JP2005272461A - Ophthalmic solution - Google Patents
Ophthalmic solution Download PDFInfo
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- JP2005272461A JP2005272461A JP2005051283A JP2005051283A JP2005272461A JP 2005272461 A JP2005272461 A JP 2005272461A JP 2005051283 A JP2005051283 A JP 2005051283A JP 2005051283 A JP2005051283 A JP 2005051283A JP 2005272461 A JP2005272461 A JP 2005272461A
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- Prior art keywords
- pranoprofen
- hydrochloride
- aqueous solution
- eye drop
- cationic drug
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- 239000002997 ophthalmic solution Substances 0.000 title claims abstract description 8
- 229940054534 ophthalmic solution Drugs 0.000 title claims abstract description 7
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229960003101 pranoprofen Drugs 0.000 claims abstract description 49
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229940079593 drug Drugs 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 26
- 125000002091 cationic group Chemical group 0.000 claims abstract description 25
- 239000007864 aqueous solution Substances 0.000 claims abstract description 21
- 229960004926 chlorobutanol Drugs 0.000 claims abstract description 14
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 13
- 239000000243 solution Substances 0.000 claims abstract description 9
- 239000003889 eye drop Substances 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims description 9
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims description 9
- 229940012356 eye drops Drugs 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 claims description 6
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 claims description 6
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 claims description 6
- 229960004760 naphazoline hydrochloride Drugs 0.000 claims description 4
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 claims description 3
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 claims description 3
- BALXUFOVQVENIU-GNAZCLTHSA-N Ephedrine hydrochloride Chemical compound Cl.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GNAZCLTHSA-N 0.000 claims description 3
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 claims description 3
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 claims description 3
- 229960002534 ephedrine hydrochloride Drugs 0.000 claims description 3
- 229960003072 epinephrine hydrochloride Drugs 0.000 claims description 3
- 229940051020 methylephedrine hydrochloride Drugs 0.000 claims description 3
- 229960003733 phenylephrine hydrochloride Drugs 0.000 claims description 3
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 claims description 3
- 229960004186 naphazoline nitrate Drugs 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 abstract description 7
- 230000002421 anti-septic effect Effects 0.000 abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 5
- 239000004327 boric acid Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 206010020565 Hyperaemia Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- -1 chondroitin Amino acids Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229940034371 sodium citrate 230 mg Drugs 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- XLRHXNIVIZZOON-WFUPGROFSA-L Flavin adenine dinucleotide disodium Chemical compound [Na+].[Na+].C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1COP([O-])(=O)OP([O-])(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 XLRHXNIVIZZOON-WFUPGROFSA-L 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 239000010624 camphor oil Substances 0.000 description 1
- 229960000411 camphor oil Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940094443 oxytocics prostaglandins 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
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 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
- 229950001574 riboflavin phosphate Drugs 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Abstract
Description
本発明は、プラノプロフェンおよびカチオン性薬物を配合した点眼剤およびその製造方法に関する。 The present invention relates to an eye drop containing pranoprofen and a cationic drug and a method for producing the same.
プラノプロフェン（化学名：α−メチル−５Ｈ−［１］ベンゾピラノ［２，３−ｂ］ピリジン−７−酢酸）は、炎症の原因物質プロスタグランジンの生成を抑制し、かゆみ、充血などの症状を緩和し、外眼部および前眼部の炎症性疾患(眼瞼炎、結膜炎、角膜炎、強膜炎、上強膜炎、前眼部ブドウ膜炎、術後炎症)の治療のため、点眼剤として臨床的に広く用いられている。プラノプロフェンは、分子内にカルボキシル基を持つアリールカルボン酸であり、カルボキシル基の解離の程度により、水への溶解性が大幅に変化する。そのためプラノプロフェンはカルボキシル基が解離しやすいｐＨが７．１以上では、水への溶解性が非常に高いが、酸性領域においては水に溶解しないことが報告されている。（非特許文献１）。そのため、プラノプロフェンを点眼剤として提供する場合、通常はｐＨ７〜８の範囲で点眼剤として使用されている。 Planoprofen (chemical name: α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid) suppresses the production of prostaglandins that cause inflammation, itching, hyperemia, etc. To relieve symptoms and treat inflammatory diseases of the external and anterior eyes (blinditis, conjunctivitis, keratitis, scleritis, suprasclerosis, anterior uveitis, postoperative inflammation) Widely used clinically as eye drops. Planoprofen is an arylcarboxylic acid having a carboxyl group in the molecule, and its solubility in water varies greatly depending on the degree of dissociation of the carboxyl group. Therefore, it has been reported that pranoprofen has a very high solubility in water when the pH at which carboxyl groups are easily dissociated is 7.1 or higher, but does not dissolve in water in the acidic region. (Non-Patent Document 1). Therefore, when pranoprofen is provided as an eye drop, it is usually used as an eye drop within a pH range of 7-8.
一般的に点眼剤のｐＨは、その使用感の点から弱酸性が好まれる。しかしながらプラノプロフェンを配合した弱酸性の点眼剤は報告されていない。 In general, the pH of eye drops is preferably weakly acidic in terms of the feeling of use. However, no weakly acidic eye drops containing pranoprofen have been reported.
ここで、点眼剤は無菌製剤であり、従来から２次汚染防止のため防腐剤を使用して防腐性を確保してきた。しかし、防腐剤として汎用される塩化ベンザルコニウムは、結膜充血、流涙、異物感などが生じる場合がある。そこで、生体への影響が緩和で、十分な防腐効果を示す成分としてクロロブタノールが注目されている。しかし、クロロブタノールは、プラノプロフェンの溶解するｐＨ７〜８では不安定であり、速やかに分解してしまうことから防腐効果を発揮できないことが知られている。 Here, the eye drop is a sterile preparation, and antiseptic properties have conventionally been secured by using a preservative for preventing secondary contamination. However, benzalkonium chloride, which is widely used as a preservative, may cause conjunctival hyperemia, lacrimation, foreign body sensation, and the like. Therefore, chlorobutanol has attracted attention as a component that has a mild effect on the living body and exhibits a sufficient antiseptic effect. However, it is known that chlorobutanol is unstable at pH 7 to 8 where pranoprofen dissolves, and cannot be preserved because it decomposes rapidly.
従来、プラノプロフェンとカチオン性薬物を配合した液剤はいくつか報告がある（特許文献１、２）が、プラノプロフェンを配合した弱酸性の点眼剤は報告されていない。 Conventionally, there have been some reports on solutions containing pranoprofen and a cationic drug (Patent Documents 1 and 2), but weakly acidic eye drops containing pranoprofen have not been reported.
本発明の目的は、弱酸性下でプラノプロフェンを配合しても、析出や白濁が生じず、経時的に安定な点眼剤を提供することにある。 An object of the present invention is to provide an eye drop which is stable over time without causing precipitation or cloudiness even when pranoprofen is blended under weak acidity.
また、本発明の目的はプラノプロフェン配合点眼剤において、クロロブタノールを配合しても十分な防腐効果を得られる点眼剤を提供することにある。 Another object of the present invention is to provide an ophthalmic solution that can provide a sufficient antiseptic effect even when chlorobutanol is incorporated into the ophthalmic formulation containing pranoprofen.
本発明者らは、課題を解決するために検討した結果、ｐＨ６．８以上でプラノプロフェンを溶解し、その溶液にカチオン性薬物を溶解させた後、ｐＨを５以上６．５以下に調整すると、驚くべきことに、通常はプラノプロフェンが析出や溶液が白濁してしまうｐＨ６．５以下であってもプラノプロフェンが溶解しており、クロロブタノールの安定性も経時的に保持された点眼剤を得ることができることを見出し、本発明を完成した。 As a result of investigations to solve the problems, the present inventors have dissolved pranoprofen at pH 6.8 or higher, dissolved a cationic drug in the solution, and then adjusted the pH to 5 or higher and 6.5 or lower. Then, surprisingly, pranoprofen is dissolved even at pH 6.5 or less, where pranoprofen usually precipitates and the solution becomes cloudy, and the stability of chlorobutanol was maintained over time. The inventors found that an eye drop can be obtained and completed the present invention.
すなわち本発明は、
１．プラノプロフェンおよびカチオン性薬物を配合し、ｐＨが５〜６．５の点眼剤。
２．カチオン性薬物が、マレイン酸クロルフェニラミン、塩酸ジフェンヒドラミン、塩酸テトラヒドロゾリン、塩酸ナファゾリン、硝酸ナファゾリン、塩酸フェニレフリン、塩酸メチルエフェドリン、塩酸エフェドリンおよび塩酸エピネフリンから選ばれる１種または２種以上である１記載の点眼剤。
３．カチオン性薬物がマレイン酸クロルフェニラミンおよび塩酸テトラヒドロゾリンから選ばれる１種または２種である１記載の点眼剤。
４．さらにクロロブタノールを配合したことを特徴とする１または２に記載の点眼剤。
５．プラノプロフェン１質量部に対して、カチオン性薬物が0.01〜10質量部である１〜４のいずれかに記載の点眼剤。
６．下記の工程
（ａ）プラノプロフェンをｐＨ調整剤でｐＨ６．８以上に調整して水に溶解し、プラノプロフェン水溶液を得る工程、
（ｂ）カチオン性薬物またはその水溶液をプラノプロフェン水溶液に加え、均一に混合する工程、
（ｃ）工程（ｂ）で得られた水溶液をｐＨ調整剤でｐＨ５〜６．５に調整する工程、
により製造されたことを特徴とする、１記載の点眼剤。
７．下記の工程
（ａ）プラノプロフェンをｐＨ調整剤でｐＨ６．８以上に調整して水に溶解し、プラノプロフェン水溶液を得る工程、
（ｂ）カチオン性薬物またはその水溶液をプラノプロフェン水溶液に加え、均一に混合する工程、
（ｃ）工程（ｂ）で得られた水溶液をｐＨ調整剤でｐＨ５〜６．５に調整する工程、
からなる、１記載の点眼剤の製造方法。
である。
That is, the present invention
1. An ophthalmic solution containing pranoprofen and a cationic drug and having a pH of 5 to 6.5.
2. Instillation according to 1, wherein the cationic drug is one or more selected from chlorpheniramine maleate, diphenhydramine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, methylephedrine hydrochloride, ephedrine hydrochloride, and epinephrine hydrochloride. Agent.
3. The eye drop according to 1, wherein the cationic drug is one or two selected from chlorpheniramine maleate and tetrahydrozoline hydrochloride.
4). The eye drop according to 1 or 2, further comprising chlorobutanol.
5). The eye drop according to any one of 1 to 4, wherein the cationic drug is 0.01 to 10 parts by mass with respect to 1 part by mass of pranoprofen.
6). The following step (a) a step of adjusting pranoprofen to pH 6.8 or higher with a pH adjuster and dissolving it in water to obtain a pranoprofen aqueous solution,
(B) adding a cationic drug or an aqueous solution thereof to an aqueous pranoprofen solution, and mixing them uniformly;
(C) a step of adjusting the aqueous solution obtained in step (b) to pH 5 to 6.5 with a pH adjusting agent;
2. The ophthalmic solution according to 1, wherein
7). The following step (a) a step of adjusting pranoprofen to pH 6.8 or more with a pH adjusting agent and dissolving in water to obtain a pranoprofen aqueous solution,
(B) adding a cationic drug or an aqueous solution thereof to an aqueous pranoprofen solution, and mixing them uniformly;
(C) a step of adjusting the aqueous solution obtained in step (b) to pH 5 to 6.5 with a pH adjusting agent;
2. A method for producing an eye drop according to 1.
It is.
本発明により、弱酸性下においてもプラノプロフェンが澄明に溶解している点眼剤を提供することができた。 According to the present invention, an eye drop in which pranoprofen is clearly dissolved even under weak acidity can be provided.
本発明で、プラノプロフェンの配合量は、製剤全体の0.005w/v%〜2.0w/v%が好ましく、0.05w/v%〜0.1w/v%がさらに好ましい。配合量が少ないと薬効が不十分になり、配合量が多すぎると沈殿が発生する可能性があるからである。 In the present invention, the blending amount of pranoprofen is preferably 0.005 w / v% to 2.0 w / v% of the whole preparation, more preferably 0.05 w / v% to 0.1 w / v%. This is because if the amount is small, the medicinal effect becomes insufficient, and if the amount is too large, precipitation may occur.
本発明で、カチオン性薬物とは、通常水溶液中でカチオン（正電荷）性を示す薬物を指す。点眼剤に配合するこのような薬物としては、一部の抗ヒスタミン剤や血管収縮剤などがある。 In the present invention, the cationic drug refers to a drug that exhibits a cationic (positive charge) property in a normal aqueous solution. Examples of such drugs to be added to eye drops include some antihistamines and vasoconstrictors.
これらの抗ヒスタミン剤や血管収縮剤などのカチオン性薬物とプラノプロフェンを配合した点眼剤は、アレルギー反応の際のかゆみ症状などを有効に抑え、さらにそれに伴う炎症や充血などを効率よく取り除くことができることが考えられる。 Eye drops containing pranoprofen and cationic drugs such as antihistamines and vasoconstrictors can effectively suppress itch symptoms during allergic reactions, and can effectively remove inflammation and hyperemia associated therewith. Can be considered.
具体的に本発明のカチオン性薬物の好ましいものとして、マレイン酸クロルフェニラミン、塩酸ジフェンヒドラミン、塩酸テトラヒドロゾリン、塩酸ナファゾリン、硝酸ナファゾリン、塩酸フェニレフリン、塩酸メチルエフェドリン、塩酸エフェドリンおよび塩酸エピネフリンから選ばれる１種または２種以上をあげることができる。 Specifically, the preferred cationic drug of the present invention is one selected from chlorpheniramine maleate, diphenhydramine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, ephedrine hydrochloride, and epinephrine hydrochloride. Two or more can be listed.
それらの中でも特にマレイン酸クロルフェニラミンおよび塩酸テトラヒドロゾリンから選ばれる１種または２種が好ましい。 Of these, one or two selected from chlorpheniramine maleate and tetrahydrozoline hydrochloride are particularly preferred.
本発明でカチオン性薬物の配合量は、プラノプロフェン１質量部に対して、0.01〜10質量部が好ましく、0.1〜5質量部がさらに好ましい。配合量が少ないと沈殿の抑制効果が不十分であるが、過剰に配合する必要も無いからである。 In the present invention, the compounding amount of the cationic drug is preferably 0.01 to 10 parts by mass, more preferably 0.1 to 5 parts by mass with respect to 1 part by mass of pranoprofen. This is because if the amount is too small, the effect of suppressing precipitation is insufficient, but it is not necessary to add too much.
本発明でクロロブタノールを配合する場合の配合量は、0.05〜0.4w/v%であり、好ましくは、0.06w/v%〜0.3w/v%である。配合量が少ないと防腐効果が不十分になるが、過剰に配合する必要もないからである。 In the present invention, when chlorobutanol is blended, the blending amount is 0.05 to 0.4 w / v%, preferably 0.06 w / v% to 0.3 w / v%. This is because when the amount is small, the antiseptic effect is insufficient, but it is not necessary to add excessively.
本発明の点眼剤は以下のように製造する。 The eye drop of the present invention is produced as follows.
はじめに、プラノプロフェンをｐＨ調整剤でｐＨ６．８以上に調整して溶解し、プラノプロフェン水溶液を得る。次にカチオン性薬物またはその水溶液をプラノプロフェン水溶液に加え、均一に混合し、得られた水溶液をｐＨ調整剤でｐＨ５以上、６．５以下に調整する。必要があれば、さらにクロロブタノールを配合することにより点眼剤を製造することができる。 First, pranoprofen is adjusted to pH 6.8 or higher with a pH adjuster and dissolved to obtain an aqueous pranoprofen solution. Next, the cationic drug or an aqueous solution thereof is added to the pranoprofen aqueous solution and mixed uniformly, and the obtained aqueous solution is adjusted to a pH of 5 or more and 6.5 or less with a pH adjuster. If necessary, an eye drop can be produced by further adding chlorobutanol.
ここで、プラノプロフェンをｐＨ６．８以上にして溶解して、そのままｐＨを６．５以下にすると、プラノプロフェンが析出してしまうが、プラノプロフェン水溶液にカチオン性薬物を配合すると、ｐＨを下げても析出が生じない。そこで、さらにクロロブタノールを配合することにより、防腐性が十分確保された点眼剤とすることができる。 Here, when pranoprofen is dissolved at pH 6.8 or higher and the pH is adjusted to 6.5 or lower as it is, pranoprofen is precipitated. However, when a cationic drug is added to the pranoprofen aqueous solution, No precipitation occurs even when the value is lowered. Therefore, by further blending chlorobutanol, an eye drop with sufficiently preserved antiseptic properties can be obtained.
ｐＨ調整剤は、点眼剤に使用する一般的なものを使用することができ、例えば、ホウ酸、リン酸、クエン酸とそれらの塩や塩酸、水酸化ナトリウムなどがあげられる。 As the pH adjuster, those commonly used for eye drops can be used, and examples thereof include boric acid, phosphoric acid, citric acid and salts thereof, hydrochloric acid, sodium hydroxide and the like.
本発明の点眼剤には、本発明の効果に影響を与えない範囲で、必要に応じて、医薬上許容される他の成分を配合することができる。そのような成分としては、例えば、イプシロンアミノカプロン酸、グリチルリチン酸二カリウム等の抗炎症薬、塩酸ピリドキシン、リン酸リボフラビン、シアノコバラミン、パンテノール、酢酸トコフェノール、フラビンアデニンジヌクレオチドナトリウム等のビタミン類、コンドロイチン硫酸ナトリウム、アミノエチルスルホン酸等のアミノ酸類、塩化ナトリウム、塩化カリウム等の無機塩、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタンモノオレート等の界面活性剤、メントール、カンフル、ユーカリ油等の精油、その他基剤成分として、ホウ砂、ホウ酸、パラオキシ安息香酸エステル（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等）などをあげることができる。 In the eye drop of the present invention, other pharmaceutically acceptable components can be blended as necessary within a range that does not affect the effects of the present invention. Examples of such components include anti-inflammatory drugs such as epsilon aminocaproic acid and dipotassium glycyrrhizinate, vitamins such as pyridoxine hydrochloride, riboflavin phosphate, cyanocobalamin, panthenol, tocophenol acetate, and flavin adenine dinucleotide sodium, chondroitin Amino acids such as sodium sulfate and aminoethylsulfonic acid, inorganic salts such as sodium chloride and potassium chloride, surfactants such as polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan monooleate, essential oils such as menthol, camphor and eucalyptus oil Other base ingredients include borax, boric acid, paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), etc. Rukoto can.
本発明の点眼剤は、１日１回〜数回、１回１滴から数滴投与して使用する。 The eye drop of the present invention is used once to several times a day, once to several drops at a time.
以下に、実施例、参考例および試験例により、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to Examples, Reference Examples and Test Examples.
処方 100mL中
プラノプロフェン 50mg
マレイン酸クロルフェニラミン 40mg
クロロブタノール 100mg
クエン酸 24mg
クエン酸ナトリウム 230mg
ホウ酸 500mg
希塩酸 適量
精製水 全100mL
製造方法
滅菌精製水(80mL)にクエン酸ナトリウムを溶解しｐＨが６．８以上になったことを確認し、プラノプロフェンを添加し、溶解させた。次にマレイン酸クロルフェニラミンを添加し溶解させ、クエン酸およびホウ酸を添加した。このときのｐＨは６程度であることを確認し、さらに、クロロブタノールを添加し溶解後、希塩酸を用いてｐＨ５．５に調製し、滅菌精製水を用いて全量を100mLとした。その後、ろ過滅菌を行い、点眼剤を得た。
Formula 100mL Planoprofen 50mg
Chlorpheniramine maleate 40mg
Chlorobutanol 100mg
Citric acid 24mg
Sodium citrate 230mg
Boric acid 500mg
Dilute hydrochloric acid appropriate amount purified water 100mL
Manufacturing method Sodium citrate was dissolved in sterilized purified water (80 mL) to confirm that the pH was 6.8 or higher, and pranoprofen was added and dissolved. Next, chlorpheniramine maleate was added and dissolved, and citric acid and boric acid were added. It was confirmed that the pH at this time was about 6, and further, chlorobutanol was added and dissolved, and then adjusted to pH 5.5 using dilute hydrochloric acid, and the total volume was adjusted to 100 mL using sterilized purified water. Thereafter, filtration sterilization was performed to obtain an eye drop.
参考例１
処方 100mL中
プラノプロフェン 50mg
マレイン酸クロルフェニラミン 40mg
クロロブタノール 100mg
クエン酸 24mg
クエン酸ナトリウム 230mg
ホウ酸 500mg
希塩酸 適量
精製水 全100mL
Reference example 1
Formula 100mL Planoprofen 50mg
Chlorpheniramine maleate 40mg
Chlorobutanol 100mg
Citric acid 24mg
Sodium citrate 230mg
Boric acid 500mg
Dilute hydrochloric acid appropriate amount purified water 100mL
製造方法
滅菌精製水(80mL)に各成分を添加し撹拌した。このときのｐＨは６程度であることを確認したが、プラノプロフェンは完全には溶解せず、希塩酸によりｐＨを５．５に調製しても溶解しなかった。
Production Method Each component was added to sterile purified water (80 mL) and stirred. Although it was confirmed that the pH at this time was about 6, pranoprofen was not completely dissolved, and even when the pH was adjusted to 5.5 with dilute hydrochloric acid, it was not dissolved.
試験例１
表１に示した処方の実施例２および比較例１の点眼液を実施例１と同様の製造方法を用いて調製し、２５℃１ヶ月での結晶などの沈殿生成の有無を目視観察により調べ、その有無を表１に示した。結晶などの沈殿生成が有る場合×を、無い場合○として記した。
Test example 1
The eye drops of Example 2 and Comparative Example 1 having the formulations shown in Table 1 were prepared using the same production method as in Example 1, and the presence or absence of precipitates such as crystals at 25 ° C. for one month was examined by visual observation. The presence or absence is shown in Table 1. When there was a precipitate such as a crystal, x was marked as ◯.
表に示したとおり、本発明の点眼剤は２５℃１ヶ月後においてもプラノプロフェンの沈殿を生じなかった。 As shown in the table, the eye drop of the present invention did not cause the precipitation of pranoprofen even after 1 month at 25 ° C.
試験例２
表２に示した処方の実施例および比較例の点眼液を実施例１と同様の製造方法を用いて調製し、５℃１週間での結晶などの沈殿生成の有無を目視観察により調べ、その有無を表２に示した。結晶などの沈殿生成が有る場合×を、無い場合○として記した。
Test example 2
Example ophthalmic solutions of the formulations shown in Table 2 and comparative examples were prepared using the same production method as in Example 1, and the presence or absence of precipitates such as crystals at 5 ° C. for 1 week was examined by visual observation. The presence or absence was shown in Table 2. When there was a precipitate such as a crystal, x was marked as ◯.
表に示したとおり、本発明の点眼剤は５℃１週間後においてもプラノプロフェンの沈殿を生じなかった。 As shown in the table, the eye drop of the present invention did not cause pranoprofen precipitation even after 1 week at 5 ° C.
本発明の点眼剤は、アレルギー症状の予防や改善のためや充血除去のための点眼剤として用いることができる。 The eye drop of the present invention can be used as an eye drop for preventing or ameliorating allergic symptoms or removing hyperemia.
Claims (7)
（ａ）プラノプロフェンをｐＨ調整剤でｐＨ６．８以上に調整して水に溶解し、プラノプロフェン水溶液を得る工程、
（ｂ）カチオン性薬物またはその水溶液をプラノプロフェン水溶液に加え、均一に混合する工程、
（ｃ）工程（ｂ）で得られた水溶液をｐＨ調整剤でｐＨ５〜６．５に調整する工程、
により製造されたことを特徴とする、請求項１に記載の点眼剤。 The following step (a) a step of adjusting pranoprofen to pH 6.8 or higher with a pH adjuster and dissolving it in water to obtain a pranoprofen aqueous solution,
(B) adding a cationic drug or an aqueous solution thereof to an aqueous pranoprofen solution, and mixing them uniformly;
(C) a step of adjusting the aqueous solution obtained in step (b) to pH 5 to 6.5 with a pH adjusting agent;
The eye drop according to claim 1, wherein the eye drop is produced by
（ａ）プラノプロフェンをｐＨ調整剤でｐＨ６．８以上に調整して水に溶解し、プラノプロフェン水溶液を得る工程、
（ｂ）カチオン性薬物またはその水溶液をプラノプロフェン水溶液に加え、均一に混合する工程、
（ｃ）工程（ｂ）で得られた水溶液をｐＨ調整剤でｐＨ５〜６．５に調整する工程、
からなる、請求項１記載の点眼剤の製造方法。 The following step (a) a step of adjusting pranoprofen to pH 6.8 or higher with a pH adjuster and dissolving it in water to obtain a pranoprofen aqueous solution,
(B) adding a cationic drug or an aqueous solution thereof to an aqueous pranoprofen solution, and mixing them uniformly;
(C) a step of adjusting the aqueous solution obtained in step (b) to pH 5 to 6.5 with a pH adjusting agent;
The manufacturing method of the eye drop of Claim 1 consisting of.
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| JP2017075145A (en) * | 2015-10-15 | 2017-04-20 | ロート製薬株式会社 | Ophthalmic composition |
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| JP2021107464A (en) * | 2015-10-15 | 2021-07-29 | ロート製薬株式会社 | Ophthalmic composition |
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