CN113786382A - Terbinafine hydrochloride gel and preparation method thereof - Google Patents
Terbinafine hydrochloride gel and preparation method thereof Download PDFInfo
- Publication number
- CN113786382A CN113786382A CN202111298496.1A CN202111298496A CN113786382A CN 113786382 A CN113786382 A CN 113786382A CN 202111298496 A CN202111298496 A CN 202111298496A CN 113786382 A CN113786382 A CN 113786382A
- Authority
- CN
- China
- Prior art keywords
- gel
- terbinafine hydrochloride
- microemulsion
- gellan gum
- aqueous solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 title claims abstract description 73
- 229960000699 terbinafine hydrochloride Drugs 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000001879 gelation Methods 0.000 title description 2
- 229920002148 Gellan gum Polymers 0.000 claims abstract description 42
- 239000000216 gellan gum Substances 0.000 claims abstract description 39
- 235000010492 gellan gum Nutrition 0.000 claims abstract description 39
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 33
- 235000019198 oils Nutrition 0.000 claims abstract description 32
- 239000007864 aqueous solution Substances 0.000 claims abstract description 24
- 238000002156 mixing Methods 0.000 claims abstract description 22
- 229920001213 Polysorbate 20 Polymers 0.000 claims abstract description 18
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims abstract description 18
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 16
- 235000020238 sunflower seed Nutrition 0.000 claims abstract description 16
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims description 17
- 239000011159 matrix material Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims 6
- 239000008346 aqueous phase Substances 0.000 claims 2
- 238000003756 stirring Methods 0.000 abstract description 20
- 229960004063 propylene glycol Drugs 0.000 abstract description 14
- 230000007794 irritation Effects 0.000 abstract description 8
- 231100000956 nontoxicity Toxicity 0.000 abstract description 3
- 239000011248 coating agent Substances 0.000 abstract description 2
- 238000000576 coating method Methods 0.000 abstract description 2
- 239000012530 fluid Substances 0.000 abstract 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000011068 loading method Methods 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 74
- 239000003814 drug Substances 0.000 description 26
- 239000003921 oil Substances 0.000 description 25
- 229940079593 drug Drugs 0.000 description 23
- 239000008213 purified water Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 9
- 229920002125 Sokalan® Polymers 0.000 description 9
- 229960001631 carbomer Drugs 0.000 description 9
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 206010040880 Skin irritation Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 231100000475 skin irritation Toxicity 0.000 description 5
- 230000036556 skin irritation Effects 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 3
- 206010015150 Erythema Diseases 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 231100000321 erythema Toxicity 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 229940089474 lamisil Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940124274 edetate disodium Drugs 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 235000020778 linoleic acid Nutrition 0.000 description 2
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000007928 solubilization Effects 0.000 description 2
- 238000005063 solubilization Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- UOFRJXGVFHUJER-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanol;hydrate Chemical compound [OH-].OCC[NH+](CCO)CCO UOFRJXGVFHUJER-UHFFFAOYSA-N 0.000 description 1
- 125000002353 D-glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Chemical group CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010017543 Fungal skin infection Diseases 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Chemical group CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- 206010040914 Skin reaction Diseases 0.000 description 1
- 241000790234 Sphingomonas elodea Species 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- PNNNRSAQSRJVSB-BXKVDMCESA-N aldehydo-L-rhamnose Chemical group C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-BXKVDMCESA-N 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001746 carotenes Chemical class 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 108010017796 epoxidase Proteins 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- YVECGMZCTULTIS-PBXRRBTRSA-N glucal Chemical group OC[C@H]1OC=C[C@@H](O)[C@@H]1O YVECGMZCTULTIS-PBXRRBTRSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 238000005504 petroleum refining Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- -1 phytosterol Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000036559 skin health Effects 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 230000035483 skin reaction Effects 0.000 description 1
- 231100000430 skin reaction Toxicity 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- 150000004044 tetrasaccharides Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 231100000054 whole-body exposure Toxicity 0.000 description 1
Images
Classifications
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/30—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
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61P31/10—Antimycotics
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the field of medicinal preparations, and particularly relates to terbinafine hydrochloride gel with biocompatibility, no toxicity and no irritation and a preparation method thereof. It is prepared by mixing microemulsion loading terbinafine hydrochloride with gellan gum aqueous solution, stirring uniformly, and cooling to room temperature. The microemulsion is prepared from tween 20, sunflower seed oil, 1, 2-propylene glycol, disodium hydrogen phosphate and water, and the preparation process is simple. The gel shows the characteristics of fluid gel, such as shear thinning non-Newtonian fluid characteristics, and further has better stability and coating property, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a novel preparation of an external medicament and a preparation method thereof, in particular to terbinafine hydrochloride gel which adopts a biocompatible, nontoxic and non-irritant matrix and a preparation method thereof.
Background
Terbinafine hydrochloride, its chemical name is (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-formamide naphthalene. Is an allylamine medicine with broad-spectrum antifungal activity artificially synthesized by Nowa company. Can specifically interfere early biosynthesis of mycosterol, inhibit ergosqualene epoxidase of fungi with high selectivity, and inhibit ergosqualene epoxidation reaction during formation of fungal cell membrane, thereby achieving the effect of killing or inhibiting fungi. It is highly hydrophobic and therefore tends to accumulate in hair, skin, nails and adipose tissue, and is used to treat dermatophyte infections and other fungal skin infections. The structural formula is as follows:
terbinafine hydrochloride is an ionic drug, has low solubility in water of only 8.8mg/ml, LogP of 3.84 and molecular weight of 327.89, and is suitable for being developed into a transdermal administration preparation. The transdermal drug delivery preparation directly acts on the affected part without passing through the digestive tract and the liver, so that the whole body exposure of the drug is greatly reduced, and the occurrence of toxic and side effects is reduced. The currently clinically common terbinafine hydrochloride skin external preparations comprise cream, spray and gel. Compared with the gel, when the cream meets acidic, alkaline or high ionic strength, the cream is often unstable and even breaks emulsion, and the moisture is easy to lose and the phenomenon of breaking emulsion and layering is easy to occur in the long-term storage process. The spray has low drug concentration, short residence time at the focus, and easy abrasion by socks, clothes, trousers, etc., and needs repeated administration to achieve ideal effect.
The terbinafine hydrochloride gel former preparation isUnder the trade name LAMISIL, developed by Kurarin SchkATThe gel matrix is carbomer, each gram of gel contains 0.01g of terbinafine, benzyl alcohol and ethanol contained in auxiliary materials can possibly cause local skin reaction, and a pH regulator sodium hydroxide contained in the gel can also generate certain stimulation to the skin.
Patent CN111557903A discloses a method for preparing terbinafine hydrochloride gel, which comprises using carbomer (type B) as gel matrix, mixing the drug with propylene glycol and polyethylene glycol 400, mixing with carbomer swelling aqueous solution containing edetate disodium, adding polysorbate 80 and ethanol, stirring and emulsifying, and finally adding triethanolamine to adjust pH value, thereby obtaining terbinafine hydrochloride gel. The gel prepared by the invention has various solubilizers and emulsifiers, and is expected to improve the transdermal penetration of the medicine.
Patent CN105342986A discloses a terbinafine hydrochloride gel and its preparation method, which comprises swelling carbomer with edetate disodium water solution until no hard core is present, and mixing the swelled carbomer with propylene glycol, polyethylene glycol 400, cetyl alcohol, and tert-butyl p-hydroxyanisole to form gel matrix. Mixing the gel matrix with terbinafine hydrochloride ethanol solution and polysorbate 80, emulsifying, adding triethanolamine water solution, and stirring for 60-120min to obtain gel preparation with fine colloid, uniform content, and easy application and removal. However, the method requires 24 hours for swelling carbomer, so that the batch-to-batch period is long, and the workshop production is not facilitated.
Patent CN102397240A discloses terbinafine hydrochloride gel, and the auxiliary materials include carbomer, benzoic acid, propylene glycol, triethanolamine, polysorbate-80, disodium edetate, 75% ethanol, and distilled water. And (3) mixing and stirring different components in multiple steps at different temperatures to obtain the gel finished product. The prepared finished product has good quality and is suitable for batch production. However, the preparation process is complicated, and the mixing sequence is easy to make mistakes. Carbomer gels are sensitive to acidic substances and benzoic acid in the composition may cause a decrease in gel adhesion.
The prior gel preparation technologies disclosed above are all traditional hydrochloric acid specific gel formulas and preparation methods, and although certain beneficial effects are obtained, some defects still exist: the proportion of ethanol in the preparation is too high, and is above 20%, and certain stimulation is inevitably brought to the focus. Ethanol is highly volatile, which causes deterioration of the moisturizing effect of the gel after application, affecting the therapeutic effect. The gel matrix is carbomer which is sensitive to mineral ions, the focus is accidentally wetted, and calcium, magnesium and other ions in water can reduce the gel consistency and easily cause falling off. Most of the additives used in the prescription are derived from petroleum refining products, which inevitably cause certain irritation to the skin on one hand and certain damage to the environment on the other hand.
To ameliorate the above disadvantages, the inventors have conceived a gel matrix of microbial origin, gellan gum, in combination with a microemulsion of solubilized drug, for the preparation of terbinafine hydrochloride gel formulations.
Gellan gum is a microbial polysaccharide that is an anionic linear polysaccharide produced by the culture and fermentation of pseudomonas elodea. The polymer chain of gellan gum consists of tetrasaccharide repeat units of D-glucose, D-glucal, D-glucose and L-rhamnose, and has a relative molecular mass of about 500 k. The formed gel has good stability, can not only resist the environments of high temperature, acid and the like, but also resist the degradation of enzyme and microorganism, and has the advantages of safety, no toxicity, high gel transparency, good biocompatibility and the like. The native form of gellan gum (high acyl gellan gum) contains two types of acyl substituents, L-glyceryl and acetyl. Removal of these two substituents by alkaline hydrolysis can result in deacetylated gellan gum, also known as low acetyl or low acyl gellan gum.
The acyl group in the high acyl gellan gum can generate a blocking effect when molecules are aggregated into the gum, so that the formed gel is soft, rich in elasticity and strong in adhesive force. Low acyl gellan gums form strong, brittle gels. In practical application, a small amount of cations are added in the cooling process to prepare the gellan gum gel with a stable structure, so that the electrostatic repulsion effect between carboxyl side chains of the gellan gum is shielded, the aggregation quantity of double helix of the gellan gum solution in the cooling process is increased, and further the gel is formed.
Tween 20 is selected as the emulsifier in the microemulsion, and the emulsifier is relatively mild and has low skin irritation although the emulsifying capacity is weak. The oil phase is sunflower seed oil which is a high-grade nutritional oil, golden in color, clear and transparent, and has aromatic smell. And contains a large amount of linoleic acid and other unsaturated fatty acids necessary for human body, and can promote regeneration and growth of human body cells, protect skin health, and reduce cholesterol deposition in blood. The sunflower seed oil also contains various substances beneficial to human beings such as sterol, vitamin, phytosterol, phospholipid, carotene and the like, wherein the content of natural vitamin E is the highest in all main vegetable oils, and the sunflower seed oil has good antioxidant capacity.
Disclosure of Invention
In view of the defects of the prior art, the inventor provides the terbinafine hydrochloride gel, and the gellan gum aqueous solution and the drug-loaded microemulsion are combined, so that the solubilization capacity of the gellan gum is improved, the advantages of the gel are exerted, the drug can be favorably adhered to a focus, the excellent skin permeability of the drug is ensured, and the curative effect is further improved.
The microemulsion phase region at room temperature is found by a method of a quasi-ternary phase diagram by taking Tween 20 as an emulsifier, 1.2 propylene glycol of an auxiliary emulsion and sunflower seed oil as oil phases and disodium hydrogen phosphate aqueous solution as a water phase. According to the proportion of the components in the phase region, the terbinafine hydrochloride is dispersed in the oil phase and the Tween 20, and then the water phase is added for uniform mixing, thus obtaining the terbinafine hydrochloride microemulsion. And mixing the gellan gum aqueous solution with the drug-loaded microemulsion to obtain the terbinafine hydrochloride gel. The preparation method is simple, and the obtained gel preparation is fine and smooth, and has good spreadability and stability and high safety.
The invention is realized by the following scheme:
a terbinafine hydrochloride gel, which is a composition of a microemulsion carrying terbinafine hydrochloride and a gel matrix aqueous solution.
The microemulsion in the gel consists of Tween 20, an oil phase and a water phase.
The gel matrix aqueous solution in the gel is an aqueous solution of gellan gum.
Preferably, the gellan gum in the gel is selected from natural gellan gums, i.e. high acyl gellan gums.
The concentration of the gellan gum aqueous solution in the gel is 0.4-1.5 wt%.
Preferably, the concentration of the gellan gum aqueous solution in the gel is 0.6 to 1.3 wt%.
The oil phase of the microemulsion in the gel is a mixture of sunflower seed oil and 1.2-propylene glycol, wherein the mixing mass ratio of the sunflower seed oil to the 1.2-propylene glycol is 7: 3.
The water phase of the microemulsion in the gel is a disodium hydrogen phosphate aqueous solution, wherein the concentration of the disodium hydrogen phosphate aqueous solution is 1.0-1.6 wt%.
The microemulsion of terbinafine hydrochloride in the gel is 2 parts, tween 20 is 20-70 parts, oil phase is 5-20 parts, and water phase is 20-80 parts.
Preferably, the microemulsion of terbinafine hydrochloride in the gel is 2 parts, tween 20 is 20-60 parts, oil phase is 5-15 parts, and water phase is 30-80 parts.
The mass ratio of the terbinafine hydrochloride-loaded microemulsion to the gellan gum aqueous solution in the gel is 1: 1.
The invention also provides a preparation method of terbinafine hydrochloride gel, which comprises the following steps:
(1) dissolving or suspending terbinafine hydrochloride in the mixed solution of oil phase and Tween 20, adding water phase, mixing, and balancing at room temperature for 1 hr to obtain terbinafine hydrochloride microemulsion.
(2) Dissolving a proper amount of gellan gum powder in hot water at the temperature of 80 ℃, cooling to below 50 ℃, mixing with the prepared terbinafine hydrochloride microemulsion according to the mass ratio of 1:1, and cooling to room temperature to obtain the stable terbinafine hydrochloride gel preparation.
Compared with the prior art, the invention has the following advantages:
(1) the gel has proper viscoelasticity and good stability. The shear dilution characteristic is convenient for the affected part to be coated; the gel matrix has increased strength when meeting calcium, magnesium and other cations, so that the risk of gel water-soaking and falling off at the focus can be reduced, and the compliance of patients is improved.
(2) The preparation has the advantages of reduced components, simple preparation process, and high controllability of related substances. Disodium hydrogen phosphate is a pH regulator and a gel enhancer. The solubilization of the microemulsion can increase the concentration gradient between the drug and the skin and promote the transdermal absorption of the drug; 1.2 propylene glycol and sunflower oil (containing linoleic acid) can also be used as skin penetration enhancer. Meanwhile, the sunflower seed oil has excellent oxidation resistance and can be used as an antioxidant.
(3) The preparation has no toxicity, no irritation, and good skin compatibility.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application.
FIG. 1 is a graph of the shear viscosity of terbinafine hydrochloride gel as a function of shear rate;
figure 2 is a graph of the change of the storage modulus and loss modulus of terbinafine hydrochloride gel with frequency.
Detailed Description
The advantages of the present invention are further described below by way of examples, it being properly understood that: the examples of the present invention are given for illustrative purposes only and are not intended to limit the present invention. Therefore, simple modifications of the present invention in the process of the present invention are within the scope of the claimed invention.
Determination of the phase region of microemulsions
Firstly, uniformly mixing 7 parts of sunflower seed oil and 3 parts of 1, 2-propylene glycol to obtain an oil phase, dissolving a proper amount of disodium hydrogen phosphate in water to obtain a water phase, accurately weighing Tween 20 and the oil phase in different transparent glass test tubes according to the mass ratio of Tween 20 to the oil phase (10:0 → 0:10), uniformly stirring in a constant-temperature water bath at 25 ℃, dropwise adding the water phase into the test tubes again, uniformly mixing, and balancing for 1-2 hours. And judging the phase state according to the characteristics of mixture fluidity, transparency and the like, and taking a transparent flowing water-like single-phase area as a micro-emulsion area.
Preparation of terbinafine hydrochloride gel
The purified water added in the following examples is divided into two parts, purified water a representing the first part and purified water b representing the second part.
Example 1
1) Prescription
2) Preparation process
(a) Uniformly dispersing a prescription amount of terbinafine hydrochloride in a mixture of tween 20, sunflower seed oil and 1, 2-propylene glycol;
(b) adding purified water a containing disodium hydrogen phosphate into the mixture in the step (a) while stirring, uniformly mixing, and standing for 1h to reach phase balance to obtain a drug-loaded microemulsion;
(c) uniformly dispersing the gellan gum in the prescription amount in hot water (purified water b) at 80 ℃, stirring for dissolving, and cooling to below 50 ℃;
(d) and transferring the drug-loaded microemulsion into the gellan gum aqueous solution, stirring uniformly, and cooling to room temperature to obtain the terbinafine hydrochloride gel.
Example 2
1) Prescription
2) Preparation process
(a) Uniformly dispersing a prescription amount of terbinafine hydrochloride in a mixture of tween 20, sunflower seed oil and 1, 2-propylene glycol;
(b) adding purified water a containing disodium hydrogen phosphate into the mixture in the step (a) while stirring, uniformly mixing, and standing for 1h to reach phase balance to obtain a drug-loaded microemulsion;
(c) uniformly dispersing the gellan gum in the prescription amount in hot water (purified water b) at 80 ℃, stirring for dissolving, and cooling to below 50 ℃;
(d) and transferring the drug-loaded microemulsion into the gellan gum aqueous solution, stirring uniformly, and cooling to room temperature to obtain the terbinafine hydrochloride gel.
Example 3
1) Prescription
2) Preparation process
(a) Uniformly dispersing a prescription amount of terbinafine hydrochloride in a mixture of tween 20, sunflower seed oil and 1, 2-propylene glycol;
(b) adding purified water a containing disodium hydrogen phosphate into the mixture in the step (a) while stirring, uniformly mixing, and standing for 1h to reach phase balance to obtain a drug-loaded microemulsion;
(c) uniformly dispersing the gellan gum in the prescription amount in hot water (purified water b) at 80 ℃, stirring for dissolving, and cooling to below 50 ℃;
(d) and transferring the drug-loaded microemulsion into the gellan gum aqueous solution, stirring uniformly, and cooling to room temperature to obtain the terbinafine hydrochloride gel.
Example 4
1) Prescription
2) Preparation process
(a) Uniformly dispersing a prescription amount of terbinafine hydrochloride in a mixture of tween 20, sunflower seed oil and 1, 2-propylene glycol;
(b) adding purified water a containing disodium hydrogen phosphate into the mixture in the step (a) while stirring, uniformly mixing, and standing for 1h to reach phase balance to obtain a drug-loaded microemulsion;
(c) uniformly dispersing the gellan gum in the prescription amount in hot water (purified water b) at 80 ℃, stirring for dissolving, and cooling to below 50 ℃;
(d) and transferring the drug-loaded microemulsion into the gellan gum aqueous solution, stirring uniformly, and cooling to room temperature to obtain the terbinafine hydrochloride gel.
Example 5
1) Prescription
2) Preparation process
(a) Uniformly dispersing a prescription amount of terbinafine hydrochloride in a mixture of tween 20, sunflower seed oil and 1, 2-propylene glycol;
(b) adding purified water a containing disodium hydrogen phosphate into the mixture in the step (a) while stirring, uniformly mixing, and standing for 1h to reach phase balance to obtain a drug-loaded microemulsion;
(c) uniformly dispersing the gellan gum in the prescription amount in hot water (purified water b) at 80 ℃, stirring for dissolving, and cooling to below 50 ℃;
(d) and transferring the drug-loaded microemulsion into the gellan gum aqueous solution, stirring uniformly, and cooling to room temperature to obtain the terbinafine hydrochloride gel.
Verification examples
1. Stability test
In order to verify the stability of the terbinafine hydrochloride gel in the invention in the extraordinary environment, the terbinafine hydrochloride gel of examples 1-5 was subjected to a centrifugal (3000r/min, 5min), heat-resistant (55 ℃, 6h), cold-resistant (-15 ℃, 24h) stability test, and the appearance and coating properties were observed.
As a result: after the terbinafine hydrochloride gel is centrifuged, no layering phenomenon occurs in the examples 1-5, and the gel is still uniform and fine, is easy to coat and has good transparency.
After cold resistance and heat resistance experiments, no layering phenomenon, no liquefaction and coarsening phenomenon, and uniform and fine gel which is easy to coat and has light transparency are observed in the terbinafine hydrochloride gel in the examples 1 to 5.
2. Long term stability test
To further prove the superiority of the invention, the inventor stores the product obtained in the embodiment of the invention at 25 ℃ +/-2 ℃ and 60% +/-5% RH for 12 months, and respectively measures the content (calculated by terbinafine hydrochloride) of the retained sample at 0 month, 3 months, 6 months and 12 months according to the measuring method under the term of terbinafine hydrochloride gel content measurement of second pharmacopoeia of China edition 2000. Specific data are shown in table 1.
The inventor stores the product obtained in the embodiment of the invention at 25 ℃ +/-2 ℃ and 60% +/-5% RH for 12 months, and measures the related substances of the reserved sample at 0 month, 3 months, 6 months, 9 months and 12 months respectively according to the measuring method under the related substance item of terbinafine hydrochloride in the second part of the 2020 edition Chinese pharmacopoeia, and the specific data are shown in Table 2.
TABLE 1. long term stability test results for terbinafine hydrochloride gel
TABLE 2. results of long-term stability test of terbinafine hydrochloride gel
3. Repeated administration skin irritation test
42 Japanese white rabbits qualified for quarantine are completely randomly divided into 2 groups according to sex and weight, each group comprises 21 rabbits, and the male rabbit and the female rabbit are respectively used for irritation tests of intact skin and broken skin. The left side and the right side of the experimental animal are coated with the test object by adopting a homomorphic left-right self-contrast method, and the right side is coated with the test object excipient (the auxiliary material of the terbinafine hydrochloride gel of the invention) as a contrast. Then, the 21 Japanese white rabbits of the intact skin group and the damaged skin group are randomly divided into 7 groups according to the weight and sex, and the groups are respectively as follows: example 1 group, example 2 group, example 3 group, example 4 group, example 5 group, substrate control group, and commercial group (LAMISIL)AT) 3 drugs are administered to each group, and the administration is carried out once a day for 4 hoursIn time, the administration was continued for 14 days. Visual observation of the administration site 1 hour after each drug removal and before re-administration was carried out, and the irritation response and the occurrence and regression times were recorded, and the irritation response at the application site was visually observed and recorded 30-60min, 24, 48 and 72 hours after the last drug administration was removed. The scoring criteria are shown in tables 2 and 3.
TABLE 2 skin irritation response score criteria
TABLE 3 skin irritation Strength Scoring criteria
As a result: during the administration period of the animals with intact skin and after the administration, no obvious irritation such as erythema, red swelling and the like can be observed by visual observation on the local appearance of the administered animals. The average skin irritation response score for each group was 0.
For the damaged skin group animals, mild erythema phenomenon can be seen in 1-3 days in the initial period of administration, and no obvious difference exists among the groups. In the middle of the administration, erythema gradually disappeared, and the average time of skin healing was more than that of the commercial group (LAMISIL) in examples 1 to 5AT) 1.5 days faster, the degree of healing was substantially consistent. After healing, no obvious irritation reaction is seen on the skin, and no obvious abnormality is seen on the skin in the observation period.
Claims (10)
1. The terbinafine hydrochloride gel is characterized in that the gel is a composition of a microemulsion carrying terbinafine hydrochloride and a gel matrix aqueous solution.
2. Terbinafine hydrochloride gel according to claim 1, wherein the microemulsion in said gel consists of tween 20, an oil phase and an aqueous phase.
3. Terbinafine hydrochloride gel according to claim 1, wherein said aqueous solution of the gel matrix in the gel is an aqueous solution of gellan gum, and wherein the gellan gum in the gel is selected from the group consisting of natural gellan gum, i.e. high acyl gellan gum.
4. Terbinafine hydrochloride gel according to claim 3, wherein the concentration of the aqueous gellan gum solution in said gel is 0.4-1.5 wt%.
5. Terbinafine hydrochloride gel according to claim 4, wherein the concentration of the aqueous gellan gum solution in said gel is 0.6-1.3 wt%.
6. The terbinafine hydrochloride gel of claim 2, wherein the oil phase of the microemulsion in the gel is a mixture of sunflower seed oil and 1.2-propylene glycol, and the mixing mass ratio of the sunflower seed oil to the 1.2-propylene glycol is 7: 3.
7. Terbinafine hydrochloride gel according to claim 2, wherein the aqueous phase of the microemulsion in said gel is an aqueous solution of disodium hydrogen phosphate, wherein the concentration of the aqueous solution of disodium hydrogen phosphate is 1.0-1.6 wt%.
8. The terbinafine hydrochloride gel of claim 1, wherein the microemulsion of terbinafine hydrochloride in the gel is 2 parts, tween 20 is 20-70 parts, oil phase is 5-20 parts, and water phase is 20-80 parts.
9. The terbinafine hydrochloride gel of claim 1, wherein the mass ratio of the terbinafine hydrochloride loaded microemulsion to the gellan gum aqueous solution in the gel is 1: 1.
10. A process for the preparation of terbinafine hydrochloride gel as claimed in any of claims 1 to 9, said process comprising the steps of:
(1) dissolving or suspending terbinafine hydrochloride in the mixed solution of oil phase and Tween 20, adding water phase, mixing, and balancing at room temperature for 1 hr to obtain terbinafine hydrochloride microemulsion.
(2) Dissolving a proper amount of gellan gum powder in hot water at the temperature of 80 ℃, cooling to below 50 ℃, and mixing with the prepared terbinafine hydrochloride microemulsion according to the mass ratio of 1:1 to obtain the terbinafine hydrochloride gel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111298496.1A CN113786382B (en) | 2021-11-04 | 2021-11-04 | Terbinafine hydrochloride gel and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111298496.1A CN113786382B (en) | 2021-11-04 | 2021-11-04 | Terbinafine hydrochloride gel and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113786382A true CN113786382A (en) | 2021-12-14 |
| CN113786382B CN113786382B (en) | 2024-05-28 |
Family
ID=79185275
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111298496.1A Active CN113786382B (en) | 2021-11-04 | 2021-11-04 | Terbinafine hydrochloride gel and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113786382B (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641237A (en) * | 2012-05-15 | 2012-08-22 | 山东大学 | Curcumin microemulsion ion sensitive in situ gel preparation for intranasal administration and preparation method thereof |
| CN102770123A (en) * | 2009-12-23 | 2012-11-07 | 纽沃研究股份有限公司 | Highly permeating terbinafine formulation for treating onychomycosis |
| US20130217655A1 (en) * | 2010-10-10 | 2013-08-22 | Dermipsor Ltd. | Compositions for treating psoriasis of the scalp |
| CN103655459A (en) * | 2013-12-19 | 2014-03-26 | 中国药科大学 | Multifunctional microemlusion gel preparation and preparation process thereof |
| US20150342871A1 (en) * | 2009-12-23 | 2015-12-03 | Nuvo Research Inc. | Highly permeating terbinafine formulation |
| CN108578356A (en) * | 2018-03-09 | 2018-09-28 | 昆药集团股份有限公司 | A kind of Artemether oral microemulsion in-situ gel and preparation method thereof |
| CN108721215A (en) * | 2017-04-17 | 2018-11-02 | 苏州旺山旺水生物医药有限公司 | End Fluconazole micro emulsion composition |
| CN109172517A (en) * | 2018-10-25 | 2019-01-11 | 山东师范大学 | A kind of preparation method of the microemulsion hydrogel as apiolin carrier with pH response |
| CN110545796A (en) * | 2017-03-07 | 2019-12-06 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | Local delivery system for active compounds |
-
2021
- 2021-11-04 CN CN202111298496.1A patent/CN113786382B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102770123A (en) * | 2009-12-23 | 2012-11-07 | 纽沃研究股份有限公司 | Highly permeating terbinafine formulation for treating onychomycosis |
| US20150342871A1 (en) * | 2009-12-23 | 2015-12-03 | Nuvo Research Inc. | Highly permeating terbinafine formulation |
| US20130217655A1 (en) * | 2010-10-10 | 2013-08-22 | Dermipsor Ltd. | Compositions for treating psoriasis of the scalp |
| CN102641237A (en) * | 2012-05-15 | 2012-08-22 | 山东大学 | Curcumin microemulsion ion sensitive in situ gel preparation for intranasal administration and preparation method thereof |
| CN103655459A (en) * | 2013-12-19 | 2014-03-26 | 中国药科大学 | Multifunctional microemlusion gel preparation and preparation process thereof |
| CN110545796A (en) * | 2017-03-07 | 2019-12-06 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | Local delivery system for active compounds |
| CN108721215A (en) * | 2017-04-17 | 2018-11-02 | 苏州旺山旺水生物医药有限公司 | End Fluconazole micro emulsion composition |
| CN108578356A (en) * | 2018-03-09 | 2018-09-28 | 昆药集团股份有限公司 | A kind of Artemether oral microemulsion in-situ gel and preparation method thereof |
| CN109172517A (en) * | 2018-10-25 | 2019-01-11 | 山东师范大学 | A kind of preparation method of the microemulsion hydrogel as apiolin carrier with pH response |
Non-Patent Citations (5)
| Title |
|---|
| BAROT B S, ET AL.: ""Microemulsion-based gel of terbinafine for the treatment of onychomycosis: optimization of formulation using D-optimal design"", 《AAPS PHARMSCITECH》, vol. 13, no. 2019, pages 184 - 192, XP035014943, DOI: 10.1208/s12249-011-9742-7 * |
| CELEBI N, ERMIŞ S, ÖZKAN S.: ""Development of topical hydrogels of terbinafine hydrochloride and evaluation of their antifungal activity"", 《DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY》, vol. 41, no. 4, pages 631 - 639 * |
| R DABHI M, ET AL.: ""Formulation optimization of topical gel formulation containing micro-emulsion of terbinafine hydrochloride with simplex lattice design"", 《MICRO AND NANOSYSTEMS》, vol. 3, no. 1, pages 1 - 7 * |
| SHRESTHA S, ET AL.: ""Formulation and evaluation of topical microemulgel loaded with terbinafine hcl microemulsion"", 《INT. J. PHARM. SCI. RES》, vol. 26, no. 2017, pages 4716 - 4723 * |
| 赵振宇, 孙浩.: ""微乳凝胶新制剂的研究进展"", 《中国医院药学杂志》, vol. 34, no. 05, pages 411 - 415 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113786382B (en) | 2024-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Singhvi et al. | Xanthan gum in drug delivery applications | |
| JP4294252B2 (en) | G-rich alginate-containing composition | |
| CN113244291A (en) | Methods of diagnosing and treating dry eye syndrome and compositions for treating human eyes | |
| JPS58208214A (en) | Pharmaceutical medicine for acne local treatment | |
| WO2024045973A1 (en) | Use of dehydroepiandrosterone in preparation of medicament for preventing and treating ocular myopia, dosage form thereof, and preparation method therefor | |
| WO2020103832A1 (en) | Method for preparing flexible lipidosome | |
| CN113056257A (en) | Semisolid oil-based pharmaceutical composition containing pirfenidone for tissue repair | |
| EP1476195A2 (en) | Enhancement of the action of central and peripheral nervous system agents | |
| JP3974431B2 (en) | Alginic acid-containing composition | |
| JP2016169188A (en) | Skin external preparation | |
| JP2017222627A (en) | Hair restorer containing shikonin or shikonin derivative as active ingredient and method for producing the same | |
| JP4681132B2 (en) | Nitric oxide synthase production promoter and cosmetic or pharmaceutical composition | |
| CN113786382A (en) | Terbinafine hydrochloride gel and preparation method thereof | |
| TWI226838B (en) | Formula and preparation method of an improved ointment for treating burns and scalds | |
| JP2009102407A (en) | G-rich alginic acid-containing composition | |
| JP2006348055A (en) | Alginic acid-containing composition | |
| US8247390B2 (en) | Modified hydrophilic polymers containing hydrophobic groups | |
| CN114177278A (en) | Liposome preparation | |
| CN101579358A (en) | Ready-to-use traditional Chinese medicine ophthalmic gel | |
| JP2002265671A (en) | Pectin-containing composition | |
| TW202042842A (en) | Topical preparation for the skin or mucosae, method for manufacturing same, and base for topical preparation for the skin or mucosae | |
| JPS63216817A (en) | Gelatinous composition | |
| TWI339125B (en) | Aqueous solution of ascorbic acid and method for producing same | |
| CN1194679C (en) | External Tranilast lipid gel prepn and its prepn process | |
| CN115212200B (en) | Puerarin-containing compound preparation for treating diabetic complications and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |