CN115944630B - Tacrolimus sustained release preparation and preparation method thereof - Google Patents
Tacrolimus sustained release preparation and preparation method thereof Download PDFInfo
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- CN115944630B CN115944630B CN202310068531.3A CN202310068531A CN115944630B CN 115944630 B CN115944630 B CN 115944630B CN 202310068531 A CN202310068531 A CN 202310068531A CN 115944630 B CN115944630 B CN 115944630B
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- tacrolimus
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- sustained
- solvent
- release preparation
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- 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 117
- 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 113
- 229960001967 tacrolimus Drugs 0.000 title claims abstract description 113
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 126
- 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 28
- 239000000600 sorbitol Substances 0.000 claims abstract description 28
- 235000010356 sorbitol Nutrition 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 13
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 13
- 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 13
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims abstract description 13
- 235000013539 calcium stearate Nutrition 0.000 claims abstract description 13
- 239000008116 calcium stearate Substances 0.000 claims abstract description 13
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 13
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 13
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 13
- 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 13
- 239000000945 filler Substances 0.000 claims abstract description 12
- 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 10
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 10
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 7
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000008117 stearic acid Substances 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 54
- 238000002791 soaking Methods 0.000 claims description 26
- 239000000843 powder Substances 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 22
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
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- 238000007906 compression Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000008213 purified water Substances 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
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- 238000000034 method Methods 0.000 claims description 13
- 238000001728 nano-filtration Methods 0.000 claims description 13
- 239000007962 solid dispersion Substances 0.000 claims description 13
- 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
- 238000002156 mixing Methods 0.000 claims description 12
- 239000002798 polar solvent Substances 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000000855 fermentation Methods 0.000 claims description 9
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- 229910017053 inorganic salt Inorganic materials 0.000 claims description 8
- 238000012856 packing Methods 0.000 claims description 8
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- 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 7
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 150000003839 salts Chemical class 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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 6
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- 238000005303 weighing Methods 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 5
- 238000000926 separation method Methods 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
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 3
- 238000005520 cutting process 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
- 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
- 238000013268 sustained release Methods 0.000 abstract description 24
- 239000012730 sustained-release form Substances 0.000 abstract description 24
- 239000003814 drug Substances 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 7
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- 230000000857 drug effect Effects 0.000 abstract description 3
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- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000002829 reductive effect Effects 0.000 abstract description 2
- 235000019441 ethanol Nutrition 0.000 description 39
- 239000002775 capsule Substances 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
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- 239000013557 residual solvent Substances 0.000 description 5
- 238000003756 stirring Methods 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
- 229930105110 Cyclosporin A Natural products 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229960001265 ciclosporin Drugs 0.000 description 4
- 238000011161 development Methods 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
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- 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
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- 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 2
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- 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
- 206010062016 Immunosuppression Diseases 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
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- 239000011575 calcium Substances 0.000 description 1
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- 229930182912 cyclosporin Natural products 0.000 description 1
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- -1 dimethyl siloxane Chemical class 0.000 description 1
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- 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
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- 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
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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. The tacrolimus sustained-release preparation provided by the invention selects sorbitol as a filling agent, hydroxypropyl methylcellulose as a solubilizer, ethyl cellulose as a sustained-release skeleton, calcium stearate and/or stearic acid as a lubricant, and croscarmellose sodium as a disintegrating agent, so that the aim of slowly releasing a main drug is fulfilled while the solubility of tacrolimus is increased, the effective control of the release rate of tacrolimus is realized, the drug effect of tacrolimus can be exerted more stably, the administration times are reduced, and the patient compliance is improved; besides, the problem of ethanol dumping easily occurring in the tacrolimus slow-release preparation is solved, the effective rate and the safety of the medicine are effectively improved, and the preparation process is simple and 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 first extracted from broth fermentation of Streptococcus tsukubaensis in 1984 by Japanese Tenzea pharmaceutical company, and is a three-pillar product for resisting graft immune rejection at home and abroad in parallel with cyclosporin and mycophenolate mofetil. Tacrolimus was approved by the FDA in 1995 for sale in the United states and entered the China market in 1998. Tacrolimus and cyclosporin A are both calcium neuraminidase inhibitors, have similar and wider immunosuppressive effects as cyclosporin A, and mainly achieve the effect of comprehensively inhibiting T lymphocytes by inhibiting interleukin-2 (L-2) release, wherein the efficacy is 10-100 times higher than that of cyclosporin A, and adverse reactions are fewer. Tacrolimus is widely applied to transplantation of solid organs such as liver, pancreas, kidney, heart, lung and the like at present, has become a first-line medicament for an organ transplantation immunosuppression 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 higher clinical application value.
However, tacrolimus has a Narrow Therapeutic Index (NTI) and its blood concentration must be maintained within a certain level, too high a concentration increases the risk of toxic reactions, while insufficient concentrations increase rejection reactions. The tacrolimus sustained-release preparation can lead the blood concentration of tacrolimus to be stable, can reduce the CV of blood concentration, reduce the administration times and has higher clinical administration advantages. However, the prescription and the production process of the tacrolimus sustained-release preparation have higher difficulty, and the difficulty of the prescription and the process is as follows: (1) The solubility of tacrolimus in water is very poor (about 1.58 mu M in water at 25 ℃), and the selected auxiliary materials need to have a slow release function while solubilizing tacrolimus; (2) the preparation product is easy to have ethanol dumping; (3) The development of the solubilization slow release auxiliary materials and the main drugs can be fully combined, and the process difficulty suitable for industrialization is high. Therefore, the development of a sustained release preparation which is suitable for industrial production, can slowly release tacrolimus and does not cause ethanol dumping has very important significance.
Disclosure of Invention
Aiming at the problems of the prior tacrolimus sustained-release preparation, the invention provides the 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 sustained release preparation of tacrolimus comprising tacrolimus or a pharmaceutically acceptable salt thereof, sorbitol, hydroxypropyl methylcellulose, ethylcellulose, calcium stearate and/or stearic acid, and croscarmellose sodium.
Compared with the prior art, the tacrolimus sustained-release preparation provided by the invention has the advantages that sorbitol is selected as a filler, hydroxypropyl methylcellulose is used as a solubilizer, ethyl cellulose is used as a sustained-release skeleton, calcium stearate and/or stearic acid are used as a lubricant, and crosslinked sodium carboxymethyl cellulose is used as a disintegrant, so that the aim of slowly releasing a main drug is fulfilled while the solubility of tacrolimus is increased, the effective control of the release speed of tacrolimus is realized, the drug effect of tacrolimus can be exerted more stably, the administration times are reduced, and the patient compliance is improved; in addition, the problem of ethanol dumping easily occurring in the tacrolimus slow-release preparation is solved, and the effective rate and the safety of the medicine are effectively improved.
Preferably, the tacrolimus sustained release preparation comprises the following components in percentage by weight: 1.02 percent of tacrolimus or medicinal salt thereof, 85 to 90 percent of sorbitol, 1 to 5 percent of hydroxypropyl methyl cellulose, 4 to 10 percent of ethyl cellulose, 0.5 to 1.0 percent of calcium stearate and/or stearic acid and 0.5 to 2.0 percent of crosslinked sodium carboxymethyl cellulose.
The preferable components are compounded in a specific proportion, so that the solubility of the tacrolimus can be effectively improved, the slow release effect of the drug is 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 within a relatively stable and durable 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 sustained-release preparation, which comprises the following steps:
step a, preparing tacrolimus raw material;
step b, crushing and sieving sorbitol to obtain sorbitol fine powder;
step c, weighing the components according to the designed proportion, dissolving the weighed tacrolimus raw materials 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 croscarmellose sodium, the calcium stearate and/or the stearic acid with the solid dispersion, and filling to obtain the tacrolimus sustained 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, low production cost, and low organic solvent residue in the prepared pentoxifylline sustained release tablet, thereby further improving the safety of the drug and being suitable for industrial production.
Preferably, the preparation method of the tacrolimus raw material comprises the following steps:
step S1, adding a short-chain alcohol solvent into mycelia obtained by separating tacrolimus fermentation liquor for soaking to obtain alcohol soaking liquor; adding an inorganic salt solution into the alcohol soaking solution, continuously soaking, and separating solid from liquid to obtain a salt soaking solution;
s2, concentrating the salt soaking solution by a nanofiltration concentrator with the cutting molecular weight of 200Da-300Da to the titer of 10-15 ten thousand mug/mL to obtain nanofiltration solution;
step S3, adding sodium dodecyl benzene sulfonate into the nanofiltration solution, uniformly mixing, adding purified water, crystallizing, separating solid from liquid, 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 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 liquid, and collecting a target component to obtain a layer of washing liquid; the packing 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 liquid to a nonpolar solvent to obtain a concentrated solution; and adding an acetate solvent into the concentrated solution for extraction, concentrating the extract until the extract is dry, adding an ethanol solution for dissolution, cooling for crystallization, performing solid-liquid separation, washing and drying to obtain the tacrolimus raw material.
According to the preparation method of the tacrolimus raw material, mycelia obtained by separating tacrolimus fermentation liquor are soaked in a short-chain alcohol solvent and an inorganic salt solution, pigments and other protein impurities contained in the mycelia are primarily removed, then a nanofiltration concentrator with the cutting molecular weight of 200Da-300Da is used for concentrating and removing ions and small molecular impurities, sodium dodecyl benzene sulfonate is added into the concentrated liquor, the distribution ratio of tacrolimus and impurities in mother liquor and crystals is changed, the solubility of the impurities in the mother liquor is increased, the tacrolimus is fully crystallized and separated out, secondary metabolites produced in the fermentation process are further removed, the quality of a target product is improved, finally dynamic axial compression columns with the filler of UniSil 10-120 C8 UItra Plus are used for purifying and separating, the impurities like such as ascomycin and dihydrotacrolimus are fully removed, the purity of tacrolimus is greatly improved, and the tacrolimus raw material with high purity which can reach more than 99.98% is finally obtained, and the clinical medicine safety of tacrolimus preparation products is facilitated to be improved.
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% -75%.
Preferably, in step S1, the addition amount of the inorganic salt solution is 4% -6% of the volume of the alcohol soaking solution.
Preferably, in the step S1, the soaking time is 2-3 hours.
The preferable short-chain alcohol solvent, inorganic salt and addition amount can sufficiently remove pigment and other protein impurities contained in mycelium.
Preferably, in step S3, the mass-to-volume ratio of the sodium dodecyl benzene sulfonate to the nanofiltration solution is 0.02-0.05:1, 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 nanofiltration solution is 0.75-1.0:1.
Preferably, in step S3, the purified water is slowly added, and the adding time is controlled to be 1h-2h.
Preferably, in step S3, the crystallization temperature is 15-35 ℃ and the crystallization time is 12-24 hours.
The preferred adding amount of the sodium dodecyl benzene sulfonate and the purified water and crystallization conditions can fully crystallize and separate out the tacrolimus, reduce the impurity content 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 the subsequent high-pressure chromatography.
Further, in the step S3, 45-50 wt% ethanol solution is adopted to wash the filter cake.
Preferably, in step S4, the loading amount of the tacrolimus coarse powder is 0.8% -1.0% of the column volume, wherein the unit of the loading amount is g, and the unit of the column volume is mL.
Preferably, in the step S4, the volume-mass ratio of the polar solvent to the tacrolimus coarse powder is 8-12:1, wherein the volume unit is mL and the mass unit is g.
Preferably, in step S4, the amount of the purified water added is 20% -25% of the volume of the dissolution solution.
Preferably, in step S4, the content of the polar solvent in the chromatographic liquid is 55wt% to 65wt%.
Preferably, in step S4, the chromatographic flow rate is 5BV/h-6BV/h.
Preferably, in step S4, the dynamic axial compression column has a diameter of 80mm, the filler has a particle diameter of 10 μm, and the filler has a pore diameter ofThe height of the filler was 250mm.
The preferred high-pressure chromatography condition is favorable for effectively separating the tacrolimus from impurities, especially the analogues of ascomycin, dihydrotacrolimus and the like, and has better separation effect in a shorter time and improved separation efficiency.
In step S4, the packing step of the dynamic axial compression column is as follows: homogenizing 900g of chromatographic packing with 2.5L of isopropanol to obtain homogenate, adding the homogenate into a dynamic axial compression column, discharging isopropanol, compacting the chromatographic packing, completing the packing of the dynamic axial compression column, and balancing the dynamic axial compression column with chromatographic liquid.
In the step S4, the high performance liquid chromatography is used for monitoring during the chromatography process, and the chromatographic liquid with ascomycin less than 0.1% and dihydrotacrolimus less than 0.1% is collected.
Preferably, in step S5, the acetate solvent is one or two of ethyl acetate and butyl acetate.
Preferably, in step S5, the volume ratio of the acetate solvent to the concentrated solution is 0.8-1.0:1.
Preferably, in the step S5, the concentration of the ethanol solution is 45-50wt%, and the titer of tacrolimus in the dissolved system is 15-30 ten thousand mug/mL.
Preferably, in 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 45wt% to 50wt% ethanol solution.
The preferred extraction solvent and crystallization conditions may further enhance the purity of tacrolimus.
In step S5, an alcohol meter is used to detect whether the concentrated solution contains a polar solvent.
Preferably, in the step b, the sorbitol is crushed and then sieved by 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 the step c, the addition amount of the organic solvent is 35-60 times of the mass of the prescription solid.
Further, in step c, the particles are crushed to a particle content of less than 40 μm of more than 90%.
Further, in the step c, the drying temperature is 40-60 ℃ and the drying time is 1.5-6 h.
The tacrolimus sustained-release preparation provided by the invention has the advantages that the formula is simple, the preparation process is simple and easy to implement, the in-vitro dissolution curve is highly consistent with that of the original development agent, the drug stability is high, the drug effect of tacrolimus can be better exerted, in the ethanol environment, the dissolution rate of the tacrolimus sustained-release preparation prepared by the invention is not obviously changed, the dissolution property is stable, the stability of the tacrolimus sustained-release preparation is effectively improved, the safety of clinical application of the tacrolimus sustained-release preparation is improved, the effective substitution of the original development agent can be realized, and the application prospect is wide.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
In order to better illustrate the present invention, the following examples are provided for further illustration.
Example 1
The embodiment provides a preparation method of tacrolimus raw material, comprising the following steps:
step a, taking 50L of tacrolimus fermentation liquor with a fermentation unit of 1024 mug/mL, carrying out vacuum suction filtration on the tacrolimus fermentation liquor, reserving mycelia, adding the mycelia into a soaking tank, adding 40L of absolute ethyl alcohol into the soaking tank, detecting 72% of the ethanol content in the soaking liquor by using 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 using a plate-frame filter, reserving 40L of soaking liquor;
step b, adding the soaking solution into a D2540 nanofiltration concentrator for pre-concentration, and then transferring the soaking solution into the D1812 nanofiltration concentrator for concentration until the titer is 138450 mug/mL and the concentrated solution volume 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 for 14h at room temperature after the adding of water is finished, filtering, leaching a filter cake with 50% ethanol solution, and drying at 40 ℃ in a vacuum drying oven to obtain 41.95g of coarse powder;
step d, taking 10g of coarse powder, dissolving the coarse powder with 100mL of absolute ethyl alcohol, adding 25mL of purified water, loading the mixture into a 1.25L dynamic axial compression column, carrying out chromatography with 60% ethanol water solution, collecting partial chromatographic liquid of a peak platform at a chromatographic flow rate of 5VB/h, and combining all the chromatographic liquids, wherein the volume is 8200mL and the titer is 4095 mug/mL;
and e, concentrating the chromatographic liquid until no ethanol exists, adding 700mL of ethyl acetate for extraction, concentrating the extract until the extract is dry, adding 170mL of 50% ethanol water solution while the extract is hot for dissolution, cooling to 6 ℃, crystallizing for 5h, carrying out suction filtration, leaching a filter cake by using the 50% ethanol solution, and drying at 40 ℃ in a vacuum drying oven to obtain 23.15g of tacrolimus product, 99.99% of HPLC purity, 0.01% of dihydrotacrolimus and 45.12% of total yield.
The preparation method of the dynamic axial compression column in the step d comprises the following steps: 900g of UniSil 10-120 C8 UItra Plus silica gel filler with the particle size of 10 μm was homogenized with 2.5L of isopropyl alcohol to obtain a homogenate, the homogenate was fed into a dynamic axial compression column (height: 650mm, diameter: 80 mm), isopropyl alcohol was discharged and the chromatographic filler was compacted, the packing height of the filler was 250mm, the packing of the dynamic axial compression column was completed, and then the dynamic axial compression column was equilibrated with a chromatographic liquid.
The tacrolimus raw material is prepared by adopting other process conditions defined by the invention, and the technical effect equivalent to that of the example 1 can be achieved as long as each parameter is within the range defined by the invention.
Example 2
The embodiment provides a tacrolimus sustained-release capsule, the prescription dosage of which is shown in the following table:
| component (A) | Prescription quantity (%, w/w) |
| Tacrolimus | 1.02 |
| Sorbitol | 88.98 |
| Hydroxypropyl methylcellulose | 3 |
| Ethylcellulose | 5 |
| Calcium stearate | 1 |
| Croscarmellose sodium | 1 |
| Solvent ethanol | 50 times the mass of the prescribed solid |
The preparation method of the tacrolimus sustained-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
step b, weighing the components according to the designed proportion, dissolving the weighed tacrolimus raw materials in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by a drying oven at the drying temperature of 40 ℃ for 6 hours, crushing the dried materials until the particle content of the dried materials is smaller than 40 mu m and is larger than 90%, and obtaining a solid dispersion;
and c, uniformly mixing the weighed croscarmellose sodium and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus sustained-release capsule.
Example 3
The embodiment provides a tacrolimus sustained-release capsule, the prescription dosage of which is shown in the following table:
the preparation method of the tacrolimus sustained-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
step b, weighing the components according to the designed proportion, dissolving the weighed tacrolimus raw materials in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by a drying oven at the drying temperature of 60 ℃ for 1.5 hours, crushing the dried materials until the particle content of the crushed materials is less than 40 mu m and is more than 90%, and obtaining a solid dispersion;
and c, uniformly mixing the weighed croscarmellose sodium and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus sustained-release capsule.
Example 4
The embodiment provides a tacrolimus sustained-release capsule, the prescription dosage of which is shown in the following table:
the preparation method of the tacrolimus sustained-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
step b, weighing the components according to the designed proportion, dissolving the weighed tacrolimus raw materials in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by a drying oven at the drying temperature of 50 ℃ for 3 hours, crushing the dried materials until the particle content of the dried materials is smaller than 40 mu m and is larger than 90%, and obtaining a solid dispersion;
and c, uniformly mixing the weighed croscarmellose sodium and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus sustained-release capsule.
Example 5
The embodiment provides a tacrolimus sustained-release capsule, the prescription dosage of which is shown in the following table:
| component (A) | Prescription quantity (%, w/w) |
| Tacrolimus | 1.02 |
| Sorbitol | 85.18 |
| Hydroxypropyl methylcellulose | 1 |
| Ethylcellulose | 10 |
| Calcium stearate | 0.8 |
| Croscarmellose sodium | 2 |
| Solvent ethanol | 60 times the mass of the prescribed solid |
The preparation method of the tacrolimus sustained-release capsule comprises the following steps:
step a, crushing and sieving sorbitol to obtain sorbitol fine powder;
step b, weighing the components according to the designed proportion, dissolving the weighed tacrolimus raw materials in absolute ethyl alcohol, sequentially adding the weighed ethyl cellulose, hydroxypropyl methyl cellulose and sorbitol fine powder, uniformly stirring, drying by a drying oven at the drying temperature of 55 ℃ for 4 hours, crushing the dried materials until the particle content of the dried materials is smaller than 40 mu m and is larger than 90%, and obtaining a solid dispersion;
and c, uniformly mixing the weighed croscarmellose sodium and calcium stearate with the solid dispersion, and filling to obtain the tacrolimus sustained-release capsule.
Comparative example 1
The comparative example provides a tacrolimus sustained-release capsule, the prescription and the preparation method of which are identical to those of example 1, except that sorbitol is replaced by mannitol in the same amount.
Examples 2 to 5 and comparative example 1 above all employed the high purity tacrolimus starting material prepared in example 1.
Residual solvent determination
The second method of the four 0861 residual solvent measurement method is carried out according to the 2020 edition of Chinese pharmacopoeia: gas chromatography, detection conditions: taking (5%) diphenyl- (95%) dimethyl siloxane as a fixing liquid, wherein the sample injection temperature is 200 ℃, the detector temperature is 250 ℃, the headspace bottle temperature is 80 ℃, and the balancing time is 60min. The residual solvent standard is not higher than 5 per mill.
The residual solvents in the solid dispersion in step b in the test examples 2 to 5 were 2.4%, 2.2%, 2.3% and 2.6%, respectively, which meet the standard requirements.
Dissolution Curve determination
In order to examine the dissolution rate of the tacrolimus sustained-release capsule prepared in the example of the present invention, the dissolution profile of examples 2 to 5 and the original preparation (An Si Tay pharmaceutical (China) Co., ltd., lot 1R 3034A) was measured with reference to the requirements of dissolution rate and release rate measurement methods (second method of the fourth edition of Chinese pharmacopoeia 2015, general rule 0931). The test results are shown in tables 1-2.
Test solution:
dissolution medium at ph 4.5: 900mL of phosphoric acid solution (containing 0.1% sodium dodecyl sulfate and 0.005% hydroxypropyl cellulose) at pH 4.5.
Dissolution medium at ph 6.8: 900mL of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer (containing 0.005% hydroxypropyl cellulose) at pH 6.8.
Dissolution temperature: 37.0.5 ℃; rotational speed: 50rpm;
chromatographic column: merck-RP18 (4.0 x 55mm,3 μm);
a detector: ultraviolet spectrophotometers (measurement wavelength: 205 nm);
injection amount: 100mL;
flow rate: 1.0mL/min;
chromatographic column temperature: 30 ℃;
mobile phase: 530ml of water and 360ml of acetonitrile are measured, 1ml of phosphoric acid solution (3 ml of phosphoric acid is precisely measured and placed in a 50ml measuring flask, and water is added for dilution to the scale) is added, and the mixture is uniformly mixed.
TABLE 1 dissolution profile data for dissolution media pH4.5
| Time | Original grinding | 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 at pH6.8
From the data, under the conditions of dissolution medium with pH of 4.5 and pH of 6.8, 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 is consistent with that of the original ground product, and the tacrolimus sustained-release capsule can be better substituted for the original ground product.
Ethanol dumping test
Dissolution medium:
ph1.2 hydrochloric acid solution+0.005% hpc (5% concentration): according to the volume ratio, 95 percent of hydrochloric acid solution with the pH value of 1.2 and 5 percent of absolute ethyl alcohol are stirred uniformly.
ph1.2 hydrochloric acid solution+0.005% hpc (20% concentration): according to the volume ratio, 80 percent of hydrochloric acid solution with the pH value of 1.2 and 20 percent of absolute ethyl alcohol are stirred uniformly.
ph1.2 hydrochloric acid solution+0.005% hpc (40% concentration): according to the volume ratio, 60 percent of hydrochloric acid solution with the pH value of 1.2 and 40 percent of absolute ethyl alcohol are stirred uniformly.
The dissolution rate at each time point was measured as described above. The results are shown in tables 3 to 5.
TABLE 3 ethanol pour test in pH1.2 Medium (ethanol concentration 5%)
Table 4 ethanol pour test in pH1.2 Medium (ethanol concentration 20%)
TABLE 5 ethanol pour test in pH1.2 Medium (ethanol concentration 40%)
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As can be seen from the above table, compared with the comparative example, the tacrolimus sustained-release capsule prepared in the example of the present invention does not find sudden release in ethanol with different concentrations, whereas the tacrolimus sustained-release capsule prepared in the comparative example shows more remarkable sudden release with increasing ethanol concentration.
Stability test
Examples 2 to 5 and comparative example 1 were subjected to long-term and accelerated tests (lot 1R3034A, style pharmaceutical Co., ltd., china) and the long-term and accelerated test conditions are shown in Table 6, and the test results are shown in tables 7 to 10.
TABLE 6 long term and accelerated experimental conditions
| Acceleration test | Placing at 40deg.C+ -2deg.C and RH75% + -5% |
| Long-term test | Placing at 30deg.C+ -2deg.C and RH65% + -5% |
Stability data of Table 7 content
| Time | Example 2 | Example 3 | Example 5 | Example 6 | Original grinding | Comparative example 1 |
| 0 | 99.7％ | 99.5％ | 99.0％ | 99.2％ | 99.5％ | 96.5％ |
| Accelerating for 3 months | 98.9％ | 98.7％ | 98.4％ | 98.9％ | 98.5％ | 95.1％ |
| Accelerating for 6 months | 97.8％ | 97.2％ | 97.0％ | 97.4％ | 97.4％ | 93.5％ |
| Long-term 6 months | 99.4％ | 99.2％ | 98.7％ | 99.0％ | 99.5％ | 95.3％ |
Table 8 stability of release data
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TABLE 9 moisture stability data
| Time | Example 2 | Example 3 | Example 5 | Example 6 | Original grinding | Comparative example 1 |
| Day 0 | 4.35％ | 4.34％ | 4.28％ | 4.35％ | 5.10％ | 5.26％ |
| Accelerating for 3 months | 4.42％ | 4.45％ | 4.39％ | 4.46％ | 5.11％ | 5.53％ |
| Accelerating for 6 months | 4.53％ | 4.55％ | 4.50％ | 4.54％ | 5.13％ | 6.01％ |
| Long-term 6 months | 4.40％ | 4.40％ | 4.33％ | 4.39％ | 5.10％ | 5.48％ |
TABLE 10 impurity stability data
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The stability investigation result of the sample shows that the tacrolimus sustained-release capsule prepared by the invention has low residual solvent content, low water content, good dissolution, small content and impurity change after long-term and acceleration, good stability and high clinical use safety.
In conclusion, the tacrolimus sustained-release capsule prepared by the embodiment of the invention has high similarity with the original ground product and good quality stability, and can realize the substitution of the original ground product; the preparation has simple production process, low process energy consumption and easy realization of industrialized mass production.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (6)
1. The preparation method of the tacrolimus sustained-release preparation is characterized by comprising the following steps:
step S1, adding a short-chain alcohol solvent into mycelia obtained by separating tacrolimus fermentation liquor for soaking to obtain alcohol soaking liquor; adding an inorganic salt solution into the alcohol soaking solution, continuously soaking, and separating solid from liquid to obtain a salt soaking solution; the short-chain alcohol solvent is at least one of methanol, ethanol or isopropanol;
s2, concentrating the salt soaking solution by a nanofiltration concentrator with the cutting molecular weight of 200Da-300Da to the titer of 10-15 ten thousand mug/mL to obtain nanofiltration solution;
step S3, adding sodium dodecyl benzene sulfonate into the nanofiltration solution, uniformly mixing, adding purified water, crystallizing, separating solid from liquid, 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 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 liquid, and collecting a target component to obtain a layer of washing liquid; the packing 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 liquid to a nonpolar solvent to obtain a concentrated solution; adding an acetate solvent into the concentrated solution for extraction, concentrating the extract until the extract is dried, adding an ethanol solution for dissolution, cooling for crystallization, performing solid-liquid separation, washing and drying to obtain a tacrolimus raw material; the acetate solvent is one or two of ethyl acetate and butyl acetate;
s6, crushing sorbitol, and sieving to obtain sorbitol fine powder;
s7, weighing the components according to the designed proportion, dissolving the weighed tacrolimus raw materials in an organic solvent, sequentially adding the weighed ethyl cellulose, hydroxypropyl methylcellulose and sorbitol fine powder, uniformly mixing, drying and crushing to obtain a solid dispersion;
step S8, uniformly mixing the croscarmellose sodium, calcium stearate and/or stearic acid with the solid dispersion, and filling to obtain the tacrolimus sustained release preparation;
the tacrolimus sustained-release preparation comprises the following components in percentage by weight: 1.02 percent of tacrolimus or medicinal salt thereof, 85 to 90 percent of sorbitol, 1 to 5 percent of hydroxypropyl methyl cellulose, 4 to 10 percent of ethyl cellulose, 0.5 to 1.0 percent of calcium stearate and/or stearic acid and 0.5 to 2.0 percent of crosslinked sodium carboxymethyl cellulose.
2. The method for preparing a tacrolimus sustained-release preparation according to claim 1, wherein in the step S1, the inorganic salt solution is at least one of an aluminum sulfate solution or a zinc sulfate solution with a mass concentration of 20% -25%; and/or
In the step S1, the content of the short-chain alcohol solvent in the alcohol soaking solution is 70% -75%; and/or
In the step S1, the adding 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 hours.
3. The method for preparing a tacrolimus sustained-release preparation according to claim 1, wherein in the step S3, the mass-volume ratio of sodium dodecyl benzene sulfonate to nanofiltration solution is 0.02-0.05:1, wherein the mass units are g and the volume units are mL; and/or
In the step S3, the volume ratio of the purified water to the nanofiltration liquid is 0.75-1.0:1; 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.
4. The method for preparing a tacrolimus sustained-release preparation according to claim 1, wherein in step S4, the loading amount of tacrolimus coarse powder is 0.8% -1.0% of the column volume, wherein the unit of loading amount is g, and the unit of column volume is mL; and/or
In the step S4, the volume-mass ratio of the polar solvent to the tacrolimus coarse powder is 8-12:1, 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 liquid is 55-65wt%; and/or
In the step S4, the chromatographic flow rate is 5BV/h-6BV/h;
in the step S4, the diameter of the dynamic axial compression column is 80mm, the particle size of the filler is 10 mu m, the pore diameter of the filler is 200A, and the height of the filler is 250mm.
5. The method for preparing a sustained-release preparation of tacrolimus as claimed in claim 1, wherein in step S5, the volume ratio of the acetate solvent to the concentrated solution is 0.8-1.0:1; and/or
In the step S5, the concentration of the ethanol solution is 45-50wt%, and the titer of tacrolimus in the dissolved system is 15-30 ten thousand mug/mL; and/or
In the step S5, the temperature of the cooling crystallization is 2-8 ℃ and the crystallization time is 4-6 h.
6. The method for preparing a sustained release preparation of tacrolimus as claimed in claim 1, wherein in step S6, the sorbitol is crushed and then sieved with a 100-200 mesh sieve; and/or
In step S7, the organic solvent is at least one of ethanol, propylene glycol or ethyl acetate; and/or
In the step S7, the addition amount of the organic solvent is 35-60 times of the mass of the prescription solid.
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Citations (5)
| 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 |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2669094A1 (en) * | 2006-11-08 | 2008-05-29 | Novavax,Inc. | Method of preparing solid dosage forms of multi-phasic pharmaceutical compositions |
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Patent Citations (5)
| 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 |
| 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 |
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| CN115944630A (en) | 2023-04-11 |
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