JP2024049405A - New inhalants - Google Patents
New inhalants Download PDFInfo
- Publication number
- JP2024049405A JP2024049405A JP2021026301A JP2021026301A JP2024049405A JP 2024049405 A JP2024049405 A JP 2024049405A JP 2021026301 A JP2021026301 A JP 2021026301A JP 2021026301 A JP2021026301 A JP 2021026301A JP 2024049405 A JP2024049405 A JP 2024049405A
- Authority
- JP
- Japan
- Prior art keywords
- inhalant
- hydrate
- sodium
- cepharanthine
- phosphate
- 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
- 239000003814 drug Substances 0.000 claims abstract description 46
- VQAWRQZAAIQXHM-UHFFFAOYSA-N Cepharanthine Natural products O1C(C=C2)=CC=C2CC(C=23)N(C)CCC3=CC=3OCOC=3C=2OC(=CC=23)C(OC)=CC=2CCN(C)C3CC2=CC=C(O)C1=C2 VQAWRQZAAIQXHM-UHFFFAOYSA-N 0.000 claims abstract description 43
- YVPXVXANRNDGTA-WDYNHAJCSA-N cepharanthine Chemical compound C1C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@H](C2=C3)N(C)CCC2=CC(OC)=C3OC2=C(OCO3)C3=CC3=C2[C@H]1N(C)CC3 YVPXVXANRNDGTA-WDYNHAJCSA-N 0.000 claims abstract description 43
- 229940079593 drug Drugs 0.000 claims abstract description 40
- 239000000843 powder Substances 0.000 claims description 14
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 12
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 10
- 229960004436 budesonide Drugs 0.000 claims description 8
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 8
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 8
- 229960004584 methylprednisolone Drugs 0.000 claims description 8
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 8
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 claims description 6
- 229960002537 betamethasone Drugs 0.000 claims description 6
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 6
- 229960003728 ciclesonide Drugs 0.000 claims description 6
- BGSOJVFOEQLVMH-VWUMJDOOSA-N cortisol phosphate Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 BGSOJVFOEQLVMH-VWUMJDOOSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- MQQNFDZXWVTQEH-UHFFFAOYSA-N nafamostat Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(C=C(C=C2)C(N)=N)C2=C1 MQQNFDZXWVTQEH-UHFFFAOYSA-N 0.000 claims description 6
- 229950009865 nafamostat Drugs 0.000 claims description 6
- 229960005294 triamcinolone Drugs 0.000 claims description 6
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims description 6
- XASIMHXSUQUHLV-UHFFFAOYSA-N camostat Chemical compound C1=CC(CC(=O)OCC(=O)N(C)C)=CC=C1OC(=O)C1=CC=C(N=C(N)N)C=C1 XASIMHXSUQUHLV-UHFFFAOYSA-N 0.000 claims description 5
- 229960000772 camostat Drugs 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- YKGYIDJEEQRWQH-UHFFFAOYSA-N 4-[6-(diaminomethylideneamino)-1-oxohexoxy]benzoic acid ethyl ester Chemical compound CCOC(=O)C1=CC=C(OC(=O)CCCCCN=C(N)N)C=C1 YKGYIDJEEQRWQH-UHFFFAOYSA-N 0.000 claims description 4
- QTQGHKVYLQBJLO-UHFFFAOYSA-N 4-methylbenzenesulfonate;(4-methyl-1-oxo-1-phenylmethoxypentan-2-yl)azanium Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC(C)CC(N)C(=O)OCC1=CC=CC=C1 QTQGHKVYLQBJLO-UHFFFAOYSA-N 0.000 claims description 4
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 claims description 4
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 4
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 claims description 4
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 4
- 229960000531 abacavir sulfate Drugs 0.000 claims description 4
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 claims description 4
- RZVPBGBYGMDSBG-GGAORHGYSA-N baloxavir marboxil Chemical compound COC(=O)OCOc1c2C(=O)N3CCOC[C@H]3N([C@H]3c4ccc(F)c(F)c4CSc4ccccc34)n2ccc1=O RZVPBGBYGMDSBG-GGAORHGYSA-N 0.000 claims description 4
- 229940008411 baloxavir marboxil Drugs 0.000 claims description 4
- 239000000920 calcium hydroxide Substances 0.000 claims description 4
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 4
- PMDQGYMGQKTCSX-HQROKSDRSA-L calcium;[(2r,3s)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3s)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate Chemical compound [Ca+2].C([C@@H]([C@H](OP([O-])([O-])=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 PMDQGYMGQKTCSX-HQROKSDRSA-L 0.000 claims description 4
- 229960003290 cortisone acetate Drugs 0.000 claims description 4
- 229960003957 dexamethasone Drugs 0.000 claims description 4
- 229950000812 dexamethasone palmitate Drugs 0.000 claims description 4
- 229960004833 dexamethasone phosphate Drugs 0.000 claims description 4
- VQODGRNSFPNSQE-CXSFZGCWSA-N dexamethasone phosphate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP(O)(O)=O)(O)[C@@]1(C)C[C@@H]2O VQODGRNSFPNSQE-CXSFZGCWSA-N 0.000 claims description 4
- 229960002656 didanosine Drugs 0.000 claims description 4
- UGWJRRXTMKRYNK-VSLILLSYSA-M dolutegravir sodium Chemical compound [Na+].C([C@@H]1OCC[C@H](N1C(=O)C1=C([O-])C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F UGWJRRXTMKRYNK-VSLILLSYSA-M 0.000 claims description 4
- 229960001976 dolutegravir sodium Drugs 0.000 claims description 4
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 claims description 4
- 229960003804 efavirenz Drugs 0.000 claims description 4
- 229960000366 emtricitabine Drugs 0.000 claims description 4
- 229960002011 fludrocortisone Drugs 0.000 claims description 4
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 claims description 4
- 229960001469 fluticasone furoate Drugs 0.000 claims description 4
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 claims description 4
- 229960000289 fluticasone propionate Drugs 0.000 claims description 4
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 claims description 4
- 229960002933 fosamprenavir calcium Drugs 0.000 claims description 4
- 229950000501 gabexate Drugs 0.000 claims description 4
- 229960000890 hydrocortisone Drugs 0.000 claims description 4
- 229960004204 hydrocortisone sodium phosphate Drugs 0.000 claims description 4
- 229960001401 hydrocortisone sodium succinate Drugs 0.000 claims description 4
- 229960000334 methylprednisolone sodium succinate Drugs 0.000 claims description 4
- 229960002744 mometasone furoate Drugs 0.000 claims description 4
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 claims description 4
- NQHXCOAXSHGTIA-SKXNDZRYSA-N nelfinavir mesylate Chemical compound CS(O)(=O)=O.CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 NQHXCOAXSHGTIA-SKXNDZRYSA-N 0.000 claims description 4
- 229960005230 nelfinavir mesylate Drugs 0.000 claims description 4
- 229960000689 nevirapine Drugs 0.000 claims description 4
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims description 4
- 229960002194 oseltamivir phosphate Drugs 0.000 claims description 4
- 229960001084 peramivir Drugs 0.000 claims description 4
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 claims description 4
- 229960003975 potassium Drugs 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229960005205 prednisolone Drugs 0.000 claims description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 4
- 229960002176 prednisolone sodium succinate Drugs 0.000 claims description 4
- FKKAEMQFOIDZNY-CODXZCKSSA-M prednisolone sodium succinate Chemical compound [Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC([O-])=O)[C@@H]4[C@@H]3CCC2=C1 FKKAEMQFOIDZNY-CODXZCKSSA-M 0.000 claims description 4
- KZVVGZKAVZUACK-BJILWQEISA-N rilpivirine hydrochloride Chemical compound Cl.CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 KZVVGZKAVZUACK-BJILWQEISA-N 0.000 claims description 4
- 229960004481 rilpivirine hydrochloride Drugs 0.000 claims description 4
- 229960000311 ritonavir Drugs 0.000 claims description 4
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 229960001203 stavudine Drugs 0.000 claims description 4
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 claims description 4
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 claims description 4
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 4
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 claims description 4
- 229960001028 zanamivir Drugs 0.000 claims description 4
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 claims description 4
- 229960002555 zidovudine Drugs 0.000 claims description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 4
- 229950005327 laninamivir octanoate hydrate Drugs 0.000 claims description 3
- UKTIJASCFRNWCB-RMIBSVFLSA-N laninamivir octanoate hydrate Chemical compound CCCCCCCC(=O)OC[C@@H](O)[C@@H](OC)[C@@H]1OC(C(O)=O)=C[C@H](N=C(N)N)[C@H]1NC(C)=O UKTIJASCFRNWCB-RMIBSVFLSA-N 0.000 claims description 3
- 229960004249 sodium acetate Drugs 0.000 claims description 3
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 229960003339 sodium phosphate Drugs 0.000 claims description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 claims description 2
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 abstract description 28
- 208000025721 COVID-19 Diseases 0.000 abstract description 15
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- 210000002345 respiratory system Anatomy 0.000 description 7
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 5
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- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 2
- 102100031780 Endonuclease Human genes 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- BGSOJVFOEQLVMH-UHFFFAOYSA-N Hydrocortisone phosphate Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)(O)C(=O)COP(O)(O)=O)C4C3CCC2=C1 BGSOJVFOEQLVMH-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000005348 Neuraminidase Human genes 0.000 description 2
- 108010006232 Neuraminidase Proteins 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 229960004648 betamethasone acetate Drugs 0.000 description 2
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
【課題】COVID-19の治療薬としての新規な吸入剤の提供。【解決手段】セファランチン及びステロイド薬類等を用いることを特徴とする吸入剤。【選択図】なしThe present invention provides a novel inhalant as a treatment for COVID-19. The present invention provides an inhalant that uses cepharanthin and steroid drugs.
Description
本発明は、吸入剤に関する。 The present invention relates to an inhalant.
COVID-19(日本名:新型コロナウイルス感染症)は、2019新型コロナウイルス(SARS-CoV-2)によって発症する感染症である。COVID-19は、2019年11月に中華人民共和国の武漢で発生が確認され、同年12月にWHOに報告された感染症であり、これ以降世界的に感染が拡大している。その症状は、発熱、空咳、疲労、喀痰、息切れ、咽頭痛、頭痛、筋肉痛、関節痛、嗅覚異常、味覚異常などから始まり、重症例では肺炎が重症化して呼吸不全に陥り、死亡の転帰をとるものである。
その感染力、罹患した際の重症化率等未だ不明な点があることに加え、新型であることから有効な治療法も未だ模索中であり、世界中の人々を不安に陥らせている。
COVID-19 (Japanese name: novel coronavirus disease) is an infectious disease caused by the 2019 novel coronavirus (SARS-CoV-2). COVID-19 was confirmed to have occurred in Wuhan, People's Republic of China in November 2019 and reported to the WHO in December of the same year, and has since spread worldwide. Symptoms include fever, dry cough, fatigue, phlegm, shortness of breath, sore throat, headache, muscle pain, joint pain, abnormal smell, and abnormal taste, and in severe cases, pneumonia worsens, leading to respiratory failure and death.
There are still many unknowns about the virus, such as its infectiousness and the rate at which it becomes severe when contracted. In addition, because it is a new type of virus, effective treatments are still being sought, causing anxiety around the world.
これまでに、多数の既存薬物のスクリーニングがなされ、最近になって、セファランチンがCOVID-19の治療薬として期待されている。SARS-CoV-2は細胞表面に存在するACE2(ACE2(Angiotensin-converting enzyme 2、アンジオテンシン変換酵素II)を受容体として結合することによって細胞内に侵入して感染する。セファランチンはSARS-CoV-2とACE2の結合を阻害することで細胞内への侵入を阻止する(非特許文献1)。
また吸入ステロイド薬もCOVID-19の治療薬として検討されている。吸入ステロイド薬は喘息など肺の局所的な炎症を抑制する作用を有し、COVID-19で確認される肺の炎症に対しても抑制する効果が期待される。また一部の吸入ステロイド薬では非構造タンパク質であるNsp15に結合することでSARS-CoV-2の増殖を抑制する(非特許文献2、3)。
ナファモスタットやカモスタット等のたん白分解酵素阻害薬もCOVID-19の治療薬として検討されている。たん白分解酵素阻害薬はSARS-CoV-2が細胞に侵入する最初の過程であるウイルス外膜と細胞膜との融合を阻害し、SARS-CoV-2の感染を阻害する(非特許文献4)。また、抗インフルエンザ薬やHIV治療薬はノイラミニダーゼ阻害作用やキャップ依存性エンドヌクレアーゼ阻害作用といった抗ウイルス作用によりCOVID-19の治療薬として検討されている。
To date, many existing drugs have been screened, and recently, cepharanthine has been shown to be a promising treatment for COVID-19. SARS-CoV-2 invades and infects cells by binding to ACE2 (angiotensin-converting enzyme 2 (ACE2)) present on the cell surface as a receptor. Cepharanthine blocks SARS-CoV-2 from invading cells by inhibiting the binding between SARS-CoV-2 and ACE2 (Non-Patent Document 1).
Inhaled steroids are also being considered as a treatment for COVID-19. Inhaled steroids have the effect of suppressing localized inflammation in the lungs, such as asthma, and are expected to be effective in suppressing lung inflammation confirmed by COVID-19. Some inhaled steroids also suppress the proliferation of SARS-CoV-2 by binding to the nonstructural protein Nsp15 (Non-Patent Documents 2 and 3).
Protease inhibitors such as nafamostat and camostat are also being considered as treatments for COVID-19. Protease inhibitors inhibit the fusion of the viral outer membrane with the cell membrane, which is the first step in SARS-CoV-2's invasion into cells, and inhibit SARS-CoV-2 infection (Non-Patent Document 4). In addition, anti-influenza drugs and HIV treatment drugs are being considered as treatments for COVID-19 due to their antiviral effects, such as neuraminidase inhibitory action and cap-dependent endonuclease inhibitory action.
本発明の課題は、SARS-CoV-2感染に基づく疾患、COVID-19の予防及び/又は治療のための新たな医薬を提供することにある。 The objective of the present invention is to provide a new medicine for the prevention and/or treatment of COVID-19, a disease caused by SARS-CoV-2 infection.
本発明者らは、SARS-CoV-2の感染抑制に効果的な薬物として考えられるセファランチン、及びセファランチンとは作用機序の異なる薬物であるステロイド薬類等を同時に最もSARS-CоV-2が感染する部位に適用することを着想した。その結果、セファランチン及びステロイド薬類等を下気道に直接適用できる配合吸入剤又は吸入剤のキット製剤とすることにより、当該目的が達成できることを見出し、さらに、セファランチン及びステロイド薬類等の空気動力学的質量中位径を0.5~10μmとすることにより、下気道に直接セファランチン及びステロイド薬類等を効率よく供給可能な吸入剤が得られることを見出し、本発明を完成した。 The inventors came up with the idea of simultaneously applying cepharanthine, which is thought to be an effective drug for suppressing infection with SARS-CoV-2, and steroid drugs, which are drugs with a different mechanism of action from cepharanthine, to the site most likely to be infected by SARS-CoV-2. As a result, they found that the above object can be achieved by preparing a combined inhalant or inhalant kit formulation that can directly apply cepharanthine and steroid drugs to the lower respiratory tract. They further found that an inhalant that can efficiently deliver cepharanthine and steroid drugs directly to the lower respiratory tract can be obtained by setting the aerodynamic mass median diameter of cepharanthine and steroid drugs to 0.5 to 10 μm, thereby completing the present invention.
すなわち、本発明は、以下の発明に係るものである。
次の成分(A)及び(B):
(A)セファランチン;
(B)シクレソニド、ブデソニド、フルチカゾンフランカルボン酸エステル、フルチカゾンプロピオン酸エステル、モメタゾンフランカルボン酸エステル、コルチゾン酢酸エステル、ヒドロコルチゾン、フルドロコルチゾン、デキサメタゾン、トリアムシノロン、ベタメタゾン、プレドニゾロン、メチルプレドニゾロン、ヒドロコルチゾンコハク酸エステルナトリウム、ヒドロコルチゾンリン酸エステルナトリウム、デキサメタゾンパルミチン酸エステル、デキサメタゾンリン酸エステル、トリアムシノロンアセトニド、ベタメタゾンリン酸エステルナトリウム、プレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロン酢酸エステルナトリウム、バロキサビルマルボキシル、オセルタミビルリン酸塩、ザナミビル水和物、ラニナミビルオクタン酸エステル水和物、ペラミビル水和物、ナファモスタットメシル酸塩、カモスタットメシル酸塩、ガベキサートメシル酸塩、アバカビル硫酸塩、エファビレンツ、エムトリシタビン、サニルブジン、ジダノシン、ジドブジン、ダナルビル エタノール付加物、テノホビル アラフェナミドフマル酸塩、テノホビル ジソプロキシルフマル酸塩、ドルテグラビルナトリウム、ネビラピン、ネルフィナビルメシル酸塩、ホスアンプレナビル カルシウム水和物、ラテグラビルカリウム、リトナビル及びリルピビリン塩酸塩よりなる群から選ばれる1種以上の薬物(以下、ステロイド薬類等ということもある。)を含有することを特徴とする吸入剤を提供するものである。
また、セファランチンやステロイド薬類等の粒子径を空気動力学的質量中位径として0.5~10μmとすると、セファランチンやステロイド薬類等が下気道に効率よく到達する。
That is, the present invention relates to the following inventions.
The following components (A) and (B):
(A) Cepharanthine;
(B) Ciclesonide, budesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, cortisone acetate, hydrocortisone, fludrocortisone, dexamethasone, triamcinolone, betamethasone, prednisolone, methylprednisolone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, dexamethasone palmitate, dexamethasone phosphate, triamcinolone acetonide, betamethasone Tamethasone sodium phosphate, prednisolone sodium succinate, methylprednisolone sodium succinate, methylprednisolone sodium acetate, baloxavir marboxil, oseltamivir phosphate, zanamivir hydrate, laninamivir octanoate hydrate, peramivir hydrate, nafamostat mesilate, camostat mesilate, gabexate mesilate, abacavir sulfate, efavirenz, emtricitabine, sanilvudine, didanosine, zidovudine, danarvir The present invention provides an inhalant characterized by containing one or more drugs (hereinafter sometimes referred to as steroid drugs, etc.) selected from the group consisting of ethanol adduct, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, dolutegravir sodium, nevirapine, nelfinavir mesylate, fosamprenavir calcium hydrate, lategravir potassium, ritonavir and rilpivirine hydrochloride.
Furthermore, when the particle size of cepharanthine, steroid drugs, etc. is set to 0.5 to 10 μm in terms of mass median aerodynamic diameter, cepharanthine, steroid drugs, etc. can efficiently reach the lower respiratory tract.
本発明の吸入剤は、SARS-CoV-2の感染抑制に効果的な薬物として考えられるセファランチン及びセファランチンとは作用機序の異なるステロイド薬類等の薬物を下気道に直接供給することができる。 The inhalant of the present invention can directly deliver drugs such as cepharanthine, which is thought to be effective in suppressing SARS-CoV-2 infection, and steroid drugs with a different mechanism of action from cepharanthine, to the lower respiratory tract.
本発明の吸入剤は(A)セファランチン、並びに(B)シクレソニド、ブデソニド、フルチカゾンフランカルボン酸エステル、フルチカゾンプロピオン酸エステル、モメタゾンフランカルボン酸エステル、コルチゾン酢酸エステル、ヒドロコルチゾン、フルドロコルチゾン、デキサメタゾン、トリアムシノロン、ベタメタゾン、プレドニゾロン、メチルプレドニゾロン、ヒドロコルチゾンコハク酸エステルナトリウム、ヒドロコルチゾンリン酸エステルナトリウム、デキサメタゾンパルミチン酸エステル、デキサメタゾンリン酸エステル、トリアムシノロンアセトニド、ベタメタゾンリン酸エステルナトリウム、プレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロン酢酸エステルナトリウム、バロキサビルマルボキシル、オセルタミビルリン酸塩、ザナミビル水和物、ラニナミビルオクタン酸エステル水和物、ペラミビル水和物、ナファモスタットメシル酸塩、カモスタットメシル酸塩、ガベキサートメシル酸塩、アバカビル硫酸塩、エファビレンツ、エムトリシタビン、サニルブジン、ジダノシン、ジドブジン、ダナルビル エタノール付加物、テノホビル アラフェナミドフマル酸塩、テノホビル ジソプロキシルフマル酸塩、ドルテグラビルナトリウム、ネビラピン、ネルフィナビルメシル酸塩、ホスアンプレナビル カルシウム水和物、ラテグラビルカリウム、リトナビル及びリルピビリン塩酸塩よりなる群から選ばれる1種以上の薬物をエアゾールとして吸入し、下気道に適用する製剤である。 The inhalant of the present invention is (A) cepharanthine, and (B) ciclesonide, budesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, cortisone acetate, hydrocortisone, fludrocortisone, dexamethasone, triamcinolone, betamethasone, prednisolone, methylprednisolone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, dexamethasone palmitate, dexamethasone phosphate, triamcinolone, betamethasone acetate, hydrocortisone phosphate, hydrocortis ... Cinolone acetonide, betamethasone sodium phosphate, prednisolone sodium succinate, methylprednisolone sodium succinate, methylprednisolone sodium acetate, baloxavir marboxil, oseltamivir phosphate, zanamivir hydrate, laninamivir octanoate hydrate, peramivir hydrate, nafamostat mesilate, camostat mesilate, gabexate mesilate, abacavir sulfate, efavirenz, emtricitabine, sanilvudine, didanosine, zidovudine, danarvir This is a formulation in which one or more drugs selected from the group consisting of ethanol adduct, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, dolutegravir sodium, nevirapine, nelfinavir mesylate, fosamprenavir calcium hydrate, lategravir potassium, ritonavir, and rilpivirine hydrochloride are inhaled as an aerosol and applied to the lower respiratory tract.
本発明で用いるセファランチン(成分(A))は、化学名を6’,12’-Dimethoxy-2,2’-dimethyl-6,7-[methylenebis(oxy)]oxyacanthanとする化学物質であり、タマサキツヅラフジ、コウトウツズラフジ、ハスノハカズラ等から抽出されうるアルカロイドの一種である。
セファランチンは、放射線による白血球減少症、円形脱毛症・粃糠性脱毛症、滲出性中耳炎、マムシ咬傷の治療に用いられている。本発明のようにセファランチンを吸入剤とした場合には、これらの適応症に加えて、SARS-CoV-2の感染抑制薬、COVID-19の予防及び/又は治療薬として特に有用である。
本発明において、セファランチンは化学合成されたものでも、タマサキツヅラフジ、コウトウツズラフジ、ハスノハカズラ等から抽出されたものでもいずれをも用いることができる。タマサキツヅラフジより抽出される場合は、セファランチンに加えて、イソテトランドリン、シクレアニン、ベルバミン等のセファランチン以外の他のアルカロイドをも含むタマサキツヅラフジ抽出物を用いることも可能である。セファランチンやタマサキツヅラフジ抽出物は市販品があり、購入して用いることが可能であり、また、タマサキツヅラフジ抽出物は公知の手法を用いることにより、タマサキツヅラフジから製造することができる。
The cepharanthine (ingredient (A)) used in the present invention is a chemical substance with the chemical name 6',12'-Dimethoxy-2,2'-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan, and is a type of alkaloid that can be extracted from Cepharantha gracilis, Cepharantha quinata, Cepharantha japonica, etc.
Cepharanthin is used to treat radiation-induced leukopenia, alopecia areata/alopecia pityriasis, serous otitis media, and viper bites. When cepharanthin is made into an inhalant as in the present invention, in addition to these indications, it is particularly useful as an infection suppressant for SARS-CoV-2 and a preventive and/or therapeutic agent for COVID-19.
In the present invention, cepharanthine may be either chemically synthesized or extracted from Cepharantha nigricans, Cepharantha quinata, Cepharantha quinata, etc. When extracted from Cepharantha nigricans, it is also possible to use Cepharantha quinata extracts containing, in addition to cepharantha, other alkaloids other than cepharantha such as isotetrandrine, cyclaine, and berbamine. Cepharantha and Cepharantha quinata extracts are commercially available and can be purchased for use, and Cepharantha quinata extracts can be produced from Cepharantha nigricans by using known methods.
本発明において、セファランチンとは作用機序の異なり、セファランチンとともに吸入する薬物(成分(B))としては、例えば、シクレソニド、ブデソニド、フルチカゾンフランカルボン酸エステル、フルチカゾンプロピオン酸エステル、モメタゾンフランカルボン酸エステル、コルチゾン酢酸エステル、ヒドロコルチゾン、フルドロコルチゾン、デキサメタゾン、トリアムシノロン、ベタメタゾン、プレドニゾロン、メチルプレドニゾロン、ヒドロコルチゾンコハク酸エステルナトリウム、ヒドロコルチゾンリン酸エステルナトリウム、デキサメタゾンパルミチン酸エステル、デキサメタゾンリン酸エステル、トリアムシノロンアセトニド、ベタメタゾンリン酸エステルナトリウム、プレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロン酢酸エステルナトリウム等のステロイド薬、バロキサビルマルボキシル、オセルタミビルリン酸塩、ザナミビル水和物、ラニナミビルオタン酸エステル水和物、ペラミビル水和物等の抗インフルエンザ薬、ナファモスタットメシル酸塩、カモスタットメシル酸塩、ガベキサートメシル酸塩等のたん白分解酵素阻害薬、アバカビル硫酸塩、エファビレンツ、エムトリシタビン、サニルブジン、ジダノシン、ジドブジン、ダナルビル エタノール付加物、テノホビル アラフェナミドフマル酸塩、テノホビル ジソプロキシルフマル酸塩、ドルテグラビルナトリウム、ネビラピン、ネルフィナビルメシル酸塩、ホスアンプレナビル カルシウム水和物、ラテグラビルカリウム、リトナビル、リルピビリン塩酸塩等のHIV治療薬等が挙げられる。
上述のステロイド薬は肺の局所的な炎症抑制作用のほか、SARS-CoV-2の増殖抑制作用を有することから、また、ナファモスタットメシル酸塩等のたん白分解酵素阻害薬は、SARS-CoV-2の感染阻害作用を有することから、抗インフルエンザ薬やHIV治療薬はノイラミニダーゼ阻害作用やキャップ依存性エンドヌクレアーゼ阻害作用といった抗ウイルス作用により、COVID-19の予防及び/又は治療薬として期待されるものである。
In the present invention, examples of drugs (component (B)) that have a different mechanism of action from cepharanthine and are inhaled together with cepharanthine include ciclesonide, budesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, cortisone acetate, hydrocortisone, fludrocortisone, dexamethasone, triamcinolone, betamethasone, prednisolone, methylprednisolone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, dexamethasone palmitate, dexamethasone phosphate, triamcinolone, betamethasone acetate, hydrocortisone phosphate ... Steroid drugs such as amcinolone acetonide, betamethasone sodium phosphate, prednisolone sodium succinate, methylprednisolone sodium succinate, methylprednisolone sodium acetate, etc.; anti-influenza drugs such as baloxavir marboxil, oseltamivir phosphate, zanamivir hydrate, laninamivir otanate hydrate, peramivir hydrate, etc.; protease inhibitors such as nafamostat mesilate, camostat mesilate, gabexate mesilate, etc.; abacavir sulfate, efavirenz, emtricitabine, sanilvudine, didanosine, zidovudine, danarvir ethanolate, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, dolutegravir sodium, nevirapine, nelfinavir mesylate, fosamprenavir calcium hydrate, lategravir potassium, ritonavir, rilpivirine hydrochloride and the like.
The above-mentioned steroid drugs have an effect of suppressing local inflammation in the lungs as well as inhibiting the proliferation of SARS-CoV-2. Furthermore, protease inhibitors such as nafamostat mesylate have an effect of inhibiting infection by SARS-CoV-2. Therefore, anti-influenza drugs and HIV treatment drugs have antiviral effects such as neuraminidase inhibition and cap-dependent endonuclease inhibition, and are therefore expected to be used as preventive and/or therapeutic agents for COVID-19.
吸入に際しては、セファランチン及びステロイド薬類等を配合した複数薬物を同時に吸入可能な配合吸入剤を用いてもよく、セファランチンの吸入剤とステロイド薬類等の吸入剤の複数の吸入剤のキット製剤を用いてもよい。 When inhaling, a combination inhalant that combines cepharanthin and steroid drugs, etc., and allows multiple drugs to be inhaled simultaneously, may be used, or a kit formulation of multiple inhalants, such as a cepharanthin inhalant and an inhalant such as a steroid drug, may be used.
本発明で用いるセファランチン及びステロイド薬類等を下気道(気管、気管支、肺臓)で適用するには、セファランチン及びステロイド薬類等の下気道への到達性の観点から、その粒子径を0.5~10μmとするのが好ましく、0.5~8μmにするのがより好ましく、0.5~6μmとするのが更に好ましい。ここで、セファランチン及びステロイド薬類等の粒子径は、粉末の場合はセファランチン及び/又はステロイド薬類等含有粉末の粒子径であり、液剤の場合はセファランチン及び/又はステロイド薬類等含有噴霧液滴の粒子径である。この粒子径は、粉末の場合は粉末製造時の粉砕、篩過などによって調整することができる。噴霧液滴の場合は、液剤を吸入する際に用いるネブライザの形態(ジェット式、超音波式、メッシュ式等)に応じて、適宜調整すればよい。ここで、粒子径は空気動力学的質量中位径である。 In order to apply the cepharanthine and steroid drugs used in the present invention to the lower respiratory tract (trachea, bronchi, lungs), the particle size is preferably 0.5 to 10 μm, more preferably 0.5 to 8 μm, and even more preferably 0.5 to 6 μm, from the viewpoint of the reach of the cepharanthine and steroid drugs to the lower respiratory tract. Here, the particle size of the cepharanthine and steroid drugs is the particle size of the powder containing cepharanthine and/or steroid drugs in the case of a powder, and is the particle size of the spray droplets containing cepharanthine and/or steroid drugs in the case of a liquid preparation. In the case of a powder, this particle size can be adjusted by pulverization, sieving, etc. during powder production. In the case of a spray droplet, it may be adjusted appropriately depending on the type of nebulizer used when inhaling the liquid preparation (jet type, ultrasonic type, mesh type, etc.). Here, the particle size is the aerodynamic mass median diameter.
吸入剤の形態としては、吸入粉末剤、吸入液剤、吸入エアゾール剤が挙げられるが、特に限定されるものではない。本発明の吸入剤を使用するに際しては、吸入投与のために適切な器具又は装置を使用するか、吸入用の器具を兼ね備えた容器に充填すればよい。 The form of the inhalant may be, but is not limited to, an inhalable powder, an inhalable liquid, or an inhalable aerosol. When using the inhalant of the present invention, an appropriate tool or device for inhalation administration may be used, or the inhalant may be filled into a container that also functions as an inhalation tool.
吸入粉末剤は、吸入量が一定となるように調製したセファランチン及びステロイド薬類等の固体粒子のエアゾールとして吸入する製剤であり、セファランチン及びステロイド薬類等はそれぞれ好ましくは0.5~10μm、より好ましくは0.5~8μm、さらに好ましくは0.5~6μmの粒子径を有する粒子として調製すればよい。ここで、粒子径は空気動力学的質量中位径である。
また、添加剤として、糖や糖アルコールを添加剤として用いることもできる。ここで、糖としては、乳糖水和物、白糖、ブドウ糖等を挙げることができ、糖アルコールとしては、エリスリトール、イソマルト、ラクチトール、マルチトール、マンニトール、ソルビトール、キシリトール等を挙げることができる。
吸入粉末剤の具体例としては、ドライパウダー吸入器(Dry Powder Inhaler;以下、DPIと略する)を挙げることができる。本発明の吸入粉末剤に用いるデバイスはDPIとして通常用いられるものを使用することができる。例えばカプセルを用いるデバイスとして、モノヘラー、ハンディヘラー、ブリーズヘラー、フローキャプス等が挙げられる。またアルミニウムのブリスターを用いるディスクヘラー、ディスカス、エリプタ等が挙げられる。粉末を容器に充填したリザーバ型のデバイスとして、タービュヘイラー、クリックヘラー、スイングヘラー、ツイストヘラーなどが挙げられる。
The powder inhalation preparation is a preparation to be inhaled as an aerosol of solid particles of cepharanthin, steroid drugs, etc., which are prepared so that the inhalation amount is constant, and cepharanthin, steroid drugs, etc. may be prepared as particles having a particle size of preferably 0.5 to 10 μm, more preferably 0.5 to 8 μm, and even more preferably 0.5 to 6 μm, respectively. Here, the particle size is the mass median aerodynamic diameter.
In addition, sugars and sugar alcohols can be used as additives. Examples of sugars include lactose hydrate, white sugar, and glucose, and examples of sugar alcohols include erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol.
A specific example of the powdered inhalation agent is a dry powder inhaler (hereinafter, abbreviated as DPI). The device used for the powdered inhalation agent of the present invention can be one that is usually used as a DPI. For example, devices using a capsule include Monohaler, Handihaler, Breezhaler, Flowcaps, etc. Other examples include Diskhaler, Diskus, Ellipta, etc., which use an aluminum blister. Examples of reservoir-type devices in which a container is filled with powder include Turbuhaler, Clickhaler, Swinghaler, Twisthaler, etc.
吸入液剤は、ネブライザ等により吸入する液状の吸入製剤である。セファランチン及びステロイド薬類等を適当な溶剤を用いて、溶解又は懸濁し、溶液又は懸濁液として調製すればよい。調製時、等張化剤やpH調節剤等を添加することができる。
吸入液剤の液滴は、ネブライザの形態(ジェット式、超音波式、メッシュ式等)に応じて、好ましくは0.5~10μm、より好ましくは0.5~8μm、更に好ましくは0.5~6μmの液滴に調整すればよい。
本発明の吸入液剤に用いるデバイスはネブライザとして通常用いられるものを使用することができる。例えば圧縮空気で薬液を霧状にするタイプ(ジェット式)、超音波振動子の振動を利用して薬液を霧状にするタイプ(ジェット式)、振動などによって薬液をメッシュの穴から押し出して霧状にするタイプ(メッシュ式)などが挙げられる。
The inhalation liquid is a liquid preparation for inhalation using a nebulizer, etc. Cepharanthin and steroid drugs, etc. may be dissolved or suspended in an appropriate solvent to prepare a solution or suspension. During preparation, an isotonicity agent, a pH adjuster, etc. may be added.
The droplets of the inhalation liquid may be adjusted to preferably 0.5 to 10 μm, more preferably 0.5 to 8 μm, and even more preferably 0.5 to 6 μm, depending on the type of nebulizer (jet type, ultrasonic type, mesh type, etc.).
The device used for the inhalation liquid of the present invention may be any device commonly used as a nebulizer, including, for example, a type that atomizes the liquid medicine with compressed air (jet type), a type that atomizes the liquid medicine using the vibration of an ultrasonic vibrator (jet type), and a type that atomizes the liquid medicine by pushing it through mesh holes using vibrations (mesh type).
吸入エアゾール剤は、容器に充填した噴射剤と共に、一定量のセファランチン及びステロイド薬類等を噴霧し得る定量噴霧式吸入剤である。セファランチン及びステロイド薬類等を適当な溶剤を用いて、溶解又は懸濁し、溶液又は懸濁液を調製し、液状の噴射剤と共に耐圧性の容器に充填し、定量バルブを装着することにより製することができる。溶液又は懸濁液を調製するに際し、分散剤や安定化剤等を添加することができる。吸入エアゾール剤の具体例としては、加圧噴霧式定量吸入器(Metered Dose Inhaler)を挙げることができる。 Inhalation aerosols are metered-dose inhalers that can spray a fixed amount of cepharanthin and steroid drugs together with a propellant filled in a container. They can be produced by dissolving or suspending cepharanthin and steroid drugs in an appropriate solvent to prepare a solution or suspension, filling a pressure-resistant container with a liquid propellant, and attaching a metered-dose valve. When preparing the solution or suspension, dispersants, stabilizers, etc. can be added. A specific example of an inhalation aerosol is a pressurized metered-dose inhaler.
本発明の吸入液剤に係るセファランチンとしては、メディサ新薬株式会社が製造販売するセファランチン(登録商標)注を用いることもできる。具体的にはセファランチン(登録商標)注そのまま、または適当な溶剤を用いて希釈して、ネブライザを用いて吸入すればよい。 Cepharanthine in the inhalation liquid of the present invention may be Cepharanthine (registered trademark) Injection manufactured and sold by Medisa Shinyaku Co., Ltd. Specifically, Cepharanthine (registered trademark) Injection may be inhaled as is or after dilution with an appropriate solvent using a nebulizer.
本発明の吸入液剤に係るステロイド薬類としては、アストラゼネカ株式会社が製造販売するパルミコート(登録商標)吸入液(有効成分:ブデソニド)も用いることができる。具体的にはパルミコート(登録商標)吸入液そのまま、または適当な溶剤を用いて希釈して、ネブライザを用いて吸入すればよい。 As a steroid drug for the inhalation solution of the present invention, Pulmicort (registered trademark) inhalation solution (active ingredient: budesonide) manufactured and sold by AstraZeneca K.K. may also be used. Specifically, Pulmicort (registered trademark) inhalation solution may be inhaled as is or after dilution with an appropriate solvent using a nebulizer.
本発明の吸入剤は、SARS-CoV-2の感染抑制薬、COVID-19の予防及び/又は治療薬として用いることができる。その投与量は、患者の体重、年齢、性別、症状などによって異なるが、通常は成人に対して、セファランチンとして1日1~20mgの範囲が挙げられる。また、ステロイド薬類等は、通常成人に対して1日0.0001mg~1000mgの範囲を挙げられる。これらの投与量は、適宜調整すればよい。 The inhalant of the present invention can be used as an infection suppressant for SARS-CoV-2, and as a preventive and/or therapeutic drug for COVID-19. The dosage varies depending on the patient's weight, age, sex, symptoms, etc., but typically ranges from 1 to 20 mg of cepharanthin per day for adults. Additionally, the dosage of steroid drugs, etc. typically ranges from 0.0001 mg to 1000 mg per day for adults. These dosages can be adjusted as appropriate.
以下、実施例により本発明を具体的に説明するが、本発明はこれら実施例により何ら限定されるものではない。以下の実施例において、%は質量%を意味する。 The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the following examples, % means % by mass.
実施例1
セファランチンを25%、ブデソニドを1%となるように乳糖水和物と混合し、混合物をジェットミルで粉砕し、粉砕物を得た。得られた粉砕物の平均粒子径D50は2.5μmであった。粉砕物と乳糖水和物をセファランチンの濃度が10%、ブデソニド0.4%となるように乳糖水和物と混合し、吸入粉末剤を得た。このとき乳糖水和物はキャリアー乳糖(平均粒子径約120μm)を用いた。また、得られた粉末0.025gをカプセルに充填し、吸入粉末剤充填カプセルを製造した。
Example 1
The lactose hydrate was mixed with cepharanthine at 25% and budesonide at 1%, and the mixture was pulverized with a jet mill to obtain a pulverized product. The average particle size D50 of the pulverized product was 2.5 μm. The pulverized product and lactose hydrate were mixed with lactose hydrate to obtain a cepharanthine concentration of 10% and budesonide concentration of 0.4%, to obtain an inhalation powder. At this time, lactose hydrate was used as a carrier (average particle size of about 120 μm). 0.025 g of the obtained powder was filled into a capsule to produce an inhalation powder-filled capsule.
試験例1
実施例1で得た吸入粉末剤について、吸入用器具であるデバイスを用いた空気動力学的性質の評価をするため、微粒子量(FPF)(%)及び空気動力学的質量中位径を測定した。微粒子量(FPF)(%)及び空気動力学的質量中位径は、日本薬局方 第十七改正第一追補の吸入剤の空気動力学的粒度測定法に準拠して、装置1のマルチステージリキッドインピンジャーを用いて評価した。
その結果、実施例1の吸入粉末剤は、微粒子量(FPF)(%)がセファランチン、ブデソニドで9.9%であり、また空気動力学的質量中位径は4.3μmであったことから肺深部まで薬剤を到達させることが可能と考えられた。
Test Example 1
For the powder inhalation preparation obtained in Example 1, the fine particle fraction (FPF) (%) and mass median aerodynamic diameter were measured to evaluate the aerodynamic properties using a device, which is an inhalation tool. The fine particle fraction (FPF) (%) and mass median aerodynamic diameter were evaluated using a multi-stage liquid impinger of Apparatus 1 in accordance with the aerodynamic particle size measurement method for inhalants in the Japanese Pharmacopoeia, Seventeenth Edition, First Supplement.
As a result, the fine particle fraction (FPF) (%) of the inhalable powder of Example 1 was 9.9% for cepharanthine and budesonide, and the aerodynamic mass median diameter was 4.3 μm, indicating that it is possible for the drug to reach the deep lungs.
実施例2
セファランチン及びシクレソニドをエチルアルコールで溶解し、クエン酸水和物及び精製水を加え、セファランチン及びシクレソニドの最終的な濃度が各々0.5%及び0.04%となるように調製して吸入液剤を製造した。
Example 2
Cepharanthin and ciclesonide were dissolved in ethyl alcohol, and citric acid hydrate and purified water were added thereto so that the final concentrations of cepharanthin and ciclesonide were 0.5% and 0.04%, respectively, to prepare an inhalation liquid.
試験例2
実施例2で得られた吸入液剤について、ネブライザを用いて、目視にて液剤が霧状に噴霧されるかを確認した。さらに霧状とした液剤を採取し、顕微鏡で粒子径を確認した。
実施例2で得た吸入液剤は霧状に噴霧され、その粒子径は2~8μmであり、実施例2の液剤は吸入液剤として適切なものであると判断した。
Test Example 2
The inhalation liquid preparation obtained in Example 2 was visually confirmed to be sprayed into a mist using a nebulizer. Furthermore, the mist liquid preparation was sampled and the particle size was confirmed under a microscope.
The inhalation liquid preparation obtained in Example 2 was sprayed in the form of a mist with a particle size of 2 to 8 μm, and it was determined that the liquid preparation in Example 2 was suitable as an inhalation liquid preparation.
製造例1
常法により、下記表1~10に記載の成分及び分量(g)を100g中に含有する吸入粉末剤(処方例1~47)を製造できる。
Production Example 1
According to a conventional method, dry powder inhalants (Formulation Examples 1 to 47) containing the ingredients and amounts (g) shown in Tables 1 to 10 per 100 g can be produced.
Claims (4)
(A)セファランチン;
(B)シクレソニド、ブデソニド、フルチカゾンフランカルボン酸エステル、フルチカゾンプロピオン酸エステル、モメタゾンフランカルボン酸エステル、コルチゾン酢酸エステル、ヒドロコルチゾン、フルドロコルチゾン、デキサメタゾン、トリアムシノロン、ベタメタゾン、プレドニゾロン、メチルプレドニゾロン、ヒドロコルチゾンコハク酸エステルナトリウム、ヒドロコルチゾンリン酸エステルナトリウム、デキサメタゾンパルミチン酸エステル、デキサメタゾンリン酸エステル、トリアムシノロンアセトニド、ベタメタゾンリン酸エステルナトリウム、プレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロンコハク酸エステルナトリウム、メチルプレドニゾロン酢酸エステルナトリウム、バロキサビルマルボキシル、オセルタミビルリン酸塩、ザナミビル水和物、ラニナミビルオクタン酸エステル水和物、ペラミビル水和物、ナファモスタットメシル酸塩、カモスタットメシル酸塩、ガベキサートメシル酸塩、アバカビル硫酸塩、エファビレンツ、エムトリシタビン、サニルブジン、ジダノシン、ジドブジン、ダナルビル エタノール付加物、テノホビル アラフェナミドフマル酸塩、テノホビル ジソプロキシルフマル酸塩、ドルテグラビルナトリウム、ネビラピン、ネルフィナビルメシル酸塩、ホスアンプレナビル カルシウム水和物、ラテグラビルカリウム、リトナビル及びリルピビリン塩酸塩よりなる群から選ばれる1種以上の薬物を含有する吸入剤。 The following components (A) and (B):
(A) Cepharanthine;
(B) Ciclesonide, budesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, cortisone acetate, hydrocortisone, fludrocortisone, dexamethasone, triamcinolone, betamethasone, prednisolone, methylprednisolone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, dexamethasone palmitate, dexamethasone phosphate, triamcinolone acetonide, betamethasone An inhalant containing one or more drugs selected from the group consisting of tamethasone sodium phosphate, prednisolone sodium succinate, methylprednisolone sodium succinate, methylprednisolone sodium acetate, baloxavir marboxil, oseltamivir phosphate, zanamivir hydrate, laninamivir octanoate hydrate, peramivir hydrate, nafamostat mesylate, camostat mesylate, gabexate mesylate, abacavir sulfate, efavirenz, emtricitabine, sanilvudine, didanosine, zidovudine, danarvir ethanolate, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, dolutegravir sodium, nevirapine, nelfinavir mesylate, fosamprenavir calcium hydrate, lategravir potassium, ritonavir, and rilpivirine hydrochloride.
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