CN109364023A - A kind of Aprepitant intravenous injection emulsion and its preparation method and application - Google Patents
A kind of Aprepitant intravenous injection emulsion and its preparation method and application Download PDFInfo
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- CN109364023A CN109364023A CN201811588409.4A CN201811588409A CN109364023A CN 109364023 A CN109364023 A CN 109364023A CN 201811588409 A CN201811588409 A CN 201811588409A CN 109364023 A CN109364023 A CN 109364023A
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- China
- Prior art keywords
- aprepitant
- emulsion
- intravenous injection
- injection
- oil
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- 239000000839 emulsion Substances 0.000 title claims abstract description 99
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 title claims abstract description 98
- 229960001372 aprepitant Drugs 0.000 title claims abstract description 98
- 238000010253 intravenous injection Methods 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 22
- 239000008215 water for injection Substances 0.000 claims abstract description 21
- 238000002347 injection Methods 0.000 claims abstract description 18
- 239000007924 injection Substances 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 206010047700 Vomiting Diseases 0.000 claims abstract description 12
- 239000003381 stabilizer Substances 0.000 claims abstract description 12
- 238000002512 chemotherapy Methods 0.000 claims abstract description 11
- -1 ethyl alcohol Chemical compound 0.000 claims abstract description 11
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 239000003921 oil Substances 0.000 claims description 35
- 235000019198 oils Nutrition 0.000 claims description 35
- 235000021277 colostrum Nutrition 0.000 claims description 27
- 210000003022 colostrum Anatomy 0.000 claims description 27
- 239000006071 cream Substances 0.000 claims description 25
- 230000001954 sterilising effect Effects 0.000 claims description 24
- 235000011187 glycerol Nutrition 0.000 claims description 17
- 239000003549 soybean oil Substances 0.000 claims description 17
- 235000012424 soybean oil Nutrition 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 239000008236 heating water Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 239000004006 olive oil Substances 0.000 claims description 11
- 235000008390 olive oil Nutrition 0.000 claims description 11
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical group CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 10
- 230000003078 antioxidant effect Effects 0.000 claims description 10
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 9
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 9
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000005642 Oleic acid Substances 0.000 claims description 9
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 9
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 9
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 9
- 238000004659 sterilization and disinfection Methods 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 8
- 238000007789 sealing Methods 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 230000008673 vomiting Effects 0.000 claims description 3
- 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 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims 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 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000010495 camellia oil Substances 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- NXMUXTAGFPJGTQ-UHFFFAOYSA-N decanoic acid;octanoic acid Chemical compound CCCCCCCC(O)=O.CCCCCCCCCC(O)=O NXMUXTAGFPJGTQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021323 fish oil Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940079827 sodium hydrogen sulfite Drugs 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 229940083466 soybean lecithin Drugs 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 229930003799 tocopherol Natural products 0.000 claims description 2
- 229960001295 tocopherol Drugs 0.000 claims description 2
- 235000010384 tocopherol Nutrition 0.000 claims description 2
- 239000011732 tocopherol Substances 0.000 claims description 2
- 229940093609 tricaprylin Drugs 0.000 claims description 2
- 150000005691 triesters Chemical class 0.000 claims description 2
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims 2
- 239000000194 fatty acid Substances 0.000 claims 2
- 229930195729 fatty acid Natural products 0.000 claims 2
- 206010028813 Nausea Diseases 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 210000000232 gallbladder Anatomy 0.000 claims 1
- 230000008595 infiltration Effects 0.000 claims 1
- 238000001764 infiltration Methods 0.000 claims 1
- 230000008693 nausea Effects 0.000 claims 1
- 125000001095 phosphatidyl group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 26
- 235000019441 ethanol Nutrition 0.000 abstract description 14
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001154 acute effect Effects 0.000 abstract description 3
- 230000003111 delayed effect Effects 0.000 abstract description 3
- 206010070834 Sensitisation Diseases 0.000 abstract description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 2
- 229960004316 cisplatin Drugs 0.000 abstract description 2
- 230000008313 sensitization Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 description 16
- 235000021313 oleic acid Nutrition 0.000 description 8
- 229960002969 oleic acid Drugs 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 238000000265 homogenisation Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 5
- 229930003427 Vitamin E Natural products 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 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 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 4
- 235000019165 vitamin E Nutrition 0.000 description 4
- 239000011709 vitamin E Substances 0.000 description 4
- 229940046009 vitamin E Drugs 0.000 description 4
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 3
- 102100037346 Substance-P receptor Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000003474 anti-emetic effect Effects 0.000 description 3
- 239000002111 antiemetic agent Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000012360 testing method 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
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 102000002188 Neurokinin NK1 receptors Human genes 0.000 description 1
- 108050009554 Neurokinin NK1 receptors Proteins 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 229940108890 emend Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K47/24—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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to a kind of Aprepitant intravenous injection emulsions and its preparation method and application, belong to pharmacy technical field.Aprepitant intravenous injection emulsion of the invention includes the component of following mass percent: Aprepitant 0.05~3%, oil phase solvent 5~30%, emulsifier 1.2~18%, stabilizer 0.03~0.6%, isotonic regulator 1~5%, the emulsion for injection also includes pH adjusting agent, surplus is water for injection, and the pH value of the emulsion for injection is 5.5~8.0.Aprepitant intravenous injection emulsion of the invention is adjusted without containing low carbon chains alcohol such as ethyl alcohol, while by process innovation, can be reached the quality requirement as commercialized product, be substantially increased the clinical use safety of Aprepitant intravenous injection emulsion；It is directly injected intravenously when clinical use, does not need to be diluted；Acute and delayed nausea and vomiting caused by the cisplatin combined high dose sensitization cancer chemotherapy of high dose can be used to treat, reduce the nausea and vomiting of chemotherapy of tumors early period and mid-term.
Description
Technical field
The present invention relates to a kind of Aprepitant intravenous injection emulsions and its preparation method and application, belong to pharmacy technology neck
Domain.
Background technique
World Health Organization 2017 is newest announce statistics indicate that, the whole world has 8,800,000 people to die of cancer every year, and it is dead every year to account for the whole world
Die nearly 1/6th of total number of persons.There are ten thousand new cancer cases more than 1400 every year, it is contemplated that this number will be added to the year two thousand thirty
More than 21000 ten thousand.
Currently, chemotherapy is considered as one of main mode for the treatment of of cancer.But chemotherapy is referred to, allow the discoloration of people's news
It is its strong nausea and vomiting side effect (Chemotherapy Induced Nausea and Vomiting, CINV).
According to investigations, about 75% chemotherapeutics will lead to symptom as Nausea and vomiting, and about 70%~80% patients undergoing chemotherapy has
The experience of nausea and vomiting, distress level not only allow patient to endure the pain on body to the fullest extent, therefore many people also hope successive treatment
And step back.Therefore, vomiting, which has become, one of needs to consider the problems of emphatically in cancer treatment procedure.
With deepening continuously for the nausea and vomiting Mechanism Study caused to chemotherapy, market has developed a plurality of types of antiemetics
Drug.Currently, the antiemetic of clinical application have dopamine-receptor antagonist, cortical steroid, 5-HT3 receptor antagonist,
The other drugs such as neurokinin nk 1 receptor antagonist, the antiemetic Olanzapine of multiple target point and cannabis.By more than 30 years
Clinical practice, there are about 70% CINV to be effectively controlled, and especially nk 1 receptor antagonistic is in clinical application, so that acute
The control rate of CINV improves 20%, and the control rate of Delayed onset CINV improves 30%.Nevertheless, in the process for the treatment of CINV
In there are still some problems, although nk 1 receptor antagonistic curative effect is prominent, there is also adverse reactions expensive, at a specified future date still not
The problems such as understanding.
Aprepitant is the first high selectivity nk 1 receptor antagonist in the whole world, and oral preparation (Emend) is by the U.S.
Mo Shadong drugmaker developed granted listing, a countries and regions of product more than covering the whole world 90 in 2003.The said firm was in last year
Aprepitant intravenous injection emulsion is developed, it is clinically complementary using formation with Aprepitant capsule preparations.Original is ground at product
Solubilizer of a large amount of phosphatide as emulsifier and ethyl alcohol as phosphatide has been used in side.Clinical vein injects ethyl alcohol may
It will lead to injection site pain, the adverse reactions such as neuritis.Therefore, inventor passes through to emulsifier in prescription and stabilizer progress
Optimization, to avoid the use of ethyl alcohol, improves the safety of clinical use.Meanwhile it is clinically to need dilute production matched that original, which grinds product,
Product, the present invention are the intravenous injection emulsions that a specification is 1000mL, and clinic can directly be transfused patient, not need dilute
Match, substantially increases the portability clinically used.
Summary of the invention
A kind of Aprepitant intravenous injection is provided it is an object of the invention to overcome above-mentioned the deficiencies in the prior art place
Emulsion and its preparation method and application, intravenous injection emulsion of the invention greatly improve A Rui without containing low carbon chains alcohol such as ethyl alcohol
The clinical use safety of smooth intravenous injection emulsion.
To achieve the above object, the technical scheme adopted by the invention is as follows: a kind of Aprepitant intravenous injection emulsion, the note
Penetrate emulsion include following mass percent component: Aprepitant 0.05~3%, oil phase solvent 5~30%, emulsifier 1.2~
18%, stabilizer 0.03~0.6%, isotonic regulator 1~5%, the emulsion for injection also include pH adjusting agent, and surplus is injection
With water, the pH value of the emulsion for injection is 5.5~8.0.
Aprepitant intravenous injection emulsion of the invention, when clinical use, can directly be injected intravenously, and not need to be diluted.
Aprepitant intravenous injection emulsion appearance of the invention is translucent or milky, and mobility is good, no wall built-up phenomenon, before sterilizing
Rear stability is good；Particle size range is 50~300nm, and latex pH is that 5.5~8.0, ZETA current potential absolute value is 25~40mV.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the emulsion for injection includes as follows
The component of mass percent: Aprepitant 0.13~1.3%, oil phase solvent 10~20%, emulsifier 1.2~12%, stabilizer
0.03~0.3%, isotonic regulator 2~3%.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the emulsion for injection also includes
0.02~0.5% antioxidant.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the quality hundred of the antioxidant
Divide than being 0.02~0.2%.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, Aprepitant intravenous injection emulsion
Composition in every 1000mL are as follows: 0.5~30g of Aprepitant, oil phase solvent 50g~300g, 12~180g of emulsifier, stabilization
0.3~6g of agent, 0.2~5g of antioxidant, isotonic regulator 10g~50g, appropriate pH adjusting agent, water for injection are settled to
1000mL。
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, Aprepitant intravenous injection emulsion
Composition in every 1000mL are as follows: Aprepitant 1.3g~13g, oil phase solvent 100g~200g, 12~120g of emulsifier, steady
Determine 0.3~3g of agent, 0.2~2g of antioxidant, 20~30g of isotonic regulator, appropriate pH adjusting agent, water for injection to be settled to
1000mL。
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the emulsion droplet grain of the emulsion for injection
Diameter is 50~300nm.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the oil phase solvent is long-chain rouge
At least one of fat acid glycerol three ester, MCT Oil.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the long-chain fat acid glycerol three
Ester is at least one of soybean oil, olive oil, tea-seed oil, fish oil, castor oil, rilanit special；The medium chain fatty acid is sweet
Oily three esters are at least one of tricaprylin, decanoin, Glycerin, mixed triester with caprylic acid capric acid, laurin.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the emulsifier is yolk lecithin
Rouge, egg PC, soybean lecithin, phosphatidyl glycerol, synthesis single fat sour component phosphatidyl choline in extremely
Few one kind；The stabilizer is at least one of oleic acid, enuatrol, poloxamer, polyoxyethylene sorbitan monoleate.Using stabilizer, make
The ZETA current potential absolute value of emulsion maintains 25~40mV.
As the preferred embodiment of Aprepitant intravenous injection emulsion of the present invention, the isotonic regulator is sweet
At least one of oil, mannitol, glucose, sodium chloride；The pH adjusting agent is hydrochloric acid or sodium hydroxide；The antioxidant
For at least one of tocopherol, sodium hydrogensulfite, sodium pyrosulfite, sodium thiosulfate.
Second aspect, the present invention provides the preparation methods of above-mentioned Aprepitant intravenous injection emulsion, comprising the following steps:
(1) oil phase solvent, emulsifier, antioxidant, heating water bath are weighed, to be emulsified dose of all dissolution is added A Rui
Smooth stirring and dissolving, as oily phase；
(2) stabilizer, isotonic regulator, pH adjusting agent are weighed, is added in water for injection, heating water bath, as water phase；
(3) oil is mutually slowly added in water phase, under stiring high speed shear, remaining water for injection is added, colostrum is made；
(4) the resulting colostrum of step (3) is subjected to microjet homogeneous, obtains whole cream；
(5) by step (4) it is resulting eventually cream carry out filling, nitrogen charging, sealing, be placed in rotation autoclave in sterilize to get Ah
Auspicious smooth intravenous injection emulsion.
In preparation method of the invention, the addition of emulsifier can be heating for dissolving in oily phase, can also be and is dispersed with stirring
It in water phase, or is partly dissolved in oil phase solvent, is partially dispersed in water phase；Oil phase and water phase in colostrum preparation process
Temperature will be consistent as far as possible.
In preparation method of the invention, colostrum uniform particle diameter is turned to using high-pressure homogeneous or micro jetting technology, to load medicine
Colostrum carries out uniform particle diameter processing.Carry out high-pressure homogeneous or microjet homogenizing process in, first using lesser pressure into
Row processing, then sample treatment is carried out using higher pressure, avoid the viscosity of sample from causing particle diameter distribution unequal greatly very much.Cream eventually
Disinfecting action is using high pressure sterilization filtration sterilization.
The preferred embodiment of preparation method as Aprepitant intravenous injection emulsion of the present invention, following (a)~
At least one of in (e):
(a) in the step (1), heating temperature is 50~80 DEG C；
(b) in the step (2), the volume of water for injection is the 60~80% of emulsion for injection total volume, and heating temperature is
50~80 DEG C；
(c) in the step (3), speed of agitator is 5000~20000rpm, and shear time is 5~25min；
(d) in the step (4), homogenizing temperature is 30~50 DEG C, and homogeneous recycles 4~10 at 8000~35000Psi
It is secondary；
(e) in the step (5), sterilising temp is 121 DEG C, sterilization time 15min.
The preferred embodiment of preparation method as Aprepitant intravenous injection emulsion of the present invention, the step
(3) in, speed of agitator is 8000~18000rpm, and shear time is 5~15min；In the step (4), homogenization pressure is
10000~25000Psi, cycle-index are 6~10 times.
The third aspect, the present invention provides the preparations of above-mentioned Aprepitant intravenous injection emulsion to dislike caused by chemotherapy treating
Application in the heart and the drug of vomiting.
Inventor has found that original is ground in prescription in the course of the research, and the dosage of ethyl alcohol is for Aprepitant intravenous injection emulsion
Last physical stability does not directly affect, and effect of the ethyl alcohol in the prescription only is used to increase the dissolubility of phosphatide.Therefore,
The present invention is by avoiding the addition of ethyl alcohol in prescription to improve the safety of emulsion for injection.Original is ground phosphatide dosage in prescription and is up to
14.44% or so, it is difficult to be directly dissolved in 9.44% oil-phase solution, it is therefore desirable to which the ethyl alcohol for being added 2.78% carrys out hydrotropy.
Result of study shows that phosphatide can be dissolved completely in oil phase solvent when ethanol consumption is 0.5% or so；Lower than 0.5%, phosphorus
Rouge cannot be completely dissolved, and drug has and can dissolve on a small quantity, but before this sterilizing for prepared Aprepitant intravenous injection cream
Rear stability does not significantly affect directly, and concrete outcome is as shown in table 1.
Table 1
Compared with prior art, the invention has the benefit that Aprepitant intravenous injection emulsion of the invention does not contain
The low carbon chains alcohol such as ethyl alcohol, while being adjusted by process innovation, the quality requirement as commercialized product can be reached, mentioned significantly
The high clinical use safety of Aprepitant intravenous injection emulsion；It is directly injected intravenously when clinical use, does not need to carry out dilute
It releases；Acute and delayed nausea and vomiting caused by the cisplatin combined high dose sensitization cancer chemotherapy of high dose can be used to treat, subtracted
The nausea and vomiting of few chemotherapy of tumors early period and mid-term.
Specific embodiment
Purposes, technical schemes and advantages in order to better illustrate the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
Embodiment 1
In the Aprepitant intravenous injection emulsion of the present embodiment, contain in every 1000mL emulsion: Aprepitant 1.3g, purification
Soybean oil 100.0g refines egg yolk lecithin 12g, and oleic acid 2.5g, 0.1N NaOH are appropriate, and glycerol 25g, water for injection is settled to
1000mL.Wherein, refined soybean oil is 10% as oily phase proportion.
The present embodiment Aprepitant intravenous injection emulsion the preparation method comprises the following steps:
(1) recipe quantity refined soybean oil, purification egg yolk lecithin and oleic acid are weighed, stirring dissolves emulsifier, at addition
The Aprepitant just measured, it is mutually stand-by that heating water bath to 70 DEG C of conducts carries medicine oil；
(2) it weighs recipe quantity glycerol to be added in 800mL water for injection, heating water bath is to 70 DEG C as water phase；
(3) oil is mutually slowly added into water phase, maintains temperature at 70 DEG C, the high speed shear 10min under 8000rpm, note
It penetrates and is settled to 1000mL with water and obtains colostrum, adjust colostrum pH to 7.5 with 0.1N NaOH；
(4) colostrum being prepared progress is high-pressure homogeneous, under the homogenization pressure of 800bar, recycle 6 times, homogenizing temperature
It is 30 DEG C；
(5) after high-pressure homogeneous cream eventually, filling, nitrogen charging gas shielded will be carried out by cream eventually, sealing is placed in rotation autoclave
High pressure sterilization 15min obtains finished product at 121 DEG C.
After high-pressure homogeneous, appearance is creamy white Aprepitant intravenous injection emulsion manufactured in the present embodiment, flowing
Property is good, does not have wall built-up phenomenon, and with apparent blue-opalescent.It is 0.027 that it, which is centrifuged stability constant, after measured, average grain diameter
For 142.22 ± 31.22nm, zeta potential absolute value is 30.22mV.Aprepitant intravenous injection emulsion manufactured in the present embodiment, goes out
Bacterium fore-and-aft stability is good, and placing 3 months its partial sizes is 149.54 ± 28.61nm, illustrates Aprepitant manufactured in the present embodiment
Intravenous injection emulsion has good stability.
Embodiment 2
In the Aprepitant intravenous injection emulsion of the present embodiment, contain in every 1000mL emulsion: Aprepitant 13g, purification
Olive oil 150g refines egg yolk lecithin 50g, and oleic acid 2.5g, 0.1N NaOH are appropriate, and glycerol 25g, water for injection is settled to
1000mL.Wherein, purification olive oil is 15% as oily phase proportion.
The present embodiment Aprepitant intravenous injection emulsion the preparation method comprises the following steps:
(1) recipe quantity purification olive oil, purification egg yolk lecithin and oleic acid are weighed, stirring dissolves emulsifier, at addition
Side's amount Aprepitant, heating water bath is to 75 DEG C as load medicine oil phase；
(2) it weighs recipe quantity glycerol to be added in 700mL water for injection, heating water bath is to 75 DEG C as water phase；
(3) oil is mutually slowly added into water phase, maintains temperature at 75 DEG C, the high speed shear 5min under 15000rpm, note
It penetrates and is settled to 1000mL with water and obtains colostrum, adjust colostrum pH to 7.5 with 0.1N NaOH；
(4) colostrum being prepared progress is high-pressure homogeneous, under the homogenization pressure of 8000psi, recycle 6 times, homogeneous temperature
Degree is 40 DEG C；
(5) after high-pressure homogeneous cream eventually, filling, nitrogen charging gas shielded will be carried out by cream eventually, sealing is placed in rotation autoclave
High pressure sterilization 15min obtains finished product at 121 DEG C.
Aprepitant intravenous injection emulsion manufactured in the present embodiment is after high-pressure homogeneous, and appearance is in shallow white, flowing
Property it is good, there is no a wall built-up phenomenon, and with apparent blue-opalescent, the fore-and-aft stability that sterilizes is good.After measured, sterilize front and back
Aprepitant intravenous injection emulsion average grain diameter is respectively 112.35 ± 24.36nm and 116.82 ± 17.68nm, illustrates this reality
Apply having good stability for an Aprepitant intravenous injection cream sterilizing front and back.
Embodiment 3
In the Aprepitant intravenous injection emulsion of the present embodiment, contain in every 1000mL emulsion: Aprepitant 20g, purification
Soybean oil 100g refines olive oil 100g, and egg PC 100g, enuatrol 5g, 0.1N NaOH are appropriate, glycerol 25g,
Water for injection is settled to 1000mL.Wherein, it is 20% that refined soybean oil and purification olive oil, which are used as oily phase proportion,.
The present embodiment Aprepitant intravenous injection emulsion the preparation method comprises the following steps:
(1) recipe quantity purification olive oil, refined soybean oil, egg PC are weighed, stirring is dissolved emulsifier, added
Enter the Aprepitant of recipe quantity, heating water bath is to 75 DEG C as load medicine oil phase；
(2) recipe quantity glycerol, enuatrol are weighed, is added in 800mL water for injection, heating water bath is to 75 DEG C as water phase；
(3) oil is mutually slowly added into water phase, maintains temperature at 75 DEG C, the high speed shear 15min under 18000rpm is obtained
To colostrum, colostrum pH to 7.5 is adjusted with 0.1N NaOH；
(4) colostrum being prepared progress is high-pressure homogeneous, under the homogenization pressure of 15000psi, recycle 6 times, homogeneous temperature
Degree is 40 DEG C；
(5) after high-pressure homogeneous cream eventually, filling, nitrogen charging gas shielded will be carried out by cream eventually, sealing is placed in rotation autoclave
High pressure sterilization 15min obtains finished product at 121 DEG C.
Aprepitant intravenous injection cream manufactured in the present embodiment is after high-pressure homogeneous, and appearance is translucent, mobility
Well, there is no wall built-up phenomenon, and with apparent blue-opalescent.After measured, the Aprepitant intravenous injection emulsion before and after sterilizing
Average grain diameter is 85.34 ± 12.43nm and 90.22 ± 16.28nm, before illustrating the intravenous injection cream sterilizing of the present embodiment Aprepitant
Having good stability afterwards.
Embodiment 4
In the Aprepitant intravenous injection emulsion of the present embodiment, contain in every 1000mL emulsion: Aprepitant 20g, middle chain
Triglycerides 150g, refined soybean oil 150g refine egg yolk lecithin 180g, and enuatrol 2.0g, 0.1N NaOH are appropriate, glycerol
25g, vitamin E 5g, water for injection are settled to 1000mL.Wherein, medium chain triglyceride and refined soybean oil are as shared by oily phase
Ratio is 30%.
The present embodiment Aprepitant intravenous injection emulsion the preparation method comprises the following steps:
(1) recipe quantity medium chain triglyceride, refined soybean oil, purification egg yolk lecithin, oleic acid and vitamin E are weighed, is stirred
Dissolution is mixed, the dissolution of Aprepitant bulk pharmaceutical chemicals is added, heating water bath is to 75 DEG C as load medicine oil phase；
(2) it weighs recipe quantity glycerol to be added in 800mL water for injection, heating water bath is to 75 DEG C as water phase；
(3) oil is mutually slowly added into water phase, maintains temperature at 75 DEG C, the high speed shear 10min under 15000rpm is obtained
To colostrum, colostrum pH to 7.5 is adjusted with 0.1N NaOH；
(4) colostrum being prepared is subjected to microjet homogeneous, under the homogenization pressure of 15000psi, recycled 6 times, homogeneous
Temperature is 30 DEG C；
(5) after high-pressure homogeneous cream eventually, filling, nitrogen charging gas shielded will be carried out by cream eventually, sealing is placed in rotation autoclave
High pressure sterilization 15min obtains finished product at 121 DEG C.
After microjet homogeneous, appearance is translucent Aprepitant intravenous injection emulsion manufactured in the present embodiment, stream
Dynamic property is good, does not have wall built-up phenomenon, and with apparent blue-opalescent.After measured, the Aprepitant after sterilizing is injected intravenously cream
The average grain diameter of agent sterilizing front and back is 101.26 ± 26.81nm and 106.37 ± 30.48nm, and the front and back that sterilizes has good stability.
Embodiment 5
In the Aprepitant intravenous injection emulsion of the present embodiment, contain in every 1000mL emulsion: Aprepitant 1.3g, purification
Soybean oil 100g refines olive oil 100g, median chain triglyceride oil 100g, egg PC 150g, enuatrol 5g, 0.1N
Appropriate NaOH, glycerol 25g, water for injection are settled to 1000mL.Wherein, refined soybean oil, purification olive oil, three acid of medium chain triglyceride
Ester is 30% as oily phase proportion.
The present embodiment Aprepitant intravenous injection emulsion the preparation method comprises the following steps:
(1) recipe quantity refined soybean oil, purification olive oil, median chain triglyceride oil, egg PC, stirring are weighed
Recipe quantity Aprepitant is added in dissolution, and heating water bath is to 75 DEG C as load medicine oil phase；
(2) recipe quantity glycerol, enuatrol are weighed, surplus egg PC is added in 800mL water for injection, water-bath
70 DEG C are heated to as water phase；
(3) oil is mutually slowly added into water phase, maintains temperature at 70 DEG C, the high speed shear 10min under 20000rpm is obtained
To colostrum, colostrum pH to 7.5 is adjusted with 0.1N NaOH；
(4) colostrum being prepared is subjected to microjet homogeneous, under the homogenization pressure of 25000psi, recycled 6 times, homogeneous
Temperature is 50 DEG C；
(5) after high-pressure homogeneous cream eventually, cream passes through 0.22 μm of membrane filtration degerming, nitrogen charging gas shielded, the finished product of sealing eventually.
Aprepitant intravenous injection emulsion manufactured in the present embodiment its translucent appearance, mobility after microjet homogeneous
Well, there is no wall built-up phenomenon, and with apparent blue-opalescent.After measured, front and back Aprepitant intravenous injection emulsion after sterilizing
Average grain diameter be 82.41 ± 27.18nm and 90.11 ± 20.66nm, illustrate the present embodiment Aprepitant intravenous injection cream sterilizing
Front and back has good stability.
Embodiment 6
In the Aprepitant intravenous injection emulsion of the present embodiment, contain in every 1000mL emulsion: Aprepitant 13g, purification
Soybean oil 100g refines egg yolk lecithin 120g, and oleic acid 2.5g, 0.1N NaOH are appropriate, glycerol 25g, vitamin E 0.2g, note
It penetrates and is settled to 1000mL with water.Wherein, refined soybean oil is 10% as oily phase proportion.
The present embodiment Aprepitant intravenous injection emulsion the preparation method comprises the following steps:
(1) purification egg yolk lecithin, oleic acid, the vitamin E of recipe quantity refined soybean oil, 1/5 recipe quantity are weighed, is stirred molten
Prescription Aprepitant is added in solution, and heating water bath is to 65 DEG C as load medicine oil phase；
(2) recipe quantity glycerol is weighed, the purification egg yolk lecithin of remaining recipe quantity is added in 60mL water for injection, and water-bath adds
Heat is to 65 DEG C as water phase；
(3) oil is mutually slowly added into water phase, maintains temperature at 70 DEG C, the high speed shear 10min under 15000rpm, note
It penetrates and is settled to 1000mL with water and obtains colostrum, adjust colostrum pH to 7.5 with 0.1N NaOH；
(4) colostrum being prepared is subjected to high pressure microjet homogeneous, under the pressure of 30000psi, recycled 8 times, homogeneous
Temperature is 30 DEG C；
(5) after high-pressure homogeneous cream eventually, filling, nitrogen charging gas shielded will be carried out by cream eventually, sealing is placed in rotation autoclave
High pressure sterilization 15min obtains finished product at 121 DEG C.
Aprepitant vein emulsion manufactured in the present embodiment is after microjet homogeneous, and appearance is creamy white, mobility
Well, there is no wall built-up phenomenon, and with apparent blue-opalescent.It is somebody's turn to do through surveying, Aprepitant intravenous injection emulsion sterilizing front and back
Average grain diameter is 104 ± 24.18nm and 105.31 ± 30.52nm, and sterilizing fore-and-aft stability is good.
Embodiment 7
Inventor investigates the dissolution mechanism of phosphatide in Aprepitant intravenous injection emulsion, by partial emulsifier phosphorus
Rouge is dissolved in the solubilizer in oily phase as drug in oil phase solvent, and rest part emulsifier phosphatide is dispersed in water phase；?
It prepares in the high speed processes of colostrum, oil is mutually slowly dropped into water phase and prepares colostrum, then pass through microjet or high-pressure homogeneous to first
Cream carries out uniform particle diameter processing.The emulsifier emulsifier evaluation result that in grease prepared by different proportion is as shown in table 2.By table
2 it is found that the sterilizing fore-and-aft stability of unsaturated fatty acid fat of triglyceride cream is good.
Table 2
Effect example 1
Inventor investigates the mass ratio of each component in Aprepitant intravenous injection emulsion, and test group and right is arranged
According to group, influence of the mass ratio of each component to Aprepitant intravenous injection emulsion stability is investigated.The system of test group and control group
For Preparation Method with embodiment 1, the quality of each component, entrapment efficiency, average grain diameter, particle diameter distribution and zeta potential are as shown in table 3.
Table 3
As shown in Table 3, when the mass ratio of Aprepitant intravenous injection emulsion each component within the scope of the present invention when, tool
There is preferable stability；When the mass percent of emulsion for injection each component are as follows: Aprepitant 0.13~1.3%, oil phase solvent 10
~20%, when emulsifier 1.2~12%, stabilizer 0.03~0.3%, isotonic regulator 2~3%, Aprepitant obtained is quiet
The optimal stability of arteries and veins emulsion for injection.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Claims (10)
1. a kind of Aprepitant intravenous injection emulsion, which is characterized in that the emulsion for injection includes the group of following mass percent
Point: Aprepitant 0.05~3%, oil phase solvent 5~30%, emulsifier 1.2~18%, stabilizer 0.03~0.6%, isotonic tune
Agent 1~5% is saved, the emulsion for injection also includes pH adjusting agent, and surplus is water for injection, and the pH value of the emulsion for injection is 5.5
~8.0.
2. Aprepitant intravenous injection emulsion as described in claim 1, which is characterized in that the emulsion for injection includes following matter
Measure the component of percentage: Aprepitant 0.13~1.3%, oil phase solvent 10~20%, emulsifier 1.2~12%, stabilizer
0.03~0.3%, isotonic regulator 2~3%.
3. Aprepitant intravenous injection emulsion as described in claim 1, which is characterized in that the emulsion for injection also includes 0.02
~0.5% antioxidant.
4. Aprepitant intravenous injection emulsion as claimed in claim 3, which is characterized in that the quality percentage of the antioxidant
Than being 0.02~0.2%.
5. such as the described in any item Aprepitant intravenous injection emulsions of Claims 1 to 4, which is characterized in that the oil phase solvent
For at least one of chain fatty acid triglycerides, MCT Oil.
6. Aprepitant intravenous injection emulsion as claimed in claim 5, which is characterized in that the chain fatty acid triglycerides
For at least one of soybean oil, olive oil, tea-seed oil, fish oil, castor oil, rilanit special；The medium chain fatty acid
Three esters are at least one of tricaprylin, decanoin, Glycerin, mixed triester with caprylic acid capric acid, laurin.
7. such as the described in any item Aprepitant intravenous injection emulsions of Claims 1 to 4, which is characterized in that the emulsifier is
Egg yolk lecithin, egg PC, soybean lecithin, phosphatidyl glycerol, synthesis single fat sour component phosphatidyl gallbladder
At least one of alkali；The stabilizer is at least one of oleic acid, enuatrol, poloxamer, polyoxyethylene sorbitan monoleate；It is described etc.
Infiltration regulator is at least one of glycerol, mannitol, glucose, sodium chloride；The pH adjusting agent is hydrochloric acid or sodium hydroxide；
The antioxidant is at least one of tocopherol, sodium hydrogensulfite, sodium pyrosulfite, sodium thiosulfate.
8. the preparation method of Aprepitant intravenous injection emulsion as described in any one of claims 1 to 7, which is characterized in that packet
Include following steps:
(1) oil phase solvent, emulsifier, antioxidant, heating water bath are weighed, to be emulsified dose of all dissolution is added Aprepitant and stirs
Dissolution is mixed, as oily phase；
(2) stabilizer, isotonic regulator, pH adjusting agent are weighed, is added in water for injection, heating water bath, as water phase；
(3) oil is mutually slowly added in water phase, under stiring high speed shear, remaining water for injection is added, colostrum is made；
(4) the resulting colostrum of step (3) is subjected to microjet homogeneous, obtains whole cream；
(5) the resulting cream eventually of step (4) is subjected to filling, nitrogen charging, sealing, is placed in the interior sterilizing of rotation autoclave to get A Rui
Smooth intravenous injection emulsion.
9. the preparation method of Aprepitant intravenous injection emulsion as claimed in claim 8, which is characterized in that following (a)~(e)
At least one of in:
(a) in the step (1), heating temperature is 50~80 DEG C；
(b) in the step (2), the volume of water for injection is the 60~80% of emulsion for injection total volume, heating temperature is 50~
80℃；
(c) in the step (3), speed of agitator is 5000~20000rpm, and shear time is 5~25min；
(d) in the step (4), homogenizing temperature is 30~50 DEG C, and homogeneous recycles 4~10 times at 8000~35000Psi；
(e) in the step (5), sterilising temp is 121 DEG C, sterilization time 15min.
Nausea caused by 10. Aprepitant intravenous injection emulsion as described in any one of claims 1 to 7 treats chemotherapy in preparation
With the application in the drug of vomiting.
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| CN110368363A (en) * | 2019-08-22 | 2019-10-25 | 北京诺康达医药科技股份有限公司 | A kind of Aprepitant fat emulsion injection and preparation method thereof |
| US11517522B2 (en) * | 2020-01-14 | 2022-12-06 | Somerset Therapeutics Llc | Aprepitant ready-to-use injection emulsion compositions |
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