JP2023001391A - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- Publication number
- JP2023001391A JP2023001391A JP2022182023A JP2022182023A JP2023001391A JP 2023001391 A JP2023001391 A JP 2023001391A JP 2022182023 A JP2022182023 A JP 2022182023A JP 2022182023 A JP2022182023 A JP 2022182023A JP 2023001391 A JP2023001391 A JP 2023001391A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- weight
- component
- polyvinylpyrrolidone
- quaternary ammonium
- 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.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 63
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 31
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 29
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 29
- 238000004383 yellowing Methods 0.000 claims abstract description 29
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 28
- 229960005274 benzocaine Drugs 0.000 claims abstract description 27
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 25
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 24
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 19
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 9
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 9
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 210000004877 mucosa Anatomy 0.000 claims description 3
- 229930003658 monoterpene Natural products 0.000 abstract description 27
- 235000002577 monoterpenes Nutrition 0.000 abstract description 27
- 150000002773 monoterpene derivatives Chemical class 0.000 abstract description 25
- 238000002156 mixing Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 3
- 239000000203 mixture Substances 0.000 description 27
- 238000009472 formulation Methods 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- -1 aldehyde monoterpene Chemical class 0.000 description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 18
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 17
- 239000003814 drug Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000002202 Polyethylene glycol Substances 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 239000003589 local anesthetic agent Substances 0.000 description 8
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 5
- 229940041616 menthol Drugs 0.000 description 5
- 239000000341 volatile oil Substances 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- NEHNMFOYXAPHSD-UHFFFAOYSA-N citronellal Chemical compound O=CCC(C)CCC=C(C)C NEHNMFOYXAPHSD-UHFFFAOYSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000004166 Lanolin Substances 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013011 aqueous formulation Substances 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 235000019388 lanolin Nutrition 0.000 description 3
- 229940039717 lanolin Drugs 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 235000019477 peppermint oil Nutrition 0.000 description 3
- 229920001296 polysiloxane Polymers 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UYZQWKKNVBJVOF-UHFFFAOYSA-N 1-decoxytetradecane Chemical compound CCCCCCCCCCCCCCOCCCCCCCCCC UYZQWKKNVBJVOF-UHFFFAOYSA-N 0.000 description 2
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- ASKIVFGGGGIGKH-UHFFFAOYSA-N 2,3-dihydroxypropyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(O)CO ASKIVFGGGGIGKH-UHFFFAOYSA-N 0.000 description 2
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- 241000723346 Cinnamomum camphora Species 0.000 description 2
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical compound C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 description 2
- 229930008380 camphor Natural products 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229940074979 cetyl palmitate Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229940043350 citral Drugs 0.000 description 2
- 235000000983 citronellal Nutrition 0.000 description 2
- 229930003633 citronellal Natural products 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 2
- 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 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 2
- 229940075495 isopropyl palmitate Drugs 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 238000000569 multi-angle light scattering Methods 0.000 description 2
- RGOVYLWUIBMPGK-UHFFFAOYSA-N nonivamide Chemical compound CCCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 RGOVYLWUIBMPGK-UHFFFAOYSA-N 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- RUMOYJJNUMEFDD-UHFFFAOYSA-N perillyl aldehyde Chemical compound CC(=C)C1CCC(C=O)=CC1 RUMOYJJNUMEFDD-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- SGAWOGXMMPSZPB-UHFFFAOYSA-N safranal Chemical compound CC1=C(C=O)C(C)(C)CC=C1 SGAWOGXMMPSZPB-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 description 1
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- DSEKYWAQQVUQTP-XEWMWGOFSA-N (2r,4r,4as,6as,6as,6br,8ar,12ar,14as,14bs)-2-hydroxy-4,4a,6a,6b,8a,11,11,14a-octamethyl-2,4,5,6,6a,7,8,9,10,12,12a,13,14,14b-tetradecahydro-1h-picen-3-one Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3C[C@@H](O)C(=O)[C@@H]1C DSEKYWAQQVUQTP-XEWMWGOFSA-N 0.000 description 1
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 description 1
- NYEPHMYJRNWPLA-UHFFFAOYSA-N (6-amino-2-ethoxyacridin-9-yl)azanium;2-hydroxypropanoate;hydrate Chemical compound O.CC(O)C([O-])=O.C1=C(N)C=CC2=C(N)C3=CC(OCC)=CC=C3[NH+]=C21 NYEPHMYJRNWPLA-UHFFFAOYSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- JPPRXACMNPYJNK-UHFFFAOYSA-N 1-docosoxydocosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC JPPRXACMNPYJNK-UHFFFAOYSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- JWKSQNWLEIABLH-UHFFFAOYSA-N 1-octan-2-yloxydodecane Chemical compound CCCCCCCCCCCCOC(C)CCCCCC JWKSQNWLEIABLH-UHFFFAOYSA-N 0.000 description 1
- LVOGXJMCDAOKSQ-UHFFFAOYSA-N 10-oxo-10-propan-2-yloxydecanoic acid Chemical compound CC(C)OC(=O)CCCCCCCCC(O)=O LVOGXJMCDAOKSQ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- ZVUNTIMPQCQCAQ-UHFFFAOYSA-N 2-dodecanoyloxyethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCC ZVUNTIMPQCQCAQ-UHFFFAOYSA-N 0.000 description 1
- IKVCSHRLYCDSFD-UHFFFAOYSA-N 2-hexadecanoyloxyethyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCCCCCC IKVCSHRLYCDSFD-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、アミノ安息香酸エチル及び第四級アンモニウム塩を含みながらも、光暴露によって生じる黄変が抑制され、優れた製剤安定性を有する医薬組成物に関する。 TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt, while suppressing yellowing caused by exposure to light and having excellent formulation stability.
アミノ安息香酸エチルは、局所麻酔剤として知られ、粘膜や皮膚の局所的な痒みや疼痛を緩和するために広く使用されており、従来、アミノ安息香酸エチルを配合した医薬組成物の処方についても、種々検討されている。例えば、特許文献1には、アミノ安息香酸エチル等の塩基性局所麻酔剤と、その塩酸塩を含有する局所麻酔組成物は、局所麻酔作用の速効性と持続性を兼ね備え得ることが報告されている。 Ethyl aminobenzoate is known as a local anesthetic and is widely used to relieve local itching and pain of mucous membranes and skin. , have been variously considered. For example, Patent Document 1 reports that a local anesthetic composition containing a basic local anesthetic such as ethyl aminobenzoate and its hydrochloride can have both rapid-acting and sustained local anesthetic action. there is
また、塩化セチルピリジニウムや塩化ベンザルコニウム等の第四級アンモニウム塩は、殺菌剤として知られており、様々な医薬品等で広く使用されており、従来、第四級アンモニウム塩を配合した医薬組成物の処方についても、種々検討されている。例えば、特許文献2には、四級アンモニウム塩を0.05~2重量%、クロルフェニラミンマレイン酸塩を0.1~4重量%および塩化物イオン供給源を0.01~10重量%含有することを特徴とする外用薬組成物は、結晶の生成を抑制した安定な製剤を実現し得ることが報告されている。 In addition, quaternary ammonium salts such as cetylpyridinium chloride and benzalkonium chloride are known as bactericidal agents and are widely used in various pharmaceuticals. Various studies have also been conducted on formulation of products. For example, Patent Document 2 contains 0.05 to 2% by weight of a quaternary ammonium salt, 0.1 to 4% by weight of chlorpheniramine maleate, and 0.01 to 10% by weight of a chloride ion source. It has been reported that a topical pharmaceutical composition characterized by
近年、医薬組成物には、多機能性が求められており、局所麻酔剤と殺菌剤を併用した製剤処方も開発されている。しかしながら、医薬組成物を実用化するには、機能性のみならず、製剤安定性についても十分な配慮する必要があるが、従来技術では、アミノ安息香酸エチル及び第四級アンモニウム塩を含む医薬組成物の製剤安定性については十分な検討がなされていないのが現状である。 In recent years, pharmaceutical compositions have been required to have multiple functions, and pharmaceutical formulations using a combination of a local anesthetic and a disinfectant have also been developed. However, in order to put a pharmaceutical composition into practical use, it is necessary to consider not only functionality but also formulation stability. At present, the formulation stability of products has not been sufficiently studied.
本発明者は、アミノ安息香酸エチル及び第四級アンモニウム塩を含む医薬組成物を実用化すべく検討を進めたところ、当該外用組成物では、光暴露によって黄色に変色(黄変)し、良好な外観性状を維持できず、製剤安定性が悪いという新たな課題に直面した。 The inventors of the present invention have conducted studies to put a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt into practical use. We faced a new problem that the appearance properties could not be maintained and the formulation stability was poor.
そこで、本発明の目的は、アミノ安息香酸エチル及び第四級アンモニウム塩を含む医薬組成物において、光暴露によって生じる黄変を抑制でき、優れた製剤安定性を備えさせる製剤技術を提供することである。 Therefore, an object of the present invention is to provide a formulation technology that can suppress yellowing caused by light exposure and provide excellent formulation stability in a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt. be.
本発明者は、前記課題を解決すべく鋭意検討を行ったところ、アミノ安息香酸エチル及び第四級アンモニウム塩と共に、多価アルコール、モノテルペン、ポリビニルピロリドン、及びヒドロキシエチルセルロースの中から1種以上を組み合わせて配合した医薬組成物は、光暴露によって生じる黄変が抑制され、優れた製剤安定性を備え得ることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 The present inventors have made intensive studies to solve the above problems, and found that one or more of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethyl cellulose are added together with ethyl aminobenzoate and quaternary ammonium salts. It has been found that a pharmaceutical composition formulated in combination can be inhibited from yellowing caused by exposure to light and have excellent formulation stability. The present invention has been completed through further studies based on such findings.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項1. (A)アミノ安息香酸エチル、(B)第四級アンモニウム塩、並びに(C)多価アルコー
ル、モノテルペン、ポリビニルピロリドン、及びヒドロキシエチルセルロースよりなる群から選択される少なくとも1種を含有する、医薬組成物。
項2. 前記(B)成分が、塩化セチルピリジニウムである、項1に記載の医薬組成物。
項3. 前記多価アルコールが、プロピレングリコール及び/又はグリセリンである、項1又は2に記載の医薬組成物。
項4. 前記モノテルペンがメントールである、項1~3のいずれかに記載の医薬組成物。
項5. 前記(C)成分として、多価アルコール及びポリビニルピロリドンを含む、項1~
4のいずれかに記載の医薬組成物。
項6. 外用医薬品又は粘膜適用医薬品である、項1~5のいずれかに記載の医薬組成物。
項7. アミノ安息香酸エチル、及び第四級アンモニウム塩を含む医薬組成物の光暴露によって生じる黄変を抑制する方法であって、
医薬組成物に、(A)アミノ安息香酸エチル、及び(B)第四級アンモニウム塩と共に、(C)
多価アルコール、モノテルペン、ポリビニルピロリドン、及びヒドロキシエチルセルロースよりなる群から選択される少なくとも1種を配合する、
前記医薬組成物の光暴露によって生じる黄変の抑制方法。
That is, the present invention provides inventions in the following aspects.
Section 1. A pharmaceutical composition containing (A) ethyl aminobenzoate, (B) a quaternary ammonium salt, and (C) at least one selected from the group consisting of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethylcellulose. thing.
Section 2. Item 2. The pharmaceutical composition according to Item 1, wherein the component (B) is cetylpyridinium chloride.
Item 3. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the polyhydric alcohol is propylene glycol and/or glycerin.
Section 4. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the monoterpene is menthol.
Item 5. Items 1 to 1, containing a polyhydric alcohol and polyvinylpyrrolidone as the component (C)
5. The pharmaceutical composition according to any one of 4.
Item 6. Item 6. The pharmaceutical composition according to any one of Items 1 to 5, which is a pharmaceutical for external use or a pharmaceutical for mucosa.
Item 7. A method for inhibiting yellowing caused by light exposure of a pharmaceutical composition comprising ethyl aminobenzoate and a quaternary ammonium salt, comprising:
In the pharmaceutical composition, together with (A) ethyl aminobenzoate and (B) a quaternary ammonium salt, (C)
Blending at least one selected from the group consisting of polyhydric alcohol, monoterpene, polyvinylpyrrolidone, and hydroxyethyl cellulose,
A method for inhibiting yellowing caused by light exposure of said pharmaceutical composition.
本発明の医薬組成物によれば、アミノ安息香酸エチルと第四級アンモニウム塩が共存していても、光暴露によって生じる黄変を抑制でき、優れた製剤安定性を備えることができる。 INDUSTRIAL APPLICABILITY According to the pharmaceutical composition of the present invention, even when ethyl aminobenzoate and a quaternary ammonium salt coexist, yellowing caused by exposure to light can be suppressed, and excellent formulation stability can be provided.
1.医薬組成物
本発明の医薬組成物は、アミノ安息香酸エチル((A)成分と表記することもある)、第
四級アンモニウム塩((B)成分と表記することもある)、並びに多価アルコール、モノテ
ルペン、ポリビニルピロリドン、及びヒドロキシエチルセルロースよりなる群から選択される少なくとも1種((C)成分と表記することもある)を含有することを特徴とする。以
下、本発明の医薬組成物について詳述する。
1. Pharmaceutical composition The pharmaceutical composition of the present invention comprises ethyl aminobenzoate (sometimes referred to as component (A)), a quaternary ammonium salt (sometimes referred to as component (B)), and a polyhydric alcohol. , monoterpene, polyvinylpyrrolidone, and hydroxyethyl cellulose (also referred to as component (C)). The pharmaceutical composition of the present invention is described in detail below.
(A)アミノ安息香酸エチル
アミノ安息香酸エチルは、エチル4-アミノベンゾエート、ベンゾカイン等とも称される公知の局所麻酔剤である。
(A) Ethyl aminobenzoate Ethyl aminobenzoate is a known local anesthetic also called ethyl 4-aminobenzoate, benzocaine and the like.
本発明の医薬組成物において、(A)成分の含有量については、特に制限されず、医薬組
成物に付与すべき局所麻酔作用の程度、医薬組成物の製剤形態や用途等に応じて適宜設定すればよいが、例えば、0.1~5重量%、好ましくは0.3~2重量%、更に好ましくは0.3~1重量%が挙げられる。
In the pharmaceutical composition of the present invention, the content of component (A) is not particularly limited, and is appropriately set according to the degree of local anesthetic action to be imparted to the pharmaceutical composition, the formulation form and application of the pharmaceutical composition, etc. For example, 0.1 to 5% by weight, preferably 0.3 to 2% by weight, more preferably 0.3 to 1% by weight.
(B)第四級アンモニウム塩
本発明で使用される第四級アンモニウム塩は、殺菌作用を有し、且つ薬学的に許容されるものであればよく、その種類については、特に制限されないが、塩化セチルピリジニウム、塩化ベンゼトニウム、塩化ベンザルコニウム、塩化デカリニウム、塩化アルキルジメチルアンモニウム、塩化アルキルトリメチルアンモニウム、塩化メチルベンゼトニウム、塩化ラウロイルコラミノホルミルメチルピリジニウム等が挙げられる。
(B) Quaternary ammonium salt The quaternary ammonium salt used in the present invention is not particularly limited as long as it has a bactericidal action and is pharmaceutically acceptable. cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, dequalinium chloride, alkyldimethylammonium chloride, alkyltrimethylammonium chloride, methylbenzethonium chloride, lauroylcolaminoformylmethylpyridinium chloride and the like.
これらの第四級アンモニウム塩は、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。 These quaternary ammonium salts may be used singly or in combination of two or more.
これらの第四級アンモニウム塩の中でも、光暴露による黄変をより一層効果的に抑制するという観点から、好ましくは塩化セチルピリジニウム、塩化ベンザルコニウム、及び塩化ベンゼトニウム、更に好ましくは塩化セチルピリジニウムが挙げられる。 Among these quaternary ammonium salts, cetylpyridinium chloride, benzalkonium chloride, and benzethonium chloride are preferred, and cetylpyridinium chloride is more preferred, from the viewpoint of more effectively suppressing yellowing due to exposure to light. be done.
本発明の医薬組成物において、(B)成分の含有量については、特に制限されず、医薬組
成物に付与すべき殺菌作用の程度、医薬組成物の製剤形態や用途等に応じて適宜設定すればよいが、例えば、0.05~1重量%、好ましくは0.1~0.5重量%、更に好ましくは0.3~0.5重量%が挙げられる。
In the pharmaceutical composition of the present invention, the content of the component (B) is not particularly limited, and may be appropriately set according to the degree of bactericidal action to be imparted to the pharmaceutical composition, the formulation form and application of the pharmaceutical composition, and the like. For example, 0.05 to 1% by weight, preferably 0.1 to 0.5% by weight, and more preferably 0.3 to 0.5% by weight.
本発明の医薬組成物において、(A)成分に対する(B)成分の比率については、(A)成分及
び(B)成分の各含有量に応じて定まるが、例えば、(A)成分100重量部当たり、(B)成分
が10~300重量部、好ましくは50~200重量部、更に好ましくは50~150重量部が挙げられる。
In the pharmaceutical composition of the present invention, the ratio of component (B) to component (A) is determined according to the respective contents of component (A) and component (B). The amount of component (B) is 10 to 300 parts by weight, preferably 50 to 200 parts by weight, and more preferably 50 to 150 parts by weight.
(C)多価アルコール、モノテルペン、ポリビニルピロリドン、及び/又はヒドロキシエチルセルロース
本発明の医薬組成物では、(C)成分として、多価アルコール、モノテルペン、ポリビニルピロリドン、及び/又はヒドロキシエチルセルロースを含有する。当該(C)成分を含むことにより、アミノ安息香酸エチル及び第四級アンモニウム塩が共存して光暴露を受けた際に生じる黄変を抑制することが可能になる。
(C) Polyhydric alcohol, monoterpene, polyvinylpyrrolidone, and/or hydroxyethylcellulose The pharmaceutical composition of the present invention contains polyhydric alcohol, monoterpene, polyvinylpyrrolidone, and/or hydroxyethylcellulose as component (C). . Inclusion of the component (C) makes it possible to suppress yellowing that occurs when ethyl aminobenzoate and a quaternary ammonium salt coexist and are exposed to light.
(C)成分として使用される多価アルコールの種類については、薬学的に許容されること
を限度として特に制限されないが、例えば、1,3-ブチレングリコール、エチレングリコール、プロピレングリコール、イソプレングリコール、ジエチレングリコール、ジプロピレングリコール、ポリエチレングリコール等の2価アルコール;グリセリン等の3価アルコール等が挙げられる。これらの多価アルコールは、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。
The type of polyhydric alcohol used as component (C) is not particularly limited as long as it is pharmaceutically acceptable. Examples include 1,3-butylene glycol, ethylene glycol, propylene glycol, isoprene glycol, and diethylene glycol. , dipropylene glycol, and polyethylene glycol; and trihydric alcohols such as glycerin. These polyhydric alcohols may be used singly or in combination of two or more.
これらの多価アルコールの中でも、光暴露による黄変をより一層効果的に抑制するという観点から、好ましくはプロピレングリコール及びグリセリンが挙げられる。 Among these polyhydric alcohols, propylene glycol and glycerin are preferred from the viewpoint of more effectively suppressing yellowing due to exposure to light.
(C)成分として使用されるモノテルペンとは、分子内にイソプレン単位が2個含まれる
構造を有し、清涼化作用等を有する公知の成分である。(C)成分として使用されるモノテ
ルペンの種類については、薬学的に許容されることを限度として、特に制限されないが、例えば、メントール、チモール、ゲラニオール、リナロール、ボルネオール、シネオール、テルピネオール等のアルコール系モノテルペン;シトラール、シトロネラール、ペリルアルデヒド、サフラナール等のアルデヒド系モノテルペン;カンフル、メントン、カルボメントン、ヨノン等のケトン系モノテルペン等が挙げられる。これらのモノテルペンは、光学異性体が存在する場合には、d体、l体、dl体のいずれであってもよい。これらのモノテルペンは、1種単独で使用してもよく、2種以上を組み合わせて使用してもよい。
The monoterpene used as the component (C) is a known component having a structure containing two isoprene units in the molecule and having a cooling effect and the like. The type of monoterpene used as component (C) is not particularly limited as long as it is pharmaceutically acceptable. monoterpene; aldehyde monoterpene such as citral, citronellal, perillaldehyde and safranal; ketone monoterpene such as camphor, menthone, carbomenthone and ionone; These monoterpenes may be d-, l-, or dl-forms when optical isomers are present. These monoterpenes may be used singly or in combination of two or more.
また、本発明では、モノテルペンとして、モノテルペンを含む精油の状態で使用してもよい。モノテルペンを含む精油は、公知のものから適宜選択して使用することができるが、例えば、メントールを含む精油としては、ハッカ油、ペパーミント油、スペアミント油等が挙げられる。なお、本明細書におけるモノテルペンの含有量や比率に関する記載は、モノテルペンを含む精油を使用する場合は、当該精油に含まれるモノテルペン量に換算した値である。 Moreover, in the present invention, the monoterpene may be used in the form of an essential oil containing the monoterpene. The essential oil containing monoterpene can be appropriately selected from known ones and used. Examples of essential oils containing menthol include peppermint oil, peppermint oil, and spearmint oil. In addition, the description about the content and ratio of monoterpene in this specification is the value converted into the amount of monoterpene contained in the said essential oil, when using the essential oil containing a monoterpene.
これらのモノテルペンの中でも、光暴露による黄変をより一層効果的に抑制するという観点から、好ましくはアルコール系モノテルペン、更に好ましくはメントール、特に好ましくはl-メントールが挙げられる。 Among these monoterpenes, alcoholic monoterpenes are preferred, menthol is more preferred, and 1-menthol is particularly preferred, from the viewpoint of more effectively suppressing yellowing due to exposure to light.
(C)成分として使用されるポリビニルピロリドンとは、N-ビニル-2-ピロリドンが
重合した水溶性の高分子化合物である。(C)成分として使用されるポリビニルピロリドン
の重量平均分子量については、特に制限されないが、例えば、5千~300万程度、更に好ましくは4万~300万程度が挙げられる。ここで、ポリビニルピロリドンの重量平均分子量は、ゲルろ過クロマトグラフィー/多角度光散乱光度計(GPC/MALLS)によって測定される値を指す。ポリビニルピロリドンのK値(粘性特性値)については、特に制限されないが、10~120程度のものを好ましく使用することができる。また、本発明において、ポリビニルピロリドンは、市販品を使用することができる。ポリビニルピロリドンの市販品としては、具体的には、第一工業製薬株式会社製の「アイフタクト K-30PH」、株式会社日本触媒製の「ポリビニルピロリドン K-30」、「ポリビニルピロリドン K-85」、「ポリビニルピロリドン K-90」、アイエスピー・ジャパン製の「PVP K-90」等が挙げられる。
Polyvinylpyrrolidone used as component (C) is a water-soluble polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone. The weight average molecular weight of polyvinylpyrrolidone used as component (C) is not particularly limited, but is, for example, about 5,000 to 3,000,000, more preferably about 40,000 to 3,000,000. Here, the weight average molecular weight of polyvinylpyrrolidone refers to a value measured by gel filtration chromatography/multi-angle light scattering photometer (GPC/MALLS). The K value (viscosity characteristic value) of polyvinylpyrrolidone is not particularly limited, but one of about 10 to 120 can be preferably used. Moreover, in this invention, a commercial item can be used for polyvinylpyrrolidone. Specific examples of commercial products of polyvinylpyrrolidone include "Eifact K-30PH" manufactured by Daiichi Kogyo Seiyaku Co., Ltd., "Polyvinylpyrrolidone K-30" and "Polyvinylpyrrolidone K-85" manufactured by Nippon Shokubai Co., Ltd., "Polyvinylpyrrolidone K-90", "PVP K-90" manufactured by ISP Japan, and the like.
(C)成分として使用されるヒドロキシエチルセルロースとは、セルロースにエチレンオ
キサイドを付加することにより水溶性を向上させたセルロース誘導体である。(C)成分と
して使用されるヒドロキシエチルセルロースの酸化エチレンの平均付加モル数、平均分子量等については、特に制限されず、医薬分野で通常使用されているものであればよいが、例えば、2.0重量%水溶液(20℃)において粘度500mPa・s以上、好ましくは、500~50000mPa・sであるものが挙げられる。ここで、当該粘度は、B型粘度計「TOKI SANGYO VISCOMETER TVB-10」(東機産業株式会社製)において、測定する粘度に応じて、ローター:M3又はM4(回転速度:12~30rpm、時間:1min、単位:mPa・s)を使用して適切に測定した値をいう。また、本発明において、ヒドロキシエチルセルロースは、市販品を使用することができる。ヒドロキシエチルセルロースの市販品としては、具体的には、住友精化株式会社製の「HEC CF-V」、「HEC CF-W」、「HEC CF-X」、「HEC CF-Y」、「HEC AH-15F」、「HEC AV-15F」、「HEC AW-15F」、「HEC SW-25F」、ダイセルファインケム株式会社製の「HECダイセル SP500」、「HECダイセル SP600」、「HECダイセル SP850」、「HECダイセル SP900」、Ashland社製の「NATROSOL 250HX」等が挙げられる。
Hydroxyethyl cellulose used as component (C) is a cellulose derivative whose water solubility is improved by adding ethylene oxide to cellulose. The average number of added moles of ethylene oxide and the average molecular weight of hydroxyethyl cellulose used as component (C) are not particularly limited as long as they are commonly used in the pharmaceutical field. Examples thereof include those having a viscosity of 500 mPa·s or more, preferably 500 to 50000 mPa·s in a weight percent aqueous solution (20° C.). Here, the viscosity is measured using a Brookfield viscometer "TOKI SANGYO VISCOMETER TVB-10" (manufactured by Toki Sangyo Co., Ltd.), rotor: M3 or M4 (rotational speed: 12 to 30 rpm, time : 1 min, unit: mPa·s). Moreover, in this invention, a commercial item can be used for hydroxyethyl cellulose. Specific examples of commercial products of hydroxyethyl cellulose include "HEC CF-V", "HEC CF-W", "HEC CF-X", "HEC CF-Y" and "HEC" manufactured by Sumitomo Seika Co., Ltd. AH-15F", "HEC AV-15F", "HEC AW-15F", "HEC SW-25F", "HEC Daicel SP500", "HEC Daicel SP600", "HEC Daicel SP850" manufactured by Daicel Finechem Co., Ltd., "HEC Daicel SP900", "NATROSOL 250HX" manufactured by Ashland, and the like.
本発明の医薬組成物において、(C)成分として、多価アルコール、モノテルペン、ポリビニルピロリドン、及びヒドロキシエチルセルロースの中から1種を選択して使用してもよく、また2種以上を組み合わせて使用してもよい。 In the pharmaceutical composition of the present invention, one of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethylcellulose may be selected and used as component (C), or two or more may be used in combination. You may
光暴露による黄変をより一層効果的に抑制するという観点から、(C)成分として、好ましくは多価アルコールとポリビニルピロリドンとの組み合わせ、更に好ましくはプロピレングリコールとポリビニルピロリドンとの組み合わせが挙げられる。 From the viewpoint of more effectively suppressing yellowing due to exposure to light, component (C) is preferably a combination of polyhydric alcohol and polyvinylpyrrolidone, more preferably a combination of propylene glycol and polyvinylpyrrolidone.
(C)成分として多価アルコールとポリビニルピロリドンとを組み合わせて使用する場合、これらの比率については、特に制限されないが、光暴露による黄変をより一層効果的に抑制するという観点から、多価アルコール100重量部当たり、ポリビニルピロリドンが通常0.1~20重量部、好ましくは0.5~10重量部、更に好ましくは0.5~5重量部となる比率が挙げられる。 When using a combination of polyhydric alcohol and polyvinylpyrrolidone as component (C), the ratio of these is not particularly limited, but from the viewpoint of more effectively suppressing yellowing due to light exposure, polyhydric alcohol The ratio of polyvinylpyrrolidone is usually 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, more preferably 0.5 to 5 parts by weight, per 100 parts by weight.
本発明の医薬組成物において、(C)成分の含有量については、使用する(C)成分の種類、医薬組成物の製剤形態や用途等に応じて適宜設定すればよいが、例えば、(C)成分の総量
で0.01~80重量%、好ましくは0.05~70重量%、更に好ましくは0.1~65重量%が挙げられる。
In the pharmaceutical composition of the present invention, the content of component (C) may be appropriately set according to the type of component (C) used, the formulation form and application of the pharmaceutical composition, etc. For example, (C ) in a total amount of 0.01 to 80% by weight, preferably 0.05 to 70% by weight, more preferably 0.1 to 65% by weight.
より具体的には、(C)成分の種類毎の含有量として、以下の範囲が挙げられる;
多価アルコールを使用する場合:1~80重量%、好ましくは5~60重量%。
・多価アルコールとして2価アルコールを使用する場合:更に好ましくは1~60重量%、特に好ましくは1~50重量%、最も好ましくは5~40重量%。
・多価アルコールとして3価アルコールを使用する場合:更に好ましくは10~60重量%、特に好ましくは30~60重量%、最も好ましくは30~50重量%。
モノテルペンを使用する場合:0.01~3重量%、好ましくは0.05~1重量%、更に好ましくは0.1~1重量%。
ポリビニルピロリドンを使用する場合:0.05~3重量%、好ましくは0.1~1重量%、更に好ましくは0.5~1重量%。
ヒドロキシエチルセルロースを使用する場合:0.05~3重量%、好ましくは0.1~1重量%、更に好ましくは0.5~1重量%。
More specifically, the content of each type of component (C) includes the following ranges;
If a polyhydric alcohol is used : 1-80% by weight, preferably 5-60% by weight.
- When a dihydric alcohol is used as the polyhydric alcohol: more preferably 1 to 60% by weight, particularly preferably 1 to 50% by weight, most preferably 5 to 40% by weight.
- When a trihydric alcohol is used as the polyhydric alcohol: more preferably 10 to 60% by weight, particularly preferably 30 to 60% by weight, most preferably 30 to 50% by weight.
If a monoterpene is used : 0.01-3% by weight, preferably 0.05-1% by weight, more preferably 0.1-1% by weight.
When polyvinylpyrrolidone is used : 0.05-3% by weight, preferably 0.1-1% by weight, more preferably 0.5-1% by weight.
When using hydroxyethyl cellulose : 0.05-3% by weight, preferably 0.1-1% by weight, more preferably 0.5-1% by weight.
本発明の医薬組成物において、(A)成分に対する(C)成分の比率については、(A)成分及び(C)成分の各含有量に応じて定まるが、例えば、(A)成分100重量部当たり、(C)成分が10~20000重量部、好ましくは15~18000重量部が挙げられる。 In the pharmaceutical composition of the present invention, the ratio of component (C) to component (A) is determined according to the respective contents of component (A) and component (C). Component (C) is 10 to 20,000 parts by weight, preferably 15 to 18,000 parts by weight.
より具体的には、(A)成分100重量部に対する(C)成分の種類毎の比率として、以下の範囲が挙げられる;
多価アルコールを使用する場合:総量で、1500~20000重量部、好ましくは3000~18000重量部。
・多価アルコールとして2価アルコールを使用する場合:総量で、更に好ましくは1500~18000重量部、特に好ましくは3000~18000重量部、最も好ましくは5000~18000重量部。
・多価アルコールとして3価アルコールを使用する場合:総量で、更に好ましくは2000~18000重量部、特に好ましくは5000~18000重量部、最も好ましくは8000~18000重量部。
モノテルペンを使用する場合:総量で、15~500重量部、好ましくは15~400重量部、更に好ましくは15~350重量部。
ポリビニルピロリドンを使用する場合:総量で、10~500重量部、好ましくは20~400重量部、更に好ましくは50~350重量部。
ヒドロキシエチルセルロースを使用する場合:総量で、30~500重量部、好ましくは50~500重量部、更に好ましくは50~400重量部。
More specifically, the ratio of each type of component (C) to 100 parts by weight of component (A) includes the following ranges;
When polyhydric alcohol is used : 1,500 to 20,000 parts by weight, preferably 3,000 to 18,000 parts by weight in total.
- When a dihydric alcohol is used as the polyhydric alcohol: the total amount is more preferably 1,500 to 18,000 parts by weight, particularly preferably 3,000 to 18,000 parts by weight, and most preferably 5,000 to 18,000 parts by weight.
- When a trihydric alcohol is used as the polyhydric alcohol: the total amount is more preferably 2,000 to 18,000 parts by weight, particularly preferably 5,000 to 18,000 parts by weight, and most preferably 8,000 to 18,000 parts by weight.
When monoterpene is used : 15 to 500 parts by weight, preferably 15 to 400 parts by weight, more preferably 15 to 350 parts by weight in total.
When polyvinylpyrrolidone is used : the total amount is 10-500 parts by weight, preferably 20-400 parts by weight, more preferably 50-350 parts by weight.
When using hydroxyethyl cellulose : 30 to 500 parts by weight, preferably 50 to 500 parts by weight, more preferably 50 to 400 parts by weight in total.
低級アルコール
本発明の医薬組成物には、アミノ安息香酸エチルを安定に溶解させるために、必要に応じて低級アルコールを含んでいてもよい。
Lower Alcohol The pharmaceutical composition of the present invention may optionally contain a lower alcohol in order to stably dissolve ethyl aminobenzoate.
本発明で使用される低級アルコールの種類については、薬学的に許容されることを限度として特に制限されないが、例えば、エタノール、プロパノール、ブタノール、ペンタノール、ヘキサノール、イソプロパノール等の炭素数2~6の低級アルコールが挙げられる。これらの低級アルコールの中でも、好ましくはエタノールが挙げられる。 The type of lower alcohol used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. lower alcohols; Among these lower alcohols, ethanol is preferred.
これらの低級アルコールは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。 These lower alcohols may be used singly or in combination of two or more.
本発明の医薬組成物に低級アルコールを含有させる場合、その含有量については、特に制限されないが、例えば、0.5~20重量%、好ましくは1~10重量%、更に好ましくは5~10重量%が挙げられる。 When the pharmaceutical composition of the present invention contains a lower alcohol, the content is not particularly limited, but is, for example, 0.5 to 20% by weight, preferably 1 to 10% by weight, more preferably 5 to 10% by weight. %.
水
本発明の医薬組成物の好適な態様として、水を含んでいること(即ち、水性製剤)が挙げられる。従来技術では、水の存在下で、アミノ安息香酸エチル及び第四級アンモニウム塩を共存させると、光暴露による黄変が顕著に生じる傾向が認められるが、本発明では、水を含む場合であっても、当該黄変を効果的に抑制することができる。
Water A preferred aspect of the pharmaceutical composition of the present invention is that it contains water (that is, an aqueous formulation). In the prior art, when ethyl aminobenzoate and a quaternary ammonium salt coexist in the presence of water, yellowing due to exposure to light tends to occur remarkably. However, the yellowing can be effectively suppressed.
本発明の医薬組成物を水性製剤にする場合、水の含有量については、特に制限されず、医薬組成物の製剤形態や用途等に応じて適宜設定すればよいが、例えば1~80重量%、好ましくは5~60重量%、更に好ましくは10~50重量%が挙げられる。 When the pharmaceutical composition of the present invention is made into an aqueous formulation, the content of water is not particularly limited, and may be appropriately set according to the formulation form and application of the pharmaceutical composition, for example 1 to 80% by weight. , preferably 5 to 60% by weight, more preferably 10 to 50% by weight.
その他の成分
本発明の医薬組成物は、前述する成分の他に、必要に応じて、他の薬理成分を含有していてもよい。このような薬理成分としては、例えば、抗ヒスタミン剤(ジフェンヒドラミン、塩酸ジフェンヒドラミン等)、アミノ安息香酸エチル以外の局所麻酔剤(プロカイン、テトラカイン、ブピパカイン、メピパカイン、クロロプロカイン、プロパラカイン、メプリルカイン又はこれらの塩、オルソカイン、オキセサゼイン、オキシポリエントキシデカン、ロートエキス、ペルカミンパーゼ、テシットデシチン、リドカイン等)、第四級アンモニウム塩以外の殺菌剤(ヨウ素、ポピドンヨード、ヨウ化カリウム、グルコン酸クロルヘキシジン、アクリノール等)、抗炎症剤(グリチルリチン酸二カリウム、グリチルレチン酸、インドメタシン、フェルビナク、ジクロフェナクナトリウム、ロキソプロフェンナトリウム等)、皮膚保護剤(コロジオン、ヒマシ油等)、血行促進成分(ノニル酸ワニリルアミド、ニコチン酸ベンジルエステル、カプサイシン、トウガラシエキス等)、ビタミン類(ビタミンA等)、ムコ多糖類(コンドロイチン硫酸ナトリウム、グルコサミン等)等が挙げられる。
Other Ingredients The pharmaceutical composition of the present invention may, if necessary, contain other pharmacological ingredients in addition to the ingredients described above. Such pharmacological components include, for example, antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics other than ethyl aminobenzoate (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, orthocaine , oxethazein, oxypolyethoxydecane, rot extract, percamimpase, tecittdecitin, lidocaine, etc.), antibacterial agents other than quaternary ammonium salts (iodine, povidone iodine, potassium iodide, chlorhexidine gluconate, acrinol, etc.), anti-inflammatory agents (glycyrrhizin) dipotassium acid, glycyrrhetinic acid, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protective agents (collodion, castor oil, etc.), blood circulation-promoting ingredients (nonylic acid vanillylamide, benzyl nicotinate, capsaicin, red pepper extract, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.), and the like.
また、本発明の医薬組成物は、所望の製剤形態にするために、必要に応じて、前述する成分以外の基材や添加剤が含まれていてもよい。このような基剤や添加剤については、薬学的に許容されることを限度として特に制限されないが、例えば、油類(オリーブ油、サフラワー油、大豆油、つばき油、とうもろこし油、なたね油、ひまわり油、綿実油、落花生油、ラード、スクワラン、魚油等)、鉱物油(流動パラフィン、パラフィン、ゲル化炭化水素、ワセリン等)、ワックス類・ロウ類(ミツロウ、カルナウバロウ、キャンデリラロウ、セレシン、ライスワックス、マイクロクリスタリンワックス等)、エステル油(ミリスチン酸イソプロピル、アジピン酸イソプロピル、セバシン酸ジエチル、セバシン酸イソプロピル、パルミチン酸イソプロピル、パルミチン酸セチル、オレイン酸エチル等)、脂肪酸アルキルエステル、脂肪酸(ステアリン酸、オレイン酸、パルミチン酸、ベヘン酸、リノール酸、ラノリン等)、脂肪酸エステル(パルミチン酸セチル、パルミチン酸イソプロピル、リノール酸エチル等)、低級アルコール(エタノール、プロパノール、イソプロパノール、ブタノール、イソブタノール等)、高級アルコール(ステアリルアルコール、セタノール、ベヘニルアルコール、ミリスチルアルコール、オレイルアルコール、ヘキサデシルアルコール、ラノリンアルコール等)、コレステロール、トリ2-エチルヘキサン酸グリセリル、2-エチルヘキサン酸セチル、シリコーンオイル(ジメチルポリシロキサン、環状シリコーン等)等の油性基剤;POE(10~50モル)フィトステロールエーテル、POE(10~50モル)ジヒドロコレステロールエーテル、POE(10~50モル)2-オクチルドデシルエーテル、POE(10~50モル)デシルテトラデシルエーテル、POE(10~50モル)オレイルエーテル、POE(2~50モル)セチルエーテル、POE(5~50モル)ベヘニルエーテル、POE(5~30モル)ポリオキシプロピレン(5~30モル)2-デシルテトラデシルエーテル、POE(10~50モル)ポリオキシプロピレン(2~30モル)セチルエーテルなどのポリオキシエチレンアルキルエーテル、これらのリン酸・リン酸塩(POEセチルエーテルリン酸ナトリウムなど)、POE(20~60モル)ソルビタンモノオレート、POE(10~60モル)ソルビタンモノイソステアレート、POE(10~80モル)グリセリルモノイソステアレート、POE(10~30モル)グリセリルモノステアレート、POE(20~100モル)・ポリオキシプロピレン変性シリコーン、POE・アルキル変性シリコーン、モノラウリン酸ポリエチレングリコール、モノパルミチン酸ポリエチレングリコール、モノステアリン酸ポリエチレングリコール、ジラウリン酸ポリエチレングリコール、ジパルミチン酸ポリエチレングリコール、ジステアリン酸ポリエチレングリコール、ジオレイン酸ポリエチレングリコール、ジリシノレイン酸ポリエチレングリコール、ポリオキシエチレン硬化ヒマシ油(5~100)、ポリソルベート(20~85)、グリセリン脂肪酸エステル(モノステアリン酸グリセリン等)、水素添加大豆リン脂質、水素添加ラノリンアルコール等の界面活性剤;清涼化剤(メントール、カンフル、ボルネオール、ハッカ水、ハッカ油等)、防腐剤(メチルパラベン、プロピルパラベン、安息香酸、安息香酸ナトリウム、ソルビン酸等)、着香剤(シトラール、1,8-シオネール、シトロネラール、ファルネソール等)、着色剤(タール色素(褐色201号、青色201号、黄色4号、黄色403号等)、カカオ色素、クロロフィル、酸化アルミニウム等)、粘稠剤(アルギン酸ナトリウム、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、カルボキシメチルセルロースナトリウム、キサンタンガム、カラギーナン、カルボキシビニルポリマー、ポリアクリル酸ナトリウム等)、pH調整剤(リン酸、塩酸、クエン酸、クエン酸ナトリウム、コハク酸、酒石酸、水酸化ナトリウム、水酸化カリウム、トリエタノールアミン、トリイソプロパノールアミン等)、湿潤剤(dl-ピロリドンカルボン酸ナトリウム液、D-ソルビトール液、マクロゴール等)、安定化剤(ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エデト酸ナトリウム、メタリン酸ナトリウム、L-アルギニン、L-アスパラギン酸、DL-アラニン、グリシン、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム、二酸化硫黄、クロロゲン酸、カテキン、ローズマリー抽出物等)、酸化防止剤、紫外線吸収剤、キレート剤、粘着剤、緩衝剤、溶解補助剤、可溶化剤、保存剤等の添加剤が挙げられる。 In addition, the pharmaceutical composition of the present invention may, if necessary, contain base materials and additives other than the components described above in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. , cottonseed oil, peanut oil, lard, squalane, fish oil, etc.), mineral oil (liquid paraffin, paraffin, gelling hydrocarbon, petrolatum, etc.), waxes and waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid) , palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), lower alcohols (ethanol, propanol, isopropanol, butanol, isobutanol, etc.), higher alcohols ( stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.) Oil base such as POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl Ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2- Polyoxyethylene alkyl ethers such as decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether, their phosphoric acid/phosphate (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl mono Stearate, POE (20-100 mol)/polyoxypropylene-modified silicone, POE/alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate , polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20-85), glycerin fatty acid ester (glyceryl monostearate, etc.), hydrogenated soybeans Surfactants such as phospholipids and hydrogenated lanolin alcohol; cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.) , flavoring agents (citral, 1,8-cioneal, citronellal, farnesol, etc.), coloring agents (tar pigments (brown No. 201, blue No. 201, yellow No. 4, yellow No. 403, etc.), cacao pigments, chlorophyll, aluminum oxide etc.), thickeners (sodium alginate, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, carboxyvinyl polymer, sodium polyacrylate, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate , succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (dl-sodium pyrrolidonecarboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizers (dibutyl Hydroxytoluene, butylated hydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rose Marie extract, etc.), antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives and other additives.
製剤形態
本発明の医薬組成物の剤型については、特に制限されず、液状、半固形状(ゲル状、軟膏状、ペースト状等)、固形状等のいずれであってもよいが、好ましくは水性製剤である液状又は半固形状が挙げられる。
Dosage form The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and may be liquid, semi-solid (gel, ointment, paste, etc.), solid, etc., but is preferably Liquid or semi-solid forms that are aqueous formulations may be mentioned.
また、本発明の医薬組成物は、外用医薬品、粘膜適用医薬品、又は内服用医薬品のいずれであってもよい。外用医薬品としては、具体的には、ジェル剤、クリーム剤、ローション剤、乳液剤、液剤、貼付剤、エアゾール剤、軟膏剤、パック剤等が挙げられる。粘膜適用医薬品としては、具体的には、ジェル剤、クリーム剤、ローション剤、乳液剤、液剤、軟膏剤等が挙げられる。内服用医薬品としては、具体的には、液剤、ゼリー剤等が挙げられる。これらの製剤形態への調製は、第十七改正日本薬局方 製剤総則等に記載の公知の
方法に従って、製剤形態に応じた添加剤を用いて製剤化することにより行うことができる。
In addition, the pharmaceutical composition of the present invention may be any of a pharmaceutical for external use, a pharmaceutical for mucous membrane application, or a pharmaceutical for internal use. Specific examples of pharmaceuticals for external use include gels, creams, lotions, emulsions, liquids, patches, aerosols, ointments, and packs. Specific examples of medicines applicable to mucous membranes include gels, creams, lotions, emulsions, liquids, ointments and the like. Specific examples of medicines for internal use include liquid medicines, jelly medicines, and the like. Preparation into these formulations can be carried out according to known methods described in the Japanese Pharmacopoeia 17th Edition, General Rules for Formulations, etc., by using additives suitable for the formulations.
これらの製剤形態の中でも、好ましくはジェル剤、クリーム剤、ローション剤、乳液剤、液剤等の皮膚外用医薬品及び粘膜適用医薬品が挙げられる。 Among these formulation forms, pharmaceuticals for external use on the skin and pharmaceuticals for mucosa, such as gels, creams, lotions, emulsions and liquids, are preferred.
2.黄変抑制方法
更に、本発明は、(A)アミノ安息香酸エチル、及び(B)第四級アンモニウム塩を含む医薬組成物の光暴露によって生じる黄変を抑制する方法であって、当該医薬組成物に、(C)多価アルコール、モノテルペン、ポリビニルピロリドン、及びヒドロキシエチルセルロースよりなる群から選択される少なくとも1種を配合することを特徴とする。
2. Method for Suppressing Yellowing Furthermore, the present invention provides a method for suppressing yellowing caused by exposure to light of a pharmaceutical composition comprising (A) ethyl aminobenzoate and (B) a quaternary ammonium salt, comprising: (C) at least one selected from the group consisting of polyhydric alcohol, monoterpene, polyvinylpyrrolidone, and hydroxyethyl cellulose.
当該黄変抑制方法において、使用する(A)~(C)の種類や含有量、配合される他の成分の種類や含有量、医薬組成物の製剤形態等については、前記「1.医薬組成物」の場合と同様である。 In the method for suppressing yellowing, the types and contents of (A) to (C) used, the types and contents of other ingredients to be blended, the formulation form of the pharmaceutical composition, etc. are described in the above "1. Pharmaceutical composition It is the same as the case of "thing".
以下に実施例を示して本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these.
試験例
1.医薬組成物の調製
表1及び2に示す医薬組成物(皮膚外用医薬品、液剤)を調製した。具体的には、所定量のアミノ安息香酸エチル及びl-メントールをそれぞれエタノールに溶解させた後、他
の成分と共に水に添加して混合することにより、医薬組成物(皮膚外用医薬品、液剤)を得た。
Test example 1. Preparation of Pharmaceutical Compositions Pharmaceutical compositions (external skin preparations, liquid formulations) shown in Tables 1 and 2 were prepared. Specifically, predetermined amounts of ethyl aminobenzoate and l-menthol are respectively dissolved in ethanol, and then added to water together with other ingredients and mixed to form a pharmaceutical composition (external skin drug, liquid formulation). Obtained.
2.光暴露による製剤安定性の評価
各医薬組成物をスクリュー管(直径24mm、高さ50mmのガラス製透明容器)に入れ、蛍光灯照射下12000lx・hr及び25℃に設定したグロースチャンバー内で96時間静置した。その後、スクリュー管を2~3回転倒混和し、医薬組成物の外観を目視にて観察し、以下の判定基準に従って光暴露による製剤安定性を評価した。
<光暴露による製剤安定性の評価基準>
◎:黄変は全く認められず、実用化に全く問題ない。
○:ほんの僅かな黄変が認められるが、実用化には問題ない。
△:明らかな黄変が認められ、実用化に不適合である。
×:著しい黄変が認められ、実用化に不適合である。
2. Evaluation of formulation stability by light exposure Put each pharmaceutical composition in a screw tube (a transparent glass container with a diameter of 24 mm and a height of 50 mm) and place it in a growth chamber set at 12000 lx · hr and 25 ° C. for 96 hours under irradiation with a fluorescent lamp. left undisturbed. After that, the screw tube was inverted 2-3 times to mix, the appearance of the pharmaceutical composition was visually observed, and the stability of the formulation due to exposure to light was evaluated according to the following criteria.
<Evaluation criteria for formulation stability by light exposure>
⊚: No yellowing is observed, and there is no problem in practical use.
◯: Slight yellowing is observed, but there is no problem in practical use.
Δ: Obvious yellowing is observed, unsuitable for practical use.
x: Significant yellowing is observed, unsuitable for practical use.
3.結果
得られた結果を表1及び2に示す。アミノ安息香酸エチルのみを溶解させた医薬組成物は、光暴露を受けても全く黄変は認められなかった(参考例1)。しかし、アミノ安息香酸エチルを塩化セチルピリジニウムと共存させた場合には、光暴露により著しい黄変が認められた(比較例1)。これに対して、アミノ安息香酸エチルと塩化セチルピリジニウムと共に、グリセリン、プロピレングリコール、メントール、ポリビニルピロリドン、ヒドロキシエチルセルロースの内1種以上を共存させると、光暴露による黄変を大幅に改善できていた(実施例1~22)。特に、光暴露による製剤安定性が◎と評価された医薬組成物の中でも、アミノ安息香酸エチル、塩化セチルピリジニウム、多価アルコール(特に、プロピレングリコール)、及びポリビニルピロリドンを組み合わせて含む場合には、格段顕著な製剤安定性が認められた。
3. Results The results obtained are shown in Tables 1 and 2. A pharmaceutical composition in which only ethyl aminobenzoate was dissolved showed no yellowing even when exposed to light (Reference Example 1). However, when ethyl aminobenzoate was allowed to coexist with cetylpyridinium chloride, significant yellowing was observed upon exposure to light (Comparative Example 1). On the other hand, when one or more of glycerin, propylene glycol, menthol, polyvinylpyrrolidone, and hydroxyethyl cellulose are allowed to coexist with ethyl aminobenzoate and cetylpyridinium chloride, yellowing due to light exposure can be greatly improved ( Examples 1-22). In particular, among pharmaceutical compositions evaluated as ◎ for formulation stability due to light exposure, when ethyl aminobenzoate, cetylpyridinium chloride, polyhydric alcohol (especially propylene glycol), and polyvinylpyrrolidone are combined, Remarkable formulation stability was observed.
処方例
表3に示す医薬組成物(口腔粘膜適用医薬品)を調製した。得られた医薬組成物について、前記試験例と同様の方法で光暴露による製剤安定性を評価したところ、いずれも黄変が認められなかった。
A pharmaceutical composition (drug for oral mucosa) shown in Formulation Example Table 3 was prepared. When the obtained pharmaceutical compositions were evaluated for formulation stability by exposure to light in the same manner as in the above test examples, yellowing was not observed in any of them.
Claims (5)
医薬組成物に、(A)アミノ安息香酸エチル、及び(B)第四級アンモニウム塩と共に、(C)ポリビニルピロリドン及び/又はヒドロキシエチルセルロースを配合する、
前記医薬組成物の光暴露によって生じる黄変の抑制方法。
A method for inhibiting yellowing caused by light exposure of a pharmaceutical composition comprising ethyl aminobenzoate and a quaternary ammonium salt, comprising:
A pharmaceutical composition is formulated with (C) polyvinylpyrrolidone and/or hydroxyethylcellulose together with (A) ethyl aminobenzoate and (B) a quaternary ammonium salt.
A method for inhibiting yellowing caused by light exposure of said pharmaceutical composition.
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