CN113214209B - 橙皮素与卡马西平共晶物及制备方法和其组合物与用途 - Google Patents
橙皮素与卡马西平共晶物及制备方法和其组合物与用途 Download PDFInfo
- Publication number
- CN113214209B CN113214209B CN202010080013.XA CN202010080013A CN113214209B CN 113214209 B CN113214209 B CN 113214209B CN 202010080013 A CN202010080013 A CN 202010080013A CN 113214209 B CN113214209 B CN 113214209B
- Authority
- CN
- China
- Prior art keywords
- hesperetin
- carbamazepine
- eutectic
- crystals
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 title claims abstract description 141
- AIONOLUJZLIMTK-AWEZNQCLSA-N hesperetin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-AWEZNQCLSA-N 0.000 title claims abstract description 139
- AIONOLUJZLIMTK-UHFFFAOYSA-N hesperetin Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-UHFFFAOYSA-N 0.000 title claims abstract description 139
- 229960001587 hesperetin Drugs 0.000 title claims abstract description 139
- 235000010209 hesperetin Nutrition 0.000 title claims abstract description 139
- FTODBIPDTXRIGS-UHFFFAOYSA-N homoeriodictyol Natural products C1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 FTODBIPDTXRIGS-UHFFFAOYSA-N 0.000 title claims abstract description 139
- 229960000623 carbamazepine Drugs 0.000 title claims abstract description 135
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 title claims abstract description 134
- 230000005496 eutectics Effects 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 39
- 239000000126 substance Substances 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 208000020925 Bipolar disease Diseases 0.000 claims abstract description 8
- 208000028683 bipolar I disease Diseases 0.000 claims abstract description 8
- 206010044652 trigeminal neuralgia Diseases 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims description 53
- 239000003826 tablet Substances 0.000 claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 239000002775 capsule Substances 0.000 claims description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000004458 analytical method Methods 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- -1 anti-inflammatory Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 238000002329 infrared spectrum Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 238000004566 IR spectroscopy Methods 0.000 claims description 2
- 230000003556 anti-epileptic effect Effects 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 238000005102 attenuated total reflection Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 239000011343 solid material Substances 0.000 claims 4
- 230000003288 anthiarrhythmic effect Effects 0.000 claims 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims 1
- 230000003561 anti-manic effect Effects 0.000 claims 1
- 239000003416 antiarrhythmic agent Substances 0.000 claims 1
- 238000013270 controlled release Methods 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 7
- 206010003119 arrhythmia Diseases 0.000 abstract description 7
- 230000006793 arrhythmia Effects 0.000 abstract description 7
- 230000003405 preventing effect Effects 0.000 abstract description 6
- 206010015037 epilepsy Diseases 0.000 abstract description 5
- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 230000004054 inflammatory process Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 238000002156 mixing Methods 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000003405 delayed action preparation Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000006069 physical mixture Substances 0.000 description 5
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 description 2
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 description 2
- 229940025878 hesperidin Drugs 0.000 description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 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
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Toxicology (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Psychiatry (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了橙皮素与卡马西平共晶物及制备方法和其组合物与用途,属于医药技术领域。具体而言,本发明公开了橙皮素与卡马西平形成的共晶物,该共晶物的分子式为(C16H14O6)·(C15H12N2O);橙皮素与卡马西平共晶物的制备方法;橙皮素与卡马西平共晶物作为药物有效成分,在制备抗肿瘤、抗氧化、抗炎症、癫痫、三叉神经痛、躁狂抑郁、防止动脉粥样硬化、心律失常疾病及并发症药物中的应用。
Description
技术领域
本发明涉及一种橙皮素与卡马西平形成的共晶物;橙皮素与卡马西平共晶物的制备方法;橙皮素与卡马西平共晶物作为药物有效成分,在制备抗肿瘤、抗氧化、抗炎症、癫痫、三叉神经痛、躁狂抑郁、防止动脉粥样硬化、心律失常疾病及并发症药物中的应用;属于医药技术领域。
背景技术
橙皮素(英文名:Hesperetin)是广泛存在于柑橘属植物果中的二氢黄酮类化合物,是橙皮苷的水解产物,结构式如a所示,能够起到抗肿瘤、抗氧化、抗炎症、防止动脉粥样硬化的作用[1-3]。
卡马西平(英文名:Carbamazepine)是一种常见的脂溶性较强的钙通道阻滞剂,是临床治疗癫痫的首选药物,常用于治疗三叉神经痛、躁狂抑郁、心律失常等病症,结构式如b所示。卡马西平的共晶物研究已经取得了一些进展,如卡马西平与烟酰胺共晶物[4],卡马西平与糖精共晶物[5],卡马西平与阿司匹林共晶物[6],卡马西平与2-羟基苯甲酸共晶物[7],等。
关于橙皮素的多晶型研究:目前发现的橙皮素具有两种晶型状态[8-9],其中研究晶A型为含一分子水的橙皮素,晶B型为不含水晶型。这两种晶型物质与本发明在物质组成上存在本质差异,本专利使用的橙皮素原料药为晶B型。
综上所述,迄今没有见到橙皮素与卡马西平形成共晶物的研究报道,在物质形态、组合比例、制备方法以及用途等方面,也未见与本发明相似或冲突研究内容。
发明内容
本发明的研究是通过将橙皮素与卡马西平制备成为具有特定非共价作用力的共晶物型固体物质,从而形成有别于橙皮素和卡马西平及二者简单联合应用的新物质,进而发现本发明的新共晶物固体物质在制备抗肿瘤、抗氧化、抗炎症、癫痫、三叉神经痛、躁狂抑郁、防止动脉粥样硬化、心律失常疾病及并发症药物中的特殊优势。
本发明要解决的技术问题:
本发明要解决的技术问题之一:提供橙皮素与卡马西平共晶物存在状态和表征方式。
本发明要解决的技术问题之二:提供橙皮素与卡马西平共晶物的制备方法。
本发明要解决的技术问题之三:提供使用橙皮素与卡马西平共晶物作为药物活性成分的药物组合物,其每次用药剂量在10-1000mg范围内。所述的药物组合物包括片剂、胶囊、丸剂、针剂、缓释或控释制剂药物。
本发明要解决的技术问题之四:提供橙皮素与卡马西平共晶物在治疗疾病过程中由于二者共晶物结合而提高生物体内血药浓度而发挥药物有效治疗作用。
本发明要解决的技术问题之五:提供了使用橙皮素与卡马西平共晶物及其混合晶型固体物质作为药物有效成分的原料,在制备抗抗肿瘤、抗氧化、抗炎症、癫痫、三叉神经痛、躁狂抑郁、防止动脉粥样硬化、心律失常疾病及并发症药物中的应用。
为解决上述技术问题,本发明采用如下技术方案:
1.橙皮素与卡马西平共晶物样品形态特征:
1.1本发明涉及的橙皮素与卡马西平共晶物,橙皮素与卡马西平以非共价键相结合形成共晶物质,二者的摩尔比为1:1。
1.2本发明涉及的橙皮素与卡马西平共晶物,不含有结晶溶剂或结晶水成分,当使用粉末X射线衍射分析,采用CuKα辐射实验条件时,表现为衍射峰位置:2-Theta值(°)或d值衍射峰相对强度峰高值(Height%)或峰面积值(Area%)具有如下特征峰值时的固体物质(表1,图1)。橙皮素和卡马西平物理混合物的粉末X射线衍射图谱数据见图2、表2。橙皮素与卡马西平共晶物以及橙皮素和卡马西平物理混合物的粉末X射线衍射图谱在衍射峰数量、衍射峰位置、衍射峰强度、衍射峰拓扑图形等方面均存在明显差异,表明橙皮素与卡马西平共晶物以及橙皮素和卡马西平物理混合物既不相同也不等同。
表1橙皮素与卡马西平共晶物的粉末X射线衍射峰数据
表2橙皮素和卡马西平物理混合物的粉末X射线衍射峰数据
1.3本发明涉及的橙皮素与卡马西平共晶物,使用衰减全反射傅立叶红外光谱法进行分析时,在3430、3348、3206、3057、3025、2969、2941、2845、2605、2252、2155、2053、1969、1677、1644、1604、1583、1514、1491、1447、1418、1401、1386、1343、1289、1273、1237、1220、1193、1160、1132、1114、1080、1067、1042、1028、1016、985、971、957、878、867、860、841、827、801、789、772、764、741、716、663cm-1处存在红外光谱特征峰,其中红外光谱特征峰的允许偏差为±2cm-1(图3)。
1.4本发明涉及的橙皮素与卡马西平共晶物,使用差示扫描量热技术分析时,在30~250℃范围内,升温速率为每分钟10℃时,其DSC图谱中在176℃±3℃处存在1个吸热峰(图4)。橙皮素与卡马西平共晶物与橙皮素、卡马西平的DSC图谱在吸/放热峰数量、位置等方面均存在明显差异,表明橙皮素与卡马西平共晶物与橙皮素及卡马西平原料既不相同也不等同(图5)。
2.橙皮素与卡马西平共晶物的制备方法特征:
2.1本发明所涉及的橙皮素与卡马西平共晶物的制备方法,采用溶剂混悬法,将橙皮素与卡马西平按摩尔比1:1混合,加入有机溶剂,室温条件下,搅拌速度为20r/min~400r/min,搅拌1小时~96小时,所获得的混悬液通过溶剂蒸发干燥、过滤自然干燥或过滤真空干燥,获得橙皮素与卡马西平共晶物。所述的有机溶剂优选自甲醇、乙醇、乙腈、丙酮、乙酸乙酯、二氧六环、正己烷、环己烷中的任意一种或多种经不同配比组合制成的混合溶剂;保持橙皮素与卡马西平总质量与有机溶剂固液比为1mg/ml-500mg/ml范围内。
2.2本发明的含有橙皮素与卡马西平共晶物的混合固体物质,是将上述方法制备获得的橙皮素与卡马西平共晶物,与其他化学物质按照任意非零比例和常规的方法进行混合。
3.含有橙皮素与卡马西平共晶物成分、给药剂量特征和药物制剂组合物特征:
3.1本发明涉及的药物组合物,含有有效剂量的橙皮素与卡马西平共晶物和药学上可接受的载体。
3.2本发明涉及的药物组合物,橙皮素与卡马西平共晶物的每日用药剂量在10mg~1000mg范围内。
3.3本发明涉及的药物组合物,所述药物组合物的剂型是片剂、胶囊、丸剂、针剂、缓释制剂或控释制剂。
3.4本发明涉及的橙皮素与卡马西平共晶物在制备抗肿瘤、抗氧化、抗炎症、癫痫、三叉神经痛、躁狂抑郁、防止动脉粥样硬化、心律失常疾病及并发症药物中的应用。
本发明涉及以本发明橙皮素与卡马西平共晶物为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明橙皮素与卡马西平共晶物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明橙皮素与卡马西平共晶物成分通常为10-90%重量范围内。
本发明橙皮素与卡马西平共晶物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、***、直肠等。
本发明的给药剂型优选是固体剂型。固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等。
本发明橙皮素与卡马西平共晶物、本发明橙皮素与卡马西平共晶物的混合固体物质可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药***。
为了将本发明橙皮素与卡马西平共晶物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、***胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明橙皮素-卡马西平共晶物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明橙皮素与卡马西平共晶物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明橙皮素与卡马西平共晶物成分片剂的各种稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明橙皮素与卡马西平共晶物的胶囊剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
4.含有橙皮素与卡马西平共晶物的用途:
本发明发现了橙皮素与卡马西平共晶物在制备和/或治疗抗肿瘤、抗氧化、抗炎症、癫痫、三叉神经痛、躁狂抑郁、防止动脉粥样硬化、心律失常疾病及并发症药物中的应用。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明橙皮素与卡马西平共晶物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明橙皮素与卡马西平共晶物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明橙皮素与卡马西平共晶物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明的技术方案具有如下有益技术效果:
本发明的橙皮素与卡马西平共晶物在安全性、溶解性、稳定性和生物活性等方面和现有技术中的橙皮素相比具有显著优势。
本发明的橙皮素与卡马西平共晶物不含任何结晶溶剂,具有良好的安全性成药优势。
本发明涉及的橙皮素与卡马西平共晶物,与橙皮素相比,具有预料不到的溶解性优势,具体体现在:在盐酸盐缓冲液(pH1.2)、醋酸盐缓冲液(pH4.5)、磷酸盐缓冲液(pH6.8)、纯水(pH7.0)等溶出体系中表现出显著的溶解度与溶解速率优势(图6)。
本发明涉及的橙皮素与卡马西平共晶物,在高温(60℃)、高湿(25℃),相对湿度(90%±5%)、光照(4500lx±500lx)条件下均可以稳定存在,具有良好的稳定性成药优势(图7)。
附图说明
图1橙皮素与卡马西平共晶物的粉末X射线衍射图谱
图2橙皮素与卡马西平物理混合物的粉末X射线衍射图谱
图3橙皮素与卡马西平共晶物的红外吸收光谱图
图4橙皮素与卡马西平共晶物的差示扫描量热图谱
图5橙皮素与卡马西平共晶物及原料的差示扫描量热图谱
图6不同条件下样品的溶解性曲线
图7橙皮素与卡马西平共晶物的稳定性图谱
具体实施方式
为更好说明本发明的技术方案,特给出以下实施例,但本发明并不仅限于此。
实施例1
橙皮素与卡马西平共晶物制备方法1
取橙皮素与卡马西平适量,二者摩尔比为1:1,室温下采用溶剂混悬法将样品加入适宜容器中,加入适量有机溶剂,于室温条件下搅拌适当时间,将所得的混悬液溶剂蒸发干燥、过滤自然干燥或过滤真空干燥,条件参数参见表3。对其进行粉末X射线衍射分析,其衍射图谱与图1一致,表明所得样品为橙皮素与卡马西平共晶物。
表3橙皮素与卡马西平共晶物制备方法1具体实例
实施例2
橙皮素与卡马西平共晶物体外溶出释放特征
考察了橙皮素与卡马西平共晶物与橙皮素原料药在纯水,pH值为1.2,pH值为4.5,pH值为6.8的溶液***中的溶解性特征。参照《普通口服固体制剂溶出度试验技术指导原则》进行实验。溶解百分含量采用用高效液相法,以外标法计算其溶解百分含量。以时间为横坐标,溶解百分含量为纵坐标分别绘制溶解曲线(图6)。数据见表4。
检测条件:检测***:Aligent 1200,色谱柱:Agilent Eclipse XDB-C18(4.6×150mm,5μm);流动相:甲醇-水(70:30,v/v);流速:1mL·min-1;柱温:30℃;检测波长:橙皮素:280nm;进样量:10μl。
表4溶出曲线数据
由实验数据可以看出,橙皮素与卡马西平共晶物在盐酸盐缓冲溶液、醋酸盐缓冲液、磷酸盐缓冲液、纯水体系中的溶解行为均优于橙皮素原料,具体体现在橙皮素与卡马西平共晶物具有更快速的溶解速率和更高的溶解量,易于更快速地吸收达到有效血药浓度,其吸收总量亦有明显增加,溶解量约为橙皮素的1.5倍,可以更好地实现药物的疾病治疗作用;橙皮素与卡马西平共晶物的溶解性曲线具有稳定的释放平台,可保证在疾病治疗过程中保持稳定的血药浓度。
实施例3
橙皮素与卡马西平共晶物的稳定性优势
高温试验:将取橙皮素与卡马西平共晶物样品置开口洁净表面皿中,在60℃温度下放置10天,并于第0天、第5天和第10天取样。将上述取样点所得样品进行粉末X射线衍射分析,结果表明橙皮素与卡马西平共晶物在高温影响因素试验下稳定。
高湿试验:将橙皮素与卡马西平共晶物样品置开口洁净表面皿中,在25℃于相对湿度90%±5%条件下放置10天,并于第0天、第5天和第10天取样。将上述取样点所得样品进行粉末X射线衍射分析,结果表明橙皮素与卡马西平共晶物在高湿条件下稳定。
光照试验:将橙皮素与卡马西平共晶物样品置开口洁净表面皿中,放在装有日光灯的光照箱,于照度为4500lx±500lx的条件放置10天,并于第0天、第5天和第10天取样。将上述取样点所得样品进行粉末X射线衍射分析,结果表明橙皮素与卡马西平共晶物在高湿条件下稳定。(图7)
实施例4
组合药物制剂的制备方法1(片剂):
一种组合药物片剂的制备方法,其特征是使用橙皮素与卡马西平共晶物纯品作为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分,按照一定比例配比制成每片含药量在10~500mg的片剂样品,表5给出片剂配方比例:
表5橙皮素与卡马西平共晶物组合药物片剂的制备配方
将橙皮素与卡马西平共晶物纯品原料药制备成片剂制剂的方法是:将几种赋形剂与原料药混合均匀,直接压片;或辅料混合干法制粒再与原料药混合均匀后压片,即得。
组合药物制剂的制备方法2(片剂):
一种组合药物片剂的制备方法,其特征是使用橙皮素与卡马西平共晶物纯品为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分,按照一定比例配比制成每片含药量在10~500mg的片剂样品,表6给出片剂配方比例:
表6橙皮素与卡马西平共晶物组合药物片剂的制备配方
将橙皮素与卡马西平共晶物纯品原料药制备成片剂制剂的方法是:将几种赋形剂与原料药混合均匀,加入1%羟甲基纤维素钠溶液适量,制成软料,过筛制粒,湿粒烘干,过筛整粒,加入硬脂酸镁和滑石粉混合均匀,压片,即得。
组合药物制剂的制备方法3(胶囊):
一种组合药物胶囊的制备方法,其特征是使用橙皮素与卡马西平共晶物纯品作为组合药物的原料药、使用几种赋形剂作为制备组合药物胶囊的辅料成分,按照一定比例配比制成每片含药量在10~500mg的胶囊样品,表7给出胶囊配方比例:
表7橙皮素与卡马西平共晶物组合药物胶囊制剂的原料药和辅料配方
将橙皮素与卡马西平共晶物原料药制备成片剂制剂的方法是:将几种赋形剂与原料药混合均匀,加入1%羟甲基纤维素钠溶液适量,制成湿粒烘干过筛整粒,加入硬脂酸镁混合均匀,***胶囊制得;或不使用制粒步骤,而直接将橙皮素与卡马西平共晶物原料药与几种赋形剂辅料混合均匀,过筛后,直接装入胶囊制得。
实施例5
橙皮素与卡马西平共晶物组合药物的给药剂量1(片剂):
使用橙皮素与卡马西平共晶物样品作为药物活性成分制备开发的药物组合物,其特征是使用橙皮素与卡马西平共晶物作为药物的活性成分,每日给药剂量为300mg,可分别制备成每日3次/每次1片100mg普通片剂,或每日1次/每次1片300mg的片剂类。
橙皮素与卡马西平共晶物组合药物的给药剂量2(胶囊):
使用橙皮素与卡马西平共晶物样品作为药物活性成分制备开发的药物组合物,其特征是使用橙皮素与卡马西平共晶物作为药物的活性成分,每日给药剂量为500mg,可分别制备成每日2次/每次1粒250mg胶囊,或每日1次/每次1粒500mg胶囊。
需要说明的问题:本发明涉及的橙皮素与卡马西平共晶物药物组合物在有效成分的给药剂量上存在有许多因素影响,例如:用于预防和治疗的用途不同而造成每日用药剂量的不同;患病性质与患病严重程度不同而造成每日用药剂量的不同;患者性别、年龄、体表面积的不同,给药途径、给药次数、治疗目的不同而造成每日用药剂量的不同;此外,晶型样品间存在的吸收和血药浓度不同等,亦造成本发明在使用橙皮素与卡马西平共晶物成分的每日合适剂量范围为0.002-20mg/kg体重,优选为0.01-10mg/kg体重。使用时应根据实际的预防与治疗不同情况需求制定不同的橙皮素与卡马西平共晶物有效成分总剂量方案,并可分为多次或一次给药方式完成。
参考文献
[1]刘正兵,宫剑滨,橙皮苷及橙皮素对心血管***保护作用及机制的研究进展[J],东南国防医药,2017,19(5):504-507.
[2]石琳琳,周菊华,橙皮素抗肿瘤药用价值研究概况[J],中国民族民间医药,2017,26(9):66-71.
[3]邹淑君,于子惠,马丽英等,橙皮苷及橙皮素清除自由基活性的研究[J],中医药学报,2013,41(1):66-67.
[4]Buanz ABM.,Parkinson GN,and Gaisford S.Characterizati on ofCarbamazepine-Nicatinamide Cocrystal Polymorphs with Rapid Heating DSC andXRPD.Cryst.Growth&Des.,2011,11,1177-1181.
[5]Childs SL,Wood PA,Hornedo NR,et al.Analysis of 50CrystalStructures Containing Carbamazepine Using the Materials Module of MercuryCSD.Cryst.Growth&Des.,2009,9(4),1869-1888.
[6]Vishweshwar P,McMahon JA,Oliveira M,et al.The Predictably ElusiveForm II of Aspirin.J.Am.Chem.Soc.,2005,127,16802-16803.
[7]McMahon JA,Bis JA,Vishweshwar P,et al.Crystal engineering of thecomposition of pharmaceutical phases.31.Primary amide supramolecularheterosynthons and their role in the design of pharmaceutical co-crystals.Z.Kristallogr.2005,220,340–350.
[8]Shin W,Kim S,Chun KS.Structure of(R,S)-Hesperetin Monohydrate.ActaCrystallogr.,Sect.C:Cryst.Struct.Commun.,1987,43(5):904-911.
[9]Fujii S,Yamagata Y,Jin GZ,et al.Novel Molecular Conformation of(R,S)-Hesperetin in Anhydrous Crystal.Chem.Pharm.Bull.,1994,42(5):1143-1145.
Claims (14)
1.一种橙皮素与卡马西平共晶物,其特征在于,橙皮素与卡马西平按照1:1摩尔比以非共价键形成共晶物,当使用粉末X射线衍射分析采用CuKα辐射实验条件时,衍射峰位置:2-Theta值(°)或d值和衍射峰相对强度:峰高值(Height%)或峰面积值(Area%)具有如下特征:
2.根据权利要求1所述的橙皮素与卡马西平共晶物,其特征在于,使用衰减全反射傅立叶红外光谱法进行分析时,在3430、3348、3206、3057、3025、2969、2941、2845、2605、2252、2155、2053、1969、1677、1644、1604、1583、1514、1491、1447、1418、1401、1386、1343、1289、1273、1237、1220、1193、1160、1132、1114、1080、1067、1042、1028、1016、985、971、957、878、867、860、841、827、801、789、772、764、741、716、663cm-1处存在红外光谱特征峰,其中红外光谱特征峰的允许偏差为±2cm-1。
3.根据权利要求1所述的橙皮素与卡马西平共晶物,其特征在于,使用差示扫描量热技术分析时,表现为在30~250℃范围内,升温速率为每分钟10℃时,其DSC图谱中在176℃±3℃处存在1个吸热峰。
4.一种如权利要求1-3任一所述的橙皮素与卡马西平共晶物的制备方法,其特征在于,橙皮素与卡马西平按照1:1的摩尔比例投料,采用溶剂混悬的化学方法制备获得橙皮素与卡马西平共晶物。
5.根据权利要求4的制备方法,所述的溶剂混悬法,其中溶剂的选择为甲醇、乙醇、乙酸乙酯、丙酮、乙腈、二氧六环、正己烷、环己烷;搅拌速度为20r/min~400r/min;搅拌时间为1小时~96小时,所获得的混悬液通过溶剂蒸发干燥、过滤自然干燥或过滤真空干燥制备获得橙皮素与卡马西平共晶物。
6.一种含有橙皮素与卡马西平共晶物的混合固体物质,其特征在于,含有权利要求1-3任一项所述的橙皮素与卡马西平共晶物的量为1-99.9%。
7.一种含有橙皮素与卡马西平共晶物的混合固体物质,其特征在于,含有权利要求1-3任一项所述的橙皮素与卡马西平共晶物的量为10-99.9%。
8.一种含有橙皮素与卡马西平共晶物的混合固体物质,其特征在于,含有权利要求1-3任一项所述的橙皮素与卡马西平共晶物的量为50-99.9%。
9.一种含有橙皮素与卡马西平共晶物的混合固体物质,其特征在于,含有权利要求1-3任一项所述的橙皮素与卡马西平共晶物的量为85-99.9%。
10.一种药物组合物,其特征在于,含有有效剂量的权利要求1-3中任一项的橙皮素与卡马西平共晶物和药学上可接受的载体。
11.一种药物组合物,其特征在于,含有有效剂量的权利要求6-9任一项所述的橙皮素与卡马西平共晶物的混合固体物质和药学上可接受的载体。
12.根据权利要求10或11的药物组合物,其特征在于,橙皮素与卡马西平共晶物的每日用药剂量在10mg~1000mg范围内。
13.根据权利要求10或11的药物组合物,其特征在于,所述药物组合物的剂型是片剂、胶囊、丸剂、粉针剂、缓释制剂或控释制剂。
14.权利要求1-3中任一项所述的橙皮素与卡马西平共晶物或权利要求6-9任一项所述的含有橙皮素与卡马西平共晶物的混合固体物质或权利要求10或11所述的药物组合物在制备抗肿瘤、抗氧化、抗炎症、抗癫痫、抗三叉神经痛、抗躁狂抑郁、防止动脉粥样硬化、抗心律失常疾病及并发症药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010080013.XA CN113214209B (zh) | 2020-02-04 | 2020-02-04 | 橙皮素与卡马西平共晶物及制备方法和其组合物与用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010080013.XA CN113214209B (zh) | 2020-02-04 | 2020-02-04 | 橙皮素与卡马西平共晶物及制备方法和其组合物与用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113214209A CN113214209A (zh) | 2021-08-06 |
CN113214209B true CN113214209B (zh) | 2024-03-26 |
Family
ID=77085409
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010080013.XA Active CN113214209B (zh) | 2020-02-04 | 2020-02-04 | 橙皮素与卡马西平共晶物及制备方法和其组合物与用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113214209B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114524769B (zh) * | 2022-02-14 | 2023-10-24 | 中国药科大学 | 塞来昔布-卡马西平共晶、制备方法、药物组合物和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1721613A1 (de) * | 2005-05-13 | 2006-11-15 | Mewicon med. wiss. Beratung GmbH | Hesperidin zur Behandlung von Epilepsie, Migräne, Schizophrenie, Depression, Drogenmissbrauch |
WO2008108639A1 (en) * | 2007-03-08 | 2008-09-12 | Avantium Holding B.V. | Co-crystalline forms of carbamazepine |
-
2020
- 2020-02-04 CN CN202010080013.XA patent/CN113214209B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1721613A1 (de) * | 2005-05-13 | 2006-11-15 | Mewicon med. wiss. Beratung GmbH | Hesperidin zur Behandlung von Epilepsie, Migräne, Schizophrenie, Depression, Drogenmissbrauch |
WO2008108639A1 (en) * | 2007-03-08 | 2008-09-12 | Avantium Holding B.V. | Co-crystalline forms of carbamazepine |
Non-Patent Citations (2)
Title |
---|
在线过程分析技术在抗生素等药物结晶中的应用;刘胜;侯静美;龚俊波;;中国抗生素杂志(11) * |
药物共晶筛选技术的研究进展;黄雨婷;徐嘉;迟宗良;范孟雪;秦昆明;蔡挺;蔡宝昌;;国际药学研究杂志(04) * |
Also Published As
Publication number | Publication date |
---|---|
CN113214209A (zh) | 2021-08-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110054624B (zh) | 盐酸小檗碱与咖啡酸共晶物及制备方法和其组合物与用途 | |
CN109988164B (zh) | 盐酸小檗碱与苹果酸共晶物及制备方法和其组合物与用途 | |
CN112851666B (zh) | 阿哌沙班与槲皮素共晶物及制备方法和其组合物与用途 | |
CN110041326B (zh) | 盐酸小檗碱与反丁烯二酸共晶物及制备方法和其组合物与用途 | |
WO2010060387A1 (zh) | 硝克柳胺化合物五种晶型、其制法和其药物组合物与用途 | |
CN110041325B (zh) | 盐酸小檗碱与布洛芬共晶物及制备方法和其组合物与用途 | |
US11236041B2 (en) | Type-G crystal form of fenolamine, preparation method, composition and use thereof | |
CN113214209B (zh) | 橙皮素与卡马西平共晶物及制备方法和其组合物与用途 | |
CN113214207B (zh) | 橙皮素与甜菜碱共晶物a及制备方法和其组合物与用途 | |
CN115124420B (zh) | 大黄酸与苦参碱共晶物水合物及制备方法和其组合物与用途 | |
CN113214208A (zh) | 橙皮素与异烟酰胺共晶物及制备方法和其组合物与用途 | |
CN115124532B (zh) | 大黄酸与苦参碱共晶物及制备方法和其组合物与用途 | |
WO2019011349A1 (zh) | 芬乐胺晶b型、制备方法和其组合物与用途 | |
CN113214206B (zh) | 橙皮素与甜菜碱共晶物b及制备方法和其组合物与用途 | |
CN111718258B (zh) | 蓓萨罗丁与聚乙烯吡咯烷酮共无定型物及制备方法和其组合物与用途 | |
CN113831336A (zh) | 吡喹酮与阿魏酸共晶物及制备方法和其组合物与用途 | |
CN115124419B (zh) | 大黄酸与金雀花碱共晶物及制备方法和其组合物与用途 | |
CN117776908A (zh) | 异阿魏酸半哌嗪盐及其制备方法和药物组合物与用途 | |
CN111718257B (zh) | 蓓萨罗丁与川芎嗪共晶物及制备方法和其组合物与用途 | |
CN117777056A (zh) | 异阿魏酸哌嗪盐及其制备方法和药物组合物与用途 | |
CN113214066B (zh) | 棉酚晶ii型物质及制备方法和其组合物与用途 | |
CN113214065B (zh) | 棉酚晶iii型物质及制备方法和其组合物与用途 | |
CN111714479B (zh) | 一种含有蓓萨罗丁的药物组合物 | |
CN110452156B (zh) | 多奈哌齐与厄贝沙坦共晶物及制备方法和其组合物与用途 | |
CN108239126B (zh) | 水杨酸甲酯乳糖苷晶ⅲ型固体物质及制备方法和其组合物与用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |