CN113133978A - Azilsartan tablets and preparation method thereof - Google Patents
Azilsartan tablets and preparation method thereof Download PDFInfo
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- CN113133978A CN113133978A CN202010063919.0A CN202010063919A CN113133978A CN 113133978 A CN113133978 A CN 113133978A CN 202010063919 A CN202010063919 A CN 202010063919A CN 113133978 A CN113133978 A CN 113133978A
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- Prior art keywords
- azilsartan
- tablets
- granulation
- stearic acid
- fluidized bed
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- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 title claims abstract description 153
- 239000005485 Azilsartan Substances 0.000 title claims abstract description 152
- 229960002731 azilsartan Drugs 0.000 title claims abstract description 152
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 34
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000008117 stearic acid Substances 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 20
- 229960003511 macrogol Drugs 0.000 claims abstract description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 239000008187 granular material Substances 0.000 claims description 30
- 238000005469 granulation Methods 0.000 claims description 28
- 230000003179 granulation Effects 0.000 claims description 28
- 238000007909 melt granulation Methods 0.000 claims description 21
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 19
- 239000002202 Polyethylene glycol Substances 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- 238000002844 melting Methods 0.000 claims description 16
- 230000008018 melting Effects 0.000 claims description 16
- 229920001223 polyethylene glycol Polymers 0.000 claims description 16
- 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 15
- 229930195725 Mannitol Natural products 0.000 claims description 15
- 239000000594 mannitol Substances 0.000 claims description 15
- 235000010355 mannitol Nutrition 0.000 claims description 15
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 14
- 125000005456 glyceride group Chemical group 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 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
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 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
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 229940075529 glyceryl stearate Drugs 0.000 claims 1
- 239000000155 melt Substances 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000007873 sieving Methods 0.000 description 30
- 239000012535 impurity Substances 0.000 description 20
- 238000002156 mixing Methods 0.000 description 19
- 238000004090 dissolution Methods 0.000 description 17
- 239000003814 drug Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012085 test solution Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000003861 C09CA09 - Azilsartan medoxomil Substances 0.000 description 6
- 229960001211 azilsartan medoxomil Drugs 0.000 description 6
- QJFSABGVXDWMIW-UHFFFAOYSA-N azilsartan medoxomil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C=3NC(=O)ON=3)C(OCC)=NC2=CC=CC=1C(=O)OCC=1OC(=O)OC=1C QJFSABGVXDWMIW-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 239000007779 soft material Substances 0.000 description 5
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 238000007907 direct compression Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229940100242 glycol stearate Drugs 0.000 description 4
- 239000002932 luster Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 210000001630 jejunum Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229940044476 poloxamer 407 Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- ANRFTTXEGCYVMQ-UHFFFAOYSA-L C(C=CC(=O)[O-])(=O)[O-].[Na+].C(CCCCCCCCCCCCCCCCC)(=O)O.[Na+] Chemical compound C(C=CC(=O)[O-])(=O)[O-].[Na+].C(CCCCCCCCCCCCCCCCC)(=O)O.[Na+] ANRFTTXEGCYVMQ-UHFFFAOYSA-L 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 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 description 1
- 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 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000059 polyethylene glycol stearate Polymers 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- ROBLTDOHDSGGDT-UHFFFAOYSA-M sodium;pentane-1-sulfonate Chemical compound [Na+].CCCCCS([O-])(=O)=O ROBLTDOHDSGGDT-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000004562 water dispersible granule Substances 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an azilsartan tablet, which is prepared from stearic acid macrogol glyceride; the azilsartan tablets prepared by the method have high solubility and stability. In addition, the preparation process provided by the invention is simple and efficient, the azilsartan raw material does not need to be subjected to micronization treatment, and is not dissolved by using an organic solvent, so that the process steps can be reduced, and the environmental protection is facilitated; the preparation process does not contact redundant water, so that the azilsartan can be effectively prevented from being degraded in a high-humidity environment, and the prepared azilsartan tablets have good stability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to azilsartan tablets, a preparation method thereof and application thereof in treating diseases such as hypertension.
Background
Azilsartan (the english name Azilsartan) is an angiotensin II receptor antagonist drug for treating hypertension, blocks the vasoconstrictive action of angiotensin II by selectively blocking the binding of angiotensin II with vascular smooth muscle AT1 receptors, and is mostly used for treating hypertension. The prodrug azilsartan medoxomil obtains FDA approval in 2011, 2 months and 25 days, and has the chemical name of 2-ethoxy-1- [ [ 2' - (4, 5-dihydro-5-oxo-1, 2, 4-oxadiazole-3-yl) biphenyl-4-yl ] methyl ] benzimidazole-7-carboxylic acid. The use of azilsartan is approved on 1 month and 18 days in 2012, the medicine is orally taken, is taken once a day, and can be used independently or together with other blood pressure lowering medicines. During absorption azilsartan medoxomil is hydrolyzed in the gastrointestinal tract to the active metabolite azilsartan. Clinical test results show that compared with the common hypertension therapeutic drugs of the same type, namely valsartan and olmesartan, the azilsartan has better blood pressure reducing effect within 24 hours.
However, azilsartan is hardly soluble in water, belongs to a poorly soluble drug, and has a solubility of about 6mg/L (20 ℃) in water. Generally, the oral bioavailability of poorly soluble drugs is low, and although many attempts can be made to improve the bioavailability, the improvement of the dissolution rate of the drug is an effective way to improve the bioavailability. Therefore, the solubility of the compound is improved by a preparation technology to meet the requirements of dissolution rate and stability, so that the product is ensured to effectively exert the treatment effect, and the preparation method has very important significance and value.
Patent document CN104306344A discloses an azilsartan tablet and a preparation method thereof, wherein the azilsartan tablet is prepared by compressing azilsartan, microcrystalline cellulose, KG1000 and other pharmaceutically acceptable auxiliary materials by a dry direct compression process. Although the introduction of moisture can be effectively avoided, and the stability of the product is ensured, the azilsartan before mixing needs micronization, so that the process steps are increased to a certain extent, and certain dust influence is generated on the production environment.
Patent document CN104523632A discloses an azilsartan tablet, which is prepared by dissolving azilsartan and povidone in diethylene glycol ethyl ether, adding silicon dioxide for adsorption, and mixing with other adjuvants for direct compression. However, the azilsartan tablets directly pressed by powder are difficult to ensure the mixing uniformity although the process is simple, and the problem of in vitro dissolution is not substantially solved because the layering phenomenon is easily generated in the tabletting process.
Patent document CN106333930A discloses an azilsartan pellet tablet and a preparation method thereof, the azilsartan pellet tablet is prepared by tabletting azilsartan pellets and pharmaceutical excipients, and the dissolution rate and bioavailability of a medicament are improved, but in the preparation process of the azilsartan pellet tablet, the medicament may generate crystal form transformation in the preparation process, and in addition, the process steps are complex and are difficult to apply to industrial production.
Therefore, although many documents disclose formulation products for improving the solubility of azilsartan and preparation methods thereof, there are still more or less disadvantages, and for azilsartan formulation products with large market demands, research is still needed to provide formulation products with excellent biocompatibility and drug efficacy and convenient and efficient preparation processes suitable for industrialization.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an azilsartan tablet which has the advantages of good dissolution characteristic, high stability, simple preparation process and high efficiency. Through a large amount of creative thinking and experiments, the inventor finds that the dissolution of the azilsartan tablets can be remarkably improved by adding the water dispersible granules of the polyethylene glycol stearate into the formula, but the azilsartan tablets still do not reach an ideal state. The absorption part of the azilsartan medoxomil in the intestinal tract is mainly the jejunum, the physiological pH of the jejunum is 5.5-7.0, and the azilsartan medoxomil can be completely dissolved out in a buffer solution with the pH of 6.0, so that the optimal absorption and utilization effects of the medicine can be ensured.
In the research process of the preparation process, the process is not selected because the process is found that although the dissolution rate is improved by crushing the medicament and the auxiliary materials together, the method sacrifices the fluidity of the granules, the granule weight is possibly unstable during filling, and meanwhile, the medicament particles are easy to aggregate. The fluidized bed process technology and the staged feeding mode can be used for keeping the particle fluidity and avoiding the problem of nonuniform mixing, and the obtained tablet product has better dissolution property.
The specific technical content of the invention is as follows:
on one hand, the invention provides an azilsartan tablet, which is characterized by comprising azilsartan, stearic acid macrogolglyceride and pharmaceutically acceptable auxiliary materials.
Preferably, the weight ratio of the azilsartan to the stearic acid macrogolglyceride in the azilsartan tablet is 1: 1-3; preferably in a weight ratio of 1: 2.
Preferably, the pharmaceutically acceptable auxiliary materials are a filler, a disintegrant and a lubricant.
More preferably, the filler is one or the combination of mannitol, microcrystalline cellulose, lactose, starch, dextrin and polyethylene glycol; preferably mannitol; the weight ratio of the azilsartan to the filler is 1: 2-10, preferably 1: 3 to 5.
Further preferably, the disintegrant is one or a combination of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose; preferably low-substituted hydroxypropyl cellulose; the weight ratio of the azilsartan and the disintegrant is 1: 0.1 to 1, preferably 1: 0.2 to 0.5.
Further preferably, the lubricant is one or a combination of hydrogenated castor oil, sodium fumarate stearate, talcum powder and magnesium stearate; preferably magnesium stearate; the weight ratio of the azilsartan to the lubricant is 1: 0.01 to 0.5; preferably 1: 0.05 to 0.1.
Preferably, the azilsartan tablet comprises the following components:
further preferably, the azilsartan tablets comprise the following components:
on the other hand, the invention provides a preparation method of azilsartan tablets, which comprises the following specific preparation processes:
adding azilsartan and partial stearic acid polyethylene glycol glyceride in a formula amount into a fluidized bed, melting and heating, and performing melt granulation in the fluidized bed; immediately adding the filler, the disintegrant and the rest of the stearic acid macrogol glyceride after melt granulation, continuing granulation, finishing granules when the granulation is finished, then adding the lubricant, and tabletting to obtain the azilsartan tablets.
Preferably, the partially stearic acid polyethylene glycol glyceride is 50-60% of the prescription amount.
Preferably, the temperature of the melting and heating is 45-60 ℃, and preferably 50 ℃.
Preferably, the time for melt granulation is 3-7 min.
Compared with the prior art, the invention has the following advantages:
(1) the azilsartan tablets are prepared by using the stearic acid macrogol glyceride, and the medicine is high in dissolution speed in a buffer solution with the pH value of 6.0 and high in bioavailability.
(2) The azilsartan tablets prepared by the method have high solubility, the dissolution rate after accelerated test is still more than 98%, and the azilsartan tablets show good dissolution property and stability.
(3) The preparation process provided by the invention is simple and efficient, the azilsartan raw material does not need micronization treatment, and does not need to be dissolved by using an organic solvent, so that the process steps can be reduced, and the environment protection is facilitated.
(4) The preparation process provided by the invention does not contact redundant moisture, so that the azilsartan can be effectively prevented from being degraded in a high-humidity environment, and the prepared azilsartan tablets have good stability.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 20g of stearic acid macrogolglyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding 20g of mannitol, low-substituted hydroxypropyl cellulose and the rest of polyethylene glycol stearate, continuously granulating for 5min, sieving the granules with a 20-mesh sieve while the granules are hot after the granulation is finished, grading, adding magnesium stearate, uniformly mixing and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets are complete and smooth in appearance and uniform in color and luster.
Example 2
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 10g of stearic acid polyethylene glycol glyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 3min, immediately adding mannitol, low-substituted hydroxypropyl cellulose and 10g of the rest of stearic acid macrogol glyceride, continuously granulating for 8min, sieving the granules with a 20-mesh sieve for granulation while the granules are hot after granulation is finished, adding magnesium stearate, uniformly mixing and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets are complete and smooth in appearance and uniform in color and luster.
Example 3
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 30g of stearic acid polyethylene glycol glyceride in a formula amount into a fluidized bed, setting the temperature to be 60 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 7min, immediately adding mannitol, low-substituted hydroxypropyl cellulose and 30g of the rest of stearic acid macrogol glyceride, continuously granulating for 3min, sieving the granules with a 20-mesh sieve for granulation while the granules are hot after granulation is finished, adding magnesium stearate, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets are complete and smooth in appearance and uniform in color.
Example 4
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 20g of stearic acid macrogolglyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding 20g of lactose, crospovidone and the rest of the stearic acid macrogol glyceride, continuously granulating for 5min, sieving granules with a 20-mesh sieve while the granules are hot after the granulation is finished, then adding hydrogenated castor oil, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the tablets are complete and smooth in appearance and uniform in color and luster.
Example 5
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 20g of stearic acid macrogolglyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding 20g of starch, croscarmellose sodium and the rest of stearic acid macrogol glyceride, continuously granulating for 3min, sieving granules with a 20-mesh sieve for granulation while the granules are hot after granulation is finished, then adding sodium stearate fumarate, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the tablets are complete and smooth in appearance and uniform in color.
Example 6
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 12g of stearic acid polyethylene glycol glyceride in a formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 3min, immediately adding microcrystalline cellulose, sodium carboxymethyl starch and 8g of the rest of stearic acid macrogol glyceride, continuously granulating for 5min, sieving the granules with a 20-mesh sieve for granulation while the granules are hot after the granulation is finished, then adding talcum powder, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets are complete and smooth in appearance and uniform in color.
Example 7
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 5g of stearic acid macrogolglyceride according to the formula amount into a fluidized bed, setting the temperature to be 45 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 3min, immediately adding mannitol, low-substituted hydroxypropyl cellulose and 5g of the rest of stearic acid macrogol glyceride, continuously granulating for 3min, sieving the granules with a 20-mesh sieve for granulation while the granules are hot after granulation is finished, adding magnesium stearate, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets are complete and smooth in appearance and uniform in color.
Example 8
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 20g of stearic acid macrogolglyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) carrying out melt granulation for 3min, immediately adding 20g of mannitol, low-substituted hydroxypropyl cellulose and the rest of polyethylene glycol stearate, continuing granulation for 3min, sieving granules with a 20-mesh sieve while the granules are hot after granulation is finished, grading, adding magnesium stearate, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the tablets have complete appearance and a few cracks and are nonuniform in color.
Example 9
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 28g of stearic acid polyethylene glycol glyceride in a formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding mannitol, low-substituted hydroxypropyl cellulose and 12g of the rest of stearic acid macrogol glyceride, continuously granulating for 5min, sieving the granules with a 20-mesh sieve for granulation after granulation is finished, adding magnesium stearate, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the tablets have complete appearance and a few cracks and are nonuniform in color.
Example 10
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 16g of stearic acid polyethylene glycol glyceride in a formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding 24g of mannitol, low-substituted hydroxypropyl cellulose and the rest of stearic acid macrogol glyceride, continuously granulating for 5min, sieving the granules with a 20-mesh sieve for granulation after granulation is finished, adding magnesium stearate, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the tablets have complete appearance and a few cracks and are nonuniform in color.
Example 11
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 20g of stearic acid macrogolglyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding pregelatinized starch, cross-linked polyvinylpyrrolidone and 20g of the rest of the stearin, continuously granulating for 5min, sieving the granules with a 20-mesh sieve for granulation after the granules are hot, adding superfine silica gel powder, uniformly mixing, and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets have good integral appearance and are occasionally cracked.
Example 12
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 20g of stearic acid macrogolglyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding 20g of sorbitol, sodium alginate and the rest of the polyoxyethylene glycol stearate, continuously granulating for 5min, sieving the granules with a 20-mesh sieve for granulation when the granules are hot after granulation is finished, then adding magnesium stearate, uniformly mixing and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets have good integral appearance and are occasionally cracked.
Example 13
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 10g of stearic acid polyethylene glycol glyceride according to the formula amount into a fluidized bed, setting the temperature to be 50 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding mannitol, low-substituted hydroxypropyl cellulose and 10g of the rest of stearic acid macrogol glyceride, continuously granulating for 5min, sieving the granules with a 20-mesh sieve for granulation when the granules are hot after granulation is finished, adding magnesium stearate, uniformly mixing and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets are complete and smooth in appearance and uniform in color and luster.
Comparative example 1 (prescription of stearic acid-free polyethylene glycol glyceride)
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. The formula amount of the azilsartan, the anhydrous direct-compression lactose, the mannitol and the low-substituted hydroxypropyl cellulose are uniformly mixed, then the magnesium stearate is added, the mixture is uniformly mixed, and the azilsartan tablet is obtained by tabletting, wherein the azilsartan tablet has good overall appearance and is occasionally cracked.
COMPARATIVE EXAMPLE 2 (PREPARATION PROCESS, WET-MIXING)
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. The azilsartan, the stearic acid macrogol glyceride, the mannitol and the low-substituted hydroxypropyl cellulose in the formula amount are uniformly mixed, 40ml of 5% hydroxypropyl cellulose aqueous solution is used for preparing a soft material, the soft material is sieved by a 20-mesh sieve for size stabilization, the soft material is dried at 40 ℃ for 1h, then the stearic acid sodium fumarate is added, the soft material and the soft material are uniformly mixed, and tabletting is carried out to obtain the azilsartan tablets.
Comparative example 3
The preparation process comprises the following steps: and carrying out micronization on azilsartan for later use. The formula amount of the azilsartan, the anhydrous direct-compression lactose, the mannitol and the low-substituted hydroxypropyl cellulose are uniformly mixed, then the magnesium stearate is added, the mixture is uniformly mixed, and the azilsartan tablet is obtained by tabletting, wherein the azilsartan tablet has good overall appearance and is occasionally cracked.
Comparative example 4
The preparation process comprises the following steps: and crushing the azilsartan and sieving the crushed azilsartan with a 80-mesh sieve for later use. Adding azilsartan and 25g of poloxamer 407 in a prescription amount into a fluidized bed, setting the temperature to be 45 ℃, and carrying out melt granulation in the fluidized bed; and (3) melting and granulating for 5min, immediately adding mannitol, crospovidone and the rest of poloxamer 407, continuously granulating for 5min, sieving the granules with a 20-mesh sieve for finishing granulation while the granules are hot, then adding magnesium stearate, uniformly mixing and tabletting to obtain the azilsartan tablets, wherein the azilsartan tablets are complete and smooth in appearance and uniform in color.
Comparative example 5
The preparation process comprises the following steps: the azilsartan is subjected to jet milling, then the azilsartan is weighed according to the prescription and fed, then the azilsartan and microcrystalline cellulose KG1000 according to the prescription are uniformly mixed in a mixer, then the crospovidone, lactose 80 and magnesium stearate according to the prescription are added and uniformly mixed, and finally the azilsartan tablets are obtained through tabletting, wherein the overall appearance of the tablets is good.
Dissolution determination
The dissolution rate is measured according to the second method of 0931, which is the appendix of the four parts of the book of Chinese pharmacopoeia 2015 edition, and specifically comprises the following steps: taking 900ml of phosphate buffer solution with pH of 6.0 as a dissolution medium, rotating at 50 revolutions per minute, operating according to the method, sampling 10ml at 15 minutes, filtering, taking 5ml of subsequent filtrate, placing in a 10ml volumetric flask, adding phosphate buffer solution with pH of 6.0 to dilute to scale, shaking up, taking as a test solution, and measuring absorbance at 247nm wavelength by ultraviolet-visible spectrophotometry (appendix 0401 of four parts of Chinese pharmacopoeia 2015 year edition). Taking another appropriate amount of azilsartan reference substance, adding methanol to dissolve and dilute the azilsartan reference substance to prepare a solution containing about 1mg of azilsartan reference substance per 1ml, precisely measuring 1ml, placing the solution in a 100ml volumetric flask, adding phosphate buffer solution with pH6.0 to dilute the solution to a scale, shaking the solution uniformly to serve as reference substance solution, and determining by the same method. The amount of elution should not be less than 75% per tablet.
TABLE 1 dissolution rate test results of azilsartan tablets
The experimental result shows that the azilsartan medoxomil tablet prepared by the invention is fast in dissolution, the dissolution rate in 15min is more than 99%, and the azilsartan medoxomil tablet still keeps good dissolution characteristics after accelerated experiments.
Stability survey
And (3) related substance detection: taking 20 tablets of the product, grinding, taking a proper amount of fine powder (about 10mg of azilsartan), putting the fine powder into a 20ml brown measuring flask, adding methanol to dissolve and dilute the fine powder to a scale, shaking up, filtering, and taking a subsequent filtrate as a test solution; precisely measuring 1ml of the test solution, placing the test solution in a 100ml brown measuring flask, adding methanol to dilute the test solution to a scale, and shaking the test solution uniformly to serve as a control solution. Performing high performance liquid chromatography (appendix VD of the second part of the 2010 edition of Chinese pharmacopoeia). Octadecylsilane chemically bonded silica is used as a filling agent; mobile phase a was pH3.0 buffer (1.36 g potassium dihydrogen phosphate and 1.74g sodium pentane sulfonate were weighed, dissolved by adding 1000ml water, pH was adjusted to 3.0 with phosphoric acid), mobile phase B was acetonitrile, and linear gradient elution was performed with a detection wavelength of 251 nm. In addition, an appropriate amount of impurity 1, impurity 2, impurity 3, impurity 4, impurity 5 and azilsartan reference substance are respectively weighed, and methanol is added for dissolving and diluting to prepare a solution containing 0.5mg of azilsartan and 5 micrograms of known impurities per 1ml, and the solution is used as a system test solution; and precisely measuring 10 mu l of system test solution, injecting the system test solution into a liquid chromatograph, recording a chromatogram, and sequentially outputting peaks of the impurity 2, the impurity 1, the azilsartan, the impurity 3, the impurity 5 and the impurity 4, wherein the separation degree among the peaks of the substances meets the requirement. Injecting 10 mul of the contrast solution into a liquid chromatograph, and adjusting the detection sensitivity to ensure that the peak height of the main component chromatographic peak is 10-25% of the full scale; then precisely measuring 10 mul of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram. After deducting the solvent peak, an impurity peak exists in a chromatogram of the sample solution, wherein the peak areas of the impurity 2 and the impurity 5 are not more than 0.5 times (0.5%) of the main peak area of the control solution, the peak areas of the impurity 1, the impurity 3 and the impurity 4 are not more than 0.2 times (0.2%) of the main peak area of the control solution, the peak areas of the other largest single impurities are not more than 0.2 times (0.2%) of the main peak area of the control solution, and the sum of the peak areas of the impurities is not more than 1.5 times (1.5%) of the main peak area of the control solution.
Table 2 results of azilsartan tablet stability experiment
According to experimental results, the azilsartan related substance prepared by the invention is small in total impurity, and the related substance is basically unchanged after accelerated experiments in all the examples, so that the azilsartan related substance embodies good stability.
Claims (10)
1. The azilsartan tablet is characterized by comprising azilsartan and stearic acid macrogolglyceride.
2. The azilsartan tablet according to claim 1, wherein the weight ratio of the azilsartan to the polyethylene glycol glyceryl stearate is 1: 1-3.
3. Azilsartan tablets according to claim 1, further comprising pharmaceutically acceptable excipients which may be fillers, disintegrants, lubricants.
4. Azilsartan tablets according to claim 3, wherein the filler is selected from one or a combination of mannitol, microcrystalline cellulose, lactose, starch, dextrin, polyethylene glycol.
5. Azilsartan tablets according to claim 3, wherein the disintegrant is selected from one or a combination of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose.
6. Azilsartan tablets according to claim 3, wherein the lubricant is selected from one or a combination of magnesium stearate, hydrogenated castor oil, sodium fumarate stearate, talc and silica.
7. A preparation method of azilsartan tablets as claimed in any of claims 1 to 6, characterized by comprising the following specific preparation processes: adding azilsartan and partial stearic acid polyethylene glycol glyceride in a formula amount into a fluidized bed, melting and heating, and performing melt granulation in the fluidized bed; immediately adding the filler, the disintegrant and the rest of the stearic acid macrogol glyceride after melt granulation, continuing granulation, finishing granules when the granulation is finished, then adding the lubricant, and tabletting to obtain the azilsartan tablets.
8. The method of claim 6, wherein the partially stearic acid macrogol glyceride is 50% to 60% of the prescribed amount.
9. The method according to claim 6, wherein the temperature of the melt heating is 45 to 60 ℃.
10. The method according to claim 6, wherein the time for melt granulation is 3 to 7 min.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046154A (en) * | 2008-06-03 | 2011-05-04 | 诺瓦提斯公司 | Pulsatile release of valsartan |
| CN105708809A (en) * | 2015-05-09 | 2016-06-29 | 张秋野 | Hot-melt granulation method of pharmaceutical adjuvant of controlled/slow-released agent |
| CN106176604A (en) * | 2016-08-30 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of Azilsartan potassium salt self-micro emulsion formulation and preparation method thereof |
| CN106389428A (en) * | 2016-10-11 | 2017-02-15 | 上海现代制药股份有限公司 | Composition capable of improving Azilsartan bioavailability and stability and preparation method of composition |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046154A (en) * | 2008-06-03 | 2011-05-04 | 诺瓦提斯公司 | Pulsatile release of valsartan |
| CN105708809A (en) * | 2015-05-09 | 2016-06-29 | 张秋野 | Hot-melt granulation method of pharmaceutical adjuvant of controlled/slow-released agent |
| CN106176604A (en) * | 2016-08-30 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of Azilsartan potassium salt self-micro emulsion formulation and preparation method thereof |
| CN106389428A (en) * | 2016-10-11 | 2017-02-15 | 上海现代制药股份有限公司 | Composition capable of improving Azilsartan bioavailability and stability and preparation method of composition |
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