JP6077081B2 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- JP6077081B2 JP6077081B2 JP2015198174A JP2015198174A JP6077081B2 JP 6077081 B2 JP6077081 B2 JP 6077081B2 JP 2015198174 A JP2015198174 A JP 2015198174A JP 2015198174 A JP2015198174 A JP 2015198174A JP 6077081 B2 JP6077081 B2 JP 6077081B2
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 56
- 210000000434 stratum corneum Anatomy 0.000 claims description 34
- 239000002674 ointment Substances 0.000 claims description 22
- 230000002209 hydrophobic effect Effects 0.000 claims description 17
- 239000003883 ointment base Substances 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 16
- YTAOBBFIOAEMLL-REQDGWNSSA-N Luliconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@H](CS\1)SC/1=C(\C#N)N1C=NC=C1 YTAOBBFIOAEMLL-REQDGWNSSA-N 0.000 claims description 12
- 229960000570 luliconazole Drugs 0.000 claims description 12
- 235000019271 petrolatum Nutrition 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000004264 Petrolatum Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229940066842 petrolatum Drugs 0.000 claims description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 9
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 9
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229940057995 liquid paraffin Drugs 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 235000013871 bee wax Nutrition 0.000 claims description 4
- 239000012166 beeswax Substances 0.000 claims description 4
- 239000004204 candelilla wax Substances 0.000 claims description 4
- 235000013868 candelilla wax Nutrition 0.000 claims description 4
- 229940073532 candelilla wax Drugs 0.000 claims description 4
- 239000004203 carnauba wax Substances 0.000 claims description 4
- 235000013869 carnauba wax Nutrition 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- IUJAMGNYPWYUPM-UHFFFAOYSA-N hentriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC IUJAMGNYPWYUPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 claims description 4
- 229940032094 squalane Drugs 0.000 claims description 4
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- -1 diester carbonate Chemical class 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 150000004650 carbonic acid diesters Chemical class 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 229940121375 antifungal agent Drugs 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 208000002474 Tinea Diseases 0.000 description 5
- 241000893966 Trichophyton verrucosum Species 0.000 description 5
- 239000003429 antifungal agent Substances 0.000 description 5
- 239000002736 nonionic surfactant Substances 0.000 description 5
- 150000005846 sugar alcohols Polymers 0.000 description 5
- 230000000843 anti-fungal effect Effects 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 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
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102000011782 Keratins Human genes 0.000 description 2
- 108010076876 Keratins Proteins 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 238000010811 Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Methods 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229940105990 diglycerin Drugs 0.000 description 2
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 2
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 208000024386 fungal infectious disease Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000006353 oxyethylene group Chemical group 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 2
- 201000004647 tinea pedis Diseases 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- BAWUFGWWCWMUNU-UHFFFAOYSA-N 1-hexylpyrrolidin-2-one Chemical compound CCCCCCN1CCCC1=O BAWUFGWWCWMUNU-UHFFFAOYSA-N 0.000 description 1
- DCALJVULAGICIX-UHFFFAOYSA-N 1-propylpyrrolidin-2-one Chemical compound CCCN1CCCC1=O DCALJVULAGICIX-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- VIZORQUEIQEFRT-UHFFFAOYSA-N Diethyl adipate Chemical compound CCOC(=O)CCCCC(=O)OCC VIZORQUEIQEFRT-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- IMQLKJBTEOYOSI-GPIVLXJGSA-N Inositol-hexakisphosphate Chemical compound OP(O)(=O)O[C@H]1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O IMQLKJBTEOYOSI-GPIVLXJGSA-N 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- IMQLKJBTEOYOSI-UHFFFAOYSA-N Phytic acid Natural products OP(O)(=O)OC1C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C1OP(O)(O)=O IMQLKJBTEOYOSI-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 229940031569 diisopropyl sebacate Drugs 0.000 description 1
- XFKBBSZEQRFVSL-UHFFFAOYSA-N dipropan-2-yl decanedioate Chemical compound CC(C)OC(=O)CCCCCCCCC(=O)OC(C)C XFKBBSZEQRFVSL-UHFFFAOYSA-N 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940068041 phytic acid Drugs 0.000 description 1
- 235000002949 phytic acid Nutrition 0.000 description 1
- 239000000467 phytic acid Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 235000002316 solid fats Nutrition 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
本発明は、医薬組成物に関し、更に詳細には、可溶化剤形の軟膏に好適な医薬組成物に関する。 The present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition suitable for a solubilizer-type ointment.
水虫などの真菌症の治療においては、患部が損傷し、体液が滲出するなどを呈するが故に、浸出液によって有効成分が拡散せず、傷口に対しても刺激性を呈しない軟膏剤形が有用であると考えられている。軟膏剤形には、ポリエチレングリコールなどの親水性軟膏基剤やワセリンなどの疎水性軟膏基剤に薬剤を直接分散させた、薬剤分散剤形、軟膏基剤となじみの良い薬剤を溶かしこんだ薬剤可溶化剤形、薬剤を溶解せしめた液滴を分散させた液滴分散剤形などが知られている。中でも、ワセリンなどの疎水性軟膏基剤に、多価アルコールなどに薬剤を溶解せしめた溶液を液滴として分散させた、疎水性液滴分散剤形はその応用範囲が広いことから、一般的に用いられている(例えば、特許文献１、特許文献２
を参照）。特に軟膏剤形は、抗真菌医薬組成物では糜爛部分に刺激無く投与できる利点を有しているため、必須のアイテムとなっている。
In the treatment of fungal diseases such as athlete's foot, an ointment dosage form in which the active ingredient is not diffused by the exudate and is not irritating to the wound because the affected part is damaged and the body fluid exudes is useful. It is thought that there is. For ointment dosage forms, drugs dispersed directly in hydrophilic ointment bases such as polyethylene glycol and hydrophobic ointment bases such as petrolatum, and drugs that dissolve well into drugs that are familiar with the ointment base A solubilizer form, a droplet dispersion form in which droplets in which a drug is dissolved are dispersed, and the like are known. In particular, hydrophobic droplet dispersion forms in which a solution in which a drug is dissolved in a polyhydric alcohol or the like is dispersed as a droplet in a hydrophobic ointment base such as petrolatum, has a wide range of applications. (For example, Patent Document 1 and Patent Document 2)
See). In particular, the ointment dosage form is an indispensable item because it has an advantage that it can be administered to the heel part without irritation in the antifungal pharmaceutical composition.
その一方で、医薬組成物においては、病巣である角層において、有効成分を長時間にわたって有効濃度を保つように設計することも重要である(例えば、特許文献３を参照）が
、軟膏においては、有効濃度の維持は大きな課題となっていた。このことは単調減少カーブで角層内濃度が減少する傾向にある軟膏製剤においては、投与直後の角層内薬剤濃度を上昇せしめることが必要であることを意味し、その様な手段の開発が望まれていたと言える。
On the other hand, in the pharmaceutical composition, it is also important to design the active ingredient to maintain an effective concentration for a long time in the stratum corneum that is a lesion (for example, see Patent Document 3). The maintenance of effective concentration has been a major issue. This means that it is necessary to increase the drug concentration in the stratum corneum immediately after administration in an ointment preparation that tends to decrease in the stratum corneum with a monotonically decreasing curve. It can be said that it was desired.
（但し、式中Ｒ1、Ｒ2はそれぞれ独立に水素原子又はハロゲン原子を表す。） (However, in the formula, R 1 and R 2 each independently represents a hydrogen atom or a halogen atom.)
本発明は、この様な状況下為されたものであり、角層内の薬剤濃度を向上せしめた軟膏剤形の医薬組成物を提供することを課題とする。 The present invention has been made under such circumstances, and an object of the present invention is to provide a pharmaceutical composition in the form of an ointment in which the drug concentration in the stratum corneum is improved.
この様な状況に鑑みて、本発明者らは、抗真菌剤を例に取り、軟膏製剤において、抗真菌剤である一般式（1）に表される化合物及び／又はその塩の濃度を高く長時間角層内に
維持する作用を有する製剤を求めて、鋭意研究努力を重ねた結果、疎水性軟膏基剤の軟膏であって、疎水性軟膏基剤において、炭酸ジエステルを含有するものにそのような特徴がみられることを見出し、発明を完成させるに至った。即ち、本発明は以下に示すとおりである。
In view of such circumstances, the present inventors have taken antifungal agents as examples, and in the ointment preparations, the concentration of the compound represented by the general formula (1) and / or a salt thereof, which is an antifungal agent, is increased. As a result of intensive research efforts to find a preparation having an action to maintain in the stratum corneum for a long time, a hydrophobic ointment base ointment containing a diester carbonate in a hydrophobic ointment base The inventors have found that such features can be seen, and have completed the invention. That is, the present invention is as follows.
＜１＞ １）疎水性軟膏基剤、２）以下に示す一般式（1）に表される化合物及び／又は
その塩、及び３）炭酸ジエステル、を含有することを特徴とする、医薬組成物。
<1> A pharmaceutical composition comprising 1) a hydrophobic ointment base, 2) a compound represented by the following general formula (1) and / or a salt thereof, and 3) a carbonic acid diester: .
（但し、式中Ｒ1、Ｒ2はそれぞれ独立に水素原子又はハロゲン原子を表す。）
＜２＞ 前記一般式（1）に表される化合物は、ルリコナゾールであることを特徴とする
、＜１＞に記載の医薬組成物。
＜３＞ 前記炭酸ジエステルは、炭酸プロピレンであることを特徴とする、＜１＞又は＜２＞に記載の医薬組成物。
＜４＞ 前記医薬組成物は、第１６改正日本薬局方における油脂性軟膏に属することを特徴とする、＜１＞〜＜３＞の何れかに記載の医薬組成物。
(However, in the formula, R 1 and R 2 each independently represents a hydrogen atom or a halogen atom.)
<2> The pharmaceutical composition according to <1>, wherein the compound represented by the general formula (1) is luliconazole.
<3> The pharmaceutical composition according to <1> or <2>, wherein the carbonic acid diester is propylene carbonate.
<4> The pharmaceutical composition according to any one of <1> to <3>, wherein the pharmaceutical composition belongs to an oily ointment according to the 16th revised Japanese pharmacopoeia.
本発明によれば、角層内の薬剤濃度を向上せしめた軟膏剤形の医薬組成物が提供できる。 ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition of the ointment form which improved the chemical | medical agent density | concentration in a stratum corneum can be provided.
＜１＞本発明の医薬組成物の必須成分である疎水性軟膏基剤
本発明の医薬組成物は、疎水性軟膏基剤を基剤とする軟膏であることを特徴とする。ここで、疎水性軟膏基剤とは、軟膏の性状を決定する組成物群であって、水とは相溶しない
ものを意味し、具体的には、ワセリン、シリコーンエラストマー、モクロウ、カルナウバワックス、ミツロウ、ゲイロウ、キャンデリラワックス流動パラフィン、スクワラン、グリセリンの脂肪酸エステル、高級アルコールの脂肪酸エステル等から選ばれる１種乃至は２種以上を混合し、ペースト状に調整したものを言う。好ましい基剤としてはワセリンが挙げられる。特に好ましい基剤としてはワセリン８０質量％以上に、流動パラフィン、スクワラン等の液体炭化水素、モクロウ、ゲイロウ、カルナウバワックス、ミツロウ、キャンデリラワックスなどの固形脂を適宜加えて、ペースト状に調整したものである。ワセリンとしては、通常のワセリンであっても、サンホワイトワセリンなどの精製ワセリンであってもよい。疎水性軟膏基剤の混合は、成分を加熱し、全成分が液体になった後に攪拌冷却して成分一様なペースト状組成物とすることが好ましい。基剤は医薬組成物全量に対して８０〜９８質量％であることが好ましく、８５〜９５質量％であることがより好ましい。
<1> Hydrophobic ointment base which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is an ointment based on a hydrophobic ointment base. Here, the hydrophobic ointment base is a group of compositions that determine the properties of the ointment, and means those that are incompatible with water. Specifically, petrolatum, silicone elastomer, mole, carnauba wax , Beeswax, gay wax, candelilla wax, liquid paraffin, squalane, fatty acid ester of glycerin, fatty acid ester of higher alcohol, and the like are mixed to prepare a paste. A preferred base is petrolatum. As a particularly preferred base, liquid hydrocarbons such as liquid paraffin and squalane, solid fats such as mole, geiwa, carnauba wax, beeswax, and candelilla wax were appropriately added to 80% by mass or more of petrolatum to prepare a paste. Is. The petrolatum may be ordinary petrolatum or purified petrolatum such as sun white petrolatum. In mixing the hydrophobic ointment base, it is preferable that the components are heated, and after all the components become liquid, they are stirred and cooled to obtain a paste-like composition having a uniform component. The base is preferably 80 to 98% by mass, more preferably 85 to 95% by mass with respect to the total amount of the pharmaceutical composition.
＜２＞本発明の医薬組成物の必須成分である一般式（１）に表される化合物及び／又はその塩
本発明の医薬組成物は軟膏剤形であって、抗真菌効果を有する一般式（１）に表される化合物及び／又はその塩を含有することを特徴とする。すなわち、本発明の医薬組成物は、抗真菌医薬組成物として使用できる。一般式（１）に表される化合物としては、例えば、式中のＲ1が塩素原子であり、Ｒ2が水素原子であるラノコナゾール、Ｒ1とＲ2とがともに塩素原子であるルリコナゾールが具体的に好ましく例示でき、取り分けルリコナゾールが好ましい。かかる化合物は、例えば、特開平０９−１００２７９号公報に記載の方法によって製造することが出来る。かかる成分の好ましい含有量は、総量で、医薬組成物全量に対して０．１〜２０質量％であり、より好ましくは０．５〜１０質量％である。これは多すぎると本発明の医薬組成物の効果を奏しない場合が存し、少なすぎると抗真菌効果を奏しない場合が存するからである。
<2> The compound represented by the general formula (1) and / or a salt thereof which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is an ointment form and has a general formula having an antifungal effect It contains the compound represented by (1) and / or a salt thereof. That is, the pharmaceutical composition of the present invention can be used as an antifungal pharmaceutical composition. Specific examples of the compound represented by the general formula (1) include lanaconazole in which R 1 is a chlorine atom and R 2 is a hydrogen atom, and luliconazole in which both R 1 and R 2 are chlorine atoms. In particular, it is preferable to use luliconazole. Such a compound can be produced, for example, by the method described in JP-A No. 09-1000027. The preferred content of these components is 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, based on the total amount of the pharmaceutical composition. This is because if the amount is too large, the effect of the pharmaceutical composition of the present invention may not be achieved, and if the amount is too small, the antifungal effect may not be achieved.
＜３＞本発明の医薬組成物の必須成分である炭酸ジエステル
本発明の医薬組成物は、軟膏剤形であって、炭酸ジエステルを必須成分として含有する。該炭酸ジエステルとしては、炭酸エチレン、炭酸プロピレンなどの環状炭酸ジエステル、炭酸ジエチル、炭酸ジカプリルなどの非環状炭酸ジエステルなどが好ましく例示できる。これらで最も好ましいものは、環状のジエステルが好ましく、炭酸エチレン、炭酸プロピレンなどが特に好適に例示できる。本発明の医薬組成物では、かかる炭酸ジエステルから選択される１種乃至は２種以上を含有する。これらの炭酸ジエステルの内で特に好ましいものは炭酸プロピレンである。これは、本発明の軟膏製剤において、初期の角層内濃度の向上作用と、長時間経過後の角層内の濃度維持の２つの作用を兼ね備えるためである。この様な作用を発揮するためには、前記炭酸ジエステルの含有量は、医薬組成物全量に対して、０．１〜１０質量％であり、より好ましくは０．５〜５質量％である。また、炭酸ジエステルは、ベンジルアルコール及びＮ−アルキル−２−ピロリドンの質量の和との質量比において、１：１０〜１０：１であることが好ましい。この様な質量比を採用することにより、投与後３０分の角層内貯留量と２４時間後の角層内貯留量の傾きを調整することが出来る。
<3> Carbonic acid diester which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is an ointment form and contains a carbonic acid diester as an essential component. Preferred examples of the carbonic acid diester include cyclic carbonic acid diesters such as ethylene carbonate and propylene carbonate, and acyclic carbonic acid diesters such as diethyl carbonate and dicapryl carbonate. Of these, cyclic diesters are preferable, and ethylene carbonate, propylene carbonate and the like can be particularly preferably exemplified. The pharmaceutical composition of the present invention contains one or more selected from such carbonic acid diesters. Of these carbonic acid diesters, propylene carbonate is particularly preferred. This is because the ointment preparation of the present invention has two effects of improving the initial concentration in the stratum corneum and maintaining the concentration in the stratum corneum after a long period of time. In order to exert such action, the content of the carbonic acid diester is 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total amount of the pharmaceutical composition. Moreover, it is preferable that carbonic acid diester is 1: 10-10: 1 in mass ratio with the sum total of the mass of benzyl alcohol and N-alkyl- 2-pyrrolidone. By adopting such a mass ratio, it is possible to adjust the slope of the retained amount in the stratum corneum 30 minutes after administration and the retained amount in the stratum corneum 24 hours later.
＜４＞本発明の医薬組成物
本発明の医薬組成物は、軟膏剤形であって多価アルコールを好ましくは含有することを特徴とする。かかる多価アルコールとしては、１分子内に水酸基を２個以上有するものであれば特段の限定はないが、１気圧２５℃で液状のものが好ましい。具体的には、プロピレングリコール、グリセリン、1，3−ブタンジオール、ジプロピレングリコール、分子量２００〜８００のポリエチレングリコール、ジグリセリン、トリグリセリンなどが好適に例示でき、プロピレングリコール、グリセリン、1，3−ブタンジオール、ジプロピレングリコール、ポリエチレングリコール及びジグリセリンから選択される１種乃至は２種以上
が特に好ましい。これらの内では、プロピレングリコールのみを含有させることが特に好ましい。かかる多価アルコールの好ましい含有量は、総量で１〜１０質量％であることが好ましく、３〜８質量％であることが特に好ましい。また、好ましい形態においては、この質量は前記一般式（１）に表される化合物及び／又はその塩の総質量に対して、４００〜７００％であることが好ましい。かかる成分は、後記非イオン界面活性剤とともに働いて、角層内における一般式（１）に表される化合物及び／又はその塩の濃度をかさ上げする作用を有する。
<4> Pharmaceutical Composition of the Present Invention The pharmaceutical composition of the present invention is an ointment dosage form and preferably contains a polyhydric alcohol. The polyhydric alcohol is not particularly limited as long as it has two or more hydroxyl groups in one molecule, but is preferably a liquid at 1 atm. Specifically, propylene glycol, glycerin, 1,3-butanediol, dipropylene glycol, polyethylene glycol having a molecular weight of 200 to 800, diglycerin, triglycerin and the like can be suitably exemplified, and propylene glycol, glycerin, 1,3- One or more selected from butanediol, dipropylene glycol, polyethylene glycol and diglycerin are particularly preferred. Among these, it is particularly preferable to contain only propylene glycol. The total content of such polyhydric alcohols is preferably 1 to 10% by mass, and particularly preferably 3 to 8% by mass. Moreover, in a preferable form, it is preferable that this mass is 400-700% with respect to the total mass of the compound represented by the said General formula (1) and / or its salt. Such a component works together with a nonionic surfactant described later and has an action of increasing the concentration of the compound represented by the general formula (1) and / or a salt thereof in the stratum corneum.
本発明の医薬組成物は、前記の必須成分以外に、非イオン界面活性剤を含有することが好ましい。かかる非イオン界面活性剤としては、ポリオキシエチレンのエステルの構造を取るものが好ましく、基剤と同程度のペースト状のものが好ましい。また、ＨＬＢ１０以上の親水性の界面活性剤であることが好ましい。具体的にはオキシエチレンの付加モル数が１４以上のポリオキシエチレン硬化ヒマシ油、オキシエチレンの付加モル数が２０以上のソルビタン脂肪酸エステル等が好適に例示できる。かかる非イオン界面活性剤は唯一種を含有させることも出来るし、二種以上を組み合わせて含有させることも出来る。これらの非イオン界面活性剤の好ましい含有量は、総量で医薬組成物全量に対して、０．５〜６質量％であることが好ましく、１．５〜３．５質量％であることが特に好ましい。この範囲において、前記多価アルコールとともに働いて、角層内の薬剤濃度のかさ上げをする作用を有する。 The pharmaceutical composition of the present invention preferably contains a nonionic surfactant in addition to the above essential components. As such a nonionic surfactant, those having a polyoxyethylene ester structure are preferable, and pastes having the same degree as the base are preferable. Moreover, it is preferable that it is a hydrophilic surfactant more than HLB10. Specifically, polyoxyethylene hydrogenated castor oil having an addition mole number of oxyethylene of 14 or more, sorbitan fatty acid ester having an addition mole number of oxyethylene of 20 or more, and the like can be preferably exemplified. Such a nonionic surfactant may contain only one species or may contain two or more species in combination. The preferred content of these nonionic surfactants is preferably 0.5 to 6% by mass, particularly 1.5 to 3.5% by mass, based on the total amount of the pharmaceutical composition. preferable. In this range, it works with the polyhydric alcohol to increase the drug concentration in the stratum corneum.
本発明の医薬組成物は、前記必須成分を含有し、通常には、１気圧２５℃でペースト状であり、液滴分散状態又は一相の状態を呈することを特徴とする。ここで、一相の状態とは、製剤を取り、顕微鏡下観察した場合、液滴を明瞭に観察し得ないことを意味する。本発明の医薬組成物では、前記必須成分以外に、溶剤類や、抗酸化剤、キレート剤、ｐＨ調整剤、紫外線吸収剤などの成分安定化の為の任意成分を含有することが出来る。ｐＨ調整剤としては、有機酸が好ましく、より好ましくは乳酸、グリコール酸、グルコン酸などのα−ヒドロキシ酸が例示できる。中でも乳酸が特に好ましい。かかるｐＨ調整剤は、抗真菌剤の含有量に対して１〜１０質量％であることが好ましい。又、安定剤としては、抗酸化成分、キレート剤が特に好ましく例示でき、抗酸化剤としては、ＢＨＴ、ＢＨＡ、トコフェロール、アスコルビン酸及びその誘導体などが好適に例示でき、キレート剤としてはエデト酸、フィチン酸、ペンテト酸などが好ましく例示できる。溶剤類としては、Ｎ−メチル−２−ピロリドン、Ｎ−エチル−２−ピロリドン、Ｎ−プロピル−２−ピロリドン、Ｎ−へキシル−２−ピロリドン等のＮ−アルキル−２−ピロリドン、アジピン酸ジエチル、アジピン酸ジイソプロピル、セバシン酸ジエチル、セバシン酸ジイソプロピル等の二塩基酸ジエステル、トリアセチン、エチルグリコール等のエチレングリコールのモノアルキルエステル、クエン酸トリエチルなどのクエン酸のトリアルキルエステル、ベンジルアルコール、フェネチルアルコール、フェノキシエタノール等を挙げることができる。中でも、Ｎ−アルキル−２−ピロリドンが好ましく、用いることができる。Ｎ−アルキル−２−ピロリドンが角層内の薬剤濃度の経時的変動を抑制し、一定の濃度を長時間維持する作用に優れるためである。この様な効果を奏するためには、Ｎ−アルキル−２−ピロリドンを総量で、医薬組成物全量に対して、０．１〜５質量％含有させることが好ましく、０．５〜３質量％が特に好ましい。 The pharmaceutical composition of the present invention contains the essential components, and is usually pasty at 1 atm. 25 ° C., and exhibits a droplet dispersion state or a one-phase state. Here, the one-phase state means that when the preparation is taken and observed under a microscope, the droplet cannot be clearly observed. In addition to the essential components, the pharmaceutical composition of the present invention may contain optional components for stabilizing components such as solvents, antioxidants, chelating agents, pH adjusters, and ultraviolet absorbers. The pH adjuster is preferably an organic acid, and more preferably an α-hydroxy acid such as lactic acid, glycolic acid or gluconic acid. Of these, lactic acid is particularly preferred. It is preferable that this pH adjuster is 1-10 mass% with respect to content of an antifungal agent. Further, as the stabilizer, antioxidant components and chelating agents can be particularly preferably exemplified, and as the antioxidant, BHT, BHA, tocopherol, ascorbic acid and derivatives thereof can be suitably exemplified, and as the chelating agent, edetic acid, Preferred examples include phytic acid and pentetic acid. As solvents, N-alkyl-2-pyrrolidone such as N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-hexyl-2-pyrrolidone, diethyl adipate Dibasic acid diesters such as diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, monoalkyl esters of ethylene glycol such as triacetin and ethyl glycol, trialkyl esters of citric acid such as triethyl citrate, benzyl alcohol, phenethyl alcohol, Mention may be made of phenoxyethanol. Among these, N-alkyl-2-pyrrolidone is preferable and can be used. This is because N-alkyl-2-pyrrolidone suppresses the temporal change in the drug concentration in the stratum corneum and is excellent in the effect of maintaining a constant concentration for a long time. In order to exert such an effect, it is preferable to contain N-alkyl-2-pyrrolidone in a total amount of 0.1 to 5% by mass, and 0.5 to 3% by mass with respect to the total amount of the pharmaceutical composition. Particularly preferred.
本発明の医薬組成物は、常法に従って製造することが出来る。上記必須成分及び任意成分は、市販のものを用いることができ、又は常法により合成したものを用いることができる。例えば、疎水性軟膏基剤を９０〜９９℃で加熱溶解する。疎水性軟膏基剤、一般式（１）に表される化合物及び／又はその塩以外の成分を同様に９０〜９９℃で加熱溶解し、これに一般式（１）に表される化合物及び／又はその塩を加えて溶解させた後、これを溶解した疎水性軟膏基剤に攪拌下徐々に加え、室温まで攪拌冷却し、ペースト状の医薬組成物とする様な方法で製造できる。この様に作製される本発明の医薬組成物は、第１６改正
日本薬局方に言う「油脂性軟膏」に分類される製剤であることが好ましい。かかる製剤は、油性基剤に有効成分を溶解又は分散させた半固形製剤を意味する。この様な製剤はクリーム製剤と異なり、水とのエマルションを形成していない。水とのエマルションを形成していないことが、角層内動態をクリーム製剤と大きく異なるものにしている。
The pharmaceutical composition of this invention can be manufactured in accordance with a conventional method. As the essential component and optional component, commercially available products can be used, or those synthesized by a conventional method can be used. For example, a hydrophobic ointment base is dissolved by heating at 90 to 99 ° C. Ingredients other than the hydrophobic ointment base, the compound represented by the general formula (1) and / or a salt thereof are similarly dissolved by heating at 90 to 99 ° C., and the compound represented by the general formula (1) and / or Alternatively, the salt can be added and dissolved, and then gradually added to the dissolved hydrophobic ointment base with stirring, and stirred and cooled to room temperature to obtain a paste-like pharmaceutical composition. The pharmaceutical composition of the present invention thus prepared is preferably a preparation classified as “oil-based ointment” as referred to in the 16th revised Japanese Pharmacopoeia. Such a preparation means a semi-solid preparation in which an active ingredient is dissolved or dispersed in an oily base. Such a formulation does not form an emulsion with water, unlike a cream formulation. The absence of an emulsion with water makes the stratum corneum dynamics significantly different from cream formulations.
本発明の医薬組成物は、ルリコナゾール等の一般式（１）に表される化合物及び／又はその塩の特性を利用し、真菌による疾病の治療又は悪化の予防に用いることが好ましい。真菌による疾病としては、水虫のような足部白癬症、カンジダ、デンプウのような体部白癬症、爪白癬のようなハードケラチン部分の白癬症が例示でき、その角層への効果が顕著なことから、足部白癬症、カンジダ、デンプウのような体部白癬症などのソフトケラチン部分、言い換えれば角層の明確な部分の処置に用いることが特に好ましい。本発明の医薬組成物の効果は皮膚に特に好適に発現されるが、爪や角質増殖部の真菌症にも及ぶので、本発明の構成を充足する爪や角質増殖部の真菌症に対する医薬組成物も本発明の技術的範囲に属する。 The pharmaceutical composition of the present invention is preferably used for the treatment of diseases caused by fungi or prevention of deterioration by utilizing the properties of the compound represented by the general formula (1) such as luliconazole and / or a salt thereof. Examples of fungal diseases include foot ringworms such as athlete's foot, body ringworms such as Candida and Denpu, and ringworms of hard keratin such as onychomycosis, and the effect on the stratum corneum is remarkable. Therefore, it is particularly preferable to use it for the treatment of soft keratin parts such as foot ringworm, Candida and body ringworm such as Denpu, in other words, a clear part of the stratum corneum. The effect of the pharmaceutical composition of the present invention is particularly preferably expressed in the skin, but also extends to mycosis of the nail and the keratinous proliferative part, so that the pharmaceutical composition for mycosis of the nail and the keratoproliferative part satisfying the configuration of the present invention Products also belong to the technical scope of the present invention.
その使用態様は、患者の体重、年令、性別、症状等を考慮して適宜選択できるが、通常成人の場合、ルリコナゾール等を１日当たり０．０１〜１ｇ投与するのが好ましい。また、真菌による疾病に通常使用されているルリコナゾール等の使用量を参考にすることができる。
例えば、一日に一回又は数回、疾病の箇所に適量を塗布することが例示でき、かかる処置は連日行われることが好ましい。
The mode of use can be appropriately selected in consideration of the patient's weight, age, sex, symptom, etc. In general, for adults, it is preferable to administer 0.01 to 1 g of luliconazole per day. Moreover, the usage-amounts, such as luliconazole normally used for the disease by fungi, can be referred.
For example, an appropriate amount can be applied to the site of the disease once or several times a day, and such treatment is preferably performed every day.
以下に、実施例を挙げて、本発明について更に詳細に説明を加えるが、本発明は以下の実施例に限定されるものではない。
＜実施例１＞
以下の処方に従って、本発明の医薬組成物である軟膏を作製した。即ち、イ、ロの成分をそれぞれ９５℃で攪拌溶解した。ロの成分にハの成分を加え可溶化を確認した後、攪拌下イに徐々に加え、攪拌冷却し、本発明の医薬組成物である、軟膏を得た。同時に、炭酸プロピレンをワセリンに置換した比較例１も同様に作製した。これらについて、ブタ耳の角層を用いて、角層内のルリコナゾールの濃度を経時的に測定した。結果を表２に示す。これより、投与後６時間、２４時間の長時間のところで炭酸プロピレンにより、角層内のルリコナゾールの濃度が高く維持されていることが判る。
Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples.
<Example 1>
An ointment that is a pharmaceutical composition of the present invention was prepared according to the following formulation. That is, components (a) and (b) were dissolved with stirring at 95 ° C., respectively. After confirming solubilization by adding the component C to the component B, the mixture was gradually added to the solution under stirring and cooled by stirring to obtain an ointment which is the pharmaceutical composition of the present invention. At the same time, Comparative Example 1 in which propylene carbonate was replaced with petrolatum was also prepared in the same manner. For these, the concentration of luliconazole in the stratum corneum was measured over time using the stratum corneum of the pig ear. The results are shown in Table 2. From this, it can be seen that the concentration of luliconazole in the stratum corneum is maintained high by propylene carbonate at a long time of 6 hours and 24 hours after administration.
＜角層内のルリコナゾールの濃度の測定方法＞
ブタの耳の角層をフランツセルに装着し、レシーバー側に生理食塩水を充填したものに検体を塗布し、経時的に角層から薬剤を抽出し、薬剤濃度を求め、角層内に貯留していた薬剤濃度を調べる。尚、角層内濃度の定量は、角層質量を秤量したのち、メタノールで抽出し、メタノール中のルリコナゾールの濃度をＬＣ−ＭＳ−ＭＳ法（装置名：UPLC-MS/MSシステムACQUITY TQD；販売社名：日本ウォーターズ株式会社）で計測した。ＬＣ−ＭＳ
−ＭＳのＬＣの条件は、ワコーシル５Ｃ１８（和光純薬工業株式会社製）を充填した４．６×２５０ｍｍのカラムを用い、カラムの温度を４０℃に調整し、５ｍＭギ酸水溶液：メタノール＝２０：８０を移動相とし、流速を１ｍｌ／ｍｉｎとした条件であった。
<Method for measuring the concentration of luliconazole in the stratum corneum>
The stratum corneum of the pig ear is attached to a Franz cell, the specimen is applied to the receiver filled with physiological saline, the drug is extracted from the stratum corneum over time, the drug concentration is obtained, and the drug is stored in the stratum corneum Check the drug concentration. To determine the concentration in the stratum corneum, weigh the stratum corneum mass and extract with methanol. The concentration of luliconazole in methanol is determined by LC-MS-MS method (device name: UPLC-MS / MS system ACQUITY TQD; (Company name: Nihon Waters Co., Ltd.). LC-MS
-The LC conditions for MS were 4.6 x 250 mm columns packed with Wakosil 5C18 (Wako Pure Chemical Industries, Ltd.), the column temperature was adjusted to 40 ° C, and 5 mM formic acid aqueous solution: methanol = 20: 80 was the mobile phase, and the flow rate was 1 ml / min.
＜実施例２＞
実施例1と同様に下記の処方に従って、本発明の医薬組成物である、軟膏を得た。
<Example 2>
In the same manner as in Example 1, according to the following formulation, an ointment which is a pharmaceutical composition of the present invention was obtained.
＜実施例３＞
実施例１、２の医薬組成物について、下記に処方を示す比較例の軟膏とともに豚の耳を用いて角層内濃度を経時的に調べた。又、市販の「ルリコンクリーム」の角層内濃度も調べた。結果を表５に示す。本発明の医薬組成物はクリーム製剤と角層内濃度の挙動が類似していることが判る。
<Example 3>
Regarding the pharmaceutical compositions of Examples 1 and 2, the concentration in the stratum corneum was examined over time by using the ears of pigs together with the ointments of Comparative Examples shown below. The concentration in the stratum corneum of commercially available “Lulicon cream” was also examined. The results are shown in Table 5. It can be seen that the pharmaceutical composition of the present invention is similar in behavior to the cream formulation and in the stratum corneum.
＜角層内濃度変化＞
豚の耳を用いて、角層内の抗真菌剤の濃度を測定した。即ち、直径2.5ｃｍの円状の部
位を作製し、検体25μＬを投与し、投与後６時間、２４時間にテープストリッピングにより角層を採取し、メタノールで抽出し、高速液体クロマトグラフィータンデム型質量分析計（装置名：UPLC-MS/MSシステムACQUITY TQD；販売社名：日本ウォーターズ株式会社）
で抗真菌剤量を定量し、皮膚１ｃｍ2あたりの角層内濃度を計測した。
<Concentration change in stratum corneum>
Using pig ears, the concentration of antifungal agent in the stratum corneum was measured. That is, a circular part with a diameter of 2.5 cm was prepared, 25 μL of sample was administered, the stratum corneum was collected by tape stripping 6 hours and 24 hours after administration, extracted with methanol, and high performance liquid chromatography tandem mass spectrometry Total (device name: UPLC-MS / MS system ACQUITY TQD; distributor: Nihon Waters Co., Ltd.)
The amount of the antifungal agent was quantified, and the concentration in the stratum corneum per 1 cm 2 of skin was measured.
本発明は、医薬組成物に応用できる。 The present invention can be applied to pharmaceutical compositions.
Claims (4)
ワセリン８０質量％以上に、流動パラフィン、スクワランから選択される液体炭化水素、及び、モクロウ、ゲイロウ、カルナウバワックス、ミツロウ、キャンデリラワックスから選択される固形脂を含有するペースト状の疎水性軟膏基剤、
２）医薬組成物全量に対して０．５〜１０質量％の以下に示す一般式（１）に表される化合物及び／又はその塩、
３）医薬組成物全量に対して０．１〜１０質量％の炭酸プロピレン、及び、
４）炭酸プロピレンと、ベンジルアルコール及びＮ−アルキル−２−ピロリドンの質量の和との質量比で１：１０〜１０：１であるベンジルアルコール及び／又はＮ−メチル−２−ピロリドン、を含有することを特徴とする、医薬組成物。
Paste hydrophobic ointment base containing 80% by mass or more of petroleum jelly, liquid hydrocarbon selected from liquid paraffin and squalane, and solid fat selected from mole, geiwa, carnauba wax, beeswax and candelilla wax Agent ,
2) 0.5 to 10% by mass of the compound represented by the following general formula (1) and / or a salt thereof with respect to the total amount of the pharmaceutical composition ,
3) 0.1 to 10% by mass of propylene carbonate with respect to the total amount of the pharmaceutical composition , and
4) Contains benzyl alcohol and / or N-methyl-2-pyrrolidone in a mass ratio of propylene carbonate to the sum of the masses of benzyl alcohol and N-alkyl-2-pyrrolidone from 1:10 to 10: 1. A pharmaceutical composition characterized in that
ワセリン８０質量％以上に、流動パラフィン、スクワランから選択される液体炭化水素、及び、モクロウ、ゲイロウ、カルナウバワックス、ミツロウ、キャンデリラワックスから選択される固形脂を含有するペースト状の疎水性軟膏基剤、
２）医薬組成物全量に対して０．５〜１０質量％の以下に示す一般式（１）に表される化合物及び／又はその塩、及び、
３）医薬組成物全量に対して０．１〜１０質量％の炭酸プロピレン、を含有することを特徴とする、医薬組成物であって、
前記医薬組成物を投与した角層における、前記一般式（１）に表される化合物及び／又はその塩の、投与後２４時間の角層内濃度が０．４μｇ／ｃｍ2以上である、医薬組成物。
Paste hydrophobic ointment base containing liquid paraffin selected from liquid paraffin and squalane and solid fat selected from moro, geiwa, carnauba wax, beeswax and candelilla wax in 80% by mass or more of petrolatum Agent,
2) 0.5 to 10% by mass of the compound represented by the following general formula (1) and / or a salt thereof with respect to the total amount of the pharmaceutical composition, and
3) A pharmaceutical composition comprising 0.1 to 10% by mass of propylene carbonate based on the total amount of the pharmaceutical composition,
In the stratum corneum administered with the pharmaceutical composition, the concentration of the compound represented by the general formula (1) and / or a salt thereof in the stratum corneum at 24 hours after administration is 0.4 μg / cm 2 or more. Composition.
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