TW201438742A - 皮膚適用製劑 - Google Patents
皮膚適用製劑 Download PDFInfo
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- TW201438742A TW201438742A TW102148455A TW102148455A TW201438742A TW 201438742 A TW201438742 A TW 201438742A TW 102148455 A TW102148455 A TW 102148455A TW 102148455 A TW102148455 A TW 102148455A TW 201438742 A TW201438742 A TW 201438742A
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- Prior art keywords
- film
- preparation
- skin
- mass
- antifungal agent
- Prior art date
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- 239000000203 mixture Substances 0.000 title description 34
- 238000002360 preparation method Methods 0.000 claims abstract description 81
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 34
- 239000003429 antifungal agent Substances 0.000 claims abstract description 34
- 229920001220 nitrocellulos Polymers 0.000 claims abstract description 15
- 239000000020 Nitrocellulose Substances 0.000 claims abstract description 13
- 229920002678 cellulose Polymers 0.000 claims abstract description 8
- 239000001913 cellulose Substances 0.000 claims abstract description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical group NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- FJWGYAHXMCUOOM-QHOUIDNNSA-N [(2s,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6s)-4,5-dinitrooxy-2-(nitrooxymethyl)-6-[(2r,3r,4s,5r,6s)-4,5,6-trinitrooxy-2-(nitrooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-3,5-dinitrooxy-6-(nitrooxymethyl)oxan-4-yl] nitrate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O)O[C@H]1[C@@H]([C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@@H](CO[N+]([O-])=O)O1)O[N+]([O-])=O)CO[N+](=O)[O-])[C@@H]1[C@@H](CO[N+]([O-])=O)O[C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O FJWGYAHXMCUOOM-QHOUIDNNSA-N 0.000 claims description 14
- 229940079938 nitrocellulose Drugs 0.000 claims description 14
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 10
- 229920002160 Celluloid Polymers 0.000 claims description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 5
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 230000035699 permeability Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000010408 film Substances 0.000 description 34
- 230000000052 comparative effect Effects 0.000 description 18
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 16
- 229960000699 terbinafine hydrochloride Drugs 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 231100000245 skin permeability Toxicity 0.000 description 14
- 239000003921 oil Substances 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 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 description 9
- 229960000570 luliconazole Drugs 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- -1 thiline Natural products 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010036790 Productive cough Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000011782 Keratins Human genes 0.000 description 2
- 108010076876 Keratins Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 2
- 229960004884 fluconazole Drugs 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- SUMAWDZJEIQACJ-UHFFFAOYSA-N 2-methylpyridine-4-carbaldehyde Chemical compound CC1=CC(C=O)=CC=N1 SUMAWDZJEIQACJ-UHFFFAOYSA-N 0.000 description 1
- BGRXBNZMPMGLQI-UHFFFAOYSA-N 2-octyldodecyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OCC(CCCCCCCC)CCCCCCCCCC BGRXBNZMPMGLQI-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
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 239000013032 Hydrocarbon resin Substances 0.000 description 1
- VPHPQNGOVQYUMG-UHFFFAOYSA-N Liranaftate Chemical compound COC1=CC=CC(N(C)C(=S)OC=2C=C3CCCCC3=CC=2)=N1 VPHPQNGOVQYUMG-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- MQHLMHIZUIDKOO-AYHJJNSGSA-N amorolfine Chemical compound C1=CC(C(C)(C)CC)=CC=C1CC(C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-AYHJJNSGSA-N 0.000 description 1
- 229960005279 amorolfine hydrochloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960003273 butenafine hydrochloride Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 description 1
- 229960003338 crotamiton Drugs 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003937 efinaconazole Drugs 0.000 description 1
- NFEZZTICAUWDHU-RDTXWAMCSA-N efinaconazole Chemical compound N1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)CCC(=C)CC1 NFEZZTICAUWDHU-RDTXWAMCSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000010696 ester oil Substances 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229920006270 hydrocarbon resin Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 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 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229950010148 liranaftate Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000000465 moulding 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
- 229940073665 octyldodecyl myristate Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
Classifications
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
- A61P31/02—Local antiseptics
-
- 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
- A61P31/10—Antimycotics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Emergency Medicine (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
含有抗真菌劑、硝化纖維素及水溶性纖維素的皮膚適用製劑,係可改善皮膚適用時之皮膜物性,而且為抗真菌劑之皮膚透過性亦提高的皮膜型製劑,亦可任意選擇調配極性油。
Description
本發明係關於含有抗真菌劑作為有效成分的皮膚適用製劑。
以癬為代表的皮膚絲狀菌係寄生於角蛋白組織,成為真菌感染症之原因。皮膚絲狀菌感染症之症狀中,癬是足趾間之病變,也有擴大至側面及腳底的可能性。癬的感染係在直接接觸以外,亦可藉由脫離到地面或浴室腳踏墊的感染皮膚等而傳染。
現在,特比萘芬鹽酸鹽(terbinafine hydrochloride)、Butenafine Hydrochloride等殺真菌力高的抗真菌劑成為主流,而且因為製劑技術之進步而以1日1次塗布就發揮效果的製品已在市面上販賣。但是,這些藥劑的劑形為液劑、乳劑、氣膠劑等,有可能因為衣類或地面等之摩擦而產生製劑剝離。無關於有高抗真菌劑的效果,有很多報告是以1日1次塗布無法治癒的例子,這被認為是劑形上也有問題。
目前開示有形成使用了硝化纖維素的皮膜而密封患部的癬治療用薄膜製劑(專利文獻1)。
〔專利文獻1〕:日本特開2007-63227
本發明者係調製調配了抗真菌劑的賽璐珞(celluloid)皮膜製劑,但在皮膚上形成的皮膜係脆而且容易剝落。而且,撥水性亦低。
本發明係改善皮膚適用時之皮膜物性,而且提供使皮膚透過性更提高的調配抗真菌劑之皮膜型製劑。
本發明者係為了解決上述課題而進行了各式各樣研討的結果,在抗真菌劑及調配了硝化纖維素的皮膜型製劑中調配水溶性纖維素,發現皮膜物性有改善,進而完成本發明。而且,藉由調配極性油,也發現抗真菌劑之皮膚透過性提高。
也就是本發明係
(1)含有抗真菌劑、硝化纖維素及水溶性纖維素的皮膚適用製劑、
(2)記載於(1)之皮膚適用製劑,其中抗真菌劑為
烯丙基胺系、苯甲基胺系、嗎啉系、硫胺甲酸系、咪唑系、唑系或三唑系。
(3)記載於(1)之皮膚適用製劑,其中硝化纖維素為賽璐珞(celluloid)、火棉膠(pyroxylin)、膠棉(Collodion)。
(4)記載於(1)~(3)任1項中的皮膚適用製劑,其中更含有極性油。
(5)記載於(4)之皮膚適用製劑,其中極性油為十四酸異丙酯或辛酸‧癸酸甘油三酯。
(6)記載於(1)~(5)項任1項之皮膚適用製劑,實質上不含水。
藉由本發明,可改善皮膜物性、更可使抗真菌劑之皮膚透過性提高。
〔第1圖〕實施例1、2、4、6及比較例1之製劑的使用無毛鼠摘出皮膚的特比萘芬鹽酸鹽之皮膚透過性試驗結果。
〔第2圖〕實施例7~9及比較例2之製劑的使用無毛鼠摘出皮膚的盧立康唑之皮膚透過性試驗結果。
本發明係含有抗真菌劑的皮膜形成型製劑,而作為抗真菌劑係例如可舉出特比萘芬鹽酸鹽(terbinafine hydrochloride)等之烯丙基胺系、例如Butenafine Hydrochloride等之苯甲基胺系、Amorolfine hydrochloride 等之嗎啉代基系、利拉萘酯(Liranaftate)等之硫胺甲酸系、盧立康唑(luliconazole)、克康那唑(ketoconazole)等之咪唑系、氟可那唑(Fluconazole)、伊曲康唑(Itraconazole)等之唑系、Efinaconazole等之三唑系等之抗真菌劑,這些藥品亦可以市售品買入。這些抗真菌劑係可單獨調配1種、亦可適宜地混合2種以上來調配。
使用於本發明的抗真菌劑之量,如可將治療上必要的量從皮膚供給則不特別限定,但對於製劑全體,通常係可以0.01質量%以上,理想為0.1質量%以上、較理想為0.2質量%以上、最理想為0.5質量%以上之量來調配,通常係可以30質量%以下,理想為15質量%以下、較理想為5質量%以下、最理想為3質量%以下之量來調配。另外,通常係0.01~30質量%,理想為0.1~15質量%、較理想為0.2~5質量%、最理想為0.5~3質量%。
為了將本發明之皮膜形成劑的硝化纖維素調配於製劑,亦可利用在硝化纖維素中混合了樟腦的賽璐珞(celluloid)、使硝化纖維素溶解於可溶的有機溶劑的火棉膠(pyroxylin)、使硝化纖維素溶解於二乙醚/乙醇溶液的膠棉(Collodion)等市售之皮膜形成劑原料。這些皮膜形成劑原料係可單獨調配1種、亦可適宜地混合2種以
上來調配。皮膜形成劑原料之調配量,如考慮皮膜之形成,通常係可以0.05質量%以上,理想為0.1質量%以上、較理想為0.2質量%以上、最理想為0.5質量%以上之量來調配,通常係可以30質量%以下,理想為20質量%以下、較理想為10質量%以下、最理想為5質量%以下之量來調配。另外,通常係0.05~30質量%,理想為0.1~20質量%、較理想為0.2~10質量%、最理想為0.5~5質量%。
作為本發明之水溶性纖維素,如為可溶解於製劑的賽璐珞類,則不管分子量等而可使用。例如可舉出羥丙基纖維素、羥丙基甲基纖維素、甲基纖維素、乙基纖維素、羧甲基纖維素、醋酸纖維素等,這些亦可以市售品買入。例如在作為水溶性纖維素而使用羥丙基纖維素的情況,可以不管羥基之取代度,但理想為中取代度的羥丙基纖維素。羥丙基纖維素之調配量,如考慮皮膜之形成,通常係可以0.1質量%以上,理想為0.5質量%以上、較理想為1質量%以上之量來調配,通常係可以20質量%以下,理想為10質量%以下、較理想為5質量%以下之量來調配。另外,通常係0.1~20質量%,理想為0.5~10質量%、較理想為1~5質量%。水溶性纖維素係可單獨調配1種、亦可適宜地混合2種以上來調配。
作為本發明之極性油係IOB值(Inorganic Organic Balance值)未達0.5的在常溫下為液體之酯油,但理想上可舉出十四酸異丙酯、辛酸‧癸酸甘油三酯、棕櫚酸異
丙酯、克羅他命酮(crotamiton)、癸二酸二乙酯、己二酸二異丙酯、辛基十二醇肉豆蔻酸酯(Octyldodecyl Myristate)等,這些亦可以市售品買入。這些極性油係可單獨調配1種、亦可適宜地混合2種以上來調配。極性油之調配量,如考慮皮膜之形成,通常係可以0.1質量%以上,理想為0.5質量%以上、較理想為1質量%以上之量來調配,通常係可以20質量%以下,理想為10質量%以下、較理想為5質量%以下之量來調配。另外,通常係0.1~20質量%,理想為0.5~10質量%、較理想為1~5質量%。
本發明之皮膜形成型製劑係藉由塗布於皮膚後溶劑迅速揮發,在皮膚上形成含有藥物的薄的皮膜的製劑。由皮膜所放出的藥物係分配至皮膚表面之角質的製劑,為被覆劑之一種。另外,硝化纖維素係不溶於水,使用這些物質的皮膜形成劑係藉由塗布後之溶劑之揮發及來自皮膚蒸散的水分而成為皮膜,所以實質上不含水的製劑為理想。所謂實質上不含有水,意味著製劑係以非水系材料構成。但是,容許在製劑中含有來自原料或製造環境的5質量%以下之水分。
在本發明之溶劑中,可使用能溶解抗真菌劑、硝化纖維素及水溶性纖維素之混合物之物。作為可溶解的溶劑,個別作為與乙醇之混合液,可舉出乙酸乙酯、乙酸丁酯、二乙醚、二甲醚、丁酮、丙酮等。這些與乙醇之混合溶劑係可單獨調配1種、亦可適宜地混合2種以上來調配。作
為理想的溶劑為乙醇/乙酸乙酯混合液、乙醇/乙酸丁酯混合液及乙醇/二乙基醚混合液。乙醇/溶劑比係乙醇之含量越多越理想,如考慮硝化纖維素之溶解性,則乙醇/溶劑比係1~99為理想,較理想為1.5~50。
本發明之皮膜形成型製劑係被要求有適度的黏度。因為若黏度低則會成為塗布時之不均勻或液體下垂之原因。在本發明之黏度不足的情況中,可適宜地調配增黏劑。作為增黏劑,可舉出聚丙烯酸系化合物(例如聚丙烯酸鈉等)、聚氧乙烯化合物(例如聚乙二醇400等)、多價醇(1,3-丁二醇及甘油等)、矽酸化合物(例如輕質無水矽酸(Light Anhydrous Silicic Acid)等)及脂環族飽和烴樹脂等。這些增黏劑係可單獨調配1種、亦可適宜地混合2種以上來調配。這些增黏劑之調配量,如考慮充分的黏度及向皮膚之刺激性,則0.05~20質量%為理想、較理想為0.1~10質量%。另外,在20~30℃測定黏度係0.1~100000mPa‧s為理想、較理想為0.5~50000mPa‧s。
以下,表示實施例及試驗例,詳細地說明本發明,但本發明係不限定於下述之例。另外,在實施例中,「%」全部指質量%。
藉由以下之組成及製法,得到調配烯丙基胺系抗真菌劑特比萘芬鹽酸鹽(terbinafine hydrochloride)的皮膜形
成型製劑。
藉由以下之組成及製法,得到調配烯丙基胺系抗真菌劑特比萘芬鹽酸鹽(terbinafine hydrochloride)的皮膜形成型製劑。
藉由以下之組成及製法,得到調配烯丙基胺系抗真菌劑特比萘芬鹽酸鹽(terbinafine hydrochloride)的皮膜形成型製劑。
藉由以下之組成及製法,得到調配烯丙基胺系抗真菌劑特比萘芬鹽酸鹽(terbinafine hydrochloride)的皮膜形成型製劑。
藉由以下之組成及製法,得到調配烯丙基胺系抗真菌劑特比萘芬鹽酸鹽(terbinafine hydrochloride)的皮膜形成型製劑。
藉由以下之組成及製法,得到調配烯丙基胺系抗真菌劑特比萘芬鹽酸鹽(terbinafine hydrochloride)的皮膜形成型製劑。
參考劃痕強度試驗鉛筆法(JIS K 5600-5-4),關於實施例1~5及比較例1,測定作成於載玻片上的皮膜之硬度。判斷為用硬鉛筆容易劃傷、剝離則皮膜脆,用軟鉛筆而皮膜容易劃傷、剝離則皮膜軟。劃痕強度試驗器係使用依據JIS K 5600-5-4的ELCOMETER 501鉛筆硬度測試器(ELCOMETER公司,德國製),鉛筆係使用從6B至6H之14種(三菱鉛筆公司製)之硬度。
將實施例1~5及比較例1之結果表示於表1。
由表1可明暸,調配了羥丙基纖維素-M的實施例1~5係比起比較例1可以更軟的鉛筆劃傷、剝離。以調配羥丙基纖維素-M而可提高皮膜之柔軟性。也就是可作成不脆的皮膜。而且即使調配極性油也不失去柔軟性。
關於實施例1~5及比較例1,於作成在載玻片上的皮膜上滴水,作成水滴。迅速地測定皮膜與水滴之接觸角。接觸角越大,成為撥水性越高的皮膜。
將實施例1~5及比較例1之結果表示於表2。
由表2可明暸,調配了羥丙基纖維素-M的實施例
1~5係比起比較例1的接觸角大。以調配羥丙基纖維素-M而可提高皮膜之撥水性。而且即使調配極性油也不失去撥水性。
藉由以下之組成及製法,得到調配烯丙基胺系抗真菌劑特比萘芬鹽酸鹽(terbinafine hydrochloride)的皮膜形成型製劑。
進行使用無毛鼠摘出皮膚的皮膚透過性試驗,關於實施例1、2、4、6及比較例1,評估特比萘芬鹽酸鹽(terbinafine hydrochloride)之皮膚透過性至72小時。試驗係藉由摘出無毛鼠之腹部皮膚,塗布各皮膜形成型製劑,安裝在改良式Franz cell上,將已移轉至受取液中的特比萘芬鹽酸鹽以液相色層分析法進行測定。在受取液中,使用pH4.0磷酸緩衝液。
將實施例1、2、4、6及比較例1之結果表示於第1圖。
由第1圖可明暸,調配了極性油及羥丙基纖維素-M的實施例1、2、4、6係表現出較比較例1高的特比萘芬鹽酸鹽(terbinafine hydrochloride)之皮膚透過性。藉由調配極性油及羥丙基纖維素-M,可提高特比萘芬鹽酸鹽(terbinafine hydrochloride)之皮膚透過性。
藉由以下之組成及製法,得到調配咪唑系抗真菌劑盧立康唑(luliconazole)的皮膜形成型製劑。
藉由以下之組成及製法,得到調配咪唑系抗真菌劑盧立康唑(luliconazole)的皮膜形成型製劑。
藉由以下之組成及製法,得到調配咪唑系抗真菌劑盧立康唑(luliconazole)的皮膜形成型製劑。
藉由以下之組成及製法,得到調配咪唑系抗真菌劑盧立康唑(luliconazole)的皮膜形成型製劑。
進行使用無毛鼠摘出皮膚的皮膚透過性試驗,關於實
施例7~9及比較例2,評估盧立康唑(luliconazole)之皮膚透過性至72小時。試驗係藉由摘出無毛鼠之腹部皮膚,塗布各皮膜形成型製劑,安裝在改良式Franz cell上,將已移轉至受取液中的盧立康唑(luliconazole)以液相色層分析法進行測定。在受取液中,使用pH4.0磷酸緩衝液。
將實施例7~9及比較例2之結果表示於第2圖。
由第2圖可明暸,調配了極性油的實施例7~9係表現出較比較例2更高的盧立康唑(luliconazole)之皮膚透過性。藉由調配極性油或羥丙基纖維素,可提高盧立康唑(luliconazole)之皮膚透過性。
藉由以下之組成及製法,得到調配苯甲基胺系抗真菌劑Butenafine Hydrochloride的皮膜形成型製劑。
關於實施例10,以與試驗例1相同之方法,測定作成於載玻片上的皮膜之硬度。其結果,實施例10之劃痕強度為6B,實施例10為與實施例1~5同樣柔軟的膜。另外,關於實施例10,以與試驗例2相同的方法測定皮膜之接觸角。其結果,實施例10之接觸角為72°,實施例10為與實施例1~實施例5同樣撥水性高的皮膜。
藉由將實施例3及比較例1之製劑添加約10mg於載玻片上後,放置30分鐘左右使其乾燥而作成皮膜。藉由將該載玻片之被膜形成部分曝露於流水中(水溫約42℃、流速約50mL/分、30秒鐘),測定殘存的被膜之重量而評估皮膜之附著性。藉由以下之公式,算出製劑殘存率(%),作為附著性之指標。
製劑殘存率(%)=製劑重量(試驗後)/製劑重量(試驗前)×100
實施例3及比較例1之製劑殘存率,個別為73.4%及0.0%,藉由調配羥丙基纖維素,可提高皮膜之附著性。
藉由本發明,皮膚適用時之皮膜物性提高,而且因為
變為可使抗真菌劑之皮膚透過性提高,所以可合適地利用作為含有抗真菌劑的皮膜形成製劑。
Claims (6)
- 一種皮膚適用製劑,其特徵為:含有抗真菌劑、硝化纖維素及水溶性纖維素。
- 如請求項1所記載之皮膚適用製劑,其中,抗真菌劑為烯丙基胺系、苯甲基胺系、嗎啉系、硫胺甲酸系、咪唑系、唑系或三唑系。
- 如請求項1所記載之皮膚適用製劑,其中,硝化纖維素為賽璐珞(celluloid)、火棉膠(pyroxylin)或膠棉(Collodion)。
- 如請求項1~3中之任1項所記載之皮膚適用製劑,其中,更含有極性油。
- 如請求項4所記載之皮膚適用製劑,其中,極性油為十四酸異丙酯或辛酸.癸酸甘油三酯。
- 如請求項1~5中之任1項所記載之皮膚適用製劑,其中,實質上不含水。
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TWI789448B (zh) * | 2017-10-30 | 2023-01-11 | 日商科研製藥股份有限公司 | 灰指甲治療用之外用製劑 |
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EP3556368B1 (en) | 2016-12-16 | 2021-05-26 | Kaneka Corporation | Onychomycosis therapeutic agent |
JP7365409B2 (ja) | 2018-06-28 | 2023-10-19 | エイアールエックス エルエルシー | 溶解性単位用量膜構造物を製造するための分配方法 |
Family Cites Families (9)
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JPS5939825A (ja) * | 1982-08-30 | 1984-03-05 | Terumo Corp | 外用基剤組成物 |
JPH02311414A (ja) * | 1989-05-29 | 1990-12-27 | Shiseido Co Ltd | 皮膚外用剤 |
JPH06211651A (ja) * | 1993-01-12 | 1994-08-02 | Hisamitsu Pharmaceut Co Inc | 爪白癬治療用組成物 |
JP3803393B2 (ja) * | 1994-01-12 | 2006-08-02 | 久光製薬株式会社 | 爪白癬治療用組成物 |
AU3673195A (en) * | 1994-10-13 | 1996-05-06 | Hisamitsu Pharmaceutical Co., Inc. | External preparation for nail ringworm |
JP5000932B2 (ja) * | 2005-06-21 | 2012-08-15 | 日東電工株式会社 | ニコチン含有経皮吸収製剤 |
WO2008050491A1 (fr) * | 2006-10-24 | 2008-05-02 | Japan Health Science Research Center.Ltd. | Préparation de film servant à former un film sur la peau |
JP5396125B2 (ja) * | 2009-03-30 | 2014-01-22 | 有限会社日本健康科学研究センター | 被膜形成型製剤 |
JP5798561B2 (ja) * | 2009-10-08 | 2015-10-21 | エムエスディー コンシューマー ケア, インコーポレイテッド | 低エーテル組成物およびデリバリー装置 |
-
2013
- 2013-12-26 JP JP2014554518A patent/JP6308137B2/ja active Active
- 2013-12-26 WO PCT/JP2013/084783 patent/WO2014104149A1/ja active Application Filing
- 2013-12-26 TW TW102148455A patent/TW201438742A/zh unknown
Cited By (1)
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TWI789448B (zh) * | 2017-10-30 | 2023-01-11 | 日商科研製藥股份有限公司 | 灰指甲治療用之外用製劑 |
Also Published As
Publication number | Publication date |
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JP6308137B2 (ja) | 2018-04-11 |
WO2014104149A1 (ja) | 2014-07-03 |
JPWO2014104149A1 (ja) | 2017-01-12 |
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