CN117100715A - Capsule containing amorphous nilotinib and preparation method thereof - Google Patents
Capsule containing amorphous nilotinib and preparation method thereof Download PDFInfo
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- CN117100715A CN117100715A CN202311137122.0A CN202311137122A CN117100715A CN 117100715 A CN117100715 A CN 117100715A CN 202311137122 A CN202311137122 A CN 202311137122A CN 117100715 A CN117100715 A CN 117100715A
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- Prior art keywords
- nilotinib
- amorphous
- capsule
- high molecular
- solid dispersion
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- 239000005536 L01XE08 - Nilotinib Substances 0.000 title claims abstract description 103
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 229960001346 nilotinib Drugs 0.000 title claims abstract description 103
- 239000002775 capsule Substances 0.000 title claims abstract description 92
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims abstract description 69
- 239000007962 solid dispersion Substances 0.000 claims abstract description 66
- 229920000642 polymer Polymers 0.000 claims abstract description 47
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003085 diluting agent Substances 0.000 claims abstract description 14
- 235000010980 cellulose Nutrition 0.000 claims abstract description 13
- 229920002678 cellulose Polymers 0.000 claims abstract description 13
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims abstract description 12
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims abstract description 12
- 239000007902 hard capsule Substances 0.000 claims abstract description 11
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 5
- 229940069328 povidone Drugs 0.000 claims abstract description 5
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 47
- 238000003756 stirring Methods 0.000 claims description 33
- 239000002245 particle Substances 0.000 claims description 28
- 238000011049 filling Methods 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 22
- 239000008187 granular material Substances 0.000 claims description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 238000007908 dry granulation Methods 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000001913 cellulose Substances 0.000 claims description 10
- 238000001694 spray drying Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 238000005429 filling process Methods 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 239000011148 porous material Substances 0.000 claims description 8
- 238000010298 pulverizing process Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000004925 Acrylic resin Substances 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 125000005591 trimellitate group Chemical group 0.000 claims description 4
- 229920000178 Acrylic resin Polymers 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims description 2
- 229920006158 high molecular weight polymer Polymers 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 208000035269 cancer or benign tumor Diseases 0.000 claims 1
- 230000001413 cellular effect Effects 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 238000005469 granulation Methods 0.000 claims 1
- 230000003179 granulation Effects 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 16
- 239000008280 blood Substances 0.000 abstract description 15
- 210000004369 blood Anatomy 0.000 abstract description 15
- 238000004090 dissolution Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 239000004490 capsule suspension Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000000291 postprandial effect Effects 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 108010010803 Gelatin Proteins 0.000 description 6
- 239000008119 colloidal silica Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 238000000227 grinding Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 206010067484 Adverse reaction Diseases 0.000 description 4
- 230000006838 adverse reaction Effects 0.000 description 4
- 239000007963 capsule composition Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 2
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 239000005434 MCC/mannitol excipient Substances 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
Abstract
The application discloses a capsule containing amorphous nilotinib and a preparation method thereof, wherein the capsule comprises a hollow hard capsule and a capsule core positioned in the hollow hard capsule, and is characterized in that the capsule core comprises an amorphous solid dispersion, an external high molecular polymer, a disintegrating agent and a diluent, wherein the external high molecular polymer is selected from one or a combination of celluloses, polyacrylic acids and povidone, the amorphous solid dispersion is prepared from amorphous nilotinib and the high molecular polymer, and the high molecular polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and/or hydroxypropyl methyl cellulose phthalate (HPMCP). The capsule has stable blood concentration, high bioavailability and stronger chemical stability.
Description
Technical field:
the application belongs to the field of medicines, and particularly relates to a capsule containing amorphous nilotinib and a preparation method thereof.
The background technology is as follows:
nilotinib is a synthetic aminopyrimidine that forms BCR-ABL kinase inhibitors by tightly binding to the inactive conformation of the ABL protein kinase site, thereby inhibiting BCR-ABL kinase mediated proliferation of leukemia cell lines and proliferation of cell lines derived from philadelphia chromosome positive chronic myelogenous leukemia (ph+cml) patients. Thus, nilotinib has high clinical value in leukemia treatment.
Nilotinib is a BCS 4 drug with low solubility, difficult permeability; meanwhile, nilotinib is a compound with various crystal forms, and under different environmental conditions, the different crystal forms can be transformed and have chemical stability problems, so that the dissolution and quality of the product are affected; in another aspect, the solubility of nilotinib is affected by pH, with the solubility decreasing with increasing pH; the existence of food in the gastrointestinal tract of a human body can change the pH of the gastrointestinal tract environment, so that the medicine dissolution difference is caused, the abnormal fluctuation of the blood medicine concentration is caused, and the adverse reaction caused by the fluctuation of the blood medicine concentration occurs. Based on this, nilotinib capsules (trade name: da-na), which are commercially available, have strict control over the mode of administration thereof, specifically, they must not be fed within 2 hours before taking the medicine and within at least 1 hour after taking the medicine, thereby avoiding the influence of the presence of food on the blood concentration.
Based on the problem of limited solubility of nilotinib, amorphous solid dispersion technology and surfactant have been studied in the prior art, for example, X-spray particle company discloses a pharmaceutical composition comprising stable amorphous hybrid nanoparticles (patent publication No. CN107115317 a), and the dissolution problem of amorphous nilotinib solid dispersion is improved by adding a solubilizer (polyethylene caprolactam-polyvinyl acetate-polyethylene glycol copolymer), so as to improve the bioavailability of nilotinib. Novartis AG discloses a pharmaceutical composition comprising nilotinib or a salt thereof (patent No. US8501760B 2) which employs a crystalline form of the drug to improve the dissolution of nilotinib by adding a surfactant in the capsule.
In contrast, the present inventors found through experimental studies that the problem of limitation of nilotinib solubility was solved by using an amorphous solid dispersion technique, and related matters are described in chinese patent publication No. CN112294971B, but the amorphous solid dispersion composition of nilotinib has a chemical stability problem and a fluctuation of abrupt blood concentration drop occurs in a drug action study, and the present application has been completed with respect to the technical problem.
The application comprises the following steps:
based on the defects existing in the prior art, the application provides a capsule containing amorphous nilotinib and a preparation method thereof.
A first object of the present application is to provide a capsule containing amorphous nilotinib, the capsule comprising a hollow hard capsule and a capsule core therein, the capsule core comprising an amorphous solid dispersion, an additional high molecular polymer, a disintegrant, a diluent; the amorphous solid dispersion is prepared from amorphous nilotinib and a high molecular polymer, wherein the high molecular polymer is a cellulose high molecular polymer, and the cellulose high molecular polymer is preferably hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and/or hydroxypropyl methyl cellulose phthalate (HPMCP).
The amorphous solid dispersion component comprises amorphous nilotinib and a high molecular polymer, wherein the amorphous nilotinib is used in an amount of 10% -30%, more preferably 15% -25%, and particularly, in some embodiments, 15% and 20% of the prescription.
In the amorphous solid dispersion, the mass ratio of nilotinib to the high molecular polymer is 1:1-1:15; further, the mass ratio of nilotinib to the high molecular polymer is from 1:2 to 1:10, in some embodiments, the mass ratio of nilotinib to the high molecular polymer is 15:30, 25:75, 30:70, 40:60. The inventors found through studies that different kinds and proportions of polymers affect the crystal form and chemical stability of the solid dispersion. Among them, the inventors found that different cellulose polymers can have a great influence on the chemical stability of nilotinib amorphous solid dispersion, cause the growth difference of related substances, and even part of cellulose can generate phthalic acid impurities, which affects the product quality.
The preparation process of the amorphous solid dispersion can select spray drying and hot melt extrusion, and is preferably a spray drying process. Specifically, nilotinib or a salt thereof and a high polymer are dissolved in a solvent, wherein the solvent can be methanol, dichloromethane or a mixture thereof, after the nilotinib or the salt thereof and the high polymer are fully mixed and react, the mixed solution is subjected to spray drying, and the spray-dried solid dispersion is further dried by an oven to obtain an amorphous solid dispersion.
The externally added high molecular polymer is one or a combination of celluloses, polyacrylic acids and povidone; further, hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitate (CAT), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose acetate phthalate (HPCAP), acrylic resin, copovidone S630; hydroxypropyl methylcellulose acetate succinate (HPMCAS), acrylic resins, hydroxypropyl methylcellulose (HPMC) are preferred in some embodiments; the prescription of the additional high molecular polymer accounts for 10% -30%, further 10% -25%, and in some embodiments 15% and 20% are selected. The inventor finds that the added high molecular polymer does not influence the crystal form stability of the amorphous solid dispersion, but can improve the chemical stability and bioavailability of the amorphous solid dispersion.
The disintegrating agent is selected from crospovidone, sodium carboxymethyl starch (CMS-Na) and croscarmellose sodium (CCNa), and accounts for 2-8 percent; further, the proportion of the disintegrating agent in the prescription is 3% -6%; in some embodiments 2%, 3%, 5% are preferred. Obviously, for the poorly soluble drugs of pH dependence, the disintegrant component and dosage suitable for the prescription process plays a great role in dissolution of the drug, which can improve the disintegration of the solid dispersion in the capsule in the medium, thereby improving the dissolution behavior of the drug in the gastrointestinal tract environment, and thus improving the bioavailability of the drug.
The lubricant is one of magnesium stearate and silicon dioxide or a combination thereof. The lubricant is formulated at a ratio of 0.25% to 3%, further selected at 0.5% to 1.5%, and in some embodiments selected in the range of 0.5% to 1%. Further, the lubricant is selected from magnesium stearate and silicon dioxide in a ratio of 2:1 to 1:2, in some embodiments 1:1 is selected.
The diluent is selected from lactose, microcrystalline cellulose, mannitol and starch; further, microcrystalline cellulose and mannitol may be selected. The prescription of the diluent accounts for 15-40 percent; further, the diluent prescription is selected to be 15% to 35%, and in some embodiments is preferably in the range of 20% to 30%.
Specifically, a capsule formulation containing amorphous nilotinib comprises the following components:
the second object of the application is to provide a preparation method of the capsule containing amorphous nilotinib
Because the amorphous nilotinib solid dispersion has hygroscopicity, the capsule is prepared by adopting a dry granulation process, the particle size range of the dry granulation is 300-2000 um, and the total mixed particles have good powder flowability by controlling the particle size and the kind proportion of the external auxiliary materials, so that the requirement of capsule filling is met. Further, the dry granulation process is to mix and granulate the solid dispersion, the diluent and the disintegrating agent, wherein the disintegrating agent and the diluent are uniformly distributed in the solid dispersion, and the diluent has a moisture absorption capacity and can reduce the moisture absorption amount of the Amorphous Solid Dispersion (ASD), so that the stability of the product is further improved; meanwhile, the disintegrating agent is placed in an Amorphous Solid Dispersion (ASD), so that the release and dissolution of the medicine from the dispersion are improved, and the speed and degree of the disintegrating and dissolution of the medicine are improved.
The method comprises the following steps:
(1) Preparation of amorphous solid dispersions
Firstly, nilotinib or a salt thereof and a high polymer are dissolved in a solvent, wherein the solvent can be methanol, dichloromethane or a mixture thereof, after the nilotinib or the salt thereof and the high polymer are fully mixed and reacted, the mixed solution is subjected to spray drying, and the spray-dried solid dispersion is further dried by a drying oven to obtain the amorphous solid dispersion.
(2) Premixing process
Adding the amorphous solid dispersion, the high molecular polymer, the disintegrating agent and the diluent into a square cone hopper, stirring at the speed of 10 rpm-20 rpm, stirring for 20 min-50 min, and fully and uniformly mixing.
(3) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 15 rpm-85 rpm;
hydraulic pressure: 8bar to 220bar; pulverizing motor rotation speed: 30 rpm-165 rpm; roller motor speed: 3rpm to 13rpm;
rotational speed of the finishing motor: 300rpm to 1200rpm; stirring motor rotation speed: 15 rpm-85 rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained.
(4) General mixing procedure
And (3) placing the dry particles and the residual materials in a 100L square cone hopper, and stirring at a stirring speed of 10 rpm-20 rpm for 20-50 min to obtain the total mixed particles.
(5) Filling process
And (3) placing the total mixed particles into a hopper of a capsule filling machine, using a hollow hard capsule, and filling to obtain the nilotinib capsule.
The application has the beneficial effects that:
1 blood concentration is stable
In the bioavailability study of postprandial and fasting, the ratio of Cmax, AUC0-T and AUC 0-infinity is 94.55%, 104.68% and 105.61% respectively, and the two preparations are considered bioequivalent when the test assumes that the 90% confidence interval of T/R specified by the ratio method is between 80% and 125%. Therefore, the self-grinding product has no difference between postprandial and fasting Cmax, AUC0-t and AUC 0-infinity, and has stable blood concentration, thereby being beneficial to reducing adverse reaction caused by fluctuation of the blood concentration. Meanwhile, compared with a capsule suspension containing amorphous nilotinib (no hydroxypropyl methylcellulose acetate succinate HPMCAS is added in the prescription), the sampling point after Cmax does not have fluctuation of blood concentration suddenly drop, and the trend of the blood concentration along with time is more similar to that of the product on the market.
2 improving bioavailability
The test of this equivalence assessment is assumed to be a ratio method, the ratio T/R of the mean values of the pharmacokinetic parameters of the tested formulation and the reference formulation, C of the fasting T/fasting R ratio of the amorphous nilotinib-containing capsule suspension (no added hydroxypropyl methylcellulose acetate succinate HPMCAS in the formulation) compared to the marketed product nilotinib capsule suspension (trade name: dactylna) max 、AUC 0-t 、AUC 0-∞ 248.76%, 147.84%, 151.02%, respectively, it can be seen that the amorphous nilotinib-containing capsules have a greater bioavailability, wherein C max About 2.5 times RLD and AUC about 1.5 times RLD.
In another aspect, the present application is administered in half the dose of RLD, but at C, which is the fasting T/fasting R ratio, as compared to the marketed product nilotinib capsule suspension (trade name: dachner) max 、AUC 0-t 、AUC 0-∞ 120.21%, 1118.03% and 118.97% respectively. Therefore, compared with nilotinib capsules which are products on the market, the application has higher bioavailability.
3 improving the chemical stability of amorphous solid dispersions
The variety and proportion of high molecular polymers in amorphous solid dispersions of nilotinib can affect the chemical stability of the product, especially the amorphous formation of nilotinib with some cellulosic polymers can produce Phthalic Acid (PA) and other unknown single impurities. The application improves the chemical stability of the amorphous solid dispersion in the product, reduces the growth of related substances and ensures the quality of the product by researching the types of the high molecular polymer in the solid dispersion and adding the types and the proportion of the high molecular polymer.
4 has good crystal form stability
The amorphous state and the crystalline state of nilotinib have energy difference, and the amorphous state is easy to be arranged into the crystalline state under the influence of some environmental conditions (such as temperature, humidity and illumination), so that the dissolution absorption of the medicine is influenced. The nilotinib provided by the application is placed for 29 days under the conditions of high temperature, high humidity, strong illumination and other influencing factors, no crystal form transformation occurs, and the crystal form stability is good.
Description of the drawings:
FIG. 1 is a dissolution profile of the capsule of example 11;
FIG. 2 is a graph showing the pharmacokinetic profile of amorphous nilotinib-containing capsules (no added hydroxypropyl methylcellulose acetate succinate HPMCAS in the formulation);
fig. 3 is a graph showing the pharmacokinetic profile of amorphous nilotinib-containing capsules (with the addition of hydroxypropyl methylcellulose acetate succinate HPMCAS to the components).
Wherein, in fig. 2 and 3, RLD represents a nilotinib capsule (trade name: da schner) which is a marketed product; TEST represents a self-grinding amorphous nilotinib-containing capsule, wherein the TEST sample T1 represents an amorphous nilotinib capsule (no added hydroxypropyl methylcellulose acetate succinate HPMCAS in the formulation), and T2 represents an amorphous nilotinib-containing capsule (added hydroxypropyl methylcellulose acetate succinate HPMCAS in the components); fast represents fasting administration and fed represents postprandial administration.
The specific embodiment is as follows:
the following is a detailed description of embodiments of the present application. The following examples are illustrative only and are not to be construed as limiting the application.
Example 1
Amorphous Solid Dispersion (ASD) preparation
(1) Material
(2) Solution preparation
The prescribed amount of the high molecular polymer was added to 150mL of the mixed solvent, and magnetically stirred until completely dissolved. Adding the prescription amount of nilotinib into the auxiliary material solution, and continuously stirring for 1h after the nilotinib is completely dissolved.
(3) Spray drying
The prepared solution was spray dried with the parameters of 80℃inlet temperature, 10mL/min feed rate, 45mm nitrogen flow, 100% suction, 0 nozzle cleaning frequency and-20℃gas condensing temperature.
(4) Vacuum drying
And carrying out vacuum drying on the spray-dried sample for 24 hours at the drying temperature of 35 ℃ to obtain the amorphous solid dispersion.
Example 2
Preparation of amorphous solid dispersions
(1) Material
(2) Solution preparation
The prescribed amount of the high molecular polymer was added to 150mL of the mixed solvent, and magnetically stirred until completely dissolved. Adding the prescription amount of nilotinib into the auxiliary material solution, and continuously stirring for 1h after the nilotinib is completely dissolved.
(3) Spray drying
The prepared solution was spray dried with the parameters of 80℃inlet temperature, 10mL/min feed rate, 45mm nitrogen flow, 100% suction, 0 nozzle cleaning frequency and-20℃gas condensing temperature.
(4) Vacuum drying
And carrying out vacuum drying on the spray-dried sample for 24 hours at the drying temperature of 35 ℃ to obtain the amorphous solid dispersion.
Example 3
Preparation of amorphous solid dispersions
(1) Material
(2) Solution preparation
A prescribed amount of hydroxypropyl methylcellulose phthalate (HPMCP) was added to 150mL of the mixed solvent and magnetically stirred until completely dissolved. Adding the prescription amount of nilotinib into the auxiliary material solution, and continuously stirring for 1h after the nilotinib is completely dissolved.
(3) Spray drying
The prepared solution was spray dried with the parameters of 80℃inlet temperature, 10mL/min feed rate, 45mm nitrogen flow, 100% suction, 0 nozzle cleaning frequency and-20℃gas condensing temperature.
(4) Vacuum drying
And carrying out vacuum drying on the spray-dried sample for 24 hours at the drying temperature of 35 ℃ to obtain the amorphous solid dispersion.
Example 4
Preparation of amorphous solid dispersions
(1) Material
(2) Solution preparation
The prescribed amount of hydroxypropyl methylcellulose acetate succinate (HPMCAS) was added to 150mL of the mixed solvent and magnetically stirred until completely dissolved. Adding the prescription amount of nilotinib into the auxiliary material solution, and continuously stirring for 1h after the nilotinib is completely dissolved.
(3) Spray drying
The prepared solution was spray dried with the parameters of 80℃inlet temperature, 10mL/min feed rate, 45mm nitrogen flow, 100% suction, 0 nozzle cleaning frequency and-20℃gas condensing temperature.
(4) Vacuum drying
And carrying out vacuum drying on the spray-dried sample for 24 hours at the drying temperature of 35 ℃ to obtain the amorphous solid dispersion.
Example 5
Preparation of amorphous solid dispersions
(1) Material
(2) Solution preparation
The prescribed amount of the high molecular polymer was added to 150mL of the mixed solvent, and magnetically stirred until completely dissolved. Adding the prescription amount of nilotinib into the auxiliary material solution, and continuously stirring for 1h after the nilotinib is completely dissolved.
(3) Spray drying
The prepared solution was spray dried with the parameters of 80℃inlet temperature, 10mL/min feed rate, 45mm nitrogen flow, 100% suction, 0 nozzle cleaning frequency and-20℃gas condensing temperature.
(4) Vacuum drying
And carrying out vacuum drying on the spray-dried sample for 24 hours at the drying temperature of 35 ℃ to obtain the amorphous solid dispersion.
Example 6
And (3) preparation of capsules:
the solid dispersion of nilotinib and hydroxypropyl methylcellulose phthalate (HPMCP) of example 3 was selected to make capsules, with the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS) in the following specific formulation proportions:
contrast prescription
The solid dispersion of nilotinib and hydroxypropyl methylcellulose phthalate (HPMCP) of example 3 was selected to prepare capsules without additional hydroxypropyl methylcellulose acetate succinate (HPMCAS), specifically formulated in the following proportions
Process steps
(1) Premixing process
Adding the amorphous solid dispersion with the prescription amount and hydroxypropyl methyl cellulose acetate succinate into a 100L square cone hopper, stirring at 15rpm for 30min, and fully and uniformly mixing.
(2) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 50rpm; hydraulic pressure: 30bar; pulverizing motor rotation speed: 80rpm; roller motor speed: 8rpm; rotational speed of the finishing motor: 600rpm;
stirring motor rotation speed: 30rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained.
(3) General mixing procedure
The dry particles, magnesium stearate and colloidal silica were stirred in a 100L square conical hopper at a stirring speed of 15rpm for 30min to obtain total mixed particles.
(4) Filling process
The total mixed particles are placed in a hopper of a capsule filling machine, a 0# gelatin hollow hard capsule is used, the filling speed is adjusted to be 1 ten thousand per hour,
and (5) filling to obtain the capsule.
Example 7
And (3) preparation of capsules:
the solid dispersion of nilotinib and hydroxypropyl methylcellulose acetate succinate (HPMCAS) of example 4 was selected to prepare capsules, with the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS) in the following specific prescription proportions:
comparative experiments
The solid dispersion of nilotinib and hydroxypropyl methylcellulose acetate succinate (HPMCAS) of example 4 was selected to prepare capsules without additional high molecular weight polymer, specifically formulated as follows:
process steps
(1) Premixing process
Adding the amorphous solid dispersion, the crospovidone, the microcrystalline cellulose and the hydroxypropyl methylcellulose acetate succinate with the prescription amount into a 100L square cone hopper, stirring at 15rpm for 30min, and fully and uniformly mixing.
(2) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 50rpm; hydraulic pressure: 30bar; pulverizing motor rotation speed: 80rpm; roller motor speed: 8rpm; rotational speed of the finishing motor: 600rpm; stirring motor rotation speed: 30rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained.
(3) General mixing procedure
The dry particles, magnesium stearate, and colloidal silica were stirred in a 100L square conical hopper at a stirring speed of 15rpm for 30min to obtain total mixed particles.
(4) Filling process
And (3) placing the total mixed particles into a hopper of a capsule filling machine, using a 0# gelatin hollow hard capsule, adjusting the filling speed to be 1 ten thousand per hour, and filling to obtain the capsule.
Example 8
The solid dispersion of nilotinib and hydroxypropyl methylcellulose acetate succinate (HPMCAS) of example 4 was selected to prepare capsules, with the addition of cellulose trimellitate (CAT), povidone S630 in the following specific formulation proportions:
process steps
(1) Premixing process
Adding amorphous solid dispersion, sodium carboxymethyl starch, microcrystalline cellulose, and additional polymer (formula 1 cellulose trimellitate (CAT) and formula 2 povidone S630) into 100L square conical hopper, stirring at 15rpm for 30min, and mixing thoroughly.
(2) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 50rpm; hydraulic pressure: 30bar; pulverizing motor rotation speed: 80rpm; roller motor speed: 8rpm; rotational speed of the finishing motor: 600rpm; stirring motor rotation speed: 30rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained.
(3) General mixing procedure
The dry particles, magnesium stearate and colloidal silica were stirred in a 100L square conical hopper at a stirring speed of 15rpm for 30min to obtain total mixed particles.
(4) Filling process
And (3) placing the total mixed particles into a hopper of a capsule filling machine, using a 0# gelatin hollow hard capsule, adjusting the filling speed to be 1 ten thousand per hour, and filling to obtain the capsule.
Example 9
The solid dispersion of nilotinib and hydroxypropyl methylcellulose acetate succinate (HPMCAS) of example 4 was selected to prepare capsules with the following specific formulation proportions:
process steps
(1) Premixing process
Adding the amorphous solid dispersion, the croscarmellose sodium, the mannitol and the hydroxypropyl methylcellulose acetate succinate with the prescription amount into a 100L square cone hopper, stirring at 15rpm for 30min, and fully and uniformly mixing.
(2) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 50rpm; hydraulic pressure: 30bar; pulverizing motor rotation speed: 80rpm; roller motor speed: 8rpm; rotational speed of the finishing motor: 600rpm; stirring motor rotation speed: 30rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained.
(3) General mixing procedure
The dry particles, magnesium stearate and colloidal silica were stirred in a 100L square conical hopper at a stirring speed of 15rpm for 30min to obtain total mixed particles.
(4) Filling process
And (3) placing the total mixed particles into a hopper of a capsule filling machine, using a 0# gelatin hollow hard capsule, adjusting the filling speed to be 1 ten thousand per hour, and filling to obtain the capsule.
Example 10
The solid dispersion of nilotinib and hydroxypropyl methylcellulose acetate succinate (HPMCAS) of example 4 was selected to prepare capsules, with the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS) in the following proportions:
process steps
(1) Premixing process
Adding the amorphous solid dispersion, the crospovidone, the microcrystalline cellulose and the hydroxypropyl methylcellulose acetate succinate with the prescription amount into a 100L square cone hopper, stirring at 15rpm for 30min, and fully and uniformly mixing.
(2) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 30rpm; hydraulic pressure: 40bar; pulverizing motor rotation speed: 80rpm; roller motor speed: 10rpm; rotational speed of the finishing motor: 1200rpm; stirring motor rotation speed: 30rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained.
(3) General mixing procedure
The dry particles, magnesium stearate and colloidal silica were stirred in a 100L square conical hopper at a stirring speed of 20rpm for 40min to obtain total mixed particles.
(4) Filling process
And (3) placing the total mixed particles into a hopper of a capsule filling machine, using a 0# gelatin hollow hard capsule, adjusting the filling speed to be 1 ten thousand per hour, and filling to obtain the capsule.
Example 11
The solid dispersion of nilotinib and hydroxypropyl methylcellulose acetate succinate (HPMCAS) of example 4 was selected to prepare capsules with the following specific formulation proportions:
process steps
(1) Premixing process
Adding the amorphous solid dispersion, the crospovidone, the microcrystalline cellulose and the additional polymer (prescription 1 hydroxypropyl methylcellulose acetate succinate, prescription 2 polyacrylic resin and prescription 3 hydroxypropyl methylcellulose) into a 100L square cone hopper, stirring at 15rpm for 30min, and fully and uniformly mixing.
(2) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 50rpm; hydraulic pressure: 30bar; pulverizing motor rotation speed: 80rpm; roller motor speed: 8rpm; rotational speed of the finishing motor: 600rpm; stirring motor rotation speed: 30rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained.
(3) General mixing procedure
The dry particles, magnesium stearate and colloidal silica were stirred in a 100L square conical hopper at a stirring speed of 15rpm for 30min to obtain total mixed particles.
(4) Filling process
And (3) placing the total mixed particles into a hopper of a capsule filling machine, using a 0# gelatin hollow hard capsule, adjusting the filling speed to be 1 ten thousand per hour, and filling to obtain the capsule.
Experimental results
1. Chemical stability of the capsule formulation:
the capsule prepared in example 6 was selected for acceleration and long-term experimental investigation, and the sample was placed under acceleration conditions (40 ℃ + -2 ℃, 75% + -5% RH) and long-term conditions (25 ℃ + -2 ℃, 60% + -5% RH) for 1 month, and the content and related substances were sampled and detected.
1) Chemical stability of the capsule formulation: amorphous nilotinib solid dispersion ASD + added hydroxypropyl methylcellulose acetate succinate (HPMCAS)
2) Chemical stability of the capsule formulation: amorphous nilotinib solid dispersion ASD
The high molecular polymer can improve the chemical stability of the amorphous solid dispersion of nilotinib and reduce the increase of total impurities of capsules and phthalic acid impurities. The sample was placed at 40 ℃ for 1 month acceleration, with the addition of 0.55% total impurities of the capsules of hydroxypropyl methylcellulose acetate succinate (HPMCAS), and 1.75% total impurities of the capsules without addition of methylcellulose acetate succinate (HPMCAS); 0.44% phthalic acid with the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS) capsules and 1.33% phthalic acid without the addition of methylcellulose acetate succinate (HPMCAS) capsules; compared with the capsules added with the high molecular polymer, the total impurity and phthalic acid increment of the capsules without the high molecular polymer after accelerating for 1 month is 3 times.
2. Dissolution behavior
The capsules prepared in example 11 were selected for dissolution experimental study, and the dissolution profile is shown in fig. 1.
Experimental results show that the difference of the added polymers in the capsule can have different effects on the dissolution of nilotinib, wherein the dissolution is 105min under the environment simulating the change of gastrointestinal tract, and the added HPMCAS, HPMC 5 and polyacrylic resin have larger dissolution amount in the environment simulating the pH of gastrointestinal tract solution, and the dissolution amount of 105min is about 30% -55%.
3. Bioavailability of the active ingredients
The capsules prepared in example 7 and the nilotinib capsules (trade name: dachner) which were marketed products were selected for animal test study. RLD in the figure represents the marketed product nilotinib capsule (trade name: dachner); TEST represents a self-grinding amorphous nilotinib-containing capsule, wherein the TEST sample T1 represents an amorphous nilotinib capsule (no added hydroxypropyl methylcellulose acetate succinate HPMCAS in the formulation), and T2 represents an amorphous nilotinib-containing capsule (added hydroxypropyl methylcellulose acetate succinate HPMCAS in the components); fast represents fasting administration and fed represents postprandial administration.
The animal experiment method comprises the following steps:
the test method of the equivalence evaluation is a ratio method, the ratio T/R of the mean value of the pharmacokinetic parameters of the tested preparation and the reference preparation, and the C of the empty stomach T/empty stomach R ratio of the capsule suspension containing amorphous nilotinib (without adding HPMCAS in the prescription) compared with the nilotinib capsule suspension (trade name: dactylna) which is the product on the market max 、AUC 0-t 、AUC 0-∞ 248.76%, 147.84%, 151.02%, respectively, it can be seen that the amorphous nilotinib-containing capsules have a greater bioavailability, wherein C max About 2.5 times greater, about 1.5 times greater AUC, and at C max The fluctuation of the blood concentration is easy to cause adverse reaction when the fluctuation of the blood concentration suddenly drops at the later time point.
Animal experiment results of amorphous nilotinib-containing suspension (additional hydroxypropyl methylcellulose acetate succinate HPMCAS in the components) and nilotinib capsule suspension (trade name: dachner) on the market show that: (1) in the study of postprandial and fasting bioavailability of the self-grinding product, C max 、AUC 0-t 、AUC 0-∞ The average ratio of postprandial to fasting was 94.55%, 104.68%, 105.61%, respectively, and the two formulations were considered bioequivalent when the test assumed that the ratio method prescribes a 90% confidence interval for T/R between (80% -125%). Thus self-grinding product postprandial and fasting C max 、AUC 0-t 、AUC 0-∞ No difference; compared with the strict administration mode of RLD, the application has consistent bioavailability after meal and empty stomach and is beneficial to improving the compliance of patients. (2) In self-polishing and RLD on empty stomach studies, C max 、AUC 0-t 、AUC 0-∞ The ratio of postprandial to fasting was 120.21%, 1118.03%, 118.97%, respectively, and the test assumed that the ratio method provided a 90% confidence interval for T/R of between 80% and 125% was considered bioequivalent for both formulations. Since the dosage of the present application is only half of the dosage of the marketed product, it can be presumed that the present application is superior to the marketed product at the same dosage,the application has higher bioavailability; therefore, the application has lower dosage effect under the same curative effect. Meanwhile, compared with the capsule suspension containing amorphous nilotinib (without additional hydroxypropyl methylcellulose acetate succinate HPMCAS in the prescription), the application has the following advantages that max The fluctuation of the sudden drop of the blood concentration does not occur at the later time point, and the trend of the blood concentration along with time is more similar to that of the products on the market, namely C at the time of reducing the dosage max And AUC does not drop equally, which is advantageous in reducing the occurrence of adverse reactions caused by fluctuations in blood concentration.
Claims (14)
1. An amorphous nilotinib-containing capsule comprising a hollow hard capsule and a capsule core positioned therein, wherein the capsule core comprises an amorphous solid dispersion, an externally added high molecular polymer, a disintegrating agent and a diluent, wherein the externally added high molecular polymer is selected from one or a combination of celluloses, polyacrylic acids and povidone, the amorphous solid dispersion is prepared from amorphous nilotinib and a high molecular polymer, the high molecular polymer is a cellulose high molecular polymer, and the cellulose high molecular polymer is preferably hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and/or hydroxypropyl methyl cellulose phthalate (HPMCP).
2. The amorphous nilotinib-containing capsule according to claim 1, wherein the additional high molecular polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitate (CAT), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose acetate phthalate (HPCAP), acrylic resins, copovidone S630.
3. The amorphous nilotinib-containing capsule according to claim 1, characterized in that the additional high molecular polymer comprises 10% -30% by weight of the capsule core formulation.
4. The amorphous nilotinib-containing capsule according to claim 1, characterized in that the weight of amorphous nilotinib is 10-30% of the prescribed dosage in the capsule core.
5. The amorphous nilotinib-containing capsule according to claim 1, characterized in that the mass ratio of nilotinib to high molecular weight polymer in the solid dispersion is 1:1-1:15; further, the mass ratio of nilotinib to the high molecular polymer is 1:2-1:10.
6. The amorphous nilotinib-containing capsule according to claim 1, characterized in that the disintegrant is selected from crospovidone, sodium carboxymethyl starch (CMS-Na), croscarmellose sodium (CCNa), the weight of disintegrant being 2% -8% of the capsule core.
7. The amorphous nilotinib-containing capsule according to claim 1, characterized in that the lubricant is one of magnesium stearate, silicon dioxide or a combination thereof, and the weight of the lubricant is 0.25% -3% of the capsule core.
8. The amorphous nilotinib-containing capsule according to claim 1, characterized in that the diluent is selected from lactose, microcrystalline cellulose, mannitol, starch; the weight of the diluent accounts for 15-40% of the capsule core.
9. A process for the preparation of an amorphous nilotinib-containing capsule according to any one of claims 1 to 8, characterized in that the capsule is prepared by a dry granulation process.
10. The method for preparing amorphous nilotinib-containing capsules according to claim 9, characterized in that the dry granulation is performed with a granulation size of 300-2000 um.
11. The method for preparing amorphous nilotinib-containing capsules according to claim 10, characterized in that the dry granulation step is to granulate the solid dispersion, the diluent, the disintegrant.
12. The method for preparing the amorphous nilotinib-containing capsule according to claim 9, comprising the following steps:
(1) Preparation of amorphous solid dispersions
Firstly, nilotinib or salt thereof and a high polymer are dissolved in a solvent, the solvent is selected from methanol and dichloromethane, one or a combination thereof is mixed, after nilotinib or salt thereof and the high polymer are fully mixed and reacted, the mixed solution is subjected to spray drying, and the spray-dried solid dispersion is further dried by a drying oven to obtain an amorphous solid dispersion;
(2) Premixing process
Adding the amorphous solid dispersion, the disintegrating agent and the diluent into a square cone hopper, stirring at the speed of 10 rpm-20 rpm, stirring for 20 min-50 min, and fully and uniformly mixing;
(3) Dry granulation process
Dry granulating the premixed powder, wherein the parameter range of a dry granulator is as follows: screw feed rotational speed: 15 rpm-85 rpm;
hydraulic pressure: 8bar to 220bar; pulverizing motor rotation speed: 30 rpm-165 rpm; roller motor speed: 3rpm to 13rpm; rotational speed of the finishing motor: 300rpm to 1200rpm; stirring motor rotation speed: 15 rpm-85 rpm; pore diameter of the granule finishing screen: 1.2mm, dry granules were obtained;
(4) General mixing procedure
Stirring the dry particles and the residual materials in a square cone hopper with the stirring speed of 10 rpm-20 rpm for 20 min-50 min to obtain total mixed particles;
(5) Filling process
The total mixed particles are placed in a hopper of a capsule filling machine to prepare capsules.
13. Use of an amorphous nilotinib-containing capsule according to any one of claims 1-12 for the preparation of a medicament for the treatment of uncontrolled cell proliferation disorders.
14. The use according to claim 13, wherein the uncontrolled cellular proliferative disease is leukemia.
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| CN104159574A (en) * | 2012-01-13 | 2014-11-19 | X喷雾微粒公司 | A method for producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component |
| CN104367557A (en) * | 2013-08-12 | 2015-02-25 | 浙江九洲药业股份有限公司 | Preparation method of amorphous composition composed of drug active component and PVP |
| CN112294971A (en) * | 2020-02-20 | 2021-02-02 | 深圳市泰力生物医药有限公司 | Nilotinib compositions having improved solubility |
| CN112939945A (en) * | 2021-02-25 | 2021-06-11 | 深圳市泰力生物医药有限公司 | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms |
| WO2022199697A1 (en) * | 2021-03-26 | 2022-09-29 | Impact Therapeutics (Shanghai) , Inc | Oral capsule of parp inhibitor and preparation method thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104159574A (en) * | 2012-01-13 | 2014-11-19 | X喷雾微粒公司 | A method for producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component |
| CN104367557A (en) * | 2013-08-12 | 2015-02-25 | 浙江九洲药业股份有限公司 | Preparation method of amorphous composition composed of drug active component and PVP |
| CN112294971A (en) * | 2020-02-20 | 2021-02-02 | 深圳市泰力生物医药有限公司 | Nilotinib compositions having improved solubility |
| CN112939945A (en) * | 2021-02-25 | 2021-06-11 | 深圳市泰力生物医药有限公司 | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms |
| WO2022199697A1 (en) * | 2021-03-26 | 2022-09-29 | Impact Therapeutics (Shanghai) , Inc | Oral capsule of parp inhibitor and preparation method thereof |
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