CN115025048A - Aprepitant ternary solid dispersion - Google Patents
Aprepitant ternary solid dispersion Download PDFInfo
- Publication number
- CN115025048A CN115025048A CN202210901132.6A CN202210901132A CN115025048A CN 115025048 A CN115025048 A CN 115025048A CN 202210901132 A CN202210901132 A CN 202210901132A CN 115025048 A CN115025048 A CN 115025048A
- Authority
- CN
- China
- Prior art keywords
- aprepitant
- solid dispersion
- polymer
- drug
- dissolution
- 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.)
- Granted
Links
- 229960001372 aprepitant Drugs 0.000 title claims abstract description 110
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 title claims abstract description 109
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 96
- 229920000642 polymer Polymers 0.000 claims abstract description 28
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 17
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 26
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 19
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 18
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 17
- -1 acetate-polyethylene Chemical group 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 229920002554 vinyl polymer Polymers 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 229920000578 graft copolymer Polymers 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 238000009474 hot melt extrusion Methods 0.000 claims description 6
- 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 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 claims description 2
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 64
- 238000004090 dissolution Methods 0.000 abstract description 50
- 239000003112 inhibitor Substances 0.000 abstract description 12
- 238000002425 crystallisation Methods 0.000 abstract description 10
- 230000008025 crystallization Effects 0.000 abstract description 10
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- 230000003111 delayed effect Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 53
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 20
- 229920003081 Povidone K 30 Polymers 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 14
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- 238000001556 precipitation Methods 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000011068 loading method Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000004570 mortar (masonry) Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001125 extrusion Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000005764 inhibitory process Effects 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
- 230000002829 reductive effect Effects 0.000 description 4
- 229910016860 FaSSIF Inorganic materials 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920003083 Kollidon® VA64 Polymers 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 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 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 description 1
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 229920000858 Cyclodextrin 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
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 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 1
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 1
- 101500027611 Homo sapiens Substance P Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 229930195725 Mannitol Natural products 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 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 1
- 239000012472 biological sample Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010586 diagram 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
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000008101 lactose 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
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000012284 sample analysis method Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical preparations, and provides an aprepitant ternary solid dispersion, which adopts a hydrophilic polymer as a dissolution promoter and an enteric polymer as a crystallization inhibitor, so that the dissolution rate is controlled from the aspect of dynamics, the overall stability of a prescription is improved, the solubility can be improved, the recrystallization of an amorphous solid dispersion is delayed, and the bioavailability of a medicament is improved.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an aprepitant ternary solid dispersion.
Background
Aprepitant (Aprepitant) is a selective high affinity antagonist of the human substance P neurokinin 1(NK 1) receptor. Having a chemical formula of C 23 H 21 F 7 N 4 O 3 The chemical name is 5- [2(R) - [1(R) - [3, 5-bis (trifluoromethyl) phenyl group]Ethoxy radical]-3(S) - (4-fluorophenyl) morpholine 64-ylmethyl]-3, 4-dihydro-2H-1, 2, 4-triazole-3-ketone, molecular weight 534.427, structural formula shown in the following figure
Aprepitant capsules were approved by the U.S. FDA for marketing at 3 months 2003 under the trade name enden, with specifications of 40mg, 80mg, 125 mg. The aprepitant dry suspension is approved by FDA in 2015, and the specification is 125 mg. The composition is mainly used for treating nausea and vomiting caused by chemotherapy and postoperative nausea and vomiting clinically, is usually combined with 5-HT 3 receptor antagonist dexamethasone and glucocorticoid ondansetron, and is a first-line medicament for treating cancer chemotherapy and vomiting.
At physiological pH of pH2.0-pH6.8, aprepitant solubility is 3-7 μ g/ml. Low water solubility is the rate limiting step in its effect on in vivo exposure and bioavailability.
In the prior art, attempts have been made to prepare aprepitant solid dispersions by using a single polymer, however, amorphous solid dispersions may cross the energy barrier due to thermodynamic instability, and transform from amorphous to stable crystalline form during storage, resulting in reduced solubility; the quick-release insoluble drug solid dispersion has low solubility and is difficult to reach a sink condition, so the quick-release insoluble drug solid dispersion has the tendency of quick release and quick crystallization in an in vitro release test, causes a parachute effect, loses the original solubility advantage of the solid dispersion and cannot be dissolved and absorbed in gastrointestinal tracts.
In addition, when poorly soluble drugs are exposed to the in vivo environment, supersaturated solutions are often induced, which have a higher chemical potential and degree of supersaturation than saturated solutions. In such supersaturated solutions, the actual concentration at which the drug is dissolved exceeds its thermodynamic equilibrium solubility. Supersaturated systems are thermodynamically unstable compared to equilibrium conditions (saturated regime) and have a tendency to return to equilibrium. Supersaturation is the driving force for precipitation and there is a tendency for the drug molecules to crystallize. The crystallization process is generally divided into two steps, the first step is nucleation and the second step is crystal growth, so that the drug precipitates out, affecting the bioavailability of the drug.
Disclosure of Invention
In order to improve the dissolution rate and the oral bioavailability of aprepitant, the invention provides a novel aprepitant ternary solid dispersion, and the system has the characteristic of remarkably improving the dissolution rate and the bioavailability of aprepitant and can keep good stability of the aprepitant solid dispersion.
The invention provides an aprepitant solid dispersion which comprises aprepitant and a polymer carrier, wherein the weight ratio of aprepitant to the polymer carrier is 1: 1-1: 10, and preferably 1: 4-1: 9. The polymer carrier is composed of an enteric polymer and a hydrophilic polymer, wherein the hydrophilic polymer is a dissolution promoter of the system, the enteric polymer is a crystallization inhibitor, and the weight ratio of the enteric polymer to the hydrophilic polymer is 1: 10-10: 1, preferably 1: 5-7: 1.
The enteric polymer is selected from one or more of methacrylic acid copolymer (Eudragit, Ewing), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose acetate phthalate (HPMCP). Among them, hydroxypropylmethylcellulose acetate succinate (HPMCAS) is preferable.
The hydrophilic polymer in the invention is selected from one or more of polyvinylpyrrolidone (povidone, PVP), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone copolymer (copovidone, PVP VA) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). Among them, one or both of polyvinylpyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) are preferable.
Preferably, the enteric polymer in the invention is selected from hydroxypropyl methyl cellulose acetate succinate, and the hydrophilic polymer is selected from polyvinylpyrrolidone; the weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the polyvinylpyrrolidone is 1: 3-7: 1, preferably 5: 3-3: 1.
Preferably, the enteric polymer in the present invention is selected from hydroxypropyl methyl cellulose acetate succinate, and the hydrophilic polymer is selected from polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1: 5-7: 1.
Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has various specifications, preferably MG, HG, more preferably MG. Polyvinylpyrrolidone (PVP) is available in a variety of formats, with PVP K12, K25, K30, K90 being preferred, and PVP K30 being more preferred.
In the solid dispersion of the invention, aprepitant exists in an amorphous form, the stability is good, and experiments show that the aprepitant still maintains the amorphous state after being placed for 3 months under the condition of accelerated stability and the relative humidity of 45 ℃/75 percent.
The aprepitant solid dispersion composition can also contain a glidant, a plasticizer and/or a surfactant, wherein the glidant can be one or more selected from talcum powder, superfine silica gel powder and magnesium stearate; the plasticizer can be one or more selected from poloxamer, polyethylene glycol and triethyl citrate; the surfactant can be one or more selected from Tween 80, Tween 20, span 20, and propylene glycol.
In certain embodiments, the aprepitant solid dispersion of the present invention is free of surfactant and/or free of cyclodextrin. In certain embodiments, the aprepitant solid dispersion of the invention consists of aprepitant, an enteric polymer, and a hydrophilic polymer only.
The content of aprepitant in the aprepitant solid dispersion is preferably 5-40%, and more preferably 10% -20%.
The aprepitant solid dispersion is preferably prepared by a hot-melt extrusion method, wherein aprepitant and a polymer carrier are pre-crushed and/or pre-mixed, and then melted and extruded in an extruder. The pre-pulverization means that the aprepitant, the enteric polymer and the water-soluble polymer are pulverized to a certain particle size before being added into a pulverizer, the pre-mixing means that the aprepitant, the enteric polymer and the water-soluble polymer are mixed according to a preset weight ratio before being added into an extruder, and the pre-pulverization and the pre-mixing processes can also be carried out simultaneously. The heating temperature of the extruder can be set to be 180-220 ℃, and the rotating speed of the screw can be set to be 50-150 rpm. After the extrudate is cooled, it can be pulverized into a pharmaceutical powder.
The aprepitant solid dispersion can be directly used as powder, granules and the like, and can also be further prepared into a pharmaceutical composition with pharmaceutically acceptable auxiliary materials.
The invention also provides a pharmaceutical composition, which comprises the aprepitant solid dispersion and pharmaceutically acceptable auxiliary materials. Wherein the adjuvants can be filler, disintegrant, lubricant, etc. Suitable fillers include starch, pregelatinized starch, dextrin, sugar powder, lactose, glucose, mannitol, microcrystalline cellulose, and the like, suitable disintegrants include croscarmellose sodium, crospovidone, sodium carboxymethyl starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and the like, and suitable lubricants include stearic acid, magnesium stearate, calcium stearate, talc, and the like.
The pharmaceutical composition of the invention is an oral solid dosage form, and can be powder, granules, tablets, capsules, powder and the like.
The ternary aprepitant solid dispersion can keep the active ingredient aprepitant in a stable amorphous state during storage and dissolution, and keep a dissolved state during the transformation of the preparation in different regions of the gastrointestinal tract, and maintain a high degree of supersaturation.
The invention adopts hydrophilic polymer as dissolution accelerating agent and enteric polymer, especially hydroxypropyl methyl cellulose acetate succinate as crystallization inhibiting agent, not only kinetically controls dissolution rate and improves the stability of the whole prescription, but also can improve solubility, delay recrystallization of amorphous solid dispersoid and improve bioavailability of the preparation.
Drawings
Preferred embodiments of the present invention are described below with reference to the accompanying drawings, in which:
fig. 1 is a dissolution curve diagram of aprepitant bulk drug, aprepitant binary solid dispersion and aprepitant ternary solid dispersion (formula 1-formula 7);
fig. 2 is a graph of the dynamic solubility of aprepitant drug substance, aprepitant binary solid dispersion, and aprepitant ternary solid dispersion ( formulas 1,2, 5, 7);
FIG. 3 is an in vitro dissolution profile of ternary solid dispersions containing aprepitant and varying proportions of a precipitation inhibitor and a dissolution enhancer;
FIG. 4 is an in vitro dissolution profile of ternary solid dispersions containing aprepitant at different drug loadings;
fig. 5 is an XRD pattern of aprepitant ternary solid dispersion;
figure 6 is a graph of aprepitant drug substance and ternary solid dispersion dosing time in rats;
fig. 7 is a dissolution profile of an aprepitant ternary solid dispersion under accelerated conditions;
figure 8 is an XRD pattern of aprepitant ternary solid dispersion (aprepitant: PVP K30: HPMCAS-MG ═ 1:1:3) under accelerated conditions.
Detailed Description
The present invention is further illustrated in detail below with reference to specific examples, which are provided for illustration only and do not limit the scope of the present invention in any way.
The test methods and apparatuses in the following examples were all conventional ones unless otherwise specified, and the starting materials, reagent materials and the like used in the following examples were all commercially available ones unless otherwise specified.
Example 1: preparation and property determination of aprepitant-containing solid dispersion
1.1 preparation of solid Dispersion containing aprepitant
The components and the contents of the components contained in the aprepitant bulk drug (formula 1), the aprepitant-containing binary solid dispersion (formula 2-formula 6) and the aprepitant-containing ternary solid dispersion (formula 7) are shown in table 1.
TABLE 1
The preparation process of the formula 2-6 comprises the following steps: aprepitant binary solid dispersion is prepared by a hot-melt extrusion method, aprepitant bulk drugs, PVP K30, PVP VA64, HPMC, HPMCAS-MG and Eudragit L100-55 are respectively and precisely weighed according to the table 1 and are placed in a mortar, and the mortar is manually ground for 10 minutes. Setting the heating temperature at 200 ℃, rotating the screw at 100rpm, manually feeding at uniform speed after the state is stable, collecting the extrudate after the extrusion state is stable, crushing the extrudate into medicine powder and storing the medicine powder in a sealed container until analysis.
Preparation process of formula 7: the aprepitant ternary solid dispersion is prepared by adopting a hot-melt extrusion method, and aprepitant raw material medicines, PVP K30 and HPMCAS-MG are precisely weighed according to the table 1 and are placed in a mortar to be manually ground for 10 minutes. Setting the heating temperature at 200 ℃, rotating the screw at 100rpm, manually feeding at uniform speed after the state is stable, collecting the extrudate after the extrusion state is stable, crushing the extrudate into medicine powder and storing the medicine powder in a sealed container until analysis.
1.2 comparison of Properties of aprepitant-containing solid Dispersion
1.2.1 in vitro dissolution assay
Precisely weighing the raw material medicine of the prescription 1 and the solid dispersion (containing 80mg of aprepitant) of the prescription 2-7, measuring 700mL of hydrochloric acid buffer solution of Tween 80 with the pH value of 1.2-0.1 according to a dissolution rate and release rate measuring method (0931 in the four-part general rule of China pharmacopoeia 2020 edition), placing the measured sample into a dissolution cup, putting the sample into the dissolution cup after the temperature of a dissolution medium is stabilized at 37 +/-0.5 ℃, setting the rotating speed to be 100rpm, and sampling at time points of 10, 20, 30, 60, 120, 130, 140, 150, 180, 240 and 300 minutes. After 120 minutes of sampling was complete, 200mL of pre-warmed, pH 6.8-0.1% Tween 80 phosphate buffer was added. Sampling 10mL of the aprepitant at each time point, supplementing a dissolution medium with the same volume, filtering by using a filter membrane (GF,0.7 mu m) to obtain 6mL of a solution, collecting a subsequent filtrate, diluting by using a proper amount of methanol, injecting into high performance liquid chromatography, measuring the content of aprepitant based on a content analysis method of HPLC, and calculating the drug cumulative release amount of aprepitant at different times according to an external standard method.
TABLE 2 recipe 1 to recipe 7 dissolution data determination
The above data were used to plot dissolution profiles (fig. 1). As can be seen from fig. 1, the binary solid dispersions (formula 2, formula 3 and formula 4) prepared from the active ingredient and the hydrophilic polymers PVP K30, PVP VA64 and HPMC were not completely released in the acidic medium, and the dissolution rate dropped significantly to the level of the drug substance (formula 1) after the pH shift; the solid dispersion (prescription 6) containing the Ettqi L100-55 is hardly released in acid, the drug dissolution is rapidly increased after the pH is changed, but the Ettqi L100-55 has no precipitation inhibition capability, so that the precipitation phenomenon is generated after supersaturation, and the drug dissolution is reduced to the level of the raw material drug (prescription 1); the binary solid dispersion containing HPMCAS-MG (formula 5) has a release amount of less than 5% in acid medium within 2 hr, and has a pH transition followed by complete release of the drug and maintenance of high supersaturation for 6 hr; the ternary solid dispersion formula (formula 7) prepared by taking the enteric polymer HPMCAS-MG as a precipitation inhibitor and PVP K30 as a dissolution promoter is released quickly in acid and almost completely released within 2 hours, a supersaturated solution with higher concentration is generated after pH conversion, the stability of the solution is maintained within the test time, and the supersaturated state is maintained.
Experiments show that compared with a binary solid dispersion, the ternary solid dispersion taking HPMCAS as the precipitation inhibitor has higher in-vitro release accumulated dissolution rate in acid, stronger capability of maintaining supersaturation degree and better crystallization inhibition capability. Considering the biopharmaceutical nature of aprepitant in vivo, aprepitant is mainly or only limited to the upper gastrointestinal absorption, and the dosage form transport time in this region is usually 2-4 hours, so that the rapid disintegration of the formulation and the rapid dissolution of the drug facilitate absorption in this narrow window. Therefore, compared with the HPMCAS-aprepitant binary solid dispersion, the ternary solid dispersion has higher dissolution speed and excellent physical stability.
1.2.2 dynamic solubility determination
Preparing 100mL of FaSSIF, weighing a bulk drug formula 1 containing 1.5mg of aprepitant, simple binary solid dispersion formulas 2 and 5 and a ternary solid dispersion formula 7, placing the bulk drug formula 1, the simple binary solid dispersion formulas 2 and 5 and the ternary solid dispersion formula 7 into a 20mL penicillin bottle, precisely measuring 10mL of FaSSIF, placing the FaSSIF into a shaking table, setting the temperature of the shaking table to be 37 ℃, the shaking frequency to be 200rpm, sampling 1mL of aprepitant at different time points within 6 hours, filtering the solution with a filter membrane (GF,0.7 mu m) to be 0.5mL, collecting the subsequent filtrate, diluting the subsequent filtrate with a proper amount of methanol, injecting the diluted solution into a high performance liquid chromatography, measuring the peak area of aprepitant based on an HPLC content measuring method, calculating the solubility C of aprepitant at different time points according to an external standard point method, and drawing a dynamic solubility curve of each formula by taking time (min) as a horizontal coordinate and solubility (mu g/mL) as a vertical coordinate.
The results of dynamic solubility in simulated intestinal fluid for the binary and ternary solid dispersion formulations prepared with HPMCAS-MG alone or PVP K30 alone are shown in fig. 2. When only PVP K30 is in the system, the drug is released rapidly in acidic medium, and after supersaturation state is generated, the drug concentration is reduced, showing spring effect after the insoluble drug is solubilized. Thus, PVP K30 does not maintain the drug supersaturation well. Compared with aprepitant-HPMCAS and aprepitant-PVP K30 binary solid dispersion, the ternary solid dispersion formula has the advantages that the dissolution speed is higher, the supersaturation level can be maintained higher, and the maintenance time is longer.
And (4) conclusion: in conclusion, compared with a binary solid dispersion, the ternary solid dispersion formula prepared from the precipitation inhibitor HPMCAS-MG and the dissolution promoter PVP K30 has stronger solubilizing capability and better crystal inhibition advantage.
Example 2: preparation of aprepitant-containing ternary solid dispersion and evaluation of dissolution property
2.1 preparation and Property ratios of ternary solid dispersions containing precipitation inhibitors and dissolution promoters in different proportions
Compared with
2.1.1 preparation of ternary solid Dispersion containing aprepitant, precipitation inhibitor and dissolution enhancer in different proportions
Prepare for
The components contained in the solid dispersion compositions (sample 7 to sample 10) and the contents of the components are shown in Table 3.
TABLE 3
The preparation process of the formula 7-10 comprises the following steps: the aprepitant ternary solid dispersion is prepared by adopting a hot-melt extrusion method, and aprepitant raw material medicines, PVP K30 and HPMCAS-MG are precisely weighed according to the table 3 and are placed in a mortar to be manually ground for 10 minutes. Setting the heating temperature at 200 ℃, rotating the screw at 100rpm, manually feeding at uniform speed after the state is stable, collecting the extrudate after the extrusion state is stable, crushing the extrudate into medicine powder and storing the medicine powder in a sealed container until analysis.
2.1.2 dissolution of ternary solid dispersions containing aprepitant and different proportions of precipitation inhibitors and dissolution promoters
Comparison of properties
The in vitro dissolution rate measurement method is the same as the method described in section 1.2.1 above, and the measurement results are as follows.
TABLE 4 recipe 7-recipe 10 dissolution data measurements
The above data were used to plot dissolution profiles (fig. 3). As can be seen in fig. 3, as the proportion of HPMCAS in the formulation increased, the cumulative dissolution of the formulation increased and the ability to maintain a high level of supersaturation also increased. When the HPMCAS/PVP K30 ratio was 2:6, the drug was released in an acidic medium by about 50%, and the drug concentration gradually decreased after the pH shift due to drug supersaturation and too low a ratio of crystallization inhibitors. When the ratio of HPMCAS/PVP K30 is 4:4, the drug is released in acid medium by about 70%, the drug is further released due to HPMCAS dissolution after pH transition, so the drug concentration is slightly increased, and the dissolution rate is reduced to 60% after 4 hours. At 5:3 and 3:1 HPMCAS/PVP K30 ratios, the release in acidic medium was over 80%, complete and rapid after pH shift, and a high level of supersaturation was maintained without drop over 4 hours. When the proportion of HPMCAS/PVP K30 is in the range of 5: 3-3: 1, the aprepitant supersaturation degree is maintained to be not obviously different from that of HPMCAS alone, and the aprepitant supersaturation degree and HPMCAS alone have good crystallization inhibition effects. Therefore, the preferred ratio of HPMCAS/PVP K30 is 5: 3-3: 1.
2.2 preparation and comparison of Properties of ternary solid dispersions of different drug loadings
2.2.1 preparation of solid dispersions of varying drug loadings
The components contained in sample 7, sample 11 to sample 13 and the contents of the components are shown in Table 5.
TABLE 5
The preparation process of the formula 7 and the preparation process of the formula 11-13 comprise the following steps: the aprepitant ternary solid dispersion is prepared by adopting a hot-melt extrusion method, and aprepitant raw material medicines, PVP K30 and HPMCAS-MG are precisely weighed according to the table 5, placed in a mortar and manually ground for 10 minutes. Setting the heating temperature at 200 ℃, rotating the screw at 100rpm, manually feeding at uniform speed after the state is stable, collecting the extrudate after the extrusion state is stable, crushing the extrudate into medicine powder, and storing the medicine powder in a sealed container until analysis.
2.2.2 comparison of dissolution Properties of ternary solid dispersions of different drug loadings
The in vitro dissolution rate measurement method was the same as that in 1.2.1, and the measurement results were as follows.
TABLE 6
The above data were used to plot dissolution profiles (fig. 4). As can be seen from fig. 4, the cumulative dissolution of formula 11 carrying 5% drug in acid over 2 hours was only 21% without changing the ratio of the crystallization inhibitor to the dissolution promoter, which is not favorable for improving the bioavailability. The formulations 7 and 12 with 10-20% of drug loading have no significant difference in the accumulative dissolution rate in alkali, and have the capacity of maintaining the supersaturation degree. The 40% drug loaded formula 13 releases only about 50% of the drug after the pH shift and the drug concentration gradually decreases within 4 hours after the pH shift. Therefore, the drug loading is preferably 10% to 20%.
Example 3: presence state of drug in aprepitant solid dispersion
Hydroxypropyl methylcellulose acetate succinate is used as a precipitation inhibitor, polyvinylpyrrolidone is used as a dissolution promoter, and the ternary solid dispersion composition is prepared according to the formula amounts shown in formula 7, formula 8, formula 9, formula 10 and formula 12 in the example 2.
The existence state of the drug in the solid dispersion is characterized by adopting a powder X-ray diffraction technology. And (3) testing conditions are as follows: Cu-K alpha rays; a graphite monochromator; pipe flow 40 mA; the voltage is 40 kV; 2-theta; the scanning speed is 20 degrees/min; the scanning range is 5-45 degrees; the step size is 0.02 °. See FIG. 5 for results.
And (4) conclusion: the drug was confirmed to be highly dispersed in the polymer matrix in an amorphous form in each formulation by PXRD technical characterization.
Example 4: pharmacokinetic experiments in rats
SD rats weighing 220 +/-10 g are 10 in total, randomly divided into 2 groups, and respectively comprise an aprepitant bulk drug group, aprepitant: HPMCAS-MG: PVP K30(1:3:1) solid Dispersion group (recipe 7). The rats were fasted without water deprivation overnight. Samples of the solid dispersion were dispersed in a solution containing 0.5% sodium carboxymethylcellulose and administered orally by gavage at a dose of 8 mg/kg. At 0.5, 1,2, 3,4, 5, 6, 12, 24 hours post-dose, about 0.2 ml of blood was drawn from the orbital orbit using heparinized capillaries. The water was fed 4 hours after the administration. All blood samples were stored on ice. After all the sampling points were taken, the centrifuge was centrifuged at 10000rpm for 5 minutes, and 100. mu.l of the supernatant was transferred to a 1.5ml centrifuge tube and stored at-80 ℃ for further analysis. After the biological sample analysis method is verified to be feasible, the concentration of the plasma sample is determined.
Table 7 aprepitant and its solid dispersion pharmacokinetic parameters after oral administration in rats (n ═ 5)
According to the results shown in fig. 6 and table 7, compared with aprepitant bulk drug, the aprepitant ternary solid dispersion has the oral relative bioavailability of 267.80%, which indicates that after aprepitant is prepared into a supersaturated drug delivery system, the initial dissolution performance is improved or the crystallization and precipitation phenomenon is improved in a high-supersaturation state, so that the concentration of free drug in gastrointestinal tract of the drug is remarkably increased, the intestinal absorption is increased, and the bioavailability is remarkably improved.
Compared with specific pharmacokinetic parameters, the Tmax of the aprepitant ternary solid dispersion and aprepitant is 2.8 hours and 4.4 hours respectively, and the Cmax is 956.42 +/-207.86 ng/mL and 244.54 +/-51.31 ng/mL respectively, so that the significant difference exists. The aprepitant ternary solid dispersion obviously shortens the drug peak reaching time, simultaneously the Cmax is 3.91 times of that of an aprepitant bulk drug, the in vivo half-lives of the aprepitant ternary solid dispersion and aprepitant are 2.31 +/-0.62 hours and 3.43 +/-0.43 hours respectively, and the average residence times (MRT) of the aprepitant ternary solid dispersion and the aprepitant ternary solid dispersion are 8.31 +/-0.84 hours and 5.82 +/-0.57 hours respectively.
In conclusion, the aprepitant ternary solid dispersion improves the solubility and dissolution rate of aprepitant, promotes absorption, remarkably improves the bioavailability of aprepitant, and is a promising solubilizing preparation.
Example 5: dissolution behavior of aprepitant solid dispersion after accelerated test and existence state of drug
Formula 7 was subjected to accelerated stability testing at 45 ℃/75% relative humidity. Samples were taken at 0 months (0M), 1 month (1M), 2 months (2M), 3 months (3M) respectively, and in vitro release experiments were performed to investigate the stability of the prescription.
The in vitro dissolution test method was the same as that described in 1.2.1 above, and the results are shown in FIG. 7.
As can be seen from fig. 7, the dissolution of the ternary solid dispersion formulation was substantially consistent and stable under the accelerated condition of 3 months.
Example 6: presence state of aprepitant solid dispersion after accelerated test
Formula 7 was subjected to accelerated stability testing at 45 ℃/75% relative humidity. Samples were taken at 0 months (0M), 1 month (1M), 2 months (2M), and 3 months (3M), respectively, and the presence of the drug in the solid dispersion was characterized by powder X-ray diffraction.
The test conditions were the same as in example 3.
As can be seen from fig. 8, the ternary solid dispersion formulation maintained the drug in an amorphous form in the polymer matrix under accelerated conditions and maintained physical stability for three months.
So far, the technical solutions of the present invention have been described in connection with the preferred embodiments shown in the drawings, but it is easily understood by those skilled in the art that the scope of the present invention is obviously not limited to these specific embodiments. Equivalent changes or substitutions of related technical features can be made by those skilled in the art without departing from the principle of the invention, and the technical scheme after the changes or substitutions can fall into the protection scope of the invention.
Claims (10)
1. An aprepitant solid dispersion comprises aprepitant and a polymer carrier, wherein the weight ratio of aprepitant to the polymer carrier is 1: 1-1: 10, the polymer carrier is composed of an enteric polymer and a hydrophilic polymer, and the weight ratio of the enteric polymer to the hydrophilic polymer is 1: 10-10: 1.
2. The aprepitant solid dispersion according to claim 1, wherein the weight ratio of aprepitant to the polymer carrier is 1: 4-1: 9, and the weight ratio of the enteric polymer to the hydrophilic polymer is 1: 5-7: 1.
3. The aprepitant solid dispersion according to claim 2, wherein the enteric polymer is selected from one or more of methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose acetate phthalate; the hydrophilic polymer is selected from one or more of polyvinylpyrrolidone, hypromellose, polyvinylpyrrolidone copolymer, and graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol.
4. The aprepitant solid dispersion according to claim 3 wherein the enteric polymer is selected from hydroxypropyl methyl cellulose acetate succinate.
5. The aprepitant solid dispersion according to claim 4, wherein the hydrophilic polymer is one or two selected from the group consisting of polyvinylpyrrolidone and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
6. Aprepitant solid dispersion according to claim 5 wherein the hydrophilic polymer is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate and polyvinylpyrrolidone in a weight ratio of 1:3 to 7:1, preferably 5:3 to 3: 1.
7. The aprepitant solid dispersion of claim 5, wherein the hydrophilic polymer is selected from a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1: 5-7: 1.
8. An aprepitant solid dispersion according to any one of claims 1 to 7 wherein aprepitant is present in amorphous form.
9. The aprepitant solid dispersion according to any one of claims 1-8, wherein the solid dispersion is prepared by a hot melt extrusion process.
10. A pharmaceutical composition comprising the aprepitant solid dispersion of any one of claims 1-9 and a pharmaceutically acceptable excipient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210901132.6A CN115025048B (en) | 2022-07-28 | 2022-07-28 | Ternary solid dispersion of aprepitant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210901132.6A CN115025048B (en) | 2022-07-28 | 2022-07-28 | Ternary solid dispersion of aprepitant |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115025048A true CN115025048A (en) | 2022-09-09 |
| CN115025048B CN115025048B (en) | 2023-12-15 |
Family
ID=83130638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210901132.6A Active CN115025048B (en) | 2022-07-28 | 2022-07-28 | Ternary solid dispersion of aprepitant |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115025048B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117717523A (en) * | 2023-12-06 | 2024-03-19 | 佛山科学技术学院 | Tilmicosin intestinal tract positioning sustained release agent and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110117194A1 (en) * | 2008-04-29 | 2011-05-19 | Hanall Biopharma Co., Ltd. | Pharmaceutical formulation containing angiotensin-ii receptor blocker |
| CN102525879A (en) * | 2010-12-31 | 2012-07-04 | 江苏正大天晴药业股份有限公司 | Method for preparing aprepitant solid dispersing composition |
| CN108324720A (en) * | 2018-06-06 | 2018-07-27 | 南京海融制药有限公司 | Aprepitant pharmaceutical composition and the method for improving its bioavilability |
| CN113350290A (en) * | 2020-03-05 | 2021-09-07 | 科贝园(北京)医药科技有限公司 | Aprepitant solid dispersion composition and preparation method thereof |
-
2022
- 2022-07-28 CN CN202210901132.6A patent/CN115025048B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110117194A1 (en) * | 2008-04-29 | 2011-05-19 | Hanall Biopharma Co., Ltd. | Pharmaceutical formulation containing angiotensin-ii receptor blocker |
| CN102525879A (en) * | 2010-12-31 | 2012-07-04 | 江苏正大天晴药业股份有限公司 | Method for preparing aprepitant solid dispersing composition |
| CN108324720A (en) * | 2018-06-06 | 2018-07-27 | 南京海融制药有限公司 | Aprepitant pharmaceutical composition and the method for improving its bioavilability |
| CN113350290A (en) * | 2020-03-05 | 2021-09-07 | 科贝园(北京)医药科技有限公司 | Aprepitant solid dispersion composition and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117717523A (en) * | 2023-12-06 | 2024-03-19 | 佛山科学技术学院 | Tilmicosin intestinal tract positioning sustained release agent and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115025048B (en) | 2023-12-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10130582B2 (en) | Complexes of abiraterone acetate, process for the preparation thereof and pharmaceutical compositions containing them | |
| US7923026B2 (en) | Embedded micellar nanoparticles | |
| AU2007312233B2 (en) | Micellar nanoparticles of chemical substances | |
| JP2016204392A (en) | Formulations of enzalutamide | |
| US20110034478A1 (en) | Oral Pharmaceutical Compositions in a Solid Dispersion Comprising Preferably Posaconazole and HPMCAs | |
| KR20010023085A (en) | Solid Pharmaceutical Dosage Forms In Forms Of A Particulate Dispersion | |
| EA028009B1 (en) | Pharmaceutical composition with improved bioavailability | |
| CN103097379A (en) | Nanostructured aprepitant compositions, process for the preparation thereof and pharmaceutical compositions containing them | |
| WO2017032908A1 (en) | Pharmaceutical composition comprising amorphous posaconazole | |
| CN115025048B (en) | Ternary solid dispersion of aprepitant | |
| CN113164394B (en) | Vilazodone solid dispersion and preparation method thereof | |
| EP4079295A1 (en) | Composition having improved solubility and bioavailability of olaparib | |
| US20230310393A1 (en) | Sorafenib pharmaceutical composition with high bioavailability and use thereof | |
| EP4257119A1 (en) | Olaparib solid dispersion composition with improved stability and bioavailability | |
| WO2022049075A1 (en) | Amorphous solid dispersion of darolutamide | |
| CN113679729A (en) | Anti-inflammatory composition and preparation method thereof | |
| EP4037659A1 (en) | Pharmaceutical composition comprising enzalutamide | |
| CN112315914A (en) | Lenalidomide pharmaceutical composition and preparation method thereof | |
| US20080299210A1 (en) | Stable nanosized amorphous drug | |
| KR102512866B1 (en) | Solubility Enhanced Oral Formulation of Aprepitant | |
| KR20230141782A (en) | Pretomanid amorphous | |
| CA3235680A1 (en) | Compositions comprising an erk inhibitor | |
| WO2021239893A1 (en) | Amorphous solid dispersion of acalabrutinib | |
| EP4251155A1 (en) | Improved wet granulation processes for apixaban comprising formulations | |
| Pushparaj | Solubility Enhancement of BCS Class II Drug By Solid Dispersion Technique–Fabrication and Evaluation. |
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 | ||
| CB02 | Change of applicant information |
Address after: 201203 5th floor, building 3, 150 Copernicus Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Applicant after: SHANGHAI ZHITONG MEDICAL TECHNOLOGY Co.,Ltd. Address before: 5th Floor, Building 3, No. 150, Copernicus Road, Zhangjiang Hi-Tech Park, Baoshan District, Shanghai, 201203 Applicant before: SHANGHAI ZHITONG MEDICAL TECHNOLOGY Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |