CN117959253A - Enzalutamide suspension and preparation method and application thereof - Google Patents
Enzalutamide suspension and preparation method and application thereof Download PDFInfo
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- CN117959253A CN117959253A CN202410137979.0A CN202410137979A CN117959253A CN 117959253 A CN117959253 A CN 117959253A CN 202410137979 A CN202410137979 A CN 202410137979A CN 117959253 A CN117959253 A CN 117959253A
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- enzalutamide
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- surfactant
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- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 title claims abstract description 155
- 229960004671 enzalutamide Drugs 0.000 title claims abstract description 154
- 239000000725 suspension Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 26
- 239000003381 stabilizer Substances 0.000 claims abstract description 24
- 239000004094 surface-active agent Substances 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000227 grinding Methods 0.000 claims description 87
- 239000002245 particle Substances 0.000 claims description 47
- 239000008188 pellet Substances 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 37
- 239000003085 diluting agent Substances 0.000 claims description 30
- 238000000576 coating method Methods 0.000 claims description 24
- 239000011248 coating agent Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 239000011324 bead Substances 0.000 claims description 21
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 19
- 239000002775 capsule Substances 0.000 claims description 19
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims description 17
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 16
- 229930006000 Sucrose Natural products 0.000 claims description 16
- 239000005720 sucrose Substances 0.000 claims description 16
- -1 polyethylene Polymers 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- 239000004793 Polystyrene Substances 0.000 claims description 8
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 229920002223 polystyrene Polymers 0.000 claims description 8
- 238000011068 loading method Methods 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 229920003081 Povidone K 30 Polymers 0.000 claims description 6
- 229920000578 graft copolymer Polymers 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 238000005507 spraying Methods 0.000 claims description 6
- 239000004698 Polyethylene Substances 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 229920000573 polyethylene Polymers 0.000 claims description 5
- 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 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 3
- 229960000878 docusate sodium Drugs 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims 6
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 18
- 239000000463 material Substances 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 6
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- 230000007613 environmental effect Effects 0.000 abstract description 4
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- 238000004090 dissolution Methods 0.000 description 29
- 230000000694 effects Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000003801 milling Methods 0.000 description 13
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 13
- 239000007901 soft capsule Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- JSFOGZGIBIQRPU-UHFFFAOYSA-N N-desmethylenzalutamide Chemical compound O=C1C(C)(C)N(C=2C=C(F)C(C(N)=O)=CC=2)C(=S)N1C1=CC=C(C#N)C(C(F)(F)F)=C1 JSFOGZGIBIQRPU-UHFFFAOYSA-N 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 3
- 238000000498 ball milling Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- 239000002159 nanocrystal Substances 0.000 description 3
- 238000005498 polishing Methods 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 229910052726 zirconium Inorganic materials 0.000 description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 208000019505 Deglutition disease Diseases 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 238000011978 dissolution method Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 229910016860 FaSSIF Inorganic materials 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 238000010812 external standard method Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
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Abstract
The invention provides an enzalutamide suspension, a preparation method and application thereof, wherein the suspension comprises enzalutamide, a hydrophilic polymer stabilizer, a surfactant and water. The invention provides the enzalutamide suspension which can remarkably improve the medication compliance and does not contain bad auxiliary materials. The pharmaceutical composition can improve the medication compliance of patients, lighten the burden of the patients, and solve the problems of solvent residue and environmental protection caused by using organic solvents in the production process.
Description
Technical Field
The invention relates to an enzalutamide suspension, and a preparation method and application thereof.
Background
Enzalutamide is white or white crystalline powder, has a molecular weight 464.44, a molecular formula of C 21H16F4N4O2 S, and a chemical name of 4- {3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thioxoimidazol-1-yl } -2-fluoro-N-methylbenzamide, and has a structural formula:
The solubility of enzalutamide in aqueous solution and buffer solutions with different pH values is low, and the dissolution of the medicament is slow and incomplete, so that the curative effect is limited.
The enzalutamide soft capsule developed by An Si telai was FDA approved in 2012 for the treatment of advanced male castration-resistant prostate cancer that has spread or recurred. The dosage form on the market is gelatin soft capsule with the specification of 40mg. Taken once a day, 4 granules are taken each time, and the total dosage is 160mg. The enzalutamide soft capsules use a large amount of caprylic capric acid polyethylene glycol glyceride, each soft capsule contains about 900mg of caprylic capric acid polyethylene glycol glyceride, namely 3600mg of surfactant is required to be taken every day, the content of the surfactant is far beyond that of common medicines, and due to the introduction of oily solvents, certain antioxidants BHT (butylated hydroxyanisole) and BHA (butylated hydroxytoluene) are required to be added to avoid rancidity. The presence of these inactive ingredients results in a very large body of soft capsules (20 mm x 9mm, about 1.3cm 3). In addition, the recommended dosage of the enzalutamide soft capsules is 160mg, and each soft capsule contains 40mg of active pharmaceutical ingredient, that is, four capsules are required to be taken once per oral administration by patients, and the capsules are required to be swallowed in whole grains and cannot be chewed, dissolved or opened. Thus, soft capsules have poor patient compliance due to the oversized unit dosage form and the multiple doses required at one time, especially for patients with dysphagia. The main drug group of the product is the elderly, the dysphagia problem is particularly remarkable, and the problem of poor compliance of the patients is more remarkable.
To improve the medication compliance problem of the enzalutamide soft capsule, an Si thai developed the enzalutamide into an oral solid formulation, which was first marketed in japan in 2018. The oral solid preparation is prepared by dissolving enzalutamide and three times of hydroxypropyl methylcellulose acetate succinate in acetone, spray-drying to form solid dispersion, adding auxiliary materials such as a disintegrating agent, a lubricant and the like, and pressing into tablets. Because of the use of acetone in the process, the environmental protection and the organic solvent residue are all problems to be solved. Meanwhile, the spray drying technology is adopted in the preparation process of the tablet, so that the requirements on equipment and personnel are high, the process difficulty is high, and the cost is high.
As described above, the enzalutamide formulations currently on the market have the disadvantages of large size, poor compliance, and use of poor excipients or organic solvents. And only enzalutamide soft capsules are marketed in China at present, and even if medical insurance is available, patients still need to spend more than 10 ten thousand per year, and the burden on the patients is high.
Patent document with publication number WO2019155416A2 discloses an enzalutamide capsule, which is prepared by preparing nano-crystalline suspension from enzalutamide, sodium dodecyl sulfate and hydroxypropyl methylcellulose and lecithin, preparing the suspension and sucrose and lactose monohydrate into particles, mixing the particles with other auxiliary materials and preparing the mixture into capsules. The wet milling process uses zirconium beads as milling media. The enzalutamide is degraded under the oxidation condition, and degradation impurities are easy to generate. During the grinding process of zirconium beads, the energy input is large, the potential impurity risks exist, and the use of hypromellose can prevent the dissolution of the preparation.
Patent document publication No. CN112402360A discloses an enzalutamide suspension, which consists of 40 mg/unit of enzalutamide, 120 mg/unit of sucrose, 20 mg/unit of sodium lauryl sulfate or HPMC, is obtained by grinding zirconium beads as grinding media through a planetary ball mill, and has a dissolution rate of less than 10% in FaSSIF pH 6.5. The planetary ball mill is used for preparing samples in small batches, and cannot be well applied to large-scale industrialization. In addition, from the aspect of dissolution, the dissolution rate of the enzalutamide in a dissolution medium is lower than 10%, which is not beneficial to improving the bioavailability of the enzalutamide in the body.
The patent document with the publication number of CN108815129A discloses an enzalutamide nanocrystal oral solid pharmaceutical composition and a preparation method thereof, wherein, purified water, 40g of enzalutamide bulk drug, 80g of polyvinyl alcohol and 16g of tyloxapol are sequentially added into a high-pressure homogenizer, homogenized under certain pressure to obtain a nano-crystalline suspension of the enzalutamide, spray-dried to obtain nano-crystalline of the enzalutamide, and 9g of crosslinked povidone, 3g of colloidal silicon dioxide and 2g of magnesium stearate are sequentially added, and uniformly mixed to obtain the nano-crystalline composition of the enzalutamide. The high-pressure homogenizing method is used for preparing the nanocrystalline, and the API is required to be subjected to micronization pretreatment before preparation, special equipment is required, the process difficulty is high, the energy consumption is high, and the requirements on operators are high. The nano-crystal grinding strength of the enzalutamide prepared by adopting the high-pressure homogenization method is high, and the nano-crystal grinding strength can be high to the nano-scale, but the risk of damaging the structure of the enzalutamide is high, so that the stability of the enzalutamide is challenging.
Aiming at the defects of the marketed products, the oral solid preparation which can obviously improve the medication compliance and avoid using bad auxiliary materials is still needed to be developed, which is used for improving the medication compliance of patients, relieving the burden of the patients and solving the problems of solvent residue and environmental protection caused by using organic solvents in the production process.
Disclosure of Invention
The invention provides an enzalutamide suspension, and a preparation method and application thereof.
In a first aspect of the invention there is provided an enzalutamide suspension comprising enzalutamide, a hydrophilic polymer stabilizer, a surfactant and water.
According to some embodiments of the suspension of the invention, the hydrophilic polymer stabilizer is selected from one or both of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone K30.
According to some embodiments of the suspension of the present invention, the hydrophilic polymer stabilizer is a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
According to some embodiments of the suspension of the invention, the surfactant is selected from one or more of sodium dodecyl sulfate, docusate sodium, poloxamers, preferably sodium dodecyl sulfate.
According to some embodiments of the suspension of the invention, the enzalutamide is a crystalline form of enzalutamide selected from form i (CN 105188699B), form ii (CN 105188699B), form iii (CN 105188699B), form R1 (CN 104768935A), form R2 (CN 104768935A), form B1 (CN 104356068 a), form a (CN 107635969B), form B (CN 107635969B), form C (CN 107635969B), form D (CN 107635969B), form E (CN 107635969B), form F (CN 107635969B), preferably form R1 (CN 104768935A).
According to some embodiments of the suspension of the invention, the enzalutamide has an average particle size of 10-500nm, such as 10nm, 20nm, 50nm, 80nm, 100nm, 150nm, 180nm, 260nm, 300nm, 380nm, 450nm, 500nm, preferably 80-240nm.
According to some embodiments of the suspension of the invention, the mass ratio of the enzalutamide to the hydrophilic polymer stabilizer is 1: (0.05-0.5), such as 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5.
According to some embodiments of the suspension of the invention, the mass ratio of the enzalutamide to the hydrophilic polymer stabilizer is 1: (0.075-0.33).
According to some embodiments of the suspension of the invention, the mass ratio of the enzalutamide to the surfactant is 1: (0.001-0.05), such as 1:0.001, 1:0.005, 1:0.01, 1:0.03, 1:0.04, 1:0.05, preferably 1: (0.0025-0.023).
According to some embodiments of the suspension of the invention, the mass concentration of the enzalutamide suspension is 10% -35%, preferably 11% -32%, based on the enzalutamide, such as: 10%, 12%, 15%, 18%, 20%, 23%, 25%, 28%, 30%, 33%, 35%.
In a second aspect of the present invention, there is provided a method of preparing an enzalutamide suspension comprising the steps of:
(1) Dissolving enzalutamide, a hydrophilic polymer stabilizer and a surfactant in water to obtain an initial suspension;
(2) Grinding the initial suspension to obtain the enzalutamide suspension.
According to some embodiments of the preparation method of the present invention, in step (1), the enzalutamide is a crystalline form of enzalutamide, and the crystalline form is selected from the group consisting of form I, form II, form III, form R1, form R2, form B1, form a, form B, form C, form D, form E, form F, and preferably form R1.
According to some embodiments of the method of preparation of the present invention, the hydrophilic polymer stabilizer is selected from one or two of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone K30.
According to some embodiments of the preparation method of the present invention, the surfactant is selected from one or more of sodium dodecyl sulfate, docusate sodium, poloxamer, preferably sodium dodecyl sulfate.
According to some embodiments of the preparation method of the present invention, the mass ratio of the enzalutamide to the hydrophilic polymer stabilizer is 1: (0.05-0.5), preferably 1: (0.075-0.33). Such as 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5.
According to some embodiments of the preparation method of the present invention, the mass ratio of the enzalutamide to the surfactant is 1: (0.001-0.05), preferably 1: (0.0025-0.023). Such as 1:0.001, 1:0.005, 1:0.01, 1:0.03, 1:0.04, 1:0.05.
According to some embodiments of the preparation method of the present invention, the mass concentration of the enzalutamide suspension is 10% -35%, preferably 11% -32%, based on the enzalutamide, such as: 10%, 12%, 15%, 18%, 20%, 23%, 25%, 28%, 30%, 33%, 35%.
According to some embodiments of the method of the invention, in step (2), the milling is performed in a media mill.
According to some embodiments of the method of preparation of the present invention, the milling media used for milling is zirconia milling beads or polystyrene milling beads.
According to some embodiments of the method of manufacture of the present invention, the grinding media has a particle size of 0.1-0.6mm, such as 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm, 0.6mm.
According to some embodiments of the method of manufacture of the invention, the grinding media has a particle size of 0.2-0.4mm.
According to some embodiments of the preparation method of the present invention, the milling time is 5 to 15 hours.
According to some embodiments of the method of manufacture of the present invention, the loading of the grinding media is 30% -90%, e.g., 30%, 40%, 50%, 60%, 80%, 90%.
According to some embodiments of the preparation process of the present invention, the average particle size of the enzalutamide in the enzalutamide suspension is 10 to 500nm, preferably 80 to 240nm. Such as 10nm, 20nm, 50nm, 80nm, 100nm, 150nm, 180nm, 260nm, 300nm, 380nm, 450nm, 500nm.
In a third aspect of the invention there is provided a pharmaceutical composition comprising a suspension according to the first aspect of the invention or a suspension obtained by a method of preparation according to the second aspect of the invention, a diluent, a lubricant and a blank pellet core.
According to some embodiments of the composition of the invention, the diluent is one or more of sucrose, lactose, mannitol, preferably sucrose.
According to some embodiments of the composition of the invention, the lubricant is selected from one or more of sodium dodecyl sulfate, talc, magnesium stearate, sodium stearyl fumarate, preferably sodium dodecyl sulfate.
According to some embodiments of the composition of the invention, the ingredients of the blank pellet core are selected from one of microcrystalline cellulose, sucrose, mannitol, preferably sucrose.
According to some embodiments of the composition of the invention, the particle size of the blank pellet core is 0.1-1.0mm, such as 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm, 0.6mm, 0.8mm, 1.0mm, preferably 0.2-0.5mm.
According to some embodiments of the composition of the invention, the mass ratio of the diluent to the enzalutamide is (0.8-1.2): 1, such as 0.8:1, 1.0:1, 1.1:1, 1.2:1. Preferably (0.9-1.1): 1.
According to some embodiments of the composition of the invention, the mass ratio of the enzalutamide to the lubricant is 1: (0.005-0.006), such as 1:0.005, 1:0.0055, 1:0.0058, 1:0.006.
According to some embodiments of the composition of the invention, the mass ratio of the enzalutamide to the blank pellet core is 1: (0.3-0.7), such as 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7. Preferably 1: (0.4-0.6).
In a fourth aspect of the invention, there is provided a pharmaceutical formulation comprising a composition according to the third aspect of the invention as a starting material.
According to some embodiments of the formulation of the invention, the formulation is in the form of a tablet, capsule or granule.
In a fifth aspect, the present invention provides a method for preparing the formulation according to the fourth aspect of the present invention, comprising the steps of:
(1) Diluting the suspension with the aqueous diluent solution to obtain a diluent;
(2) Coating the blank pill core with the diluent to obtain a pellet;
(3) Mixing the pellets with the lubricant.
According to some embodiments of the preparation method of the present invention, in step (1), the mass concentration of the aqueous diluent solution is 10% -70%, preferably 15% -65%, such as 10%, 15%, 20%, 25%, 30%, 38%, 43%, 55%, 62%, 65%, 70%.
According to some embodiments of the preparation method of the present invention, the dilution liquid has a mass concentration of 5% to 30%, preferably 6% to 22%, calculated as enzalutamide. For example 5%, 10%, 15%, 18%, 20%, 28%, 30%.
According to some embodiments of the method of the invention, in step (2), the coating is: and (5) coating by fluidized bed bottom spraying coating.
Some embodiments of the preparation method according to the invention comprise the following steps:
(1) Preparing an initial grinding fluid: taking 240-900g of purified water, adding a hydrophilic polymer stabilizer, sodium dodecyl sulfate and stirring at 15-30 ℃ until the solution is completely dissolved; adding the enzalutamide raw material medicine, and uniformly dispersing to obtain an initial grinding liquid;
(2) Adding grinding media into a grinding cavity of a media grinder, wherein the loading amount of the grinding media is 30% -90% of the volume of the grinding cavity, the grain size of the grinding media is 0.2-0.4mm, and a gap separator with 0.1mm is arranged, and adding initial grinding liquid into the grinding cavity for grinding;
(3) Grinding to the target particle size to obtain the enzalutamide suspension, wherein the mass concentration of the enzalutamide is 10% -35%;
(4) 120g of sucrose is added with a proper amount of purified water to prepare a sucrose aqueous solution with 15-65% of solid content, and then the sucrose aqueous solution and the enzalutamide suspension are prepared into a diluent, and the concentration of the diluent is 7-21% by the enzalutamide meter;
(5) Coating the diluted suspension on the surface of a blank pill core with the particle size of 0.2-0.5mm by a fluidized bed bottom spraying coating process to prepare a drug-containing pellet; mixing the drug-containing pellets with sodium dodecyl sulfate, and encapsulating to obtain the enzalutamide capsule.
The beneficial effects of the invention are as follows: the invention provides the enzalutamide suspension which can remarkably improve the medication compliance, does not contain bad auxiliary materials and has good stability. The enzalutamide pharmaceutical composition can improve the medication compliance of patients, lighten the burden of the patients, and solve the problems of solvent residue and environmental protection caused by using organic solvents in the production process.
Drawings
FIG. 1 is a graph showing the microscopic disintegration of the enzalutamide pharmaceutical composition of example 3 of the present invention;
FIG. 2 is a graph showing the microscopic disintegration of the enzalutamide pharmaceutical composition of example 4 of the present invention;
FIG. 3 is a graph showing the microscopic disintegration of the enzalutamide pharmaceutical composition of example 5 of the present invention;
FIG. 4 is a graph showing the microscopic disintegration of the enzalutamide pharmaceutical composition of example 6 of the present invention;
FIG. 5 is a graph showing the microscopic disintegration of the enzalutamide pharmaceutical composition of example 7 of the present invention;
Fig. 6 is a graph showing the microscopic disintegration of the enzalutamide pharmaceutical composition of example 8 of the present invention.
Detailed Description
The present invention will be further described in detail with reference to the following examples and the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the concepts of the present disclosure. Such structures and techniques are also described in a number of publications.
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. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the concepts of the present disclosure. Such structures and techniques are also described in a number of publications.
The particle size measurement method used in the embodiment of the invention comprises the following steps: particle size measurement was performed using a malvern nanosize meter (malvern Zetasizer Pro), 0.1mL of the solution was dispersed in 100mL of water, stirred manually until no visible suspended particles were apparent to the naked eye, 1mL was taken in a cuvette, and particle size was measured by sample injection. Wherein: refractive index 1.629, absorptivity 0.01; the results of the particle size measurement are expressed as average particle size.
Unless otherwise specified, the starting material, enzalutamide, used in the examples was all the R1 form disclosed in CN 104768935A.
Preparation process
(1) Preparing an initial grinding fluid: 360g of purified water is taken, hydrophilic polymer stabilizer, sodium dodecyl sulfate and stirring at 15-30 ℃ until the solution is complete; adding the enzalutamide raw material medicine, and uniformly dispersing to obtain an initial grinding liquid;
(2) Adding grinding media into a grinding cavity of a media grinder, wherein the loading amount of the grinding media is 90% of the volume of the grinding cavity, the grain size of the grinding media is 0.3mm, and a gap separator with the size of 0.1mm is arranged, and adding initial grinding liquid into the grinding cavity for grinding;
(3) Grinding to the target particle size to obtain the enzalutamide suspension, wherein the concentration of the enzalutamide suspension is 23% by weight;
(4) 120g of sucrose is added with a proper amount of purified water to prepare a sucrose water solution with 36 percent of solid content, and then the sucrose water solution and the enzalutamide suspension are prepared into a diluent, wherein the concentration of the diluent is 14 percent by the enzalutamide meter;
(5) Coating the diluted suspension on the surface of a blank pill core with the particle size of 0.2-0.5mm by a fluidized bed bottom spraying coating process to prepare a drug-containing pellet; mixing the drug-containing pellets with sodium dodecyl sulfate, and encapsulating to obtain the enzalutamide capsule.
The following examples were prepared according to this preparation procedure, unless otherwise indicated.
Examples 1-2: comparison of different grinding beads
The raw material components and the amounts of the enzalutamide capsules described in examples 1-2 are shown in Table 1:
TABLE 1
Remarks: concentration of aqueous diluent = mass of diluent/(mass of diluent + amount of aqueous diluent added) ×100% of the aqueous diluent
Suspension concentration (in enzalutamide) =drug substance mass/(drug substance mass+polymer mass+surfactant mass+suspension added water amount) ×100%
The concentration of the diluent (in terms of enzalutamide) =mass of drug substance/(mass of drug substance+mass of polymer+mass of surfactant+mass of suspension plus water amount+mass of diluent+mass of diluent plus water amount of aqueous solution) ×100%.
Examples 3 to 8: comparison of different Water-soluble Polymer stabilizers
The raw material components and amounts used for the enzalutamide capsules described in examples 3-8 are shown in table 2:
TABLE 2
Remarks: the concentration of the enzalutamide suspension after milling was 24% in examples 3-6 and 8.
Examples 8 to 12: comparison of the amounts of hydrophilic Polymer stabilizers
The raw material components and amounts used for the enzalutamide capsules described in examples 9-12 are shown in Table 3:
TABLE 3 Table 3
Remarks: examples 8-10 had 24% enzalutamide suspension after milling and 14%, 15% and 15% enzalutamide in the dilutions, respectively.
Enzalutamide pharmaceutical composition grinding particle size test
The particle size measurement method comprises the following steps: particle size measurement was performed using a malvern nanosize meter (malvern Zetasizer Pro), 0.1mL of the solution was dispersed in 100mL of water, stirred manually until no visible suspended particles were apparent to the naked eye, 1mL was taken in a cuvette, and particle size was measured by sample injection. Wherein: refractive index 1.629, absorptivity 0.01; the results of the particle size measurement are expressed as average particle size. The results are shown in Table 4:
Table 4 grinding particle size test of enzalutamide pharmaceutical composition
As can be seen from table 4: the grinding efficiency using zirconia grinding beads is higher than that of polystyrene grinding beads; when the water-soluble polymer is hydroxypropyl cellulose, hypromellose and polyvinyl alcohol, the grinding efficiency is obviously lower than that of povidone and Soluplus. Enzalutamide pharmaceutical composition related substance testing
The enzalutamide related impurities were tracked by high performance liquid chromatography using the following chromatographic method:
the enzalutamide capsules obtained in example 1 and example 2 were dissolved in a 50v/v% acetonitrile and water mixture, respectively, to obtain enzalutamide solutions having a concentration of about 0.6 mg/mL. Using Waters Xselect C18,250mm 4.6mm,3.5 μm column and maintaining column temperature at 35℃with a flow rate of 1.0mL/min, mobile phase A was 0.05v/v% aqueous trifluoroacetic acid and mobile phase B was acetonitrile. The elution procedure was as follows: mobile phase a (%)/time (min): 77%/0min;42%/35min;15%/50min;0%/60min;77%/67min. The detection wavelength 254nm was set for the detection period, and the relevant impurities were calculated by the enzalutamide external standard method, and the results are shown in Table 5.
Table 5 impurity content of enzalutamide pharmaceutical compositions
As can be seen from table 5: the polystyrene grinding beads are used as grinding media, and in the grinding process, related substances have no obvious change compared with the raw materials; when the zirconia grinding beads are adopted for grinding, the related substances are obviously increased compared with the raw materials, and the stability of the enzalutamide is destroyed.
Enzalutamide pharmaceutical composition dissolution test
The dissolution rate of the preparation was measured by high performance liquid chromatography using ChromCore C18, 4.6mm.times.150mm, 5 μm column chromatography; taking 0.05% trifluoroacetic acid aqueous solution-0.05% trifluoroacetic acid acetonitrile solution (40:60) as a mobile phase; the flow rate is 1.0 mL/min, and the column temperature is 30 ℃; the detection wavelength was 260nm.
The dissolution conditions used in the test formulations for the test examples and comparative examples were:
Dissolution condition 1:0.1M HCl, basket method, 100rpm,900mL volume medium.
Dissolution condition 2:0.1M HCl+0.5% SDS (sodium dodecyl sulfate), basket method, 50rpm,900mL volume medium.
The micro-disintegration diagrams and time periods of the enzalutamide capsules obtained in examples 3 to 8 are shown in fig. 1 to 6 and table 6, respectively.
Placing 1 pellet in a groove of a concave glass slide, placing under an electron microscope, dripping medium with pH of 6.8 in the groove, observing the disintegration state of the pellet, starting timing until the pellet is completely disintegrated, and recording the disintegration time of the pellet.
As can be seen from FIGS. 1-3, the enzalutamide pellets have agglomeration phenomenon, and the enzalutamide pellets shown in FIGS. 4-6 have complete disintegration and no agglomeration phenomenon.
Table 6 disintegration schedule of enzalutamide pharmaceutical compositions
| Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | Example 8 | |
| Disintegration time | 10min | 10min | 10min | 2min | 2min | 2min |
Dissolution conditions of the enzalutamide capsules obtained in examples 3 to 8 are shown in Table 7 (dissolution condition 1).
Table 7 dissolution profile comparison table of enzalutamide pharmaceutical compositions
As can be seen from tables 6 and 7, none of examples 3-5 disintegrated completely in the pH6.8 medium for 10min and there was a significant particulate. Whereas examples 6-8 disintegrated completely in 2min, the dissolution was fine and free of particles. Example 8 has significantly higher dissolution in dissolution medium than examples 3-7. Samples of examples 3, 4, and 5, each using hypromellose, and polyvinyl alcohol as a stabilizer for hydrophilic polymers, had a cumulative dissolution rate of <15% in the dissolution medium, and could not be released quickly to reach the dissolution plateau. The samples of examples 6-7, which used povidone K30 as a stabilizer for the hydrophilic polymer, were able to reach a dissolution plateau rapidly in the dissolution medium, but the dissolution rate was significantly lower than in example 8. Therefore, the use of Soluplus as a hydrophilic polymer stabilizer has significant advantages.
Enzalutamide pharmaceutical composition stability test
Dissolution stability (dissolution condition 2) of the enzalutamide pharmaceutical compositions obtained in examples 7 and 8 during stability is shown in table 8.
Table 8 dissolution stability test of enzalutamide pharmaceutical compositions
As can be seen from Table 8, in the accelerated stability process examination of the sample of example 8, the dissolution rate is accelerated for 1 month without obvious change from 0 day, the product quality is stable, and the dissolution rate is accelerated for 1 month and is obviously lower than 0 day by adopting povidone K30 as a hydrophilic polymer stabilizer in example 7, so that the adoption of Soluplus as the hydrophilic polymer stabilizer has obvious advantages.
Enzalutamide pharmaceutical composition hydrophilic Polymer dosage test
The effect of the amount of hydrophilic polymer used in the enzalutamide pharmaceutical composition on the fluidized bed coating effect was tested, and the test results are shown in table 9.
According to the embodiment of the application, the pellets are prepared by fluidized bed bottom spray coating. The bottom spray coating equipment of the fluidized bed controls the air inlet temperature to be 50-90 ℃, the atomization pressure to be 100-180KPa, the material temperature to be 40-70 ℃ and the air inlet quantity to be 40-70m 3/h.
Table 9 measurement of hydrophilic Polymer usage in Enzalutamide pharmaceutical compositions
Remarks: polymer ratio = polymer mass/total mass of the components of the formulation
Target particle size pellet yield = target particle size pellet mass ≡ (coating liquid dry solid mass + blank pellet core mass)
Coated weight gain= (coated pellet material collection quality-blank pellet core quality)/(blank pellet core quality)
Coating efficiency = (coated pellet material receiving quality-blank pellet core quality)/(coated liquid dry solid matter weight)
As can be seen from table 9: EZLA and the mass ratio of the polymer is 1: within the range of (0.075-0.33), good coating effect can be maintained.
Examples 13 to 14: comparison of surfactant usage
The raw material components and amounts used for the enzalutamide capsules of examples 13-14 are shown in table 10:
table 10
Remarks: examples 13-14 the concentration of the enzalutamide suspension after milling was 24%.
The effect of the different amounts of surfactant on the stability of the enzalutamide drug ball milling solution is shown in Table 11.
Table 11 stability test of enzalutamide pharmaceutical composition ball milling solution
As can be seen from Table 11, EZLA and surfactant amounts are 1: in the range of (0.0025-0.023), the ball milling liquid can keep better stability, and is beneficial to development of subsequent processes.
The effect of varying amounts of surfactant on the grinding efficiency of enzalutamide drug is shown in table 12.
Table 12 research on grinding efficiency of enzalutamide drug
As is clear from table 12, the polishing efficiency can be improved or reduced by adjusting the amount of the surfactant, and the polishing time can be shortened or prolonged. The polishing efficiency of the examples was within an acceptable range.
Examples 15 to 17: comparison of particle size of grinding fluid
The raw material components and amounts used for the enzalutamide capsules of examples 15-17 are shown in Table 13:
TABLE 13
Grinding liquid with different particle sizes is prepared by using 0.3mm polystyrene grinding beads, grinding media account for 90% of the volume of a grinding cavity, the grinding liquid is coated according to the same coating parameters, the micropills with different particle size compositions are obtained, and the dissolution detection is carried out on the micropills.
The effect of different particle size enzalutamide pharmaceutical compositions on dissolution rates are shown in table 15 and 14:
TABLE 14 Effect of Enzalutamide pharmaceutical compositions of different particle sizes on dissolution (dissolution method 1)
TABLE 15 influence of Enzalutamide pharmaceutical compositions of different particle sizes on dissolution (dissolution method 2)
From tables 14 and 15, it can be seen that: the control of the grinding particle size of example 17 was 241.8nm, the elution amount was reduced in the elution method 1, but the dissolution was still very fast in the elution method 2, and there was no significant difference from examples 15 and 16. Namely, the grinding particle size of the enzalutamide pharmaceutical composition has smaller influence on the dissolution rate of the enzalutamide pharmaceutical composition within the range of 80-240 nm.
Examples 18 to 19: comparison of the amount of grinding beads
The raw material components and amounts used for the enzalutamide capsules of examples 18-19 are shown in table 16:
Table 16
Grinding fluid with the same particle size is prepared according to the same process, and the grinding efficiency is evaluated. Polystyrene grinding beads of 0.3mm were used as grinding media.
The effect of different amounts of grinding beads on the grinding effect is shown in Table 17:
TABLE 17 influence of different amounts of grinding beads on grinding effect
| Example 16 | Example 18 | Example 19 | |
| Grinding time (h) | 8 | 16 | 35 |
| Grinding particle size (nm) | 115.3 | 118.8 | 119.3 |
As can be seen from table 17: the higher the loading of the grinding beads, the higher the grinding efficiency. Different grinding bead loading amounts only affect the grinding efficiency, and have no obvious influence on the final particle size of grinding.
Examples 20 to 21: comparison of the amount of water added
The raw material components and amounts used for the enzalutamide capsules of examples 20-21 are shown in table 18:
TABLE 18
Grinding fluid with the same particle size is prepared according to the same process, and the grinding efficiency is evaluated. Polystyrene grinding beads of 0.3mm were used as grinding media. The loading of grinding media was 90% of the grinding chamber volume.
The effect of different suspension concentrations on the milling effect is shown in table 19:
TABLE 19 influence of different suspension concentrations on the milling effect
As can be seen from table 19: different suspension concentrations have an impact on the milling efficiency. The lower the concentration, the higher the grinding efficiency, but only the grinding efficiency is affected, and the final particle size of grinding is not obviously affected.
TABLE 20 effect of different diluent concentrations (in terms of enzalutamide) on coating efficiency
Remarks: target particle size pellet yield = target particle size pellet mass ≡ (coating liquid dry solid mass + blank pellet core mass)
Coated weight gain= (coated pellet material collection quality-blank pellet core quality)/(blank pellet core quality)
Coating efficiency = (coated pellet mass received-blank pellet core mass)/(coating liquid dry solid mass).
As can be seen from table 20: different concentrations of the diluent have a certain influence on the coating efficiency. At a dilution concentration of 7%, the coating efficiency was the lowest. However, the final dosage form is prepared at the pellet intermediate level so that the coating efficiency does not affect the quality of the final dosage form, and the diluent concentration is acceptable at 7%.
Bioavailability test of enzalutamide pharmaceutical compositions
Healthy male beagle dogs having a body weight of 10±2kg were selected and randomly divided into two groups, one group was given 1 granule (40 mg) of the enzalutamide capsule prepared in example 6 under the condition of empty stomach, and the other group was given 1 granule of commercially available soft capsule (commercially available "ankaramide soft capsule, 40 mg"). 1.5mL of blood was taken from the veins of the anterior or posterior limbs at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, l0h, 16h, 24h, 32h, 40h, 48h, 60h, 72h, 96h, 144h, 168h, 192h, 216h, placed in a centrifuge tube with EDTA-K2 for 10 minutes, plasma was separated, and the plasma samples were analyzed by LC-MS to determine the amounts of the proto-drug enzalutamide and the metabolite N-desmethylenzalutamide, and the results are shown in Table 21.
Table 21 bioequivalence evaluation parameters of enzalutamide in plasma after oral administration of enzalutamide by beagle dogs
Table 22 bioequivalence evaluation parameters of N-desmethylenzalutamide in plasma after oral administration of enzalutamide to beagle dogs
As can be seen from tables 21 and 22: beagle dogs after oral administration of example 6 and commercial soft capsules, the blood levels and in vivo exposure of enzalutamide and N-desmethylenzalutamide in plasma were substantially consistent.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (10)
1. An enzalutamide suspension comprises enzalutamide, a hydrophilic polymer stabilizer, a surfactant and water.
2. Suspension according to claim 1, characterized in that the hydrophilic polymer stabilizer is selected from one or two of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone K30, preferably polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;
And/or the surfactant is selected from one or more of sodium dodecyl sulfate, docusate sodium and poloxamer, preferably sodium dodecyl sulfate;
And/or, the enzalutamide is a crystalline form of enzalutamide; the crystal forms of the crystal forms are selected from crystal forms I, II, III, R1, R2, B1, A, B, C, D, E and F, and preferably form R1;
And/or the average particle size of the enzalutamide is 10-500nm, preferably 80-240nm.
3. Suspension according to claim 1 or 2, characterized in that the mass ratio of enzalutamide to the hydrophilic polymer stabilizer is 1: (0.05-0.5), preferably 1: (0.075-0.33);
And/or, the mass ratio of the enzalutamide to the surfactant is 1: (0.001-0.05), preferably 1: (0.0025-0.023);
And/or, the mass concentration of the enzalutamide suspension is 10% -35%, preferably 11% -32% based on the enzalutamide.
4. A method for preparing enzalutamide suspension, comprising the following steps:
(1) Dissolving enzalutamide, a hydrophilic polymer stabilizer and a surfactant in water to obtain an initial suspension;
(2) Grinding the initial suspension to obtain the enzalutamide suspension.
5. The process according to claim 4, wherein in the step (1),
The enzalutamide is a crystalline form of the enzalutamide; the crystal forms of the crystal forms are selected from crystal forms I, II, III, R1, R2, B1, A, B, C, D, E and F, and preferably form R1;
And/or the hydrophilic polymer stabilizer is selected from one or two of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and povidone K30;
And/or the surfactant is selected from one or more of sodium dodecyl sulfate, sodium docusate and poloxamer;
And/or, the mass ratio of the enzalutamide to the hydrophilic polymer stabilizer is 1: (0.05-0.5), preferably 1: (0.075-0.33);
And/or, the mass ratio of the enzalutamide to the surfactant is 1: (0.001-0.05), preferably 1: (0.0025-0.023);
And/or, the concentration of the enzalutamide suspension is 10% -35%, preferably 11% -32%, based on the enzalutamide.
6. The method of claim 4 or 5, wherein in step (2), the grinding is performed in a media mill;
And/or the grinding medium used for the grinding is zirconia grinding beads or polystyrene grinding beads, preferably polystyrene grinding beads;
and/or the particle size of the grinding media is 0.1-0.6mm, preferably 0.2-0.4mm;
and/or the loading of the grinding media is 30% -90%;
And/or the average particle size of the enzalutamide in the enzalutamide suspension is 10-500nm, preferably 80-240nm.
7. A pharmaceutical composition comprising a suspension according to any one of claims 1 to 3 or a suspension obtained by a process according to any one of claims 4 to 6, a diluent, a lubricant and a blank pellet core.
8. The composition according to claim 7, wherein the diluent is one or more of sucrose, lactose, mannitol, preferably sucrose;
And/or the lubricant is selected from one or more of sodium dodecyl sulfate, talcum powder, magnesium stearate and sodium stearyl fumarate, preferably sodium dodecyl sulfate;
and/or the ingredients of the blank pellet core are selected from one of microcrystalline cellulose, sucrose and mannitol, and preferably sucrose;
Preferably, the particle size of the blank pellet core is 0.1-1.0mm, preferably 0.2-0.5mm;
And/or the mass ratio of the diluent to the enzalutamide is (0.8-1.2): 1, preferably (0.9-1.1): 1, a step of;
And/or the mass ratio of the enzalutamide to the lubricant is 1: (0.005-0.006);
And/or, the mass ratio of the enzalutamide to the blank pellet core is 1: (0.3-0.7), preferably 1: (0.4-0.6).
9. A pharmaceutical formulation, the preparation raw material of which comprises the composition according to claim 7 or 8, preferably the formulation is in the form of a tablet, capsule or granule.
10. A method of preparing the pharmaceutical formulation of claim 9, comprising the steps of:
(1) Diluting the suspension with the aqueous diluent solution to obtain a diluent;
(2) Coating the blank pill core with the diluent to obtain a pellet;
(3) Mixing the pellets with the lubricant;
Preferably, in step (1), the mass concentration of the aqueous diluent solution is 10% to 70%, preferably 15% to 65%;
Preferably, the mass concentration of the diluent is 5% -30%, preferably 6% -22% based on the enzalutamide;
Preferably, in step (2), the coating is: and (5) coating by fluidized bed bottom spraying coating.
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|---|---|---|---|
| CN202410137979.0A Pending CN117959253A (en) | 2024-02-01 | 2024-02-01 | Enzalutamide suspension and preparation method and application thereof |
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| Country | Link |
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| CN (1) | CN117959253A (en) |
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