CN113456601A - Preparation method of candesartan cilexetil hydrochlorothiazide compound tablet - Google Patents
Preparation method of candesartan cilexetil hydrochlorothiazide compound tablet Download PDFInfo
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- CN113456601A CN113456601A CN202110575869.9A CN202110575869A CN113456601A CN 113456601 A CN113456601 A CN 113456601A CN 202110575869 A CN202110575869 A CN 202110575869A CN 113456601 A CN113456601 A CN 113456601A
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- Prior art keywords
- candesartan cilexetil
- hydrochlorothiazide
- aqueous solution
- preparation
- compound tablet
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- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 79
- 229960002003 hydrochlorothiazide Drugs 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- -1 candesartan cilexetil hydrochlorothiazide compound Chemical class 0.000 title claims abstract description 13
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 claims abstract description 69
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000000463 material Substances 0.000 claims abstract description 21
- 239000007864 aqueous solution Substances 0.000 claims abstract description 19
- 239000000725 suspension Substances 0.000 claims abstract description 18
- 239000000853 adhesive Substances 0.000 claims abstract description 13
- 230000001070 adhesive effect Effects 0.000 claims abstract description 13
- 239000003381 stabilizer Substances 0.000 claims abstract description 12
- 239000008187 granular material Substances 0.000 claims abstract description 11
- 238000005507 spraying Methods 0.000 claims abstract description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 238000005469 granulation Methods 0.000 claims description 17
- 230000003179 granulation Effects 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 14
- 238000007873 sieving Methods 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 229920002261 Corn starch Polymers 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 239000008120 corn starch Substances 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 9
- 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 9
- 239000008101 lactose Substances 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000003086 colorant Substances 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229940099112 cornstarch Drugs 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 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 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 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 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229940067573 brown iron oxide Drugs 0.000 claims 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 16
- 239000006185 dispersion Substances 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 230000008569 process Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 229960001375 lactose Drugs 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 235000013980 iron oxide Nutrition 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000004080 punching Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960002478 aldosterone Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-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
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010018366 Glomerulonephritis acute Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 231100000851 acute glomerulonephritis Toxicity 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229940112147 atacand hct Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010064 diabetes insipidus Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a candesartan cilexetil hydrochlorothiazide compound tablet, which comprises the steps of adding candesartan cilexetil into an adhesive aqueous solution or an adhesive aqueous solution added with a stabilizer to prepare a suspension, spraying the suspension into an auxiliary material by adopting a fluidized bed to granulate, and tabletting after adding hydrochlorothiazide, wherein the prepared tablet is high in uniformity. The dispersion degree of the candesartan cilexetil can be improved by adding the candesartan cilexetil into the aqueous solution of the adhesive to prepare a suspension, the hydrochlorothiazide is added into the prepared granules of the candesartan cilexetil, the direct contact area of the hydrochlorothiazide and the candesartan cilexetil is reduced, the dissolution behavior of the candesartan cilexetil is improved, and the content uniformity of the obtained sample is high.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to candesartan cilexetil hydrochlorothiazide tablets and a preparation method thereof.
Background
Candesartan cilexetil (also known as Candesartan cilexetil, Candesartan cilexetil). Is a new novel antihypertensive drug which specifically blocks the vasoconstriction and aldosterone secretion mediated by angiotensin II to lower blood pressure, is a white crystalline powder, is readily soluble in chloroform, is slightly soluble in anhydrous ethanol, and is practically insoluble in water. The structural formula is as follows:
candesartan cilexetil is a drug which is difficult to dissolve in water, and in order to improve the bioavailability of the difficult-to-dissolve drug, patent application CN101890024A discloses a composition containing a solid dispersion and a preparation method thereof, all raw and auxiliary materials need to be crushed, the sieving process adopted for making the appearance color of the tablet surface uniform is relatively complex, the temperature of the dried material is preferably higher than 50-60 ℃, and certain risk exists in the stability of the material.
Hydrochlorothiazide (6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide-1, 1-dioxide, hydrochlorothiazide) which is soluble in acetone, slightly soluble in ethanol, and insoluble in water, chloroform or diethyl ether; dissolving in sodium hydroxide solution. The structural formula is as follows:
hydrochlorothiazide is a diuretic and antihypertensive drug. It is mainly applicable to cardiogenic edema, hepatogenic edema and renal edema: such as nephrotic syndrome, acute glomerulonephritis, chronic renal failure and edema caused by an excess of adrenocortical hormone and estrogen; hypertension; diabetes insipidus. The potassium salt is preferably supplemented for long-term application. The action mechanism is that the reabsorption of electrolyte by renal tubules is influenced, the secretion of sodium ions and chloride ions is directly increased, the urine volume is increased, and the blood volume is reduced. Meanwhile, hydrochlorothiazide reduces plasma volume through the diuretic effect, indirectly increases the activity of plasma renin, increases aldosterone secretion, increases urinary potassium excretion and reduces blood potassium. The action of the renin-aldosterone system is angiotensin II mediated, and therefore, hydrochlorothiazide in combination with the angiotensin II receptor antagonist candesartan cilexetil enhances the pharmacological effect and reverses the potassium deprivation effects of hydrochlorothiazide.
Patent application CN1714789A discloses a candesartan cilexetil hydrochlorothiazide dispersible tablet and a preparation method thereof. Weighing candesartan cilexetil, hydrochlorothiazide, lactose, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, aerosil, magnesium stearate and the like, uniformly mixing, adding 2% hydroxypropyl methyl cellulose to prepare a soft material, granulating by using a sieve of 18-24 meshes, drying at 40-60 ℃, and then finishing by using a sieve of 16-24 meshes; adding magnesium stearate or silica gel micropowder, mixing, and tabletting. The candesartan cilexetil and hydrochlorothiazide dispersible tablet has the characteristics of rapid disintegration in water, uniform dispersion, high dissolution rate, rapid absorption after administration and the like.
Patent application CN101612151A discloses a solid oral preparation containing candesartan cilexetil or candesartan cilexetil hydrochlorothiazide and a preparation method thereof. The solid oral preparation containing the candesartan cilexetil or the candesartan cilexetil hydrochlorothiazide comprises the following components in percentage by weight: 1 to 25 percent of candesartan cilexetil, 0 to 20 percent of hydrochlorothiazide, 3 to 75 percent of filling agent, 0.5 to 30 percent of adhesive, 0 to 20 percent of stabilizer and 0 to 10 percent of disintegrant. Wet granulation is adopted, and an alcohol-containing solution is preferably used for granulation in the granulation process.
Patent application CN102329283A discloses a hydrochlorothiazide crystal and a candesartan cilexetil hydrochlorothiazide medicinal composition thereof. The characteristic peaks in an X-ray powder diffraction pattern obtained by measuring the hydrochlorothiazide crystal by using Cu-Kalpha rays are shown at 2 theta of 4.1 degrees, 8.2 degrees, 9.8 degrees, 12.1 degrees, 15.1 degrees, 16.7 degrees, 19.3 degrees, 20.0 degrees, 22.1 degrees, 23.3 degrees and 26.8 degrees. The composition comprises 4-20 parts of candesartan cilexetil, 10-15 parts of hydrochlorothiazide crystal, 10-50 parts of compressible starch, 10215-35 parts of microcrystalline cellulose PH, 10-45 parts of cross-linked polyvinylpyrrolidone and 0.5-1 part of magnesium stearate. The powder direct tabletting process is adopted, and the disintegration time limit and the dissolution rate are better.
The developed candesartan cilexetil/hydrochlorothiazide (16mg/12.5mg) compound tablet jointly developed by martian and astelazericon company in Japan, which has been approved by the U.S. food and drug administration at 9/5 of 2000 under the trade name of Atacand HCT, can be used as a second-line drug for treating hypertension. Ataland HCT was marketed in two fixed dose formulations: 32mg of candesartan cilexetil and 25mg of hydrochlorothiazide, 32mg of candesartan cilexetil and 12.5mg of hydrochlorothiazide and 16mg of candesartan cilexetil and 12.5mg of hydrochlorothiazide. The compound tablet is also approved by the european union for the treatment of hypertension. A plurality of clinical tests show that the candesartan cilexetil-hydrochlorothiazide compound preparation has small side effect and good safety and tolerance, and is an ideal first-line medicament for treating hypertension.
The candesartan cilexetil and the hydrochlorothiazide are both water-insoluble medicines, and the hydrochlorothiazide also has certain hydrophobicity, when the candesartan cilexetil and the hydrochlorothiazide are combined to prepare a tablet, the candesartan cilexetil is further slowly dissolved out due to the hydrophobic effect of the candesartan cilexetil and the hydrochlorothiazide, and an auxiliary material are granulated together, so that the contact area between the hydrochlorothiazide and the candesartan cilexetil is increased, and the dissolution of the candesartan cilexetil is reduced to a certain extent.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of a candesartan cilexetil and hydrochlorothiazide compound tablet, the candesartan cilexetil is added into an aqueous solution of a binder or an aqueous solution of the binder added with a stabilizer, so that the dispersion degree of the candesartan cilexetil can be improved, the hydrochlorothiazide is added into prepared granules of the candesartan cilexetil, the direct contact area of the hydrochlorothiazide and the candesartan cilexetil is reduced, and the dissolution behavior of the candesartan cilexetil is improved. And the colorant is also added into the solution to prepare a sample with uniform sheet surface color, and the process flow is simple and easy to operate.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
the candesartan cilexetil hydrochlorothiazide tablet comprises the following components in percentage by weight:
5-15% of candesartan cilexetil
5 to 10 percent of hydrochlorothiazide
1 to 5 percent of stabilizer
0 to 2 percent of coloring agent
1 to 6 percent of adhesive
50 to 80 percent of filler
1 to 5 percent of disintegrating agent
0.5 to 1 percent of lubricant. A preparation method of a candesartan cilexetil hydrochlorothiazide compound tablet comprises the following steps:
step (1) preparing an adhesive aqueous solution;
the adhesive can be one or more of hydroxypropyl cellulose, polyvinylpyrrolidone and hydroxypropyl methyl cellulose; the stabilizing agent is polyethylene glycol.
Step (2), dispersing the colorant into the prepared adhesive aqueous solution under the stirring state; the colorant can be one or more of red iron oxide and yellow iron oxide.
And (3) adding candesartan cilexetil into the aqueous solution under a stirring state to prepare a suspension.
And (4) adding auxiliary materials, mixing, sieving by a 30-mesh sieve, adding into a fluidized bed, spraying the suspension containing candesartan cilexetil into the auxiliary materials, and granulating.
The internal auxiliary materials comprise a filling agent and a disintegrating agent. The filler can be one or more of microcrystalline cellulose and lactose, mannitol, and the disintegrant can be one or more of corn starch and pregelatinized starch.
The temperature of the fluid bed granulation material is 25-35 deg.C, preferably 25-30 deg.C.
And (5) sieving by a 30-mesh sieve after the granulation is finished, and granulating.
And (6) adding hydrochlorothiazide and additional auxiliary materials according to the weight of the granules, and uniformly mixing.
The additional auxiliary materials comprise a disintegrating agent and a lubricating agent.
The disintegrant may be one or more of calcium carboxymethylcellulose, croscarmellose sodium, and corn starch.
The lubricant may be one or more of magnesium stearate and talc.
And (7) punching the sheet by 8.5 x 5mm to obtain the product.
The prepared suspension containing the bulk drugs is stable in the whole granulation process, and the stability data under the stirring state is determined as follows:
| Time | 0h | 2h | 4h | 23h | 26h |
| total impurities (%) | 0.18 | 0.19 | 0.19 | 0.19 | 0.20 |
Has the advantages that: the candesartan cilexetil is dispersed in the aqueous solution of the adhesive, the hydrochlorothiazide is added to the prepared granules containing the candesartan cilexetil, the dissolution rate of the candesartan cilexetil is improved, the coloring agent is dispersed in the solution and granulated, and the prepared sample is attractive in appearance, simple in process and beneficial to commercial production.
Detailed Description
The technical solution of the present invention will be described with reference to the following specific examples:
example 1:
the following formulations, as shown in Table 1, were used to compare the effect of the different processes of examples 1-5 on the in vitro dissolution and appearance of the tablets.
TABLE 1
The preparation process comprises the following steps:
(1) dissolving polyethylene glycol in 835g of water until the polyethylene glycol is completely dissolved, adding hydroxypropyl cellulose, and dissolving until the mixture is clear to obtain a binder solution added with a stabilizer;
(2) dispersing yellow iron oxide and red iron oxide into the aqueous solution in the step (1) under a stirring state;
(3) adding candesartan cilexetil into the solution in the step (2) under a stirring state to prepare a suspension;
(4) mixing lactose and corn starch, sieving with a 30-mesh sieve, adding into a fluidized bed, and spraying the suspension containing candesartan cilexetil into the fluidized bed at 25-30 deg.C for granulation;
(5) drying to water content of about 1% after granulation is finished, and sieving with a 30-mesh sieve for granulation;
(6) adding hydrochlorothiazide, calcium carboxymethylcellulose and magnesium stearate according to the weight of the granules, and uniformly mixing;
(7) punching into sheets with 8.5 × 5 mm.
Example 2:
the preparation process comprises the following steps:
(1) dissolving polyethylene glycol in 835g of water until the polyethylene glycol is completely dissolved, and adding hydroxypropyl cellulose to dissolve until the mixture is clear;
(2) dispersing yellow iron oxide and red iron oxide into the aqueous solution in the step (1) under a stirring state;
(3) mixing candesartan cilexetil, lactose and corn starch, sieving with a 30-mesh sieve, adding into a fluidized bed, and spraying the prepared solution (2) into the fluidized bed at the material temperature of 25-30 ℃ for granulation; (example 1 is adding candesartan cilexetil to an aqueous solution of a binder and a stabilizer, example 2 is adding candesartan cilexetil and lactose, corn starch mixed in dry powder form to a fluidized bed);
(5) drying to water content of about 1% after granulation is finished, and sieving with a 30-mesh sieve for granulation;
(6) adding hydrochlorothiazide, calcium carboxymethylcellulose and magnesium stearate according to the weight of the granules, and uniformly mixing;
(7) punching into sheets with 8.5 × 5 mm.
The results of the dissolution data measured by the paddle method at 50rpm using 900mL of the phosphate buffer solution with pH6.5 containing 0.35% Tween 20 as the dissolution medium of the candesartan cilexetil hydrochlorothiazide tablets of examples 1 and 2 respectively are as follows:
comparing the dissolution data of example 1 and example 2, it was found that the dissolution of example 1 was faster than example 2, i.e. the dissolution rate was improved by the process of adding candesartan cilexetil to an aqueous binder solution with added stabilizer to make a suspension.
Example 3:
the preparation process comprises the following steps:
(1) dissolving polyethylene glycol in 835g of water until the polyethylene glycol is completely dissolved, and adding hydroxypropyl cellulose to dissolve until the mixture is clear;
(2) dispersing yellow iron oxide and red iron oxide into the aqueous solution in the step (1) under a stirring state;
(3) adding candesartan cilexetil into the solution in the step (2) under a stirring state to prepare a suspension;
(4) mixing hydrochlorothiazide, lactose and corn starch, sieving with a 30-mesh sieve, adding into a fluidized bed, and spraying the suspension containing candesartan cilexetil into the fluidized bed at the material temperature of 25-30 ℃ for granulation;
(5) drying to water content of about 1% after granulation is finished, and sieving with a 30-mesh sieve for granulation;
(6) adding calcium carboxymethylcellulose and magnesium stearate according to the weight of the granules, and uniformly mixing;
(7) punching into sheets with 8.5 × 5 mm.
The dissolution data of the Karadixil hydrochlorothiazide tablets of example 1 and 3 are respectively measured by using 900mL of pH6.5 phosphate buffer solution containing 0.35% Tween 20 as solvent and rotating speed of 50rpm, and the results are as follows:
comparing the dissolution data of example 1 and example 3, it was found that the dissolution of example 1 was faster than example 3, i.e., the dissolution rate of candesartan cilexetil was increased using a process that would employ the addition of hydrochlorothiazide.
The principle is as follows: the candesartan cilexetil and the hydrochlorothiazide are both water-insoluble medicines, and the hydrochlorothiazide also has certain hydrophobicity, when the candesartan cilexetil and the hydrochlorothiazide are combined to prepare a tablet, the candesartan cilexetil is further slowly dissolved out due to the hydrophobic effect of the candesartan cilexetil and the hydrochlorothiazide, and an auxiliary material are granulated together, so that the contact area between the hydrochlorothiazide and the candesartan cilexetil is increased, and the dissolution of the candesartan cilexetil is reduced to a certain extent.
Example 4
The preparation process comprises the following steps:
(1) dissolving polyethylene glycol in 835g of water until the polyethylene glycol is completely dissolved, and adding hydroxypropyl cellulose to dissolve until the mixture is clear;
(2) adding candesartan cilexetil into the solution in the step (1) under a stirring state to prepare a suspension;
(3) sieving red, yellow ferric oxide and corn starch with 200 mesh sieve, mixing with lactose, sieving with 30 mesh sieve, and adding into fluidized bed;
(4) spraying the suspension containing candesartan cilexetil into a fluidized bed at the material temperature of 25-30 ℃ for granulation; (in distinction to example 1, example 1 is where red and yellow iron oxides are added to the stabilizer solution, and example 4 is where red and yellow iron oxides are sieved together as a dry powder with lactose and corn starch);
(5) drying to water content of about 1% after granulation is finished, and sieving with a 30-mesh sieve for granulation;
(6) adding hydrochlorothiazide, calcium carboxymethylcellulose and magnesium stearate according to the weight of the granules, and uniformly mixing;
(7) punching into sheets with 8.5 × 5 mm.
The one-sided appearance of comparative example 1 and example 4 shows that the one-sided color of example 1 is uniform and beautiful compared to example 4, i.e., the one-sided appearance can be greatly improved by the process of dispersing the colorant in the solution.
Claims (8)
1. A preparation method of a candesartan cilexetil and hydrochlorothiazide compound tablet is characterized in that candesartan cilexetil is added into an adhesive aqueous solution or an adhesive aqueous solution added with a stabilizer to prepare a suspension, the suspension is sprayed into an auxiliary material by a fluidized bed to granulate, and hydrochlorothiazide is added to carry out tabletting, so that the prepared tablet is high in uniformity.
2. The preparation method of the candesartan cilexetil hydrochlorothiazide compound tablet according to claim 1, which is characterized by comprising the following specific preparation processes:
(1) preparing an aqueous solution of the adhesive or an aqueous solution of the adhesive added with a stabilizer;
(2) adding candesartan cilexetil into the aqueous solution under stirring to prepare a suspension;
(3) adding auxiliary materials, mixing, sieving, adding into a fluidized bed, spraying the suspension containing candesartan cilexetil into the auxiliary materials, granulating, sieving and grading;
(4) adding hydrochlorothiazide and an additional auxiliary material according to the weight of the granules and uniformly mixing;
(5) tabletting to obtain the final product.
3. The method for preparing the candesartan cilexetil hydrochlorothiazide compound tablet according to claim 2, wherein the colorant is dispersed into the aqueous binder solution under stirring, and then the candesartan cilexetil is added into the aqueous solution under stirring to prepare the suspension.
4. The method for preparing the candesartan cilexetil hydrochlorothiazide compound tablet according to claim 1 or 2, wherein the binder is one or more of hydroxypropyl cellulose, polyvinylpyrrolidone and hydroxypropyl methylcellulose, and the stabilizer is polyethylene glycol.
5. The method for preparing the candesartan cilexetil hydrochlorothiazide compound tablet according to claim 3, wherein the coloring agent is one or more of red iron oxide, yellow iron oxide and brown iron oxide.
6. The preparation method of the candesartan cilexetil hydrochlorothiazide compound tablet according to claim 2, characterized in that auxiliary materials are added, including a filler and a disintegrant, wherein the filler is one or more of microcrystalline cellulose, lactose and mannitol, and the disintegrant is one or more of corn starch or pregelatinized starch.
7. The method for preparing the candesartan cilexetil hydrochlorothiazide compound tablet according to claim 2, wherein the fluidized bed granulation temperature is 25-35 ℃.
8. The preparation method of the candesartan cilexetil hydrochlorothiazide compound tablet according to claim 2, wherein the additional auxiliary materials comprise a disintegrant and a lubricant, the disintegrant is one or more of carboxymethylcellulose calcium, croscarmellose sodium and corn starch; the lubricant is one or more of magnesium stearate and talcum powder.
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| CN117442577A (en) * | 2023-12-21 | 2024-01-26 | 山东则正医药技术有限公司 | Candesartan cilexetil microchip and preparation method and application thereof |
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| WO2008129077A2 (en) * | 2007-04-24 | 2008-10-30 | Krka, D.D. Novo Mesto | Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation |
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Application publication date: 20211001 |