CN117442577B - Candesartan cilexetil microchip and preparation method and application thereof - Google Patents
Candesartan cilexetil microchip and preparation method and application thereof Download PDFInfo
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- CN117442577B CN117442577B CN202311767678.8A CN202311767678A CN117442577B CN 117442577 B CN117442577 B CN 117442577B CN 202311767678 A CN202311767678 A CN 202311767678A CN 117442577 B CN117442577 B CN 117442577B
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- candesartan cilexetil
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- 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 title claims abstract description 101
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 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 abstract description 36
- 239000004480 active ingredient Substances 0.000 claims abstract description 36
- 239000008101 lactose Substances 0.000 claims abstract description 36
- 239000003381 stabilizer Substances 0.000 claims abstract description 25
- 239000000725 suspension Substances 0.000 claims abstract description 23
- 239000008187 granular material Substances 0.000 claims abstract description 21
- 229920002472 Starch Polymers 0.000 claims abstract description 18
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000008107 starch Substances 0.000 claims abstract description 18
- 235000019698 starch Nutrition 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000000314 lubricant Substances 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000000945 filler Substances 0.000 claims abstract description 12
- 208000019505 Deglutition disease Diseases 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 239000000853 adhesive Substances 0.000 claims abstract description 6
- 230000001070 adhesive effect Effects 0.000 claims abstract description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 26
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 26
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 26
- 238000002156 mixing Methods 0.000 claims description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 239000011230 binding agent Substances 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- 238000005507 spraying Methods 0.000 claims description 11
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 8
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 7
- 238000000889 atomisation Methods 0.000 claims description 6
- 229920002261 Corn starch Polymers 0.000 claims description 4
- 239000008120 corn starch Substances 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 238000007730 finishing process Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 20
- 238000005469 granulation Methods 0.000 abstract description 6
- 230000003179 granulation Effects 0.000 abstract description 6
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 64
- 229960001375 lactose Drugs 0.000 description 26
- 238000004090 dissolution Methods 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 20
- 239000008118 PEG 6000 Substances 0.000 description 19
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 19
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 19
- 239000008185 minitablet Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000008213 purified water Substances 0.000 description 12
- 238000009472 formulation Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 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 4
- -1 caprylic acid-capric acid-polyethylene Chemical group 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 238000009775 high-speed stirring Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229960000932 candesartan Drugs 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 238000005563 spheronization Methods 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 241001075517 Abelmoschus Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar 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
- 229940058087 atacand Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- 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
- A61K9/2031—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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a candesartan cilexetil microchip and a preparation method and application thereof, belonging to the technical field of pharmaceutical preparations. The candesartan cilexetil micro-tablet consists of an active ingredient, a filler, an adhesive, a disintegrating agent, a stabilizer and a lubricant, wherein the filler is starch and lactose. The preparation process adopts fluidized bed granulation, starch is placed in a fluidized bed, aqueous solution of a stabilizing agent and suspension of lactose, active ingredients and an adhesive are sequentially sprayed, granules are prepared, a disintegrating agent and a lubricant are added, and the mixture is mixed and tabletted to obtain candesartan cilexetil micro-tablets. The candesartan cilexetil micro tablet with good content uniformity and stability can be prepared by optimizing the granulating process, particularly the adding time of active ingredients and lactose and adding the stabilizing agent on the basis of ensuring the product quality of the candesartan cilexetil micro tablet to be consistent with that of the original candesartan cilexetil tablet, has good medicine taking compliance, is suitable for patients with children, dysphagia and the like to take medicine, and is suitable for commercial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a candesartan cilexetil microchip and a preparation method and application thereof.
Background
Candesartan cilexetil (Candesartan Cilexet)il), chemical name: (±) -1- [ [ (cyclohexyloxy) carbonyl]Oxo-radicals]Ethyl-2-ethoxy-1- [ [2 '- (1H-tetrazolyl-5) - [1, 1' -biphenyl ]]-4-yl]Methyl group]-1H-benzimidazole-7-carboxylate. The molecular formula: c (C) 33 H 34 N 6 O 6 . Candesartan cilexetil is a prodrug which is rapidly and completely converted into the active metabolite candesartan during the absorption process, and is suitable for the treatment of essential hypertension. Clinically, candesartan cilexetil is an angiotensin ii receptor antagonist, and is combined with a receptor to antagonize the vasoconstriction, thereby reducing peripheral vascular resistance and lowering blood pressure.
Candesartan cilexetil is a poorly soluble drug with low oral bioavailability. The invention patent CN1044088C discloses a preparation method of candesartan cilexetil tablets, which is developed by the combination of Katsumada pharmaceutical industry Co Ltd in Japan and Abelmoschus UK, and adds an oily compound with low melting point to increase the stability of candesartan cilexetil drugs, so that the original candesartan cilexetil tablets with better stability can be prepared. The original candesartan cilexetil tablet is marketed in the United kingdom 4 months 1997, and is marketed in the United states after approval by the FDA in 1998 under the trade name Atacand, which is commercially available as "Bilos" from Toku Kogyo Kagaku in Japanese in 2002. At present, candesartan cilexetil tablets are marketed in more than 70 countries worldwide. Currently, tablets on the market in China are not approved for children patients. Improvements in candesartan cilexetil formulations continue to progress.
Patent CN116492336a discloses a candesartan cilexetil pharmaceutical composition, which contains candesartan cilexetil, caprylic acid-capric acid-polyethylene glycol glyceride, propylene glycol, lactose, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethylcellulose calcium and magnesium stearate, wherein the D90 of candesartan cilexetil is 25-50 μm, and the mass ratio of candesartan cilexetil, caprylic acid-capric acid-polyethylene glycol glyceride and propylene glycol is 1 (1.25-2) (1-1.5). The invention refers to the design concept of self-emulsification and microemulsion and improves the design concept, and the emulsifying agent and the auxiliary emulsifying agent are added into the solid preparation components to improve the solubility of the raw materials and the absorption of the medicines. The patent prepares tablets with the diameter of 7mm, and the weight of each tablet can reach 100-150mg.
Patent CN115671063A discloses a candesartan cilexetil pharmaceutical composition and a preparation method thereof, and is characterized in that a unit dose tablet contains 8mg of candesartan cilexetil crystal form I, 0.8-1.8mg of agar, 2-6mg of guar gum, 83-91mg of lactose, 17-28mg of microcrystalline cellulose, 5-7mg of crospovidone and 1.2mg of magnesium stearate, and the maximum average hardness of the prepared candesartan cilexetil tablet can reach about 90N, and the tablet still has quality stability superior to that of an original preparation under high tablet-making pressure, thereby ensuring medication safety, and simultaneously has simple process and is suitable for industrial production, storage and transportation.
Patent CN112294769a discloses a candesartan cilexetil orally disintegrating tablet and a preparation method thereof, which is characterized by comprising: micropellets of candesartan cilexetil in a therapeutically effective amount, the remainder of candesartan cilexetil mixed with the micropellets, and other pharmaceutically acceptable excipients; making into pill core by fluidized bed granulation method, and coating with HPMC. The pharmaceutically acceptable auxiliary materials comprise diluents, binders, disintegrants, flavoring agents, lubricants and glidants. The prepared candesartan cilexetil orally disintegrating tablet has smooth surface morphology, can be rapidly disintegrated in the oral cavity without gritty feel, can be completely disintegrated in 1min, and has a dissolution rate of more than 90% in phosphate buffer solution within 30 min.
Patent CN110917170a discloses a capsule preparation containing candesartan cilexetil and a preparation method thereof, wherein 2-32 parts by weight of candesartan cilexetil, 110-150 parts by weight of diluent, 210-150 parts by weight of diluent, 0.5-8 parts by weight of disintegrating agent, 1-10 parts by weight of binder and 0.5-10 parts by weight of low-melting-point oily compound are mixed, and then prepared into pellets by an extrusion spheronization method, 0.05-4 parts by weight of lubricant is added into the pellets to be mixed, and the mixture is filled into a capsule shell to prepare the capsule preparation. The preparation process of extrusion spheronization has high dissolution, and compared with the commercial candesartan cilexetil preparation, the bioavailability of the candesartan cilexetil is greatly improved.
As can be seen, the studies on candesartan cilexetil formulations in the prior art have focused on improvements of the original candesartan cilexetil tablet or candesartan cilexetil capsule, which are not suitable for patients suffering from children, dysphagia, etc.
Minitablets (minitablets) are generally less than 3mm in diameter and are typically multi-unit formulations. The microchip has the advantages of easy swallowing, accurate dosage, flexible dosage adjustment and the like, and can be applied to patients with dysphagia and the like. According to clinical requirements, the micro-tablets can be developed into quick-release, slow-release, enteric-coated micro-tablets and the like; it can be filled in capsules, bags and bottles, and a tablet counter can be arranged according to the requirement to measure the number of micro tablets for administration.
Compared with the conventional tablet, the micro tablet (1) is easy to swallow and is suitable for children and old people; (2) small diameter, smooth and beautiful surface and accurate dosage; (3) the preparation process is simple, the coating consumable is less, and the efficiency is high; (4) the volume is small, and the transportation, the carrying and the storage are convenient; (5) has the advantages of common tablets and micropills; (6) the taste masking technology for the bad taste of bitter, astringent and other medicines is simpler.
Based on the characteristics of the dosage form and clinical treatment requirements, functional indexes affecting the fluidity, compressibility and the like of auxiliary materials are focused when the auxiliary materials are selected, and indexes affecting the fluidity such as crystal form, density, granularity, distribution and the like of the raw material medicines are focused. The minitablets may be coated for reasons of increased palatability, altered dissolution behavior of the drug or production requirements. The production flow of the micro tablet is the same as that of a common tablet, and the processes of powder direct compression, wet granulation tabletting, dry granulation tabletting, fluidized bed granulation tabletting and the like are generally adopted.
Compared with the common tablet, the microchip has higher requirements on production and quality control, especially the content uniformity of the microchip with small specification is a technical problem, and the adoption of the preparation process can lead the content uniformity of the microchip to be difficult to control, and can easily produce products with unqualified content uniformity.
Therefore, the candesartan cilexetil microchip provided with stable product quality, reliable curative effect, qualified content uniformity, reasonable dissolution rate and simple preparation process can meet the medication requirements of patients with children, dysphagia and the like, and has great economic and social benefits.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a candesartan cilexetil microchip and a preparation method and application thereof. The candesartan cilexetil micro-tablet consists of an active ingredient, a filler, an adhesive, a disintegrating agent, a stabilizer and a lubricant, wherein the filler is starch and lactose. The preparation process adopts fluidized bed granulation, starch is placed in a fluidized bed, aqueous solution of a stabilizing agent and suspension of lactose, active ingredients and an adhesive are sequentially sprayed, granules are prepared, a disintegrating agent and a lubricant are added, and the mixture is mixed and tabletted to obtain candesartan cilexetil micro-tablets. By optimizing the granulating process, especially the adding time of the active ingredients and lactose and adding the stabilizer, the candesartan cilexetil microchip with good content uniformity and stability can be prepared on the basis of ensuring the product quality of the candesartan cilexetil microchip to be consistent with that of the original candesartan cilexetil tablet, the medicine taking compliance is good, and the candesartan cilexetil microchip is suitable for patients with children, dysphagia and the like, is suitable for commercial production, and can be continuously and effectively produced.
In order to achieve the above purpose, in a first aspect, the present invention provides a preparation method of candesartan cilexetil micro-tablet, wherein the candesartan cilexetil micro-tablet comprises, by weight, 1-4% of active ingredient, 65-90% of filler, 4-12% of binder, 2-10% of disintegrating agent, 1-10% of stabilizer and 0.1-1% of lubricant, and the filler is starch and lactose;
the preparation method comprises the following steps:
1) Preparing an aqueous solution of a stabilizer;
2) Preparing a suspension of lactose, active ingredient and binder;
3) Granulating by a fluidized bed: placing starch in a fluidized bed, sequentially spraying aqueous solution of stabilizer, suspension of lactose, active ingredient and binder, drying, granulating, and making into granule;
4) Total mixing: sequentially adding a disintegrating agent and a lubricant into the granules obtained in the step 3), mixing, and tabletting to obtain the candesartan cilexetil micro-tablets.
In a preferred embodiment, the candesartan cilexetil micro-tablet consists of 1-4% by weight of active ingredient, 76-89% by weight of filler, 5-9% by weight of binder, 2-4% by weight of disintegrant, 2-7% by weight of stabilizer and 0.3-0.8% by weight of lubricant.
In a preferred embodiment, the starch is corn starch; the mass ratio of lactose to starch in the filler is 50-75:15-35.
In a preferred embodiment, the binder comprises at least one of povidone, hypromellose, hydroxypropyl cellulose, gelatin, more preferably hydroxypropyl cellulose.
In a preferred embodiment, the disintegrant comprises at least one of calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, polyvinylpyrrolidone, low substituted hydroxypropyl cellulose, more preferably calcium carboxymethyl cellulose.
In a preferred embodiment, the stabilizer is a low melting point oily substance including at least one of hydrocarbon, higher fatty acid, higher alcohol, fatty acid ester of polyhydroxy compound, polyol ether of higher alcohol, high polymer of ethylene oxide or copolymer of ethylene oxide, more preferably polyethylene glycol 6000.
In a preferred embodiment, the stabilizer has a melting point of 20 ℃ to 90 ℃.
In a preferred embodiment, the lubricant comprises at least one of magnesium stearate, stearic acid, calcium stearate, talc, more preferably magnesium stearate.
In a preferred embodiment, the concentration of the aqueous solution of the stabilizer in step 1) is 1-10wt%, more preferably 9wt%.
In a preferred embodiment, in step 2), the concentration of binder in the suspension of lactose, active ingredient and binder is 1-10wt%, more preferably 4wt%.
In a preferred embodiment, in step 3), the process parameters of spraying the aqueous solution of the stabilizer, and the suspension of lactose, active ingredient and binder in succession are: the air inlet temperature is 45-65 ℃, the material temperature is 25-40 ℃, the air inlet quantity is 15-35Hz, the air outlet temperature is 30-40 ℃, the atomization pressure is 0.10-0.20MPa, the liquid supply rotating speed is 5-25rpm, and the liquid supply flow is 5-20g/min; the drying conditions are as follows: drying until the moisture content is less than or equal to 3%; the grain finishing process comprises the following steps: using a 0.8-2.0mm screen for finishing.
In a preferred embodiment, in step 4), the mixing conditions for adding the disintegrant are 5-15rpm,10-20min; the mixing conditions for adding the lubricant are 5-15rpm,2-8min.
In a preferred embodiment, the candesartan cilexetil micro-tablet in step 4) has a tablet weight of 25.+ -. 1.875mg, a tablet weight difference of within.+ -. 7.5%, a smooth surface and a hardness of 15.+ -. 20N.
In a preferred embodiment, the effective amount of active ingredient in the candesartan cilexetil minitablet is 0.5 mg/tablet.
In a second aspect, the invention provides candesartan cilexetil micro-tablets prepared by the preparation method.
In a third aspect, the invention provides the use of a candesartan cilexetil minitablet as described above in the manufacture of a medicament for use in children, dysphagia patients.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the invention, by optimizing the granulating process, especially the adding time of the active ingredients and lactose and adding the stabilizer, the candesartan cilexetil microchip with good content uniformity and stability can be prepared on the basis of ensuring the product quality of the candesartan cilexetil microchip to be consistent with that of the original candesartan cilexetil tablet, the medicine taking compliance is good, and the candesartan cilexetil microchip is suitable for patients with children, dysphagia and the like to take medicine, is suitable for commercial production, and can be continuously and effectively produced.
2. The invention can greatly improve the stability of the active ingredient by adding the low-melting-point oily substance.
3. The active ingredient of the candesartan cilexetil micro-tablet has dissolution behavior which is not inferior to that of a control preparation through the selection of the filling agent, and particularly, the active ingredient can be quickly and completely dissolved in a medium in which the active ingredient is insoluble.
4. The candesartan cilexetil micro-tablet is a multi-unit preparation, has the advantages of common tablets and micro-pills, has accurate dosage, is beneficial to swallowing, can improve patient compliance, is particularly suitable for the elderly and children to take, and has higher product quality and economic benefit compared with the micro-pills.
5. The candesartan cilexetil microchip of the invention has small diameter, smooth and beautiful surface, small volume and convenient transportation, carrying and storage.
6. The candesartan cilexetil micro-tablet of the invention is not inferior to the original candesartan cilexetil tablet in quality and curative effect.
7. The invention ensures that the content uniformity of the microchip is good by adjusting the adding mode of the active ingredient and lactose in the fluidized bed granulation process.
Detailed Description
It is worth to say that the medicinal materials used in the invention are all common commercial products, and the sources are not particularly limited.
The following raw material sources are exemplary illustrations:
candesartan cilexetil: purchased from zhuhuadu pharmaceutical stock, inc;
starch: corn starch, purchased from Anhui mountain river pharmaceutical excipients stock company;
lactose: lactose monohydrate, model 100M, purchased from di-auxiliary trade (Shanghai) limited;
hydroxypropyl cellulose: model L, purchased from Anhui mountain river pharmaceutical excipients stock Co., ltd;
carboxymethylcellulose calcium: purchased from Prachin Chemical;
polyethylene glycol 6000: purchased from Jiangxi alpha Gao Kogyo pharmaceutical Co., ltd;
magnesium stearate, purified water: are commercially available;
control formulation: candesartan cilexetil tablet is produced in situ by Tianjin Wuta medicine Co., ltd.
Test case
1. And (3) dissolution detection: all dissolution studies were performed using a USP-II apparatus, 50 rpm, medium: the pH value of the phosphate buffer solution with the height difference is 6.5, the dissolution volume is 900 mL, and the temperature is 37.5+/-0.5 ℃;
2. stability experiment: the impurity content at the completion of the preparation and the impurity content after sealing and standing for 10 days at 50 ℃ are detected according to high performance liquid chromatography (the rule 0512 of four parts in 2020 edition of Chinese pharmacopoeia).
3. Content detection: the unit is measured by high performance liquid chromatography (the rule 0512 of the fourth edition of the 2020 edition of Chinese pharmacopoeia).
EXAMPLES 1-4 preparation of candesartan cilexetil minitablets
The composition of candesartan cilexetil minitablets of examples 1-4 are shown in table 1, and the preparation process is as follows:
1) Slowly adding PEG6000 into the stirred purified water, stirring until the PEG6000 is dissolved, and preparing an aqueous solution of PEG6000 with the concentration of 9 weight percent;
2) Slowly adding hydroxypropyl cellulose into the stirred purified water, stirring until the hydroxypropyl cellulose is dissolved, slowly adding lactose and active ingredients under high-speed stirring, and continuously stirring to prepare suspension of lactose, active ingredients and hydroxypropyl cellulose, wherein the concentration of the hydroxypropyl cellulose in the suspension is 4wt%;
3) Granulating by a fluidized bed: placing starch in a fluidized bed, sequentially spraying aqueous solution of PEG6000 and suspension of lactose, active ingredient and hydroxypropyl cellulose, wherein the parameters are as follows: the air inlet temperature is 55 ℃, the material temperature is 30 ℃, the air inlet quantity is 25Hz, the air outlet temperature is 35 ℃, the atomization pressure is 0.15MPa, the liquid supply rotating speed is 15rpm, the liquid supply flow rate is 10g/min, and the residual purified water is used for rinsing the pipeline after the liquid spraying is finished; finishing drying when the moisture is 2%, finishing the granules by using a screen with the diameter of 1.5mm, and preparing the granules;
4) Total mixing: adding the granules obtained in the step 3) and the carboxymethylcellulose calcium into a mixer, and mixing for 15min at 10 rpm; continuously adding magnesium stearate into the mixer, mixing for 5min at 10rpm, and tabletting to obtain candesartan cilexetil micro-tablets; the tablet weight is 25mg, the difference of the tablet weights is maintained within +/-7.5 percent, the surface of the tablet is smooth, and the hardness is 15+/-20N.
TABLE 1 composition of candesartan cilexetil minitablets of examples 1 to 4
The dissolution behavior of candesartan cilexetil minitablets of examples 1-4 with the control formulation was examined based on the dissolution behavior in highly differential phosphate buffer, ph6.5, and the product dissolution behavior was evaluated with a similar factor f2, and the results are shown in table 2.
Table 2 dissolution behavior of candesartan cilexetil minitablets of examples 1 to 4 and control formulation
The dissolution results show that when the binder amount is 5% and 9%, the product dissolves rapidly, and the dissolution behavior is similar to that of the control preparation, wherein the similar factor is highest at 5% of the binder amount; when the dosage of the disintegrating agent is 2 percent and 4.0 percent, the dissolution behavior is similar to that of a control preparation, wherein the dissolution curve of a prescription with the dosage of 4.0 percent is more similar to that of the prescription.
Verification of the Effect of example 1 stabilizers
Several sets of experiments (examples 4-6 and comparative example 1) were designed to examine the effect of the stabilizer in the formulation on dissolution behavior and API stability, the relevant experimental design is shown in table 3, the preparation processes of examples 5-6 are the same as examples 1-4, and the corresponding configuration and injection processes of PEG6000 omitted aqueous solution in comparative example 1:
TABLE 3 composition of candesartan cilexetil minitablets of examples 4 to 6 and comparative example 1
The dissolution behavior of candesartan cilexetil minitablets of examples 4 to 6 and comparative example 1 with the control formulation was examined based on the dissolution behavior in highly discriminating phosphate buffer at ph6.5, and the product dissolution behavior was evaluated with a similar factor f2, and the results are shown in table 4; the stability of examples 4-6 and comparative example 1 was tested and the results are shown in Table 5.
TABLE 4 dissolution behavior of candesartan cilexetil minitablets of examples 4-6 and control formulation
Table 5 stability data for examples 4-6, comparative example 1 and control formulation
The research result shows that the dissolution curves of the polyethylene glycol 6000 in the dosage range of 2.6-6.58% are similar to those of the control preparation, and the candesartan cilexetil micro-tablet prepared by the embodiment of the invention has lower impurity content than that of the control preparation, namely, the stability of the candesartan cilexetil micro-tablet prepared by the embodiment of the invention is superior to that of the control preparation, and the impurity growth is faster under the condition of 50 ℃ in the comparative example 1 without adding PEG6000, so that the result shows that the PEG6000 can effectively increase the stability of the active ingredients in the prescription.
Verification of the Effect of example 2 preparation Process
Several groups of experiments (example 4 and comparative examples 2-5) were designed to examine the effect of the feeding regime on the uniformity of the product content, and the relevant experimental design was as follows:
comparative example 2
The candesartan cilexetil minitablet of comparative example 2 has the same composition as that of example 4 except that the lactose is added in a different manner, i.e., the preparation process is as follows:
1) Slowly adding PEG6000 into the stirred purified water, stirring until the PEG6000 is dissolved, and preparing an aqueous solution of PEG6000 with the concentration of 9 weight percent;
2) Slowly adding hydroxypropyl cellulose into the stirred purified water, stirring until the hydroxypropyl cellulose is dissolved, slowly adding the active ingredient under high-speed stirring, and continuously stirring to prepare suspension of the active ingredient and the hydroxypropyl cellulose, wherein the concentration of the hydroxypropyl cellulose in the suspension is 4wt%;
3) Granulating by a fluidized bed: mixing lactose and starch, and sequentially spraying aqueous solution of PEG6000 and suspension of active ingredient and hydroxypropyl cellulose into fluidized bed, wherein the parameters are as follows: the air inlet temperature is 55 ℃, the material temperature is 30 ℃, the air inlet quantity is 25Hz, the air outlet temperature is 35 ℃, the atomization pressure is 0.15MPa, the liquid supply rotating speed is 15rpm, the liquid supply flow rate is 10g/min, and the residual purified water is used for rinsing the pipeline after the liquid spraying is finished; finishing drying when the moisture is 2%, finishing the granules by using a screen with the diameter of 1.5mm, and preparing the granules;
4) Total mixing: adding the granules obtained in the step 3) and the carboxymethylcellulose calcium into a mixer, and mixing for 15min at 10 rpm; continuously adding magnesium stearate into the mixer, mixing for 5min at 10rpm, and tabletting to obtain candesartan cilexetil micro-tablets; the tablet weight is 25mg, the difference of the tablet weights is maintained within +/-7.5 percent, the surface of the tablet is smooth, and the hardness is 15+/-20N.
Comparative example 3
The candesartan cilexetil minitablet of comparative example 3 has the same composition as that of example 4 except that the active ingredients are added in the different manner, specifically as follows:
1) Slowly adding PEG6000 into the stirred purified water, stirring until the PEG6000 is dissolved, and preparing an aqueous solution of PEG6000 with the concentration of 9 weight percent;
2) Slowly adding hydroxypropyl cellulose into the stirred purified water, stirring until the hydroxypropyl cellulose is dissolved, slowly adding lactose under high-speed stirring, and continuously stirring to prepare a suspension of lactose and hydroxypropyl cellulose, wherein the concentration of the hydroxypropyl cellulose in the suspension is 4wt%;
3) Granulating by a fluidized bed: mixing active ingredient and starch, and sequentially spraying aqueous solution of PEG6000 and suspension of lactose and hydroxypropyl cellulose into fluidized bed, wherein the parameters are as follows: the air inlet temperature is 55 ℃, the material temperature is 30 ℃, the air inlet quantity is 25Hz, the air outlet temperature is 35 ℃, the atomization pressure is 0.15MPa, the liquid supply rotating speed is 15rpm, the liquid supply flow rate is 10g/min, and the residual purified water is used for rinsing the pipeline after the liquid spraying is finished; finishing drying when the moisture is 2%, finishing the granules by using a screen with the diameter of 1.5mm, and preparing the granules;
4) Total mixing: adding the granules obtained in the step 3) and the carboxymethylcellulose calcium into a mixer, and mixing for 15min at 10 rpm; continuously adding magnesium stearate into the mixer, mixing for 5min at 10rpm, and tabletting to obtain candesartan cilexetil micro-tablets; the tablet weight is 25mg, the difference of the tablet weights is maintained within +/-7.5 percent, the surface of the tablet is smooth, and the hardness is 15+/-20N.
Comparative example 4
The candesartan cilexetil minitablet of comparative example 4 has the same composition as that of example 4 except that PEG6000, active ingredient and lactose are added in the same manner as follows:
1) Slowly adding the hydroxypropyl cellulose into the stirred purified water, stirring until the hydroxypropyl cellulose is dissolved, slowly adding the PEG6000 under high-speed stirring, and continuously stirring to prepare a suspension of the PEG6000 and the hydroxypropyl cellulose, wherein the concentration of the hydroxypropyl cellulose in the suspension is 4wt%;
2) Granulating by a fluidized bed: mixing active ingredients, starch and lactose, placing in a fluidized bed, spraying suspension of PEG6000 and hydroxypropyl cellulose, and the parameters are as follows: the air inlet temperature is 55 ℃, the material temperature is 30 ℃, the air inlet quantity is 25Hz, the air outlet temperature is 35 ℃, the atomization pressure is 0.15MPa, the liquid supply rotating speed is 15rpm, the liquid supply flow rate is 10g/min, and the residual purified water is used for rinsing the pipeline after the liquid spraying is finished; finishing drying when the moisture is 2%, finishing the granules by using a screen with the diameter of 1.5mm, and preparing the granules;
3) Total mixing: adding the granules obtained in the step 3) and the carboxymethylcellulose calcium into a mixer, and mixing for 15min at 10 rpm; continuously adding magnesium stearate into the mixer, mixing for 5min at 10rpm, and tabletting to obtain candesartan cilexetil micro-tablets; the tablet weight is 25mg, the difference of the tablet weights is maintained within +/-7.5 percent, the surface of the tablet is smooth, and the hardness is 15+/-20N.
Comparative example 5
The candesartan cilexetil minitablet of comparative example 5 has the same composition as in example 4 and is prepared by the following process:
1) Weighing candesartan cilexetil, lactose, corn starch, hydroxypropyl cellulose and carboxymethyl cellulose calcium with a prescription amount, and sieving with a 50-mesh sieve three times by using a swinging type granulator for standby;
2) Dissolving polyethylene glycol 6000 in a prescription amount in 95% ethanol (the mass ratio of 95% ethanol to polyethylene glycol 6000 is 6.5:1), stirring, controlling the temperature to 50-60 ℃, and heating in water bath to dissolve to prepare a wetting agent for later use;
3) Drying and mixing the sieved and mixed raw and auxiliary materials obtained in the step 1) in a granulator for 5 minutes, setting the stirring speed of the granulator to 160rpm, setting the shearing speed to 1500rpm, adding a 95% ethanol solution of polyethylene glycol 6000 at the liquid adding speed of 7.5kg/min for granulating for 5 minutes, sieving with a 24-mesh sieve for wet granule finishing, drying the wet granules in a fluidized bed, setting the fan frequency of 35HZ in the fluidized bed drying granulator, and starting hot air after all the wet granules are added; the air inlet temperature is set at 55 ℃, the material temperature is controlled at 50 ℃, the material is dried to moisture of 2%, the dried material is sieved by a 30-mesh sieve for finishing, the prescribed amount of magnesium stearate is added for mixing for 15min, the candesartan cilexetil tablet is obtained by tabletting, the tablet weight is 25mg, and the tablet weight difference is maintained within +/-7.5%.
The results of content uniformity tests of candesartan cilexetil minitablets of examples 1 to 6 and comparative examples 2 to 5 were tested, wherein a+2.2s should be not more than 15.0, and if it is more than 15.0, the results are shown in tables 6 to 7, according to pharmacopoeia requirements.
TABLE 6 content uniformity of candesartan cilexetil micro-tablets of examples 1 to 6
TABLE 7 content uniformity of candesartan cilexetil micro-tablets of example 4 and comparative examples 2 to 5
Conclusion: the candesartan cilexetil micro tablets prepared in examples 1 to 6 all meet the requirement that the content uniformity of A+2.2S is not more than 15.0, and the content uniformity is qualified. Comparative examples 2 to 4 respectively examine the addition mode of the API and the addition mode of lactose under the fluidized bed granulation process, and comparative example 5 adopts the wet granulation process-fluidized bed drying, and the content uniformity detection results are all unqualified, so that the process disclosed by the invention can effectively improve the content uniformity of the microchip, and the content uniformity of the microchip accords with the pharmacopoeia regulation.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (6)
1. The preparation method of the candesartan cilexetil micro-tablet is characterized in that the candesartan cilexetil micro-tablet consists of, by weight, 1-4% of an active ingredient, 76-89% of a filler, 5-9% of an adhesive, 2-4% of a disintegrating agent, 2-7% of a stabilizer and 0.3-0.8% of a lubricant, wherein the filler is starch and lactose;
the preparation method comprises the following steps:
1) Preparing an aqueous solution of a stabilizer;
2) Preparing a suspension of lactose, active ingredient and binder;
3) Granulating by a fluidized bed: placing starch in a fluidized bed, sequentially spraying aqueous solution of stabilizer, suspension of lactose, active ingredient and binder, drying, granulating, and making into granule;
4) Total mixing: sequentially adding a disintegrating agent and a lubricant into the granules obtained in the step 3), mixing, and tabletting to obtain candesartan cilexetil micro-tablets;
the starch is corn starch; the mass ratio of lactose to starch in the filler is 50-75:15-35;
the adhesive is hydroxypropyl cellulose; the disintegrating agent is carboxymethylcellulose calcium; the stabilizer is polyethylene glycol 6000; the lubricant is magnesium stearate.
2. The method of preparing candesartan cilexetil micro tablet according to claim 1 wherein said stabilizer has a melting point of 20 ℃ to 90 ℃.
3. The method for preparing candesartan cilexetil micro tablet according to claim 1 wherein in step 1), the concentration of the aqueous solution of the stabilizer is 1 to 10% by weight; in step 2), the concentration of the binder in the suspension of lactose, active ingredient and binder is 1-10wt%; in step 3), the aqueous solution of the stabilizer and the suspension of lactose, active ingredient and binder are sprayed in sequence with the following technological parameters: the air inlet temperature is 45-65 ℃, the material temperature is 25-40 ℃, the air inlet quantity is 15-35Hz, the air outlet temperature is 30-40 ℃, the atomization pressure is 0.10-0.20MPa, the liquid supply rotating speed is 5-25rpm, and the liquid supply flow is 5-20g/min; the drying conditions are as follows: drying until the moisture content is less than or equal to 3%; the grain finishing process comprises the following steps: finishing the grains by using a sieve with 0.8-2.0 mm; in the step 4), the mixing condition of adding the disintegrating agent is 5-15rpm,10-20min; adding lubricant under the mixing condition of 5-15rpm for 2-8min; the candesartan cilexetil micro tablet weight in the step 4) is 25+/-1.875 mg, and the hardness is 15+/-20N.
4. The method for preparing candesartan cilexetil micro tablet according to claim 3 wherein in step 1), the concentration of the aqueous solution of the stabilizer is 9% by weight; in step 2), the concentration of binder in the suspension of lactose, active ingredient and binder is 4wt%.
5. Candesartan cilexetil micro-tablet prepared by the method for preparing candesartan cilexetil micro-tablet according to any one of claims 1 to 4.
6. Use of candesartan cilexetil micro tablet according to claim 5 in the manufacture of a medicament for children, dysphagia patients.
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Address after: Floor 4, Building D, Biomedical Innovation Park, No. 1, Lutai Avenue, High tech Zone, Zibo City, Shandong Province 255,035 Patentee after: SHANDONG HI-QUAL PHARMATECH CO.,LTD. Country or region after: China Patentee after: Shanghai Zezheng Pharmaceutical Technology Co.,Ltd. Address before: Floor 4, Building D, Biomedical Innovation Park, No. 1, Lutai Avenue, High tech Zone, Zibo City, Shandong Province 255,035 Patentee before: SHANDONG HI-QUAL PHARMATECH CO.,LTD. Country or region before: China Patentee before: Shanghai Zezheng Biopharmaceutical Co.,Ltd. |