CN114053243A - Enzalutamide soft capsule and preparation method thereof - Google Patents
Enzalutamide soft capsule and preparation method thereof Download PDFInfo
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- CN114053243A CN114053243A CN202010778827.0A CN202010778827A CN114053243A CN 114053243 A CN114053243 A CN 114053243A CN 202010778827 A CN202010778827 A CN 202010778827A CN 114053243 A CN114053243 A CN 114053243A
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- enzalutamide
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- purified water
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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 65
- 229960004671 enzalutamide Drugs 0.000 title claims abstract description 63
- 239000007901 soft capsule Substances 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000008213 purified water Substances 0.000 claims abstract description 34
- 125000005456 glyceride group Chemical group 0.000 claims abstract description 17
- 239000002775 capsule Substances 0.000 claims abstract description 16
- 239000012046 mixed solvent Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 9
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 238000004090 dissolution Methods 0.000 claims description 18
- 239000003292 glue Substances 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 8
- 235000006708 antioxidants Nutrition 0.000 claims description 8
- 239000003605 opacifier Substances 0.000 claims description 7
- 239000004014 plasticizer Substances 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 235000011187 glycerol Nutrition 0.000 claims description 6
- 238000009849 vacuum degassing Methods 0.000 claims description 6
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 5
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 5
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 5
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 239000004408 titanium dioxide Substances 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 238000003825 pressing Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- 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 2
- 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 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229930003427 Vitamin E Natural products 0.000 claims description 2
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 2
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 2
- 229940110767 coenzyme Q10 Drugs 0.000 claims description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 229940068968 polysorbate 80 Drugs 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 235000013772 propylene glycol Nutrition 0.000 claims description 2
- 238000007493 shaping process Methods 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229940035024 thioglycerol Drugs 0.000 claims description 2
- 235000019165 vitamin E Nutrition 0.000 claims description 2
- 229940046009 vitamin E Drugs 0.000 claims description 2
- 239000011709 vitamin E Substances 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 12
- 239000000126 substance Substances 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 14
- 206010060862 Prostate cancer Diseases 0.000 description 11
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 102000001307 androgen receptors Human genes 0.000 description 7
- 108010080146 androgen receptors Proteins 0.000 description 7
- 238000009472 formulation Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000013329 compounding Methods 0.000 description 4
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 3
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000003098 androgen Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229940085728 xtandi Drugs 0.000 description 2
- USPSDZQQNLMVMK-UHFFFAOYSA-N 1-Monolinolein Natural products CCCCCC=CC=CCCCCCCCC(=O)OCC(O)CO USPSDZQQNLMVMK-UHFFFAOYSA-N 0.000 description 1
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 description 1
- -1 4-cyano-3-trifluoromethylphenyl Chemical group 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229940123407 Androgen receptor antagonist Drugs 0.000 description 1
- LKUNXBRZDFMZOK-GFCCVEGCSA-N Capric acid monoglyceride Natural products CCCCCCCCCC(=O)OC[C@H](O)CO LKUNXBRZDFMZOK-GFCCVEGCSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000009167 androgen deprivation therapy Methods 0.000 description 1
- 239000003936 androgen receptor antagonist Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an enzalutamide soft capsule and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The invention provides an enzalutamide soft capsule, which comprises a content and a capsule shell, wherein the content comprises an active ingredient enzalutamide and pharmaceutically acceptable pharmaceutic adjuvants, and the enzalutamide accounts for 3.5% -4.5% of the total weight of the content; the pharmaceutic adjuvant comprises long-chain fatty glyceride, purified water M and an antioxidant, wherein the dosage of the purified water M is 0.5-5.0% of the total weight of the contents. The invention also provides a preparation method of the pharmaceutical composition. In the preparation process of the contents, the purified water M and the long-chain fatty glyceride solvent are added and mixed to serve as the mixed solvent of the medicine, so that the dissolving time of the medicine can be obviously shortened, the production efficiency of the enzalutamide soft capsule is improved, the production cost is reduced, and the industrial production is facilitated. The finally prepared enzalutamide soft capsule has stable and reliable quality, and the content of related substances meets the requirement.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an enzalutamide soft capsule and a preparation method thereof.
Background
Prostate cancer is the most common malignancy in north american and european males, second only to lung cancer row 2 in deaths resulting from cancer. In recent years, the incidence of prostate cancer in China is obviously and continuously increased, and the prostate cancer is becoming a malignant tumor of the urinary system which seriously affects the health of men in China. The primary metastatic prostate cancer is mainly endocrine therapy, and most prostate cancer patients have a remission stage of 18-24 months after Androgen Deprivation Therapy (ADT) and finally develop Castration Resistant Prostate Cancer (CRPC). The AR (androgen receptor) pathway plays a key role in the process of the occurrence and the progression of the prostate cancer and can even enable cancer cells to continue to grow under the minimum androgen level, so the AR signaling pathway is an ideal target for developing a novel prostate cancer medicament.
Enzalutamide (MDV 3100, trade name Xtandi) is a 2 nd generation androgen receptor antagonist, a novel drug directed to the Androgen Receptor (AR) signaling pathway, which acts at different stages of the androgen receptor signaling pathway, competitively inhibits androgen binding to the receptor, and inhibits androgen receptor nuclear translocation and DNA interaction. Enzalutamide shows stronger anti-tumor effect and smaller adverse reaction in clinical trials, is approved by the FDA in the united states and marketed in 8-31/2012 and is indicated as metastatic castration-resistant prostate cancer, and is additionally approved by the FDA in 9-10/2014 as a first-line drug for patients with metastatic castration-resistant prostate cancer who do not receive chemotherapy. In the same year, the final guidelines of the National Institute for Clinical Efficacy (NICE) in the uk recommend enzalutamide for the treatment of prostate cancer.
The enzalutamide has good clinical effect on treating castration-resistant prostate cancer, but some technical problems of the enzalutamide pharmaceutical preparation are not solved. According to the data published by FDA, enzalutamide belongs to BCS II, the solubility is poor, the dissolution time in the preparation process is long, the process cost is increased, and the sample quality risks such as reduction of drug content, increase of related substances and overproof microorganisms are increased due to the long dissolution time of enzalutamide in the dosing process.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the enzalutamide soft capsule which is simple in process, high in production efficiency, stable in quality and suitable for large-scale production, and the preparation method thereof.
The inventor discovers that purified water and long-chain fatty glyceride are added to be mixed as a mixed solvent of the medicine in the batching process, so that batching time can be obviously shortened, the production efficiency of the enzalutamide soft capsule is improved, the production cost is reduced, and the industrial production is facilitated.
In the context of the present invention, the term "contents" refers to the substance enclosed in the capsule shell.
The innovation points of the invention are as follows: the enzalutamide is difficult to dissolve in water, the solubility of the enzalutamide in oil and fat solvents such as long-chain fatty glyceride, such as monolinolein, soybean oil, caprylic capric acid monoglyceride and medium diglyceride, and the dissolution process has certain difficulty. Based on the fact that enzalutamide is insoluble in water, purified water should not be introduced during compounding, but the inventors found that: according to the preparation method disclosed by the invention, purified water is added in the preparation process of the content, but the medicine can be rapidly dissolved in the mixed solvent, and the dissolving speed is greatly increased compared with that of the method without adding the purified water, so that the production efficiency is improved on the basis of ensuring the product quality. The enzalutamide soft capsule prepared by the preparation method controls the content moisture to be 2.0-5.0%, and the product quality is stable.
The invention provides an enzalutamide soft capsule which comprises a content and a capsule shell, wherein the content comprises an active ingredient enzalutamide and pharmaceutically acceptable pharmaceutic adjuvants, and the active ingredient enzalutamide accounts for 3.5% -4.5% of the total weight of the content. The pharmaceutic adjuvant comprises long-chain fatty glyceride, purified water M and an antioxidant, wherein the dosage of the purified water M is 0.5-5.0% of the total weight of the contents. Preferably, the amount of purified water M is 1.0% to 3.0% by weight of the total content.
The long-chain fatty glyceride is selected from one of polyethylene glycol 40, polysorbate 80, caprylic/capric polyethylene glycol glyceride or any combination thereof, preferably caprylic/capric polyethylene glycol glyceride. The dosage of the long-chain fatty glyceride accounts for 85-95% of the total weight of the content.
The antioxidant is selected from one of vitamin E, coenzyme Q10, butylated hydroxyanisole, thioglycerol, dibutyl hydroxy toluene, propyl gallate or any combination thereof, preferably the combination of butylated hydroxyanisole and dibutyl hydroxy toluene. The dosage of the antioxidant is 0.01-0.1% of the total weight of the content.
The invention also provides a preparation method of the enzalutamide soft capsule, which comprises the following steps:
(1) uniformly mixing long-chain fatty glyceride with a prescription amount and purified water M to obtain a mixed solvent;
(2) adding prescription amount of enzalutamide and an antioxidant into the mixed solvent obtained in the step (1), stirring and dissolving, and after the enzalutamide is completely dissolved, performing vacuum degassing to obtain a content containing the enzalutamide;
(3) adding a plasticizer and purified water N in a formula amount into a glue melting tank, heating to 60-85 ℃, stirring and dissolving until the solution is clear, adding an opacifier, stirring until the solution is uniformly dispersed, adding gelatin, stirring and dissolving until no obvious particles exist in the glue solution, vacuum degassing until no bubbles float up in the glue solution for at least 30 minutes, and standing for 2-20 hours to obtain a standby glue solution;
(4) pressing and forming the content containing the enzalutamide obtained in the step (2) and the standby glue solution obtained in the step (3) by using a soft capsule filling and sealing machine to obtain a soft capsule initial product;
(5) and (5) shaping and drying the soft capsule primary product obtained in the step (4) to obtain the final product of the enzalutamide soft capsule.
Wherein, the stirring dissolution in the step (2) is preferably stirring dissolution at 35-45 ℃.
In some preferred embodiments, the moisture content of the soft capsule initial product obtained in step (4) is controlled to be 2.0-5.0% of the total weight of the content after the drying step of step (5). Further preferably, the moisture content of the soft capsule primary product obtained in the step (4) is controlled to be 3.5-4.5% of the total weight of the content after the drying step in the step (5).
In some embodiments, the plasticizer in step (3) is selected from one of glycerin, sorbitol, sorbitan, maltitol, mannitol, propylene glycol, polyethylene glycol, or any combination thereof. In some preferred embodiments, the plasticizer in step (3) is selected from a mixture of glycerin and sorbitan. The dosage of the plasticizer accounts for 20 to 40 percent of the weight of the prescription feed of the capsule shell.
In some embodiments, the opacifier in step (3) is titanium dioxide. The dosage of the opacifier accounts for 0.2 to 2.0 percent of the weight of the prescription feed of the capsule shell. In some preferred embodiments, the amount of opacifier is 0.2% to 1.0% by weight of the formula charge for the capsule shell.
In some embodiments, purified water N is used in an amount of 25% to 45% by weight of the prescription charge for the capsule shell. In some preferred embodiments, purified water N is used in an amount of 30% to 40% by weight of the prescription charge for the capsule shell. In other preferred embodiments, purified water N is used in an amount of 30% to 35% by weight of the prescription charge for the capsule shell.
In some preferred embodiments, nitrogen protection is filled in the whole process of the steps (2) and (4) for preparing the contents, so as to further improve the stability of the enzalutamide soft capsule.
The invention has the beneficial effects that:
in the process of preparing the contents, purified water M and a long-chain fatty acid glyceride solvent are added and mixed to serve as a mixed solvent of the medicine, so that the dissolving time of the medicine can be obviously shortened, the production efficiency of the enzalutamide soft capsule is improved, the production cost is reduced, and the industrial production is facilitated.
In addition, the moisture content of the enzalutamide soft capsule is controlled within a certain range after the drying step, such as 2.0% -5.0%, especially 3.5% -4.5%, and the quality stability of the enzalutamide soft capsule product can be effectively ensured.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodologies, protocols, and reagents described herein, as modifications of the invention which are obvious from the present disclosure are within the scope of the invention. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Examples 1-4 and comparative example 1: comparison of drug dissolution times for different amounts of purified Water M
See table 1 for the recipes and compositions of the samples of examples 1-4 and comparative example 1.
Table 1 contents recipes of examples 1 to 4 and comparative example 1
| Components | Example 1 | Example 2 | Example 3 | Example 4 | Comparative example 1 |
| Enzalutamide | 40g | 40g | 40g | 40g | 40g |
| Caprylic capric acid polyethylene glycol glyceride | 905.81g | 905.81g | 905.81g | 905.81g | 905.81g |
| Dibutylhydroxytoluene | 0.095g | 0.095g | 0.095g | 0.095g | 0.095g |
| Butylated hydroxyanisole | 0.095g | 0.095g | 0.095g | 0.095g | 0.095g |
| Purified water M | 9.0g | 12g | 18.1g | 27.2g | / |
The preparation method comprises the following steps:
(1) uniformly mixing caprylic/capric polyethylene glycol glyceride with a prescription amount and purified water M with different contents to obtain a mixed solvent;
(2) adding the prescription amount of the mixture of enzalutamide and antioxidant-dibutyl hydroxy toluene and butyl hydroxy anisole into the mixed solvent obtained in the step (1), stirring and dissolving at 45 ℃, and after the enzalutamide is completely dissolved, vacuum degassing to obtain the content containing the enzalutamide.
The corresponding contents are prepared according to the prescriptions of the examples 1 to 4 and the prescription of the comparative example 1The dissolution time of the raw materials and the quality of the contents in the compounding process are examined, the related substances are measured by High Performance Liquid Chromatography (HPLC), and the measurement results are shown in Table 2. Wherein the chemical name of the impurity DO is 4- [3- (4-cyano-3-trifluoromethylphenyl) -5, 5-dimethyl-2, 4-dioxo-1 imidazolinyl]-2-fluoro-N-methylbenzamide with the molecular formula C21H16F4N4O3Molecular weight of 448.37, and structural formula as follows:
TABLE 2 comparison of compounding time and content quality for examples 1-4 and comparative example 1
The results show that, compared with comparative example 1, examples 1-4 of the present invention have significantly faster drug dissolution rate during the compounding process in examples 1-4. It is shown that the introduction of purified water during the preparation process is advantageous for increasing the dosing speed. In addition, related substances are not obviously changed, and the introduction of the purified water M can ensure that the product quality is not changed, and is suitable for large-scale production.
Examples 5-8 and comparative example 2: saturation solubility experiment of enzalutamide in mixed solvents with different purified water M contents
According to the above experimental results, the saturated solubility of enzalutamide in solvents with different water contents was examined, and preparation examples 5 to 8 and comparative example 2 were prepared, and the results are shown in table 3.
TABLE 3 statistical tables of solubility results for examples 5-8 and comparative example 2
The result shows that the higher the content of the purified water is, the higher the solubility of the enzalutamide in a certain proportion range of the mixed solvent prepared by adding the purified water with different contents is.
Examples 9-12 and reference formulations: comparison of stability and dissolution behavior of enzalutamide soft capsules
The required ready-to-use glue solution for preparing the capsule shell is shown in table 4:
TABLE 4 recipe for the preparation of capsule shell
| Components | Amount of prescription |
| Gelatin | 6.0kg |
| Dehydrated sorbitol solution | 1.2kg |
| Glycerol | 3.0kg |
| Titanium dioxide | 71.37g |
| Purified water N | 4.9kg |
Preparing a standby glue solution: adding glycerol, a sorbitan solution and purified water N in a formula amount into a glue melting tank, heating to 70 ℃, stirring and dissolving until the solution is clear, adding titanium dioxide, stirring until the solution is uniformly dispersed, adding gelatin, stirring and dissolving until no obvious particles exist in the glue solution, vacuum degassing until no bubbles float upwards in the glue solution for at least 30 minutes, and standing for 2 hours to obtain a standby glue solution;
preparing the enzalutamide soft capsule: respectively pressing and molding the content containing the enzalutamide obtained in the examples 1-4 by using the standby glue solution by using a soft capsule filling and sealing machine to obtain a soft capsule initial product; the initial soft capsule was shaped and dried to obtain the final product, enzalutamide soft capsule, which corresponds to examples 9-12, respectively.
The final product of the Enzalutamide soft capsules obtained in examples 9-12 above was aluminum-plastic packaged. The reference formulation Xtandi was enzalutamide soft capsule developed by procurement of anslatay. The products of examples 9 to 12 were placed under accelerated conditions (40 ℃ C., 75. + -. 5% RH) together with the reference preparation, and sampled at 0 day and 6 months, respectively, to examine the dissolution profiles of the substances, contents, and 0.1mol/L hydrochloric acid solution. Wherein the dissolution rate is determined by High Performance Liquid Chromatography (HPLC), the content water content is determined by Karl Fischer method, and the results are shown in Table 5.
TABLE 5 comparison of the quality of examples 9 to 12 with the reference formulation
In addition, see table 6 for dissolution for examples 9-12 and the reference formulation:
table 6 comparison of dissolution profiles of examples 7-9 with reference formulations
The results show that the substances of examples 9 to 12 of the present invention have no significant change and the dissolution behavior is consistent compared with the reference formulation. After the contents of the examples 9-12 are added with different contents of the purified water M, prepared into soft capsules and dried, detection shows that the contents of the soft capsules of the examples 7-9 are basically consistent in moisture content, and the quality difference of final products caused by different dosages of the purified water M added into the contents is avoided. Namely: a small amount of purified water M is added during preparation of contents, so that the dissolution speed of the raw materials can be effectively improved, and the quality of an enzalutamide soft capsule sample prepared by adopting the burdening mode is stable.
Examples 13 to 15: investigating the influence of different drying times on the soft capsules
Soft capsule samples were prepared according to the recipe in table 7, using different drying times during the preparation of the contents, respectively, resulting in different percentages of moisture in the contents, and the final resulting enzalutamide soft capsules were used as examples 13-15, respectively, see table 8.
Table 7 example recipe
TABLE 8 examples 13 to 15
| Examples | Drying time | The water content of the contents is% |
| Example 13 | About 85h | 4.5 |
| Example 14 | About 110h | 3.9 |
| Example 15 | About 140h | 3.5 |
The aluminum-plastic packages of examples 13 to 15 were placed under accelerated conditions (40 ℃ C., 75. + -. 5% RH), and samples were taken at 0 day and 6 months, respectively, to examine the dissolution rates of the relevant substances, contents, and 0.1mol/l hydrochloric acid solution for 30 minutes, and the results are shown in Table 9.
TABLE 9 statistics of the results of the tests of examples 13-15
The result shows that the quality of the enzalutamide soft capsule product prepared from the contents with different moisture contents is stable, and the moisture of the contents and the water of the capsule shell can mutually migrate to reach a certain balance in the placing process. Therefore, the moisture of the content is controlled within a certain range, so that the product quality is not influenced and is stable.
Claims (10)
1. An enzalutamide soft capsule comprises a content and a capsule shell, wherein the content comprises an active ingredient enzalutamide and pharmaceutically acceptable pharmaceutic adjuvants, and the active ingredient enzalutamide accounts for 3.5% -4.5% of the total weight of the content; the pharmaceutic adjuvant comprises long-chain fatty glyceride, purified water M and an antioxidant, wherein the dosage of the purified water M is 0.5% -5.0% of the total weight of the contents, and preferably 1.0% -3.0%.
2. The enzalutamide soft capsule according to claim 1, wherein the long chain fatty acid glyceride is selected from one of polyethylene glycol 40, polysorbate 80, caprylic capric polyethylene glycol glyceride or any combination thereof, preferably caprylic capric polyethylene glycol glyceride; the dosage of the long-chain fatty glyceride accounts for 85-95% of the total weight of the contents.
3. The enzalutamide soft capsule according to claim 1, the antioxidant is selected from one of vitamin E, coenzyme Q10, butyl hydroxyanisole, thioglycerol, dibutyl hydroxytoluene, propyl gallate or any combination thereof, preferably the combination of butyl hydroxyanisole and dibutyl hydroxytoluene; the dosage of the antioxidant is 0.01-0.1% of the total weight of the content.
4. The preparation method of enzalutamide soft capsules according to any one of claims 1 to 3, comprising the steps of:
(1) uniformly mixing long-chain fatty glyceride with a prescription amount and purified water M to obtain a mixed solvent;
(2) adding prescription amount of enzalutamide and an antioxidant into the mixed solvent obtained in the step (1), stirring and dissolving, and after the enzalutamide is completely dissolved, performing vacuum degassing to obtain a content containing the enzalutamide;
(3) adding a plasticizer and purified water N in a formula amount into a glue melting tank, heating to 60-85 ℃, stirring and dissolving until the solution is clear, adding an opacifier, stirring until the solution is uniformly dispersed, adding gelatin, stirring and dissolving until no obvious particles exist in the glue solution, vacuum degassing until no bubbles float up in the glue solution for at least 30 minutes, and standing for 2-20 hours to obtain a standby glue solution;
(4) pressing and forming the content containing the enzalutamide obtained in the step (2) and the standby glue solution obtained in the step (3) by using a soft capsule filling and sealing machine to obtain a soft capsule initial product;
(5) and (5) shaping and drying the soft capsule primary product obtained in the step (4) to obtain the final product of the enzalutamide soft capsule.
5. The production method according to claim 4, wherein the agitation dissolution in the step (2) is an agitation dissolution at 35 ℃ -45 ℃.
6. The process for preparing according to claim 4, wherein the moisture content of the soft capsule is controlled to 2.0-5.0% of the total weight of the contents, preferably 3.5-4.5% of the total weight of the contents after the drying step of step (5).
7. The preparation method according to claim 4, 5 or 6, wherein the plasticizer in step (3) is selected from one of glycerin, sorbitol, sorbitan, maltitol, mannitol, propylene glycol, polyethylene glycol or any combination thereof, preferably a mixture of glycerin and sorbitan; the dosage of the plasticizer accounts for 20-40% of the weight of the prescription feed of the capsule shell.
8. The production method according to claim 4, 5 or 6, wherein the opacifier in the step (3) is titanium dioxide; the dosage of the opacifier accounts for 0.2 to 2.0 percent of the weight of the prescription feed of the capsule shell, and preferably 0.2 to 1.0 percent.
9. The preparation method according to claim 4, 5 or 6, wherein the amount of purified water N used in step (3) is 25-45%, preferably 30-40%, more preferably 30-35% of the weight of the prescription charge of the capsule shell.
10. The preparation method according to claim 4, 5 or 6, wherein the nitrogen gas is filled for protection at the whole time of the steps (2) and (4) of preparing the content.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014043208A1 (en) * | 2012-09-11 | 2014-03-20 | Medivation Prostate Therapeutics, Inc. | Formulations of enzalutamide |
| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
| CN104857517A (en) * | 2015-05-14 | 2015-08-26 | 南京海纳医药科技有限公司 | Enzalutamide soft capsule and preparation method thereof |
| CN110478347A (en) * | 2018-05-14 | 2019-11-22 | 成都海创药业有限公司 | A kind of HC-1119 preparation and its preparation method and application |
| CN111217757A (en) * | 2020-01-06 | 2020-06-02 | 武汉大学 | Enzalutamide compound and pharmaceutical composition preparation thereof |
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2020
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014043208A1 (en) * | 2012-09-11 | 2014-03-20 | Medivation Prostate Therapeutics, Inc. | Formulations of enzalutamide |
| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
| CN104857517A (en) * | 2015-05-14 | 2015-08-26 | 南京海纳医药科技有限公司 | Enzalutamide soft capsule and preparation method thereof |
| CN110478347A (en) * | 2018-05-14 | 2019-11-22 | 成都海创药业有限公司 | A kind of HC-1119 preparation and its preparation method and application |
| CN111217757A (en) * | 2020-01-06 | 2020-06-02 | 武汉大学 | Enzalutamide compound and pharmaceutical composition preparation thereof |
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