JP5922505B2 - Glycyrrhizic acid-containing aqueous ophthalmic composition - Google Patents
Glycyrrhizic acid-containing aqueous ophthalmic composition Download PDFInfo
- Publication number
- JP5922505B2 JP5922505B2 JP2012134601A JP2012134601A JP5922505B2 JP 5922505 B2 JP5922505 B2 JP 5922505B2 JP 2012134601 A JP2012134601 A JP 2012134601A JP 2012134601 A JP2012134601 A JP 2012134601A JP 5922505 B2 JP5922505 B2 JP 5922505B2
- Authority
- JP
- Japan
- Prior art keywords
- ophthalmic composition
- aqueous ophthalmic
- castor oil
- present
- component
- 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.)
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- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 title claims description 47
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 title claims description 47
- 239000001685 glycyrrhizic acid Substances 0.000 title claims description 47
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- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 title claims description 47
- 235000019410 glycyrrhizin Nutrition 0.000 title claims description 47
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title claims description 47
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 150000001340 alkali metals Chemical class 0.000 description 3
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- 229910052749 magnesium Inorganic materials 0.000 description 1
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- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
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- 229960005016 naphazoline Drugs 0.000 description 1
- 229960004760 naphazoline hydrochloride 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
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000006353 oxyethylene group Chemical group 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
- 229960004811 pemirolast potassium Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 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
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000001782 photodegradation Methods 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920001230 polyarylate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000011112 polyethylene naphthalate Substances 0.000 description 1
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- 229920001721 polyimide Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate 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
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 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
- 230000002335 preservative effect Effects 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 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
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 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
- 238000011160 research 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
- 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
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 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
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 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
- WTWSHHITWMVLBX-DKWTVANSSA-M sodium;(2s)-2-aminobutanedioate;hydron Chemical compound [Na+].[O-]C(=O)[C@@H](N)CC(O)=O WTWSHHITWMVLBX-DKWTVANSSA-M 0.000 description 1
- 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 1
- LARLNXOUTTUXPN-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(5-methyl-1,2-oxazol-3-yl)azanide Chemical compound [Na+].O1C(C)=CC([N-]S(=O)(=O)C=2C=CC(N)=CC=2)=N1 LARLNXOUTTUXPN-UHFFFAOYSA-N 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
- 230000003381 solubilizing effect Effects 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
- 229960002920 sorbitol Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- 229940021790 tetrahydrozoline 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
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- WYXIGTJNYDDFFH-UHFFFAOYSA-Q triazanium;borate Chemical compound [NH4+].[NH4+].[NH4+].[O-]B([O-])[O-] WYXIGTJNYDDFFH-UHFFFAOYSA-Q 0.000 description 1
- 229940074777 tripotassium glycyrrhizinate Drugs 0.000 description 1
- ZXHXYXSTAYNRLQ-DWJAGBRCSA-K tripotassium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxylato-4,5-dihydroxyoxan-3-yl]oxy-3,4, Chemical compound [K+].[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 ZXHXYXSTAYNRLQ-DWJAGBRCSA-K 0.000 description 1
- IYKMDRMCUIFHRA-UHFFFAOYSA-H tripotassium;trisodium;2-hydroxypropane-1,2,3-tricarboxylate;hydrate Chemical compound O.[Na+].[Na+].[Na+].[K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O IYKMDRMCUIFHRA-UHFFFAOYSA-H 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
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- CCXAYLQLOLXXKE-DWJAGBRCSA-K trisodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxylato-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-t Chemical compound [Na+].[Na+].[Na+].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 CCXAYLQLOLXXKE-DWJAGBRCSA-K 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 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
- 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
- 239000004711 α-olefin Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は水性眼科組成物に関する。更に詳しくは、本発明は、熱及び光に対する安定性が改善され、消泡時間が短縮された水性眼科組成物に関する。 The present invention relates to an aqueous ophthalmic composition. More particularly, the present invention relates to an aqueous ophthalmic composition having improved heat and light stability and reduced defoaming time.
グリチルリチン酸及びその塩は、抗炎症作用を有する成分であり、さらには抗アレルギー作用も有し、安全性も高いことから、従来から眼科組成物において使用されている（特許文献１）。グリチルリチン酸及び／又はその塩を含有する眼科組成物としては、眼科用薬製造（輸入）承認基準にも収載されている成分であり、抗ヒスタミン成分であるマレイン酸クロルフェニラミン、持続性抗菌剤であるスルファメトキサゾールナトリウム、角膜保護成分であるコンドロイチン硫酸ナトリウム等を含む配合点眼剤等が市販されている。 Glycyrrhizic acid and a salt thereof are components having an anti-inflammatory action, and further have an anti-allergic action and high safety, and thus have been conventionally used in ophthalmic compositions (Patent Document 1). As an ophthalmic composition containing glycyrrhizic acid and / or a salt thereof, chlorpheniramine maleate, which is an antihistamine component, and a long-lasting antibacterial agent are listed in the ophthalmic drug manufacturing (import) approval standards A combination ophthalmic solution containing sulfamethoxazole sodium as a corneal protective component and sodium chondroitin sulfate as a corneal protective component is commercially available.
また、眼科分野において、溶解補助剤は、多くの処方に配合されている。特に水性眼科組成物においては、水溶性の比較的低い生理活性成分、添加物等の溶解補助を目的に、様々な溶解補助剤の配合が工夫されている。眼科分野において用いられる溶解補助剤の一つとして、界面活性剤が挙げられる。ポリオキシエチレンヒマシ油は非イオン界面活性剤の一種であり、他の配合成分の溶解補助等を目的として、水性眼科組成物に配合されることが知られている（特許文献２）。 In the ophthalmology field, solubilizing agents are blended in many formulations. In particular, in an aqueous ophthalmic composition, various solubilizing agents have been devised for the purpose of assisting dissolution of physiologically active components and additives having relatively low water solubility. One of the solubilizing agents used in the ophthalmic field is a surfactant. Polyoxyethylene castor oil is a kind of nonionic surfactant and is known to be blended into an aqueous ophthalmic composition for the purpose of assisting dissolution of other blended components (Patent Document 2).
界面活性剤を配合した水性製剤は泡立ちやすいことが知られており、製造時又は流通時において、振動又は衝撃を与えることにより泡が発生する。一般に、水性眼科組成物は、眼に対して安全に適用するために、製造時の溶解確認が重視される。また、水性眼科組成物の中でも点眼剤、洗眼剤などの医薬品においては、製造工程での異物検査が必須である。しかしながら、製造中の水性眼科組成物において泡が発生し、泡の消える速度が遅い場合、配合成分又は異物と泡との見分けがつき難いために、溶解確認、異物検査の工程などで長時間を要し、製造が効率的に行えないのが現状である。 It is known that an aqueous preparation containing a surfactant easily foams, and foam is generated by applying vibration or impact during production or distribution. In general, in order to apply an aqueous ophthalmic composition to the eye safely, emphasis is placed on confirmation of dissolution during production. In addition, foreign substances in the manufacturing process are indispensable for pharmaceuticals such as eye drops and eye wash agents among aqueous ophthalmic compositions. However, when bubbles are generated in the aqueous ophthalmic composition being manufactured and the rate at which the bubbles disappear is slow, it is difficult to distinguish between the blended components or the foreign material and the foam. In other words, the current situation is that manufacturing cannot be performed efficiently.
また、水性眼科組成物では、製造工程、市場流通工程での安定性、開封後の長期安定性を担保することが重要である。このため、加熱した状態で保存する場合や、光に晒された場合に生じる含有成分の分解が、品質へ及ぼす影響は無視できない。従って、熱分解や光分解を防いで溶液を長期間安定に保存する方法が望まれている。 In the case of an aqueous ophthalmic composition, it is important to ensure stability in the manufacturing process and market distribution process and long-term stability after opening. For this reason, the influence which the decomposition | disassembly of the contained component produced when it preserve | saves in the heated state, or when it exposes to light cannot ignore a quality. Therefore, a method for stably storing a solution for a long period of time while preventing thermal decomposition and photolysis is desired.
しかしながら、水性眼科組成物に、グリチルリチン酸又はその塩と特定の界面活性剤とを配合した場合に、安定性や消泡時間に及ぼす影響についてはこれまで明らかにされておらず、該水性眼科組成物に対して如何なる影響が及ぼされるかについては容易には推認できないのが現状である。 However, when glycyrrhizic acid or a salt thereof and a specific surfactant are added to an aqueous ophthalmic composition, the effects on stability and antifoaming time have not been clarified so far, and the aqueous ophthalmic composition The current situation is that it is not easy to guess what kind of effect will be given to things.
本発明者等は、グリチルリチン酸又はその塩を含有する水性眼科組成物に関して、種々の検討を行ってきた。その結果、グリチルリチン酸又はその塩を含有する水性眼科組成物を加熱した状態で保存する場合や光に晒した場合に、グリチルリチン酸又はその塩が分解することがあることが確認された。 The present inventors have conducted various studies on an aqueous ophthalmic composition containing glycyrrhizic acid or a salt thereof. As a result, it was confirmed that glycyrrhizic acid or a salt thereof may be decomposed when the aqueous ophthalmic composition containing glycyrrhizic acid or a salt thereof is stored in a heated state or exposed to light.
水性眼科組成物における含有成分の熱分解や光分解は、安全性を含む品質の低下や商品価値の低下を招来し、更に、含有成分が本来有する性能を発揮することを妨げることから、これらの現象を抑制することは極めて重要な課題である。 Thermal decomposition and photolysis of the components in the aqueous ophthalmic composition lead to deterioration of quality including safety and reduction of commercial value, and further prevent the performance of the inherent components from being contained. Suppressing the phenomenon is a very important issue.
従って、本発明の主な目的は、グリチルリチン酸及び／又はその塩を含有する水性眼科組成物であって、熱安定性及び光安定性が改善された水性眼科組成物を提供すること、及び該水性眼科組成物の熱安定性及び光安定性を向上させる方法を提供することである。 Accordingly, a main object of the present invention is to provide an aqueous ophthalmic composition containing glycyrrhizic acid and / or a salt thereof, which has improved thermal stability and light stability, and It is to provide a method for improving the thermal stability and light stability of an aqueous ophthalmic composition.
また、上記したような水性眼科組成物における溶解確認、異物検査の工程の重要性により、溶解補助剤が配合された泡立ちし易い水性眼科組成物において、消泡時間を短縮させることは重要な課題である。 In addition, due to the importance of the dissolution confirmation and foreign substance inspection process in the aqueous ophthalmic composition as described above, it is an important problem to shorten the defoaming time in the aqueous ophthalmic composition that is easily foamed with the dissolution aid. It is.
従って、本発明のその他の目的は、溶解補助剤が配合された水性眼科組成物であって、振動又は衝撃により泡が発生した場合において消泡時間が短縮された水性眼科組成物を提供すること、及び該水性眼科組成物における消泡時間を短縮する方法を提供することである。 Accordingly, another object of the present invention is to provide an aqueous ophthalmic composition containing a solubilizing agent, wherein the defoaming time is shortened when bubbles are generated by vibration or impact. And a method of reducing the defoaming time in the aqueous ophthalmic composition.
本発明者等は、上記の課題を解決すべく鋭意研究を重ねてきた。その結果、グリチルリチン酸及びその塩からなる群から選択される少なくとも一種の成分（以下、「(A)成分」ということがある）を含有する水性眼科組成物に、酸化エチレンの平均付加モル数が２〜３０のポリオキシエチレンヒマシ油（以下、「(B)成分」ということがある）を配合することにより、該水性眼科組成物における(A)成分の熱分解及び光分解を抑制できることを見出した。 The inventors of the present invention have made extensive studies to solve the above problems. As a result, an aqueous ophthalmic composition containing at least one component selected from the group consisting of glycyrrhizic acid and a salt thereof (hereinafter sometimes referred to as “component (A)”) has an average added mole number of ethylene oxide. It has been found that by adding 2 to 30 polyoxyethylene castor oil (hereinafter sometimes referred to as “component (B)”), thermal decomposition and photolysis of component (A) in the aqueous ophthalmic composition can be suppressed. It was.
更に、本発明者等は、非イオン性界面活性剤として(B)成分を含有する水性眼科組成物に、(A)成分を配合することによって、振動又は衝撃により泡が発生した場合に、該水性眼科組成物における消泡時間を顕著に短縮でき、溶解確認、異物確認等を短時間で行うことが可能となることを見出した。また、泡が発生した状態の点眼剤等の水性眼科組成物は、使用時に１回ごとの滴下量のバラツキが大きくなり、特に１回の使用量が比較的少ない点眼剤、コンタクトレンズ装着液において、１回毎の使用量を使用者自身がコントロールし難く、扱いづらいなどの不都合が生じ、特に水性眼科組成物が医薬品の場合などはコンプライアンスの低下等に繋がる可能性もある。本発明によれば、消泡時間が短縮される結果、該水性眼科組成物における滴下量のバラツキをも抑制することができる。 Furthermore, the present inventors have added the component (A) to the aqueous ophthalmic composition containing the component (B) as a nonionic surfactant, and when foam is generated by vibration or impact, It has been found that the defoaming time in the aqueous ophthalmic composition can be remarkably shortened, and dissolution confirmation, foreign matter confirmation, etc. can be performed in a short time. In addition, aqueous ophthalmic compositions such as eye drops in the state where bubbles are generated have a large variation in the amount of dripping each time when used, especially in eye drops and contact lens mounting liquids where the amount used per time is relatively small. It is difficult for the user himself to control the amount of each use, and inconveniences such as difficulty in handling occur. In particular, when the aqueous ophthalmic composition is a pharmaceutical, there is a possibility that it may lead to a decrease in compliance. According to the present invention, as a result of shortening the defoaming time, variations in the amount of dripping in the aqueous ophthalmic composition can be suppressed.
本発明は、これらの知見に基づいて更に研究を重ねた結果完成されたものである。 The present invention has been completed as a result of further research based on these findings.
即ち、本発明は、下記に掲げる態様の水性眼科組成物を提供するものである。
項1-1．(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と、(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を含む水性眼科組成物。
項1-2. (B)成分が、酸化エチレンの平均付加モル数が２〜１２であるポリオキシエチレンヒマシ油である、項1-1に記載の水性眼科組成物。
項1-3．水性眼科組成物の総量を基準として、(A) 成分の総含有量が０．０００５〜２w/v％である、項1-1又は1-2に記載の水性眼科組成物。
項1-4．水性眼科組成物の総量を基準として、(B)成分の総含有量が０．０００５〜５w/v％である、項1-1乃至1-3のいずれかに記載の水性眼科組成物。
項1-5．(A)成分の総含有量１重量部に対して、(B)成分の総含有量が０．０００２〜１００００重量部である、項1-1乃至1-4のいずれかに記載の水性眼科組成物。
項1-6．(A)成分の総含有量１重量部に対して、(B)成分の総含有量が０．０５〜５０重量部である、項1-1乃至1-5のいずれかに記載の水性眼科組成物。
項1-7．更に緩衝剤を含有する、項1-1乃至1-6のいずれかに記載の水性眼科組成物。
項1-8．緩衝剤がホウ酸緩衝剤である、項1-7に記載の水性眼科組成物。
項1-9．水性眼科組成物の総量を基準として、緩衝剤の総含有量が０．０１〜１０w/v％である、項1-7又は1-8に記載の水性眼科組成物。
項1-10． 更に(B)成分以外の非イオン性界面活性剤を含有する、項1-1乃至1-9のいずれかに記載の水性眼科組成物。
項1-11．(B)成分以外の非イオン性界面活性剤が、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、酸化エチレンの平均付加モル数が３０を上回るポリオキシエチレンヒマシ油、及び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からなる群より選択される少なくとも１種である、項1-10に記載の水性眼科組成物。
項1-12．水性眼科組成物の総量を基準として、(B)成分以外の非イオン性界面活性剤の総含有量が０．００１〜３w/v％である、項1-10又は1-11に記載の水性眼科組成物。
項1-13．ポリエチレンテレフタレート製容器に充填されてなる、項1-1乃至1-12のいずれかに記載の水性眼科組成物。
項1-14．ポリエチレン製ノズルが装着された容器に充填されてなる、項1-1乃至1-13のいずれかに記載の水性眼科組成物。
項1-15．点眼剤である項1-1乃至1-14のいずれかに記載の水性眼科組成物。
項1-16．洗眼剤である項1-1乃至1-14のいずれかに記載の水性眼科組成物。
項1-17．コンタクトレンズ装着液である項1-1乃至1-14のいずれかに記載の水性眼科組成物。
項1-18．コンタクトレンズケア用剤である項1-1乃至1-14のいずれかに記載の水性眼科組成物。
That is, this invention provides the aqueous ophthalmic composition of the aspect hung up below.
Item 1-1. An aqueous ophthalmic composition comprising (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 mol.
Item 1-2. The aqueous ophthalmic composition according to Item 1-1, wherein the component (B) is polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 12.
Item 1-3. The aqueous ophthalmic composition according to Item 1-1 or 1-2, wherein the total content of the component (A) is 0.0005 to 2 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-4. Item 4. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-3, wherein the total content of the component (B) is 0.0005 to 5 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-5. Item 5. The aqueous ophthalmologic according to any one of Items 1-1 to 1-4, wherein the total content of component (B) is 0.0002 to 10,000 parts by weight with respect to 1 part by weight of the total content of component (A) Composition.
Item 1-6. The aqueous ophthalmologist according to any one of Items 1-1 to 1-5, wherein the total content of the component (B) is 0.05 to 50 parts by weight with respect to 1 part by weight of the total content of the component (A) Composition.
Item 1-7. Item 7. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-6, further comprising a buffer.
Item 1-8. Item 8. The aqueous ophthalmic composition according to Item 1-7, wherein the buffer is a borate buffer.
Item 1-9. Item 9. The aqueous ophthalmic composition according to Item 1-7 or 1-8, wherein the total content of the buffer is 0.01 to 10 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-10. Item 10. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-9, further comprising a nonionic surfactant other than the component (B).
Item 1-11. The nonionic surfactant other than the component (B) is a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene hydrogenated castor oil, a polyoxyethylene castor oil having an average addition mole number of ethylene oxide of more than 30, and a polyoxyethylene- Item 11. The aqueous ophthalmic composition according to Item 1-10, which is at least one selected from the group consisting of polyoxypropylene block copolymers.
Item 1-12. The aqueous solution according to Item 1-10 or 1-11, wherein the total content of the nonionic surfactant other than the component (B) is 0.001 to 3 w / v% based on the total amount of the aqueous ophthalmic composition. Ophthalmic composition.
Item 1-13. Item 13. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-12, which is filled in a polyethylene terephthalate container.
Item 1-14. Item 14. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-13, which is filled in a container equipped with a polyethylene nozzle.
Item 1-15. Item 15. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-14, which is an eye drop.
Item 1-16. Item 15. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-14, which is an eye wash.
Item 1-17. Item 15. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-14, which is a contact lens mounting solution.
Item 1-18. Item 15. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-14, which is a contact lens care agent.
また、本発明は、下記に掲げる態様の、水性眼科組成物における熱安定性を向上させる方法を提供するものである。
項２． (A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種を含有する水性眼科組成物に、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における熱安定性を向上させる方法。
項３． 水性眼科組成物中に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における熱安定性を向上させる方法。
Moreover, this invention provides the method of improving the thermal stability in the aqueous | water-based ophthalmic composition of the aspect hung up below.
Item 2. (A) An aqueous ophthalmic composition containing at least one selected from the group consisting of glycyrrhizic acid and salts thereof is blended with (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 A method for improving the thermal stability of the aqueous ophthalmic composition.
Item 3. In the aqueous ophthalmic composition, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 are blended. A method for improving the thermal stability of the aqueous ophthalmic composition.
また、本発明は、下記に掲げる態様の、水性眼科組成物における光安定性を向上させる方法を提供するものである。
項４． (A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種を含有する水性眼科組成物に、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における光安定性を向上させる方法。項５． 水性眼科組成物中に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における光安定性を向上させる方法。
Moreover, this invention provides the method of improving the light stability in the aqueous | water-based ophthalmic composition of the aspect hung up below.
Item 4. (A) An aqueous ophthalmic composition containing at least one selected from the group consisting of glycyrrhizic acid and salts thereof is blended with (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 A method for improving light stability in the aqueous ophthalmic composition. Item 5. In the aqueous ophthalmic composition, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 are blended. A method for improving light stability in the aqueous ophthalmic composition.
また、本発明は、下記に掲げる態様の、水性眼科組成物における消泡時間の短縮方法、及び使用時の滴下量のバラツキ抑制方法を提供するものである。
項６．(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を、水性眼科組成物に配合することを含む、該水性眼科組成物における消泡時間を短縮させる方法。
項７．(B) 酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を含有する水性眼科組成物に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種を配合することを含む、該水性眼科組成物における消泡時間を短縮させる方法。
項８．(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と、(B) 酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を、水性眼科組成物に配合することを含む、該水性眼科組成物における使用時の滴下量のバラツキを抑制する方法。
Moreover, this invention provides the shortening method of the defoaming time in the aqueous | water-based ophthalmic composition of the aspect hung up below, and the variation suppression method of the dripping amount at the time of use.
Item 6. (A) At least one selected from the group consisting of glycyrrhizic acid and salts thereof and (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 are added to the aqueous ophthalmic composition. A method for reducing the defoaming time in the aqueous ophthalmic composition.
Item 7. (B) An aqueous ophthalmic composition containing polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 is blended with (A) at least one selected from the group consisting of glycyrrhizic acid and its salts. A method for reducing the defoaming time in the aqueous ophthalmic composition.
Item 8. (A) At least one selected from the group consisting of glycyrrhizic acid and salts thereof and (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 are added to the aqueous ophthalmic composition. A method for suppressing variation in the amount of dripping when used in the aqueous ophthalmic composition.
更に、本発明は、下記の掲げる態様の使用も提供する。
項９. 水性眼科組成物の製造のための、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油の使用。
項１０． 水性眼科組成物が、上記項1-1乃至1-18のいずれかに記載の組成物である、項９に記載の使用。
Furthermore, the present invention also provides the use of the following aspects.
Item 9. For the production of an aqueous ophthalmic composition, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) a poly (ethylene oxide) having an average added mole number of ethylene oxide of 2 to 30 moles Use of oxyethylene castor oil.
Item 10. Item 10. The use according to Item 9, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-18.
更に、本発明は、下記に掲げる態様の使用も提供する。
項１１. 水性眼科組成物としての、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を含む組成物の使用。
項１２. 組成物が、上記項1-1乃至1-18のいずれかに記載の組成物である、項１１に記載の使用。
Furthermore, the present invention also provides the use of the embodiments listed below.
Item 11. As an aqueous ophthalmic composition, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) polyoxyethylene castor having an average added mole number of ethylene oxide of 2 to 30 mol Use of a composition comprising oil.
Item 12. The use according to Item 11, wherein the composition is the composition according to any one of Items 1-1 to 1-18.
更に、本発明は、下記に掲げる態様の組成物も提供する。
項１３. 水性眼科組成物としての使用のための、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を含む組成物。
項１４. 上記項1-1乃至1-18のいずれかに記載されたものである、項１３に記載の組成物。
Furthermore, this invention also provides the composition of the aspect hung up below.
Item 13. For use as an aqueous ophthalmic composition, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) an average added mole number of ethylene oxide is 2 to 30 moles A composition comprising polyoxyethylene castor oil.
Item 14. The composition according to Item 13, which is described in any one of Items 1-1 to 1-18.
更に、本発明は、下記に掲げる態様の水性眼科組成物の製造方法も提供する。
項１５. 水を含む担体に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を添加することを含む、水性眼科組成物の製造方法。
項１６. 水性眼科組成物が、上記項1-1乃至1-18のいずれかに記載の組成物である、項１５に記載の製造方法。
Furthermore, this invention also provides the manufacturing method of the aqueous ophthalmic composition of the aspect hung up below.
Item 15. A polyoxyethylene castor oil in which the carrier containing water is (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) the average added mole number of ethylene oxide is 2 to 30 moles A method for producing an aqueous ophthalmic composition comprising adding
Item 16. The method according to Item 15, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-18.
本発明によれば、以下に示す各種の効果が奏される。
（１）本発明によれば、グリチルリチン酸及び／又はその塩を含有する水性眼科組成物において、保存時や光を晒した場合に生じ易いグリチルリチン酸及びその塩の熱分解及び光分解を抑制することができる。よって、本発明の水性眼科組成物は、安全性や品質を低下させることなく、グリチルリチン酸及び／又はその塩の有する優れた性能を長期間安定して発揮することができる。
（２）本発明によれば、ポリオキシエチレンヒマシ油を含有する水性眼科組成物における消泡時間を短縮させることができる。その結果、水性眼科組成物の製造時の溶解確認又は異物確認を短時間で行うことが可能となり、製造効率を改善することができる。更に、消泡時間が短縮されることにより、滴下量のバラツキをも抑制することができる。
According to the present invention, the following various effects are exhibited.
(1) According to the present invention, in an aqueous ophthalmic composition containing glycyrrhizic acid and / or a salt thereof, thermal decomposition and photolysis of glycyrrhizic acid and a salt thereof that are likely to occur during storage or when exposed to light are suppressed. be able to. Therefore, the aqueous ophthalmic composition of the present invention can stably exhibit excellent performance of glycyrrhizic acid and / or a salt thereof for a long period of time without deteriorating safety and quality.
(2) According to the present invention, the defoaming time in the aqueous ophthalmic composition containing polyoxyethylene castor oil can be shortened. As a result, it is possible to perform dissolution confirmation or foreign matter confirmation during the production of the aqueous ophthalmic composition in a short time, and the production efficiency can be improved. Furthermore, variation in the amount of dripping can be suppressed by reducing the defoaming time.
本発明の水性眼科組成物は、上述した各種の優れた効果を有するものであり、より安全且つ快適に、長期に亘って有効に使用することができる。 The aqueous ophthalmic composition of the present invention has the above-described various excellent effects, and can be used safely and comfortably over a long period of time.
本明細書において含有量の単位「％」は「w/v％」を意味し、「g/１００mL」と同義である。 In the present specification, the unit “%” of content means “w / v%” and is synonymous with “g / 100 mL”.
本明細書中、特に記載の無い限り、略号「ＰＯＥ」はポリオキシエチレンを意味する。 In the present specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene.
本明細書中、特に記載の無い限り、略号「ＰＯＰ」はポリオキシプロピレンを意味する。 In this specification, unless otherwise specified, the abbreviation “POP” means polyoxypropylene.
本明細書中、特に記載の無い限り、コンタクトレンズとは、ハード、酸素透過性ハード、ソフト（シリコーンハイドロゲルレンズを含む）、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。 In the present specification, unless otherwise specified, the contact lens is meant to include all types of contact lenses such as hard, oxygen-permeable hard, soft (including silicone hydrogel lenses), and color.
以下、本発明について、具体的に説明する。 Hereinafter, the present invention will be specifically described.
［１．水性眼科組成物］
本発明の水性眼科組成物は、グリチルリチン酸及びその塩からなる群から選択される少なくとも一種（(A)成分）を含有するものである。これを、後述する酸化エチレンの平均付加モル数が２〜３０のポリオキシエチレンヒマシ油と併用することによって、上記した本発明の優れた効果が発揮される。
[1. Aqueous ophthalmic composition]
The aqueous ophthalmic composition of the present invention contains at least one (component (A)) selected from the group consisting of glycyrrhizic acid and salts thereof. By using this together with polyoxyethylene castor oil having an average added mole number of ethylene oxide described later of 2 to 30, the above-described excellent effects of the present invention are exhibited.
グリチルリチン酸は、20β-カルボキシ-11-オキソ-30-ノルオレアナ-12-エン-3β-イル=(β-D-グルコピラノシルウロン酸)-(1→2)-α-D-グルコピラノシドウロン酸とも称される公知の化合物である。グリチルリチン酸及びその塩は、市販品を購入することができ、周知の方法に従い合成することもでき、さらにカンゾウの根などから抽出することもできる。 Glycyrrhizic acid is 20β-carboxy-11-oxo-30-noroleana-12-en-3β-yl = (β-D-glucopyranosyluronic acid)-(1 → 2) -α-D-glucopyranoside uronic acid It is a known compound also called. Glycyrrhizic acid and its salt can be purchased commercially, can be synthesized according to well-known methods, and can also be extracted from licorice roots.
本発明に用いられるグリチルリチン酸の塩としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されることを限度として、特に制限されるものではない。このような塩として、具体的には、有機塩基との塩（例えば、メチルアミン、トリエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン、トリピリジン、ピコリン等の有機アミンとの塩等）、無機塩基との塩［例えば、アンモニウム塩；アルカリ金属（ナトリウム、カリウム等）、アルカリ土類金属（カルシウム、マグネシウム等）、アルミニウム等の金属との塩等］等が挙げられる。これらの塩の中でも、好ましくは無機塩基との塩、更に好ましくは、ナトリウムやカリウム等のアルカリ金属との塩；アンモニウム塩等が挙げられる。より具体的には、グリチルリチン酸二ナトリウム、グリチルリチン酸三ナトリウム、グリチルリチン酸二カリウム、グリチルリチン酸三カリウム等のアルカリ金属との塩；グリチルリチン酸モノアンモニウム等のアンモニウム塩等が例示される。これらの中でも、好ましくはグリチルリチン酸のアルカリ金属塩、更に好ましくはグリチルリチン酸二カリウムが挙げられる。本発明において、グリチルリチン酸及びその塩は、これらの中から１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 The salt of glycyrrhizic acid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include salts with organic bases (for example, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, and picoline), inorganic bases, and the like. [For example, ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.] and the like. Among these salts, preferred are salts with inorganic bases, more preferred are salts with alkali metals such as sodium and potassium; ammonium salts and the like. More specifically, examples include salts with alkali metals such as disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, and tripotassium glycyrrhizinate; ammonium salts such as monoammonium glycyrrhizinate. Among these, Preferably the alkali metal salt of glycyrrhizic acid, More preferably, dipotassium glycyrrhizinate is mentioned. In this invention, glycyrrhizic acid and its salt may be used individually by 1 type from these, and may be used in combination of 2 or more types arbitrarily.
本発明の水性眼科組成物における、(A)成分の含有量は特に限定はなく、(A)成分の種類、併用する(B)成分の種類及び含有量、該水性眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の水性眼科組成物の総量を基準として、(A)成分の総含有量として、０．０００５〜２w/v％、好ましくは０．００１〜１w/v％、更に好ましくは０．００５〜０． ５w/v％、特に好ましくは０．０１〜０．２５w/v％である。 In the aqueous ophthalmic composition of the present invention, the content of the component (A) is not particularly limited, the type of the component (A), the type and content of the component (B) to be used in combination, the use and formulation of the aqueous ophthalmic composition It is appropriately set according to the form, usage method, and the like. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of component (A) is 0.0005 to 2 w / v%, preferably 0.001 to 1 w / v%, more preferably 0.00. 005-0. 5 w / v%, particularly preferably 0.01 to 0.25 w / v%.
上記(A)成分の含有量は、水性眼科組成物において、熱分解及び光分解を抑制し、消泡時間を短縮させるという効果の観点から好適である。 The content of the component (A) is preferable from the viewpoint of the effect of suppressing thermal decomposition and photolysis and shortening the defoaming time in the aqueous ophthalmic composition.
本発明の水性眼科組成物は、上記(A)成分に加えて、酸化エチレンの平均付加モル数が２〜３０のポリオキシエチレンヒマシ油（(B)成分）を含有することが必要である。このように、(A)成分と(B)成分を併用することによって、水性眼科組成物に含まれる(A)成分の熱分解及び光分解を抑制でき、更に、(B)成分を含む水性眼科組成物における消泡時間を短縮させることができる。 The aqueous ophthalmic composition of the present invention needs to contain polyoxyethylene castor oil (component (B)) having an average addition mole number of ethylene oxide of 2 to 30 in addition to the component (A). Thus, by using the component (A) and the component (B) in combination, the thermal decomposition and photolysis of the component (A) contained in the aqueous ophthalmic composition can be suppressed, and further, the aqueous ophthalmology containing the component (B) The defoaming time in the composition can be shortened.
ポリオキシエチレンヒマシ油は、ヒマシ油に酸化エチレンを付加重合することによって得られる公知の化合物であり、酸化エチレンの平均付加モル数が異なるいくつかの種類が知られている。本発明では、(B)成分として、酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を用いる。具体的には酸化エチレンの平均付加モル数が３であるポリオキシエチレンヒマシ油３、酸化エチレンの平均付加モル数が４であるポリオキシエチレンヒマシ油４、酸化エチレンの平均付加モル数が６であるポリオキシエチレンヒマシ油６、酸化エチレンの平均付加モル数が７であるポリオキシエチレンヒマシ油７、酸化エチレンの平均付加モル数が１０であるポリオキシエチレンヒマシ油１０、酸化エチレンの平均付加モル数が１３．５であるポリオキシエチレンヒマシ油１３．５、酸化エチレンの平均付加モル数が１７であるポリオキシエチレンヒマシ油１７、酸化エチレンの平均付加モル数が２０であるポリオキシエチレンヒマシ油２０、酸化エチレンの平均付加モル数が２５であるポリオキシエチレンヒマシ油２５、酸化エチレンの平均付加モル数が３０であるポリオキシエチレンヒマシ油３０などを用いることができる。 Polyoxyethylene castor oil is a known compound obtained by addition polymerization of ethylene oxide to castor oil, and several types having different average added mole numbers of ethylene oxide are known. In this invention, the polyoxyethylene castor oil whose average added mole number of ethylene oxide is 2-30 mol is used as (B) component. Specifically, polyoxyethylene castor oil 3 having an average addition mole number of ethylene oxide of 3, polyoxyethylene castor oil 4 having an average addition mole number of ethylene oxide of 4, and an average addition mole number of ethylene oxide of 6. A certain polyoxyethylene castor oil 6, polyoxyethylene castor oil 7 with an average addition mole number of ethylene oxide of 7, polyoxyethylene castor oil 10 with an average addition mole number of ethylene oxide of 10, an average addition mole of ethylene oxide Polyoxyethylene castor oil 13.5 having a number of 13.5, polyoxyethylene castor oil 17 having an average addition mole number of ethylene oxide of 17, polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 20 20. Polyoxyethylene castor oil 25 having an average added mole number of ethylene oxide of 25, Molar number of addition can be used as the polyoxyethylene castor oil 30, 30.
これらのポリオキシエチレンヒマシ油の内で、本発明の効果を特に良好に発揮できる成分の一例として、酸化エチレンの平均付加モル数が２〜１２モルのポリオキシエチレンヒマシ油を挙げることができる。 Among these polyoxyethylene castor oils, an example of a component that can exhibit the effects of the present invention particularly well is a polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 12 moles.
本発明において、これらのポリオキシエチレンヒマシ油は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。尚、本発明で用いるポリオキシエチレンヒマシ油は、硬化ヒマシ油に酸化エチレンを付加重合することにより得られるポリオキシエチレン硬化ヒマシ油とは異なる化合物であり、これとは区別される。 In the present invention, these polyoxyethylene castor oils may be used alone or in any combination of two or more. In addition, the polyoxyethylene castor oil used by this invention is a compound different from the polyoxyethylene hydrogenated castor oil obtained by addition-polymerizing ethylene oxide to hydrogenated castor oil, and is distinguished from this.
本発明の水性眼科組成物における、(B)成分の含有量は特に限定はなく、(B)成分の種類、併用する(A)成分の種類及び含有量、該水性眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の水性眼科組成物の総量を基準として、(B)成分の総含有量として、０．０００５〜５w/v％、好ましくは０．００１〜３w/v％、より好ましくは０．００２〜２w/v％、更に好ましくは０．００５〜１w/v％、特に好ましくは０．０１〜０．５w/v％である。 In the aqueous ophthalmic composition of the present invention, the content of the component (B) is not particularly limited, the type of the component (B), the type and content of the component (A) to be used in combination, the use and formulation of the aqueous ophthalmic composition It is appropriately set according to the form, usage method, and the like. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the component (B) is 0.0005 to 5 w / v%, preferably 0.001 to 3 w / v%, more preferably 0.00. 002 to 2 w / v%, more preferably 0.005 to 1 w / v%, particularly preferably 0.01 to 0.5 w / v%.
上記(B)成分の含有量は、本発明の効果をより一層高めるという観点から好適である。 The content of the component (B) is suitable from the viewpoint of further enhancing the effects of the present invention.
また、本発明の水性眼科組成物における、(A)成分に対する(B)成分の含有比率は特に限定はなく、(A)成分及び(B)成分の種類、該水性眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の水性眼科組成物に含まれる(A)成分の総含有量１重量部に対して、(B)成分の総含有量として、０．０００２〜１００００重量部、好ましくは０．００２〜１０００重量部、更に好ましくは０．０１〜２００重量部、特に好ましくは０．０５〜５０重量部である。 Further, the content ratio of the component (B) to the component (A) in the aqueous ophthalmic composition of the present invention is not particularly limited, the types of the components (A) and (B), the use of the aqueous ophthalmic composition, and the preparation It is appropriately set according to the form, usage method, and the like. For example, with respect to 1 part by weight of the total content of the component (A) contained in the aqueous ophthalmic composition of the present invention, the total content of the component (B) is 0.0002 to 10000 parts by weight, preferably 0.002 -1000 parts by weight, more preferably 0.01-200 parts by weight, particularly preferably 0.05-50 parts by weight.
上記 (A)成分に対する(B)成分の含有比率は、本発明の効果をより一層高めるという観点から好適である。 The content ratio of the component (B) to the component (A) is preferable from the viewpoint of further enhancing the effect of the present invention.
本発明の水性眼科組成物には、後述する通り、その使用目的に応じて、種々の薬理活性成分、生理活性成分等を配合することができ、更に、各種の添加剤も配合することができる。この場合、生理活性成分、添加物等の溶解性を向上させるために、溶解補助剤として、(B)成分以外に、更に、その他の界面活性剤を配合することができる。このような界面活性剤を配合すると通常泡立ちが多くなるが、本発明によれば、(B)成分以外の界面活性剤を配合することによって泡立ちし易くなった水性眼科組成物についても、 (A)成分と（B）成分を同時に含有させることによって、消泡時間を短縮させることができ、製造効率を改善し、滴下量のバラツキを抑制することができる。 In the aqueous ophthalmic composition of the present invention, as described later, various pharmacologically active ingredients, physiologically active ingredients and the like can be blended according to the purpose of use, and various additives can be blended. . In this case, in order to improve the solubility of physiologically active ingredients and additives, in addition to the component (B), other surfactants can be further blended as a solubilizing agent. When such a surfactant is blended, foaming usually increases.According to the present invention, an aqueous ophthalmic composition that is easily foamed by blending a surfactant other than the component (B) is also (A ) Component and (B) component are contained at the same time, the defoaming time can be shortened, the production efficiency can be improved, and the variation in dripping amount can be suppressed.
本発明の水性眼科組成物に配合することができる、(B)成分以外の界面活性剤としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば特に制限されず、非イオン性界面活性剤、両性界面活性剤、陰イオン性界面活性剤、陽イオン性界面活性剤のいずれであってもよい。 The surfactant other than the component (B) that can be incorporated into the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. However, any of nonionic surfactants, amphoteric surfactants, anionic surfactants, and cationic surfactants may be used.
本発明の水性眼科組成物に配合可能な(B)成分以外の非イオン性界面活性剤としては、具体的には、モノラウリン酸POE(20)ソルビタン（ポリソルベート20）、モノパルミチン酸POE（20）ソルビタン（ポリソルベート40）、モノステアリン酸POE（20）ソルビタン（ポリソルベート60）、トリステアリン酸POE（20）ソルビタン（ポリソルベート65）、モノオレイン酸POE(20)ソルビタン(ポリソルベート80)等のPOEソルビタン脂肪酸エステル；POE(40)硬化ヒマシ油（ポリオキシエチレン硬化ヒマシ油40）、POE(60)硬化ヒマシ油（ポリオキシエチレン硬化ヒマシ油60）等のPOE硬化ヒマシ油；POE(9)ラウリルエーテル等のPOEアルキルエーテル；POE(20)POP(4)セチルエーテル等のPOE-POPアルキルエーテル；POE（196）POP（67）グリコール（ポロクサマー４０７、プルロニックＦ１２７）、POE（200）POP（70）グリコール等の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ヒマシ油３５、ポリオキシエチレンヒマシ油４０、ポリオキシエチレンヒマシ油５０、ポリオキシエチレンヒマシ油６０、ポリオキシエチレンヒマシ油７０等の酸化エチレンの平均付加モル数が３０を上回るポリオキシエチレンヒマシ油等が挙げられる。なお、上記で例示する化合物において、括弧内の数字は付加モル数を示す。 Specific examples of nonionic surfactants other than the component (B) that can be blended in the aqueous ophthalmic composition of the present invention include monolauric acid POE (20) sorbitan (polysorbate 20) and monopalmitic acid POE (20). POE sorbitan fatty acid esters such as sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80) ; POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), etc .; POE (9) POE such as lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE (196) POP (67) glycol (poloxamer 407, Pluronic F127) Polyoxyethylene polyoxypropylene block copolymers such as POE (200) POP (70) glycol; polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60, Examples thereof include polyoxyethylene castor oil such as polyoxyethylene castor oil 70 whose average added mole number of ethylene oxide exceeds 30. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.
また、本発明の水性眼科組成物に配合可能な両性界面活性剤としては、具体的には、アルキルジアミノエチルグリシン又はその塩（例えば、塩酸塩等）等が例示される。 Specific examples of the amphoteric surfactant that can be incorporated into the aqueous ophthalmic composition of the present invention include alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride).
また、本発明の水性眼科組成物に配合可能な陽イオン性界面活性剤としては、具体的には、塩化ベンザルコニウム、塩化ベンゼトニウム等が例示される。 Specific examples of the cationic surfactant that can be blended in the aqueous ophthalmic composition of the present invention include benzalkonium chloride and benzethonium chloride.
また、本発明の水性眼科組成物に配合可能な陰イオン性界面活性剤としては、具体的には、アルキルベンゼンスルホン酸塩、アルキル硫酸塩、ポリオキシエチレンアルキル硫酸塩、脂肪族α−スルホメチルエステル、α−オレフィンスルホン酸等が例示される。 本発明の水性眼科組成物に配合可能な(B)成分以外の界面活性剤として、好ましくは、非イオン性界面活性剤であり、更に好ましくは、POEソルビタン脂肪酸エステル、POE硬化ヒマシ油、POE・POPブロックコポリマーであり、特に好ましくは、ポリソルベート８０、ポリオキシエチレン硬化ヒマシ油６０、ポロクサマー４０７である。 Specific examples of the anionic surfactant that can be incorporated into the aqueous ophthalmic composition of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, and aliphatic α-sulfomethyl ester. And α-olefin sulfonic acid. The surfactant other than the component (B) that can be blended in the aqueous ophthalmic composition of the present invention is preferably a nonionic surfactant, more preferably POE sorbitan fatty acid ester, POE hydrogenated castor oil, POE POP block copolymers, particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and poloxamer 407.
本発明の水性眼科組成物において、上記(B)成分以外の界面活性剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 In the aqueous ophthalmic composition of the present invention, surfactants other than the component (B) may be used singly or in combination of two or more.
本発明の水性眼科組成物に上記(B)成分以外の界面活性剤を配合する場合、その含有量は、該界面活性剤の種類、他の配合成分の種類及び含有量、該水性眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の水性眼科組成物の総量を基準として、(B)成分以外の界面活性剤の総含有量として、０．００１〜３w/v％、好ましくは０．０１〜２w/v％、更に好ましくは０．０５〜１w/v％、特に好ましくは０．１〜１w/v％である。 When a surfactant other than the component (B) is blended in the aqueous ophthalmic composition of the present invention, the content thereof is the type of the surfactant, the type and content of other blended components, the aqueous ophthalmic composition. Is appropriately set according to the use, formulation form, method of use and the like. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, 0.001 to 3 w / v%, preferably 0.01 to 2 w / v%, as the total content of the surfactant other than the component (B), More preferably, it is 0.05-1 w / v%, Most preferably, it is 0.1-1 w / v%.
本発明の水性眼科組成物は、更に緩衝剤を含有することができる。これにより、本発明の水性眼科組成物のｐＨを調整できる。本発明の水性眼科組成物に配合できる緩衝剤としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。このような緩衝剤の一例として、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、アスパラギン酸、アスパラギン酸塩等が挙げられる。これらの緩衝剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。ホウ酸緩衝剤としては、ホウ酸、又はホウ酸アルカリ金属塩、ホウ酸アルカリ土類金属塩等のホウ酸塩が挙げられる。リン酸緩衝剤としては、リン酸、又はリン酸アルカリ金属塩、リン酸アルカリ土類金属塩等のリン酸塩が挙げられる。炭酸緩衝剤としては、炭酸、又は炭酸アルカリ金属塩、炭酸アルカリ土類金属塩等の炭酸塩が挙げられる。クエン酸緩衝剤としては、クエン酸、又はクエン酸アルカリ金属塩、クエン酸アルカリ土類金属塩等が挙げられる。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。より具体的な例として、ホウ酸緩衝剤として、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、ホウ酸アンモニウム、ホウ砂等)；リン酸緩衝剤として、リン酸又はその塩(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、リン酸三ナトリウム、リン酸二カリウム、リン酸一水素カルシウム、リン酸二水素カルシウム等)；炭酸緩衝剤として、炭酸又はその塩（炭酸水素ナトリウム、炭酸ナトリウム、炭酸アンモニウム、炭酸カリウム、炭酸カルシウム、炭酸水素カリウム、炭酸マグネシウム等）；クエン酸緩衝剤として、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、クエン酸カルシウム、クエン酸二水素ナトリウム、クエン酸二ナトリウム等）；酢酸緩衝剤として、酢酸又はその塩（酢酸アンモニウム、酢酸カリウム、酢酸カルシウム、酢酸ナトリウム等）；アスパラギン酸又はその塩（アスパラギン酸ナトリウム、アスパラギン酸マグネシウム、アスパラギン酸カリウム等）等が例示できる。これらの緩衝剤の中でも、ホウ酸緩衝剤（特に、ホウ酸とホウ砂の組合せ）、リン酸緩衝剤（特に、リン酸水素二ナトリウムとリン酸二水素ナトリウムの組合せ）が好ましい。 The aqueous ophthalmic composition of the present invention can further contain a buffer. Thereby, pH of the aqueous ophthalmic composition of this invention can be adjusted. The buffer that can be incorporated into the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, aspartate, aspartate and the like. These buffering agents may be used alone or in any combination of two or more. Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.); with acetate buffer Examples thereof include acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). Among these buffering agents, boric acid buffering agents (particularly a combination of boric acid and borax) and phosphoric acid buffering agents (particularly a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferable.
本発明の水性眼科組成物に緩衝剤を配合する場合、その含有量は、該緩衝剤の種類、他の配合成分の種類及び含有量、該水性眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の水性眼科組成物の総量を基準として、該緩衝剤の総含有量として、０．０１〜１０w/v％、好ましくは０．０５〜５w/v％、更に好ましくは０．１〜２．５w/v％、特に好ましくは０．１〜１w/v％である。 When a buffering agent is blended in the aqueous ophthalmic composition of the present invention, the content thereof includes the type of the buffering agent, the type and content of other blending components, the use of the aqueous ophthalmic composition, the formulation form, the method of use, etc. It is set appropriately according to For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the buffer is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1. It is -2.5 w / v%, Most preferably, it is 0.1-1 w / v%.
また、本発明の水性眼科組成物は、更に等張化剤を含有していてもよい。本発明の水性眼科組成物に配合できる等張化剤としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。このような等張化剤の具体例として、例えば、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、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、グリセリン、プロピレングリコール等が挙げられる。これらの等張化剤の中でも、好ましくは、グリセリン、プロピレングリコール、塩化ナトリウム、塩化カリウム、塩化カルシウム、及び塩化マグネシウムが挙げられ、更に好ましくは塩化ナトリウム又はグリセリンが挙げられ、特に好ましくは塩化ナトリウムが挙げられる。これらの等張化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 The aqueous ophthalmic composition of the present invention may further contain an isotonic agent. The isotonic agent that can be incorporated into the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride Potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like. Among these isotonic agents, preferably, glycerin, propylene glycol, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride are mentioned, more preferably sodium chloride or glycerin is mentioned, and sodium chloride is particularly preferred. Can be mentioned. These isotonic agents may be used alone or in any combination of two or more.
本発明の水性眼科組成物に等張化剤を配合する場合、その含有量は、該等張化剤の種類、他の配合成分の種類及び含有量、該水性眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定される。例えば、本発明の水性眼科組成物の総量を基準として、該等張化剤の総含有量として０．０１〜１０w/v％、好ましくは０．０５〜５w/v％、更に好ましくは０．１〜３w/v％である。 When an isotonic agent is blended in the aqueous ophthalmic composition of the present invention, the content thereof includes the type of tonicity agent, the type and content of other compounding ingredients, the use of the aqueous ophthalmic composition, and the formulation form. It is set as appropriate according to the method of use. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the tonicity agent is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0. 1 to 3 w / v%.
本発明の水性眼科組成物のｐＨについては、医薬上、薬理学的に（製薬上）又は生理学的に許容される範囲内であれば特に限定されるものではない。本発明の水性眼科組成物のｐＨの一例として、４．０〜９．５、好ましくは５．０〜８．５となる範囲が挙げられ、更に好ましくは、５．５〜７．５である。 The pH of the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. As an example of the pH of the aqueous ophthalmic composition of the present invention, a range of 4.0 to 9.5, preferably 5.0 to 8.5 is mentioned, and more preferably 5.5 to 7.5. .
また、本発明の水性眼科組成物の浸透圧については、生体に許容される範囲内であれば、特に制限されない。本発明の水性眼科組成物の浸透圧比の一例として、０．５〜５．０、好ましくは０．６〜３．０、更に好ましくは０．７〜２．０である。浸透圧の調整は、無機塩、多価アルコール、糖アルコール、糖等を用いて、当該技術分野で既知の方法で行うことができる。浸透圧比は、第十六改正日本薬局方に基づき、２８６ｍOsm（０．９ w/v％塩化ナトリウム水溶液の浸透圧）に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法（氷点降下法）を参考にして測定する。なお、浸透圧比測定用標準液（０．９ w/v％塩化ナトリウム水溶液）については、塩化ナトリウム（日本薬局方標準試薬）を５００〜６５０℃で４０〜５０分間乾燥した後、デシケーター（シリカゲル）中で放冷し、その０．９００ｇを正確に量り、精製水に溶かし正確に１００ｍＬとして調製するか、市販の浸透圧比測定用標準液（０．９w/v％塩化ナトリウム水溶液）を用いればよい。 In addition, the osmotic pressure of the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is within a range acceptable for a living body. As an example of the osmotic pressure ratio of the aqueous ophthalmic composition of the present invention, it is 0.5 to 5.0, preferably 0.6 to 3.0, and more preferably 0.7 to 2.0. The adjustment of the osmotic pressure can be performed by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopeia. Measured with reference to the method (freezing point depression method). In addition, about the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, it is a desiccator (silica gel). It is allowed to cool, and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) may be used. .
本発明の水性眼科組成物の粘度については、生体に許容される範囲内であれば特に制限されない。例えば、回転粘度計（ＲＥ５５０型粘度計、東機産業社製、ローター：1°34‘ｘ24）で測定した２５℃における粘度が、０．０１〜１０００ｍＰａ・ｓ、好ましくは０．０５〜１００ｍＰａ・ｓ、更に好ましくは０．１〜１０ｍＰａ・ｓである。 The viscosity of the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is within a range acceptable for a living body. For example, the viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × 24) is 0.01 to 1000 mPa · s, preferably 0.05 to 100 mPa · s. s, more preferably 0.1 to 10 mPa · s.
本発明の水性眼科組成物は、本発明の効果が奏される限り、上記成分の他に、種々の薬理活性成分及び／又は生理活性成分を単独又は適宜組み合わせて適当量含有してもよい。このような成分は特に制限されず、具体的には、眼科用薬において用いられる成分としては、次のような成分が挙げられる。 The aqueous ophthalmic composition of the present invention may contain an appropriate amount of various pharmacologically active ingredients and / or physiologically active ingredients in addition to the above ingredients, as long as the effects of the present invention are exhibited. Such components are not particularly limited, and specific examples of components used in ophthalmic drugs include the following components.
抗ヒスタミン剤又は抗アレルギー剤：例えば、イプロヘプチン、塩酸ジフェンヒドラミン、マレイン酸クロルフェニラミン、フマル酸ケトチフェン、ペミロラストカリウム等。 Antihistamine or antiallergic agent: for example, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, pemirolast potassium and the like.
充血除去剤：例えば、塩酸テトラヒドロゾリン、塩酸ナファゾリン、硫酸ナファゾリン塩酸エピネフリン、塩酸エフェドリン、塩酸メチルエフェドリン等。 Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
眼筋調節薬剤：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。 Eye muscle modulating agent: for example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien.
ビタミン：例えば、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、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、パンテノール、パントテン酸カルシウム、酢酸トコフェロール等。 Vitamins: for example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate, etc.
アミノ酸：例えば、アスパラギン酸カリウム、アスパラギン酸マグネシウム、アミノエチルスルホン酸、イプシロン-アミノカプロン酸等。 Amino acids: for example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid, epsilon-aminocaproic acid and the like.
消炎剤：例えば、硫酸亜鉛、乳酸亜鉛、ブロムフェナクナトリウム、グリチルリチン酸二カリウム、プラノプロフェン、アラントイン、アズレン、アズレンスルホン酸ナトリウム、グアイアズレン、塩化ベルベリン、硫酸ベルベリン、塩化リゾチーム、甘草等。 Anti-inflammatory agents: for example, zinc sulfate, zinc lactate, bromfenac sodium, dipotassium glycyrrhizinate, pranoprofen, allantoin, azulene, sodium azulenesulfonate, guaiazulene, berberine chloride, berberine sulfate, lysozyme chloride, licorice, etc.
その他：例えば、クロモグリク酸ナトリウム、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム、スルファメトキサゾール、スルファメトキサゾールナトリウム等。 Other: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole and the like.
また、本発明の水性眼科組成物には、発明の効果が奏される範囲であれば、その用途、製剤形態等に応じて、常法に従い、様々な添加物を適宜選択し、１種又はそれ以上を併用して適当量含有させてもよい。代表的な成分として次の添加物が挙げられる。 Further, in the aqueous ophthalmic composition of the present invention, various additives are appropriately selected according to conventional methods depending on the use, formulation form, etc., as long as the effects of the invention are exerted, and one type or An appropriate amount may be added in combination. Typical additives include the following additives.
担体：例えば、水、含水エタノール等の水性担体。 Carrier: An aqueous carrier such as water or hydrous ethanol.
糖：例えば、シクロデキストリン等。 Sugar: For example, cyclodextrin and the like.
糖アルコール：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。 Sugar alcohol: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
防腐剤、殺菌剤又は抗菌剤：例えば、セチルピリジニウム、塩化ベンザルコニウム、塩化ベンゼトニウム、塩酸クロルヘキシジン、グルコン酸クロルヘキシジン、塩酸ポリヘキサニド、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、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、グローキル（商品名、ローディア社）等。 Preservatives, bactericides or antibacterial agents: for example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexanide hydrochloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorhexidine gluconate, chlorobutanol , Sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, glowul (trade name, Rhodia) etc.
粘稠化剤又は増粘剤：アラビアゴム末、アルギン酸ナトリウム、アルギン酸プロピレングリコールエステル、コンドロイチン硫酸ナトリウム、ソルビトール、デキストラン７０、トラガント末、メチルセルロース、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシビニルポリマー、ポリビニルアルコール、ポリビニルピロリドン、マクロゴール４０００等。 Thickening agent or thickener: gum arabic powder, sodium alginate, propylene glycol alginate, sodium chondroitin sulfate, sorbitol, dextran 70, tragacanth powder, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyvinyl Alcohol, polyvinyl pyrrolidone, macrogol 4000, etc.
油類：ゴマ油、ヒマシ油等。 Oils: sesame oil, castor oil, etc.
本発明の水性眼科組成物は、所望量の上記(A)成分及び(B)成分、及び必要に応じて他の配合成分を所望の濃度となるように担体に添加することにより調製される。例えば、点眼剤、コンタクトレンズ装着液、洗眼剤又はコンタクトレンズケア用剤の場合、精製水で前記成分を溶解又は懸濁させ、所定のｐＨ及び浸透圧に調整し、濾過滅菌等により滅菌処理することで調製できる。上記(A)成分及び(B)成分の溶解及びその他疎水性の高い成分の溶解に関しては、予め界面活性剤などの溶解補助作用のある成分とあわせて攪拌を行なってから、さらに精製水を加えて溶解又は懸濁させてもよい。 The aqueous ophthalmic composition of the present invention is prepared by adding a desired amount of the above components (A) and (B) and, if necessary, other blending components to a desired concentration. For example, in the case of eye drops, contact lens mounting solution, eye wash or contact lens care agent, the above components are dissolved or suspended in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization, etc. Can be prepared. Regarding the dissolution of the above component (A) and component (B) and other highly hydrophobic components, stir in advance with a component having a solubilizing action such as a surfactant, and then add purified water. It may be dissolved or suspended.
従って、本発明は、別の観点から、水を含む担体に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を添加することを含む、水性眼科組成物の製造方法を提供するものである。 Therefore, the present invention, from another point of view, in a carrier containing water, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) an average added mole number of ethylene oxide is 2-30. A method for producing an aqueous ophthalmic composition comprising adding polyoxyethylene castor oil that is molar.
本発明において水性眼科組成物とは、水の含有量が、該水性眼科組成物の総量に対して、８５w/v％以上の眼科組成物を意味する。該水性眼科組成物における水の含有量は、好ましくは９０w/v％以上、より好ましくは９２w/v％以上、更に好ましくは９４w/v％以上、特に好ましくは９６w/v％以上である。本発明の水性眼科組成物に用いられる水としては、医薬上、薬理学的に（製薬上）又は生理学的に許容される水を使用すればよく、このような水として、具体的には、蒸留水、常水、精製水、滅菌精製水、注射用水、注射用蒸留水等が例示される。また本発明における水性眼科組成物の剤型については、眼科分野で使用可能である限り特に制限されないが、液状が好ましい。これらの定義は第十六改正日本薬局方に基づく。 In the present invention, the aqueous ophthalmic composition means an ophthalmic composition having a water content of 85 w / v% or more based on the total amount of the aqueous ophthalmic composition. The water content in the aqueous ophthalmic composition is preferably 90 w / v% or more, more preferably 92 w / v% or more, still more preferably 94 w / v% or more, and particularly preferably 96 w / v% or more. As water used in the aqueous ophthalmic composition of the present invention, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used, and as such water, specifically, Examples include distilled water, ordinary water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like. In addition, the dosage form of the aqueous ophthalmic composition in the present invention is not particularly limited as long as it can be used in the ophthalmic field, but a liquid form is preferable. These definitions are based on the 16th revised Japanese Pharmacopoeia.
本発明の水性眼科組成物の具体例として、点眼剤（点眼液又は点眼薬ともいう）［但し、点眼剤にはコンタクトレンズ装用中に点眼可能な点眼剤を含む］、洗眼剤（洗眼液又は洗眼薬ともいう）［但し、洗眼剤にはコンタクトレンズ装用中に洗眼可能な洗眼剤を含む］、コンタクトレンズ装着液、コンタクトレンズケア用品（コンタクトレンズ消毒剤、コンタクトレンズ用保存剤、コンタクトレンズ用洗浄剤、コンタクトレンズ用洗浄保存剤、コンタクトレンズ用消毒・保存・洗浄剤（コンタクトレンズ用マルチパーパスソリューション））等が挙げられる。本発明の水性眼科組成物は、消泡時間が短縮され、使用時の滴下量のバラツキが少ないため、他の剤型と比較して特に一回の使用量が少ない、点眼剤、コンタクトレンズ装着液に好適に用いられる。特に点眼剤が好ましい。 Specific examples of the aqueous ophthalmic composition of the present invention include eye drops (also referred to as eye drops or eye drops) [however, eye drops include eye drops that can be applied while wearing contact lenses], eye wash (eye wash or eye drops) (It is also called eye wash) [However, eye wash includes eye wash that can be washed while wearing contact lenses], contact lens mounting solution, contact lens care products (contact lens disinfectant, contact lens preservative, contact lens use) Cleaning agents, contact lens cleaning preservatives, contact lens disinfecting / preserving / cleaning agents (multipurpose solutions for contact lenses)) and the like. The aqueous ophthalmic composition of the present invention has a shorter defoaming time and less variation in the amount of dripping during use, so that the amount of use at one time is particularly small compared to other dosage forms. It is suitably used for liquids. Eye drops are particularly preferable.
本発明の水性眼科組成物を収容する容器としては、水性眼科組成物を収容する容器として通常用いられる容器を用いることができ、ガラス製であってもよく、またプラスチック製であってもよい。本発明の水性眼科組成物を収容する容器として、プラスチック製を使用する場合、該プラスチック容器の構成材質については、特に制限されないが、例えば、ポリエチレンナフタレート、ポリアリレート、ポリエチレンテレフタレート、ポリプロピレン、ポリエチレン、ポリイミドのいずれか１種、これらの共重合体、または２種以上の混合体が挙げられる。また、上記共重合体としては、エチレン−２，６−ナフタレート単位、アリレート単位、エチレンテレフタレート単位、プロピレン単位、エチレン単位、イミド単位のいずれか１種を主体として、他のポリエステル単位、イミド単位を含む共重合体が挙げられる。尚、本発明において例えばポリエチレンテレフタレート製容器と記載する場合は、容器の構成材質全体の重量に対し、ポリエチレンテレフタレートが５０w/w％以上であるものを意味する。 As a container for containing the aqueous ophthalmic composition of the present invention, a container usually used as a container for containing the aqueous ophthalmic composition can be used, and it may be made of glass or plastic. When the plastic container is used as the container for storing the aqueous ophthalmic composition of the present invention, the constituent material of the plastic container is not particularly limited. For example, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, Any one of polyimides, a copolymer thereof, or a mixture of two or more types can be given. In addition, as the copolymer, ethylene-2,6-naphthalate unit, arylate unit, ethylene terephthalate unit, propylene unit, ethylene unit, imide unit is mainly used, and other polyester units and imide units are included. Examples of the copolymer include. In the present invention, for example, a container made of polyethylene terephthalate means that the polyethylene terephthalate is 50 w / w% or more based on the weight of the entire material constituting the container.
また、本発明の水性眼科組成物を収容する容器に備えられているノズルなどの容器注口周辺部についても、その構造、構成素材等については特に制限されるものではない。ノズルなどの容器注口周辺部の構造については、眼科組成物用容器(例えば点眼剤容器)の注出口(例えばノズル)として一般的に採用されている構造であればよく、容器本体と一体に成形されていてもよく、容器本体とは別に成形されていても良い。注口周辺部また注出口(例えばノズル)の構成素材については、例えば、上記プラスチック容器の構成素材と同様のものが例示される。 In addition, the structure, constituent materials, and the like of the peripheral portion of the container inlet such as a nozzle provided in the container for storing the aqueous ophthalmic composition of the present invention are not particularly limited. The structure around the container inlet such as a nozzle may be a structure generally employed as a spout (for example, a nozzle) of a container for an ophthalmic composition (for example, an eye drop container), and is integrated with the container body. It may be molded or may be molded separately from the container body. As the constituent material of the spout peripheral portion or the spout (for example, nozzle), for example, the same material as that of the plastic container is exemplified.
特に、柔軟性、コスト面、及び／又は滴下量のバラツキ抑制効果を一層良好にさせるという観点からは、ポリエチレン又はポリプロピレンを構成素材として含む注出口が好適である。ポリエチレンの種類としては、高密度ポリエチレン、低密度ポリエチレン等が挙げられるが、中でも低密度ポリエチレンを構成素材として含む注出口が好適である。また、注出口としては、点眼剤容器に用いられるノズルが好適である。 In particular, from the viewpoint of further improving the flexibility, cost, and / or the effect of suppressing variation in the amount of dripping, a spout containing polyethylene or polypropylene as a constituent material is suitable. Examples of the type of polyethylene include high-density polyethylene and low-density polyethylene. Among these, spouts containing low-density polyethylene as a constituent material are suitable. Moreover, as a spout, the nozzle used for an eye drop container is suitable.
本発明の水性眼科組成物を収容する容器及び容器注口周辺部の好ましい組み合わせとしては、ポリエチレンテレフタレート製容器とポリエチレン製容器注口周辺部の組み合わせ、より好ましくはポリエチレンテレフタレート製点眼容器とポリエチレン製ノズルの組み合わせ、特に好ましくはポリエチレンテレフタレート製点眼容器と低密度ポリエチレン製ノズルの組み合わせであり、このような組み合わせとすることで、本発明における滴下量のバラツキ抑制効果を良好に発揮することができる。 As a preferred combination of the container for containing the aqueous ophthalmic composition of the present invention and the peripheral part of the container spout, a combination of a polyethylene terephthalate container and a peripheral part of the polyethylene container spout, more preferably a polyethylene terephthalate eye drop container and a polyethylene nozzle This combination is particularly preferably a combination of a polyethylene terephthalate eye drop container and a low density polyethylene nozzle, and by using such a combination, the effect of suppressing variation in the amount of dripping in the present invention can be exhibited well.
本発明の水性眼科組成物は、消泡時間が短縮されており、使用時の滴下量のバラツキを抑制し、毎回の使用で一定量を点眼することができるので、特に薬理活性成分及び／又は生理活性成分を含有する点眼剤として適するものである。このような点眼剤の用途として、ドライアイ用点眼剤、充血除去用点眼剤、抗菌用点眼剤、抗炎症用点眼剤、痒み抑制用点眼剤、疲れ目抑制用点眼剤などが挙げられる。 The aqueous ophthalmic composition of the present invention has a short defoaming time, suppresses variations in the amount of dripping during use, and can be instilled in a certain amount for each use. It is suitable as an eye drop containing a physiologically active ingredient. Uses of such eye drops include eye drops for dry eye, eye drops for removing hyperemia, eye drops for antibacterial use, eye drops for anti-inflammation, eye drops for suppressing itchiness, eye drops for suppressing fatigue eyes, and the like.
また、本発明は、別の観点から、水性眼科組成物の製造のための、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と、(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油の使用も提供する。 In another aspect, the present invention provides (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof for the production of an aqueous ophthalmic composition, and (B) the average added mole number of ethylene oxide. Also provided is the use of polyoxyethylene castor oil wherein is from 2 to 30 moles.
更に、本発明は、別の観点から、水性眼科組成物としての、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を含む組成物の使用も提供する。 Further, according to another aspect of the present invention, as an aqueous ophthalmic composition, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) an average added mole number of ethylene oxide is 2 to 2. Also provided is the use of a composition comprising polyoxyethylene castor oil that is 30 moles.
更に、本発明は、別の観点から、水性眼科組成物としての使用のための、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B) 酸化エチレンの平均付加モル数が２〜３０モルであるポリオキシエチレンヒマシ油を含む組成物を提供する。 Furthermore, the present invention provides, from another viewpoint, for use as an aqueous ophthalmic composition, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) an average addition mole of ethylene oxide. Provided is a composition comprising polyoxyethylene castor oil having a number of 2 to 30 moles.
［２．熱安定化方法］
前述した通り、水性眼科組成物中に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と共に、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することによって、(A)成分を含有する水性眼科組成物を加熱した状態で保存した場合に生じ易い(A)成分の熱分解を抑制することができる。
従って、本発明は、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種を含有する水性眼科組成物に、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における熱安定性を向上させる方法を提供するものである。
[2. Thermal stabilization method]
As described above, in the aqueous ophthalmic composition, (A) polyoxyethylene castor having at least one selected from the group consisting of glycyrrhizic acid and a salt thereof and (B) an average added mole number of ethylene oxide of 2 to 30 By blending the oil, thermal decomposition of the component (A), which is likely to occur when the aqueous ophthalmic composition containing the component (A) is stored in a heated state, can be suppressed.
Accordingly, the present invention provides an aqueous ophthalmic composition containing at least one selected from the group consisting of (A) glycyrrhizic acid and salts thereof, and (B) polyoxyethylene having an average added mole number of ethylene oxide of 2 to 30. The present invention provides a method for improving the thermal stability of the aqueous ophthalmic composition, comprising blending ethylene castor oil.
また、本発明は、水性眼科組成物中に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における熱安定性を向上させる方法を提供するものである。 In the aqueous ophthalmic composition, the present invention provides (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) a polyoxyethylene having an average addition mole number of ethylene oxide of 2 to 30. The present invention provides a method for improving the thermal stability of the aqueous ophthalmic composition, comprising blending ethylene castor oil.
これらの方法において、(A)成分及び(B)成分が共存するのであれば、それらの添加は同時であっても、別々であってもよく、その順序も特に限定されない。使用する(A)成分及び(B)成分の種類、それらの含有量（または配合量）、それらの比率、その他に含有させる成分の種類、含有量（または配合量）、水性眼科組成物の製剤形態、容器の種類、組み合わせ、実施方法等については、前記「１．水性眼科組成物」と同様である。 In these methods, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Types of component (A) and component (B) to be used, their content (or blending amount), ratio thereof, other types of components to be included, content (or blending amount), formulation of aqueous ophthalmic composition The form, type of container, combination, method of implementation, and the like are the same as in “1. Aqueous ophthalmic composition”.
なお、本明細書において、水性眼科組成物における熱安定性が改善されているか否かは、後述の実施例に記載の方法によって判定することが可能である。 In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the thermal stability in an aqueous ophthalmic composition is improved.
［３．光安定化方法］
前述した通り、水性眼科組成物中に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と共に、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することによって、該水性眼科組成物に含まれる(A)成分の光分解を抑制することができる。
[3. Light stabilization method]
As described above, in the aqueous ophthalmic composition, (A) polyoxyethylene castor having at least one selected from the group consisting of glycyrrhizic acid and a salt thereof and (B) an average added mole number of ethylene oxide of 2 to 30 By blending oil, photodegradation of component (A) contained in the aqueous ophthalmic composition can be suppressed.
従って、本発明は、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種を含有する水性眼科組成物に、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における光安定性を向上させる方法を提供するものである。 Accordingly, the present invention provides an aqueous ophthalmic composition containing at least one selected from the group consisting of (A) glycyrrhizic acid and salts thereof, and (B) polyoxyethylene having an average added mole number of ethylene oxide of 2 to 30. The present invention provides a method for improving the light stability in the aqueous ophthalmic composition, comprising blending ethylene castor oil.
また、本発明は、水性眼科組成物中に、(A) グリチルリチン酸及びその塩からなる群から選択される少なくとも一種、並びに(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を配合することを含む、該水性眼科組成物における光安定性を向上させる方法を提供するものである。 In the aqueous ophthalmic composition, the present invention provides (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) a polyoxyethylene having an average addition mole number of ethylene oxide of 2 to 30. The present invention provides a method for improving the light stability in the aqueous ophthalmic composition, comprising blending ethylene castor oil.
これらの方法において、(A)成分及び(B)成分が共存するのであれば、それらの添加は同時であっても、別々であってもよく、その順序も特に限定されない。使用する(A)成分及び(B)成分の種類、それらの含有量（または配合量）、それらの比率、その他に含有させる成分の種類、含有量（または配合量）、水性眼科組成物の製剤形態、容器の種類、組み合わせ、実施方法等については、前記「１．水性眼科組成物」と同様である。 In these methods, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Types of component (A) and component (B) to be used, their content (or blending amount), ratio thereof, other types of components to be included, content (or blending amount), formulation of aqueous ophthalmic composition The form, type of container, combination, method of implementation, and the like are the same as in “1. Aqueous ophthalmic composition”.
なお、本明細書において、水性眼科組成物における光安定性が改善されているか否かは、後述の実施例に記載の方法によって判定することが可能である。 In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the light stability in the aqueous ophthalmic composition is improved.
［４．消泡時間の短縮方法］
前述したように、本発明の水性眼科組成物では、(A)成分及び(B)成分を併用することによって、(B)成分を含有する水性眼科組成物における消泡時間を短縮させることができ、更に、その結果、使用時の滴下量のバラツキを抑制することができる。
[4. Method for shortening defoaming time]
As described above, in the aqueous ophthalmic composition of the present invention, the antifoaming time in the aqueous ophthalmic composition containing the component (B) can be shortened by using the component (A) and the component (B) in combination. Furthermore, as a result, variations in the amount of dripping during use can be suppressed.
従って、本発明は、更に別の観点から、 (A)グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を、水性眼科組成物に配合することを含む、該水性眼科組成物における消泡時間を短縮させる方法を提供する。 Accordingly, the present invention provides, from another viewpoint, (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) a polyoxyethylene having an average added mole number of ethylene oxide of 2 to 30 There is provided a method for reducing the defoaming time in an aqueous ophthalmic composition comprising incorporating castor oil into the aqueous ophthalmic composition.
また、本発明は、(B)酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を含有する水性眼科組成物に、(A)グリチルリチン酸及びその塩からなる群から選択される少なくとも一種を配合することを含む、該水性眼科組成物における消泡時間を短縮させる方法をも提供する。 Further, the present invention provides an aqueous ophthalmic composition containing (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30, selected from the group consisting of (A) glycyrrhizic acid and a salt thereof. There is also provided a method for reducing the defoaming time in the aqueous ophthalmic composition, which comprises blending at least one of the above.
また、本発明は、(A)グリチルリチン酸及びその塩からなる群から選択される少なくとも一種と、(B) 酸化エチレンの平均付加モル数が２〜３０であるポリオキシエチレンヒマシ油を、水性眼科組成物に配合することを含む、該水性眼科組成物における使用時の滴下量のバラツキを抑制する方法を提供する。 The present invention also provides (A) at least one selected from the group consisting of glycyrrhizic acid and salts thereof, and (B) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30, Provided is a method for suppressing variations in dripping amount during use in the aqueous ophthalmic composition, which comprises blending into the composition.
これらの方法において、(A)成分及び(B)成分が共存するのであれば、それらの添加は同時であっても、別々であってもよく、その順序も特に限定されない。使用する(A)成分及び(B)成分の種類、それらの含有量（または配合量）、それらの比率、その他に含有させる成分の種類、含有量（または配合量）、水性眼科組成物の製剤形態、容器の種類、組み合わせ、実施方法等については、前記「１．水性眼科組成物」と同様である。 In these methods, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Types of component (A) and component (B) to be used, their content (or blending amount), ratio thereof, other types of components to be included, content (or blending amount), formulation of aqueous ophthalmic composition The form, type of container, combination, method of implementation, and the like are the same as in “1. Aqueous ophthalmic composition”.
なかでも、これらの方法は、水性眼科組成物が、点眼剤、コンタクトレンズ装着液の場合に好適に適用される。 Among these, these methods are suitably applied when the aqueous ophthalmic composition is an eye drop or a contact lens mounting solution.
なお、本明細書において、水性眼科組成物における消泡時間が短縮されているか否かは、後述の実施例に記載の方法によって判定することが可能である。 In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the defoaming time in an aqueous ophthalmic composition is shortened.
以下に、実施例及び試験例を挙げて本発明を詳細に説明するが、本発明はこれらの実施例等によって限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.
［試験例１ 熱安定性に関する試験］
下記表1に示される水性眼科組成物を常法により調製し、熱安定性を評価した。グリチルリチン酸二カリウムとしては、ＷＡＫＯ製のものを用いた。なお、ポリオキシエチレンヒマシ油１０及びポリオキシエチレンヒマシ油３５としては、医薬品添加物規格２００３のポリオキシエチレンヒマシ油の規格に適合するものであって、酸化エチレンの平均付加モル数が１０と３５のものを用いた。
[ Test Example 1 Test for Thermal Stability ]
The aqueous ophthalmic composition shown in Table 1 below was prepared by a conventional method, and the thermal stability was evaluated. As dipotassium glycyrrhizinate, a product manufactured by WAKO was used. The polyoxyethylene castor oil 10 and the polyoxyethylene castor oil 35 conform to the standard of polyoxyethylene castor oil of the pharmaceutical additive standard 2003, and the average added mole number of ethylene oxide is 10 and 35. The thing of was used.
次いで、調製した水性眼科組成物を１０ｍL容量のガラスヘッドスペースバイアルに５ｍLずつ充填し、７０℃の恒温器内に遮光下にて保存した。保存７、１４日後に、ＨＰＬＣを用いて水性眼科組成物におけるグリチルリチン酸二カリウムの含有量を定量し、下記式に従い、グリチルリチン酸二カリウムの残存率を算出した。算出の結果を表１に併せて示す。 Next, the prepared aqueous ophthalmic composition was filled into a 10 mL capacity glass headspace vial by 5 mL, and stored in a thermostat at 70 ° C. under light shielding. Seven and 14 days after storage, the content of dipotassium glycyrrhizinate in the aqueous ophthalmic composition was quantified using HPLC, and the residual rate of dipotassium glycyrrhizinate was calculated according to the following formula. The calculation results are also shown in Table 1.
残存率（％）＝（保存後のグリチルリチン酸二カリウム含有量）/（保存前のグリチルリチン酸二カリウム１０含有量）×１００ Residual rate (%) = (dipotassium glycyrrhizinate content after storage) / (dipotassium glycyrrhizinate content before storage) × 100
表１に示す通り、比較例１に示すグリチルリチン酸二カリウムを含有する水性眼科組成物では、７日保存後と１４日保存後のいずれにおいてもグリチルリチン酸二カリウムの分解が認められた。これに対して、グリチルリチン酸二カリウムと共に、ポリオキシエチレンヒマシ油１０を含有する水性眼科組成物では、７日保存後と１４日保存後のいずれにおいても、比較例１と比べてグリチルリチン酸二カリウムの残存率が顕著に向上しており、グリチルリチン酸二カリウムを含有する水性眼科組成物の熱安定性が向上したことが確認できた（実施例１）。また、グリチルリチン酸二カリウムと共に、ポリオキシエチレンヒマシ油３５を含有する水性眼科組成物では、グリチルリチン酸二カリウムの分解が抑制されず、熱安定性の向上は認められなかった（比較例２）。 As shown in Table 1, in the aqueous ophthalmic composition containing dipotassium glycyrrhizinate shown in Comparative Example 1, degradation of dipotassium glycyrrhizinate was observed both after storage for 7 days and after storage for 14 days. On the other hand, in the aqueous ophthalmic composition containing polyoxyethylene castor oil 10 together with dipotassium glycyrrhizinate, dipotassium glycyrrhizinate compared to Comparative Example 1 both after 7 days storage and after 14 days storage. It was confirmed that the thermal stability of the aqueous ophthalmic composition containing dipotassium glycyrrhizinate was improved (Example 1). Moreover, in the aqueous ophthalmic composition containing polyoxyethylene castor oil 35 together with dipotassium glycyrrhizinate, decomposition of dipotassium glycyrrhizinate was not suppressed, and no improvement in thermal stability was observed (Comparative Example 2).
［試験例２ 光安定性に関する試験］
下記表２に示す組成の水性眼科組成物を常法により調製し、光安定性を評価した。なお、グリチルリチン酸二カリウム、ポリオキシエチレンヒマシ油１０、及びポリオキシエチレンヒマシ油３５としては、試験例１と同じものを用いた。
[ Test Example 2 Photostability Test ]
An aqueous ophthalmic composition having the composition shown in Table 2 below was prepared by a conventional method, and photostability was evaluated. In addition, as dipotassium glycyrrhizinate, the polyoxyethylene castor oil 10, and the polyoxyethylene castor oil 35, the same thing as the test example 1 was used.
次いで、調製した水性眼科組成物を１０ｍL容量のガラスヘッドスペースバイアルに５ｍLずつ充填した。光安定性試験装置（「Light-Tron LT-120 D3CJ型」、ナガノ科学株式会社製）を用いて、D６５ランプを光源として、室温の下、５０００lxの光を１２０時間連続照射し、水性眼科組成物に対して積算照射量６０万lx・hrの光を曝光した。曝光後、ＨＰＬＣを用いて水性眼科組成物におけるグリチルリチン酸二カリウムの含有量を定量し、下記式に従い、グリチルリチン酸二カリウムの残存率を算出した。算出の結果を表２に併せて示す。 Next, 5 mL each of the prepared aqueous ophthalmic composition was filled into a 10 mL glass headspace vial. Using an optical stability tester (“Light-Tron LT-120 D3CJ”, manufactured by Nagano Science Co., Ltd.), using a D65 lamp as a light source, irradiating 5000 lx light continuously at room temperature for 120 hours to produce an aqueous ophthalmic composition The object was exposed to light with an integrated irradiation amount of 600,000 lx · hr. After exposure, the content of dipotassium glycyrrhizinate in the aqueous ophthalmic composition was quantified using HPLC, and the residual rate of dipotassium glycyrrhizinate was calculated according to the following formula. The calculation results are also shown in Table 2.
残存率（％）＝（光照射後のグリチルリチン酸二カリウム含有量）/（光照射前のグリチルリチン酸二カリウム含有量）×１００ Residual rate (%) = (dipotassium glycyrrhizinate after light irradiation) / (dipotassium glycyrrhizinate before light irradiation) × 100
表２に示す通り、比較例３に示すグリチルリチン酸二カリウムを含有する水性眼科組成物では、光照射後にグリチルリチン酸二カリウム含有量が低下し、曝光によるグリチルリチン酸二カリウムの分解が認められた。これに対して、グリチルリチン酸二カリウムと共に、ポリオキシエチレンヒマシ油１０を含有する水性眼科組成物では、グリチルリチン酸二カリウムの残存率が顕著に向上し、光安定性が向上したことが確認できた（実施例２）。また、グリチルリチン酸二カリウムと共に、ポリオキシエチレンヒマシ油３５を含有する水性眼科組成物では、グリチルリチン酸二カリウムの分解が抑制されておらず、光安定性の向上は認められなかった（比較例４）。 As shown in Table 2, in the aqueous ophthalmic composition containing dipotassium glycyrrhizinate shown in Comparative Example 3, the dipotassium glycyrrhizinate content decreased after light irradiation, and decomposition of dipotassium glycyrrhizinate by exposure was observed. On the other hand, in the aqueous ophthalmic composition containing polyoxyethylene castor oil 10 together with dipotassium glycyrrhizinate, it was confirmed that the residual rate of dipotassium glycyrrhizinate was significantly improved and the photostability was improved. (Example 2). Moreover, in the aqueous ophthalmic composition containing polyoxyethylene castor oil 35 together with dipotassium glycyrrhizinate, decomposition of dipotassium glycyrrhizinate was not suppressed, and no improvement in light stability was observed (Comparative Example 4). ).
［試験例３ 消泡時間に関する試験］
下記表３に示す組成の水性眼科組成物を常法により調製し、消泡時間を評価した。なお、グリチルリチン酸二カリウム及びポリオキシエチレンヒマシ油１０としては、試験例１と同じものを用いた。
[ Test Example 3 Test for Defoaming Time ]
An aqueous ophthalmic composition having the composition shown in Table 3 below was prepared by a conventional method, and the defoaming time was evaluated. In addition, the same thing as Test Example 1 was used as dipotassium glycyrrhizinate and polyoxyethylene castor oil 10.
次いで、５０mL容量のガラス製遠沈管に各水性眼科組成物を３０ｍＬずつ充填し、それらをＲＥＣＩＰＡＤ ＳＨＡＫＥＲ ＳＲ−２ｗ（ＴＡＩＴＥＣ）を用いて、１５００回振とうした。振とう終了直後、目視により、泡部分と水溶液部分を確認し、泡部分の容積を測定した。次いで、当初の泡の容積が半減するまでの所要時間を泡半減期として測定し、比較例及び実施例の泡半減期の測定結果に基づいて、泡半減期の短縮率を下記式から算出した。短縮率が大きいほど、泡の消える速度が速いことを意味する。 Next, 30 mL of each aqueous ophthalmic composition was filled in a 50 mL glass centrifuge tube, and they were shaken 1500 times using RECIPAD SHAKER SR-2w (TAITEC). Immediately after the end of shaking, the foam part and the aqueous solution part were visually confirmed, and the volume of the foam part was measured. Next, the time required until the initial foam volume was reduced by half was measured as the foam half-life, and the reduction rate of the foam half-life was calculated from the following formula based on the measurement results of the foam half-life of the comparative example and the example. . The larger the shortening rate, the faster the bubbles disappear.
泡半減期短縮率（％）＝（比較例５の泡半減期−実施例３の泡半減期）/（比較例５の泡半減期）×１００ Foam half-life shortening rate (%) = (foam half-life of Comparative Example 5−foam half-life of Example 3) / (foam half-life of Comparative Example 5) × 100
表３に示す通り、ポリオキシエチレンヒマシ油１０を含有し、グリチルリチン酸二カリウムを含有しない水性眼科組成物（比較例５）と比較して、ポリオキシエチレンヒマシ油１０と共に、グリチルリチン酸二カリウムを含有する水性眼科組成物では、大幅に泡半減期が短縮されることが確認できた（実施例３）。 As shown in Table 3, compared with the aqueous ophthalmic composition (Comparative Example 5) containing polyoxyethylene castor oil 10 and not containing dipotassium glycyrrhizinate, dipotassium glycyrrhizinate together with polyoxyethylene castor oil 10 was used. In the aqueous ophthalmic composition contained, it was confirmed that the foam half-life was significantly shortened (Example 3).
製剤例
表４及び表５に記載の処方で、常法により、点眼剤（製剤例１〜１０）を調製する。
Formulation Examples Eye drops (Formulation Examples 1 to 10) are prepared by a conventional method with the formulations shown in Tables 4 and 5.
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