CN114028400B - 一种含有细胞周期蛋白激酶抑制剂的药物组合物及其制备方法 - Google Patents
一种含有细胞周期蛋白激酶抑制剂的药物组合物及其制备方法 Download PDFInfo
- Publication number
- CN114028400B CN114028400B CN202111451044.2A CN202111451044A CN114028400B CN 114028400 B CN114028400 B CN 114028400B CN 202111451044 A CN202111451044 A CN 202111451044A CN 114028400 B CN114028400 B CN 114028400B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- preparation
- cancer
- weight
- diluent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 102000016736 Cyclin Human genes 0.000 title description 5
- 108050006400 Cyclin Proteins 0.000 title description 5
- 229940043355 kinase inhibitor Drugs 0.000 title description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 5
- 239000003814 drug Substances 0.000 claims abstract description 19
- 238000004090 dissolution Methods 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 7
- 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 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000007787 solid Substances 0.000 abstract description 3
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 abstract description 2
- 238000007908 dry granulation Methods 0.000 abstract description 2
- 238000005550 wet granulation Methods 0.000 abstract description 2
- 229940122560 Cyclin inhibitor Drugs 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 16
- 239000002775 capsule Substances 0.000 description 11
- 108091007914 CDKs Proteins 0.000 description 10
- 238000011049 filling Methods 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 239000008187 granular material Substances 0.000 description 7
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 6
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 238000005457 optimization Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- 108010068106 Cyclin T Proteins 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 2
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
- 241000282567 Macaca fascicularis Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229940076006 cell cycle modulator Drugs 0.000 description 2
- 230000006369 cell cycle progression Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 238000001303 quality assessment method Methods 0.000 description 2
- 230000022983 regulation of cell cycle Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 description 1
- 229940126074 CDK kinase inhibitor Drugs 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 108010068192 Cyclin A Proteins 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 102000002428 Cyclin C Human genes 0.000 description 1
- 108010068155 Cyclin C Proteins 0.000 description 1
- 102000003910 Cyclin D Human genes 0.000 description 1
- 108090000259 Cyclin D Proteins 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108010058544 Cyclin D2 Proteins 0.000 description 1
- 108010058545 Cyclin D3 Proteins 0.000 description 1
- 102000003909 Cyclin E Human genes 0.000 description 1
- 108090000257 Cyclin E Proteins 0.000 description 1
- 108010068237 Cyclin H Proteins 0.000 description 1
- 102000029995 Cyclin L1 Human genes 0.000 description 1
- 108091014810 Cyclin L1 Proteins 0.000 description 1
- 102000002435 Cyclin T Human genes 0.000 description 1
- 102100025191 Cyclin-A2 Human genes 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 102100038254 Cyclin-F Human genes 0.000 description 1
- 102100036883 Cyclin-H Human genes 0.000 description 1
- 102100036876 Cyclin-K Human genes 0.000 description 1
- 102100021899 Cyclin-L2 Human genes 0.000 description 1
- 102100024112 Cyclin-T2 Human genes 0.000 description 1
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 102100033145 Cyclin-dependent kinase 19 Human genes 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 description 1
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 1
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- 102100034770 Cyclin-dependent kinase inhibitor 3 Human genes 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 1
- 102100024185 G1/S-specific cyclin-D2 Human genes 0.000 description 1
- 102100037859 G1/S-specific cyclin-D3 Human genes 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 101000884183 Homo sapiens Cyclin-F Proteins 0.000 description 1
- 101000713127 Homo sapiens Cyclin-K Proteins 0.000 description 1
- 101000897452 Homo sapiens Cyclin-L2 Proteins 0.000 description 1
- 101000944345 Homo sapiens Cyclin-dependent kinase 19 Proteins 0.000 description 1
- 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 description 1
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
- 101000945639 Homo sapiens Cyclin-dependent kinase inhibitor 3 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 206010043515 Throat cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 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 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000036403 neuro physiology Effects 0.000 description 1
- 208000016065 neuroendocrine neoplasm Diseases 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Abstract
本发明涉及一种含有细胞周期蛋白抑制剂的药物组合物及其制备方法，具体而言，该药物组合物以N‑环戊基‑5‑（2‑（（5‑（（4‑乙基哌嗪‑1‑基）甲基）吡啶‑2‑基）氨基）‑5‑氟嘧啶‑4‑基）‑4‑甲基噻唑‑2‑胺或其盐为活性成分，制备得到的口服固体制剂具有优异的溶出行为和良好的生物利用度，符合临床应用需求，并且该药物组合物杂质含量极低、稳定性较好，能够保证药物的质量可控；同时湿法/干法制粒的制备工艺简单易操作，有利于药物的工业化生产。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种含有细胞周期蛋白激酶抑制剂的药物组合物及其制备方法。
背景技术
细胞周期蛋白依赖性激酶(CDKs)是与细胞周期进程相对应的一套Ser/Thr激酶***。它们与各种细胞周期蛋白亚基相关，在细胞各种重要的调节通路中起关键作用，包括细胞周期控制、细胞凋亡、神经元生理机能、分化和转录。目前共有超过20种CDK，按功能主要分为细胞周期调节剂CDK和转录调节剂CDK两大类。细胞周期调节剂CDK包括CDK1、CDK2、CDK3、CDK4和CDK6，它们与细胞周期蛋白配体(例如细胞周期蛋白A、B、D1、D2、D3、E和F)共同作用调节细胞周期进程。转录调节剂CDK包括CDK7、CDK8、CDK9和CDK11，它们与细胞周期蛋白C、H、K、L1、L2、T1和T2共同作用，主要参与转录调节。基于此可以断定CDK与细胞增殖性疾病和病症特别是癌症密切相关。细胞增殖是细胞***周期直接或间接失控的结果，CDK在该周期的各个阶段调节中起关键作用。因此，CDK及其相关细胞周期蛋白的抑制剂被认为是癌症治疗的有效靶向药物。
CDK4/6作为抗肿瘤靶点的优势在于：(1)CDK4/6抑制剂不表现出泛CDK抑制剂的细胞毒性，如骨髓抑制和肠道反应；(2)细胞cyclin D水平升高或者P161NK4a失活，能够增加细胞对药物的敏感性，肿瘤细胞相对于正常细胞存在上述现象，所以一定程度增加了药物的靶向性。
式I化合物是一种靶向型CDK4/6激酶抑制剂，能够选择性抑制细胞周期蛋白依赖性激酶4/6，恢复细胞周期控制，阻断肿瘤细胞增殖。
然而，式I化合物及其盐的水中溶解度约为40μg/mL，不溶或几乎不溶，这直接影响了该化合物在体内的吸收和生物利用度，因此需通过对处方、剂型及处方工艺进行层层筛选和优化，以获得具有优异的溶出度和生物利用度的药物组合物。
发明内容
本发明的目的在于提供一种稳定性良好、溶出迅速、生物利用度高的含有CDK4/6激酶抑制剂的药物组合物，并且该药物组合物的制备工艺简单，更适合工业化生产。
本发明解决上述技术问题的技术方案如下：
本发明的第一方面提供了一种药物组合物，其含有活性成分式I化合物或其可药用盐，以及药学上可接受的赋形剂，所述活性成分占药物组合物重量的25％～75％，
进一步的，所述式I化合物的盐为琥珀酸盐，所述赋形剂包括崩解剂、稀释剂或润滑剂中的一种或几种；
进一步的，所述稀释剂选自糖、糖醇、淀粉或纤维素中的一种或几种，所述稀释剂占药物组合物重量的15％～60％；
进一步的，所述崩解剂选自聚维酮类或纤维素类衍生物中的一种或几种，所述崩解剂占药物组合物重量的1％～15％；
进一步的，所述润滑剂选自滑石粉，所述润滑剂占药物组合物重量的0.1％～5％；
本发明的第二方面提供了一种药物组合物，按重量份数计，含有如下组分：
其中，所述稀释剂选自乳糖、微晶纤维素或淀粉中的一种或几种；所述崩解剂选自交联聚维酮或交联羧甲基纤维素钠中的一种或几种；所述润滑剂选自滑石粉；
在优选的实施方案中，本发明提供了一种药物组合物，按重量份数计，含有如下组分：
任选的，所述药物组合物中还可以包括矫味剂、着色剂或包衣剂中的一种或几种；
同时，为了保证药物组合物具有良好的生物利用度，本发明所述的药物组合物优选制成口服固体制剂，更优选制成片剂或胶囊剂；
本发明所述药物组合物的溶出度根据中国药典2020版四部通则0931法溶出度测定第二法(桨法)进行测定，所述活性成分的溶出度在30分钟大于或等于90％，优选大于或等于95％；
本发明的第三方面提供了两种上述药物组合物的制备方法：
第一种方法通过湿法制粒完成，包括如下步骤：
(1)在料斗混合机或湿法制粒机中预混合式I化合物或其盐和包括崩解剂在内的大多数赋形剂，获得预混合物；
(2)添加润湿剂，将步骤(1)预混合物在湿法制粒机或流化床中制粒；
(3)在流化床干燥器或干燥箱中干燥步骤(2)的颗粒；
(4)任选的，整粒机粉碎筛分步骤(3)的干燥颗粒；
(5)在料斗混合机混合步骤(4)的干燥颗粒与剩余赋形剂，获得最终混合物；
(6)任选的，通过合适的胶囊灌装机灌装上述步骤(5)的混合物，制备胶囊剂；
(7)任选的，通过合适的压片机压制上述步骤(5)的混合物，压片制得片芯；
(8)任选的，用膜包衣对步骤(7)的片芯进行薄膜包衣。
第二种方法通过干法制粒完成，包括如下步骤：
(1)在料斗混合机中混合式I化合物或其盐和包括崩解剂在内的大多数赋形剂，获得预混合物；
(2)在合适的干法制粒机中将步骤(1)的混合物压实获得带状物；
(3)用干法制粒机通过合适的粉碎或筛分步骤，将步骤(2)的带状物碎成颗粒；
(4)在混合机中混合步骤(3)和剩余赋形剂，获得最终混合物；
(5)任选的，通过合适的胶囊灌装机灌装上述步骤(4)的混合物，制备胶囊剂；
(6)任选的，通过合适的压片机压制上述步骤(4)的混合物，压片制得片芯；
(7)任选的，用膜包衣对步骤(6)的片芯进行薄膜包衣。
本发明的第四方面提供了上述药物组合物在制备治疗和预防增殖性紊乱引起的疾病或病症的药物中的用途，优选在制备抗癌症药物中的用途。
本发明中化合物的中文命名与结构式有冲突的，以结构式为准；结构式有明显错误的除外。
本发明的有益效果在于：本发明提供了一种以N-环戊基-5-(2-((5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)氨基)-5-氟嘧啶-4-基)-4-甲基噻唑-2-胺或其盐为活性成分的药物组合物，该药物组合物具有优异的溶出行为和良好的生物利用度，符合临床应用需求，并且该药物组合物杂质含量极低、稳定性较好，能够保证药物的安全性、有效性和质量可控性；同时制备工艺简单，有利于药物的规模化生产。
具体实施方式
以下结合实例说明本发明，但不限制本发明。在本领域内，技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
定义
术语“癌症”包括但不限于下述癌症：白血病、乳腺癌、卵巢癌、***、***癌、睾丸癌、食道癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、咽癌、唇癌、舌癌、口腔癌、咽喉癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑和中枢神经***癌症、恶性脑胶质瘤、膀胱癌、肝癌、肾癌、淋巴癌、神经内分泌肿瘤等。
实施例1：基准处方的筛选
难溶性药物开发成为口服固体制剂，由于药物溶解性较低，提高其在动物体内生物利用度显得尤为关键。在制剂处方筛选的动物体内试验中，设计真溶液组和混悬液组，分别与制剂处方的基准处方组进行对比。各处方组成及制备方法如下表所示。
将上述制备得到的各处方由食蟹猴经口给药，测试生物利用度，对处方进行预评价，结果如下表所示。食蟹猴口服胶囊制剂后的血浆药物暴露量较高，生物利用度均值为50％，相比真溶液组和混悬液组高出1倍，获得了意想不到的结果。通过动物体内试验对比，筛选出用于处方优化和工艺开发的基准处方，按药物组合物重量计，该基准处方包括40.0％式I化合物的琥珀酸盐、40.0％微晶纤维素、17.0％乳糖和3.0％交联聚维酮。
实施例2：处方的筛选优化
(1)单位处方组成(单位：mg)
注：“/”代表未添加
(2)制备
将上述1000片处方量式I化合物的琥珀酸盐和其他赋形剂投入料斗混合机混合均匀，中控含量、均匀度，灌装胶囊。
(3)质量评估
按处方表中的比例进行混合后，获得的制剂颗粒的松装密度在0.29～0.30g/cm3，休止角在46.67°至48.18°，尚需对处方工艺进行优化。
溶出度测定结果显示，对于100mg规格的胶囊，以上各处方30分钟溶出度均能符合预期要求。
实施例3：处方工艺的优化
(1)单位处方的组成(单位：mg)
(2)制备
将上述1000片处方量式I化合物的琥珀酸盐和其他赋形剂投入湿法制粒机中混合均匀后，湿法制粒、整粒，经流化床干燥后整粒，总混后获得总混颗粒，中控含量、均匀度，灌装胶囊。
(3)质量评估
影响因素试验考察，按照中国药典2020版对上述处方进行影响因素稳定性考察，于高温、高湿和光照条件下分别在第5天和第10天取样检测，检测结果如下表：
上述不同处方工艺获得的胶囊流动性较好，松装密度符合灌装要求，获得的胶囊成品在30分钟内溶出均符合要求。在高温、高湿和光照条件下进行影响因素试验考察，单杂和总杂均在可接受范围内，30分钟内的溶出也都符合要求。
实施例4：润滑剂的最优化
(1)单位处方的组成(单位：mg)
(2)制备
将上述1000片处方量式I化合物的琥珀酸盐和其他赋形剂投入湿法制粒机中混合均匀后，湿法制粒、整粒，经流化床干燥后整粒，总混后获得总混颗粒，中控含量、均匀度，灌装胶囊。
(3)溶出数据
(4)稳定性考察
按照原料药与制剂稳定性试验指导原则(中国药典2020版四部通则)对实施例4进行加速稳定性试验，在加速条件40±2℃/75％±5％RH下放置6个月，取样时间点为1、2、3及6月，检测结果，如下表所示。
上述实验结果可看出，本发明得到的组合物具有杂质含量低、溶出度高、稳定性好等优点。因药物溶出度测定结果与药物体内生物利用度密切相关，溶出度测定法能够用于对药物生物利用度进行评价以及研究替代。因此上述结果也表明，经过处方及工艺筛选后得到的含有细胞周期蛋白激酶抑制剂的药物组合物也具有良好的生物利用度，符合临床用药需求。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (4)
1.一种药物组合物，含有活性成分式I化合物可药用盐，以及药学上可接受的赋形剂，所述活性成分占药物组合物重量的25％～75％，所述式I化合物的盐为琥珀酸盐，所述赋形剂包括崩解剂、稀释剂和润滑剂，所述稀释剂为乳糖和微晶纤维素，所述稀释剂占药物组合物重量的15％～60％，所述崩解剂为交联聚维酮，所述崩解剂占药物组合物重量的1％～15％，所述润滑剂选自滑石粉，所述润滑剂占药物组合物重量的0.1％～5％，
2.一种药物组合物，其特征在于，按重量份数计，含有如下组分：
其中，所述稀释剂为乳糖和微晶纤维素；所述崩解剂选自交联聚维酮；所述润滑剂选自滑石粉。
3.根据权利要求1～2任一项所述的药物组合物，其特征在于，所述药物组合物的溶出度根据中国药典2020版四部通则0931法溶出度测定第二法(桨法)进行测定，所述活性成分的溶出度在30分钟大于或等于90％。
4.根据权利要求1～2任一项所述的药物组合物在制备抗癌症药物中的用途。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111451044.2A CN114028400B (zh) | 2021-12-01 | 2021-12-01 | 一种含有细胞周期蛋白激酶抑制剂的药物组合物及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111451044.2A CN114028400B (zh) | 2021-12-01 | 2021-12-01 | 一种含有细胞周期蛋白激酶抑制剂的药物组合物及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114028400A CN114028400A (zh) | 2022-02-11 |
| CN114028400B true CN114028400B (zh) | 2023-10-31 |
Family
ID=80139425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111451044.2A Active CN114028400B (zh) | 2021-12-01 | 2021-12-01 | 一种含有细胞周期蛋白激酶抑制剂的药物组合物及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114028400B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115636826A (zh) * | 2022-10-31 | 2023-01-24 | 常州英诺升康生物医药科技有限公司 | 一种cdk抑制剂的制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108349964A (zh) * | 2015-08-04 | 2018-07-31 | 常州千红生化制药股份有限公司 | N-（吡啶-2-基）-4-（噻唑-5-基）嘧啶-2-胺类化合物作为治疗性化合物 |
| CN112239466A (zh) * | 2020-11-10 | 2021-01-19 | 常州千红生化制药股份有限公司 | 选择性cdk4/6抑制剂的琥珀酸盐及其晶型 |
| WO2021222967A1 (en) * | 2020-05-06 | 2021-11-11 | Aucentra Therapeutics Pty Ltd | Treatment of proliferative diseases of the cns |
-
2021
- 2021-12-01 CN CN202111451044.2A patent/CN114028400B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108349964A (zh) * | 2015-08-04 | 2018-07-31 | 常州千红生化制药股份有限公司 | N-（吡啶-2-基）-4-（噻唑-5-基）嘧啶-2-胺类化合物作为治疗性化合物 |
| WO2021222967A1 (en) * | 2020-05-06 | 2021-11-11 | Aucentra Therapeutics Pty Ltd | Treatment of proliferative diseases of the cns |
| CN112239466A (zh) * | 2020-11-10 | 2021-01-19 | 常州千红生化制药股份有限公司 | 选择性cdk4/6抑制剂的琥珀酸盐及其晶型 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114028400A (zh) | 2022-02-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102036962B (zh) | 血管生成抑制剂和紫杉烷的组合使用 | |
| CN109776432B (zh) | 一种多靶点激酶抑制剂、药物组合物及多靶点激酶抑制剂的制备方法和应用 | |
| CN105748435B (zh) | 一种帕布昔利布药物组合物及其制备方法 | |
| CN106687117A (zh) | 利用噻吩并***并二氮杂*化合物治疗耐受性非霍奇金淋巴瘤、髓母细胞瘤和/或alk+非小细胞肺癌的方法 | |
| CN113508114B (zh) | 以氮杂环丁烷衍生物为活性成分的口服药物组合物、其制备方法及用途 | |
| CN106852120A (zh) | 利用噻吩并***并二氮杂*化合物治疗三阴性乳腺癌的方法 | |
| CN114028400B (zh) | 一种含有细胞周期蛋白激酶抑制剂的药物组合物及其制备方法 | |
| TWI704918B (zh) | 含有細胞周期蛋白抑制劑的藥物製劑及其製備方法 | |
| CN110179796B (zh) | 一种苯并呋喃类衍生物的组合物及制备方法 | |
| KR20120099219A (ko) | 조합물 | |
| KR20180036633A (ko) | 용출율이 향상된 라록시펜, 및 비타민 d 또는 그 유도체를 포함하는 복합 캡슐제 및 이의 제조방법 | |
| TWI738729B (zh) | 一種含有吡咯并六員雜環化合物或其可藥用鹽的藥物組成物的製備方法 | |
| CN112552287B (zh) | 一种吲哚类衍生物药物制剂及其制备方法 | |
| CN105813643A (zh) | 利用含有噻吩并***二氮杂*化合物的药物制剂治疗非小细胞肺癌的方法 | |
| KR20230131253A (ko) | 리디닐라졸의 고체 정제 투여 형태 | |
| Lavan et al. | Development of a Pediatric Mini-Tablet Formulation for Expedited Preclinical Studies | |
| US10973807B2 (en) | Pharmaceutical composition comprising pyrrolo-fused six-membered heterocyclic compound | |
| CN112675171B (zh) | 抑制vegfr活性化合物药物制剂及其制备方法 | |
| WO2022042738A1 (zh) | 一种含cdk4/6抑制剂的药物组合物 | |
| WO2023186031A1 (zh) | 多靶点蛋白激酶抑制剂的药物组合物及其用途和制备方法 | |
| CN107648237B (zh) | 氨基嘧啶类化合物的药物组合物及其制备方法 | |
| CN114699374B (zh) | 一种猫犬专用盐酸氟西汀固体制剂及其制备和应用 | |
| CN117298115A (zh) | CDKs抑制剂的药物组合物及制备方法 | |
| CN114832112A (zh) | 含有alk激酶抑制剂的药物制剂组合物及其制备方法 | |
| JP2024501690A (ja) | 多標的タンパク質キナーゼ阻害剤の医薬組成物及びその使用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |