CN115364066A - Capsule containing abiraterone acetate and delivery agent - Google Patents
Capsule containing abiraterone acetate and delivery agent Download PDFInfo
- Publication number
- CN115364066A CN115364066A CN202110547249.4A CN202110547249A CN115364066A CN 115364066 A CN115364066 A CN 115364066A CN 202110547249 A CN202110547249 A CN 202110547249A CN 115364066 A CN115364066 A CN 115364066A
- Authority
- CN
- China
- Prior art keywords
- abiraterone acetate
- capsule
- delivery agent
- phospholipid
- parts
- 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.)
- Pending
Links
- 229960004103 abiraterone acetate Drugs 0.000 title claims abstract description 80
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 title claims abstract description 80
- 239000002775 capsule Substances 0.000 title claims abstract description 49
- 229940124447 delivery agent Drugs 0.000 title claims abstract description 25
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 19
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 13
- 229930195729 fatty acid Natural products 0.000 claims abstract description 13
- 239000000194 fatty acid Substances 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims description 34
- 239000007901 soft capsule Substances 0.000 claims description 25
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 11
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 11
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 10
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 9
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 claims description 9
- -1 polyoxyethylene glycerol laurate Polymers 0.000 claims description 9
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 claims description 6
- 229940083466 soybean lecithin Drugs 0.000 claims description 5
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 claims description 5
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 claims description 4
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 3
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 claims description 3
- MUHFRORXWCGZGE-KTKRTIGZSA-N 2-hydroxyethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCO MUHFRORXWCGZGE-KTKRTIGZSA-N 0.000 claims 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 claims description 2
- 229940095098 glycol oleate Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940099578 hydrogenated soybean lecithin Drugs 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 32
- 238000004090 dissolution Methods 0.000 abstract description 26
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 abstract description 12
- 229960000853 abiraterone Drugs 0.000 abstract description 11
- 206010067125 Liver injury Diseases 0.000 abstract description 6
- 231100000753 hepatic injury Toxicity 0.000 abstract description 5
- 208000024891 symptom Diseases 0.000 abstract description 3
- 230000037406 food intake Effects 0.000 abstract description 2
- 235000012631 food intake Nutrition 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 210000002381 plasma Anatomy 0.000 abstract description 2
- 239000000725 suspension Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 17
- 238000005303 weighing Methods 0.000 description 11
- 238000011049 filling Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 125000005456 glyceride group Chemical group 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000007962 solid dispersion Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 3
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 229940117972 triolein Drugs 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229920001531 copovidone Polymers 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000006190 sub-lingual tablet Substances 0.000 description 2
- 229940098466 sublingual tablet Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229920006197 POE laurate Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 102000001854 Steroid 17-alpha-Hydroxylase Human genes 0.000 description 1
- 108010015330 Steroid 17-alpha-Hydroxylase Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940080812 glyceryl caprate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 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
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- LKUNXBRZDFMZOK-UHFFFAOYSA-N rac-1-monodecanoylglycerol Chemical compound CCCCCCCCCC(=O)OCC(O)CO LKUNXBRZDFMZOK-UHFFFAOYSA-N 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Polymers [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229940051084 zytiga Drugs 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
- A61K9/48—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The application belongs to the field of pharmaceutical preparations, and particularly relates to a capsule containing abiraterone acetate and a delivery agent. The capsule comprises abiraterone acetate, a delivery agent, phospholipid and fatty acid glyceride. The capsule has stable physicochemical properties and simple preparation process, and can improve the dissolution rate and bioavailability of abiraterone acetate, and improve the influence of food intake on Cmax and exposure of abiraterone in blood plasma; phospholipid is added into the prescription to improve symptoms such as liver injury caused by taking abiraterone acetate.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a capsule containing a delivery agent, in particular to a capsule containing abiraterone acetate and the delivery agent.
Background
Abiraterone acetate has the chemical name of 17- (3-pyridyl) -androstane-5,16-diene-3 beta-acetate, has high affinity and high selectivity for CYP17, is a Centocor Ortho company, is approved by the FDA in the United states on 28 th 4 th 2011 and is sold in zeke (Zytiga), and is indicated as castration-resistant prostate cancer (cRPC) which can not control the disease progression when the Abiraterone acetate is combined with prednisone to treat docetaxel. The abiraterone acetate serving as a prodrug of the abiraterone acetate can be rapidly absorbed after being taken orally, and is deacetylated in the liver to obtain an active ingredient, namely the abiraterone acetate.
Abiraterone acetate is white crystalline powder, has solubility of 0.02mg/ml in aqueous medium, is slightly soluble in 0.1N hydrochloric acid, and is easily soluble in organic solvents such as tetrahydrofuran, dichloromethane, etc., especially alcohols; the abiraterone acetate has the characteristics of water insolubility and lipid insolubility, so that the permeability is low, the bioavailability is poor, and the absolute bioavailability is about 45%, so that the bottleneck of pharmaceutical preparation research is how to improve the dissolution rate and the bioavailability.
CN103070828a solid dispersion is prepared by dissolving 1. Although the dissolution rate is improved, the solid dispersion prepared by the process uses chloroform as a solvent, is not beneficial to safe production in a workshop and labor protection of workers, and has limited dissolution improvement, namely 64% is dissolved in a medium with pH4.5 and added with a surfactant within 10 min.
CN106913537A discloses an abiraterone acetate sublingual tablet, which is prepared by heating and melting abiraterone acetate and solid acid, mixing with filler, disintegrant and adhesive, granulating, drying, adding lubricant, and tabletting.
CN106913539A discloses an abiraterone acetate sublingual tablet and a preparation method thereof, wherein abiraterone acetate and polyethylene glycol 1000 vitamin E succinate are dissolved in an organic solvent, the organic solvent is removed by drying under reduced pressure, the dried substance is mixed with a filler and a disintegrating agent, then a lubricant is added for mixing and tabletting, although complete dissolution can be realized within 15min, a large amount of organic solvent can not be avoided, labor protection is not facilitated, the impurity content is obviously increased in the long-term storage process, and the stability is poor.
CN110354094A discloses an abiraterone acetate capsule, which is prepared by dissolving abiraterone acetate in fatty glyceride, and using fatty glyceride in the soft capsule, so that the in vivo dissolution and solubility are improved, the retention time in stomach and intestine is prolonged, lymphatic transport is stimulated, the metabolic influence is reduced, and the bioavailability of abiraterone acetate is further improved.
CN109125276A discloses an abiraterone acetate tablet, which is prepared by preparing solid dispersion from copovidone and abiraterone acetate, and then preparing the solid dispersion, a diluent, an adhesive, a disintegrating agent and a lubricant into a mixture and tabletting. Although the stability is improved to some extent, the dissolution rate of the tablet obtained by the preparation method is too low, the dissolution rate in 20min is about 25% in hydrochloric acid solution with pH of 1.0, and the dissolution rate in 20min only reaches about 50% in pure water (0.5% SDS), so that the dissolution rate needs to be improved.
CN110917152A discloses an abiraterone acetate tablet, which is prepared by preparing solid dispersion from abiraterone acetate and copovidone by a hot-melt extrusion method, and then preparing the tablet with other auxiliary materials, and can greatly improve the dissolution of the abiraterone acetate tablet and further improve the bioavailability of the abiraterone acetate.
CN111012745A discloses an abiraterone oral emulsion, which comprises abiraterone or abiraterone acetate, a solubilizer, an emulsifier and an antioxidant. The oral emulsion is stable and has small influence on digestion, reduces adverse influence of abiraterone acetate hydrolysis on drug dissolution, can improve drug dissolution in gastrointestinal tract, promotes drug absorption, and improves bioavailability, but needs to add a large amount of emulsifier and solubilizer which are surfactants, and cannot ensure clinical medication safety.
CN111481523A discloses a soft capsule for treating prostatic cancer and a preparation method thereof, abiraterone acetate is dissolved in fatty glyceride and a small amount of surfactant to prepare the soft capsule, and the bioavailability of the soft capsule is still to be improved.
CN111617257a discloses an abiraterone or its derivative pharmaceutical composition, which contains abiraterone or its derivative, an absorption enhancer and lactose, wherein the dosage of lactose accounts for 15-80% of the total weight of the pharmaceutical composition, the optimal prescription (prescription 2) of the obtained preparation has a poor dissolution rate, the dissolution rate in an in vitro dissolution experiment for 60min is 95%, and the dissolution rate reflects the bioavailability to a certain extent, so the bioavailability thereof still needs to be improved.
CN111617258A discloses a method for preparing abiraterone or its derivative pharmaceutical composition, which comprises mixing a nano suspension containing abiraterone or its derivative with an absorption enhancer and optionally at least one excipient, and granulating by a fluidized bed, wherein the particle size D90 value of the abiraterone or its derivative is less than 1000nm, preferably 400-600 nm, the obtained pharmaceutical composition has improved bioavailability and improved individual variability of administration patients compared with the commercially available preparation, but the dissolution rate of the obtained preparation (such as formula 1) is still poor, and the dissolution rate is 98% in an in vitro dissolution experiment for 60min, which is not beneficial to the improvement of the bioavailability.
The existing abiraterone acetate oral preparation has the defects of slow medicine dissolution, low bioavailability and the like, and the preparation process of the liquid capsule is complex and the industrial production difficulty is high. In addition, in the existing preparations, the abiraterone acetate preparation must be taken on an empty stomach, because compared with the empty stomach, the Cmax and AUC of the abiraterone taken by meals are respectively increased to 17 times and 10 times, so that the taking safety risk is increased. Therefore, the abiraterone acetate preparation with high dissolution rate, high bioavailability and high medication safety needs to be provided, and a better treatment scheme is provided for clinic.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a capsule containing abiraterone acetate and a delivery agent, which has stable physicochemical property and simple preparation process, so as to improve the dissolution rate and bioavailability of the abiraterone acetate and improve the influence of food intake on the Cmax and exposure of the abiraterone in blood plasma; meanwhile, phospholipid is added into the prescription, so that symptoms such as liver injury caused by taking abiraterone acetate can be improved.
The technical scheme of the invention is as follows: a capsule comprising abiraterone acetate and a delivery agent, the capsule comprising abiraterone acetate, the delivery agent, a phospholipid and a fatty acid glyceride.
Preferably, in the capsule, the delivery agent is selected from one or more of sodium 8-N- (2-hydroxybenzoyl) aminocaprylate (SNAC), sodium caprate, polyoxyethylene-gamma-lauryl ether, sodium taurocholate, methylated beta-cyclodextrin or polyacrylate.
Further preferably, in the capsule, the delivery agent is selected from one or more of 8-N- (2-hydroxybenzoyl) amino sodium caprylate, sodium caprate or polyoxyethylene-gamma-lauryl ether.
Preferably, the weight ratio of the abiraterone acetate to the delivery agent in the capsule is 1:1-3.
Further preferably, in the capsule, the weight ratio of the abiraterone acetate to the delivery agent is 1.5-2.
Preferably, in the capsule, the phospholipid is selected from one or more of soybean lecithin, egg yolk lecithin, hydrogenated soybean phospholipid or phosphatidyl glycerol.
Further preferably, in the capsule, the phospholipid is soybean lecithin or egg yolk lecithin.
Preferably, the weight ratio of the abiraterone acetate to the phospholipid in the capsule is 1:1-30.
Further preferably, in the capsule, the weight ratio of the abiraterone acetate to the phospholipid is 1:1-10.
Preferably, in the capsule, the fatty glyceride is one or more selected from glycerol monolinoleate, glycerol monooleate, polyethylene glycol oleate, polyoxyethylene laurate, glycerol trioleate and polyoxyethylene glycerol oleate.
Further preferably, in the capsule, the fatty acid glyceride is glycerol monolinoleate, polyoxyethylene glycerol laurate or polyethylene glycol glycerol oleate.
Preferably, in the capsule, the weight ratio of the abiraterone acetate to the fatty acid glyceride is 1:1-50.
More preferably, in the capsule, the weight ratio of the abiraterone acetate to the fatty acid glyceride is 1:1-20.
Preferably, the capsule contains the following components in parts by weight: 1 part of abiraterone acetate, 1-3 parts of delivery agent, 1-30 parts of phospholipid and 1-50 parts of fatty acid glyceride.
Further preferably, the capsule contains the following components in parts by weight: 1 part of abiraterone acetate, 1.5-2 parts of delivery agent, 1-10 parts of phospholipid and 1-20 parts of fatty acid glyceride.
More preferably, the capsule comprises the following components in parts by weight: 1 part of abiraterone acetate, 1.5-2 parts of 8-N- (2-hydroxybenzoyl) amino sodium caprylate, 1-10 parts of phospholipid and 1-20 parts of fatty glyceride.
The invention also provides a method for preparing the capsule containing the abiraterone acetate and the delivery agent, which comprises the following steps: stirring phospholipid and fatty glyceride according to the prescription amount to dissolve, adding abiraterone acetate to dissolve, then adding micronized delivery agent, stirring uniformly, and filling into soft capsules.
The invention has the advantages that:
(1) The capsule containing the abiraterone acetate and the delivery agent has high dissolution rate, can reduce the influence of food on the bioavailability of the abiraterone, and improves the medication safety of patients;
(2) The phospholipid is added in the prescription of the invention, so that the symptoms such as liver injury and the like caused by taking abiraterone acetate can be improved;
(3) The prescription of the invention has less dosage of auxiliary materials, can reduce the pill burden of patients, reduce the accumulation of toxicity in vivo, improve the safety of the medicine, and improve the treatment compliance and the treatment efficiency;
(4) The preparation method is simple and feasible, and is suitable for industrial production.
Detailed Description
The present invention is further described below by way of examples, which are not intended to limit the scope of the invention in any way, and various modifications or improvements can be made by those skilled in the art based on the basic idea of the invention, but they are within the scope of the invention, unless they depart from the basic idea of the invention.
Example 1
1) Prescription
2) Preparation process
Weighing soybean lecithin and glycerol monolinoleate in the prescribed amount, stirring to dissolve into uniform clear solution, adding abiraterone acetate, stirring to dissolve, adding micronized sodium caprate, stirring to form suspension, and encapsulating the suspension into soft capsule.
Example 2
1) Prescription
2) Preparation process
Weighing egg yolk lecithin and oleic acid macrogol glyceride according to the prescription amount, stirring to dissolve the egg yolk lecithin and the oleic acid macrogol to form a uniform clear solution, adding abiraterone acetate, stirring to dissolve the solution, then adding micronized SNAC, stirring uniformly to form a suspension, and filling the suspension into soft capsules to obtain the soft capsule.
Example 3
1) Prescription
2) Preparation process
Weighing egg yolk lecithin and polyoxyethylene glycerol laurate according to the prescription amount, stirring to dissolve the egg yolk lecithin and the polyoxyethylene glycerol laurate into a uniform clear solution, adding abiraterone acetate, stirring to dissolve, then adding micronized polyoxyethylene-gamma-lauryl ether, stirring uniformly to form a suspension, and filling the suspension into soft capsules to obtain the soft capsule.
Example 4
1) Prescription
2) Preparation process
Weighing hydrogenated soybean phospholipid, glyceryl monooleate and polyoxyethylene glyceryl oleate according to the prescription amount, stirring to dissolve the hydrogenated soybean phospholipid, the glyceryl monooleate and the polyoxyethylene glyceryl oleate into a uniform clear solution, adding abiraterone acetate, stirring to dissolve, then adding micronized sodium taurocholate and polyacrylate, stirring uniformly to form a suspension, and filling the suspension into soft capsules to obtain the finished product.
Example 5
1) Prescription
2) Preparation process
Weighing the prescription dose of phosphatidyl glycerol, hydrogenated soybean phospholipid and triolein, stirring to dissolve into a uniform clear solution, adding abiraterone acetate, stirring to dissolve, then adding micronized methylated beta-cyclodextrin, stirring uniformly to form a suspension, and filling the suspension into soft capsules to obtain the capsule.
Example 6
1) Prescription
2) Preparation process
Weighing egg yolk lecithin and polyethylene glycol glyceryl oleate according to the prescription amount, stirring to dissolve into a uniform clear solution, adding abiraterone acetate, stirring to dissolve, adding micronized SNAC, stirring uniformly to form a suspension, and filling the suspension into soft capsules to obtain the soft capsule.
Example 7
1) Prescription
2) Preparation process
Weighing egg yolk lecithin and polyethylene glycol glyceryl oleate according to the prescription amount, stirring to dissolve into a uniform clear solution, adding abiraterone acetate, stirring to dissolve, adding micronized SNAC, stirring uniformly to form a suspension, and filling the suspension into soft capsules to obtain the soft capsule.
Example 8
1) Prescription
2) Preparation process
Weighing the formula amount of phosphatidyl glycerol, hydrogenated soybean phospholipid and triolein, stirring to dissolve into a uniform clear solution, adding abiraterone acetate, stirring to dissolve, adding micronized decyl methyl sulfoxide, stirring uniformly to obtain a suspension, and filling the suspension into soft capsules.
Example 9
1) Prescription
2) Preparation process
Weighing glycerol monolinoleate according to the prescription amount, adding abiraterone acetate, stirring for dissolving, then adding micronized sodium caprate, stirring uniformly to form suspension, and filling the suspension into soft capsules to obtain the soft capsule.
Example 10
1) Prescription
2) Preparation process
Weighing soybean lecithin and glycerol monolinoleate in the prescribed amount, stirring to dissolve into uniform clear solution, adding abiraterone acetate, stirring to dissolve, adding micronized sodium caprate, stirring to form suspension, and encapsulating the suspension into soft capsule.
Comparative example 1
1) Prescription
Content of the components
Abiraterone acetate 10g
Glycerol monooleate 40g
2) Preparation process
The abiraterone acetate and the glycerol monooleate are weighed according to the prescription amount, stirred to be dissolved into a uniform clear solution, and the solution is filled into soft capsules.
Comparative example 2
1) Prescription
2) Preparation process
The abiraterone acetate, the glyceryl monooleate and the polyethylene glycol glyceryl caprate are weighed according to the prescription amount, stirred to be dissolved into a uniform clear solution, and the solution is filled into soft capsules.
Comparative example 3
1) Prescription
2) Preparation process
Weighing and dissolving the abiraterone acetate and BHT with the prescription amount in a mixed solution of glyceryl trioleate and PEG400 which is heated to 60 ℃, uniformly stirring, and encapsulating in a soft capsule to obtain the abiraterone acetate soft capsule.
Verification examples
1. Dissolution test:
dissolution rates of the abiraterone acetate capsules obtained in examples 1 to 10 and comparative examples 1 to 3 were measured by the following method. Taking the product, determining according to dissolution method, taking 500ml of pure water as dissolution medium, rotating speed is 50 rpm, operating according to the method, taking 10ml of solution after 15 minutes, filtering, and taking the subsequent filtrate as sample solution. Taking a proper amount of abiraterone acetate reference substance, placing the abiraterone acetate reference substance into a 10ml measuring flask, adding methanol for dissolving and diluting to a scale, precisely measuring 1ml, placing the abiraterone acetate reference substance into the 10ml measuring flask, adding a dissolving medium for diluting to the scale, and shaking up to obtain a reference substance solution. According to the chromatographic conditions under the content determination item, 10 mul of each of the test solution and the reference solution is taken and injected into a liquid chromatograph, the chromatogram is recorded, and the dissolution rate of each tablet is calculated by the peak area according to an external standard method, and the result is shown in table 1. The limit is 80% of the indicated amount and should be met.
Table 1 dissolution test results
2. Pharmacokinetic testing
Taking the preparations prepared in the invention examples 1-10 and comparative examples 1-3 and commercially available zecade @ to perform fasting and postprandial pharmacokinetic tests, 6 healthy Beagle dogs in each group were taken with a weight of 12.5-15Kg once 12h before taking the preparation, another group was taken 30 minutes after taking the preparation, taking 250mg of abiraterone acetate orally and 25ml of warm water simultaneously, taking blood samples of about 3ml in subcutaneous veins of forelimb measurement 5min, 15min, 30min, 45min, 60min, 90min, 120min, 240min, 480min and 720min after taking the preparation, placing the blood samples in heparinized test tubes, measuring blood concentration, calculating Cmax and AUC, comparing the blood samples with the commercially available abiraterone acetate (trade name: zecade @), and further calculating the ratio of Cmax and AUC for zecade or fasting, and the results are shown in Table 2.
TABLE 2 pharmacokinetic test results
3. Protective action against liver damage
60 ICR mice were randomly divided into 6 groups: blank group, model group (0.5%CMCNa), administration group (capsules obtained in examples 1 and 9 and commercially available zecade @). Except for the blank group, each group was subjected to intraperitoneal injection once with 0.1% CCl4 to prepare a liver injury model, and after 7 days of continuous administration, liver tissues were taken for pathological examination. Liver tissue is fixed by 10% formaldehyde solution, and is sliced by conventional paraffin embedding, HE staining and tissue damage degree is observed under a light microscope.
TABLE 3 liver injury test results
Claims (10)
1. A capsule comprising abiraterone acetate and a delivery agent, wherein the capsule comprises abiraterone acetate, the delivery agent, a phospholipid and a fatty acid glyceride.
2. The capsule according to claim 1, wherein the delivery agent is selected from one or more of sodium 8-N- (2-hydroxybenzoyl) aminocaprylate, sodium caprate, polyoxyethylene- γ -lauryl ether, sodium taurocholate, methylated β -cyclodextrin or polyacrylate.
3. The capsule according to claim 1, wherein the weight ratio of abiraterone acetate to the delivery agent in the capsule is 1:1-3.
4. The capsule according to claim 1, wherein the phospholipid is selected from one or more of soybean lecithin, egg yolk lecithin, hydrogenated soybean lecithin, and phosphatidylglycerol.
5. The capsule according to claim 1, wherein the weight ratio of abiraterone acetate to phospholipid in the capsule is 1:1-30.
6. The capsule according to claim 1, wherein the fatty acid glyceride in the capsule is one or more selected from glycerol monolinoleate, glycerol monooleate, polyethylene glycol oleate, polyoxyethylene glycerol laurate, glycerol trioleate and polyoxyethylene glycerol oleate.
7. The capsule according to claim 1, wherein the weight ratio of abiraterone acetate to fatty acid glyceride in the capsule is 1:1-50.
8. The capsule according to any one of claims 1 to 7, wherein the capsule comprises the following components in parts by weight: 1 part of abiraterone acetate, 1-3 parts of delivery agent, 1-30 parts of phospholipid and 1-50 parts of fatty acid glyceride.
9. The capsule according to claim 8, wherein the capsule comprises the following components in parts by weight: 1 part of abiraterone acetate, 1.5-2 parts of delivery agent, 1-10 parts of phospholipid and 1-20 parts of fatty acid glyceride.
10. A process for preparing the capsule of claim 1, wherein the phospholipid and the fatty acid glyceride are dissolved in the prescribed amounts with stirring, the abiraterone acetate is added and dissolved with stirring, the micronized delivery agent is added and mixed until uniform, and the mixture is filled into soft capsules.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110547249.4A CN115364066A (en) | 2021-05-19 | 2021-05-19 | Capsule containing abiraterone acetate and delivery agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110547249.4A CN115364066A (en) | 2021-05-19 | 2021-05-19 | Capsule containing abiraterone acetate and delivery agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115364066A true CN115364066A (en) | 2022-11-22 |
Family
ID=84058549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110547249.4A Pending CN115364066A (en) | 2021-05-19 | 2021-05-19 | Capsule containing abiraterone acetate and delivery agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115364066A (en) |
-
2021
- 2021-05-19 CN CN202110547249.4A patent/CN115364066A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102470103B (en) | Pharmaceutical composition as hcv protease inhibitors | |
| CN107308132A (en) | A kind of phosphatide chitosan drug delivery system and its production and use | |
| CN116033925B (en) | Abiraterone acetate soft capsule and preparation method and application thereof | |
| WO2011050735A1 (en) | Paclitaxel/steroidal complex | |
| CN110917152A (en) | CYP17 inhibitor tablet and preparation method thereof | |
| CN110354094B (en) | CYP17 inhibitor soft capsule and preparation method thereof | |
| US9913814B2 (en) | Tamper resistant immediate release capsule formulation comprising tapentadol | |
| CN115364066A (en) | Capsule containing abiraterone acetate and delivery agent | |
| TW201513894A (en) | A pharmaceutical composition for skin external use comprising icotinib and the application thereof | |
| CN112022833B (en) | Enzalutamide pharmaceutical composition and preparation method thereof | |
| CN106309395A (en) | Tacrolimus sustained-release tablets and preparation method thereof | |
| CN112043679B (en) | Soft capsule preparation containing quinazoline compound and preparation method thereof | |
| CN115227652A (en) | Midosurin tablet and preparation method thereof | |
| CN111481523B (en) | Soft capsule for treating prostatic cancer and preparation method thereof | |
| CN101108224A (en) | Plants natural base extractive and formulated product and use thereof | |
| CN113133983B (en) | Pharmaceutical composition for treating prostate cancer | |
| CN109419771B (en) | Testosterone undecanoate sustained-release pharmaceutical composition, and preparation method and application thereof | |
| CN115364108A (en) | Composition containing CYP inhibitor and delivery agent and preparation method thereof | |
| CN113133984A (en) | CYP17 inhibitor preparation | |
| CN112206233A (en) | Ibrutinib oral preparation and preparation method thereof | |
| CN113546037A (en) | Abiraterone acetate suppository and preparation method thereof | |
| CN107970225B (en) | Dabigatran etexilate solid lipid nanoparticle and preparation method thereof | |
| CN113967198A (en) | Steroid CYP17 inhibitor capsule and preparation method thereof | |
| CN114948905A (en) | Microsphere containing capecitabine and application thereof in liver cancer | |
| CN102697764A (en) | Enteric solid preparation containing phenethyl isothiocyanate |
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 |