CN115944630A - Tacrolimus sustained-release preparation and preparation method thereof - Google Patents
Tacrolimus sustained-release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN115944630A CN115944630A CN202310068531.3A CN202310068531A CN115944630A CN 115944630 A CN115944630 A CN 115944630A CN 202310068531 A CN202310068531 A CN 202310068531A CN 115944630 A CN115944630 A CN 115944630A
- Authority
- CN
- China
- Prior art keywords
- tacrolimus
- solution
- release preparation
- sustained
- preparation
- 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
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 title claims abstract description 125
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 title claims abstract description 125
- 229960001967 tacrolimus Drugs 0.000 title claims abstract description 125
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 130
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 29
- 239000000600 sorbitol Substances 0.000 claims abstract description 29
- 235000010356 sorbitol Nutrition 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 238000013268 sustained release Methods 0.000 claims abstract description 18
- 239000012730 sustained-release form Substances 0.000 claims abstract description 18
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 14
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 14
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 14
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims abstract description 14
- 235000013539 calcium stearate Nutrition 0.000 claims abstract description 14
- 239000008116 calcium stearate Substances 0.000 claims abstract description 14
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 14
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 14
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 14
- 239000000945 filler Substances 0.000 claims abstract description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 14
- 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 abstract description 14
- 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 claims abstract description 9
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 9
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 8
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000008117 stearic acid Substances 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 60
- 239000000843 powder Substances 0.000 claims description 24
- 238000002791 soaking Methods 0.000 claims description 24
- 239000002775 capsule Substances 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000007906 compression Methods 0.000 claims description 16
- 230000006835 compression Effects 0.000 claims description 16
- 238000004090 dissolution Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 15
- 239000008213 purified water Substances 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 13
- 239000007962 solid dispersion Substances 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- 239000002798 polar solvent Substances 0.000 claims description 11
- 238000004587 chromatography analysis Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000000855 fermentation Methods 0.000 claims description 9
- 230000004151 fermentation Effects 0.000 claims description 9
- 239000012266 salt solution Substances 0.000 claims description 9
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 8
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 7
- 238000001728 nano-filtration Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 229940080264 sodium dodecylbenzenesulfonate Drugs 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- 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 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 238000013461 design Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 5
- 238000011068 loading method Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000005520 cutting process Methods 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 235000012247 sodium ferrocyanide Nutrition 0.000 claims description 2
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 2
- 229960001763 zinc sulfate Drugs 0.000 claims description 2
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000000857 drug effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 239000000314 lubricant Substances 0.000 abstract description 2
- 230000002829 reductive effect Effects 0.000 abstract description 2
- 239000007884 disintegrant Substances 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000012535 impurity Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000012856 packing Methods 0.000 description 5
- 239000013557 residual solvent Substances 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 229960001265 ciclosporin Drugs 0.000 description 4
- RQYGKZGKXDOUEO-HHRHWXIDSA-N dihydro-fk 506 Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)OC([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CCC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 RQYGKZGKXDOUEO-HHRHWXIDSA-N 0.000 description 4
- RQYGKZGKXDOUEO-UHFFFAOYSA-N dihydrotacrolimus Natural products CC1C(O)CC(=O)C(CCC)C=C(C)CC(C)CC(OC)C(C(CC2C)OC)OC2(O)C(=O)C(=O)N2CCCCC2C(=O)OC1C(C)=CC1CCC(O)C(OC)C1 RQYGKZGKXDOUEO-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- ZDQSOHOQTUFQEM-PKUCKEGBSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-PKUCKEGBSA-N 0.000 description 3
- ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- -1 dimethyl siloxane Chemical class 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- BUCIWTBCUUHRHZ-UHFFFAOYSA-K potassium;disodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O BUCIWTBCUUHRHZ-UHFFFAOYSA-K 0.000 description 1
- 238000004094 preconcentration Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a tacrolimus sustained-release preparation and a preparation method thereof. According to the tacrolimus sustained-release preparation provided by the invention, sorbitol is selected as a filling agent, hydroxypropyl methylcellulose is used as a solubilizer, ethyl cellulose is used as a sustained-release framework, calcium stearate and/or stearic acid are used as a lubricant, and croscarmellose sodium is used as a disintegrant, so that the aim of slowly releasing the main drug is fulfilled while the solubility of tacrolimus is increased, the effective control on the release speed of tacrolimus is realized, the drug effect of tacrolimus can be more stably exerted, the administration frequency is reduced, and the compliance of patients is improved; in addition, the problem that the tacrolimus slow-release preparation is easy to cause ethanol dumping is solved, the effective rate and the safety of the tacrolimus slow-release preparation are effectively improved, the preparation process is simple, and the tacrolimus slow-release preparation is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a tacrolimus sustained-release preparation and a preparation method thereof.
Background
Tacrolimus is firstly extracted from broth fermentation products of streptococcus bulgaricus in 1984 by Japan Tacroze pharmaceutical company, and is a three-pillar product for resisting graft immune rejection reaction at home and abroad together with cyclosporine and mycophenolate mofetil. Tacrolimus was approved by the FDA for marketing in the United states in 1995 and entered the Chinese market in 1998. Tacrolimus and cyclosporin A are both calcium neuraminidase inhibitors, have the similar and wider immunosuppressive action as cyclosporin A, achieve the effect of comprehensively inhibiting T lymphocytes mainly by inhibiting the release of interleukin-2 (L-2), have the efficacy 10-100 times higher than that of cyclosporin A, and have fewer adverse reactions. At present, tacrolimus is widely applied to transplantation of solid organs such as liver, pancreas, kidney, heart, lung and the like, becomes a first-line medicament for organ transplantation immunosuppressive therapy, plays a positive role in treating autoimmune diseases such as Atopic Dermatitis (AD), systemic Lupus Erythematosus (SLE), autoimmune eye diseases and the like, and has high clinical application value.
However, tacrolimus has a Narrow Therapeutic Index (NTI), and blood levels of tacrolimus must be maintained within certain levels, with too high a concentration increasing the risk of toxic reactions and too low a concentration increasing rejection. The tacrolimus sustained-release preparation can lead the blood concentration of the tacrolimus to be stable, reduce the blood concentration CV and reduce the times of taking the medicine, and has higher clinical medication advantages. However, the tacrolimus slow-release preparation has higher difficulty in prescription and production process, and the difficulties in the prescription and process are as follows: (1) The solubility of the tacrolimus in water is very poor (about 1.58 mu M of tacrolimus is dissolved in water at 25 ℃), and the selected auxiliary materials need to have a slow release function while the tacrolimus is dissolved; (2) the preparation product is easy to cause ethanol pouring; (3) The solubilization slow-release auxiliary materials and the main drugs can be fully combined in the development process, and the process suitable for industrialization is difficult. Therefore, it is of great importance to develop a sustained release preparation which is suitable for industrial production, can slowly release tacrolimus and does not cause ethanol dumping.
Disclosure of Invention
Aiming at the problems of the existing tacrolimus sustained-release preparation, the invention provides a tacrolimus sustained-release preparation and a preparation method thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a slow-release tacrolimus preparation contains tacrolimus or its medicinal salt, sorbitol, hydroxypropyl methylcellulose, ethyl cellulose, calcium stearate and/or stearic acid, and croscarmellose sodium.
Compared with the prior art, the sustained-release preparation of tacrolimus provided by the invention has the advantages that sorbitol is selected as a filling agent, hydroxypropyl methylcellulose is used as a solubilizer, ethylcellulose is used as a sustained-release skeleton, calcium stearate and/or stearic acid are/is used as a lubricant, and croscarmellose sodium is used as a disintegrating agent, so that the purpose of sustained-release of main drugs is achieved while the solubility of tacrolimus is increased, the effective control on the release speed of tacrolimus is realized, the drug effect of tacrolimus can be exerted more stably, the administration frequency is reduced, and the compliance of patients is improved; in addition, the problem that the tacrolimus slow-release preparation is easy to cause ethanol dumping is solved, and the effective rate and the safety of the tacrolimus slow-release preparation are effectively improved.
Preferably, the tacrolimus slow-release preparation comprises the following components in percentage by weight: 1.02% of tacrolimus or medicinal salt thereof, 85% -90% of sorbitol, 1% -5% of hydroxypropyl methyl cellulose, 4% -10% of ethyl cellulose, 0.5% -1.0% of calcium stearate and/or stearic acid and 0.5% -2.0% of croscarmellose sodium.
The preferable components are compounded in a specific ratio, so that the solubility of the tacrolimus can be effectively improved, the slow release effect of the drug can be better controlled, and particularly the slow release effect of the tacrolimus slow release preparation in an ethanol environment is improved, so that the blood concentration of the tacrolimus slow release preparation in the ethanol environment can be kept in a relatively stable and lasting effective range, and the safety of the drug is improved.
Preferably, the sustained release preparation is a sustained release capsule.
The invention also provides a preparation method of the tacrolimus slow-release preparation, which comprises the following steps:
step a, preparing a tacrolimus raw material;
b, crushing and sieving the sorbitol to obtain sorbitol fine powder;
step c, weighing the components according to a design ratio, dissolving the weighed tacrolimus raw material in an organic solvent, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly mixing, drying and crushing to obtain a solid dispersion;
and d, uniformly mixing the cross-linked sodium carboxymethyl cellulose, the calcium stearate and/or the stearic acid with the solid dispersion, and filling to obtain the tacrolimus slow-release preparation.
The preparation method of the tacrolimus sustained-release preparation provided by the invention has the advantages of simple process, good stability, no need of special equipment and low production cost, and the prepared pentoxifylline sustained-release tablet has low organic solvent residue, so that the safety of the medicine is further improved, and the preparation method is suitable for industrial production.
Preferably, the preparation method of the tacrolimus raw material comprises the following steps:
step S1, adding mycelium obtained by separation of tacrolimus fermentation liquor into a short-chain alcohol solvent for soaking to obtain an alcohol soaking solution; adding an inorganic salt solution into the alcohol soaking solution, continuously soaking, and carrying out solid-liquid separation to obtain a salt soaking solution;
s2, concentrating the salt soaking solution to the titer of 10-15 ten thousand mu g/mL by using a nanofiltration concentrator with the cutting molecular weight of 200-300 Da to obtain sodium filtrate;
s3, adding sodium dodecyl benzene sulfonate into the nanofiltration solution, uniformly mixing, adding purified water, crystallizing, carrying out solid-liquid separation, washing and drying to obtain tacrolimus coarse powder;
s4, dissolving the tacrolimus coarse powder by using a polar solvent, adding purified water, uniformly mixing, adding into a dynamic axial compression column, eluting by using a mixed solution of the polar solvent and the purified water as a chromatographic solution, and collecting a target component to obtain a layer washing liquid; wherein the filler of the dynamic axial compression column is UniSil C8 UItra Plus, and the polar solvent is at least one of ethanol, methanol or acetonitrile;
s5, concentrating the chromatographic solution to a non-polar solvent to obtain a concentrated solution; and adding an acetate solvent into the concentrated solution for extraction, concentrating the extract liquor to be dry, adding an ethanol solution for dissolution, cooling for crystallization, carrying out solid-liquid separation, washing, and drying to obtain the tacrolimus raw material.
The preparation method of the tacrolimus raw material provided by the invention comprises the steps of soaking mycelium obtained by separating a tacrolimus fermentation liquor in a short-chain alcohol solvent and an inorganic salt solution, preliminarily removing pigments and other protein impurities contained in the mycelium, then concentrating by using a nanofiltration concentrator with the cutting molecular weight of 200Da-300Da to remove ions and small molecular impurities, adding sodium dodecyl benzene sulfonate into a concentrated solution, changing the distribution ratio of tacrolimus and impurities in a mother solution and crystals, increasing the solubility of the impurities in the mother solution, fully crystallizing and separating the tacrolimus, further removing secondary metabolites generated in the fermentation process, improving the quality of a target product, finally performing purification and separation by using a dynamic axial compression column with UniSil 10-120 C8 UItra Plus as a filler, fully removing similar impurities such as ascomycin and dihydrotacrolimus, greatly improving the purity of the tacrolimus, and finally obtaining the high-purity tacrolimus with the content of more than 99.98%, which is beneficial to the improvement of the clinical safety of tacrolimus preparation products.
Preferably, in step S1, the short-chain alcohol solvent is at least one of methanol, ethanol or isopropanol.
Preferably, in step S1, the inorganic salt solution is at least one of an aluminum sulfate solution, a yellow blood salt solution or a zinc sulfate solution with a mass concentration of 20% -25%.
Preferably, in step S1, the content of the short-chain alcohol solvent in the alcohol soaking solution is 70% to 75%.
Preferably, in step S1, the amount of the inorganic salt solution added is 4% to 6% of the volume of the alcohol soaking solution.
Preferably, in step S1, the soaking time is 2h-3h.
The preferred short-chain alcohol solvent, inorganic salt and addition amount can sufficiently remove pigment and other protein impurities contained in the mycelium.
Preferably, in step S3, the mass-to-volume ratio of the sodium dodecylbenzenesulfonate to the sodium filtrate is 0.02 to 0.05, wherein the mass unit is g, and the volume unit is mL.
Preferably, in step S3, the volume ratio of the purified water to the sodium filtrate is 0.75-1.0.
Preferably, in step S3, the purified water is slowly added, and the adding time is controlled to be 1h-2h.
Preferably, in the step S3, the crystallization temperature is 15-35 ℃, and the crystallization time is 12-24 h.
The preferable addition amount of the sodium dodecyl benzene sulfonate and the purified water and the crystallization conditions can ensure that the tacrolimus is fully crystallized and separated out, reduce the content of impurities in the crystals, improve the separation effect of the tacrolimus and the impurities, and further be beneficial to improving the purification effect and efficiency of subsequent high-pressure chromatography.
Further, in step S3, the filter cake is washed with 45wt% to 50wt% ethanol solution.
Preferably, in step S4, the loading amount of the tacrolimus coarse powder is 0.8 to 1.0 percent of the column volume, wherein the unit of the loading amount is g, and the unit of the column volume is mL.
Preferably, in step S4, the volume-to-mass ratio of the polar solvent to the tacrolimus coarse powder is 8 to 12, wherein the volume unit mL and the mass unit g are as follows.
Preferably, in step S4, the amount of the added purified water is 20% to 25% of the volume of the dissolving solution.
Preferably, in step S4, the content of the polar solvent in the chromatography liquid is 55wt% to 65wt%.
Preferably, in step S4, the flow rate of chromatography is 5BV/h to 6BV/h.
Preferably, in step S4, the diameter of the dynamic axial compression column is 80mm, the particle diameter of the filler is 10 μm, and the pore diameter of the filler is
The height of the filler was 250mm.
The optimized high-pressure chromatography condition is favorable for effectively separating tacrolimus from impurities, particularly analogs such as ascomycin, dihydrotacrolimus and the like, and a better separation effect is obtained in a shorter time, so that the separation efficiency is improved.
In step S4, the dynamic axial compression column packing step includes: homogenizing 900g of chromatographic packing with 2.5L of isopropanol to obtain homogenate, adding the homogenate into a dynamic axial compression column, discharging the isopropanol and compacting the chromatographic packing to complete the filling of the dynamic axial compression column, and then balancing the dynamic axial compression column with a chromatographic solution.
In step S4, the chromatography process is monitored by high performance liquid chromatography, and the chromatography solution containing ascomycin less than 0.1% and dihydrotacrolimus less than 0.1% is collected.
Preferably, in step S5, the acetate solvent is one or both of ethyl acetate and butyl acetate.
Preferably, in step S5, the volume ratio of the acetate solvent to the concentrated solution is 0.8 to 1.0.
Preferably, in the step S5, the concentration of the ethanol solution is 45wt% to 50wt%, and the titer of tacrolimus in the dissolved system is 15 mu g/mL to 30 ten thousand mu g/mL.
Preferably, in the step S5, the crystallization temperature is 2-8 ℃, and the crystallization time is 4-6 h.
Illustratively, in step S5, the filter cake is washed with a 45wt% to 50wt% ethanol solution.
The preferred extraction solvent and crystallization conditions further enhance the purity of tacrolimus.
In step S5, whether or not the concentrated solution contains a polar solvent is detected by an alcohol meter.
Preferably, in step b, the sorbitol is crushed and then sieved through a 100-200 mesh sieve.
Preferably, in step c, the organic solvent is at least one of ethanol, propylene glycol or ethyl acetate.
Preferably, in step c, the amount of the organic solvent added is 35 to 60 times of the mass of the prescribed solid.
Further, in step c, the content of particles pulverized to less than 40 μm is more than 90%.
Furthermore, in the step c, the drying temperature is 40-60 ℃, and the drying time is 1.5-6 h.
The tacrolimus slow-release preparation provided by the invention has the advantages of simple formula, simple and feasible preparation process, high in-vitro dissolution curve consistent with the original preparation, high drug stability and capability of better exerting the drug effect of tacrolimus, and in an ethanol environment, the prepared tacrolimus slow-release preparation has no obvious change in dissolution rate, is stable in dissolution property and effectively improves the stability of the tacrolimus slow-release preparation, so that the safety of clinical application of the tacrolimus slow-release preparation is favorably improved, the effective substitution of the original preparation can be realized, and the tacrolimus slow-release preparation has wide application prospect.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In order to better illustrate the invention, the following examples are given by way of further illustration.
Example 1
The embodiment provides a preparation method of a tacrolimus raw material, which comprises the following steps:
step a, taking 50L of tacrolimus fermentation liquor with the fermentation unit of 1024 mu g/mL, carrying out vacuum filtration on the tacrolimus fermentation liquor, reserving mycelium, adding the mycelium into a soaking tank, adding 40L of absolute ethyl alcohol into the soaking tank, detecting the content of the ethyl alcohol in the soaking liquor by an alcohol meter, soaking for 2h at room temperature, adding 2L of aluminum sulfate solution (450 g of aluminum sulfate is dissolved in 2L of deionized water) into the fermentation tank, soaking for 2h at room temperature, filtering by adopting a plate and frame filter, and reserving 40L of soaking liquor;
step b, adding the soak solution into a D2540 nanofiltration concentrator for preconcentration, and then transferring the soak solution into a D1812 nanofiltration concentrator for concentration until the titer is 138450 mu g/mL and the volume of concentrated liquid is 300mL;
step c, adding 6g of sodium dodecyl benzene sulfonate into the concentrated solution, stirring, slowly adding 225mL of purified water, controlling the adding time to be 1h, crystallizing at room temperature for 14h after the water is added, filtering, leaching a filter cake by using a 50% ethanol solution, and drying in a vacuum drying oven at 40 ℃ to obtain 41.95g of coarse powder;
step d, taking 10g of each batch of coarse powder, dissolving the coarse powder by using 100mL of absolute ethyl alcohol, adding 25mL of purified water, loading the coarse powder into a 1.25L dynamic axial compression column, carrying out chromatography by using 60% ethanol water solution at the chromatography flow rate of 5VB/h, collecting part of chromatographic solution of a peak platform, combining all the chromatographic solutions, wherein the volume is 8200mL, and the titer is 4095 mu g/mL;
and e, concentrating the chromatographic solution until no ethanol exists, adding 700mL of ethyl acetate for extraction, concentrating the extract liquid until the extract liquid is dry, adding 170mL of 50% ethanol aqueous solution for dissolution while the extract liquid is hot, cooling to 6 ℃, crystallizing for 5 hours, performing suction filtration, leaching a filter cake by using 50% ethanol solution, and drying at 40 ℃ in a vacuum drying oven to obtain 23.15g of tacrolimus product with the HPLC purity of 99.99%, 0.01% of dihydrotacrolimus and the total yield of 45.12%.
The preparation method of the dynamic axial compression column in the step d comprises the following steps: homogenizing 900g UniSil 10-120 C8 UItra Plus silica gel filler with particle size of 10 μm with 2.5L isopropanol to obtain homogenate, adding the homogenate to a dynamic axial compression column (height 650mm, diameter 80 mm), discharging isopropanol and compacting chromatographic filler, wherein the packing height of the filler is 250mm, completing packing of the dynamic axial compression column, and then balancing the dynamic axial compression column with chromatography liquid.
The tacrolimus raw material prepared by adopting other process conditions defined by the invention can achieve the technical effect equivalent to that of the example 1 as long as all parameters are within the range defined by the invention.
Example 2
The present embodiment provides a tacrolimus sustained-release capsule, wherein the dosage of the formula is as shown in the following table:
| components | Prescription amount (%, w/w) |
| Tacrolimus | 1.02 |
| Sorbitol | 88.98 |
| Hydroxypropyl methylcellulose | 3 |
| Ethyl cellulose | 5 |
| Calcium stearate | 1 |
| Croscarmellose sodium | 1 |
| Solvent ethanol | 50 times of the solid mass of the prescription |
The preparation method of the tacrolimus slow-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
b, weighing the components according to a design ratio, dissolving the weighed tacrolimus raw material in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by using a drying oven at the drying temperature of 40 ℃ for 6 hours, crushing the dried material, and crushing until the content of particles smaller than 40 mu m is larger than 90%, so as to obtain a solid dispersion;
and c, uniformly mixing the weighed cross-linked sodium carboxymethyl cellulose and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus slow-release capsule.
Example 3
The present embodiment provides a tacrolimus sustained-release capsule, wherein the dosage of the formula is as shown in the following table:
the preparation method of the tacrolimus slow-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
b, weighing the components according to a design ratio, dissolving the weighed tacrolimus raw material in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by using a drying oven at a drying temperature of 60 ℃ for 1.5h, crushing the dried material, and crushing to obtain a solid dispersion body, wherein the particle content of the crushed material is less than 40 mu m and is more than 90%;
and c, uniformly mixing the weighed cross-linked sodium carboxymethyl cellulose and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus slow-release capsule.
Example 4
The present embodiment provides a tacrolimus sustained-release capsule, the dosage of which is shown in the following table:
the preparation method of the tacrolimus slow-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
b, weighing the components according to a design ratio, dissolving the weighed tacrolimus raw material in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by using a drying box at a drying temperature of 50 ℃ for 3 hours, crushing the dried material, and crushing the crushed material until the content of particles smaller than 40 mu m is larger than 90% to obtain a solid dispersion;
and c, uniformly mixing the weighed croscarmellose sodium and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus slow-release capsule.
Example 5
The present embodiment provides a tacrolimus sustained-release capsule, the dosage of which is shown in the following table:
| components | Prescription amount (%, w/w) |
| Tacrolimus | 1.02 |
| Sorbitol | 85.18 |
| Hydroxypropyl methylcellulose | 1 |
| Ethyl cellulose | 10 |
| Calcium stearate | 0.8 |
| Croscarmellose sodium | 2 |
| Solvent ethanol | 60 times of the solid mass of the prescription |
The preparation method of the tacrolimus slow-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
b, weighing the components according to a design ratio, dissolving the weighed tacrolimus raw material in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by using a drying oven at a drying temperature of 55 ℃ for 4 hours, crushing the dried material, and crushing to obtain a solid dispersion body, wherein the particle content of the crushed material is less than 40 mu m and is more than 90%;
and c, uniformly mixing the weighed cross-linked sodium carboxymethyl cellulose and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus slow-release capsule.
Comparative example 1
This comparative example provides a tacrolimus sustained release capsule whose formulation and preparation method are completely the same as those of example 1 except that sorbitol is replaced with mannitol in an equal amount.
The high purity tacrolimus starting material prepared in example 1 was used in each of examples 2 to 5 and comparative example 1.
Residual solvent determination
According to the second method of determination of residual solvent in the four 0861 parts of China pharmacopoeia 2020 edition: gas chromatography, detection conditions: taking (5%) diphenyl- (95%) dimethyl siloxane as a stationary liquid, feeding the sample at 200 deg.C, detecting at 250 deg.C, and balancing for 60min at 80 deg.C. The standard of the residual solvent is not higher than 5 per mill.
The residual solvent in the solid dispersion in step b of example 2-5 was detected to be 2.4%, 2.2%, 2.3% and 2.6% respectively, and met the standard requirements.
Determination of dissolution Curve
In order to examine the dissolution rate of the tacrolimus sustained-release capsules prepared in the examples of the present invention, the dissolution profile was measured for examples 2 to 5 and the original pharmaceutical preparation (anstai pharmaceutical (china) ltd., lot No. 1R 3034A) in accordance with the requirements of the dissolution rate and release rate measurement method (the second method of 0931, the fourth general rule of chinese pharmacopoeia 2015). The test results are shown in tables 1 to 2.
Test solutions:
ph4.5 dissolution medium: 900mL of phosphoric acid solution (containing 0.1% sodium lauryl sulfate and 0.005% hydroxypropyl cellulose) at pH 4.5.
ph6.8 dissolution medium: 900mL of potassium dihydrogenphosphate-disodium hydrogenphosphate buffer (containing 0.005% hydroxypropylcellulose) was added at pH 6.8.
Dissolution temperature: 37.0 second 0.5 ℃; rotating speed: 50rpm;
a chromatographic column: merck-RP18 (4.0 x 55mm,3 μm);
a detector: an ultraviolet spectrophotometer (measurement wavelength: 205 nm);
injection amount: 100mL;
flow rate: 1.0mL/min;
temperature of the column: 30 ℃;
mobile phase: weighing 530ml of water, 360ml of acetonitrile, 1ml of phosphoric acid solution (precisely weighing 3ml of phosphoric acid, placing in a 50ml measuring flask, adding water to dilute to scale), and mixing uniformly.
TABLE 1 dissolution Profile data for dissolution media pH4.5
| Time | Original research | Example 2 | Example 3 | Example 4 | Example 5 | Comparative example 1 |
| 0h | 0 | 0 | 0 | 0 | 0 | 0 |
| 0.5h | 22 | 24 | 18 | 23 | 23 | 26 |
| 1h | 38 | 38 | 35 | 41 | 42 | 40 |
| 1.5h | 49 | 50 | 46 | 49 | 52 | 55 |
| 4h | 66 | 69 | 65 | 68 | 67 | 75 |
| 8h | 76 | 77 | 75 | 80 | 78 | 83 |
| 12h | 83 | 85 | 85 | 84 | 85 | 86 |
| 18h | 85 | 90 | 84 | 90 | 87 | 90 |
| 24h | 85 | 89 | 84 | 91 | 89 | 91 |
| F2 | - | 81 | 79 | 76 | 74 | 62 |
TABLE 2 dissolution Profile data for dissolution media pH6.8
From the above data, it can be seen that under the conditions of the dissolution medium of ph4.5 and ph6.8, the dissolution curve of the tacrolimus sustained-release capsule prepared by the embodiment of the invention is similar to that of the original ground product, the quality of the tacrolimus sustained-release capsule can be consistent with that of the original ground product, and the tacrolimus sustained-release capsule can be better substituted for the original ground product.
Ethanol pour test
Dissolution medium:
pH1.2 hydrochloric acid solution +0.005% HPC (5% concentration): 95% pH1.2 hydrochloric acid solution +5% anhydrous ethanol by volume ratio, and stirring well.
ph1.2 hydrochloric acid solution +0.005% hpc (20% concentration): according to the volume ratio, 80 percent of hydrochloric acid solution with pH1.2 +20 percent of absolute ethyl alcohol is stirred evenly.
pH1.2 hydrochloric acid solution + 0.005%/HPC (40% concentration): according to the volume ratio, 60 percent of hydrochloric acid solution with pH1.2 +40 percent of absolute ethyl alcohol is stirred evenly.
The dissolution rate at each time point was measured as above. The results are shown in tables 3 to 5.
TABLE 3 test for ethanol decantation in pH1.2 Medium (5% ethanol concentration)
TABLE 4pH1.2 Medium ethanol pour test (20% ethanol concentration)
TABLE 5test for ethanol decantation in pH1.2 Medium (ethanol concentration 40%)
As can be seen from the above table, the tacrolimus sustained-release capsules prepared in the examples of the present invention did not show burst release in ethanol of different concentrations, compared to the comparative examples, whereas the tacrolimus sustained-release capsules prepared in the comparative examples showed more significant burst release with the increase of ethanol concentration.
Stability test
Examples 2 to 5 and comparative example 1, and the original research (Sitelai pharmaceutical (China) Co., ltd., lot No. 1R 3034A) were subjected to long-term and accelerated tests, conditions of which are shown in Table 6, and test results are shown in tables 7 to 10.
TABLE 6 Long-term and accelerated test conditions
| Accelerated test | Placing at 40 + -2 deg.C and RH75% + -5% |
| Long term test | Placing at 30 + -2 deg.C and RH65% + -5% |
Stability data in Table 7 contents
| Time | Example 2 | Example 3 | Example 5 | Example 6 | Original research | Comparative example 1 |
| 0 | 99.7％ | 99.5％ | 99.0％ | 99.2％ | 99.5％ | 96.5％ |
| Accelerated for 3 months | 98.9％ | 98.7％ | 98.4％ | 98.9％ | 98.5％ | 95.1％ |
| Accelerated for 6 months | 97.8％ | 97.2％ | 97.0％ | 97.4％ | 97.4％ | 93.5％ |
| Long term of 6 months | 99.4％ | 99.2％ | 98.7％ | 99.0％ | 99.5％ | 95.3％ |
Table 8 release stability data
TABLE 9 moisture stability data
| Time | Example 2 | Example 3 | Example 5 | Example 6 | Original research | Comparative example 1 |
| Day 0 | 4.35％ | 4.34％ | 4.28％ | 4.35％ | 5.10％ | 5.26％ |
| Accelerated for 3 months | 4.42％ | 4.45％ | 4.39％ | 4.46％ | 5.11％ | 5.53％ |
| Accelerated for 6 months | 4.53％ | 4.55％ | 4.50％ | 4.54％ | 5.13％ | 6.01％ |
| Long term of 6 months | 4.40％ | 4.40％ | 4.33％ | 4.39％ | 5.10％ | 5.48％ |
TABLE 10 impurity stability data
The stability examination result of the sample shows that the tacrolimus slow-release capsule prepared by the invention has low residual solvent content, low moisture content, good dissolution, small content and impurity change after long-term and acceleration, good stability and high safety in clinical use.
In conclusion, the tacrolimus slow-release capsule prepared by the embodiment of the invention has high similarity with the original ground product and good quality stability, and can replace the original ground product; the preparation has simple production process and low energy consumption, and is easy to realize industrial mass production.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A tacrolimus sustained release preparation is characterized by comprising tacrolimus or medicinal salts thereof, sorbitol, hydroxypropyl methylcellulose, ethyl cellulose, calcium stearate and/or stearic acid and croscarmellose sodium.
2. The tacrolimus sustained-release preparation of claim 1, which is characterized by comprising the following components in percentage by weight: 1.02% of tacrolimus or medicinal salt thereof, 85% -90% of sorbitol, 1% -5% of hydroxypropyl methyl cellulose, 4% -10% of ethyl cellulose, 0.5% -1.0% of calcium stearate and/or stearic acid and 0.5% -2.0% of croscarmellose sodium.
3. The tacrolimus sustained-release preparation according to claim 1 or 2, wherein the sustained-release preparation is a sustained-release capsule.
4. A method for preparing a tacrolimus sustained release formulation as claimed in any one of claims 1 to 3 which comprises the steps of:
step a, preparing a tacrolimus raw material;
b, crushing and sieving the sorbitol to obtain sorbitol fine powder;
step c, weighing the components according to a design ratio, dissolving the weighed tacrolimus raw material in an organic solvent, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly mixing, drying and crushing to obtain a solid dispersion;
and d, uniformly mixing the cross-linked sodium carboxymethyl cellulose, the calcium stearate and/or the stearic acid with the solid dispersion, and filling to obtain the tacrolimus slow-release preparation.
5. The method for preparing a tacrolimus sustained release preparation according to claim 4, wherein in the step a, the method for preparing the tacrolimus raw material comprises the following steps:
step S1, adding mycelium obtained by separation of tacrolimus fermentation liquor into a short-chain alcohol solvent for soaking to obtain an alcohol soaking solution; adding an inorganic salt solution into the alcohol soaking solution, continuously soaking, and carrying out solid-liquid separation to obtain a salt soaking solution;
s2, concentrating the salt soaking solution to the titer of 10-15 ten thousand mu g/mL by using a nanofiltration concentrator with the cutting molecular weight of 200-300 Da to obtain sodium filtrate;
s3, adding sodium dodecyl benzene sulfonate into the nanofiltration solution, uniformly mixing, adding purified water, crystallizing, carrying out solid-liquid separation, washing and drying to obtain tacrolimus coarse powder;
step S4, dissolving the tacrolimus coarse powder by using a polar solvent, adding purified water, uniformly mixing, adding the mixture into a dynamic axial compression column, eluting by using a mixed solution of the polar solvent and the purified water as a chromatographic solution, and collecting a target component to obtain a layer washing liquid; wherein the filler of the dynamic axial compression column is UniSil C8 UItra Plus, and the polar solvent is at least one of ethanol, methanol or acetonitrile;
s5, concentrating the chromatographic solution to a non-polar solvent to obtain a concentrated solution; and adding an acetate solvent into the concentrated solution for extraction, concentrating the extract liquor to be dry, adding an ethanol solution for dissolution, cooling for crystallization, carrying out solid-liquid separation, washing, and drying to obtain the tacrolimus raw material.
6. The method for preparing a tacrolimus sustained release formulation according to claim 5, wherein in the step S1, the short-chain alcohol solvent is at least one of methanol, ethanol or isopropanol; and/or
In the step S1, the inorganic salt solution is at least one of an aluminum sulfate solution, a yellow blood salt solution or a zinc sulfate solution with the mass concentration of 20-25%; and/or
In the step S1, the content of short-chain alcohol solvent in the alcohol soak solution is 70-75%; and/or
In the step S1, the addition amount of the inorganic salt solution is 4-6% of the volume of the alcohol soaking solution; and/or
In the step S1, the soaking time is 2-3 h.
7. The method for preparing a tacrolimus sustained release preparation according to claim 5, wherein in the step S3, the mass-to-volume ratio of the sodium dodecylbenzenesulfonate to the sodium filtrate is 0.02 to 0.05, wherein the mass unit is g, and the volume unit is mL; and/or
In step S3, the volume ratio of the purified water to the sodium filtrate is 0.75-1.0; and/or
In the step S3, the purified water is slowly added, and the adding time is controlled to be 1-2 h; and/or
In the step S3, the crystallization temperature is 15-35 ℃, and the crystallization time is 12-24 h.
8. The method for preparing the tacrolimus sustained-release preparation according to claim 5, wherein in the step S4, the loading amount of the tacrolimus coarse powder is 0.8 to 1.0 percent of the column volume, wherein the unit of the loading amount is g, and the unit of the column volume is mL; and/or
In the step S4, the volume-mass ratio of the polar solvent to the tacrolimus coarse powder is 8-12, wherein the volume unit is mL, and the mass unit is g; and/or
In the step S4, the adding amount of the purified water is 20-25% of the volume of the dissolving solution; and/or
In the step S4, the content of the polar solvent in the chromatographic solution is 55-65 wt%; and/or
In the step S4, the chromatography flow rate is 5BV/h-6BV/h;
in step S4, the diameter of the dynamic axial compression column is 80mm, the grain diameter of the filler is 10 mu m, and the pore diameter of the filler is
The height of the filler was 250mm.
9. The method for preparing a tacrolimus sustained release preparation according to claim 5, wherein in the step S5, the acetate solvent is one or both of ethyl acetate and butyl acetate; and/or
In the step S5, the volume ratio of the acetate solvent to the concentrated solution is 0.8-1.0; and/or
In the step S5, the concentration of the ethanol solution is 45wt% -50wt%, and the titer of tacrolimus in the dissolved system is 15 mu g/mL-30 ten thousand mu g/mL; and/or
In the step S5, the temperature of the cooling crystallization is 2-8 ℃, and the crystallization time is 4-6 h.
10. The method for preparing a tacrolimus sustained-release preparation according to claim 4, wherein in the step b, the sorbitol is crushed and then sieved by a 100-200 mesh sieve; and/or
In the step c, the organic solvent is at least one of ethanol, propylene glycol or ethyl acetate; and/or
In the step c, the adding amount of the organic solvent is 35-60 times of the mass of the prescription solid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310068531.3A CN115944630B (en) | 2023-02-06 | 2023-02-06 | Tacrolimus sustained release preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310068531.3A CN115944630B (en) | 2023-02-06 | 2023-02-06 | Tacrolimus sustained release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115944630A true CN115944630A (en) | 2023-04-11 |
| CN115944630B CN115944630B (en) | 2024-04-05 |
Family
ID=87282639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310068531.3A Active CN115944630B (en) | 2023-02-06 | 2023-02-06 | Tacrolimus sustained release preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115944630B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101481715A (en) * | 2009-01-20 | 2009-07-15 | 南京工业大学 | Method for purifying tacrolimus by biofermentation |
| US20100143481A1 (en) * | 2006-11-08 | 2010-06-10 | Dinesh Shenoy | Method of preparing solid dosage forms of multi-phasic pharmaceutical compositions |
| CN102936253A (en) * | 2012-11-12 | 2013-02-20 | 华北制药集团新药研究开发有限责任公司 | Preparation method of high-purity tacrolimus |
| CN106137971A (en) * | 2015-11-17 | 2016-11-23 | 南京瑞捷医药科技有限公司 | A kind of tacrolimus dispersion and slow releasing composition thereof and preparation method |
| CN107595784A (en) * | 2017-08-29 | 2018-01-19 | 杭州中美华东制药有限公司 | Tacrolimus slow releasing medicinal compositions |
| CN112351773A (en) * | 2018-06-22 | 2021-02-09 | 株式会社钟根堂 | Sustained release pharmaceutical formulation comprising tacrolimus |
-
2023
- 2023-02-06 CN CN202310068531.3A patent/CN115944630B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100143481A1 (en) * | 2006-11-08 | 2010-06-10 | Dinesh Shenoy | Method of preparing solid dosage forms of multi-phasic pharmaceutical compositions |
| CN101481715A (en) * | 2009-01-20 | 2009-07-15 | 南京工业大学 | Method for purifying tacrolimus by biofermentation |
| CN102936253A (en) * | 2012-11-12 | 2013-02-20 | 华北制药集团新药研究开发有限责任公司 | Preparation method of high-purity tacrolimus |
| CN106137971A (en) * | 2015-11-17 | 2016-11-23 | 南京瑞捷医药科技有限公司 | A kind of tacrolimus dispersion and slow releasing composition thereof and preparation method |
| CN107595784A (en) * | 2017-08-29 | 2018-01-19 | 杭州中美华东制药有限公司 | Tacrolimus slow releasing medicinal compositions |
| CN112351773A (en) * | 2018-06-22 | 2021-02-09 | 株式会社钟根堂 | Sustained release pharmaceutical formulation comprising tacrolimus |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115944630B (en) | 2024-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SK7662001A3 (en) | Stabilization of macrolides | |
| CN102382082B (en) | Novel potassium sodium dehydroandroan drographolide succinate compound and drug combination thereof | |
| WO2019242439A1 (en) | Crystal form of arn-509, preparation method therefor and use thereof | |
| KR102011855B1 (en) | Compositions Containing Nitrogen Heterocyclic Hexapeptide Precursors and Methods and Uses of the Same | |
| CN102643255B (en) | Andrographolide compound | |
| US20170158711A1 (en) | Novel industrial crystallization method of cefuroxime sodium and preparation thereof | |
| CN110711176A (en) | Cilnidipine nanosuspension and preparation method thereof | |
| CN115944630A (en) | Tacrolimus sustained-release preparation and preparation method thereof | |
| CN106432276A (en) | Cefazolin sodium compound prepared according to novel intelligent crystallization technology and preparation of cefazolin sodium compound | |
| CN105828827A (en) | Solid preparation comprising tofogliflozin and method for producing same | |
| CN110652496A (en) | Solid dispersion of cryptotanshinone and preparation method and application thereof | |
| CN101805387A (en) | Methylprednisolone aceponate new crystal form and preparation method thereof | |
| WO2020086931A1 (en) | Polymorph of echinocandin antifungal agent | |
| US20180111949A1 (en) | Novel industrial crystallization method of cefuroxime sodium and preparation thereof | |
| CN114644642B (en) | Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition thereof | |
| WO2016008443A1 (en) | Coix seed oil comprising 16 glycerides, formulation and application thereof | |
| CN106963766B (en) | Azaspiroanone pharmaceutical composition and preparation method thereof | |
| CN104892632B (en) | A kind of everolimus of crystal form and preparation method thereof | |
| CN102659886A (en) | New crystal form of methylprednisolone aceponate and preparation method | |
| CN111285832A (en) | Preparation method and novel medical application of myricetin derivative | |
| CN115010689B (en) | Compound kurarinol A and preparation method and application thereof | |
| CN113195484B (en) | Crystal form of propionamide derivative and preparation method thereof | |
| WO2008122425A2 (en) | Oral compositions containing tacrolimus in amorphous form | |
| CN113368066A (en) | Icaritin tablet and preparation method thereof | |
| CN115804760A (en) | Tacrolimus nanocrystal capsule and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |