KR20230158920A - Stabilized pharmaceutical composition for topical administration comprising efinaconazole - Google Patents
Stabilized pharmaceutical composition for topical administration comprising efinaconazole Download PDFInfo
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- KR20230158920A KR20230158920A KR1020220058647A KR20220058647A KR20230158920A KR 20230158920 A KR20230158920 A KR 20230158920A KR 1020220058647 A KR1020220058647 A KR 1020220058647A KR 20220058647 A KR20220058647 A KR 20220058647A KR 20230158920 A KR20230158920 A KR 20230158920A
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- pharmaceutical composition
- topical administration
- efinaconazole
- present
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 39
- 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 title claims abstract description 37
- 229960003937 efinaconazole Drugs 0.000 title claims abstract description 37
- 238000011200 topical administration Methods 0.000 title claims abstract description 30
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 claims description 50
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 26
- 229940087068 glyceryl caprylate Drugs 0.000 claims description 25
- 239000003963 antioxidant agent Substances 0.000 claims description 19
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical group O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 18
- 239000002738 chelating agent Substances 0.000 claims description 18
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical group CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 claims description 17
- 229940031578 diisopropyl adipate Drugs 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 16
- 230000003078 antioxidant effect Effects 0.000 claims description 13
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 claims description 11
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 11
- 229940086555 cyclomethicone Drugs 0.000 claims description 11
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 8
- 235000010199 sorbic acid Nutrition 0.000 claims description 8
- 239000004334 sorbic acid Substances 0.000 claims description 8
- 229940075582 sorbic acid Drugs 0.000 claims description 8
- 159000000000 sodium salts Chemical class 0.000 claims description 7
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 6
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical group COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 6
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 6
- 229930195729 fatty acid Natural products 0.000 abstract description 6
- 239000000194 fatty acid Substances 0.000 abstract description 6
- -1 fatty acid ester Chemical class 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 abstract description 4
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 10
- 231100000245 skin permeability Toxicity 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 229940100613 topical solution Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 5
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 5
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 5
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229940074928 isopropyl myristate Drugs 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000002075 main ingredient Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- LXAHHHIGZXPRKQ-UHFFFAOYSA-N 5-fluoro-2-methylpyridine Chemical compound CC1=CC=C(F)C=N1 LXAHHHIGZXPRKQ-UHFFFAOYSA-N 0.000 description 2
- CFCWODSWPMKRNT-UHFFFAOYSA-N 6-oxo-6-propoxyhexanoic acid Chemical group CCCOC(=O)CCCCC(O)=O CFCWODSWPMKRNT-UHFFFAOYSA-N 0.000 description 2
- 208000010195 Onychomycosis Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940057917 medium chain triglycerides Drugs 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 201000005882 tinea unguium Diseases 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 102000017168 Sterol 14-Demethylase Human genes 0.000 description 1
- 108010013803 Sterol 14-Demethylase Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K9/08—Solutions
-
- 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
- A61K31/33—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Abstract
본 발명은 에피나코나졸 또는 이의 약학적 허용 가능한 염을 포함하고 비휘발성 성분으로 지방산에스테르인 글리세릴모노카르릴레이트를 함유하는 용액 형태의 국소 투여용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole or a pharmaceutically acceptable salt thereof and glyceryl monocarrylate, a fatty acid ester, as a non-volatile component.
Description
본 발명은 에피나코나졸 또는 이의 약학적 허용 가능한 염을 함유하고 국소 투여용 약학 조성물에 관한 것이다. 더욱 상세히는 비휘발성 용매로서 글리세릴모노카프릴레이트를 포함하는 국소투여용 약학조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for topical administration containing efinaconazole or a pharmaceutically acceptable salt thereof. More specifically, it relates to a pharmaceutical composition for topical administration containing glyceryl monocaprylate as a non-volatile solvent.
에피나코나졸(efinaconazole)은 하기 화학식 1의 구조를 갖는 트리아졸계 항진균제로서, 화학명은 (2R,3R)-2- (2,4-디플루오로페닐)-3-(4-메틸렌피페리딘-1-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올[(2R,3R)-2-(2,4- difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol]이다.Efinaconazole is a triazole antifungal agent having the structure of the following formula (1), and its chemical name is (2R,3R)-2- (2,4-difluorophenyl)-3-(4-methylenepiperidine- 1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol[(2R,3R)-2-(2,4-difluorophenyl)-3-(4- methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol].
[화학식 1][Formula 1]
에피나코나졸은 에르고스테롤 생합성 경로에서 라노스테롤 14α-디메틸라아제(lanosterol 14α-demethylase)를 저해하는 활성을 가지며, 조갑진균증(onychomycosis)의 치료를 위한 10% 국소 용액 제제(상품명: JUBLIATM , Kaken Pharmaceutical Co., Ltd.)로서 시판되고 있다.Epinaconazole has the activity of inhibiting lanosterol 14α-demethylase in the ergosterol biosynthetic pathway, and is a 10% topical solution preparation for the treatment of onychomycosis (Product name: JUBLIA TM , Kaken) Pharmaceutical Co., Ltd.).
상기 국소 용액 제제는, 에피나코나졸과 함께, 휘발성 용매로서 에탄올; 젖음제(wetting agent)로서 사이클로메티콘; 및 비휘발성 용매로 오일상의 디이소프로필 아디페이트 및 C12-C15 알킬 락테이트를 함유한다.The topical solution formulation contains, along with efinaconazole, ethanol as a volatile solvent; Cyclomethicone as a wetting agent; and diisopropyl adipate and C12-C15 alkyl lactate in the oil phase as non-volatile solvents.
그러나 JUBLIATM (Kaken Pharmaceutical Co., Ltd.)의 경우, 휘발성용제인 에탄올이 있어 도표 후 용매가 쉽게 휘발되어 끈적거림 없이 사용감이 좋은 점이 있으나 피부 및 조갑 침투속도 및 투과도가 여전히 만족스럽지 못한 문제가 있다.But JUBLIA TM In the case of (Kaken Pharmaceutical Co., Ltd.), there is ethanol, a volatile solvent, so the solvent is easily volatilized after application, giving a good feeling of use without stickiness. However, there is a problem in that the penetration rate and permeability into the skin and nails are still unsatisfactory.
또한, 에피나코나졸 함유 용액제제는 짧은 저장 기간 내에 변색되어 황색으로부터 진한 적색 또는 갈색 범위의 조성물 색을 발생시키는 성상 변화 등 안정성에 대한 문제점이 있다.In addition, solution formulations containing efinaconazole have problems with stability, such as discoloration within a short storage period and changes in composition color ranging from yellow to dark red or brown.
이러한 안정성 문제를 해결하기 위하여, 종래기술인 미국특허 제US 9,662,394호는 킬레이트화제, 항산화제, 및 에틸렌디아민테트라아세트산(EDTA) 또는 이의 염, 부틸화 히드록시톨루엔(butylated hydroxytoluene, BHT), 및 시트르산을 포함하는 액체 또는 반고체 조성물을 개시한 바 있다.To solve this stability problem, the prior art, US Patent No. US 9,662,394, uses a chelating agent, an antioxidant, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, butylated hydroxytoluene (BHT), and citric acid. A liquid or semi-solid composition containing
이에 따라, 본 발명자들은 종래기술의 피부 및 조갑 침투속도 및 투과도가 여전히 만족스럽지 못한 문제를 해결한 약학 조성물 및 이의 제조방법을 제공하는 것이다.Accordingly, the present inventors provide a pharmaceutical composition and a manufacturing method thereof that solve the problem that the skin and nail penetration rate and permeability of the prior art are still unsatisfactory.
또한, 본 발명자들은 에피나코나졸 또는 이의 약학적 허용 가능한 염을 활성성분으로 함유하며 국소 투여시 변색과 유연물질 생성을 감소시켜 제품의 안정성, 투과도가 개선된 약학 조성물 및 이의 제조방법을 제공하는 것이다.In addition, the present inventors provide a pharmaceutical composition containing efinaconazole or a pharmaceutically acceptable salt thereof as an active ingredient and improving the stability and permeability of the product by reducing discoloration and production of related substances upon topical administration, and a method for manufacturing the same. .
본 발명의 상술한 종래기술의 문제점을 해결하기 위해 안출된 것으로서,The present invention was devised to solve the problems of the prior art described above,
본 발명은 특정 지방산, 구체적으로 적어도 하나의 지방산의 에스테르 화합물인 글리세릴모노카프릴레이트는 난용성 약물의 용해도 개선, 피부 투과도 증진 효과와 더불어 광범위한 항균 활성을 나타내고 있어 본 발명의 개시내용의 구체예에서 지방산 에스테르 화합물인 글리세릴 모노카프릴레이트를 포함하는 약학조성물이 제공된다.The present invention relates to a specific fatty acid, specifically glyceryl monocaprylate, which is an ester compound of at least one fatty acid, and has the effect of improving the solubility of poorly soluble drugs and improving skin permeability, as well as exhibiting broad-spectrum antibacterial activity. In an embodiment of the disclosure of the present invention, A pharmaceutical composition containing glyceryl monocaprylate, a fatty acid ester compound, is provided.
그 결과, 에피나코나졸, 에탄올, 사이클로메티콘, 비휘발성 용매를 포함하는 용액 형태의 국소 투여용 약학 조성물에 있어서, 상기 비휘발성 용매가 글리세릴 모노카프릴레이트; 및/또는 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드으로 이루어지는 군으로부터 선택되는 1종 이상의 조합인 것을 특징으로 하는 용액 형태의 국소 투여용 약학 조성물이 제공된다.As a result, in the pharmaceutical composition for topical administration in the form of a solution containing efinaconazole, ethanol, cyclomethicone, and a non-volatile solvent, the non-volatile solvent is glyceryl monocaprylate; and/or a combination of at least one selected from the group consisting of isopropyl myristate, diisopropyl adipate, and medium chain triglyceride. A pharmaceutical composition for topical administration in the form of a solution is provided.
본 발명의 약학 조성물에 있어서 상기 비휘발성 용매가 글리세릴 모노카프릴레이트; 및/또는 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종의 조합이고 글리세릴 모노카프릴레이트는 조성물 총 중량에 대하여 8 ∼20 중량%의 범위로 존재할 수 있다. 본 발명의 약학 조성물에 있어서, 상기 비휘발성 용매가 글리세릴 모노카프릴레이트는 조성물 총 중량에 대하여 8 ∼20 중량%의 범위로 존재 하고, 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종은 조성물 총 중량에 대하여 5 ∼25 중량%의 범위로 존재할 수 있다.In the pharmaceutical composition of the present invention, the non-volatile solvent is glyceryl monocaprylate; and/or a combination of one selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride, and glyceryl monocaprylate may be present in the range of 8 to 20% by weight based on the total weight of the composition. In the pharmaceutical composition of the present invention, the non-volatile solvent glyceryl monocaprylate is present in the range of 8 to 20% by weight based on the total weight of the composition, and isopropyl myristate, diisopropyl adipate, and medium chain triglyceride One type selected from may be present in the range of 5 to 25% by weight based on the total weight of the composition.
본 발명의 약학 조성물은 킬레이트화제, 항산화제, 및 산으로 이루어진 군으로부터 1종 이상 선택된 첨가제를 추가로 포함할 수 있다. 상기 킬레이트화제는 에틸렌디아민테트라아세트산 또는 이의 소듐염으로 이루어진 군으로부터 선택될 수 있다. 상기 항산화제는 부틸화 히드록시아니솔 일 수 있다. 또한, 상기 산은 소르빈산 또는 시트르산일 수 있다. The pharmaceutical composition of the present invention may further include one or more additives selected from the group consisting of chelating agents, antioxidants, and acids. The chelating agent may be selected from the group consisting of ethylenediaminetetraacetic acid or its sodium salt. The antioxidant may be butylated hydroxyanisole. Additionally, the acid may be sorbic acid or citric acid.
본 발명은 피부 투과도 및 안정성이 개선 된 에피나코나졸을 함유하는 용액 형태의 국소 투여용 약학 조성물을 제공하기 위해 다양한 연구를 수행하였다.The present invention conducted various studies to provide a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole with improved skin permeability and stability.
도 1은 실시예 1에 따른 조성물의 성상 평가 결과를 나타낸 것이다.Figure 1 shows the results of evaluating the properties of the composition according to Example 1.
이하, 본 발명에 대하여 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 에피나코나졸, 및 비휘발성 용매를 포함하는 용액 형태의 국소 투여용 약학 조성물이다.The present invention is a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole and a non-volatile solvent.
본 발명의 약학 조성물은 활성성분으로서 에피나코나졸을 함유한다. 에피나코나졸은 치료학적으로 유효한 양 (therapeutically effective amounts)로 함유될 수 있으며, 예를 들어 조성물 총 중량에 대하여 8 ∼12 중량% 의 범위, 바람직하게는 약 10 중량%로 함유될 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention contains efinaconazole as an active ingredient. Efinaconazole may be contained in therapeutically effective amounts, for example, in the range of 8 to 12% by weight, preferably about 10% by weight, based on the total weight of the composition. It is not limited.
상기 비휘발성 용매는 글리세릴모노카프릴레이트를 필수적으로 포함하고, 여기에서, 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 이상의 조합을 더 포함할 수 있다.The non-volatile solvent essentially includes glyceryl monocaprylate, and may further include one or more combinations selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride.
비휘발성 용매로서 글리세릴 모노카프릴레이트; 및/또는 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종을 조합하여 제제화할 경우, 에피나코나졸의 피부 침투속도 및 투과도를 현저 하게 증가시킬 수 있고 우수한 물리화학적 안정성을 갖는 국소 투여용 제제로서 유용하게 사용될 수 있다. Glyceryl monocaprylate as a non-volatile solvent; and/or when formulated by combining one type selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride, the skin penetration rate and permeability of efinaconazole can be significantly increased and excellent physical and chemical stability It can be usefully used as a preparation for topical administration.
여기서, 상기 글리세릴모노카프릴레이트는 조성물 총 중량에 대하여 8∼20 중량%의 범위로 존재할 수 있고,Here, the glyceryl monocaprylate may be present in the range of 8 to 20% by weight based on the total weight of the composition,
이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 이상의 조합은 조성물 총 중량에 대하여 5 ∼ 25 중량%의 범위로 존재할 수 있다.A combination of one or more types selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride may be present in the range of 5 to 25% by weight based on the total weight of the composition.
바람직하게는, 글리세릴 모노카프릴레이트는 조성물 총 중량에 대하여 10 ∼15 중량%의 범위로 존재하고,Preferably, glyceryl monocaprylate is present in the range of 10 to 15% by weight based on the total weight of the composition,
이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종은 조성물 총 중량에 대하여 6 ∼20 중량%의 범위로 존재할 수 있다.One type selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride may be present in the range of 6 to 20% by weight based on the total weight of the composition.
구체적인 구현예에서 본 발명의 국소 투여용 약학 조성물은,In a specific embodiment, the pharmaceutical composition for topical administration of the present invention,
에피나코나졸 7∼13 중량%;7 to 13% by weight of efinaconazole;
에탄올 50∼70 중량%;50 to 70% by weight of ethanol;
사이클로메티콘 10∼16 중량%;10 to 16% by weight of cyclomethicone;
글리세릴모노카프릴레이트 8∼20 중량%; 및8 to 20% by weight of glyceryl monocaprylate; and
이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 5∼25 중량%를 포함하는 용액 형태의 국소 투여용 약학 조성물일 수 있다.It may be a pharmaceutical composition for topical administration in the form of a solution containing 5 to 25% by weight of one type selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride.
또한, 본 발명의 약학 조성물은 다양한 조합의 킬레이트화제, 항산화제, 및 유기산을 사용할 수 있다. 즉, 항산화제, 및 유기산으로 이루어진 군으로부터 1종 이상 선택된 첨가제를 추가로 더 포함할 수도 있다.Additionally, the pharmaceutical composition of the present invention may use various combinations of chelating agents, antioxidants, and organic acids. That is, it may further include one or more additives selected from the group consisting of antioxidants and organic acids.
본 발명의 약학 조성물은 우수한 안정성을 가지고, 다양한 조합의 킬레이트화제, 항산화제, 및 유기산을 사용하여, EDTA/BHT/시트르산을 포함하는 공지의 제제와 동등한 안정성을 갖는다. The pharmaceutical composition of the present invention has excellent stability and, using various combinations of chelating agents, antioxidants, and organic acids, has equivalent stability to known formulations containing EDTA/BHT/citric acid.
이에 따라, 본 발명의 약학 조성물은 킬레이트화제, 항산화제, 및 산으로 이루어진 군으로부터 1종 이상 선택된 첨가제를 추가로 포함할 수 있다. 또한, 필요할 경우, 소량(예를 들어 약 1.0 중량% 이하)의 물을 추가로 포함할 수도 있다. Accordingly, the pharmaceutical composition of the present invention may further include one or more additives selected from the group consisting of chelating agents, antioxidants, and acids. Additionally, if necessary, a small amount of water (for example, about 1.0% by weight or less) may be additionally included.
상기 킬레이트화제는 이 기술 분야에서 통상적으로 사용되는 킬레이트화제라면 제한되지 않으나 에틸렌디아민테트라아세트산(EDTA) 또는 이의 소듐염을 사용할 수 있다. The chelating agent is not limited as long as it is a chelating agent commonly used in this technical field, but ethylenediaminetetraacetic acid (EDTA) or its sodium salt may be used.
상기 항산화제는 이 기술 분야에서 통상적으로 사용되는 항산화제라면 제한되지 않으나 부틸화 히드록시아니솔(butylated hydroxyanisole, BHA)일 수 있다. 또한, 상기 산의 종류도 이 기술분야에서 통상적으로 사용되는 산이라면 제한되지 않으나 소르빈산(sorbic acid) 또는 시트르산(citric acid)을 사용할 수 있다.The antioxidant is not limited as long as it is an antioxidant commonly used in this technical field, but may be butylated hydroxyanisole (BHA). Additionally, the type of acid is not limited as long as it is an acid commonly used in this technical field, but sorbic acid or citric acid can be used.
반드시 이에 제한되는 아니지만, 상기 킬레이트화제는 에틸렌디아민테트라아세트산 또는 이의 소듐염인 것을 예시할 수 있고, 상기 항산화제는 부틸화 히드록시아니솔인 것을 예시할 수 있으며, 상기 유기산은 소르빈산 또는 시트르산인 것을 예시할 수 있다.Although not necessarily limited thereto, the chelating agent may be ethylenediaminetetraacetic acid or its sodium salt, the antioxidant may be butylated hydroxyanisole, and the organic acid may be sorbic acid or citric acid. It can be exemplified.
상기 킬레이트화제는 조성물 총 중량에 대하여 0.0001 ∼1.5 중량%, 바람직하게는 0.0001 ∼0.0025 중량%, 더욱 바람직하게는 약 0.00025 중량%의 양으로 존재할 수 있다.The chelating agent may be present in an amount of 0.0001 to 1.5% by weight, preferably 0.0001 to 0.0025% by weight, and more preferably about 0.00025% by weight, based on the total weight of the composition.
상기 유기산은 조성물 총 중량에 대하여 0.05 ∼0.25 중량%, 바람직하게는 약 0.1 중량%의 양으로 존재할 수 있다.The organic acid may be present in an amount of 0.05 to 0.25% by weight, preferably about 0.1% by weight, based on the total weight of the composition.
다른 구현예에서 본 발명의 국소 투여용 약학 조성물은,In another embodiment, the pharmaceutical composition for topical administration of the present invention,
에피나코나졸 7∼13 중량%;7 to 13% by weight of efinaconazole;
에탄올 50∼66 중량%;50 to 66% by weight of ethanol;
사이클로메티콘 10∼16 중량%;10 to 16% by weight of cyclomethicone;
글리세릴모노카프릴레이트 8∼20 중량%;8 to 20% by weight of glyceryl monocaprylate;
이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 5~25 중량%;5 to 25% by weight of one kind selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride;
킬레이트화제 0.0001∼0.05 중량%;Chelating agent 0.0001 to 0.05% by weight;
항산화제 0.05∼0.3 중량%;Antioxidant 0.05 to 0.3% by weight;
유기산 0.05∼0.3 중량%; 및Organic acid 0.05 to 0.3% by weight; and
물을 잔량(구체적인 예로 0∼3.0 중량%) 포함하는 용액 형태의 국소 투여용 약학 조성물일 수 있다.It may be a pharmaceutical composition for topical administration in the form of a solution containing a residual amount of water (specifically, 0 to 3.0% by weight).
또 다른 구현예에서, 에피나코나졸 8 ∼12 중량%, 에탄올 50 ∼65 중량%, 사이클로메티콘 8 ∼20 중량%, 글리세릴 모노카프릴레이트 8 ∼20 중량%, 킬레이트화제 0.00025 ∼0.05 중량%, 항산화제 0.1 ∼0.2 중량%, 산 0.1 ∼0.2 중량%, 및 물 0 ∼1.0 중량%를 포함하는 용액 형태의 국소 투여용 약학 조성물이 제공된다. In another embodiment, 8-12% by weight efinaconazole, 50-65% by weight ethanol, 8-20% by weight cyclomethicone, 8-20% by weight glyceryl monocaprylate, 0.00025-0.05% by weight chelating agent. , a pharmaceutical composition for topical administration in the form of a solution containing 0.1 to 0.2% by weight of antioxidant, 0.1 to 0.2% by weight of acid, and 0 to 1.0% by weight of water is provided.
또 다른 구현예에서, 에피나코나졸 8 ∼12 중량%, 에탄올 40 ∼65 중량%, 사이클로메티콘 8 ∼20 중량%, 글리세릴 모노카프릴레이트 8 ∼20 중량%, 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 5 ∼25 중량%, 킬레이트화제 0.00025 ∼0.05 중량%, 항산화제 0.1 ∼0.2 중량%, 산 0.1 ∼0.2 중량%, 및 물 0 ∼1.0 중량%를 포함하는 용액 형태의 국소 투여용 약학 조성물이 제공된다. In another embodiment, 8-12% by weight of efinaconazole, 40-65% by weight of ethanol, 8-20% by weight of cyclomethicone, 8-20% by weight of glyceryl monocaprylate, isopropyl myristate, diiso 5 to 25% by weight of one kind selected from propyl adipate and medium chain triglyceride, 0.00025 to 0.05% by weight of chelating agent, 0.1 to 0.2% by weight of antioxidant, 0.1 to 0.2% by weight of acid, and 0 to 1.0% by weight of water. A pharmaceutical composition for topical administration in the form of a solution comprising:
또 다른 구현예에서, 에피나코나졸 8 ∼12 중량%, 에탄올 40 ∼65 중량%, 사이클로메티콘 8 ∼20 중량%, 글리세릴 모노카프릴레이트 10 ∼15 중량%, 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 6 ∼20 중량%, 킬레이트화제 0.00025 ∼0.05 중량%, 항산화제 0.1 ∼0.2 중량%, 산 0.1 ∼0.2 중량%, 및 물 0 ∼1.0 중량%를 포함하는 용액 형태의 국소 투여용 약학 조성물이 제공된다.In another embodiment, 8-12% by weight of efinaconazole, 40-65% by weight of ethanol, 8-20% by weight of cyclomethicone, 10-15% by weight of glyceryl monocaprylate, isopropyl myristate, diiso 6 to 20% by weight of one kind selected from propyl adipate and medium chain triglyceride, 0.00025 to 0.05% by weight of chelating agent, 0.1 to 0.2% by weight of antioxidant, 0.1 to 0.2% by weight of acid, and 0 to 1.0% by weight of water. A pharmaceutical composition for topical administration in the form of a solution comprising:
본 발명의 바람직한 하나의 구현예에서, 에피나코나졸 10 중량%, 에탄올 52.75 중량%, 사이클로메티콘 15 중량 %, 글리세릴 모노카프릴레이트 12 중량%, 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 10 중량%, 에틸렌디아민테트라아세트산 또는 이의 소듐염 0.05 중량%, 부틸화 히드록시아니솔 0.1 중량%, 및 시트르산 (또는 소르빈산) 0.1 중량%로 구성된 용액 형태의 국소 투여용 약학 조성물이 제공된다. In one preferred embodiment of the present invention, 10% by weight of efinaconazole, 52.75% by weight of ethanol, 15% by weight of cyclomethicone, 12% by weight of glyceryl monocaprylate, isopropyl myristate, diisopropyl adipate, and 10% by weight of one selected from medium chain triglycerides, 0.05% by weight of ethylenediaminetetraacetic acid or its sodium salt, 0.1% by weight of butylated hydroxyanisole, and 0.1% by weight of citric acid (or sorbic acid). Pharmaceutical compositions for administration are provided.
본 발명의 바람직한 다른 구현예에서, 에피나코나졸 10 중량%, 에탄올 52.29975 중량%, 사이클로메티콘 15 중량%, 글리세릴 모노카프릴레이트 12 중량%, 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 10 중량%, 에틸렌디아민테트라아세트산 또는 이의 소듐염 0.00025 중량%, 부틸화 히드록시아니솔 0.1 중량%, 및 시트르산 (또는 소르빈산) 0.1 중량%, 및 물 0.5 중량%로 구성된 용액 형태의 국소 투여용 약학 조성물이 제공된다. In another preferred embodiment of the present invention, 10% by weight efinaconazole, 52.29975% by weight ethanol, 15% by weight cyclomethicone, 12% by weight glyceryl monocaprylate, isopropyl myristate, diisopropyl adipate, and 10% by weight of one selected from medium chain triglycerides, 0.00025% by weight of ethylenediaminetetraacetic acid or its sodium salt, 0.1% by weight of butylated hydroxyanisole, 0.1% by weight of citric acid (or sorbic acid), and 0.5% by weight of water. A pharmaceutical composition for topical administration in the form of a solution is provided.
본 발명의 약학 조성물은 상기한 성분을 사용하여 통상의 방법에 따라 혼합함으로써 제조될 수 있다. 필요할 경우, 킬레이트화제를 함유하는 스톡 용액 및 에피나코나졸을 함유하는 스톡 용액을 각각 제조한 후, 다른 성분들과 적절히 혼합하여 용액을 형성함으로써, 본 발명의 약학 조성물을 제조할 수 있다. The pharmaceutical composition of the present invention can be prepared by mixing the above ingredients according to a conventional method. If necessary, the pharmaceutical composition of the present invention can be prepared by preparing a stock solution containing a chelating agent and a stock solution containing efinaconazole, respectively, and then appropriately mixing them with other ingredients to form a solution.
이하, 본 발명을 실시예 및 실험예를 통하여 더욱 상세히 설명한다. 그러나, 이들 실시예 및 실험예는 본 발명을 예시하는 것이며, 본 발명이 이들에 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, these examples and experimental examples are illustrative of the present invention, and the present invention is not limited to these.
실시예Example 1 내지 10 - 1 to 10 - 에피나코나졸 Efinaconazole 국소 투여용 조성물 제조 Preparation of compositions for topical administration
하기 표 1의 성분 및 함량에 따라, 에피나코나졸을 함유하는 국소 투여용 조성물을 제조하였다.A composition for topical administration containing efinaconazole was prepared according to the ingredients and contents in Table 1 below.
상기 표 1의 각 성분의 함량은 용액 중 중량%를 나타낸다.The content of each component in Table 1 represents weight percent in the solution.
에틸렌디아민테트라아세트산 또는 이의 소듐염을 정제수에 0.025 mg/mL의 농도로 용해시켜 스톡 용액을 제조하였다.A stock solution was prepared by dissolving ethylenediaminetetraacetic acid or its sodium salt in purified water at a concentration of 0.025 mg/mL.
또한, 에피나코나졸(0.2 g)을 에탄올(0.076 g)에 용해시켜 에피나코나졸-함유 스톡 용액을 제조하였다. 에피나코나졸-함유 에탄올 용액에 글리세릴 모노카프릴레이트과 이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종을 첨가하여 마크네틱 교반기로 교반하면서 실온에서 용해시키고 차례로 부틸화 히드록시아니솔 (BHA), 소르빈산, 및 EDTA 디소듐 (스톡 용액 형태로 첨가)을 차례로 가하고 혼합하여 에피나코나졸을 함유하는 용액을 제조하였다.Additionally, an efinaconazole-containing stock solution was prepared by dissolving efinaconazole (0.2 g) in ethanol (0.076 g). Glyceryl monocaprylate, isopropyl myristate, diisopropyl adipate, and one selected from medium chain triglyceride are added to the efinaconazole-containing ethanol solution, dissolved at room temperature while stirring with a magnetic stirrer, and then butylated. Hydroxyanisole (BHA), sorbic acid, and EDTA disodium (added as a stock solution) were sequentially added and mixed to prepare a solution containing efinaconazole.
비교예Comparative example - 시판중인 국소 용액 제제의 준비 - Preparation of commercially available topical solution preparations
조갑진균증의 치료에 사용되고 있는 시판 중인 국소 용액 제제 JUBLIA TM (Kaken Pharmaceutical Co., Ltd.) (에 피나코나졸 10% 함유, 국소 용액 제제)를 준비하였다. A commercially available topical solution preparation, JUBLIA TM (Kaken Pharmaceutical Co., Ltd.) (containing 10% pinaconazole, topical solution preparation), which is used in the treatment of onychomycosis, was prepared.
실험예Experiment example 1 - 안정성 평가 1 - Stability evaluation
실시예 1 내지 10에서 제조한 용액을 각각 65℃에서 4주 동안 보관한 후, 용액에 대한 500 nm 및 600 nm에서 의 흡광도를 측정하였다. 그 결과는 다음 표 3과 같다. The solutions prepared in Examples 1 to 10 were each stored at 65°C for 4 weeks, and then the absorbance of the solutions was measured at 500 nm and 600 nm. The results are shown in Table 3 below.
상기 표 2의 결과로부터, 항산화제로서 부틸화 히드록시아니솔(BHA)을 사용하고 산으로서 소르빈산 또는 시트르산을 사용을 하더라도 흡광도의 변화가 거의 없이 투명하고 맑은 무색을 보이고 함량 변화 없이 안정성이 우수하였다. 다만, 비휘발성 용제로 지방산 에스테르 화합물인 프로필렌글리콜모노카프릴레이트액을 사용한 실시예 5와 실시예 10는 어두운 오렌지색을 나타내는 성상적인 변화로 안정성이 떨어짐이 확인되었다. 즉, 동일한 지방산 에스테르 화합물일지라도 글리세릴모노카프릴레이트가 색상 변화 없이 안정성이 우수함을 알 수 있다.From the results in Table 2 above, even when butylated hydroxyanisole (BHA) was used as an antioxidant and sorbic acid or citric acid were used as acids, it was transparent, clear, and colorless with little change in absorbance, and had excellent stability with no change in content. . However, in Examples 5 and 10, which used propylene glycol monocaprylate, a fatty acid ester compound, as a non-volatile solvent, it was confirmed that stability was reduced due to a characteristic change to a dark orange color. In other words, even if it is the same fatty acid ester compound, it can be seen that glyceryl monocaprylate has excellent stability without color change.
실험예Experiment example 2 - 인공 피부를 이용한 피부 투과도 평가 2 - Evaluation of skin permeability using artificial skin
인공 피부를 사용하여, 프란즈 확산 셀(Franz diffusion cell)에서 비교예와 실시예 1내지 4에서 제조한 용액의 피부 투과도를 평가하였다. 비교예로서 JUBLIATM (에피나코나졸 10% 함유 국소 용액 제제, Kalen Pharmaceutical Co., Ltd.)를 사용하였다. 인공 피부로서 Strat-MTM Membrane(transdermal diffusion test membrane, Millipore)을 사용하였으며, 1시간 이상 충분히 수화(hydration)시킨 후 각각의 도너 컴파트먼트(donor compartment)에 200 μL씩 도포하였다. 피부 투과도 시험은 각각 3회 수행하였으며 (n=4), 프란즈 확산 셀을 사용한 반자동 경피흡수시스템 (LOGAN Instruments, DHC-6T, USA)으로 피부 투과도 시험을 진행하였으며 시험 조건은 다음과 같다.Using artificial skin, the skin permeability of the solutions prepared in Comparative Examples and Examples 1 to 4 was evaluated in a Franz diffusion cell. As a comparative example, JUBLIA TM (topical solution preparation containing 10% efinaconazole, Kalen Pharmaceutical Co., Ltd.) was used. Strat-M TM Membrane (transdermal diffusion test membrane, Millipore) was used as artificial skin, and after sufficient hydration for more than 1 hour, 200 μL was applied to each donor compartment. The skin permeability test was performed three times each (n=4), and the skin permeability test was conducted with a semi-automatic transdermal absorption system (LOGAN Instruments, DHC-6T, USA) using a Franz diffusion cell. The test conditions were as follows.
- 확산 면적(Diffusion area): 0.636 cm2 - Diffusion area: 0.636 cm 2
- 샘플 로딩: 비교예와 실시예 1~4에서 제조한 용액 각 200 μL - Sample loading: 200 μL each of the solutions prepared in Comparative Examples and Examples 1 to 4
- 리시버 용액(Receiver fluid)의 종류 및 조성: 1.5 %(w/v) Brij TM O20 (Sigma-Aldrich) 및 0.1 %(w/v) 소듐 아지드를 포함하는 인산염완충액(phosphate buffered saline, PBS) (pH 7.4) 5 mL; - Type and composition of receiver fluid: phosphate buffered saline (PBS) containing 1.5 % (w/v) Brij TM O20 (Sigma-Aldrich) and 0.1 % (w/v) sodium azide. (pH 7.4) 5 mL;
- 리시버 컴파트먼트의 교반속도 600 rpm - Stirring speed of receiver compartment 600 rpm
- 온도: 32℃- Temperature: 32℃
- 검체 채취: 6시간, 12시간 및 24시간에 각각의 리시버 컴파트먼트로부터 5 mL씩 전량 채취 후, 상기 1.5 %(w/v) Brij TM O20 (Sigma-Aldrich) 및 0.1 %(w/v) 소듐 아지드를 포함하는 인산염완충액 5mL씩 보충.- Sample collection: After collecting the entire amount of 5 mL from each receiver compartment at 6 hours, 12 hours, and 24 hours, the above 1.5 % (w/v) Brij TM O20 (Sigma-Aldrich) and 0.1 % (w/v) ) Supplement with 5 mL of phosphate buffer containing sodium azide.
얻어진 검체는 HPLC로 아래와 같이 분석하였으며, 얻어진 결과는 표 2와 같다.The obtained sample was analyzed by HPLC as follows, and the obtained results are shown in Table 2.
<HPLC 분석조건><HPLC analysis conditions>
- 컬럼: Capcell pak C18 UG120 (5 μm, 4.6 mm x 250 mm) - Column: Capcell pak C18 UG120 (5 μm, 4.6 mm x 250 mm)
- 이동상: Acetonitrile : D.W. = 8 : 2 - Mobile phase: Acetonitrile: D.W. =8:2
- 온도: 30℃- Temperature: 30℃
- 유속: 1 mL/min - Flow rate: 1 mL/min
- 검출기: 210 nm -Detector: 210 nm
- 분석시간: 10 min- Analysis time: 10 min
- 주입부피: 20 ul- Injection volume: 20 ul
- 샘플러 온도: 4℃- Sampler temperature: 4℃
성상이 변한 실시예 5와 10을 제외하였으며 또한 산으로서 시트르산, 항산화제로서 부틸화 히드록시아니솔(BHA)를 사용한 실시예 1 내지 4의 조성물에 대해 인공 피부를 사용한 피부 투과도 시험을 진행하였다.Examples 5 and 10, which had changed properties, were excluded, and a skin permeability test was conducted using artificial skin for the compositions of Examples 1 to 4, which used citric acid as the acid and butylated hydroxyanisole (BHA) as the antioxidant.
상기 표 3의 결과로부터 알 수 있는 바와 같이, 모두 시간이 경과함에 따라 투과량이 증가됨이 관찰되었다. 본 발명에 따라 얻어진 용액은 비교예에 비하여 피부 투과도가 유사하거나 현저하게 증가하였다. 특히, 실시예 1은 24시간째의 피부 투과도가 비교예에 비하여 2배가량 증가하였다.As can be seen from the results in Table 3, it was observed that the permeation amount increased with time. The solution obtained according to the present invention had similar or significantly increased skin permeability compared to the comparative example. In particular, in Example 1, skin permeability at 24 hours increased by about two times compared to the comparative example.
실험예Experiment example 3 - 3 - 유연물질Related substances 분석 analyze
실시예 1 내지 3에서 제조한 용액을 65℃에서 4주 동안 보관한 후, 총 유연물질의 양을 초고성능 액체크로마토그래피 (HPLC)를 이용하여 측정하였다.The solutions prepared in Examples 1 to 3 were stored at 65°C for 4 weeks, and then the total amount of related substances was measured using ultra-high performance liquid chromatography (HPLC).
또한, 비교예로서 JUBLIA TM (에피나코나졸 10% 함유-국소 용액 제제, EDTA 디소듐, 부틸화 히드록시톨루엔(BHT), 및 시트르산을 함유, Kaken Pharmaceutical Co., Ltd.)를 사용하였다.Additionally, as a comparative example, JUBLIA TM (topical solution formulation containing 10% efinaconazole, containing EDTA disodium, butylated hydroxytoluene (BHT), and citric acid, Kaken Pharmaceutical Co., Ltd.) was used.
초고성능 액체크로마토그래피(UPLC) 분석 조건은 다음과 같다. Ultra-performance liquid chromatography (UPLC) analysis conditions are as follows.
- 컬럼: ACQUITY UPLC BEH C18 (1.7 um, .5 cm x 2.1 mm) - Column: ACQUITY UPLC BEH C18 (1.7 um, .5 cm x 2.1 mm)
- 이동상 A: 3g 옥탄-1-술폰산 나트륨염(octane-1-sulfonic acid sodium salt)과 6.8g KH2PO4을 물 1L에 녹인 완충액 (pH 4.0) - Mobile phase A: Buffer solution (pH 4.0) containing 3g octane-1-sulfonic acid sodium salt and 6.8g KH2PO4 dissolved in 1L of water.
- 이동상 B: 메탄올: 아세토니트릴 (4:6, v/v)- Mobile phase B: Methanol: Acetonitrile (4:6, v/v)
-온도: 30℃-Temperature: 30℃
- 유속: 0.5 mL/min- Flow rate: 0.5 mL/min
- 주입량 : 3 μL - Injection volume: 3 μL
- 검출: 자외부흡광광도계 (측정파장 : 210 nm) - Detection: ultraviolet absorption spectrophotometer (measurement wavelength: 210 nm)
상기와 같이 총 유연물질의 양을 측정한 결과는 하기 표 5와 같다.The results of measuring the total amount of related substances as described above are shown in Table 5 below.
상기 표 5의 결과로부터, 본 발명에 따라 얻어진 비휘발성 용매인 글리세릴모노카프릴레이트를 포함한 실시예 1내지 3에서 비교예 비하여 현저하게 낮은 총 유연물질의 양 (%)을 나타냄으로써 65℃의 가혹조건에서도 우수한 안정성이 확인되었다.From the results in Table 5, the amount (%) of total related substances in Examples 1 to 3 containing glyceryl monocaprylate, a non-volatile solvent obtained according to the present invention, was significantly lower than that of the comparative example, indicating that the Excellent stability was confirmed even under harsh conditions.
실험예Experiment example 4 - 성상 및 안정성 평가 (stability test) 4 - Property and stability evaluation (stability test)
상기 실험예 2와 실험예 3를 통해 인공 피부를 사용한 피부 투과성 시험에서 매우 우수 결과를 보이고 유연물질 분석시험에서도 유연물질 발생이 비교예보다 상대적으로 더 적게 발생되는 등 우수한 안정성이 확인된 실시예 1 조성물의 성상 및 함량 안정성을 평가하기 위하여, 상기 실시예 1에 따른 조성물을 가속보관조건 (온도 40℃상대습도 75%)과 장기보관조건 (온도 25℃상대습도 60%)에 6개월까지 보관하여 성상 및 주성분 함량 변화를 각각 육안 평가와 HPLC 분석법을 통해 평가하였다.Through Experimental Examples 2 and 3, excellent results were shown in the skin permeability test using artificial skin, and excellent stability was confirmed in the related material analysis test, with relatively less generation of related materials than the comparative example. In order to evaluate the properties and content stability of the composition, the composition according to Example 1 was stored for up to 6 months under accelerated storage conditions (temperature 40°C, relative humidity 75%) and long-term storage conditions (temperature 25°C, relative humidity 60%). Changes in appearance and main ingredient content were evaluated through visual evaluation and HPLC analysis, respectively.
보관 6개월 시점에 성상과 활성물질의 함량을 평가한 결과를 표 6과 도 1에 나타내었다.The results of evaluating the properties and content of active substances at 6 months of storage are shown in Table 6 and Figure 1.
6개월간 보관 후에도 모든 보관 조건 (장기보관조건, 가속보관조건)에서 실시예 1은 성상 및 주성분의 함량이 보관 전과 거의 동일하게 유지됨을 확인하였다.It was confirmed that the properties and content of main ingredients of Example 1 remained almost the same as before storage under all storage conditions (long-term storage conditions, accelerated storage conditions) even after 6 months of storage.
따라서, 실시예 1의 조성물은 장기간 성상 변화와 같은 경시 변화가 없을 뿐만 주성분의 함량도안정적으로 유지됨에 따라 항진균성 효과를 나타내는 적합한 조성물임을 알 수 있다.Therefore, it can be seen that the composition of Example 1 is a suitable composition that exhibits an antifungal effect as there is no change over time such as a change in long-term properties and the content of the main ingredient is maintained stably.
이상, 본 발명을 바람직한 실시예 및 실험예를 통해 상세히 설명하였으나, 본 발명의 범위는 특정실시 예에 한정되는 것은 아니며, 첨부된 특허청구범위에 의하여 해석되어야 할 것이다. 또한, 이 기술분야에서 통상의 지식을 습득한 자라면, 본 발명의 범위에서 벗어나지 않으면서도 많은 수정과 변형이 가능함을 이해하여야 할 것이다.Above, the present invention has been described in detail through preferred embodiments and experimental examples, but the scope of the present invention is not limited to the specific embodiments and should be interpreted in accordance with the appended claims. Additionally, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.
Claims (10)
에탄올 50∼70 중량%;
사이클로메티콘 10∼16 중량%;
글리세릴모노카프릴레이트 8∼20 중량%; 및
이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 5∼25 중량%를 포함하는 용액 형태의 국소 투여용 약학 조성물.7 to 13% by weight of efinaconazole;
50 to 70% by weight of ethanol;
10 to 16% by weight of cyclomethicone;
8 to 20% by weight of glyceryl monocaprylate; and
A pharmaceutical composition for topical administration in the form of a solution containing 5 to 25% by weight of one type selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride.
에탄올 50∼66 중량%;
사이클로메티콘 10∼16 중량%;
글리세릴모노카프릴레이트 8∼20 중량%;
이소프로필 미리스테이트, 디이소프로필 아디페이트, 및 중쇄트리글리세라이드로부터 선택되는 1종 5~25 중량%;
킬레이트화제 0.0001∼0.05 중량%;
항산화제 0.05∼0.3 중량%;
유기산 0.05∼0.3 중량%; 및
물 0∼3.0 중량%를 포함하는 용액 형태의 국소 투여용 약학 조성물.7 to 13% by weight of efinaconazole;
50 to 66% by weight of ethanol;
10 to 16% by weight of cyclomethicone;
8 to 20% by weight of glyceryl monocaprylate;
5 to 25% by weight of one kind selected from isopropyl myristate, diisopropyl adipate, and medium chain triglyceride;
Chelating agent 0.0001 to 0.05% by weight;
Antioxidant 0.05 to 0.3% by weight;
Organic acid 0.05 to 0.3% by weight; and
A pharmaceutical composition for topical administration in the form of a solution containing 0 to 3.0% by weight of water.
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