノエタノールアミン、モノステアリン酸アルミニウムなど。
溶解剤、基剤:オクチルドデカノール、酸化チタン、臭化カリウム、パラフィン、プラスチベース、ラノリン、ワセリンなど。
Although the typical component used for the mucosa application composition of this invention is illustrated below, it is not limited to these.
Thickeners: for example, cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose or pharmacologically acceptable salts thereof, carboxyvinyl polymer, alginic acid , Polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
These may be d-form, l-form or dl-form.
Surfactant: For example, glycine-type amphoteric surfactant such as alkyldiaminoethylglycine; alkyl quaternary ammonium salt (specifically, cationic surfactant such as benzalkonium chloride, benzethonium chloride, etc.) The number indicates the number of moles added.
Preservatives, bactericides or antibacterials: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowyl (product of Rhodia) Name) etc.
pH adjuster: For example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, borax, triethanolamine, monoethanolamine and the like.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
Perfume or refreshing agent: for example, camphor, geraniol, borneol, menthol, leopard, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.
Buffer: aminoethyl sulfonic acid, epsilon-aminocaproic acid, citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer, etc. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate Such.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.
Solubilizer, base: octyldodecanol, titanium oxide, potassium bromide, paraffin, plastibase, lanolin, petrolatum, etc.
増粘剤:例えば、0.0005〜50%、好ましくは、0.001〜10%
糖類:例えば、0.001〜10%、好ましくは、0.01〜5%
界面活性剤:例えば、0.0001〜10%、好ましくは、0.005〜5%
防腐剤、殺菌剤又は抗菌剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%
pH調節剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%
等張化剤:例えば、0.001〜10%、好ましくは、0.01〜5%
香料または清涼化剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%
キレート剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%
緩衝剤:例えば、0.001〜10%、好ましくは、0.01〜5%
Thickener: 0.0005 to 50%, for example, preferably 0.001 to 10%
Saccharides: for example 0.001 to 10%, preferably 0.01 to 5%
Surfactant: For example, 0.0001 to 10%, preferably 0.005 to 5%
Preservative, bactericidal agent or antibacterial agent: for example, 0.00001-5%, preferably 0.0001-2%
pH regulator: for example, 0.00001-5%, preferably 0.0001-2%
Isotonizing agent: for example 0.001 to 10%, preferably 0.01 to 5%
Perfume or refreshing agent: for example, 0.00001-5%, preferably 0.0001-2%
Chelating agent: for example, 0.00001-5%, preferably 0.0001-2%
Buffer: for example 0.001-10%, preferably 0.01-5%
本発明の粘膜適用組成物は、必要に応じて、生体に許容される範囲内の浸透圧に調整して用いる。浸透圧は、100〜1200mOsm、好ましくは100〜600mOsm、特に好ましくは150〜400mOsm程度であり、生理食塩液に対する浸透圧比は、通常、0.3〜4.1、好ましくは0.3〜2.1、特に好ましくは0.5〜1.4程度である。 The mucosa-applied composition of the present invention is used after adjusting to an osmotic pressure within a range acceptable for a living body, if necessary. The osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.4.
本発明の粘膜適用組成物は、必要に応じて、生体に適用可能な範囲内の浸透圧に調整して用いる。pHは、通常、pH4.0〜10.0、好ましくは4.5〜9.5、特に好ましくは5.0〜9.0である。pHの調整は、緩衝剤、前記pH調整剤などを用いて行うことができる。
ここで、緩衝剤としては、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤などが挙げられる。好ましい緩衝剤は、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤及びクエン酸緩衝剤である。特に好ましい緩衝剤は、ホウ酸緩衝剤またはリン酸緩衝剤である。ホウ酸緩衝剤としては、ホウ酸、ホウ酸アルカリ金属塩、ホウ酸アルカリ土類金属塩などのホウ酸塩、ホウ酸とホウ酸塩との組み合わせが挙げられる。リン酸緩衝剤としては、リン酸、リン酸アルカリ金属塩、リン酸アルカリ土類金属塩などのリン酸塩、リン酸とリン酸塩との組み合わせが挙げられる。また、ホウ酸緩衝剤又はリン酸緩衝剤として、ホウ酸塩又はリン酸塩の水和物を用いてもよい。より具体的には、ホウ酸又はその塩 (ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウムなど) 、リン酸又はその塩 (リン酸水素ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウムなど)、炭酸又はその塩(炭酸水素ナトリウム、炭酸ナトリウムなど)、クエン酸又はその塩(クエン酸ナトリウム、クエン酸カリウムなど)が挙げられる。緩衝剤として、ホウ酸緩衝剤又はリン酸緩衝剤を用いる場合、本発明の眼科用組成物中におけるこれらの緩衝剤の濃度は、例えば、0.0001〜10.0%程度である。
The mucosa-applied composition of the present invention is used after adjusting to an osmotic pressure within a range applicable to a living body, if necessary. The pH is usually pH 4.0 to 10.0, preferably 4.5 to 9.5, particularly preferably 5.0 to 9.0. The pH can be adjusted using a buffer, the pH adjuster, or the like.
Here, examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer. Particularly preferred buffering agents are borate buffers or phosphate buffers. Examples of the boric acid buffer include borates such as boric acid, alkali metal borates, and alkaline earth metal borates, and combinations of boric acid and borates. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.). When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the ophthalmic composition of the present invention is, for example, about 0.0001 to 10.0%.
本発明の粘膜適用組成物は、公知の方法により製造できる。半固形剤、液剤は、基剤と各成分とを混合し、調製できる。さらに、必要により、ろ過滅菌処理工程や、容器への充填工程等を加えることができる。 The composition applied to mucosa of the present invention can be produced by a known method. Semi-solid and liquid preparations can be prepared by mixing the base and each component. Furthermore, if necessary, a filtration sterilization treatment process, a container filling process, and the like can be added.
また、本発明は、ヒアルロン酸又はその塩とともにヒマシ油、ゴマ油、オリブ油、ダイズ油、ラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油またはヤシ油から選ばれる少なくとも一種の植物油を組成物中に配合することにより、ヒアルロン酸又はその塩を安定化する方法である。さらに、ヒアルロン酸又はその塩とともにヒマシ油、ゴマ油、オリブ油、ダイズ油、ラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油またはヤシ油から選ばれる少なくとも一種の植物油を組成物中に配合することにより、組成物の粘度低下を防止する方法である。なお、含有する本発明は、ヒアルロン酸又はその塩の種類、非イオン性界面活性剤の種類、特定の植物油、これらの使用量等は、本発明の組成物に関する前述の記載に従って行うことができる。 In addition, the present invention includes hyaluronic acid or a salt thereof together with castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or coconut oil. This is a method of stabilizing hyaluronic acid or a salt thereof by blending at least one selected vegetable oil in the composition. Further, at least one selected from castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or palm oil together with hyaluronic acid or a salt thereof It is a method of preventing the viscosity fall of a composition by mix | blending vegetable oil of this in a composition. In the present invention, the type of hyaluronic acid or a salt thereof, the type of nonionic surfactant, the specific vegetable oil, the amount of these used, etc. can be carried out according to the above description regarding the composition of the present invention. .
以下に、試験例及び実施例に基づいて本発明を詳細に説明するが、本発明はこれらの実施例によって限定されるものではない。
粘度の測定方法
粘度測定方法は円すい一平板形回転粘度計を用いる方法(第十四改正日本薬局法に記載の、一般試験法、45.粘度測定法、第2法回転粘度計法、「(3)円すい−平板形回転粘度計」の項に記載の方法)に従った。具体的には、市販の円すい−平板形回転粘度計と適宜選択されたロータとを用いて測定した。
なお、粘度の測定においては、市販の粘度計、例えば、E型粘度計[トキメック(TOKIMEC)製、東機産業(日本)から販売]、シンクローレクトリックPC型(ブルックフィールド、米)、フェランティシャーリー(フェランティ、英)、ロートビスコR (ハーケ、独)、IGK ハイシャーレオメーター(石田技研、日本)、島津レオメーターR (島津製作所、日本)、ワイセンベルグレオゴニオメーター(サンガモ、英)、メカニカルスペクトロメーター(レオメトリックス、米)等を利用できる。そして、これらの市販の粘度計とローターを適宜選択し、披検試料測定毎にJIS Z8809により規定されている石油系の炭化水素油(ニュートン流体)を校正用標準液として適宜調整することにより、20℃における粘度を測定することができる。
Hereinafter, the present invention will be described in detail based on test examples and examples, but the present invention is not limited to these examples.
Viscosity measurement method Viscosity measurement method is a method using a cone-and-plate rotational viscometer (general test method, 45. Viscosity measurement method, second method rotational viscometer method described in the 14th revised Japanese pharmacy method, "( 3) The method described in the section “Cone-plate rotational viscometer” was followed. Specifically, the measurement was performed using a commercially available cone-plate type rotational viscometer and an appropriately selected rotor.
In measuring the viscosity, commercially available viscometers such as E-type viscometers [manufactured by Tokimec, sold by Toki Sangyo (Japan)], Synchronic PC type (Brookfield, USA), Ferran Tishari (Feranti, UK), Rot Visco R (Haake, Germany), IGK Hischer Rheometer (Ishida Giken, Japan), Shimadzu Rheometer R (Shimadzu Corporation, Japan), Weissenberg Greo Goniometer (Sangamo, UK), Mechanical spectrometers (Rheometrics, US) can be used. Then, by appropriately selecting these commercially available viscometers and rotors, by appropriately adjusting the petroleum-based hydrocarbon oil (Newtonian fluid) defined by JIS Z8809 for each test sample measurement as a calibration standard solution, The viscosity at 20 ° C. can be measured.
具体的には、円すいと平円板との間の角度αの隙間に試料を入れ、円すい又は平円板を一定の角速度ω若しくはトルクTで回転させ、定常状態に達したときの平円板又は円すいが受けるトルク若しくは角速度を測定し、試料の粘度ηを次式により算出することによって粘度を測定した。
η =100×(3α/2πR3)・(T /ω)
η :試料の粘度(mPa ・s)(Pa ・s =103 mPa・s )
α :平円板と円すいがなす角度(rad)
π :円周率
R :円すいの半径(cm)
T :平円板又は円すい面に作用するトルク(10−7N・m)
ω :角速度(rad/s)
Specifically, a sample is put in a gap of an angle α between a cone and a flat disc, and the cone or the flat disc is rotated at a constant angular velocity ω or torque T, and the flat disc when a steady state is reached. Alternatively, the torque or angular velocity received by the cone was measured, and the viscosity was measured by calculating the viscosity η of the sample by the following equation.
η = 100 × (3α / 2πR 3 ) · (T / ω)
η: Viscosity of sample (mPa · s) (Pa · s = 10 3 mPa · s)
α: Angle between the flat disk and the cone (rad)
π: Circumference ratio R: Conical radius (cm)
T: Torque acting on a flat disk or a conical surface (10 −7 N · m)
ω: Angular velocity (rad / s)
本試験における各比較例、各実施例の粘度は、E型粘度計の1種であるTVE−20L形粘度計コーンプレートタイプ(トキメック(TOKIMEC)製、東機産業(日本))を用いて、以下の測定条件の下で測定を行った。
測定条件:
TVE−20L形粘度計コーンプレートタイプに付属の標準コーンロータ(平円板と円すいがなす角度=1°34'、半径(R)=24mm)をフルスケール・トルク6.737×10-7 Nm のスプリングを介してモータで回転させる。測定時、粘度計は回転軸が水平面に対して垂直になるように設置する。
被検試料1mlをコーンロータの所定の平円板に載置し、温度が20.0℃になるまで放置する。次いで、装置を被検試料の粘度に応じた回転数で回転させ、4分後に、表示された粘度を読み取る。高精度の測定結果を得るために、被検試料測定前に、JIS Z 8809 により規定されている石油系の炭化水素油(ニュートン流体)を校正用標準液として用い、測定値が標準液の粘度に一致するように調整する。なお、TVE-20L形粘度計コーンプレートタイプ以外の市販の機種を用い、上記と同様にコーンロータを選択して実施し、適宜校正することにより、同等の結果を得ることもできる。
使用ローター:標準ローター(1°34′、R=24mm)
回転数 :10rpm
試料量 :1ml
測定温度 :20℃
時間 :3分間後の粘度を測定値とした。
The viscosity of each comparative example and each example in this test is a TVE-20L type viscometer cone plate type (manufactured by TOKIMEC, Toki Sangyo (Japan)), which is a type of E-type viscometer. Measurement was performed under the following measurement conditions.
Measurement condition:
Standard cone rotor (angle between flat disc and cone = 1 ° 34 ', radius (R) = 24mm) attached to TVE-20L viscometer cone plate type with full scale torque 6.737 × 10 -7 Nm Rotate with motor through During measurement, the viscometer is installed so that the rotation axis is perpendicular to the horizontal plane.
1 ml of the test sample is placed on a predetermined flat disk of the cone rotor and left until the temperature reaches 20.0 ° C. Next, the apparatus is rotated at a rotation speed corresponding to the viscosity of the test sample, and after 4 minutes, the displayed viscosity is read. In order to obtain highly accurate measurement results, use a petroleum-based hydrocarbon oil (Newtonian fluid) stipulated by JIS Z 8809 as the standard solution for calibration before measuring the test sample, and the measured value is the viscosity of the standard solution. Adjust to match. The same result can be obtained by using a commercially available model other than the TVE-20L viscometer cone plate type, selecting a cone rotor in the same manner as described above, and performing calibration appropriately.
Rotor used: Standard rotor (1 ° 34 ', R = 24mm)
Rotation speed: 10rpm
Sample volume: 1 ml
Measurement temperature: 20 ° C
Time: Viscosity after 3 minutes was taken as a measured value.
試験例1 粘度安定性試験
試験に用いた各実施例及び試験例の調製は、表1に示す処方に従った。具体的には、実施例2の調製方法を示す。0.2gのヒアルロン酸ナトリウム(商品名「バイオヒアルロン酸ナトリウム」資生堂株式会社製、平均分子量110〜160万)を100mlの精製水中にて攪拌溶解した(調整液A)。1.0gのポリソルベート80(商品名「ニッコールTO−10M」 日本サーファクタント製)と、0.1gのゴマ油(商品名「日局ごま油」 かどや製油株式会社製)を攪拌溶解しつつ精製水50mlを加え攪拌溶解した(調整液B)。調整液Bを調整液Aに加え、さらに精製水を加えて全体を200mlとした(pH=7.2)。粘度を測定した後、ガラス瓶に100mlずつ充填した。さらに実施例2に従い、他の実施例及び比較例も調製した。ヒマシ油は、商品名「ヒマシ油」 小堺製薬製、オリブ油は、商品名「オリブ油」小堺製薬製、ダイズ油は、商品名「ダイズ油」小堺製薬製のものである。ラッカセイ油は、商品名「ラッカセイ油」小堺製薬製のものである。
Test Example 1 Viscosity Stability Test Each Example and Test Example used in the test were prepared according to the formulation shown in Table 1. Specifically, the preparation method of Example 2 is shown. 0.2 g of sodium hyaluronate (trade name “sodium biohyaluronate” manufactured by Shiseido Co., Ltd., average molecular weight 1.1 to 1.6 million) was stirred and dissolved in 100 ml of purified water (conditioning solution A). Add 1.0 ml of polysorbate 80 (trade name “Nikkor TO-10M” manufactured by Nippon Surfactant) and 0.1 g of sesame oil (trade name “Nippon Sesame Oil” manufactured by Kadoya Oil Co., Ltd.) to 50 ml of purified water while stirring and dissolving. The mixture was dissolved with stirring (conditioning liquid B). Adjustment liquid B was added to adjustment liquid A, and purified water was further added to make a total of 200 ml (pH = 7.2). After measuring the viscosity, each glass bottle was filled with 100 ml. Further, according to Example 2, other examples and comparative examples were also prepared. Castor oil is a product name “castor oil” manufactured by Kominato Pharmaceutical Co., Ltd. Olive oil is a product name “Olive Oil” manufactured by Kominato Pharmaceutical Co., Ltd., and soybean oil is a product name “Soybean Oil” manufactured by Kominato Pharmaceutical Co., Ltd. Peanut oil is a product name “Peanut oil” manufactured by Kosuge Pharmaceutical.
表1に示す処方で調製した各実施例、各比較例のそれぞれの粘度を測定した。その後、透明ガラス瓶に10mL充填し密栓して、50℃の恒温槽(ナガノ科学機械製作所製 CH20−11M)内にて7日間保管した。7日間保管後に再度粘度を測定した。熱処理前前後における粘度測定値から、粘度残存率(%)=50℃7日間保管後の粘度÷50℃保管前粘度×100を算出した。
結果は、表1に示す。
The viscosity of each Example and each Comparative Example prepared with the formulation shown in Table 1 was measured. Then, 10 mL was filled in a transparent glass bottle, sealed, and stored for 7 days in a thermostatic bath at 50 ° C. (CH20-11M manufactured by Nagano Kagaku Kikai Seisakusho). The viscosity was measured again after storage for 7 days. From the viscosity measured values before and after the heat treatment, the residual viscosity ratio (%) = viscosity after storage at 50 ° C. for 7 days ÷ viscosity before storage at 50 ° C. × 100 was calculated.
The results are shown in Table 1.
試験の結果、ヒアルロン酸又はその塩の粘度低下は、ゴマ油を含有することによって抑制できることが確認された。さらに、ヒアルロン酸又はその塩の粘度低下はポリソルベート80等の非イオン性界面活性剤の存在下で促進されるが、ゴマ油を含有することによって粘度低下を防止できることが確認された。また、ゴマ油同様に、ヒマシ油、ダイズ油、ラッカセイ油、オリブ油も、ヒアルロン酸又はその塩の粘度低下を抑制することができることが示された。 As a result of the test, it was confirmed that the decrease in the viscosity of hyaluronic acid or a salt thereof can be suppressed by containing sesame oil. Furthermore, although the viscosity reduction of hyaluronic acid or a salt thereof is promoted in the presence of a nonionic surfactant such as polysorbate 80, it has been confirmed that the viscosity reduction can be prevented by containing sesame oil. Moreover, it was shown that castor oil, soybean oil, peanut oil, and olive oil, like sesame oil, can suppress a decrease in the viscosity of hyaluronic acid or a salt thereof.
下記表2〜表5に示す処方(表中の単位 g/100ml)の配合成分を精製水に溶解させ全量を100mlとし、滅菌濾過して容器に充填して、点眼剤(または点眼薬)、洗眼剤(または洗眼薬)を調製した。実施例6〜実施例25において、組成物の粘度低下が抑制されていた。なお、各実施例において用いたヒアルロン酸ナトリウムは、実施例6〜10(点眼剤)は平均分子量60〜120万(商品名「ヒアルロンサンHA−QA」キューピー株式会社製)、実施例11〜15(点眼剤)は平均分子量110〜160万(商品名「バイオヒアルロン酸ナトリウム」資生堂株式会社製)、実施例16〜20(点眼剤)は平均分子量160〜220万、実施例21〜25(点眼剤または洗眼剤)は平均分子量50〜100万である。 The formulation components shown in Tables 2 to 5 below (units in the table, g / 100 ml) are dissolved in purified water to make a total amount of 100 ml, sterilized, filtered, and filled into a container, eye drops (or eye drops), An eye wash (or eye wash) was prepared. In Example 6 to Example 25, the viscosity reduction of the composition was suppressed. In addition, sodium hyaluronate used in each of Examples 6 to 10 (eye drops) has an average molecular weight of 60 to 1,200,000 (trade name “Hyaluron Sun HA-QA” manufactured by Kewpie Co., Ltd.), Examples 11 to 15 ( Eye drops) have an average molecular weight of 1.1 to 1.6 million (trade name “Sodium Biohyaluronate” manufactured by Shiseido Co., Ltd.), Examples 16 to 20 (eye drops) have an average molecular weight of 1.6 to 2.2 million, and Examples 21 to 25 (eye drops) Or eye wash) has an average molecular weight of 500 to 1,000,000.
使用感試験
試験に用いた試験用点眼剤の調製は表6に示す処方(表中の各成分の単位は、g/100mL)に従った。具体的には試験用点眼剤2の調製方法を示す。ヒアルロン酸ナトリウム(分子量110万〜160、商品名「バイオヒアルロン酸ナトリウム」資生堂株式会社製)、エデト酸ナトリウム(日本薬局方)、ポリソルベート80、ホウ酸、ホウ砂、0.47gのゴマ油(商品名「日局ごま油」 かどや製油株式会社製)及びホウ酸を50mlの精製水中にて攪拌溶解して、攪拌溶解させ、ホウ砂を攪拌溶解しながら添加後、精製水及び塩酸/水酸化ナトリウムを適量加えてpH=7.5に調整して全体を100mlとした。試験用点眼剤3は、ゴマ油の代わりに、ヒマシ油(商品名「ヒマシ油」 小堺製薬製)を用いて調整した。
The preparation of the eye drop for test used in the usability test was in accordance with the formulation shown in Table 6 (the unit of each component in the table was g / 100 mL). Specifically, the preparation method of the test eye drop 2 is shown. Sodium hyaluronate (molecular weight 1.1 million to 160, trade name “Bio Sodium Hyaluronate” manufactured by Shiseido Co., Ltd.), sodium edetate (Japan Pharmacopoeia), polysorbate 80, boric acid, borax, 0.47 g sesame oil (trade name) “Japan sesame oil” (made by Kadoya Oil Refinery Co., Ltd.) and boric acid are stirred and dissolved in 50 ml of purified water, stirred and dissolved, and borax is added while stirring and dissolved, and then appropriate amounts of purified water and hydrochloric acid / sodium hydroxide are added. In addition, the whole was adjusted to pH = 7.5 to 100 ml. Test eye drop 3 was prepared by using castor oil (trade name “castor oil” manufactured by Kominato Pharmaceutical Co., Ltd.) instead of sesame oil.
調整した試験用点眼剤を点眼容器に濾過充填して試験用点眼剤を製し、各試験用点眼剤を、ヒアルロン酸ナトリウム含有点眼剤の適用で痒みを生じる10名の専用モニター(裸眼5名、コンタクトレンズ装用者5名)に点眼してもらい、使用感を評価した。比較用点眼剤を両眼に1滴点眼した30分後に、試験用点眼剤1、2及び3を両眼に点眼して、先に点眼した比較用点眼剤と試験用点眼剤との使用感を比較して、以下の評価基準により使用感を評価した。表7には、コンタクトレンズを装用していない裸眼のモニター及びコンタクトレンズ装用モニターの評価点の平均値を表に示す。 The prepared test eye drops are filtered and filled into eye drops containers to produce test eye drops, and each test eye drop is treated with 10 dedicated monitors (5 naked eyes) that cause itchiness when sodium hyaluronate-containing eye drops are applied. And 5 contact lens wearers) to evaluate the usability. 30 minutes after instilling one drop of the comparative eye drop into both eyes, the test eye drops 1, 2 and 3 are instilled into both eyes, and the feeling of use of the comparative eye drop and the test eye drop previously applied. The usability was evaluated according to the following evaluation criteria. Table 7 shows the average value of the evaluation points of the naked eye monitor not wearing the contact lens and the contact lens wearing monitor.
評価基準
使用感(点眼時のかゆみの程度)
試験用点眼剤は、かゆみを感じない 5点
試験用点眼剤の方が、かゆみが弱い 4点
比較用点眼剤の痒みと試験用点眼剤の痒みが同程度である 3点
試験用点眼剤の方が、かゆみが強い 2点
試験用点眼剤の方が、非常にかゆい 1点
Evaluation criteria feeling of use (degree of itchiness when instilled)
Test eyedrops do not feel itching 5-point test eyedrops are less itchy 4-point comparison eyedrops have the same degree of itchiness as test eyedrops. 3-point test eyedrops Itching is more itchy. Eyedrops for 2-point test are much more itchy 1 point
試験の結果、ヒアルロン酸ナトリウムを含有する点眼剤を眼粘膜適用時に生じる痒みに対して、非イオン性界面活性剤を含有しても痒みは抑制されないが、ゴマ油やヒマシ油といった植物油を含有する点眼剤において点眼時の痒みが軽減し抑制されるすることがわかった。 As a result of the test, it is not suppressed even if a nonionic surfactant is added to the itch produced when the ophthalmic solution containing sodium hyaluronate is applied to the ocular mucosa, but the ophthalmic solution containing vegetable oil such as sesame oil or castor oil is not suppressed. It was found that itching was reduced and suppressed in the preparation.
Claims (10)
b)非イオン性界面活性剤、および
c)ヒマシ油、ゴマ油、オリブ油、ダイズ油、ラッカセイ油、アルモンド油、小麦胚芽油、ツバキ油、トウモロコシ油、ナタネ油、ヒマワリ油、綿実油またはヤシ油から選ばれる少なくとも1種の植物油を含有する粘膜適用組成物。 a) hyaluronic acid or a salt thereof;
b) nonionic surfactants and c) from castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or coconut oil A mucosa-applied composition containing at least one selected vegetable oil.
Hyaluronic acid or a salt thereof and at least one selected from castor oil, sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or coconut oil The method of stabilizing the viscosity of a composition by mix | blending together vegetable oil in a composition.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005280056A JP4999304B2 (en) | 2004-09-27 | 2005-09-27 | Mucosal composition containing hyaluronic acid or a salt thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004278894 | 2004-09-27 | ||
JP2004278894 | 2004-09-27 | ||
JP2005280056A JP4999304B2 (en) | 2004-09-27 | 2005-09-27 | Mucosal composition containing hyaluronic acid or a salt thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2006117656A true JP2006117656A (en) | 2006-05-11 |
JP4999304B2 JP4999304B2 (en) | 2012-08-15 |
Family
ID=36535882
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2005280056A Active JP4999304B2 (en) | 2004-09-27 | 2005-09-27 | Mucosal composition containing hyaluronic acid or a salt thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP4999304B2 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011001951A1 (en) * | 2009-06-30 | 2011-01-06 | ライオン株式会社 | Ophthalmic composition |
JP2012149102A (en) * | 2004-11-09 | 2012-08-09 | Novagali Pharma Sa | Ophthalmic oil-in-water type emulsion with stable positive zeta potential |
JP2013010756A (en) * | 2011-06-01 | 2013-01-17 | Rohto Pharmaceutical Co Ltd | Ophthalmic aqueous composition |
WO2013008715A1 (en) | 2011-07-08 | 2013-01-17 | ロート製薬株式会社 | Aqueous ophthalmic composition |
WO2013047568A1 (en) * | 2011-09-27 | 2013-04-04 | 参天製薬株式会社 | Inhibitor for corneal epithelial cell death, inhibitor characterized by combining hyaluronic acid and flavin adenine dinucleotide |
WO2013047567A1 (en) * | 2011-09-27 | 2013-04-04 | 参天製薬株式会社 | Corneal epithelial cell death inhibitor containing flavin adenine dinucleotide or salt thereof as active ingredient |
JP2014009162A (en) * | 2012-06-27 | 2014-01-20 | Rohto Pharmaceut Co Ltd | Aqueous composition for ophthalmology |
JP2014028789A (en) * | 2012-06-27 | 2014-02-13 | Rohto Pharmaceut Co Ltd | Aqueous ophthalmic composition |
WO2014110454A1 (en) * | 2013-01-11 | 2014-07-17 | Carbylan Biosurgery, Inc. | Stabilized compositions comprising hyaluronic acid |
JP2014136684A (en) * | 2013-01-16 | 2014-07-28 | Toray Ind Inc | Liquid agent |
US9427473B2 (en) | 2012-12-04 | 2016-08-30 | Rohto Pharmaceutical Co., Ltd. | Aqueous ophthalmic composition |
JP2019182825A (en) * | 2018-03-30 | 2019-10-24 | ロート製薬株式会社 | Ophthalmic composition |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61180705A (en) * | 1985-02-06 | 1986-08-13 | Shiseido Co Ltd | Cosmetic |
JPH07316038A (en) * | 1994-05-23 | 1995-12-05 | Ikeda Mohandou:Kk | Medicine composition for mucosal administration |
JP2001302518A (en) * | 2000-02-15 | 2001-10-31 | Rohto Pharmaceut Co Ltd | Method for improving action and agent for improving action |
US20040185068A1 (en) * | 2003-03-18 | 2004-09-23 | Zhi-Jian Yu | Self-emulsifying compositions, methods of use and preparation |
-
2005
- 2005-09-27 JP JP2005280056A patent/JP4999304B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61180705A (en) * | 1985-02-06 | 1986-08-13 | Shiseido Co Ltd | Cosmetic |
JPH07316038A (en) * | 1994-05-23 | 1995-12-05 | Ikeda Mohandou:Kk | Medicine composition for mucosal administration |
JP2001302518A (en) * | 2000-02-15 | 2001-10-31 | Rohto Pharmaceut Co Ltd | Method for improving action and agent for improving action |
US20040185068A1 (en) * | 2003-03-18 | 2004-09-23 | Zhi-Jian Yu | Self-emulsifying compositions, methods of use and preparation |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012149102A (en) * | 2004-11-09 | 2012-08-09 | Novagali Pharma Sa | Ophthalmic oil-in-water type emulsion with stable positive zeta potential |
JP2014088450A (en) * | 2004-11-09 | 2014-05-15 | Santen Sas | Ophthalmic oil-in-water type emulsion with stable positive zeta potential |
JP5673531B2 (en) * | 2009-06-30 | 2015-02-18 | ライオン株式会社 | Ophthalmic composition |
KR20120069656A (en) * | 2009-06-30 | 2012-06-28 | 라이온 가부시키가이샤 | Ophthalmic composition |
US9119827B2 (en) | 2009-06-30 | 2015-09-01 | Lion Corporation | Ophthalmic composition |
TWI463978B (en) * | 2009-06-30 | 2014-12-11 | Lion Corp | Ophthalmic composition |
KR101690817B1 (en) * | 2009-06-30 | 2016-12-28 | 라이온 가부시키가이샤 | Ophthalmic composition |
WO2011001951A1 (en) * | 2009-06-30 | 2011-01-06 | ライオン株式会社 | Ophthalmic composition |
JP2013010756A (en) * | 2011-06-01 | 2013-01-17 | Rohto Pharmaceutical Co Ltd | Ophthalmic aqueous composition |
WO2013008715A1 (en) | 2011-07-08 | 2013-01-17 | ロート製薬株式会社 | Aqueous ophthalmic composition |
CN103826643A (en) * | 2011-09-27 | 2014-05-28 | 参天制药株式会社 | Inhibitor for corneal epithelial cell death, inhibitor characterized by combining hyaluronic acid and flavin adenine dinucleotide |
JP2013082697A (en) * | 2011-09-27 | 2013-05-09 | Santen Pharmaceut Co Ltd | Inhibitor for corneal epithelial cell death, inhibitor characterized by combining hyaluronic acid and flavin adenine dinucleotide |
WO2013047567A1 (en) * | 2011-09-27 | 2013-04-04 | 参天製薬株式会社 | Corneal epithelial cell death inhibitor containing flavin adenine dinucleotide or salt thereof as active ingredient |
WO2013047568A1 (en) * | 2011-09-27 | 2013-04-04 | 参天製薬株式会社 | Inhibitor for corneal epithelial cell death, inhibitor characterized by combining hyaluronic acid and flavin adenine dinucleotide |
CN103826643B (en) * | 2011-09-27 | 2016-01-20 | 参天制药株式会社 | Be characterised in that it is the inhibitor of corneal epithelial cell death hyaluronic acid and flavin adenine dinucleotide (FAD) combined |
JP2014028789A (en) * | 2012-06-27 | 2014-02-13 | Rohto Pharmaceut Co Ltd | Aqueous ophthalmic composition |
JP2014009162A (en) * | 2012-06-27 | 2014-01-20 | Rohto Pharmaceut Co Ltd | Aqueous composition for ophthalmology |
US9050369B2 (en) | 2012-06-27 | 2015-06-09 | Rohto Pharmaceutical Co., Ltd. | Aqueous ophthalmic composition |
JP2016188259A (en) * | 2012-06-27 | 2016-11-04 | ロート製薬株式会社 | Aqueous ophthalmic composition |
US9345779B2 (en) | 2012-06-27 | 2016-05-24 | Rohto Pharmaceutical Co., Ltd. | Aqueous ophthalmic composition |
US9427473B2 (en) | 2012-12-04 | 2016-08-30 | Rohto Pharmaceutical Co., Ltd. | Aqueous ophthalmic composition |
WO2014110454A1 (en) * | 2013-01-11 | 2014-07-17 | Carbylan Biosurgery, Inc. | Stabilized compositions comprising hyaluronic acid |
CN105026480A (en) * | 2013-01-11 | 2015-11-04 | 卡比兰治疗公司 | Stabilized compositions comprising hyaluronic acid |
JP2014136684A (en) * | 2013-01-16 | 2014-07-28 | Toray Ind Inc | Liquid agent |
JP2019182825A (en) * | 2018-03-30 | 2019-10-24 | ロート製薬株式会社 | Ophthalmic composition |
JP7104553B2 (en) | 2018-03-30 | 2022-07-21 | ロート製薬株式会社 | Ophthalmic composition |
Also Published As
Publication number | Publication date |
---|---|
JP4999304B2 (en) | 2012-08-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4999304B2 (en) | Mucosal composition containing hyaluronic acid or a salt thereof | |
JP2017206547A (en) | Ophthalmic composition | |
JP5649261B2 (en) | High viscosity eye drops | |
JP2020172532A (en) | Ophthalmologic or otolaryngologic aqueous composition | |
JP5382972B2 (en) | Composition with reduced viscosity prevention | |
JPWO2015152155A1 (en) | Ophthalmic or otolaryngeal aqueous composition | |
JP5513702B2 (en) | Antibacterial eye drops | |
JP5116211B2 (en) | Mucosal composition | |
JP5314349B2 (en) | Ophthalmic composition | |
JP3974431B2 (en) | Alginic acid-containing composition | |
JP5318850B2 (en) | Composition with reduced viscosity prevention | |
JP2006225323A (en) | Aqueous external composition | |
JP5382973B2 (en) | Composition with reduced viscosity prevention | |
JP5853084B2 (en) | Composition with reduced viscosity prevention | |
JP2006348055A (en) | Alginic acid-containing composition | |
EP3675872B1 (en) | Compositions providing improved eye comfort | |
JP5764532B2 (en) | Mucosal composition | |
JP2006143590A (en) | Composition for mucosal application | |
JP2007277233A (en) | Ophthalmic composition | |
JP4847703B2 (en) | Aqueous external composition | |
RU2806029C2 (en) | Compositions providing increased comfort for the eyes | |
JP2006104114A (en) | Mucous membrane application composition | |
JP5847211B2 (en) | Mucosal composition | |
JP2006193475A (en) | Aqueous external composition | |
JP2023067803A (en) | Ophthalmologic composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20080717 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20110927 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20111118 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20111118 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120214 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120424 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20120515 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 4999304 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150525 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150525 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |