CN108324687B - 一种特立氟胺微乳、制备方法及应用 - Google Patents
一种特立氟胺微乳、制备方法及应用 Download PDFInfo
- Publication number
- CN108324687B CN108324687B CN201810273403.1A CN201810273403A CN108324687B CN 108324687 B CN108324687 B CN 108324687B CN 201810273403 A CN201810273403 A CN 201810273403A CN 108324687 B CN108324687 B CN 108324687B
- Authority
- CN
- China
- Prior art keywords
- teriflunomide
- microemulsion
- emulsifier
- preparation
- oil phase
- 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.)
- Active
Links
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 title claims abstract description 62
- 229960000331 teriflunomide Drugs 0.000 title claims abstract description 60
- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 32
- 229940079593 drug Drugs 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 10
- 239000008367 deionised water Substances 0.000 claims abstract description 9
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 239000007957 coemulsifier Substances 0.000 claims abstract description 6
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000008347 soybean phospholipid Substances 0.000 claims description 10
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 3
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 3
- 239000005642 Oleic acid Substances 0.000 claims description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 3
- 229940093471 ethyl oleate Drugs 0.000 claims description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 2
- 229940083466 soybean lecithin Drugs 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 9
- 230000002209 hydrophobic effect Effects 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 239000000232 Lipid Bilayer Substances 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract description 2
- 230000035699 permeability Effects 0.000 abstract description 2
- 238000010587 phase diagram Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 210000003491 skin Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 206010067484 Adverse reaction Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 230000006838 adverse reaction Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000037317 transdermal delivery Effects 0.000 description 4
- 102000003390 tumor necrosis factor Human genes 0.000 description 4
- 230000006378 damage Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000001503 joint Anatomy 0.000 description 3
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000003435 antirheumatic agent Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229960000681 leflunomide Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 231100000245 skin permeability Toxicity 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000013271 transdermal drug delivery Methods 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010051728 Bone erosion Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 description 1
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 206010023203 Joint destruction Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229940057415 aubagio Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000004064 cosurfactant Substances 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 230000008407 joint function Effects 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- -1 nipagin methyl ester Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 208000037922 refractory disease Diseases 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 231100000274 skin absorption Toxicity 0.000 description 1
- 230000037384 skin absorption Effects 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
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
- A61K9/10—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
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
- A61K47/24—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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种特立氟胺微乳、制备方法及应用,将乳化剂、助乳化剂混合均匀后加入油相;将特立氟胺溶于去离子水中得到特立氟胺溶液水相;搅拌过程中,逐滴将特立氟胺溶液加入到混合油相中,形成透明的含药微乳;其中,油相、水相、乳化剂、助乳化剂的比例根据伪三元相图进行优选。通过皮肤给药,微乳能增大难溶性药物的溶解性,形成较高的浓度梯度,促进药物的吸收,微乳疏水部分与角质层相互作用,干扰脂质双分子层结构,亲水部分可水化角质层,两者的共同作用可增强药物在角质层的透过性,有利于药物的渗透及吸收。本发明为特立氟胺的临床应用提供了一种新的剂型。
Description
技术领域
本发明涉及一种特立氟胺的新剂型,尤其涉及的是一种特立氟胺微乳、制备方法及应用。
背景技术
类风湿性关节炎(rheumatoid arthritis RA)是一种自身免疫***疾病,以关节和关节周围组织炎症为特征,呈反复发作性,引起骨侵蚀与关节功能障碍,是全球难治性疾病之一,RA的致病机制尚未完全明确。但患者的滑液组织中存在大量的肿瘤坏死因子(TNF-a)和T细胞,是引起关节发炎损伤的重要因素。RA的治疗目标是防止关节破坏和保持关节功能,早期规范化治疗可使绝大多数RA患者病情得到控制,甚至治愈。改善病情抗风湿药(disease-modifying anti-rheu-matic drugs DMARDs)通过抑制炎症因子(TNF-a,IL-1b等)来减缓、阻止关节肿胀和损伤。而来氟米特是一种新型的免疫调节剂,由美国HMR公司研制开发,并于1998年10月在美国首先上市。该药为二氢乳清酸脱氢酶可逆性抑制剂,具有抑制淋巴细胞增殖和抗炎作用,常用于治疗关节炎。但来氟米特水溶性差,一般只能以口服剂的形式给药。而特立氟胺(A771726)具有弱酸性,可以钠盐的形式存在,水溶性较好,有利于制成注射剂、软膏剂等其他制剂,且A771726为来氟米特的活性代谢产物,能阻止T细胞增殖、活化和关节细胞中细胞因子(如TNF-a,IL-1b的产生。美国FDA(Food and DrugAdministration,FDA)于2012年9月12日批准Sanofi-Aventis开发A771726(特立氟胺)口服片剂Aubagio,但因其半衰期长,常引起胃肠道刺激(如恶心、呕吐、腹泻)、肝脏丙氨酸转氨酶水平增加等,有研究结果显示,一年内超过60%的患者因无法耐受而中止服用。该药物己被FDA添加一项有关肝脏毒性风险的黑框警告。
经皮传递***是一种能够延长释药并能够避免首过消除的传递方式。经皮传递***可分为两种,一种是透皮给药***(transdermal drug delivery systems,TDDS)或称透皮治疗***(trandermal therapeutic systems,TTS)是药物通过皮肤吸收的一种方法,药物经由皮肤吸收进入人体血液循环并达到有效血药浓度,实现疾病治疗或预防的一类制剂;另一种是皮肤靶向传递***,这类传递***能够在作用部位定位传递药品、化妆品等,达到局部传递的目的。
微乳(microemulsion,ME)是水、油、表面活性剂和助表面活性剂按适当的比例混合,自发形成的各向同性、透明、热力学稳定的分散体系,粒径在10~100nm之间。微乳在结构上可以分为两类:水包油(O/W)型微乳和油包水(W/O)型微乳。微乳的特点包括它能够自发形成、贮存期长、黏度低、粒径小、具有较强的增溶作用、能够增加药物的生物利用度、生产成本低等。
许多研究表明微乳对于药物的透皮传递具有十分重要的意义,与其他可用于透皮给药的剂型如:脂质体、醇质体和囊泡等相比,微乳更稳定且对一些药物的经皮渗透具有更好的促进作用;此外,微乳用于透皮给药可降低口服给药引起的胃肠道不良反应,减少全身性不良反应发生率,可使一些具有上述不良反应但疗效好的药物在临床上得以广泛应用。
发明内容
本发明所要解决的技术问题在于:为了增加特立氟胺的溶解性和透皮传递性,提供了一种特立氟胺微乳、制备方法及应用。
本发明是通过以下技术方案解决上述技术问题的,本发明的一种特立氟胺微乳的制备方法,包括以下步骤:
(1)将乳化剂、助乳化剂混合均匀后加入油相;
(2)将特立氟胺溶于去离子水中得到特立氟胺溶液水相;
(3)搅拌过程中,逐滴将特立氟胺溶液加入到步骤(1)的混合油相中,形成透明的含药微乳。
作为本发明的优选方式之一,所述油相选自油酸、肉豆蔻酸异丙酯IPM、辛癸酸甘油酯DOD、油酸乙酯中的任一种。
作为本发明的优选方式之一,所述助乳化剂选自异丙醇、丙三醇、聚乙二醇400、无水乙醇中的任一种。
作为本发明的优选方式之一,所述乳化剂选自大豆磷脂、司盘80、吐温80、司盘80中的任一种或两种以上的混合物。
作为本发明的优选方式之一,所述油相、水相、乳化剂、助乳化剂的质量分数g/g分别为:肉豆蔻酸异丙酯IPM42.12%、去离子水15.76%、大豆磷脂21.06%、无水乙醇21.06%。
一种如所述的制备方法制得的特立氟胺微乳,所述特立氟胺微乳的粒径为10~100nm。
所述特立氟胺微乳的制备和存储温度为室温。符合国家药典规定的温度范围。
一种特立氟胺微乳在制备经皮给药制剂中的应用。为特立氟胺微乳的临床应用提供了新剂型。
本发明相比现有技术具有以下优点:本发明进行了离体鼠皮的透皮吸收实验,利用Franz扩散池,通过比较0.1%、0.25%特立氟胺微乳与0.1%特立氟胺普通乳剂、水溶液的单位面积累积渗透量(Qn),观察不同浓度下、不同制剂下特立氟胺的皮肤渗透性。实验结果表明微乳制剂对促进药物的透皮吸收具有积极作用。透皮给药可加快药物的溶出速度,减小药物的体内波动;
本发明将特立氟胺制成微乳,通过皮肤给药制剂中的肉豆蔻酸异丙酯,大豆磷脂等辅料度人体无毒害作用,可在体内降解和吸收,并可提高药物在血液***中的循环时间,缩短药物在血液中达到有效浓度的时间。通过皮肤给药,微乳能增大难溶性药物的溶解性,形成较高的浓度梯度,促进药物的吸收,微乳疏水部分与角质层相互作用,干扰脂质双分子层结构,亲水部分可水化角质层,两者的共同作用可增强药物在角质层的透过性,有利于药物的渗透及吸收。本发明为特立氟胺的临床应用提供了一种新的剂型。
附图说明
图1为手工滴加法制备的含药微乳粒径图;
图2为透射电镜下含药微乳的微观表征;
图3为内标法下特立氟胺标准品和特立氟胺微乳的HPLC图;
图4为促渗透吸收试验中各浓度和剂型下药物渗透累积量图。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
本发明所用主要仪器与材料:
仪器:
LC-20A型高效液相色谱仪(日本岛津);Franz扩散池(自制);NanoZS90型激光纳米粒度仪(英国马尔文公司);电子天平(德国赛多利斯公司);79HW-1型恒温磁力搅拌器(江苏金坛金城国胜实验仪器厂);DDS-11AW型电导率仪(上海般特仪器有限公司);PHS-3C型pH计(上海雷磁仪器厂);超纯水机(美国Millipore公司)。
药品和试剂:
特立氟胺对照品(自制,质量分数为99%);辛癸酸甘油酯(ODO,山东西亚试剂,批号:T0809);大豆磷脂(Lecithin,上海艾韦特有限公司,批号:170103);吐温80(天津光复精细化工研究所,批号:20170301);大豆油、油酸、油酸乙酯、无水乙醇、甲醇由阿拉丁试剂上海有限公司提供;肉豆蔻酸异丙酯(IPM)、司盘80、异丙醇、1,2-丙二醇、聚乙二醇400(PEG400)由国药集团化学试剂有限公司提供;甲醇为色谱纯;水为双蒸水;其余试剂为分析纯。
动物:
雄性SD大鼠,普通级,体重200~250g,取腹部皮肤,由安徽医科大学实验动物中心提供。
实施例1
本实施例包括以下组分:
特立氟胺:5mg,肉豆蔻酸异丙酯:2.106g,大豆磷脂:1.053g,无水乙醇:1.053g,去离子水:0.783g。
制备过程如下:
精密称取IPM、大豆磷脂、无水乙醇。先将大豆磷脂与无水乙醇混合溶解,再加入IPM充分混合。将特立氟胺对照品加入去离子水中,超声溶解,在磁力搅拌器搅拌下将特立氟胺水溶液缓慢滴入上述液体中,搅拌30min,即得透明的质量比0.1%特立氟胺微乳样品。对特立氟胺微乳粒径分布采用动态光散射法进行检测,如图1所示,微乳粒径范围在10~100nm,粒径大小均匀,外观澄澈,如图2(a)所示。
实施例2
本实施例包括以下组分:
特立氟胺:12.5mg,肉豆蔻酸异丙酯:2.106g,大豆磷脂:1.053g,无水乙醇:1.053g,去离子水:0.783g。
制备过程如下:
精密称取IPM、大豆磷脂、无水乙醇。先将大豆磷脂与无水乙醇混合溶解,再加入IPM充分混合。将特立氟胺对照品加入去离子水中,超声溶解,在磁力搅拌器搅拌下将特立氟胺水溶液缓慢滴入上述液体中,搅拌30min,即得透明的0.25%特立氟胺微乳样品。对特立氟胺微乳粒径分布采用动态光散射法进行检测,微乳粒径范围在10~100nm,粒径大小均匀,外观澄澈,结果如图2(b)所示。
特立氟胺微乳的电镜形态观察:
常温下取适量稀释5倍的特立氟胺ME滴在铜网上(覆有支持膜),静置15min,待自然晾干后用1%磷钨酸溶液负染10min,自然挥干,透射电镜下观察。拍摄照片如图2,在电镜下ME乳滴为表面完整的圆球形,大小分布均匀,且符合微乳的粒径要求。
本发明的特立氟胺含量测定方法:
色谱条件
色谱柱:ODS-C18色谱柱(250mm×4.6mm,5μm),流动相:0.01mol/L磷酸盐缓冲液(PH=7.4)∶甲醇=43.8∶56.2;流速1.00mL·min-1;柱温40℃;检测波长294.0nm;进样量:20μL;内标:尼泊金甲酯(10.0μg·mL-1),结果如图3所示。
标准曲线的制备和方法学研究:
标准溶液的制备:精密称取特立氟胺对照品25mg,用适量甲醇溶解,置25mL容量瓶中,加甲醇定容摇匀,精密量取5ml置25mL容量瓶中,加甲醇定容,即得100μg·mL-1的特立氟胺对照品储备液,置4℃冰箱保存。精密量取特立氟胺对照品储备液,依次用甲醇稀释,得100.00、50.00、25.00、12.50、6.25、3.125μg·mL-1的系列标准液,依次进样20μL,以药物峰面积(A)对药物浓度(C,μg·mL-1)进行线性回归,得回归方程:A=8.2639C+4.2487(R2=0.9996),结果显示特立氟胺在3.125~100μg·mL-1范围内线性良好。精密度、重复性、稳定性试验RSD均小于3%,符合方法学要求。
体外经皮渗透研究:
(1)离体鼠皮的制备:
取大鼠,断颈后刮净背部毛发,剥离背部皮肤(避免损伤),小心去除黏连物和皮下脂肪,用0.9%氯化钠溶液冲洗干净,置0.9%氯化钠溶液中4℃保存,7天内用完。
(2)体外透皮实验:
采用自制Franz扩散池,将离体皮肤固定在供给池和接收池间,表皮层面向供给池,真皮层紧贴接收液,接收液为0.01mol/L磷酸盐缓冲液(PH7.4)17.8ml,扩散池的有效接收面积为2.58cm2。供给池中分别加入0.1%、0.25%特立氟胺微乳和0.1%特立氟胺普通乳剂、水溶液1ml,装置置于恒温水浴中(30±1℃),300r/min搅拌,于0.5,1,2,4,6,8,12,24h分别取样2ml,同时加入等温等体积上述磷酸盐缓冲液。样品经微孔滤膜(0.45μm)过滤,20μL进样,使用HPLC测定并计算特立氟胺单位面积的累积渗透量(Qn,μg/cm2)。
公式中cn为第n个取样点的渗透浓度,V0为接收池的容积,ci为第i个取样点的药物浓度,V为每次取样量,S为有效接收容积。结果如图4所示。
综上所述,本发明通过改变特立氟胺给药途径,制备了特立氟胺微乳,此微乳作为一种新的剂型,具备一定的载药量,可显著增加皮肤渗透率,避开肝脏及胃肠道吸收,减少达到有效血药浓度时间,从而降低肝毒性,减少胃肠道不良反应,还可提供局部治疗,对需要长期给药人群带来很大的方便,是一种新型的局部外用新剂型。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种特立氟胺微乳的制备方法,其特征在于,包括以下步骤:
(1)将乳化剂、助乳化剂混合均匀后加入油相;
(2)将特立氟胺溶于去离子水中得到特立氟胺溶液水相;
(3)搅拌过程中,逐滴将特立氟胺溶液加入到步骤(1)的混合油相中,形成透明的含药微乳;
所述油相、水相、乳化剂、助乳化剂的质量分数g/g分别为:肉豆蔻酸异丙酯IPM42.12%、去离子水15.76%、大豆磷脂21.06%、无水乙醇21.06%;
制得的特立氟胺微乳的粒径为10~100nm。
2.根据权利要求1所述的一种特立氟胺微乳的制备方法,其特征在于,所述油相选自油酸、肉豆蔻酸异丙酯IPM、辛癸酸甘油酯DOD、油酸乙酯中的任一种。
3.根据权利要求1所述的一种特立氟胺微乳的制备方法,其特征在于,所述助乳化剂选自异丙醇、丙三醇、聚乙二醇400、无水乙醇中的任一种。
4.根据权利要求1所述的一种特立氟胺微乳的制备方法,其特征在于,所述乳化剂选自大豆磷脂、司盘80、吐温80中的任一种或两种以上的混合物。
5.根据权利要求1所述的一种特立氟胺微乳的制备方法,其特征在于,所述特立氟胺微乳的制备和存储温度为室温。
6.如权利要求1所述的方法制得的特立氟胺微乳在制备经皮给药制剂中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810273403.1A CN108324687B (zh) | 2018-03-29 | 2018-03-29 | 一种特立氟胺微乳、制备方法及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810273403.1A CN108324687B (zh) | 2018-03-29 | 2018-03-29 | 一种特立氟胺微乳、制备方法及应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108324687A CN108324687A (zh) | 2018-07-27 |
CN108324687B true CN108324687B (zh) | 2020-04-07 |
Family
ID=62931669
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810273403.1A Active CN108324687B (zh) | 2018-03-29 | 2018-03-29 | 一种特立氟胺微乳、制备方法及应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108324687B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020095319A1 (en) * | 2018-11-05 | 2020-05-14 | Sarudbhava Formulations Private Limited | Teriflunomide topical pharmaceutical compositions |
KR20220118210A (ko) | 2021-02-18 | 2022-08-25 | (주)아모레퍼시픽 | 트랜스퍼좀을 포함하는 난용성 효능물질 전달체 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100998592B (zh) * | 2007-01-04 | 2010-05-19 | 中国人民解放军第二军医大学 | 苦参碱微乳 |
CN101675918A (zh) * | 2008-09-18 | 2010-03-24 | 上海药明康德新药开发有限公司 | 一种自乳化微乳组合物及其制备方法和用途 |
DE102009008094A1 (de) * | 2009-02-09 | 2010-08-19 | Barnikol-Keuten, Doris, Dr. | In situ Haft-Gelbildende Zubereitungen, insbesondere zur topischen Anwendung auf befeuchtete Haut/Schleimhaut |
CN101564415A (zh) * | 2009-03-12 | 2009-10-28 | 江西中医学院 | 一种高经皮渗透性中药微乳制剂及其制备方法 |
CN103520137B (zh) * | 2012-07-03 | 2016-02-03 | 沈阳药科大学 | 治疗类风湿性关节炎的复方特立氟胺透皮贴剂及制备方法 |
CN103656657A (zh) * | 2013-12-18 | 2014-03-26 | 北京科源创欣科技有限公司 | 特立氟胺药物组合物及制备方法 |
CN104069065B (zh) * | 2014-04-30 | 2017-01-11 | 中国人民解放军第四军医大学 | 一种注射用桂皮醛亚微乳剂的制备方法及其应用 |
CN104856954B (zh) * | 2015-05-29 | 2017-11-28 | 四川九章生物科技有限公司 | 一种绿原酸微乳及其制备工艺和应用 |
-
2018
- 2018-03-29 CN CN201810273403.1A patent/CN108324687B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN108324687A (zh) | 2018-07-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kreilgaard | Influence of microemulsions on cutaneous drug delivery | |
ES2300820T3 (es) | Composicion farmaceutica transdermica. | |
Lala et al. | Nanoemulsion-based gel formulations of COX-2 inhibitors for enhanced efficacy in inflammatory conditions | |
Liu et al. | Preparation of a ligustrazine ethosome patch and its evaluation in vitro and in vivo | |
KR20000070137A (ko) | 트랜스더멀 치료 시스템 | |
CN107397718A (zh) | 基于半氟化烷烃类的外用药物组合物 | |
JP2020514342A (ja) | 活性化合物のための局所送達系 | |
CN108324687B (zh) | 一种特立氟胺微乳、制备方法及应用 | |
WO2020103832A1 (zh) | 一种制备柔性脂质体的方法 | |
CN103690483A (zh) | 白花前胡甲素微乳及其制备方法 | |
Fan et al. | Correlation between in vivo microdialysis pharmacokinetics and ex vivo permeation for sinomenine hydrochloride transfersomes with enhanced skin absorption | |
CN104958257B (zh) | 一种隐丹参酮皮肤角质类脂体制剂及其制备方法 | |
CN101601652A (zh) | 糠酸莫米松脂质体乳膏 | |
CN108743534B (zh) | 一种雷公藤红素或雷公藤红素衍生物囊泡及其制备方法 | |
CN108969396A (zh) | 一种含nmn的凝胶护肤品及其制备方法 | |
Chandira et al. | Design, optimization and evaluation of microemulgel containing antifungal drugs | |
WO2020089942A2 (en) | A liquid injectable composition | |
CN104382850B (zh) | 一种罗替戈汀微乳及微乳凝胶 | |
CN108938456A (zh) | 一种组合物及其制备方法及应用 | |
CN105476957B (zh) | 一种阿可拉定注射剂及其制备方法和用途 | |
Nimase et al. | A Recent Review on Film Forming Topical Formulation | |
CN113785975B (zh) | 精胺、亚精胺脂质体在抗氧化、抗衰老中的应用 | |
Nishigandha et al. | An Overview on Microemulsion as a Topical Drug Delivry System | |
Suriyaamporn et al. | Computer-aided design and optimization of estradiol valerate nanoemulsion-loaded core-shell microneedle patches for controlled release transdermal drug delivery | |
CN101601653A (zh) | 泼尼卡酯脂质体乳膏 |
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 |