JP6279337B2 - Nasal composition - Google Patents
Nasal composition Download PDFInfo
- Publication number
- JP6279337B2 JP6279337B2 JP2014019412A JP2014019412A JP6279337B2 JP 6279337 B2 JP6279337 B2 JP 6279337B2 JP 2014019412 A JP2014019412 A JP 2014019412A JP 2014019412 A JP2014019412 A JP 2014019412A JP 6279337 B2 JP6279337 B2 JP 6279337B2
- Authority
- JP
- Japan
- Prior art keywords
- composition
- nasal
- acid
- monoterpene
- salts
- 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.)
- Active
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- 239000000203 mixture Substances 0.000 title claims description 86
- 238000002360 preparation method Methods 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 35
- 229920000642 polymer Polymers 0.000 claims description 32
- 229930003658 monoterpene Natural products 0.000 claims description 29
- 150000002773 monoterpene derivatives Chemical class 0.000 claims description 29
- 235000002577 monoterpenes Nutrition 0.000 claims description 29
- 229940092705 beclomethasone Drugs 0.000 claims description 28
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 claims description 27
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 26
- 229920002678 cellulose Polymers 0.000 claims description 23
- 239000001913 cellulose Substances 0.000 claims description 23
- 239000007923 nasal drop Substances 0.000 claims description 19
- 229960000265 cromoglicic acid Drugs 0.000 claims description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 11
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000872 buffer Substances 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 229940041616 menthol Drugs 0.000 claims description 8
- 229940100662 nasal drops Drugs 0.000 claims description 8
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 7
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 6
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 5
- 241000723346 Cinnamomum camphora Species 0.000 claims description 5
- 229930008380 camphor Natural products 0.000 claims description 5
- 229960000846 camphor Drugs 0.000 claims description 5
- 239000002736 nonionic surfactant Substances 0.000 claims description 4
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 claims description 3
- 229940109248 cromoglycate Drugs 0.000 claims 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 claims 1
- 230000002708 enhancing effect Effects 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 description 35
- 230000000694 effects Effects 0.000 description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- -1 organic acid salts Chemical class 0.000 description 16
- 238000002156 mixing Methods 0.000 description 15
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 11
- 229960004958 ketotifen Drugs 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 6
- 239000004327 boric acid Substances 0.000 description 6
- 235000010338 boric acid Nutrition 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000006172 buffering agent Substances 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 239000002826 coolant Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- 239000002294 steroidal antiinflammatory agent Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 239000006173 Good's buffer Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 229910021538 borax Inorganic materials 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007979 citrate buffer Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 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 3
- 235000011083 sodium citrates Nutrition 0.000 description 3
- 235000010339 sodium tetraborate Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 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 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-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
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- LVYLCBNXHHHPSB-UHFFFAOYSA-N 2-hydroxyethyl salicylate Chemical compound OCCOC(=O)C1=CC=CC=C1O LVYLCBNXHHHPSB-UHFFFAOYSA-N 0.000 description 2
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ZFMSMUAANRJZFM-UHFFFAOYSA-N Estragole Chemical compound COC1=CC=C(CC=C)C=C1 ZFMSMUAANRJZFM-UHFFFAOYSA-N 0.000 description 2
- 239000005770 Eugenol Substances 0.000 description 2
- 239000005792 Geraniol Substances 0.000 description 2
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 2
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- CKZXONNJVHXSQM-UHFFFAOYSA-N Ledol Natural products CC(C)C1CCC(C)(O)C2C3CC(C)CC123 CKZXONNJVHXSQM-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 2
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 2
- 229940116229 borneol Drugs 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 229920003174 cellulose-based polymer Polymers 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960002217 eugenol Drugs 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940113087 geraniol Drugs 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
- 239000004615 ingredient Substances 0.000 description 2
- 229960003630 ketotifen fumarate Drugs 0.000 description 2
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- UWKAYLJWKGQEPM-LBPRGKRZSA-N linalyl acetate Chemical compound CC(C)=CCC[C@](C)(C=C)OC(C)=O UWKAYLJWKGQEPM-LBPRGKRZSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 210000002850 nasal mucosa Anatomy 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- GGHMUJBZYLPWFD-UHFFFAOYSA-N patchoulialcohol Chemical compound C1CC2(C)C3(O)CCC(C)C2CC1C3(C)C GGHMUJBZYLPWFD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000007981 phosphate-citrate buffer Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- ZMQAAUBTXCXRIC-UHFFFAOYSA-N safrole Chemical compound C=CCC1=CC=C2OCOC2=C1 ZMQAAUBTXCXRIC-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 description 2
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- AYXPYQRXGNDJFU-QTPLKFIXSA-N (-)-Globulol Chemical compound [C@H]1([C@](CC[C@@H]2[C@H]3C2(C)C)(C)O)[C@H]3[C@H](C)CC1 AYXPYQRXGNDJFU-QTPLKFIXSA-N 0.000 description 1
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Description
本発明は、ベクロメタゾンプロピオン酸エステルと、クロモグリク酸およびその塩類、ケトチフェン並びにその塩類からなる群より選ばれる少なくとも一種と、セルロース系高分子とを含有し、モノテルペンを含有してもよい点鼻用組成物に関する。 The present invention comprises beclomethasone propionate, at least one selected from the group consisting of cromoglycic acid and salts thereof, ketotifen and salts thereof, and a cellulosic polymer, which may contain a monoterpene. Relates to the composition.
ベクロメタゾンは2010年にOTC配合が可能になったステロイド系抗炎症薬である。当該化合物はプロピオン酸エステルの形態で医薬品等に配合されているが、ベクロメタゾンプロピオン酸エステルは水に不溶性の薬物であり、点鼻薬へ配合する場合は懸濁製剤として使用されている。懸濁製剤については一定期間保存すると多数の粒子が凝集した二次粒子を形成して再分散性が悪くなることや、容器のノズルのつまりが問題となる。その結果、製剤が残っているにも関わらず噴霧等の吐出が出来ない、製剤が均一に吐出できず効果にむらが出るなどの問題が起こる。 Beclomethasone is a steroidal anti-inflammatory drug that became available in 2010 with OTC. The compound is formulated in the form of propionate in pharmaceuticals and the like, but beclomethasone propionate is a water-insoluble drug and is used as a suspension preparation when blended into nasal drops. When the suspension preparation is stored for a certain period of time, secondary particles in which a large number of particles aggregate are formed, resulting in poor redispersibility and clogging of the nozzle of the container. As a result, there are problems such that spraying or the like cannot be performed even though the preparation remains, and the preparation cannot be discharged uniformly, resulting in uneven effects.
それらの改善のために、界面活性剤の配合により固体−液体間の吸着力を抑制する方法や、増粘剤などの配合により分散性を良くする方法がとられる。しかしながら、それらを多量に配合すると、製剤の泡立ちや糸引きなどが起こり、使用時に不便や不快感を伴う問題が新たに起こる。 In order to improve them, a method of suppressing the adsorption force between the solid and the liquid by blending a surfactant and a method of improving dispersibility by blending a thickener or the like are taken. However, blending them in large amounts causes foaming of the preparation, stringing, and the like, resulting in new problems with inconvenience and discomfort during use.
さらに界面活性剤を配合した懸濁点鼻剤を使用すると、鼻粘膜を介して口中に界面活性剤などに起因する不快感を感じる場合があり、これを解消したり清涼感を付与するために、点鼻剤にはメントールなどの清涼化剤が広く配合されている。 Furthermore, when using a suspension nasal drop containing a surfactant, there may be a feeling of discomfort due to the surfactant in the mouth through the nasal mucosa, in order to eliminate this or to give a refreshing feeling, Nasal drops contain a wide range of refreshing agents such as menthol.
例えば特許文献１には、分散性が良好で、使用感も良好であり、長期保存しても、ノズルの先の固化や噴霧異常がなく、物理的にも安定で、良好な分散性が損なわれることがないような水性懸濁剤として、難水溶性の薬効成分（例えばプロピオン酸ベクロメタゾン）、多価アルコール、結晶セルロース・カルメロースナトリウム、および清涼化剤を含有する水性懸濁剤が開示されている。前記結晶セルロース・カルメロースナトリウムの配合量は０．３〜３．５重量％である。 For example, Patent Document 1 shows good dispersibility, good usability, no solidification of the tip of the nozzle or spray abnormality even after long-term storage, is physically stable, and good dispersibility is impaired. An aqueous suspension containing a sparingly water-soluble medicinal ingredient (for example, beclomethasone propionate), a polyhydric alcohol, crystalline cellulose / carmellose sodium, and a cooling agent is disclosed ing. The blending amount of the crystalline cellulose / carmellose sodium is 0.3 to 3.5% by weight.
また、懸濁製剤は一般に軽く振って内容物を再分散させてから使用するが、当該製剤の内容物は光安定性が十分でないために光透過性の低い容器、例えば不透明の容器に製剤が充填されるので、軽く振っても中身が十分に再分散したか肉眼で確認するのが困難である。 Suspension preparations are generally used after lightly shaking to redisperse the contents. However, since the contents of the preparations are not sufficiently light-stable, the preparations are placed in containers with low light transmission, such as opaque containers. Since it is filled, it is difficult to confirm with the naked eye whether the contents are sufficiently redispersed even if it is shaken lightly.
ところでOTC医薬品においては、製剤の効果の持続性に加えて、効果感（使用してすぐに効果を感じる即効性）と使用感が重視される傾向にあり、医薬品有効成分の単味製剤よりも、配合剤で前記のバランスを調整した製剤へのニーズも高い。ベクロメタゾンは持続性には優れているものの即効性が感じにくいことから、効果感を求めるあまり、ユーザーが用法用量を超えて使用してしまう可能性があり、予期せぬ副作用の発生が懸念される。 By the way, in OTC medicines, in addition to the sustainability of the effect of the preparation, there is a tendency to emphasize the feeling of effect (immediate effect that feels immediate effect after use) and the feeling of use, rather than a simple preparation of active pharmaceutical ingredients There is also a great need for a preparation in which the above balance is adjusted with a combination drug. Although beclomethasone is excellent in sustainability, it is difficult to feel the immediate effect. Therefore, there is a possibility that the user may use it beyond the dosage amount, and there is concern about unexpected side effects. .
ここで、特許文献２において、ステロイド系抗炎症剤に、清涼化剤として従来使用されているメントールを組み合わせることで、ステロイド系抗炎症剤の即効性が高まることが記載されているが、その即効性はいまだ不十分である。なお、特許文献２の実施例２において、プロピオン酸ベクロメタゾンを０．１質量％、ｌ−メントールを０．０１質量％、クロモグリク酸ナトリウムを１．０質量％及び結晶セルロースを２．０質量％含む点鼻薬が調製されている。 Here, Patent Document 2 describes that the steroid anti-inflammatory agent is combined with menthol, which is conventionally used as a cooling agent, to increase the immediate effect of the steroidal anti-inflammatory agent. Sex is still inadequate. In Example 2 of Patent Document 2, 0.1% by mass of beclomethasone propionate, 0.01% by mass of 1-menthol, 1.0% by mass of sodium cromoglycate, and 2.0% by mass of crystalline cellulose Nasal drops have been prepared.
本発明は、長期間保存しても分散性が良好であり、効果感にも優れ、さらに肉眼で再分散を容易に確認できるような容器に充填可能な点鼻用組成物を提供することを目的とする。 It is an object of the present invention to provide a nasal composition that can be filled in a container that has good dispersibility even when stored for a long period of time, is excellent in effect, and can be easily confirmed for re-dispersion with the naked eye. Objective.
前述の通りステロイド系抗炎症剤を単独で点鼻薬に配合したのでは、例えメントールをあわせて配合しても即効性が不十分なため効果感が不十分であり、ユーザーが用法用量を超えて点鼻薬を使用してしまう危険性がある。 As mentioned above, when a steroidal anti-inflammatory agent is added alone to a nasal drop, even if it is combined with menthol, the immediate effect is insufficient and the effect is insufficient, and the user exceeds the dosage. Risk of using nasal drops.
本発明者はこの問題を解決するため、ステロイド系抗炎症剤であるベクロメタゾンプロピオン酸エステルに加えて即効性のあるクロモグリク酸またはケトチフェンを配合したところ、特許文献１に示された組成を利用しても長期間保存後の良好な分散性が達成されないことを知見した。 In order to solve this problem, the present inventor formulated cromoglycic acid or ketotifen having an immediate effect in addition to beclomethasone propionate, which is a steroidal anti-inflammatory agent, using the composition shown in Patent Document 1. It was also found that good dispersibility after long-term storage was not achieved.
そこで当該問題点を解決するため鋭意検討したところ、本発明者は、ベクロメタゾンプロピオン酸エステルとクロモグリク酸またはケトチフェンを含む点鼻用組成物においては、従来採用されている配合量よりもかなり少量のセルロース系高分子を、クロモグリク酸等に対して所定の割合としたうえで配合することで、又は、従来採用されている配合量よりもかなり少量のセルロース系高分子と、モノテルペンとを配合することで、長期保存した後にも分散性が良好であり、効果感にも優れ、しかも光安定性に優れているためにユーザーが肉眼で再分散を容易に確認できるような容器に充填可能な点鼻用組成物が得られることを見出し、本発明を完成するにいたった。 Accordingly, as a result of diligent studies to solve the problem, the present inventor found that a nasal composition containing beclomethasone propionate and cromoglycic acid or ketotifen has a considerably smaller amount of cellulose than the conventionally used amount. By blending the polymer based on a predetermined ratio with respect to cromoglycic acid or the like, or by blending a considerably smaller amount of cellulose polymer and monoterpene than conventionally employed Because it has good dispersibility even after long-term storage, excellent effect, and excellent light stability, it can be filled into a container that allows the user to easily confirm redispersion with the naked eye. It was found that a composition for use was obtained and the present invention was completed.
すなわち本発明の要旨は以下の通りである。
＜１＞ （Ａ）ベクロメタゾンプロピオン酸エステルと、
（Ｂ）クロモグリク酸およびその塩類、ケトチフェン並びにその塩類からなる群より選ばれる少なくとも一種と、
（Ｃ）０．００１〜０．１ｗ／ｖ％のセルロース系高分子とを含有し、
（Ｄ）モノテルペンを含有してもよい
ことを特徴とする点鼻用組成物（ただし、前記モノテルペン（Ｄ）を含有しない場合には、前記（Ｂ）成分１重量部に対して、前記セルロース系高分子（Ｃ）が０．０００１〜０．０５重量部含有される）。
That is, the gist of the present invention is as follows.
<1> (A) beclomethasone propionate,
(B) at least one selected from the group consisting of cromoglycic acid and salts thereof, ketotifen and salts thereof,
(C) 0.001-0.1 w / v% of a cellulosic polymer,
(D) A nasal composition characterized in that it may contain a monoterpene (however, when it does not contain the monoterpene (D), Cellulosic polymer (C) is contained in an amount of 0.0001 to 0.05 parts by weight).
＜２＞前記セルロース系高分子（Ｃ）が、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、ヒドロキシエチルセルロース（ＨＥＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、カルボキシメチルセルロース（ＣＭＣ）及びその塩類、並びに結晶セルロースからなる群より選ばれる少なくとも一種であることを特徴とする＜１＞に記載の点鼻用組成物。 <2> The cellulose polymer (C) is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) and salts thereof, and crystalline cellulose. The composition for nasal drop according to <1>, wherein the composition is at least one kind.
＜３＞前記点鼻用組成物が前記モノテルペン（Ｄ）を含有し、該モノテルペン（Ｄ）が、メントール及び／又はカンフルであることを特徴とする＜１＞又は＜２＞に記載の点鼻用組成物。 <3> The nasal composition contains the monoterpene (D), and the monoterpene (D) is menthol and / or camphor, Nasal composition.
＜４＞懸濁製剤であることを特徴とする、＜１＞〜＜３＞のいずれかに記載の点鼻用組成物。 <4> The nasal composition according to any one of <1> to <3>, which is a suspension preparation.
本発明によれば、長期間保存した後にも分散性が良好であり、効果感にも優れ、さらに肉眼で再分散を確認できるような容器に充填可能な点鼻用組成物が提供される。 According to the present invention, there is provided a nasal composition that can be filled in a container that has good dispersibility after storage for a long period of time, is excellent in effect, and can be confirmed with the naked eye.
以下本発明の点鼻用組成物の必須成分である（Ａ）〜（Ｃ）成分、任意成分である（Ｄ）成分、その他の成分や組成物の特性等について詳細に説明する。 Hereinafter, components (A) to (C) which are essential components of the nasal composition of the present invention, component (D) which is an optional component, characteristics of other components and compositions, and the like will be described in detail.
［点鼻用組成物］
＜（Ａ）ベクロメタゾンプロピオン酸エステル＞
ベクロメタゾンプロピオン酸エステル（Ａ）は従来使用されているステロイド系抗炎症剤である。抗炎症作用について即効性はないものの持続性に優れているので、本発明の点鼻用組成物は一度の適用で効果が持続する。
[Nose composition]
<(A) Beclomethasone propionate>
Beclomethasone propionate (A) is a conventionally used steroidal anti-inflammatory agent. Although there is no immediate effect on the anti-inflammatory action, it is excellent in sustainability, so that the effect of the nasal composition of the present invention is sustained once applied.
本発明の点鼻用組成物において、ベクロメタゾンプロピオン酸エステル（Ａ）の含有量は、その効果及び良好な分散性の観点から、点鼻用組成物全体に対して通常０．００１〜０．２ｗ／ｖ％であり、好ましくは０．０１〜０．１ｗ／ｖ％である。 In the nasal composition of the present invention, the content of beclomethasone propionate (A) is usually 0.001 to 0.2 w relative to the total nasal composition from the viewpoint of its effect and good dispersibility. / V%, preferably 0.01 to 0.1 w / v%.
＜（Ｂ）クロモグリク酸およびその塩類、ケトチフェン並びにその塩類からなる群より選ばれる少なくとも一種＞
本発明の点鼻用組成物はクロモグリク酸およびその塩類、ケトチフェン並びにその塩類からなる群より選ばれる少なくとも一種（Ｂ）を含有する。これらは従来広く使用されている抗アレルギー剤であるが、即効性に優れ、本発明の点鼻用組成物に良好な効果感を付与する。
<(B) at least one selected from the group consisting of cromoglycic acid and salts thereof, ketotifen and salts thereof>
The nasal composition of the present invention contains at least one (B) selected from the group consisting of cromoglycic acid and salts thereof, ketotifen and salts thereof. These are antiallergic agents that have been widely used in the past, but are excellent in immediate effect and impart a good effect to the nasal drop composition of the present invention.
前記クロモグリク酸の塩類は、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。そのような塩類としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属との塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属との塩等が挙げられる。好ましくはクロモグリク酸ナトリウムである。 The salt of cromoglycic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include salts with alkali metals such as sodium salts and potassium salts; salts with alkaline earth metals such as calcium salts and magnesium salts. Preferably, cromoglycate sodium.
なお、クロモグリク酸及び／又はその塩類は、水和物の形態でも使用でき、またこれらは単独で又は二種以上を組み合わせて使用できる。 In addition, cromoglycic acid and / or its salt can be used also in the form of a hydrate, and these can be used alone or in combination of two or more.
次に、前記ケトチフェンの塩類としては、医薬上、薬理学的に又は生理学的に許容される塩が使用できる。このような塩類としては、有機酸塩［例えば、モノカルボン酸塩（酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩など）、多価カルボン酸塩（フマル酸塩、マレイン酸塩など）、オキシカルボン酸塩（乳酸塩、酒石酸塩、クエン酸塩、コハク酸塩、マロン酸塩など）、有機スルホン酸塩（メタンスルホン酸塩、トルエンスルホン酸塩、トシル酸塩など）など］、無機酸塩（例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩など）、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、ピコリンなどの有機アミンとの塩など）、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、カリウムなど）、アルカリ土類金属（カルシウム、マグネシウムなど）、アルミニウムなどの金属との塩など］などが例示できる。 Next, as the ketotifen salt, a pharmaceutically, pharmacologically or physiologically acceptable salt can be used. Examples of such salts include organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate). Acid salt), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.) Etc.], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, Salts with organic amines such as pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.) Alkaline earth metals (calcium, magnesium etc.) and salts with metals such as aluminum or the like].
ケトチフェンの塩類のうち、有機酸塩、特にフマル酸ケトチフェンなどが好ましい。これらのケトチフェンの塩類は、単独で又は二種以上を組み合わせて使用できる。ケトチフェン又はその塩は、水和物の形態で使用することができる。 Of the salts of ketotifen, organic acid salts, particularly ketotifen fumarate is preferred. These ketotifen salts can be used alone or in combination of two or more. Ketotifen or a salt thereof can be used in the form of a hydrate.
本発明の点鼻用組成物における（Ｂ）成分の含有量は、溶解性の点から点鼻用組成物全体に対して通常０．００１〜５ｗ／ｖ％、好ましくは０．０１〜２ｗ／ｖ％、より好ましくは０．０５〜１ｗ／ｖ％である。 The content of the component (B) in the nasal composition of the present invention is usually 0.001 to 5 w / v%, preferably 0.01 to 2 w /% with respect to the total nasal composition from the viewpoint of solubility. v%, more preferably 0.05 to 1 w / v%.
＜（Ｃ）セルロース系高分子＞
本発明の点鼻用組成物は、０．００１〜０．１ｗ／ｖ％のセルロース系高分子（Ｃ）を含有している。従来は難溶性成分であるベクロメタゾンプロピオン酸エステルを配合した点鼻薬について、多価アルコール、０．３〜３．５ｗ／ｖ％の結晶セルロース・カルメロースナトリウム、および清涼化剤を配合することで、ベクロメタゾンプロピオン酸エステルの良好な分散性を維持していた。
<(C) Cellulose polymer>
The nasal composition of the present invention contains 0.001 to 0.1 w / v% of a cellulosic polymer (C). About nasal drops containing beclomethasone propionate, which is a hardly soluble component, by adding polyhydric alcohol, 0.3 to 3.5 w / v% crystalline cellulose / carmellose sodium, and a cooling agent, The good dispersibility of beclomethasone propionate was maintained.
しかしながら本発明のようにベクロメタゾンプロピオン酸エステルに加えてクロモグリク酸等を配合した組成においては、前記のような組成を採用しても良好な分散性を達成することはできない。結晶セルロース等のセルロース系高分子は増粘剤であり、これは［背景技術］の項で述べた通り増粘剤として機能し難溶性成分の分散性を高める物質であるが、本発明者は驚くべきことに、セルロース系高分子（Ｃ）の配合量を従来のものよりも低減することによって、かえって分散性を高めることができ、しかも組成物の光安定性を高めることができることをも見出した。光安定性に優れることで、本発明の点鼻用組成物は透明な容器にも充填可能であり、この場合には容器を振ったときに内容物が再分散したかどうかが一目瞭然である。 However, in the composition in which cromoglycic acid or the like is blended in addition to beclomethasone propionic acid ester as in the present invention, good dispersibility cannot be achieved even if such a composition is adopted. Cellulose polymers such as crystalline cellulose are thickeners, which are substances that function as thickeners and increase the dispersibility of poorly soluble components as described in the section of “Background Art”. Surprisingly, it has also been found that the dispersibility can be improved by reducing the blending amount of the cellulosic polymer (C) as compared with the conventional one, and the light stability of the composition can be increased. It was. Due to its excellent light stability, the nasal composition of the present invention can be filled into a transparent container. In this case, it is obvious whether the contents are redispersed when the container is shaken.
なお、後述する通り本発明の点鼻用組成物はモノテルペン（Ｄ）を含有してもよく、当該成分を含有する場合には、セルロース系高分子（Ｃ）の含有量は、上記の点鼻用組成物全体に対して０．００１〜０．１ｗ／ｖ％という範囲を満たす限り、それ以上限定されず、他の成分との配合割合も任意の割合でよい。 In addition, as described later, the nasal composition of the present invention may contain a monoterpene (D), and when the component is contained, the content of the cellulosic polymer (C) is as described above. As long as the range of 0.001 to 0.1 w / v% is satisfied with respect to the entire nasal composition, the composition is not further limited, and the blending ratio with other components may be any ratio.
一方本発明の点鼻用組成物においては、前記モノテルペン（Ｄ）は必ずしも必須の成分ではなく、（Ａ）〜（Ｃ）成分の３成分によっても、長期間保存した後にも分散性が良好であり、効果感にも優れ、さらに肉眼で再分散を確認できるような容器に充填可能な点鼻用組成物とすることができる。なお、モノテルペン（Ｄ）を含有しない場合には、セルロース系高分子（Ｃ）の配合量は、上記のように少量であることに加えて、（Ｂ）成分１重量部に対して、セルロース系高分子（Ｃ）が０．０００１〜０．０５重量部の割合であることが必要である。なお、その場合にモノテルペン（Ｄ）がさらに含有されていてもよいことは言うまでもない。 On the other hand, in the nasal composition of the present invention, the monoterpene (D) is not necessarily an essential component, and the dispersibility is good even after being stored for a long time even with the three components (A) to (C). It is excellent in effect and can be made into a composition for nasal drop that can be filled in a container so that redispersion can be confirmed with the naked eye. When the monoterpene (D) is not contained, the amount of the cellulosic polymer (C) is small as described above, and in addition to 1 part by weight of the component (B), cellulose is added. It is necessary that the polymer (C) is in a proportion of 0.0001 to 0.05 parts by weight. In addition, it cannot be overemphasized that the monoterpene (D) may contain further in that case.
このようにモノテルペン（Ｄ）を含まずとも良好な分散性等を達成する観点からは、セルロース系高分子（Ｃ）は、（Ｂ）成分１重量部に対して、セルロース系高分子（Ｃ）が０．０００５〜０．０５重量部の割合で含有されていることが好ましい。 Thus, from the viewpoint of achieving good dispersibility without including the monoterpene (D), the cellulosic polymer (C) is composed of the cellulosic polymer (C) with respect to 1 part by weight of the component (B). ) Is preferably contained in a proportion of 0.0005 to 0.05 parts by weight.
また、セルロース系高分子（Ｃ）は分散性を良くするだけではなく、増粘剤として機能し、点鼻用組成物の粘性を付与して点鼻後の液ダレを防止することができる。このような各種の機能や、分散性の観点から、本発明の点鼻用組成物におけるセルロース系高分子（Ｃ）の含有量は、好ましくは０．００１〜０．１ｗ／ｖ％、さらに好ましくは、０．００１〜０．０５ｗ/ｖ％である。 In addition, the cellulosic polymer (C) not only improves dispersibility, but also functions as a thickener, and can impart the viscosity of the composition for nasal drop to prevent dripping after nasal drop. In view of such various functions and dispersibility, the content of the cellulosic polymer (C) in the nasal composition of the present invention is preferably 0.001 to 0.1 w / v%, more preferably. Is 0.001 to 0.05 w / v%.
前記セルロース系高分子（Ｃ）は、通常医薬品、医薬部外品、化粧品において用いられるものであれば特に制限されないが、具体的には、メチルセルロース、エチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシエチルセルロース（ＨＥＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、カルボキシメチルセルロース（ＣＭＣ）及びその塩類（例えば、カルメロースナトリウム、カルメロースカルシウム、カルメロースアンモニウム）、ステアロキシヒドロキシプロピルメチルセルロース並びに結晶セルロース等が挙げられる。 The cellulosic polymer (C) is not particularly limited as long as it is usually used in pharmaceuticals, quasi drugs, and cosmetics. Specifically, methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose (HEC), Examples thereof include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and salts thereof (for example, carmellose sodium, carmellose calcium, carmellose ammonium), stearoxyhydroxypropylmethylcellulose, and crystalline cellulose. .
これらの中でも、良好な分散性等を達成する観点からはセルロース系高分子（Ｃ）としては、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロース及びその塩類、並びに結晶セルロースが好ましい。 Among these, from the viewpoint of achieving good dispersibility and the like, the cellulose polymer (C) is preferably hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and salts thereof, and crystalline cellulose.
また、セルロース系高分子（Ｃ）は１種または２種類以上を組み合わせて使用することもできる。その場合は、点鼻用組成物の使用感等も考慮し、適宜、配合割合を調整することが望ましい。 Cellulose polymer (C) can be used alone or in combination of two or more. In that case, it is desirable to adjust the blending ratio as appropriate in consideration of the feeling of use of the nasal composition.
＜（Ｄ）モノテルペン＞
本発明の点鼻用組成物はモノテルペン（Ｄ）を含有していてもよい。
ベクロメタゾンプロピオン酸エステル（Ａ）と（Ｂ）成分とを併用すると、特許文献１で採用されているような、所定量の結晶セルロースおよび清涼化剤を含有する組成においては、良好な分散性が達成されなくなる。
<(D) Monoterpene>
The nasal composition of the present invention may contain a monoterpene (D).
When the beclomethasone propionate (A) and the component (B) are used in combination, good dispersibility is achieved in a composition containing a predetermined amount of crystalline cellulose and a cooling agent as employed in Patent Document 1. It will not be done.
本発明においては、上述の通り従来採用されている量よりも少ない、所定量のセルロース系高分子（Ｃ）を配合することによって、ベクロメタゾンプロピオン酸エステル（Ａ）及び（Ｂ）成分を含有する組成であるにもかかわらず、優れた分散性を達成している。 In the present invention, as described above, a composition containing the beclomethasone propionate (A) and (B) components by blending a predetermined amount of the cellulosic polymer (C) which is less than the amount conventionally employed. Nevertheless, excellent dispersibility is achieved.
さらに本発明の点鼻用組成物がモノテルペン（Ｄ）を含まない場合には、上述の通り（Ｂ）成分とセルロース系高分子（Ｃ）の含有割合が所定の範囲であることが必要であるが、モノテルペン（Ｄ）を含有することで、前記含有割合の範囲を満たす必要はなくなり、前記セルロース系高分子（Ｃ）の含有量の自由度が高まり、また分散性や光安定性、特に光安定性が高まる。 Furthermore, when the nasal composition of the present invention does not contain a monoterpene (D), the content ratio of the component (B) and the cellulosic polymer (C) needs to be within a predetermined range as described above. However, by containing the monoterpene (D), it is not necessary to satisfy the range of the content ratio, the degree of freedom of the content of the cellulose-based polymer (C) is increased, dispersibility and light stability, In particular, light stability is increased.
本発明で使用されるモノテルペン（Ｄ）の具体例としては、メントール、ボルネオール、カンフル、ゲラニオール、シネオール、アネトール、リモネン、オイゲノールが挙げられ、これらのモノテルペンは１種単独で又は２種以上を組み合わせて用いてもよい。これらは前記分散性に寄与すると考えられるほか、清涼化剤としても機能するので、不快感を与えない、使用感に優れた点鼻用組成物を与えることができる。 Specific examples of the monoterpene (D) used in the present invention include menthol, borneol, camphor, geraniol, cineol, anethole, limonene, eugenol. These monoterpenes may be used alone or in combination of two or more. You may use it in combination. These are considered to contribute to the dispersibility, and also function as a refreshing agent, so that a composition for nasal drops that does not give discomfort and is excellent in use feeling can be provided.
以上挙げた中でもメントール、ボルネオール、ゲラニオール及びカンフルから選択される少なくとも１種のモノテルペンが好ましく、メントール及びカンフルがより好ましい。これらのモノテルペン（Ｄ）は、ｄ体、ｌ体、dl体のいずれでもよく、また、これらのモノテルペンを含有した精油（ペパーミント油やユーカリ油、ベルガモット油やローズ油など）としても本発明の点鼻用組成物に配合することができる。 Among these, at least one monoterpene selected from menthol, borneol, geraniol, and camphor is preferable, and menthol and camphor are more preferable. These monoterpenes (D) may be any of d-form, l-form, and dl-form, and also as essential oils (such as peppermint oil, eucalyptus oil, bergamot oil, and rose oil) containing these monoterpenes. It can mix | blend with the composition for nasal drops.
モノテルペン（Ｄ）の本発明の点鼻用組成物における含有量は、その効果の観点から通常０．０００１〜１ｗ／ｖ％、好ましくは０．００１〜１ｗ／ｖ％、より好ましくは０．０１〜０．５ｗ／ｖ％である。 The content of the monoterpene (D) in the nasal composition of the present invention is usually 0.0001 to 1 w / v%, preferably 0.001 to 1 w / v%, more preferably 0.00 from the viewpoint of its effect. 01-0.5 w / v%.
＜点鼻用組成物のｐＨ＞
本発明の点鼻用組成物は、鼻腔粘膜に適用した場合に不快な刺激を生じにくくするためにｐＨを調整することができ、ｐＨは通常４．０〜９．０、好ましくは４．０〜７．５、より好ましくは４．５〜７．０、特に好ましくは４．５〜６．５である。ｐＨ調整剤としては、ホウ酸、ホウ砂、リン酸、酢酸、プロピオン酸、シュウ酸、グルコン酸、フマル酸、乳酸、クエン酸、コハク酸、酒石酸、リンゴ酸、グルコノラクトン、酢酸アンモニウム、塩酸、硫酸、ポリリン酸、炭酸カリウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素アンモニウム、リン酸水素カリウム、乳酸ナトリウム、クエン酸ナトリウム、水酸化カリウム、水酸化ナトリウム、モノエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、トリイソプロパノールアミンなどが例示できる。
<PH of nasal composition>
When applied to the nasal mucosa, the nasal composition of the present invention can be adjusted in pH to make it less likely to cause unpleasant irritation, and the pH is usually 4.0 to 9.0, preferably 4.0. It is -7.5, More preferably, it is 4.5-7.0, Most preferably, it is 4.5-6.5. As pH adjusters, boric acid, borax, phosphoric acid, acetic acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, citric acid, succinic acid, tartaric acid, malic acid, gluconolactone, ammonium acetate, hydrochloric acid , Sulfuric acid, polyphosphoric acid, potassium carbonate, sodium bicarbonate, sodium carbonate, ammonium bicarbonate, potassium hydrogen phosphate, sodium lactate, sodium citrate, potassium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine, diisopropanol Examples thereof include amines and triisopropanolamine.
また、本発明の点鼻用組成物のｐＨ調整には緩衝剤を用いてもよい。緩衝剤としては、公知のホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、グッド緩衝剤などが挙げられ、好ましくは、グッド緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤またはクエン酸緩衝剤、特に好ましくは、グッド緩衝剤、ホウ酸緩衝剤、リン酸緩衝剤またはクエン酸緩衝剤である。「グッド緩衝剤」とは、緩衝能を有する双性イオン構造のアミノエタンスルホン酸誘導体及びアミノプロパンスルホン酸誘導体の総称であり、グッドらにより考案された緩衝剤である。グッド緩衝剤としては、ＭＥＳ、ＭＯＰＳ（３−モルホリノプロパンスルホン酸）、ＰＩＰＥＳ、ＨＥＰＥＳ（２−［４−（２−ヒドロキシエチル）−１−ピペラジニル］エタンスルホン酸）、ＢＥＳ、ＴＥＳなどが挙げられる。 In addition, a buffer may be used for adjusting the pH of the nasal composition of the present invention. Examples of the buffer include known borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Good buffer, etc., preferably Good buffer, borate buffer, Phosphate buffer, carbonate buffer or citrate buffer, particularly preferably Good buffer, borate buffer, phosphate buffer or citrate buffer. “Good buffering agent” is a general term for aminoethanesulfonic acid derivatives and aminopropanesulfonic acid derivatives having a zwitterionic structure having buffering ability, and is a buffering agent devised by Good et al. Good buffering agents include MES, MOPS (3-morpholinopropanesulfonic acid), PIPES, HEPES (2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid), BES, TES and the like. .
前記ホウ酸緩衝剤としては、ホウ酸、ホウ酸アルカリ金属塩、ホウ酸アルカリ土類金属塩などのホウ酸塩、ホウ酸及びホウ酸塩の組み合わせなどが挙げられる。 Examples of the boric acid buffer include borates such as boric acid, alkali metal borates, and alkaline earth metal borates, and combinations of boric acid and borates.
前記リン酸緩衝剤としては、リン酸、リン酸アルカリ金属塩、リン酸アルカリ土類金属塩などのリン酸塩、リン酸及びリン酸塩の組み合わせなどが挙げられる。 Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates.
前記クエン酸緩衝剤としては、クエン酸、クエン酸アルカリ金属塩、クエン酸アルカリ土類金属塩などのクエン酸塩、クエン酸及びクエン酸塩の組み合わせなどが挙げられる。 Examples of the citrate buffer include citrates such as citric acid, alkali metal citrate salts, and alkaline earth metal citrate salts, and combinations of citric acid and citrate salts.
また、ホウ酸緩衝剤、リン酸緩衝剤又はクエン酸緩衝剤として、ホウ酸塩、リン酸塩又はクエン酸塩の水和物を用いてもよい。より具体的には、ホウ酸又はその塩（ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウムなど）、リン酸又はその塩（リン酸水素ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウムなど）、炭酸又はその塩（炭酸水素ナトリウム、炭酸ナトリウムなど）、クエン酸またはその塩（クエン酸一ナトリウム、クエン酸三ナトリウムなど）などが挙げられる。 Further, borate, phosphate or citrate hydrate may be used as borate buffer, phosphate buffer or citrate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium hydrogencarbonate, sodium carbonate, etc.), citric acid or a salt thereof (monosodium citrate, trisodium citrate, etc.).
本発明においては、これらのｐＨ調整剤や緩衝剤を１種単独で又は２種以上を組み合わせて用いて、好適なｐＨ範囲とすることができる。 In the present invention, these pH adjusting agents and buffering agents can be used in a suitable pH range by using one kind alone or in combination of two or more kinds.
＜その他の成分＞
さらに、本発明の点鼻用組成物には、本発明の効果を妨げない範囲で、必要に応じて点鼻剤に用いられる有効成分、防腐剤、非イオン性界面活性剤、香料等を１種又は２種以上組み合わせて用いることができる。
<Other ingredients>
Furthermore, the nasal composition of the present invention contains 1 active ingredient, antiseptic, nonionic surfactant, fragrance and the like used in the nasal spray as necessary, as long as the effects of the present invention are not hindered. It can be used in combination of two or more species.
前記有効成分としては、エピネフリン、エフェドリン、テトラヒドロゾリン、ナファゾリン、フェニレフリン、メチルエフェドリン、シュードエフェドリンなどの血管収縮剤、イプロヘプチン、ジフェンヒドラミン、クロルフェニラミンなどの抗ヒスタミン剤、アクリノール、セチルピリジニウム、ベンザルコニウム、ベンゼトニウム、クロルヘキシジンなどの殺菌剤、グリチルレチン酸、グリチルリチン酸、サリチル酸メチル、サリチル酸グリコール、アラントイン、アズレン、アズレンスルホン酸、グアイアズレン、トラネキサム酸、ε−アミノカプロン酸、ベルベリン、リゾチーム、甘草などの消炎剤、亜鉛華、乳酸亜鉛、硫酸亜鉛などの収斂剤、インドメタシン、イブプロフェン、イブプロフェンピコノール、ブフェキサマク、フルフェナム酸ブチル、ベンダザック、ピロキシカム、ケトプロフェン、フェルビナク、紫根、セイヨウトチノキ、およびこれらの塩などが挙げられる。 Examples of the active ingredient include vasoconstrictors such as epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, and pseudoephedrine, antihistamines such as iproheptin, diphenhydramine, and chlorpheniramine, acrinol, cetylpyridinium, benzalkonium, benzethonium, Disinfectants such as, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, glycol salicylate, allantoin, azulene, azulene sulfonic acid, guaiazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice and other anti-inflammatory agents, zinc white, zinc lactate , Astringents such as zinc sulfate, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, full Enamu butyl, bendazac, piroxicam, ketoprofen, felbinac, lithospermi radix, horse chestnut, and salts thereof, and the like.
前記防腐剤としては、安息香酸ナトリウム、パラオキシ安息香酸エステル、ソルビン酸カリウム、フェノキシエタノール、ヘキサンジオール、ホウ酸、ホウ砂などが挙げられる。 Examples of the preservative include sodium benzoate, paraoxybenzoic acid ester, potassium sorbate, phenoxyethanol, hexanediol, boric acid, and borax.
前記非イオン性界面活性剤としては、ポリオキシエチレン（ＰＯＥ）−ポリオキシプロピレン（ＰＯＰ）ブロックコポリマー（例えば、ポロクサマー407、ポロクサマー235、ポロクサマー188、ポロキサミンなど）；モノラウリン酸ＰＯＥ(20)ソルビタン（ポリソルベート20）、モノオレイン酸ＰＯＥ(20)ソルビタン（ポリソルベート80）などのＰＯＥソルビタン脂肪酸エステル類；ＰＯＥ(60)ヒマシ油、ＰＯＥ(60)硬化ヒマシ油などのＰＯＥヒマシ油又は硬化ヒマシ油；ＰＯＥ(9)ラウリルエーテルなどのＰＯＥアルキルエーテル類；ＰＯＥ(20)ＰＯＰ(4)セチルエーテルなどのＰＯＥ・ＰＯＰアルキルエーテル類；ＰＯＥ(10)ノニルフェニルエーテルなどのＰＯＥアルキルフェニルエーテル類などが挙げられる。 Examples of the nonionic surfactant include polyoxyethylene (POE) -polyoxypropylene (POP) block copolymers (for example, poloxamer 407, poloxamer 235, poloxamer 188, poloxamine, etc.); POE (20) sorbitan monolaurate (polysorbate) 20), POE sorbitan fatty acid esters such as monooleic acid POE (20) sorbitan (polysorbate 80); POE castor oil such as POE (60) castor oil, POE (60) hydrogenated castor oil or hydrogenated castor oil; POE (9 POE alkyl ethers such as lauryl ether; POE / POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE alkyl phenyl ethers such as POE (10) nonylphenyl ether.
前記香料としては、カジネン、アネソール、サフロール、オイゲノール、シンナムアルデヒド、エストラゴール、パチョリアルコール、ベンジルアセテート、リナリルアセテート、ジャスモン、インドール、オクタノール、カルバクロール、エチルフラン、ファルネソール、グアイオール、サンタロール、セドロール、ツヨプセン、グロブロール、セドレン、エピグロブロール、精油などが挙げられる。 Examples of the fragrances include kazinene, anesole, safrole, eugenol, cinnamaldehyde, estragole, patchouli alcohol, benzyl acetate, linalyl acetate, jasmon, indole, octanol, carvacrol, ethyl furan, farnesol, guayol, santalol, cedrol, tyopsen Globulol, cedrene, epiglobulol, essential oil and the like.
＜点鼻用組成物の光安定性＞
本発明の点鼻用組成物は難溶性成分であるベクロメタゾンプロピオン酸エステルを含有しているため、通常界面活性剤（例えば上記非イオン性界面活性剤）を配合して懸濁製剤として用いられる。
<Photostability of nasal composition>
Since the nasal composition of the present invention contains beclomethasone propionate which is a poorly soluble component, it is usually used as a suspension preparation by blending a surfactant (for example, the nonionic surfactant).
懸濁製剤は一般に使用時にその容器を振って内容物を再分散させてから使用するが、内容物の光分解を防ぐために容器が不透明であるので、従来再分散が十分に行われたかを簡単に確認することが困難であった。 Suspension preparations are generally used after shaking the container to redisperse the contents before use, but the container is opaque to prevent photodecomposition of the contents, so it is easy to see if redispersion has been performed sufficiently in the past. It was difficult to confirm.
本発明においては、ベクロメタゾンプロピオン酸エステル（Ａ）及び（Ｂ）成分が配合された点鼻用組成物において、さらに従来採用されている量よりも少量のセルロース系高分子（Ｃ）を、（Ｂ）成分に対して所定の割合で配合するか、又は少量のセルロース系高分子（Ｃ）及びモノテルペン（Ｄ）を配合することによって、分散性を良好に保ちつつ、しかも良好な光安定性を達成している。 In the present invention, in the nasal composition in which the beclomethasone propionate (A) and (B) components are blended, the cellulose-based polymer (C) in a smaller amount than the conventionally employed amount (B) ) In a predetermined ratio with respect to the component, or by blending a small amount of the cellulosic polymer (C) and monoterpene (D), while maintaining good dispersibility and good light stability Have achieved.
このため本発明の点鼻用組成物は透明な容器にも充填が可能であり、そのような容器に充填すれば、使用時に容器を振った場合に再分散が十分に行われたか、ユーザーは簡単に確認することができる。 For this reason, the nasal composition of the present invention can be filled into a transparent container, and if such a container is filled, if the container is shaken at the time of use, redispersion is sufficiently performed, It can be easily confirmed.
＜点鼻用組成物の製剤形態＞
本発明の点鼻用組成物は、スプレー式製剤、滴下式製剤、塗布式製剤等の種々の製剤形態をとることができる。また、前記スプレー式の製剤形態には、容器に付属されたポンプを手動で動かして液剤を噴出する機構のある手動ポンプ式点鼻剤、圧縮ガス（空気や酸素、窒素、炭酸や、混合ガス）等の噴射剤を容器内に充填しておいて容器に付属して設けた弁を動かして液剤を自動噴出する機構のあるエアゾール式点鼻剤なども含まれる。
<Form of formulation for nasal composition>
The nasal composition of the present invention can take various preparation forms such as a spray preparation, a drop preparation, and an application preparation. In addition, the spray-type preparation form includes a manual-pump nasal drop, a compressed gas (air, oxygen, nitrogen, carbonic acid, mixed gas, etc.) having a mechanism for ejecting the liquid by manually moving the pump attached to the container. An aerosol type nasal spray having a mechanism in which a liquid agent is automatically ejected by moving a valve provided with the container and filling a propellant in the container.
＜点鼻用組成物の用法・用量＞
本発明の点鼻用組成物は、その製剤形態に従い適切な方法で投与され、また例えば１回当たりの各鼻腔への投与量が、
ベクロメタゾンプロピオン酸エステル（Ａ）が好ましくは１〜１００μｇ、より好ましくは５〜５０μｇ、さらに好ましくは１０〜２５μｇとなるような量で、
また１日当たりの各鼻腔への投与量が、
ベクロメタゾンプロピオン酸エステル（Ａ）が好ましくは１０〜１０００μｇ、より好ましくは５０〜８００μｇ、さらに好ましくは１００〜４００μｇとなり、
（Ｂ）成分としてケトチフェン及び／又はその塩類を使用する場合にはその総量として好ましくは０．０１〜１５ｍｇ程度となり、
（Ｂ）成分としてクロモグリク酸及び／又はその塩類を使用する場合にはその総量として好ましくは０．０１〜１５ｍｇとなるような量で、投与される。
<Dosage and dosage of nasal composition>
The nasal composition of the present invention is administered by an appropriate method according to the formulation form, and for example, the dose to each nasal cavity per administration is
The amount of beclomethasone propionate (A) is preferably 1-100 μg, more preferably 5-50 μg, and even more preferably 10-25 μg,
The daily dose to each nasal cavity is
The beclomethasone propionate (A) is preferably 10 to 1000 μg, more preferably 50 to 800 μg, still more preferably 100 to 400 μg,
When (B) ketotifen and / or salts thereof are used, the total amount is preferably about 0.01 to 15 mg,
When cromoglycic acid and / or a salt thereof is used as the component (B), the total amount is preferably 0.01 to 15 mg.
＜点鼻用組成物の製造方法＞
本発明の点鼻用組成物の製造方法は特に制限されるものではなく、公知の方法によって前記組成物を製造することができる。例えば、以上説明した本発明における必須成分（Ａ）〜（Ｃ）及び必要に応じて（Ｄ）成分やその他の成分等を、常法により水または温水中、必要に応じて油性基剤中に、溶解・懸濁させた後、ｐＨや浸透圧などを適宜調整して液剤を製し、さらに必要に応じて無菌ろ過を行い、点鼻用容器に充填して製造することができる。
<Method for producing nasal composition>
The method for producing the nasal composition of the present invention is not particularly limited, and the composition can be produced by a known method. For example, the essential components (A) to (C) and, if necessary, the component (D) and other components in the present invention described above are added to water or warm water by a conventional method, and if necessary, to an oily base. After dissolving and suspending, the solution can be prepared by appropriately adjusting pH, osmotic pressure, etc., and further subjected to aseptic filtration as necessary, and filling into a nasal container.
以下実施例により本発明をさらに詳細に説明するが、本発明は何らこれらに限定されない。 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.
［参考例（試験製剤１〜３）］
下記表１の組成に従って試験製剤１〜３を公知の方法により調製し、それぞれの分散性について評価した。具体的には以下の通り、各試験製剤の光照射前後における、分散性を確認することで評価を行った。なお、以下の表において数値の単位は、他に記載しない限り「ｗ／ｖ％」である。
[Reference Example (Test Preparations 1-3)]
Test preparations 1 to 3 were prepared by a known method according to the composition shown in Table 1 below, and the dispersibility of each was evaluated. Specifically, the evaluation was performed by confirming dispersibility before and after the light irradiation of each test preparation as follows. In the following table, the unit of numerical values is “w / v%” unless otherwise stated.
各試験製剤をガラス製スクリューキャップ試験管に７ｍＬずつ充填後、室温・遮光条件下で１日程度静置した。このサンプルについて試験開始時の濁度を測定した。具体的には、測定直前にサンプル容器を振盪し、その容器の上下方向の中央付近にある製剤の濁度を測定し、「製剤調製後の濁度」とし、分散性を確認するため、さらに「製剤調製後の濁度」を測定したサンプルを３時間静置した後に再度サンプル容器の上下方向の中央付近にある製剤の濁度を測定し、「分散後の濁度」とした。これらの測定値を元に、次式により試験開始時の分散性を算出した。
試験開始時の分散性（％）＝（分散後の濁度）/（製剤調製後の濁度）×１００
Each test preparation was filled in a glass screw cap test tube by 7 mL, and allowed to stand for about 1 day at room temperature under light-shielding conditions. The turbidity at the start of the test was measured for this sample. Specifically, the sample container is shaken immediately before the measurement, and the turbidity of the preparation in the vicinity of the center in the vertical direction of the container is measured to obtain `` turbidity after preparation of preparation '' to confirm dispersibility. The sample for which the “turbidity after preparation preparation” was measured was allowed to stand for 3 hours, and then the turbidity of the preparation in the vicinity of the center in the vertical direction of the sample container was measured again to obtain “turbidity after dispersion”. Based on these measured values, the dispersibility at the start of the test was calculated by the following formula.
Dispersibility at start of test (%) = (turbidity after dispersion) / (turbidity after preparation of preparation) × 100
次に、「試験開始時の分散性」を評価したサンプルを用いて、光照射による分散性への影響を確認した。具体的には、各試験製剤に対し、光照射装置であるサンテスター（SUNTEST XLS+；東洋精機製作所）を用いて放射照度７６５Ｗ／ｍ２で３時間、光を照射した（照射エネルギーの合計は１００００ｋＪ／ｍ２に相当）。この光照射を行ったサンプルについて、測定直前に振盪したサンプル容器の上下方向の中央付近にある製剤の濁度を測定して「光照射後の濁度」とし、この「光照射後の濁度」を測定したサンプルを３時間静置した後に再度サンプル容器の上下方向の中央付近にある製剤の濁度を測定して「光照射後 分散後の濁度」とした。これらの測定値を元に、次式により光照射後の分散性を算出した。
光照射後の分散性（％）＝（光照射後 分散後の濁度）/（光照射後の濁度）×１００
Next, using a sample evaluated for “dispersibility at the start of the test”, the influence of the light irradiation on the dispersibility was confirmed. Specifically, each test preparation was irradiated with light at a irradiance of 765 W / m 2 for 3 hours using a sun tester (SUNTEST XLS +; Toyo Seiki Seisakusho) (total irradiation energy was 10,000 kJ). / M 2 ). For the sample that had been irradiated with light, the turbidity of the preparation in the vicinity of the center in the vertical direction of the sample container shaken immediately before the measurement was measured as “turbidity after light irradiation”. The sample was measured for 3 hours, and the turbidity of the preparation in the vicinity of the center in the vertical direction of the sample container was measured again to obtain “turbidity after dispersion after light irradiation”. Based on these measured values, the dispersibility after light irradiation was calculated by the following formula.
Dispersibility after light irradiation (%) = (Turbidity after dispersion after light irradiation) / (Turbidity after light irradiation) × 100
以上の結果を下記表１に示す。なお、以下の表において「残量」とは、製剤全体の量を１００ｗ／ｖ％とするのに必要な量である。 The above results are shown in Table 1 below. In the following table, “remaining amount” is an amount necessary to make the total amount of the preparation 100 w / v%.
［実施例１〜４、比較例１〜４］
下記表２の組成に従って実施例１〜４及び比較例１〜４の試験製剤を公知の方法により調製し、それぞれの試験開始時の分散性及び光照射後の分散性について、上記参考例と同様にして評価した。結果を下記表２に示す。
[Examples 1-4, Comparative Examples 1-4]
Test preparations of Examples 1 to 4 and Comparative Examples 1 to 4 were prepared by known methods according to the composition in Table 2 below, and the dispersibility at the start of each test and the dispersibility after light irradiation were the same as in the above Reference Example. And evaluated. The results are shown in Table 2 below.
表２に示される通り、ベクロメタゾンプロピオン酸エステルや、それとクロモグリク酸ナトリウムを配合した製剤は分散性が悪い（比較例１及び２）。これに、従来分散性を高めるために使用されているカルメロースナトリウムや、セルロース系高分子であるヒドロキシプロピルメチルセルロース（ＨＰＭＣ）を配合しても、分散性を高めることは出来ない（比較例３及び４）。また、一部の比較例では光照射によって分散性は試験開始時からさらに悪化しているが、これは光照射によって、懸濁物（ベクロメタゾンプロピオン酸エステル）が凝集したり、粘度変化が起きたためと考えられる。 As shown in Table 2, preparations containing beclomethasone propionate and sodium cromoglycate have poor dispersibility (Comparative Examples 1 and 2). Even if it mix | blends the carmellose sodium currently used in this to improve a dispersibility, and hydroxypropyl methylcellulose (HPMC) which is a cellulosic polymer | macromolecule, a dispersibility cannot be improved (Comparative Example 3 and 4). In some comparative examples, dispersibility was further deteriorated by light irradiation from the beginning of the test. This was because suspension (beclomethasone propionate) aggregated or viscosity changed due to light irradiation. it is conceivable that.
一方セルロース系高分子（ＨＰＭＣ又はカルメロースナトリウム）を従来配合されている量よりも少量で配合し、かつクロモグリク酸ナトリウム１重量部に対するセルロース系高分子の配合量を本発明で規定される範囲内とすることで、分散性は良好になる（実施例１及び３）。また、セルロース系高分子に加えてモノテルペンであるｌ−メントールを配合することによっても、分散性、特に光照射後の分散性が良好になる（実施例２及び４）。 On the other hand, cellulosic polymer (HPMC or carmellose sodium) is blended in a smaller amount than conventionally blended, and the blending amount of cellulosic polymer per 1 part by weight of sodium cromoglycate is within the range specified by the present invention. Thus, dispersibility is improved (Examples 1 and 3). Further, by adding 1-menthol, which is a monoterpene, in addition to the cellulosic polymer, the dispersibility, particularly the dispersibility after light irradiation, is improved (Examples 2 and 4).
［実施例５、比較例５〜８］
下記表３の組成に従って実施例５及び比較例５〜８の試験製剤を公知の方法により調製し、それぞれの試験開始時の分散性及び光照射後の分散性について、上記参考例と同様にして評価した。結果を下記表３に示す。
[Example 5, Comparative Examples 5 to 8]
Test preparations of Example 5 and Comparative Examples 5 to 8 were prepared by known methods according to the compositions in Table 3 below, and the dispersibility at the start of each test and the dispersibility after light irradiation were the same as in the above Reference Example. evaluated. The results are shown in Table 3 below.
比較例８に示される通り、ベクロメタゾンプロピオン酸エステルとクロモグリク酸ナトリウムの両方を配合し、さらに結晶セルロースを本発明で規定される少量で配合しても、クロモグリク酸ナトリウム（（Ｂ）成分）及び結晶セルロース（（Ｃ）成分）の配合割合が本発明で規定される範囲内にないと（比較例８では（Ｂ）成分１重量部に対して（Ｃ）成分が０．１重量部含まれている）、分散性は不良となる。 As shown in Comparative Example 8, even when both beclomethasone propionate and sodium cromoglycate were blended, and even when crystalline cellulose was blended in a small amount as defined in the present invention, sodium cromoglycate (component (B)) and crystals If the blending ratio of cellulose (component (C)) is not within the range defined by the present invention (in Comparative Example 8, 0.1 part by weight of component (C) is included with respect to 1 part by weight of component (B)). Dispersibility is poor.
一方実施例５に示される通り、そのような配合であってもさらにＬ−メントールを配合すると、（Ｂ）成分と（Ｃ）成分の配合比率に関係なく、分散性は良好になる。 On the other hand, as shown in Example 5, even in such a blend, when L-menthol is further blended, the dispersibility becomes good regardless of the blend ratio of the component (B) and the component (C).
［実施例６・７、比較例９］
下記表４の組成に従って実施例６及び７並びに比較例９の試験製剤を公知の方法により調製し、それぞれの試験開始時の分散性について、上記参考例と同様にして評価した。結果を下記表４に示す。
[Examples 6 and 7, Comparative Example 9]
Test formulations of Examples 6 and 7 and Comparative Example 9 were prepared by known methods according to the compositions shown in Table 4 below, and the dispersibility at the start of each test was evaluated in the same manner as in the above Reference Example. The results are shown in Table 4 below.
比較例９に示される通り、本発明で規定される（Ａ）〜（Ｄ）成分を全て含有していても、結晶セルロースの配合量が本発明の範囲を超えると、良好な分散性を達成することはできない。 As shown in Comparative Example 9, even when all the components (A) to (D) defined in the present invention are contained, when the blending amount of the crystalline cellulose exceeds the range of the present invention, good dispersibility is achieved. I can't do it.
［製剤例１］
下記の各成分を秤量したものに、精製水を全量で１００ｍｌとなるように加え、混合して懸濁液を調製（ｐＨ５．５）し、本発明の点鼻用組成物を得た。
プロピオン酸ベクロメタゾン ２５ｍｇ（０．０２５ｗ／ｖ％）
クロモグリク酸ナトリウム １０００ｍｇ（１．０ｗ／ｖ％）
ヒドロキシプロピルメチルセルロース １ｍｇ（０．００１ｗ／ｖ％）
l-メントール ２０ｍｇ（０．０２ｗ／ｖ％）
ポリソルベート８０ １００ｍｇ（０．１ｗ／ｖ％）
プロピレングリコール ２００００ｍｇ（２０．０ｗ／ｖ％）
クエン酸 適量
クエン酸ナトリウム 適量
[Formulation Example 1]
To each of the following components weighed, purified water was added to a total amount of 100 ml and mixed to prepare a suspension (pH 5.5) to obtain the nasal composition of the present invention.
Beclomethasone propionate 25mg (0.025w / v%)
Sodium cromoglycate 1000mg (1.0w / v%)
Hydroxypropyl methylcellulose 1mg (0.001w / v%)
l-Menthol 20mg (0.02w / v%)
Polysorbate 80 100mg (0.1w / v%)
Propylene glycol 20000 mg (20.0 w / v%)
Citric acid appropriate amount Sodium citrate appropriate amount
［製剤例２］
下記の各成分を秤量したものに、精製水を全量で１００ｍｌとなるように加え、混合し
て懸濁液を調製（ｐＨ５．８）し、本発明の点鼻用組成物を得た。
プロピオン酸ベクロメタゾン ５０ｍｇ（０．０５ｗ／ｖ％）
ケトチフェンフマル酸塩 ７５．６ｍｇ（０．０７５６ｗ／ｖ％）
ナファゾリン塩酸塩 ２５ｍｇ（０．０２５ｗ／ｖ％）
ヒドロキシプロピルメチルセルロース １ｍｇ（０．００１ｗ／ｖ％）
l-メントール １０ｍｇ（０．０１ｗ／ｖ％）
ポリソルベート８０ １００ｍｇ（０．１ｗ／ｖ％）
プロピレングリコール ５０００ｍｇ（５．０ｗ／ｖ％）
クエン酸 適量
クエン酸ナトリウム 適量
[Formulation Example 2]
To each of the following components weighed, purified water was added to a total volume of 100 ml and mixed to prepare a suspension (pH 5.8), thereby obtaining the nasal composition of the present invention.
Beclomethasone propionate 50mg (0.05w / v%)
Ketotifen fumarate 75.6 mg (0.0756 w / v%)
Naphazoline hydrochloride 25mg (0.025w / v%)
Hydroxypropyl methylcellulose 1mg (0.001w / v%)
l-Menthol 10mg (0.01w / v%)
Polysorbate 80 100mg (0.1w / v%)
Propylene glycol 5000mg (5.0w / v%)
Citric acid appropriate amount Sodium citrate appropriate amount
Claims (7)
（Ｂ）クロモグリク酸およびその塩類からなる群より選ばれる少なくとも一種と、
（Ｃ）０．００１〜０．１ｗ／ｖ％のセルロース系高分子とを含有し、
（Ｄ）モノテルペンを含有してもよい
ことを特徴とする点鼻用組成物（ただし、前記モノテルペン（Ｄ）を含有しない場合には、前記（Ｂ）成分１重量部に対して、前記セルロース系高分子（Ｃ）が０．０００１〜０．０５重量部含有される）。 (A) beclomethasone propionate,
(B) at least one selected from cromoglycate and its salts such or Ranaru group,
(C) 0.001-0.1 w / v% of a cellulosic polymer,
(D) A nasal composition characterized in that it may contain a monoterpene (however, when it does not contain the monoterpene (D), Cellulosic polymer (C) is contained in an amount of 0.0001 to 0.05 parts by weight).
（Ａ）ベクロメタゾンプロピオン酸エステルと、(A) beclomethasone propionate,
（Ｂ）クロモグリク酸およびその塩類からなる群より選ばれる少なくとも一種と、(B) at least one selected from the group consisting of cromoglycic acid and its salts;
（Ｃ）０．００１〜０．１ｗ／ｖ％のセルロース系高分子とを含有し、(C) 0.001-0.1 w / v% of a cellulosic polymer,
（Ｄ）モノテルペンを含有してもよい（ただし、前記モノテルペン（Ｄ）を含有しない場合には、前記（Ｂ）成分１重量部に対して、前記セルロース系高分子（Ｃ）が０．０００１〜０．０５重量部含有される）(D) The monoterpene may be contained (however, when the monoterpene (D) is not contained, the cellulose polymer (C) is added to 0.1 part by weight of the component (B). 0001 to 0.05 parts by weight contained)
ことを特徴とする、点鼻用組成物の分散性を高める方法。A method for enhancing the dispersibility of a composition for nasal drop.
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