WO2022105877A1 - 包含银杏内酯类成分的药物组合物和制剂及其用途 - Google Patents
包含银杏内酯类成分的药物组合物和制剂及其用途 Download PDFInfo
- Publication number
- WO2022105877A1 WO2022105877A1 PCT/CN2021/131779 CN2021131779W WO2022105877A1 WO 2022105877 A1 WO2022105877 A1 WO 2022105877A1 CN 2021131779 W CN2021131779 W CN 2021131779W WO 2022105877 A1 WO2022105877 A1 WO 2022105877A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ginkgolide
- pharmaceutical
- pharmaceutical formulation
- preparation
- pharmaceutical composition
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 46
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 18
- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 51
- 239000003937 drug carrier Substances 0.000 claims abstract description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 229930184727 ginkgolide Natural products 0.000 claims description 69
- 229940097496 nasal spray Drugs 0.000 claims description 32
- 239000007922 nasal spray Substances 0.000 claims description 32
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 18
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 12
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical group [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 12
- 235000011187 glycerol Nutrition 0.000 claims description 12
- 229960005150 glycerol Drugs 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 10
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 10
- 229940068968 polysorbate 80 Drugs 0.000 claims description 10
- 229920000053 polysorbate 80 Polymers 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000000306 component Substances 0.000 claims description 8
- SQOJOAFXDQDRGF-WJHVHIKBSA-N ginkgolide B Natural products O=C1[C@@H](C)[C@@]2(O)[C@@H]([C@H](O)[C@]34[C@@H]5OC(=O)[C@]23O[C@H]2OC(=O)[C@H](O)[C@@]42[C@H](C(C)(C)C)C5)O1 SQOJOAFXDQDRGF-WJHVHIKBSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- LMEHVEUFNRJAAV-HOSIAMDISA-N ginkgolide J Natural products O=C1[C@H](C)[C@@]2(O)[C@H](O1)C[C@@]13[C@H]4[C@@H](O)[C@@H](C(C)(C)C)[C@@]51[C@@H](O)C(=O)O[C@@H]5O[C@@]23C(=O)O4 LMEHVEUFNRJAAV-HOSIAMDISA-N 0.000 claims description 7
- 230000003204 osmotic effect Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 6
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 claims description 5
- 208000004929 Facial Paralysis Diseases 0.000 claims description 5
- 108010003541 Platelet Activating Factor Proteins 0.000 claims description 5
- 208000036826 VIIth nerve paralysis Diseases 0.000 claims description 5
- 230000003042 antagnostic effect Effects 0.000 claims description 5
- 230000003712 anti-aging effect Effects 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 230000000840 anti-viral effect Effects 0.000 claims description 5
- 150000002632 lipids Chemical class 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- AMOGMTLMADGEOQ-FNZROXQESA-N Ginkgolide C Chemical compound O([C@H]1O2)C(=O)[C@H](O)C31[C@]14[C@@H](O)[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@@H](O)[C@H]3C(C)(C)C AMOGMTLMADGEOQ-FNZROXQESA-N 0.000 claims description 4
- CBAUUWCEZZNYTD-OOWJTCQTSA-N Ginkgolide M Natural products O=C1[C@@H](C)[C@@H]2[C@@H]([C@@H](O)[C@@]34[C@H]5[C@@H](O)[C@@H](CC(C)C)[C@@]63[C@@H](O)C(=O)O[C@@H]6O[C@@]24C(=O)O5)O1 CBAUUWCEZZNYTD-OOWJTCQTSA-N 0.000 claims description 4
- KDKROYXEHCYLJQ-DYXVGVPESA-N Ginkgolide M Chemical compound C[C@H]1[C@H]2[C@H]([C@@H](C34[C@]25C(=O)O[C@@H]3[C@@H]([C@H](C46[C@H](C(=O)O[C@H]6O5)O)C(C)(C)C)O)O)OC1=O KDKROYXEHCYLJQ-DYXVGVPESA-N 0.000 claims description 4
- 230000003064 anti-oxidating effect Effects 0.000 claims description 4
- 239000000022 bacteriostatic agent Substances 0.000 claims description 4
- 239000008139 complexing agent Substances 0.000 claims description 4
- FPUXKXIZEIDQKW-MFJLLLFKSA-N ginkgolide A Natural products O=C1[C@H](C)[C@@]2(O)[C@@H](O1)C[C@]13[C@@H]4OC(=O)[C@]21O[C@@H]1OC(=O)[C@H](O)[C@]31[C@@H](C(C)(C)C)C4 FPUXKXIZEIDQKW-MFJLLLFKSA-N 0.000 claims description 4
- AMOGMTLMADGEOQ-DPFZUGDXSA-N ginkgolide C Natural products O=C1[C@@H](C)[C@]2(O)[C@H]([C@H](O)[C@@]34[C@H]5[C@H](O)[C@@H](C(C)(C)C)[C@]63[C@H](O)C(=O)O[C@H]6O[C@@]24C(=O)O5)O1 AMOGMTLMADGEOQ-DPFZUGDXSA-N 0.000 claims description 4
- PMHYHZBGMYBWAJ-VKMVSBOZSA-N ginkgolide P Natural products C[C@@H]1C(=O)O[C@H]2C[C@@]34[C@H]5C[C@@H](C(C)(C)CO)[C@@]36[C@@H](O)C(=O)O[C@H]6O[C@@]4(C(=O)O5)[C@@]12O PMHYHZBGMYBWAJ-VKMVSBOZSA-N 0.000 claims description 4
- JBMLUACQJLODAG-MMQTXUMRSA-N ginkgolide Q Natural products C[C@@H]1C(=O)O[C@H]2[C@H](O)[C@@]34[C@H]5C[C@@H](C(C)(C)CO)[C@]36[C@@H](OC(=O)[C@@H]6O)O[C@@]4(C(=O)O5)[C@@]12O JBMLUACQJLODAG-MMQTXUMRSA-N 0.000 claims description 4
- FPUXKXIZEIDQKW-VKMVSBOZSA-N ginkgolide-a Chemical group O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13C[C@@H]1OC(=O)[C@@H](C)[C@]21O FPUXKXIZEIDQKW-VKMVSBOZSA-N 0.000 claims description 4
- SQOJOAFXDQDRGF-MMQTXUMRSA-N ginkgolide-b Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13[C@@H](O)[C@@H]1OC(=O)[C@@H](C)[C@]21O SQOJOAFXDQDRGF-MMQTXUMRSA-N 0.000 claims description 4
- 229910021645 metal ion Inorganic materials 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 239000000375 suspending agent Substances 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 238000000265 homogenisation Methods 0.000 claims description 3
- -1 pH regulators Substances 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 3
- 150000002596 lactones Chemical class 0.000 claims 1
- 239000002357 osmotic agent Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 48
- 239000008213 purified water Substances 0.000 description 25
- 239000000203 mixture Substances 0.000 description 18
- 241000700159 Rattus Species 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical group O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 210000005013 brain tissue Anatomy 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000010410 reperfusion Effects 0.000 description 5
- 229910001220 stainless steel Inorganic materials 0.000 description 5
- 239000010935 stainless steel Substances 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 238000004659 sterilization and disinfection Methods 0.000 description 5
- 208000006011 Stroke Diseases 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- LMEHVEUFNRJAAV-UKWFQYJJSA-N ginkgolide-j Chemical compound O([C@H]1O2)C(=O)[C@H](O)[C@@]31[C@]14C[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@H](O)[C@H]3C(C)(C)C LMEHVEUFNRJAAV-UKWFQYJJSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000002850 nasal mucosa Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000001168 carotid artery common Anatomy 0.000 description 2
- 210000000269 carotid artery external Anatomy 0.000 description 2
- 210000004004 carotid artery internal Anatomy 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical group O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 230000003188 neurobehavioral effect Effects 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 238000013077 scoring method Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 235000008100 Ginkgo biloba Nutrition 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 206010052437 Nasal discomfort Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000027744 congestion Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- XWTSVDOFVXEEPO-UHFFFAOYSA-M diazanium potassium phosphate Chemical compound P(=O)([O-])([O-])[O-].[NH4+].[NH4+].[K+] XWTSVDOFVXEEPO-UHFFFAOYSA-M 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000003657 middle cerebral artery Anatomy 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000000956 olfactory bulb Anatomy 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present application relates to the field of medicine, in particular to pharmaceutical compositions and preparations containing ginkgolides and uses thereof.
- Ginkgolide is a terpenoid lactone compound extracted from Ginkgo biloba leaves, including Ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide D, Ginkgolide J, Ginkgolide M, Ginkgolide Ester K, ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, bilobalide and other ingredients.
- Ginkgolide has various pharmacological effects such as antioxidant, antagonizing platelet activating factor, lowering blood lipids, improving circulation, protecting the heart, improving immunity, anti-inflammatory, anti-viral, anti-tumor and anti-aging.
- Ginkgolide injection has problems such as inconvenient operation and difficulty for patients to self-administer, which greatly limits the use of ginkgolide products and reduces the patient's medication compliance. opportunity. Therefore, the pharmaceutical preparation of ginkgolide products still needs to expand its route of administration.
- nasal spray is one of the new types of nasal administration. It does not contain propellants, and only uses the power generated by the compressed air to atomize and spray the liquid medicine through the atomizing device. When the nasal spray is administered, the liquid medicine is directly and evenly distributed on the nasal mucosa, and the drug has a wide dispersion and dispersal area, which can reduce the amount of liquid medicine and do not need to tilt the head back. Therefore, the nasal spray is not only convenient for administration, the patient can complete the administration by himself, and there will be no complications caused by the medicinal liquid flowing into the pharynx to produce a bitter taste or the medicinal liquid being inhaled into the trachea.
- compositions and pharmaceutical preparations containing ginkgolides which have the advantages of rapid action, good absorption, and convenient use, and have good therapeutic effects on diseases such as stroke and facial paralysis.
- the nasal spray drug preparation provided by one or more embodiments of the present application will not precipitate crystals during long-term storage, which is not only conducive to the rapid absorption of the drug, but also less likely to block the spray pump port.
- One or more embodiments of the present application provide a pharmaceutical composition comprising a ginkgolide component and a pharmaceutically acceptable carrier or excipient.
- One or more embodiments of the present application provide a pharmaceutical formulation comprising a ginkgolide component, comprising a ginkgolide component, a pharmaceutically acceptable carrier or excipient, and water.
- the pharmaceutical compositions or pharmaceutical formulations of the present application are for nasal administration.
- the pharmaceutical formulation is a spray.
- the pharmaceutically acceptable carrier or excipient includes bacteriostatic agents, antioxidants, surfactants, solubilizers, osmotic pressure regulators, metal ion complexing agents, thickening agents One or more of a pH adjusting agent, a suspending agent.
- the ginkgolide components are ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide D, ginkgolide J, ginkgolide M, ginkgolide One or more in K, ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, bilobalide;
- the bacteriostatic agent is benzalkonium chloride.
- the surfactant is polysorbate 80.
- the solubilizer is ethanol, propylene glycol, or a combination thereof.
- the osmotic pressure modifier is glycerol.
- the metal ion complexing agent is disodium edetate.
- the thickener is HPMC 60 SH-4000.
- the suspending agent is Avicel RC591.
- each 1000 mL of the pharmaceutical formulation comprises:
- each 1000 mL of the pharmaceutical formulation comprises:
- the pharmaceutical formulation is dispensed into nasal spray bottles.
- step (3) adding ginkgolide and Avicel RC591 to the solution obtained in step (2) to obtain suspension, vacuum homogenization, until it is completely homogenized, to obtain the pharmaceutical preparation;
- the pharmaceutical formulation is dispensed into nasal spray bottles.
- One or more embodiments of the present application provide that the pharmaceutical composition or pharmaceutical preparation of the present application is used in the preparation of anti-oxidation, antagonizing platelet activating factor, lowering blood lipids, improving circulation, protecting the heart, improving immunity, anti-inflammatory and anti-viral , use in anti-tumor or anti-aging drugs.
- One or more embodiments of the present application provide the use of the pharmaceutical composition or pharmaceutical formulation of the present application in the manufacture of a medicament for the treatment of facial paralysis or stroke.
- One or more embodiments of the present application provide a pharmaceutical composition or pharmaceutical formulation of the present application for use as a medicament.
- One or more embodiments of the present application provide the pharmaceutical composition or pharmaceutical preparation of the present application, which is used for anti-oxidation, antagonizing platelet activating factor, lowering blood lipid, improving circulation, protecting heart, improving immunity, anti-inflammatory and anti-viral , anti-tumor or anti-aging.
- One or more embodiments of the present application provide a pharmaceutical composition or pharmaceutical formulation of the present application for use in the treatment of facial paralysis or stroke.
- One or more embodiments of the present application provide methods for anti-oxidation, antagonizing platelet activating factor, lowering blood lipids, improving circulation, protecting the heart, improving immunity, anti-inflammatory, anti-viral, anti-tumor or anti-aging, comprising adding the present
- the claimed pharmaceutical composition or pharmaceutical formulation is administered to a subject in need thereof.
- One or more embodiments of the present application provide a method of treating facial paralysis or stroke, comprising administering to a subject in need thereof a pharmaceutical composition or pharmaceutical formulation of the present application.
- the nasal spray pharmaceutical preparation provided by one or more embodiments of the present application has a uniform content, and the content of the main drug in each spray is uniform after spraying.
- the nasal spray pharmaceutical preparation provided by one or more embodiments of the present application has no edema, congestion, etc. of the nasal mucosa after use, and has good safety.
- carrier refers to a material that is not appreciably irritating to an organism and that does not abrogate the biological activity and properties of the administered compound.
- ginkgolides include ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide D, ginkgolide J, ginkgolide M, ginkgolide K, ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, bilobalide, etc., and their stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or Eutectic.
- the ginkgolide components used in the following examples are the raw materials of ginkgolide injection (Jingelai) from Chengdu Baiyu Pharmaceutical Co., Ltd. (batch number: 10200601).
- Avicel RC591 used in the following examples was purchased from DuPont Nutrition & Health and contained 88.4% microcrystalline cellulose and 11.4% sodium carboxymethylcellulose (Lot DN17831154).
- composition of the nasal spray solution containing ginkgolides is:
- step 2 (4) adding the solution of step 2 to the solution of step 3, and stirring with a stirrer until the mixture is uniform, for subsequent use;
- composition of the nasal spray solution containing ginkgolides is:
- Ginkgolide is added in propylene glycol, ethanol, uses ultrasonic oscillator to shake (Delta/DC400H) until forming clear and transparent solution, for subsequent use;
- step 2 (4) adding the solution of step 2 to the solution of step 3, and stirring with a stirrer until the mixture is uniform, for subsequent use;
- composition of the nasal spray solution containing ginkgolides is:
- Ginkgolide is added in propylene glycol, ethanol, uses ultrasonic oscillator to shake (Delta/DC400H) until forming clear and transparent solution, for subsequent use;
- step (2) adding the solution of step (2) to the solution of step (3), using a stirrer to stir until uniformly mixed, for subsequent use;
- composition of the nasal spray solution containing ginkgolides is:
- step (2) adding the solution of step (2) to the solution of step (3), using a stirrer to stir until uniformly mixed, for subsequent use;
- composition of the nasal spray solution containing ginkgolides is:
- the preparation method is the same as that of Example 2.
- composition of the nasal spray solution containing ginkgolides is:
- the preparation method is the same as in Example 1.
- composition of the nasal spray solution containing ginkgolides is:
- the preparation method is the same as in Example 1.
- composition of the nasal spray solution containing ginkgolides is:
- ginkgolide is added in propylene glycol, use ultrasonic oscillator to shake (Delta/DC400H), until forming clear and transparent solution, for subsequent use;
- step (2) Add the solution of step (2) to the solution of step (3), stir with a stirrer until the mixture is uniform, and set aside.
- composition of the nasal spray solution containing ginkgolides is:
- the preparation method is the same as in Example 1.
- composition of the nasal spray solution containing ginkgolides is:
- the preparation method is the same as in Example 1.
- Ginkgolide Nasal Spray Suspension The ingredients of Ginkgolide Nasal Spray Suspension are:
- step 2 (3) Ginkgolide and Avicel RC591 are added to the solution of step 2, and purified water is added to adjust the suspension to 1000 mL, and vacuum homogenization is performed until it is completely homogenized;
- Ginkgolide Nasal Spray Suspension The ingredients of Ginkgolide Nasal Spray Suspension are:
- the preparation method is the same as that of Example 11.
- Ginkgolide Nasal Spray Suspension The ingredients of Ginkgolide Nasal Spray Suspension are:
- the preparation method is the same as that of Example 11.
- Viscosity The sample was measured at 25°C using a viscometer (LVDV-I1+PRO), three measurements were made and the average viscosity value (mPas or cp) was determined.
- Osmotic pressure Use an osmometer to measure the osmotic pressure value of the sample, carry out three measurements and determine the average osmotic pressure value.
- Buffer solution Dissolve 1.19g disodium hydrogen phosphate and 8.25g potassium diammonium phosphate in 900mL of water, adjust the pH to 5.8 with dilute phosphoric acid or 1N sodium hydroxide, add water to dilute to 1000mL, and mix well.
- Dilution solution Mix methanol and water at a ratio of 1:1 (v/v).
- Reference solution accurately weigh about 60 mg of ginkgolide reference substance, put it in a 50 mL beaker, add 10 mL of buffer solution and sonicate for 5 minutes, transfer the solution to a suitable separator, rinse the beaker with 5 mL of buffer solution and then put the washing solution Transfer to separator. After 15 minutes, 50.0 mL of ethyl acetate was added for extraction. After the layers were separated, the ethyl acetate solution was collected, evaporated to dryness in a water bath at 50°C, and the residue was dissolved in 20.0 mL of diluted solution; 5.0 mL of this solution was accurately drawn and placed in 100 mL. Dilute to the mark with diluent solution in the measuring flask and shake well.
- Test solution accurately weigh a sample containing about 3 mg of ginkgolide, place it in a suitable separator, add 20 mL of buffer solution and mix well. After 15 minutes, it was extracted with 50.0 mL of ethyl acetate. After the layers were separated, the ethyl acetate solution was collected and evaporated to dryness in a water bath at 50°C. The residue was dissolved in 20.0 mL of the diluted solution and filtered.
- Chromatographic column packing is octadecylsilane-bonded porous silica gel or ceramic particles, 4.6mm ⁇ 250mm color
- mice 3 healthy adult SD rats, weighing 296 g, 303 g, and 292 g, respectively.
- Test sample Ginkgolide nasal spray solution (Example 8)
- the rats in the model group and the administration group were anesthetized with 6% chloral hydrate (7 mL/kg), and their limbs were fixed in a supine position.
- the skin of the rat's neck was cut from the middle to the right, the internal carotid artery and external carotid artery were separated along the distal end of the common carotid artery, an incision was made in the external carotid artery, and the suture was inserted along the direction of the internal carotid artery. , the suture was completely removed to achieve ischemia-reperfusion.
- the animals in the sham-operated group were anesthetized with 6% chloral hydrate, only the common carotid artery was isolated and exposed, and the middle artery was not embolized.
- Group design sham operation group, model group, edaravone group, and Example 13 group;
- Grouping method The animals were randomly grouped according to body weight.
- Example 13 The animals in Example 13 were administered immediately after reperfusion, intranasal drip administration, once on the day of modeling, and then twice a day (BID), 100 ⁇ L each time, for a total of 3 days;
- BID twice a day
- the edaravone group was given the drug immediately after reperfusion, intravenous injection (i.v.), once a day (QD), for a total of 3 days;
- the model group was given a blank solvent, and the mode and frequency of administration were different from those of the test drug. same group.
- Testing time 24 hours after reperfusion; testing animals: all animals in the group; scoring method: Longa scoring method.
- Detection time 72 hours after reperfusion; detection animals: all surviving animals after modeling;
- Detection method The hearts were perfused with pre-cooled PBS, and brain tissues were taken from the surviving animals in each group. The olfactory bulb, cerebellum and lower brain stem were removed, and the wet weight of the brain tissues was weighed. The dry weight of the brain tissue was weighed, and the relative brain water content of the rat was calculated according to the dry-wet weight method. The calculation formula is as follows:
- Relative brain water content (g) (wet weight of brain tissue - dry weight of brain tissue) - average water content of brain tissue in sham operation group
- intranasal administration of the preparation of the present application in rats can improve neurological function and brain edema, and achieve the same level as intravenous injection. Similar potency to daravone.
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Abstract
本申请公开了包含银杏内酯类成分以及药学上可接受的载体或赋形剂的药物组合物以及包含银杏内酯类成分、药学上可接受的载体或赋形剂、以及水的银杏内酯类成分的药物制剂，以及该药物组合物和药物制剂的用途。
Description
本申请涉及药物领域，具体涉及包含银杏内酯类成分的药物组合物和制剂及其用途。
银杏内酯是从银杏叶中提取得到的萜类内酯化合物，包括银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯等成分。研究表明，银杏内酯具有抗氧化、拮抗血小板活化因子、降血脂、改善循环、保护心脏、提高免疫力、抗炎、抗病毒、抗肿瘤及抗衰老等多种药理作用，存在多种潜在的医药用途，但由于水溶性差、分子稳定性差、在体内易被代谢降解、不容易透过生物膜等缺陷，导致其临床开发的剂型种类及临床应用受到限制，目前市售的银杏内酯类产品以静脉注射制剂为主，被批准的适应症也仅为缺血性脑卒中。
银杏内酯注射剂存在操作不便、患者难以自行给药等问题，大大限制了银杏内酯类产品的使用，降低了患者的用药依从性，同时还可能导致患者因无法及时用药，而错过最佳治疗时机。因此，银杏内酯类产品的药物制剂仍有待拓展其给药途径。
鼻腔黏膜薄，粘膜下血管丰富，通过鼻腔给药，药物吸收迅速，直接进入体内循环，避免遭受胃肠道破坏和肝脏首过代谢作用，可大大提高生物利用度。鼻喷剂是新型的鼻腔给药方式之一，其不含抛射剂，仅通过雾化装置借助压缩空气产生的动力使药液雾化并喷出。鼻喷剂给药时药液直接均匀地分布到鼻腔黏膜上，药物的弥散度和分散面积较广泛，可减少药液的用量且不需要头部后仰。因此，鼻喷剂不仅给药方便，患者可自行完成给药，且不会出现药液流到咽部产生苦味或者药液吸入气管带来的并发症。
发明内容
本申请的一个或多个实施方式提供包含银杏内酯类成分的药物组合物和药物制剂，其具有作用迅速、吸收良好、使用方便等优点，对卒中、面瘫等疾病均有良好的治疗效果。
本申请的一个或多个实施方式提供的鼻喷药物制剂，在长期存放过程中，不会析出结晶，不仅利于药物的快速吸收，而且不容易堵塞喷雾泵口。
本申请的一个或多个实施方案提供了药物组合物，其包含银杏内酯类成分以及药学上可接受的载体或赋形剂。
本申请的一个或多个实施方案提供了包含银杏内酯类成分的药物制剂，其包含银杏内酯类成分、药学上可接受的载体或赋形剂、以及水。
在一个或多个实施方案中，本申请药物组合物或药物制剂其用于鼻部给药。
在一个或多个实施方案中，所述药物制剂为喷雾剂。
在一个或多个实施方案中，所述药学上可接受的载体或赋形剂包括抑菌剂、抗氧剂、表面活性剂、增溶剂、渗透压调节剂、金属离子络合剂、增稠剂、pH调节剂、助悬剂中的一种或者多种。
在一个或多个实施方案中，所述银杏内酯类成分为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯中的一种或多种；
在一个或多个实施方案中，所述抑菌剂为苯扎氯铵。
在一个或多个实施方案中，所述表面活性剂为聚山梨酯80。
在一个或多个实施方案中，所述增溶剂为乙醇、丙二醇或其组合。
在一个或多个实施方案中，所述渗透压调节剂为甘油。
在一个或多个实施方案中，所述金属离子络合剂为依地酸二钠。
在一个或多个实施方案中，所述增稠剂为HPMC 60 SH-4000。
在一个或多个实施方案中，所述助悬剂为Avicel RC591。
在一个或多个实施方案中，每1000mL所述药物制剂包含：
在一个或多个实施方案中，每1000mL所述药物制剂包含：
本申请的一个或多个实施方案提供了制备药物制剂的方法，其包括：
(1)准确称量银杏内酯类成分、药学上可接受的载体或赋形剂、以及水；
(2)将银杏内酯类成分加入增溶剂中，搅拌或者震荡，直到形成澄清透明溶液；
(3)依次加入水、苯扎氯铵、依地酸二钠、HPMC 60 SH-4000、甘油和吐温-8，搅拌至完全溶解；
(4)将步骤(2)中得到的溶液加入步骤(3)中得到的溶液，搅拌至混合均匀；
(5)使用水清洗容器内残留药液；
(6)过滤，除菌，得到所述药物制剂；
(7)任选地，将所述药物制剂分装至鼻喷瓶中。
本申请的一个或多个实施方案提供了制备药物制剂的方法，其包括：
(1)准确称量银杏内酯类成分、药学上可接受的载体或赋形剂、以及水；
(2)将水加入容器中，接着加入苯扎氯铵、依地酸二钠、甘油及聚山梨酯80，真空搅拌物料，直到其完全溶解；
(3)将银杏内酯、Avicel RC591加入步骤(2)中得到的溶液中，得到混悬液，真空均质化，直到其完全均质，得到所述药物制剂；
(4)任选地，将所述药物制剂分装至鼻喷瓶中。
本申请的一个或多个实施方案提供了本申请的药物组合物或药物制剂在制备用于抗氧化、拮抗血小板活化因子、降血脂、改善循环、保护心脏、提高免疫力、抗炎、抗病毒、抗肿瘤或抗衰老的药物中的用途。
本申请的一个或多个实施方案提供了本申请的药物组合物或药物制剂在制备用于治疗面瘫或中风的药物中的用途。
本申请的一个或多个实施方案提供了本申请的药物组合物或药物制剂，其用作药物。
本申请的一个或多个实施方案提供了本申请的药物组合物或药物制剂，其用于抗氧化、拮抗血小板活化因子、降血脂、改善循环、保护心脏、提高免疫力、抗炎、抗病毒、抗肿瘤或抗衰老。
本申请的一个或多个实施方案提供了本申请的药物组合物或药物制剂，其用于治疗面瘫或中风。
本申请的一个或多个实施方案提供了抗氧化、拮抗血小板活化因子、降血脂、改善循环、保护心脏、提高免疫力、抗炎、抗病毒、抗肿瘤或抗衰老的方法，其包括将本申请的药物组合物或药物制剂给予有此需要的对象。
本申请的一个或多个实施方案提供治疗面瘫或中风的方法，其包括将本申请的药物组合物或药物制剂给予有此需要的对象。
本申请的一个或多个实施方式提供的鼻喷药物制剂，含量均一，喷雾后每喷主药含量均匀。
本申请的一个或多个实施方式提供的鼻喷药物制剂，使用后鼻腔黏膜无水肿、充血等情况，安全性良好。
在一个或多个实施方式中，“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
在一个或多个实施方式中，“银杏内酯类成分”包括银杏内酯A、银杏内酯B、银杏内 酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯等，及其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶。
以下实施例详细说明本申请的技术方案，但本申请的保护范围包括但是不限于此。
在以下实施例中使用的银杏内酯类成分为成都百裕制药股份有限公司的银杏内酯注射剂(金阁莱)原料(批号：10200601)。
在以下实施例中使用的Avicel RC591购于DuPont Nutrition&Health公司，含有88.4％的微晶纤维素和11.4％的羧甲基纤维素钠(批号DN17831154)。
实施例1
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法：
(1)准确称量各个组分，备用；
(2)将银杏内酯加入乙醇中，使用超音波震荡器震荡(Delta/DC400H)，直到形成澄清透明溶液，备用；
(3)将纯化水加入不锈钢调制桶中，并将苯扎氯铵、依地酸二钠、HPMC 60 SH-4000、甘油及聚山梨酯80加入桶中，使用搅拌器搅拌，直到物料完全溶解，备用；
(4)将步骤2的溶液加入步骤3的溶液中，使用搅拌器搅拌，直到混合均匀，备用；
(5)使用纯化水清洗搅拌叶，并调整溶液调整至1000mL，备用；
(6)过滤除菌后，分装至鼻喷瓶中。
实施例2
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法：
(1)准确称量各个组分，备用；
(2)将银杏内酯加入丙二醇、乙醇中，使用超音波震荡器震荡(Delta/DC400H)直到形成澄清透明溶液，备用；
(3)将纯化水加入不锈钢调制桶中，并将苯扎氯铵、依地酸二钠、HPMC 60 SH-4000、甘油及聚山梨酯80加入桶中，使用搅拌器搅拌，直到物料完全溶解，备用；
(4)将步骤2的溶液加入步骤3的溶液中，使用搅拌器搅拌，直到混合均匀，备用；
(5)使用纯化水清洗搅拌叶，并调整溶液调整至1000mL，备用；
(6)过滤除菌后，分装至鼻喷瓶中。
实施例3
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法：
(1)准确称量各个组分，备用；
(2)将银杏内酯加入丙二醇、乙醇中，使用超音波震荡器震荡(Delta/DC400H)直到形成澄清透明溶液，备用；
(3)将纯化水加入不锈钢调制桶中，并将苯扎氯铵、依地酸二钠、HPMC 60 SH-4000、甘油及聚山梨酯80加入桶中，使用搅拌器搅拌，直到物料完全溶解，备用；
(4)将步骤(2)的溶液加入步骤(3)的溶液中，使用搅拌器搅拌，直到混合均匀，备用；
(5)使用纯化水清洗搅拌叶，并调整溶液调整至1000mL，备用；
(6)过滤除菌后，分装至鼻喷瓶中。
实施例4
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法：
(1)准确称量各个组分，备用；
(2)将银杏内酯加入乙醇中，使用超音波震荡器震荡(Delta/DC400H)直到形成澄清透明溶液，备用；
(3)将纯化水加入不锈钢调制桶中，并将苯扎氯铵、依地酸二钠、HPMC 60 SH-4000、甘油及聚山梨酯80加入桶中，使用搅拌器搅拌，直到物料完全溶解，备用；
(4)将步骤(2)的溶液加入步骤(3)的溶液中，使用搅拌器搅拌，直到混合均匀，备用；
(5)使用纯化水清洗搅拌叶，并调整溶液调整至1000mL，备用；
(6)过滤除菌后，分装至鼻喷瓶中。
实施例5
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法同实施例2。
实施例6
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法同实施例1。
实施例7
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法同实施例1。
实施例8
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法：
(1)准确称量各个组分，备用；
(2)将银杏内酯加入丙二醇中，使用超音波震荡器震荡(Delta/DC400H)，直到形成澄清透明溶液，备用；
(3)将纯化水加入不锈钢调制桶中，并将苯扎氯铵、依地酸二钠、HPMC 60 SH-4000、甘油及聚山梨酯80加入桶中，使用搅拌器搅拌，直到物料完全溶解，备用。
(4)将步骤(2)的溶液加入步骤(3)的溶液中，使用搅拌器搅拌，直到混合均匀，备用。
(5)使用纯化水清洗搅拌叶，并调整溶液调整至1000mL，备用。
(6)过滤除菌后，分装至鼻喷瓶中。
实施例9
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法同实施例1。
实施例10
含银杏内酯类成分的鼻喷溶液的成分组成为：
纯化水余量
制备方法同实施例1。
实施例11
银杏内酯鼻喷悬浮液的成分组成为：
纯化水余量
制备方法：
(1)准确称量各个组分，备用；
(2)将适量纯化水加入容器中，接着加入苯扎氯铵、依地酸二钠、甘油及聚山梨酯80，真空搅拌物料，直到其完全溶解；
(3)将银杏内酯、Avicel RC591加入步骤二的溶液中，并加入纯化水调整悬浮液至1000mL，真空均质化，直到其完全均质；
(4)分装至鼻喷瓶中。
实施例12
银杏内酯鼻喷悬浮液的成分组成为：
纯化水余量
制备方法同实施例11。
实施例13
银杏内酯鼻喷悬浮液的成分组成为：
纯化水余量
制备方法同实施例11。
试验例
1.处方性质测试
1.1粘度：使用粘度计(LVDV-I1+PRO)在25℃下测定样品，进行三次测定并确定平均粘度值(mPas或cp)。
1.2渗透压：使用渗透压计测定样品的渗透压值，进行三次测定并确定平均渗透压值。
1.3含量分析方法(HPLC)：
缓冲溶液：将1.19g磷酸氢二钠和8.25g磷酸二氨钾溶解于900mL水中，使用稀磷酸或1N氢氧化钠调整pH至5.8，加水稀释至1000mL，混匀。
稀释溶液：甲醇与水以1:1(v/v)的比例混匀。
对照品溶液：精确称量约60mg银杏内酯对照品，置50mL烧杯中，加入10mL缓冲溶液并超声处理5分钟将溶液转移至合适的分离器中，用5mL的缓冲溶液冲洗烧杯然后将洗液转移到分离器中。15分钟后，加入50.0mL乙酸乙酯萃取，待分层后收集乙酸乙酯溶液，于50℃的水浴中蒸发至干将残留物溶于20.0mL稀释溶液中；精确吸取该溶液5.0mL，置100mL量瓶中用稀释溶液稀释至刻度，摇匀。
供试品溶液：精确称量约含3mg银杏内酯之样品，置于合适的分离器中，加入20mL缓冲溶液并混合均匀。15分钟后，用50.0mL乙酸乙酯萃取，待分层后收集乙酸乙酯溶液，于50℃的水浴中蒸发至干。将残留物溶于20.0mL稀释溶液中，过滤。
流动相：使用水和甲醇的混合物。
检测器：UV 216nm；流速：1.0mL/min；柱温：25℃
色谱柱：填料为十八烷基硅烷键合多孔硅胶或陶瓷微粒，4.6mm×250mm色
谱柱，粒径5μm；进样量：100μL
含量分析测定法：
精密量取供试品溶液与对照品溶液各100μL，分别注入液相色谱仪，记录色谱图，按外标法以峰面积计算，即得。
表1
N.D.表示未测试。
结论：(1)本申请的银杏内酯鼻喷制剂在40℃或60℃下放置6-10天后，其pH值、黏度值和渗透压数值均无明显变化；银杏内酯降解量小于10％。这表明本申请方法制备获得的鼻喷溶液较稳定。
2.大鼠药代动力学测试
试验动物：健康成年SD大鼠3只，体重分别296g、303g、292g。
受试样品：银杏内酯鼻喷溶液(实施例8)
给药途径：鼻腔给药(i.n.)
给药剂量：100μL/只
试验方法：
健康成年SD大鼠3只，给药前对动物进行呼吸麻醉，麻醉后对每只大鼠进行受试样品滴鼻给药，50μL/鼻孔。于不同时间点采血0.1mL经EDTA-K2抗凝，4℃离心5min分离血浆，于-80℃保存待测。给药前(0h)、给药后15min、0.5h、1h、2h、4h、8h，采用 LC/MS/MS法测定血浆的药物浓度。
表2
结论：通过鼻内给予大鼠本申请制剂后，银杏内酯在大鼠体内被迅速吸收，并在8小时内维持较好的血药浓度，且未发现大鼠鼻部刺激和充血现象。
3大鼠脑缺血再灌注神经损伤模型药效试验
3.1实验动物
取SPF级SD大鼠35只；雄性；年龄为6-8周；体重261-292g；购于北京维通利华实验动物技术有限公司，许可证号：SCXK(浙)2019-0001；环境适应6天。
3.2试验设计
3.2.1模型建立
模型组及给药组的大鼠用6％水合氯醛麻醉(7mL/kg)，仰卧姿固定四肢。大鼠颈部正中偏右剪开皮肤，沿颈总动脉远心端分离出颈内动脉和颈外动脉，在颈外动脉做切口，将线栓沿颈内动脉方向插入，缺血2小时后，将线栓完全取出，实现缺血再灌注。假手术组动物6％水合氯醛麻醉后，仅分离暴露颈总动脉，不做中动脉栓塞处理。
3.2.2分组给药信息
组别设计：假手术组、模型组、依达拉奉组、实施例13组；
分组方法：根据动物体重随机分组。
给药方法：实施例13组动物复灌后即刻给药，鼻腔滴注给药，造模当天给药1次，之后每天给药2次(BID)，每次100μL，共给药3天；依达拉奉组复灌后即刻给药，静脉注射给药(i.v.)，每天给药1次(QD)，共给药3天；模型组给予空白溶剂，给药方式及频次与受试药组相同。
表3试验设计表
3.3观察指标
3.3.1神经功能评分
检测时间：再灌注后第24小时；检测动物：所有入组动物；评分方法：Longa评分法。
3.3.2相对脑含水量检测
检测时间：再灌注后第72小时；检测动物：造模后所有存活动物；
检测方法：预冷的PBS灌注心脏，各组存活动物取脑组织，去除嗅球、小脑和低位脑干，称取脑组织湿重，然后将脑组织切为6片，72℃烘烤24小时，称取脑组织干重，根据干湿重法计算大鼠相对脑含水量，计算公式如下：
相对脑含水量(g)＝(脑组织湿重－脑组织干重)－假手术组脑组织平均含水量
3.4统计分析
试验所获数据采用IBM SPSS Statistics 22.0进行数据统计分析。
3.5试验结果
3.5.1 Longa神经行为学评分结果
表4各组动物Longa神经行为学评分统计结果(Mean±SEM)
vs假手术组：****p≤0.0001；vs模型组：#p≤0.05。
3.5.2相对脑含水量结果
表5各组动物相对脑含水量统计结果(Mean±SEM,g)
vs假手术组：****p≤0.0001；vs模型组：##p≤0.01。
3.6试验结论
综上所述，线栓法引起的大鼠大脑中动脉脑缺血(MCAO)再灌注神经损伤模型中，鼻内给予大鼠本申请的制剂能改善神经功能和脑水肿，达到和静脉注射依达拉奉相似的药效。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (12)
- 药物组合物，其包含银杏内酯类成分以及药学上可接受的载体或赋形剂。
- 包含银杏内酯类成分的药物制剂，其包含银杏内酯类成分、药学上可接受的载体或赋形剂、以及水。
- 如权利要求1所述的药物组合物或权利要求2所述的药物制剂，其用于鼻部给药。
- 如权利要求2所述的药物制剂，其中所述药物制剂为喷雾剂。
- 如权利要求1所述的药物组合物或权利要求2所述的药物制剂，其中所述药学上可接受的载体或赋形剂包括抑菌剂、抗氧剂、表面活性剂、增溶剂、渗透压调节剂、金属离子络合剂、增稠剂、pH调节剂、助悬剂中的一种或者多种。
- 如权利要求5所述的药物组合物或权利要求5所述的药物制剂，其中所述银杏内酯类成分为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯中的一种或多种；所述抑菌剂为苯扎氯铵；所述表面活性剂为聚山梨酯80；所述增溶剂为乙醇、丙二醇或其组合；所述渗透压调节剂为甘油；所述金属离子络合剂为依地酸二钠；所述增稠剂为HPMC 60 SH-4000；所述助悬剂为Avicel RC591。
- 如权利要求6所述的药物制剂，其中每1000mL所述药物制剂包含：
- 如权利要求6所述的药物制剂，其中每1000mL所述药物制剂包含：
- 制备药物制剂的方法，其包括：(1)准确称量银杏内酯类成分、药学上可接受的载体或赋形剂、以及水；(2)将银杏内酯类成分加入增溶剂中，搅拌或者震荡，直到形成澄清透明溶液；(3)依次加入水、苯扎氯铵、依地酸二钠、HPMC 60 SH-4000、甘油和吐温-8，搅拌至完全溶解；(4)将步骤(2)中得到的溶液加入步骤(3)中得到的溶液，搅拌至混合均匀；(5)使用水清洗容器内残留药液；(6)过滤，除菌，得到所述药物制剂；(7)任选地，将所述药物制剂分装至鼻喷瓶中。
- 制备药物制剂的方法，其包括：(1)准确称量银杏内酯类成分、药学上可接受的载体或赋形剂、以及水；(2)将水加入容器中，接着加入苯扎氯铵、依地酸二钠、甘油及聚山梨酯80，真空搅 拌物料，直到其完全溶解；(3)将银杏内酯、Avicel RC591加入步骤(2)中得到的溶液中，得到混悬液，真空均质化，直到其完全均质，得到所述药物制剂；(4)任选地，将所述药物制剂分装至鼻喷瓶中。
- 权利要求1、3、5或6所述的药物组合物或者权利要求2-8中任一项所述的药物制剂在制备用于抗氧化、拮抗血小板活化因子、降血脂、改善循环、保护心脏、提高免疫力、抗炎、抗病毒、抗肿瘤或抗衰老的药物中的用途。
- 权利要求1、3、5或6所述的药物组合物或者权利要求2-8中任一项所述的药物制剂在制备用于治疗面瘫或中风的药物中的用途。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024067579A1 (zh) * | 2022-09-29 | 2024-04-04 | 成都百裕制药股份有限公司 | 银杏萜内酯在制备预防或治疗糖尿病及糖尿病并发症药物上的用途 |
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