CN107184549A - A kind of Nintedanib self-micro emulsion formulation and its soft capsule being made and preparation method - Google Patents
A kind of Nintedanib self-micro emulsion formulation and its soft capsule being made and preparation method Download PDFInfo
- Publication number
- CN107184549A CN107184549A CN201710233806.9A CN201710233806A CN107184549A CN 107184549 A CN107184549 A CN 107184549A CN 201710233806 A CN201710233806 A CN 201710233806A CN 107184549 A CN107184549 A CN 107184549A
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- China
- Prior art keywords
- nintedanib
- self
- micro emulsion
- emulsion formulation
- emulsifying agent
- 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.)
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- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 160
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 title claims abstract description 158
- 229960004378 nintedanib Drugs 0.000 title claims abstract description 157
- 239000000203 mixture Substances 0.000 title claims abstract description 107
- 238000009472 formulation Methods 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 239000007901 soft capsule Substances 0.000 title claims abstract description 28
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 36
- 239000003381 stabilizer Substances 0.000 claims abstract description 11
- 239000003921 oil Substances 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 5
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 4
- 239000004359 castor oil Chemical group 0.000 claims description 4
- 235000019438 castor oil Nutrition 0.000 claims description 4
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 4
- 229940093471 ethyl oleate Drugs 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 4
- 235000011187 glycerol Nutrition 0.000 claims description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Chemical group 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 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 4
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 claims description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 3
- 229940113115 polyethylene glycol 200 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
- 239000004744 fabric Substances 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims 1
- 229960005150 glycerol Drugs 0.000 claims 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical group CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 27
- 210000002784 stomach Anatomy 0.000 abstract description 9
- 210000000936 intestine Anatomy 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- 238000004945 emulsification Methods 0.000 description 13
- 101100248253 Arabidopsis thaliana RH40 gene Proteins 0.000 description 12
- 239000002245 particle Substances 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- 238000002156 mixing Methods 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 description 4
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 4
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 229920003081 Povidone K 30 Polymers 0.000 description 3
- 229920003082 Povidone K 90 Polymers 0.000 description 3
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 239000004064 cosurfactant Substances 0.000 description 3
- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 150000004667 medium chain fatty acids Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000007908 nanoemulsion Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000010587 phase diagram Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 241001646826 Isodon rubescens Species 0.000 description 1
- NYGZYUAVZPIKBZ-BDJLRTHQSA-N Kushenin Natural products O(C)c1c(O)cc2O[C@H]3[C@@H](c2c1)COc1c3ccc(O)c1 NYGZYUAVZPIKBZ-BDJLRTHQSA-N 0.000 description 1
- NYGZYUAVZPIKBZ-UHFFFAOYSA-N Lespedezol D1 Natural products C1OC2=CC(O)=CC=C2C2C1C(C=C(C(=C1)O)OC)=C1O2 NYGZYUAVZPIKBZ-UHFFFAOYSA-N 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 241000241413 Propolis Species 0.000 description 1
- 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 description 1
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960001777 castor oil Drugs 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 230000003694 hair properties Effects 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- NYGZYUAVZPIKBZ-ZBEGNZNMSA-N lespedezol D1 Chemical compound C1OC2=CC(O)=CC=C2[C@H]2[C@@H]1C(C=C(C(=C1)O)OC)=C1O2 NYGZYUAVZPIKBZ-ZBEGNZNMSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940015847 ofev Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940069949 propolis Drugs 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 description 1
- 229960004245 silymarin Drugs 0.000 description 1
- 235000017700 silymarin Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 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
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Biochemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a kind of Nintedanib self-micro emulsion formulation and its soft capsule being made and preparation method, and concentration of the Nintedanib in Nintedanib self-micro emulsion formulation is by mass percentage 2% 3%；Ratio of the oil phase in Nintedanib self-micro emulsion formulation is 10% 30% (w/w)；Ratio of the emulsifying agent in Nintedanib self-micro emulsion formulation is 20% 40% (w/w)；Ratio of the assistant for emulsifying agent in Nintedanib self-micro emulsion formulation is 20% 60% (w/w)；Ratio of the stabilizer in Nintedanib self-micro emulsion formulation is 0 3% (w/w).The present invention by the preparation Nintedanib self-micro emulsion formulation of preparation from microemulsion technology by being made Nintedanib self-microemulsion soft capsules, Nintedanib self-micro emulsion formulation can be emulsified rapidly when running into the aqueous environments of intestines and stomach, so as to reduce the excitant produced after medicine is contacted for a long time with intestines and stomach, it can both improve the dissolution rate of medicine from micro emulsion drug carrying system, the speed and degree of drug absorption can be improved again, so as to improve the bioavilability of medicine.
Description
Technical field
The invention belongs to pharmaceutical preparation research field, and in particular to a kind of Nintedanib self-micro emulsion formulation and its be made it is soft
Capsule and preparation method.
Background technology
In June, 2014, Boehringer Ingelheim company announced, ethyl sulfonic acid Nintedanib treatment idiopathic pulmonary fibrosis (IPF)
Listing license application obtains the confirmation of European drug administration (EMA) and EMA includes acceleration examination ＆ approval list.October 15 in 2014
Day, food and medicine Surveillance Authority of U.S. FDA approval ethyl sulfonic acid Nintedanib (trade names:Ofev) new oral drugs are used for spy
Hair property pulmonary fibrosis (IPF) treatment.
Dihydro-the 3- of Nintedanib chemistry entitled (3Z) -2,3 one [[[4- [methyl [2- (4- methyl isophthalic acids-croak prolixity base) second phthalein]
Amino] phenyl] amino] benzylidene] one 1H-- indoles -6- formic acid first vinegar of -2- oxos, its structural formula is:
Based on Biopharmaceutics Classification system, bulk drug can be divided into four major classes according to its solubility and the difference of permeability.
Low solubility, the medicine of high-permeability belong to the class ii of Biopharmaceutics Classification, and it absorbs the low dissolution that speed limit is medicine suddenly
Speed.Formulation plays decisive role for the absorption of this kind of medicine in the gastrointestinal tract, and conventional tablet is difficult to improve this kind of medicine
Bioavilability, appropriate formulation is the key that such drug products is successfully developed.(Lv mends all etc., insoluble drug administration
The research of strategy, world's clinical medicine, 2009,30 (1):41-45).
Micro emulsion (Micro Emulsion, ME), also referred to as nano-emulsion (Nanoemulsion), are between emulsion and glue
A kind of dispersion system of colloid of stabilization between beam solution.The size droplet diameter of micro emulsion is between 10-100nm, by increasing capacitance it is possible to increase medicine
The solubility of thing, promotes medicine to be absorbed in intestines and stomach.
Self-micro emulsion formulation, also referred to as self-micro-emulsification medicine-releasing system (SMEDDS).After oral administration, self-micro emulsion formulation is in intestines and stomach
In run into gastric juice, the self-emulsifying microemulsion under the wriggling of stomach and intestine forms o/w types and carries medicine micro emulsion, its particle size is micro- with constituting identical
It is newborn consistent, and then improve the bioavilability of medicine.Self-micro emulsion formulation typically comprises oil phase, surfactant, helps surface to live
Property agent and medicine.With microemulsion phase ratio, SMEDDS stability is improved, and the requirement preserved for a long time can be met, while it can also be straight
It is hinged with the convenient administration system such as soft capsule or hard shell capsules.
CN101091696A is prepared for a kind of Rabdosia rubescens first using auxiliary materials such as oil phase, surfactant, cosurfactants
Plain self-micro emulsion formulation.CN101130059A utilize absolute ethyl alcohol, propane diols, sapn 1, Crodaret RH40,
Medium chain fatty acid three extremely wait auxiliary material be prepared for the self-emulsification soft capsules o CN101019833A of cyclosporin A using oil phase,
Surfactant, cosurfactant are prepared for the Nonaqueous microemulsion of Puerarin, propolis, kushenin etc..CN100536921C is disclosed
The yellow self-emulsified drug delivery system for answering former times, glycyrrhizic acid and silymarin etc., auxiliary material includes oil phase, surfactant, helps surface to live
Property agent, cationic surfactant and high molecular polymer.CN101596177A (2009.12.9) discloses a kind of Co-Q10
Self-emulsifying composition, auxiliary material is cruel etc. including phosphatide, surfactant, cosolvent and medium chain fatty acid three.In profits such as Aiwas
With oil phase (peanut oil, castor oil, ethyl oleate, liquid paraffin) and surfactant, cosurfactant first by Puerarin system
It is standby to be adsorbed (development of Puerarin Solid Self-microemulsion, Chinese medicine, 2006,29 (8) 834-838) into from micro emulsion, then with solid adjuvant material.
The content of the invention
It is an object of the invention to provide a kind of Nintedanib self-micro emulsion formulation and its soft capsule being made and preparation method,
By preparing Nintedanib self-microemulsion soft capsules from microemulsion technology, Nintedanib enteron aisle solubility is improved, so that it is biological to improve it
Availability.
The technical scheme is that：A kind of Nintedanib self-micro emulsion formulation is a kind of liquid self-microemulsion soft capsules preparation.
The Nintedanib self-micro emulsion formulation includes Nintedanib, oil phase, emulsifying agent, assistant for emulsifying agent and stabilizer；It is described
Concentration of the Nintedanib in Nintedanib self-micro emulsion formulation is 2%-3%, preferably 2.5% by mass percentage；Oil phase is in Buddhist nun
Ratio in Da Nibu self-micro emulsion formulations is 10%-30% (w/w)；Ratio of the emulsifying agent in Nintedanib self-micro emulsion formulation be
20%-40% (w/w)；Ratio of the assistant for emulsifying agent in Nintedanib self-micro emulsion formulation is 20%-60% (w/w)；Stabilizer exists
Ratio in Nintedanib self-micro emulsion formulation is 0-3% (w/w).
Wherein, the oil phase be Sefsol 218 (Capryol 90), castor oil, medium chain triglyceride (MCT) or
One kind in ethyl oleate；
The emulsifying agent is caprylic/capric ester LABRAFIL M 1944CS (LABRASOL), Tween 80 (Tween 80), tween
20 (Tween 20), Emulsifier EL-35 (EL35), polyoxyl 40 hydrogenated castor oil (RH40), sorbester p17 (Span
80) one or more of mixtures or in isopropyl myristate, one or two kinds of mixtures preferably wherein.
The assistant for emulsifying agent is ethanol, ethylene glycol (EG), propane diols (PG), polyethylene glycol 400 (PEG 400), glycerine
(GI) or one or more of mixtures in polyethylene glycol 200 (PEG200), one or two kinds of mixing preferably wherein
Thing.
The stabilizer is 30 POVIDONE K 30 BP/USP 90 (PVP K90).
A kind of Nintedanib self-microemulsion soft capsules being made according to the Nintedanib self-micro emulsion formulation, including the Buddhist nun reach
Buddhist nun's cloth self-micro emulsion formulation and soft capsule shell；The Nintedanib self-micro emulsion formulation is sealed in soft capsule shell in fluid form.
A kind of preparation method according to the Nintedanib self-microemulsion soft capsules, is that Nintedanib is added into oil phase, breast
After being dissolved in agent or assistant for emulsifying agent, the well mixed obtained Nintedanib self-micro emulsion formulation of other raw materials is added, and using normal
Rule method produces Nintedanib self-microemulsion soft capsules by the Nintedanib self-micro emulsion formulation is filling in soft capsule shell.Specifically may be used
Comprise the following steps：
Step (1) is according to Nintedanib described in the following proportions of prescription, oil phase, emulsifying agent, assistant for emulsifying agent and/or stably
Agent,
Concentration of the Nintedanib in Nintedanib self-micro emulsion formulation is 2%-3% by mass percentage,
Ratio of the oil phase in Nintedanib self-micro emulsion formulation is 10%-30% by mass percentage,
Ratio of the emulsifying agent in Nintedanib self-micro emulsion formulation is 20%-40% by mass percentage,
Ratio of the assistant for emulsifying agent in Nintedanib self-micro emulsion formulation is 20%-60% by mass percentage,
Ratio of the stabilizer in Nintedanib self-micro emulsion formulation is 0-3% by mass percentage；
The Nintedanib of prescription is dissolved in the assistant for emulsifying agent by step (2)；
Step (3) adds the emulsifying agent and oil phase of prescription in the solution that step (2) is obtained, and is well mixed；
Step (4) adds the stabilizer if prescription includes stabilizer in the solution that step (3) is obtained, molten
Solution is well mixed, produces Nintedanib self-micro emulsion formulation；
The filling Nintedanib obtained in soft capsule shell of Nintedanib self-micro emulsion formulation that step (5) obtains step (4)
Self-microemulsion soft capsules.
Compared with prior art, beneficial effects of the present invention are：The present invention provides a kind of Nintedanib self-microemulsion soft capsules
Preparation method, using the modern times from microemulsion technology, develop Nintedanib self-micro emulsion formulation and the rational technological process of production, Buddhist nun
Da Nibu self-micro emulsion formulations can be emulsified rapidly when running into the aqueous environments of intestines and stomach, form O/W type emulsion droplets.Tiny oil droplet can
The rapid deflation from stomach, makes medicine widely distributed in whole intestines and stomach, so as to reduce after medicine and intestines and stomach contact for a long time
The excitant of generation.It can both improve the dissolution rate of medicine from micro emulsion drug carrying system (SMEDDS), the speed of drug absorption can be improved again
Rate and degree, so as to improve the bioavilability of medicine.The Nintedanib self-microemulsion soft capsules of the present invention can be to a certain degree
On make up the blank of China's Nintedanib medicine, there is important strategy to the Case treatment for promoting China's idiopathic pulmonary fibrosis
Meaning, being made from the Nintedanib bioavilability of micro emulsion to increase, and add Nintedanib treatment idiopathic lung fiber
Chemical drug is imitated, and this project implementation has obviously social favorable to the people benefit.
Brief description of the drawings
Fig. 1 can draw blank from the ternary phase diagrams of micro emulsion effective coverage for the present invention；
Fig. 2 for the present invention can obtain Nintedanib concentration 2.5% Nintedanib from the three of microemulsion formulation proportion
First phasor.
Embodiment
The present invention is described in further detail with reference to the accompanying drawings and detailed description, but protection scope of the present invention
It is not limited to this.
Embodiment 1
It is emulsification with polyoxyl 40 hydrogenated castor oil (RH40) with Sefsol 218 (Capryol 90) for oil phase
Agent, with propane diols (PG) for assistant for emulsifying agent.By emulsifying agent and assistant for emulsifying agent by weight 2:1、1:1、1:2 are well mixed, then with
Oil phase is by weight 1:9、2:8、3:7、4:6、5:5、6:4、7:3、8:2、9:1 mixes, in 50rmin-1Stirring is lower to instill preheating
Into 37 DEG C of water, micro emulsion situation is observed into.The situation of change and state of different proportion hybrid system are recorded, and limits emulsifying agent
Ratio 20%-40%, the ratio of assistant for emulsifying agent is in more than 20%-60%, and the ratio of oil phase is between 10%-30%, by this
A little proportioning data draw ternary phase diagrams, select blank from micro emulsion effective coverage and the effective coverage of Nintedanib self-emulsifying microemulsion, see
Dash area in Fig. 1.
As can be seen from Figure 2, the component ratio in selection dash area region can obtain Buddhist nun of the Nintedanib concentration 2.5%
Da Nibu is from microemulsion formulation proportion.
By the filling Nintedanib self-microemulsion soft capsules obtained in soft capsule shell of obtained Nintedanib self-micro emulsion formulation.
Embodiment 2
Nintedanib concentration is 2% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PG of recipe quantity, the MCT and RH40 of recipe quantity is added,
It is well mixed, produce Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 18.3nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 3
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PG of recipe quantity, the MCT and RH40 of recipe quantity is added,
It is well mixed, produce Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 18.1nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 4
Nintedanib concentration is 2.9% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PG of recipe quantity, the MCT and RH40 of recipe quantity is added,
It is well mixed, the PVP K90 of recipe quantity are added, dissolving and mixing produces Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 23.1nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 5
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PEG 400 of recipe quantity, the EL of recipe quantity is added,
RH40 and MCT, is well mixed, produces Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 20.8nm.Nintedanib is taken from micro emulsion 5ml, in 50rmin-1Stir
The lower water for adding 10 times of 37 DEG C of amounts is mixed, can be in 1min internal emulsifications completely from micro emulsion stoste, the O/W types for forming transparent slightly blueing light are micro-
Breast, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 6
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PEG 400 of recipe quantity, the Tween of recipe quantity is added
80, RH40 and MCT, is well mixed, produces Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 22.1nm.Nintedanib is taken from micro emulsion 5ml, in 50rmin-1Stir
The lower water for adding 10 times of 37 DEG C of amounts is mixed, can be in 1min internal emulsifications completely from micro emulsion stoste, the O/W types for forming transparent slightly blueing light are micro-
Breast, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 7
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PFG 400 of recipe quantity and the mixing assistant for emulsifying agent of ethanol
In, the RH40 of recipe quantity, Tween 20 and caprylic/capric ester LABRAFIL M 1944CS are added, is well mixed, recipe quantity is added
PVP K30, dissolving and mixing produces Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 25.7nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 8
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PG of recipe quantity, the castor oil and meat of recipe quantity is added
Isopropyl myristate, is well mixed, produces Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is faint yellow transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 24.2nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 9
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the EG of recipe quantity, add recipe quantity ethyl oleate and
RH40, is well mixed, produces Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 21.0nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-14h keeps stable under stirring, and no crystal is separated out.
Embodiment 10
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PFG 200 of recipe quantity and the mixing assistant for emulsifying agent of glycerine
In, the RH40, Tween 20 and MCT of recipe quantity are added, is well mixed, the PVP K30 of recipe quantity are added, mixes equal after dissolving
It is even, produce Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 20.9nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
Embodiment 11
Nintedanib concentration is 2.5% Nintedanib self-micro emulsion formulation prescription
Raw material is chosen according to following ratios：
Preparation method：The Nintedanib of recipe quantity is dissolved in the PEG400 of recipe quantity, add recipe quantity MCT and
RH40, is well mixed, and adds the PVP K90 of recipe quantity, and dissolving and mixing produces Nintedanib self-micro emulsion formulation.
The Nintedanib self-micro emulsion formulation of preparation is colourless transparent and homogeneous liquid.The Nintedanib of preparation is taken from micro emulsion system
Agent, is diluted with water 100 times, determines particle diameter, average grain diameter is 27.8nm.Nintedanib self-micro emulsion formulation 5ml is taken, in 50r
min-1The lower water for adding 10 times of 37 DEG C of amounts of stirring, transparent slightly blueing light can be formed from micro emulsion stoste in 1min internal emulsifications completely
O/W type micro emulsions, and in 50rmin-18h keeps stable under stirring, and no crystal is separated out.
It should be understood that, although this specification is described according to each embodiment, but not each embodiment only includes one
Individual independent technical scheme, this narrating mode of specification is only that for clarity, those skilled in the art will should say
Bright book is as an entirety, and the technical solutions in the various embodiments may also be suitably combined, and forming those skilled in the art can be with
The other embodiment of understanding.
The a series of detailed description of those listed above illustrating only for the possible embodiments of the present invention,
They simultaneously are not used to limit the scope of the invention, all equivalent embodiments made without departing from skill spirit of the present invention or change
It should be included in the scope of the protection.
Claims (7)
1. a kind of Nintedanib self-micro emulsion formulation, it is characterised in that including Nintedanib, oil phase, emulsifying agent, assistant for emulsifying agent and steady
Determine agent；
Concentration of the Nintedanib in Nintedanib self-micro emulsion formulation is 2%-3% by mass percentage；
Ratio of the oil phase in Nintedanib self-micro emulsion formulation is 10%-30% by mass percentage；
Ratio of the emulsifying agent in Nintedanib self-micro emulsion formulation is 20%-40% by mass percentage；
Ratio of the assistant for emulsifying agent in Nintedanib self-micro emulsion formulation is 20%-60% by mass percentage；
Ratio of the stabilizer in Nintedanib self-micro emulsion formulation is 0-3% by mass percentage.
2. a kind of Nintedanib self-micro emulsion formulation according to claim 1, it is characterised in that the emulsifying agent for octanoic acid/
Decylate LABRAFIL M 1944CS, Tween 80, polysorbas20, Emulsifier EL-35, the rilanit special of polyethylene glycol 40, sapn
80 or isopropyl myristate in one or more of mixtures.
3. a kind of Nintedanib self-micro emulsion formulation according to claim 1, it is characterised in that the assistant for emulsifying agent is second
One or more of mixtures in alcohol, ethylene glycol, propane diols, polyethylene glycol 400, glycerine or polyethylene glycol 200.
4. a kind of Nintedanib self-micro emulsion formulation according to claim 1, it is characterised in that the oil phase is propane diols list
One kind in caprylate, castor oil, medium chain triglyceride or ethyl oleate.
5. a kind of Nintedanib self-micro emulsion formulation according to claim 1, it is characterised in that the Nintedanib reaches in Buddhist nun
Concentration in Buddhist nun's cloth self-micro emulsion formulation is 2.5% by mass percentage.
6. the Nintedanib self-microemulsion soft capsules that a kind of self-micro emulsion formulation of Nintedanib according to claim 1 is made, it is special
Levy and be, including the Nintedanib self-micro emulsion formulation and soft capsule shell；The Nintedanib self-micro emulsion formulation is with the shape of liquid
Formula is sealed in soft capsule shell.
7. a kind of a kind of preparation method of Nintedanib self-microemulsion soft capsules according to claim 6, it is characterised in that bag
Include following steps：
Step (1) according to Nintedanib, oil phase, emulsifying agent, assistant for emulsifying agent and/or stabilizer described in following proportions,
Concentration of the Nintedanib in Nintedanib self-micro emulsion formulation is 2%-3% by mass percentage,
Ratio of the oil phase in Nintedanib self-micro emulsion formulation is 10%-30% by mass percentage,
Ratio of the emulsifying agent in Nintedanib self-micro emulsion formulation is 20%-40% by mass percentage,
Ratio of the assistant for emulsifying agent in Nintedanib self-micro emulsion formulation is 20%-60% by mass percentage,
Ratio of the stabilizer in Nintedanib self-micro emulsion formulation is 0-3% by mass percentage；
The Nintedanib is dissolved in the assistant for emulsifying agent by step (2)；
Step (3) adds the emulsifying agent and oil phase in the solution that step (2) is obtained, and is well mixed；
Step (4) adds the stabilizer in the solution that step (3) is obtained, and dissolving is well mixed, produces Nintedanib from micro-
Emulsion formulation；
Nintedanib self-micro emulsion formulation that step (5) obtains step (4) is filling to be made Nintedanib from micro- in soft capsule shell
Newborn soft capsule.
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| WO2022116987A1 (en) * | 2020-12-02 | 2022-06-09 | 湖南慧泽生物医药科技有限公司 | Self-microemulsion composition of axitinib |
| CN112618490A (en) * | 2020-12-31 | 2021-04-09 | 苏州中化药品工业有限公司 | Itraconazole self-microemulsion preparation and preparation method thereof |
| CN114569573A (en) * | 2022-03-09 | 2022-06-03 | 重庆师范大学 | Coenzyme Q prepared by self-microemulsifying10Method for preparing vitamin E soft capsule |
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