CN117482057B - Stable granisetron hydrochloride tablet and preparation method thereof - Google Patents
Stable granisetron hydrochloride tablet and preparation method thereof Download PDFInfo
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- CN117482057B CN117482057B CN202311620709.7A CN202311620709A CN117482057B CN 117482057 B CN117482057 B CN 117482057B CN 202311620709 A CN202311620709 A CN 202311620709A CN 117482057 B CN117482057 B CN 117482057B
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- granisetron hydrochloride
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- lactose
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- 229960003607 granisetron hydrochloride Drugs 0.000 title claims abstract description 117
- QYZRTBKYBJRGJB-UHFFFAOYSA-N hydron;1-methyl-n-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)indazole-3-carboxamide;chloride Chemical compound Cl.C1=CC=C2C(C(=O)NC3CC4CCCC(C3)N4C)=NN(C)C2=C1 QYZRTBKYBJRGJB-UHFFFAOYSA-N 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000002156 mixing Methods 0.000 claims abstract description 42
- 239000000853 adhesive Substances 0.000 claims abstract description 25
- 230000001070 adhesive effect Effects 0.000 claims abstract description 25
- 239000000463 material Substances 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 23
- 239000000945 filler Substances 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000000314 lubricant Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000005550 wet granulation Methods 0.000 claims abstract description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 82
- 239000008101 lactose Substances 0.000 claims description 81
- 239000011248 coating agent Substances 0.000 claims description 51
- 238000000576 coating method Methods 0.000 claims description 51
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 50
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 41
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 41
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 41
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 41
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 28
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 28
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 28
- 229920002472 Starch Polymers 0.000 claims description 25
- 235000019359 magnesium stearate Nutrition 0.000 claims description 25
- 239000008107 starch Substances 0.000 claims description 25
- 235000019698 starch Nutrition 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 24
- 229910052708 sodium Inorganic materials 0.000 claims description 24
- 239000002245 particle Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 21
- 238000004806 packaging method and process Methods 0.000 claims description 19
- 239000007888 film coating Substances 0.000 claims description 18
- 238000009501 film coating Methods 0.000 claims description 18
- 238000007873 sieving Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 239000011230 binding agent Substances 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 13
- 239000007779 soft material Substances 0.000 claims description 13
- 229960003943 hypromellose Drugs 0.000 claims description 11
- 229920001328 Polyvinylidene chloride Polymers 0.000 claims description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 10
- 229910052782 aluminium Inorganic materials 0.000 claims description 10
- 239000002131 composite material Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 239000011888 foil Substances 0.000 claims description 10
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 10
- 239000004800 polyvinyl chloride Substances 0.000 claims description 10
- 239000005033 polyvinylidene chloride Substances 0.000 claims description 10
- 238000007908 dry granulation Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 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
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims 1
- 229940032147 starch Drugs 0.000 claims 1
- 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 71
- 229960001375 lactose Drugs 0.000 description 71
- 239000003826 tablet Substances 0.000 description 71
- 238000004513 sizing Methods 0.000 description 28
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 23
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 21
- 239000000843 powder Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 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 description 17
- 230000000052 comparative effect Effects 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 3
- -1 nonan-3-yl Chemical group 0.000 description 3
- 239000006191 orally-disintegrating tablet Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000005414 inactive ingredient Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 210000002322 enterochromaffin cell Anatomy 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (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 discloses a stable granisetron hydrochloride tablet and a preparation method thereof, wherein the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight: 0.5 to 1.7 portions of granisetron hydrochloride, 80.4 to 102.4 portions of filler, 2 to 7 portions of disintegrating agent, 1 to 5 portions of adhesive and 0.6 to 1.4 portions of lubricant. The granisetron hydrochloride tablet and the preparation method thereof provided by the invention have the advantages that the quality is stable, the granisetron hydrochloride tablet with good uniformity is prepared by uniformly mixing raw material medicine granisetron hydrochloride auxiliary materials through the methods of premixing, wet granulation and the like, and the uniformity and the stability of the product are improved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to granisetron hydrochloride tablets and a preparation method thereof.
Background
Granisetron hydrochloride (Granisetron Hydrochloride), chemical name 1-methyl-N- (endo-9-methyl-9-azabicyclo [3.3.1] nonan-3-yl) -IH-indazole-3-carboxamide hydrochloride, molecular formula C 18H34N4 O. HCl, molecular weight 348.87, is a selective 5-hydroxytryptamine (5-HT 3) receptor antagonist for the treatment of nausea and vomiting caused by chemotherapy and radiotherapy, and prevention of nausea after surgery. Chemotherapy and radiotherapy can enable the enterochromaffin cells to release 5-HT and activate 5-HT 3 receptors to cause emesis reflex, and granisetron hydrochloride can prevent and treat nausea and emesis by antagonizing 5-HT 3 receptors of peripheral and central nervous systems.
Granisetron hydrochloride tablet was originally developed by the company SMITHKLINE BEECHAM in the united kingdom (now GlaxoSmithKline) and the tablet was first marketed in italy.
The granisetron hydrochloride serving as a pharmaceutical active ingredient in the granisetron hydrochloride tablet is 1mg, the granisetron hydrochloride tablet is a tablet with low drug loading, the mixing uniformity is a problem to be solved in the preparation process of the granisetron hydrochloride tablet, and in addition, the granisetron hydrochloride tablet has certain hygroscopicity and critical relative humidity of 67 percent according to the compound characteristics of the granisetron hydrochloride.
The prior preparation method of granisetron hydrochloride tablets is mainly orally disintegrating tablets, such as Chinese patent application number CN200310121906, and discloses granisetron hydrochloride orally disintegrating tablets and a preparation method thereof, and microcrystalline cellulose, crosslinked polyvinylpyrrolidone, low-substituted polypropylene cellulose, crosslinked carboxymethyl starch sodium or a mixture of the microcrystalline cellulose, the crosslinked polyvinylpyrrolidone, the low-substituted polypropylene cellulose and the crosslinked carboxymethyl starch sodium are adopted as disintegrating agents, and the preparation method is characterized in that the granisetron hydrochloride tablets can be rapidly disintegrated in an oral cavity without water or with a small amount of water. Chinese patent application No. CN201110176824 discloses a granisetron hydrochloride freeze-dried tablet and a preparation method thereof, glycine or mannitol or a mixture thereof, pullulan or sodium alginate or a mixture thereof are adopted as a skeleton support agent and an adhesive, and prepared matrix liquid is subjected to prefreezing and freeze-drying processes to obtain the granisetron hydrochloride freeze-dried tablet, which is characterized in that the granisetron hydrochloride freeze-dried tablet can be rapidly disintegrated in an oral cavity without water.
However, the orally disintegrating tablets prepared by tabletting or freeze drying have the problems of small hardness, low mechanical strength and high friability due to the characteristics of the process, and the problems of strict requirements on the production process and conditions, strict requirements on the processes of packaging, storage, transportation and the like are brought along with high cost, so that the wide application of the product is limited. Therefore, there is still a need to develop a stable granisetron hydrochloride tablet with simple preparation process and good mixing uniformity, and a moisture-proof and light-proof packaging method. No patent is disclosed before on the preparation method of the granisetron hydrochloride oral solid tablet.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problem of providing a stable granisetron hydrochloride tablet and a preparation method thereof aiming at the defects of the prior art.
In order to solve the technical problems, the invention discloses the following technical scheme:
in a first aspect, the present invention discloses a granisetron hydrochloride tablet.
In some embodiments, the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight:
wherein the filler comprises lactose.
In some embodiments, the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight:
wherein the filler comprises lactose.
In some embodiments, the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight:
wherein the filler comprises lactose.
In some embodiments, the preparation raw materials of the granisetron hydrochloride tablet further comprise a coating material; preferably, the weight part of granisetron hydrochloride to the coating material is 0.5-1.7:2-4, preferably 0.8-1.4:2.5-3.5, preferably 1.1:3.
In some embodiments, the granisetron hydrochloride tablet is prepared by the following method:
(1) Mixing the granisetron hydrochloride bulk drug with part of lactose to obtain a premix; the partial lactose accounts for 40% -60% of the total mass of lactose;
(2) Mixing the residual lactose with other fillers, and the obtained premix, and granulating to obtain a mixture;
(3) Wet granulating the obtained mixture, a disintegrating agent and a binder solution to obtain an intermediate;
(4) Mixing the obtained intermediate with a lubricant, and tabletting;
(5) The obtained plain tablet is coated by a coating material;
(6) And after coating, adopting polyvinyl chloride/polyvinylidene chloride solid medicinal composite hard tablets and medicinal aluminum foil for packaging.
In a second aspect, the invention discloses a preparation method of granisetron hydrochloride tablets.
In some embodiments, the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight:
wherein the filler comprises lactose.
In some embodiments, the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight:
wherein the filler comprises lactose.
In some embodiments, the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight:
wherein the filler comprises lactose.
In some embodiments, the preparation raw materials of the granisetron hydrochloride tablet further comprise a coating material; preferably, the weight part of granisetron hydrochloride to the coating material is 0.5-1.7:2-4, preferably 0.8-1.4:2.5-3.5, preferably 1.1:3.
In some embodiments, the preparation method of granisetron hydrochloride comprises the following steps:
(1) Pulverizing granisetron hydrochloride raw material, and mixing with part of lactose to obtain a premix; the partial lactose accounts for 40% -60% of the total mass of lactose;
(2) Mixing the residual lactose with other fillers, and the obtained premix, and granulating to obtain a mixture;
(3) Wet granulating the obtained mixture, a disintegrating agent and a binder solution to obtain an intermediate;
(4) Mixing the obtained intermediate with a lubricant, and tabletting;
(5) The obtained plain tablet is coated by a coating material;
(6) And after coating, adopting polyvinyl chloride/polyvinylidene chloride solid medicinal composite hard tablets and medicinal aluminum foil for packaging.
In the first technical problem and the second technical problem described above,
The granisetron hydrochloride is obtained by crushing granisetron hydrochloride bulk drugs and sieving the crushed bulk drugs with a 60-80-mesh sieve; preferably, the D90 of the granisetron hydrochloride is 10-20 mu m; preferably, the D50 of granisetron hydrochloride is 10 μm or more.
The filler also comprises starch and/or microcrystalline cellulose, preferably microcrystalline cellulose; preferably, the mass ratio of the starch and/or microcrystalline cellulose to lactose is 1:1.1-4.3, preferably 1:1.3-3.8, preferably 1:1.5-3.3; preferably, the lactose has a particle size of 90 μm or less; preferably, the particle size of the starch and microcrystalline cellulose is 40 to 80 μm.
The disintegrating agent is any one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium, preferably carboxymethyl starch sodium, and preferably carboxymethyl starch sodium with sodium content of 2.0-4.0%.
The adhesive is any one or more of hydroxypropyl cellulose, ethyl cellulose and hypromellose, preferably hypromellose, and preferably has a viscosity of 3 to 20 cPs.
The lubricant is any one or more of stearic acid, magnesium stearate and sodium stearate fumarate, preferably magnesium stearate, and preferably lubricant passing through a 60-80 mesh sieve.
The coating material is gastric-soluble film coating premix.
In step (1), the fraction of lactose is 45% -55%, preferably 50% of the total mass of lactose.
In the step (2), the premix is sieved by a sieve with 30 meshes in a granulator, the rest lactose is added for repeated sieving for 2-5 times, and the rest filling agent is added for granulating and sieving to obtain a mixture; the rotation speed is 800-1200 rpm, preferably 1000rpm.
In the step (3), the adhesive solution is an aqueous solution of an adhesive; the binder solution has a binder solids content of 3%g to 13% g/ml, preferably 5 to 10% g/ml, preferably 7%g/ml.
In the step (3), the wet granulation is to premix the obtained mixture with a disintegrating agent in a wet granulator, add a binder solution to prepare a soft material, wet granulation, drying and dry granulation; preferably, during premixing, the rotation speed of the stirring blade is 90-120 rpm, and the rotation speed of the chopping blade is 800-1000 rpm; preferably, when the soft material is prepared, the rotating speed of the stirring knife is 100-150 rpm, the rotating speed of the chopping knife is 1000-1500 rpm, and the mixing time is more than 10 min; preferably, the mesh size of the wet granulation screen is 3mm; preferably, the screen mesh size at the time of dry granulation is 1mm; preferably, the drying temperature is 40-50 ℃.
In the step (4), the mixing is carried out for 1 to 3 times in a mixer; preferably, the charging coefficient of the mixer is 45% -70%; preferably, the rotation speed of the mixer is 10-20 rpm during mixing; preferably, the mixing time is 1-5 min; preferably, during the tabletting process, the ambient humidity is controlled below 65%, such as 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, etc.; preferably, in the tabletting process, the weight difference of tablets is controlled to be +/-5%, and the hardness is controlled to be 3.0-6.0 kg.
In the step (5), the weight is increased by 2.0-5.0% after coating.
The beneficial effects are that:
the granisetron hydrochloride tablet and the preparation method thereof provided by the invention have the advantages that the quality is stable, the granisetron hydrochloride tablet with good uniformity is prepared by uniformly mixing raw material medicine granisetron hydrochloride auxiliary materials through the methods of premixing, wet granulation and the like, and the uniformity and the stability of the product are improved.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings and detailed description.
FIG. 1 is a dissolution profile of example 1 and comparative examples 1-4.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, are commercially available.
The weight of the tablet is 104mg, the granisetron hydrochloride active ingredient is removed, the dosage of auxiliary materials is large, the lactose used in the preparation method is spray-dried lactose, the particle size is smaller than 90 mu m, the particle size of microcrystalline cellulose is 40-80 mu m, and the viscosity of hydroxypropyl methylcellulose is 3-20 cPs; the dosage is within the published range of FDA inactive ingredient database (INACTIVE INGREDIENT SEARCH for Approved Drug Products).
The hydroxypropyl methylcellulose is an excellent water-soluble adhesive and gastric-soluble coating material, is prepared from natural cellulose through chemical modification, has greatly improved water solubility and stability compared with the natural cellulose, has the characteristics and application of emulsification, adhesion, gel, suspension, tackifying, film forming and the like, and is widely applied in the field of pharmacy. The hydroxypropyl methylcellulose has stronger viscosity, can strengthen the particle viscosity of raw materials, and improves the compressibility of the hydroxypropyl methylcellulose; the aqueous solution has excellent film forming performance, and the formed film has the characteristics of no color, toughness and stable chemical property, can greatly improve the stability of the medicine as an isolating layer, and is a good coating material for tablets.
The carboxymethyl starch sodium is a common tablet disintegrating agent with excellent performance, has very remarkable water absorption expansion effect, can expand to 300 times of the original volume, does not form colloidal solution, and does not prevent the continuous infiltration of moisture, so that the further disintegration of the tablet is not affected.
The magnesium stearate has good lubrication effect, is easy to mix with particles uniformly, can lead the surface of the tablet to be smooth and beautiful, has no incompatibility with granisetron, and has good compatibility.
The lactose accounting for 50% of the formula weight in the invention is 50% of the total mass of lactose in the formula unless otherwise specified.
The unit of the solid content is g/ml in the invention.
The film coating premix described in the examples below is a karekang YS-1-7-003-CN gastric-soluble film coating premix.
The sodium content of carboxymethyl starch sodium in the examples described below is 3.2%.
The parameters for crushing by the hammer crusher in the following examples are 7000-9000rpm, which can be specifically controlled according to the particle size requirement.
Example 1
A preparation method of stable granisetron hydrochloride tablets, when 10,00 tablets are produced, comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: weighing 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of microcrystalline cellulose, 4 parts of carboxymethyl starch sodium, 2 parts of hydroxypropyl methylcellulose, 1 part of magnesium stearate and 3 parts of film coating premix according to the weight ratio. Wherein the lactose particle size is smaller than 90 mu m, the microcrystalline cellulose particle size is 40-60 mu m, and the hydroxypropyl methylcellulose viscosity is 4.9mP.s. The granisetron hydrochloride bulk drug is crushed into micro powder by a hammer crusher, the micro powder is sieved by a 60-mesh sieve, D90 is 10-20 mu m, D50 is more than 10 mu m, and the micro powder is mixed with lactose with the formula amount of 50% to obtain granisetron hydrochloride lactose premix. Magnesium stearate was sieved through a 60 mesh screen. Adhesive configuration: the formulated amount of hypromellose and purified water were placed in a beaker and formulated into a binder solution having a solids content (g/ml) of 7%.
(2) Mixing and granulating: and (3) taking the granisetron hydrochloride lactose premix rotary granulator in the step (1), sieving by a 30-mesh sieve, continuously putting the rest lactose into the rotary granulator, continuously repeatedly sieving for 3 times, putting microcrystalline cellulose into the rotary granulator again for granulating, and obtaining the granisetron hydrochloride lactose microcrystalline cellulose mixture at the rotating speed of 1000 rpm.
(3) Granulating: adding the granisetron hydrochloride microcrystalline cellulose mixture and carboxymethyl starch sodium in the step (2) into a wet granulator for premixing, wherein the rotation speed of a stirring knife is 100rpm, the rotation speed of a chopping knife is 900rpm, adding the adhesive solution prepared in the step (1) after premixing, preparing a soft material, wherein the rotation speed of the stirring knife is 130rpm, the rotation speed of the chopping knife is 1200rpm, and granulating for 15 minutes. Wet sizing is carried out by a mobile sizing machine through a 3mm screen, the wet sizing is carried out in a drying oven at 50 ℃ until the water content is less than 3%, and then dry sizing is carried out through a 1mm screen.
(4) Total mixing: and (3) adding the intermediate obtained in the step (3) into a total mixer, adding magnesium stearate with the formula amount, mixing for 2 minutes at 12rpm, and setting the charging coefficient to be 45% -70%.
(5) Tabletting: and (3) loading the intermediate obtained in the step (4) into a die for tabletting, wherein the ambient humidity is 53%, calculating the weight of the tablet according to the intermediate content result, controlling the weight difference of the tablet to be +/-5%, and controlling the hardness to be 3.0-6.0 kg/mm.
(6) Coating: and (3) preparing a proper amount of coating liquid by using a formula amount of a film coating premix of the karekang YS-1-7-003-CN, and adding the plain tablets obtained in the step (5) into a coating machine for coating, wherein the weight of the coating is increased by 2.0-5.0%.
(7) And (3) packaging: the polyvinyl chloride/polyvinylidene chloride solid medical composite hard sheet and medical aluminum foil are adopted for packaging.
Example 2
A preparation method of stable granisetron hydrochloride tablets, when 10,00 tablets are produced, comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: weighing 1.1 parts of granisetron hydrochloride, 55.4 parts of lactose, 37 parts of microcrystalline cellulose, 4 parts of carboxymethyl starch sodium, 2 parts of hydroxypropyl methylcellulose, 1 part of magnesium stearate and 3 parts of film coating premix according to the weight ratio. Wherein the lactose particle size is smaller than 90 mu m, the microcrystalline cellulose particle size is 40-60 mu m, and the hydroxypropyl methylcellulose viscosity is 4.9mP.s. The granisetron hydrochloride bulk drug is crushed into micro powder by a hammer crusher, the micro powder is sieved by a 60-mesh sieve, D90 is 10-20 mu m, D50 is more than 10 mu m, and the micro powder is mixed with lactose with the formula amount of 50% to obtain granisetron hydrochloride lactose premix. Magnesium stearate was sieved through a 60 mesh screen. Adhesive configuration: the formulated amount of hypromellose and purified water were placed in a beaker and formulated into a binder solution having a solids content (g/ml) of 7%.
(2) Mixing and granulating: and (3) taking the granisetron hydrochloride lactose premix rotary granulator in the step (1), sieving by a 30-mesh sieve, continuously putting the rest lactose into the rotary granulator, continuously repeatedly sieving for 3 times, putting microcrystalline cellulose into the rotary granulator again for granulating, and obtaining the granisetron hydrochloride lactose microcrystalline cellulose mixture at the rotating speed of 1000 rpm.
(3) Granulating: adding the granisetron hydrochloride microcrystalline cellulose mixture and carboxymethyl starch sodium in the step (2) into a wet granulator for premixing, wherein the rotation speed of a stirring knife is 100rpm, the rotation speed of a chopping knife is 900rpm, adding the adhesive solution prepared in the step (1) after premixing, preparing a soft material, wherein the rotation speed of the stirring knife is 130rpm, the rotation speed of the chopping knife is 1200rpm, and granulating for 15 minutes. Wet sizing is carried out by a mobile sizing machine through a 3mm screen, the wet sizing is carried out in a drying oven at 50 ℃ until the water content is less than 3%, and then dry sizing is carried out through a 1mm screen.
(4) Total mixing: and (3) adding the intermediate obtained in the step (3) into a total mixer, adding magnesium stearate with the formula amount, mixing for 2 minutes at 12rpm, and setting the charging coefficient to be 45% -70%.
(5) Tabletting: and (3) loading the intermediate obtained in the step (4) into a die for tabletting, wherein the ambient humidity is 57%, calculating the weight of the tablet according to the intermediate content result, controlling the weight difference of the tablet to be +/-5%, and controlling the hardness to be 3.0-6.0 kg/mm.
(6) Coating: and (3) preparing a proper amount of coating liquid by using a formula amount of a film coating premix of the karekang YS-1-7-003-CN, and adding the plain tablets obtained in the step (5) into a coating machine for coating, wherein the weight of the coating is increased by 2.0-5.0%.
(7) And (3) packaging: the polyvinyl chloride/polyvinylidene chloride solid medical composite hard sheet and medical aluminum foil are adopted for packaging.
Example 3
A preparation method of stable granisetron hydrochloride tablets, when 10,00 tablets are produced, comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: weighing 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 21 parts of microcrystalline cellulose, 5 parts of carboxymethyl starch sodium, 3 parts of hydroxypropyl methylcellulose, 1 part of magnesium stearate and 3 parts of film coating premix according to the weight ratio. Wherein the lactose particle size is smaller than 90 mu m, the microcrystalline cellulose particle size is 40-60 mu m, and the hydroxypropyl methylcellulose viscosity is 4.9mP.s. The granisetron hydrochloride bulk drug is crushed into micro powder by a hammer crusher, the micro powder is sieved by a 60-mesh sieve, D90 is 10-20 mu m, D50 is more than 10 mu m, and the micro powder is mixed with lactose with the formula amount of 50% to obtain granisetron hydrochloride lactose premix. Magnesium stearate was sieved through a 60 mesh screen. Adhesive configuration: the formulated amount of hypromellose and purified water were placed in a beaker and formulated into a binder solution having a solids content (g/ml) of 7%.
(2) Mixing and granulating: and (3) taking the granisetron hydrochloride lactose premix rotary granulator in the step (1), sieving by a 30-mesh sieve, continuously putting the rest lactose into the rotary granulator, continuously repeatedly sieving for 3 times, putting microcrystalline cellulose into the rotary granulator again for granulating, and obtaining the granisetron hydrochloride lactose microcrystalline cellulose mixture at the rotating speed of 1000 rpm.
(3) Granulating: adding the granisetron hydrochloride microcrystalline cellulose mixture and carboxymethyl starch sodium in the step (2) into a wet granulator for premixing, wherein the rotation speed of a stirring knife is 100rpm, the rotation speed of a chopping knife is 900rpm, adding the adhesive solution prepared in the step (1) after premixing, preparing a soft material, wherein the rotation speed of the stirring knife is 130rpm, the rotation speed of the chopping knife is 1200rpm, and granulating for 15 minutes. Wet sizing is carried out by a mobile sizing machine through a 3mm screen, the wet sizing is carried out in a drying oven at 50 ℃ until the water content is less than 3%, and then dry sizing is carried out through a 1mm screen.
(4) Total mixing: and (3) adding the intermediate obtained in the step (3) into a total mixer, adding magnesium stearate with the formula amount, mixing for 2 minutes at 12rpm, and setting the charging coefficient to be 45% -70%.
(5) Tabletting: and (3) loading the intermediate obtained in the step (4) into a die for tabletting, wherein the ambient humidity is 52%, calculating the weight of the tablet according to the intermediate content result, controlling the weight difference of the tablet to be +/-5%, and controlling the hardness to be 3.0-6.0 kg/mm.
(6) Coating: and (3) preparing a proper amount of coating liquid by using a formula amount of a film coating premix of the karekang YS-1-7-003-CN, and adding the plain tablets obtained in the step (5) into a coating machine for coating, wherein the weight of the coating is increased by 2.0-5.0%.
(7) And (3) packaging: the polyvinyl chloride/polyvinylidene chloride solid medical composite hard sheet and medical aluminum foil are adopted for packaging.
Comparative example 1
The preparation method of granisetron hydrochloride tablet wet granulation comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: weighing 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 21 parts of microcrystalline cellulose, 5 parts of carboxymethyl starch sodium, 3 parts of hydroxypropyl methylcellulose, 1 part of magnesium stearate and 3 parts of film coating premix according to the weight ratio. Wherein the lactose particle size is smaller than 90 mu m, the microcrystalline cellulose particle size is 40-60 mu m, and the hydroxypropyl methylcellulose viscosity is 4.9mP.s. The granisetron hydrochloride bulk drug is crushed into micro powder by a hammer crusher, and the micro powder is sieved by a 60-mesh sieve, wherein D90 is 10-20 mu m, and D50 is more than 10 mu m. Magnesium stearate was sieved through a 60 mesh screen. Adhesive configuration: the formulated amount of hypromellose and purified water were placed in a beaker and formulated into a binder solution having a solids content (g/ml) of 7%.
(2) Mixing and granulating: and (3) respectively taking the granisetron hydrochloride rotary granulator in the step (1), sieving by a 30-mesh sieve, putting lactose into the rotary granulator, putting microcrystalline cellulose into the rotary granulator, and granulating at the rotating speed of 1000rpm to respectively obtain granisetron hydrochloride, lactose and microcrystalline cellulose.
(3) Granulating: adding granisetron hydrochloride, lactose, microcrystalline cellulose and carboxymethyl starch sodium in the step (2) into a wet granulator for premixing, wherein the rotation speed of a stirring knife is 100rpm, the rotation speed of a chopping knife is 900rpm, adding the adhesive solution prepared in the step (1) after premixing, preparing a soft material, wherein the rotation speed of the stirring knife is 130rpm when preparing the soft material, the rotation speed of the chopping knife is 1200rpm, and granulating for 15 minutes. Wet sizing is carried out by a mobile sizing machine through a 3mm screen, the wet sizing is carried out in a drying oven at 50 ℃ until the water content is less than 3%, and then dry sizing is carried out through a 1mm screen.
(4) Total mixing: and (3) adding the intermediate obtained in the step (3) into a total mixer, adding magnesium stearate with the formula amount, mixing for 2 minutes at 12rpm, and setting the charging coefficient to be 45% -70%.
(5) Tabletting: and (3) loading the intermediate obtained in the step (4) into a die for tabletting, wherein the ambient humidity is 52%, calculating the weight of the tablet according to the intermediate content result, controlling the weight difference of the tablet to be +/-5%, and controlling the hardness to be 3.0-6.0 kg/mm.
(6) Coating: and (3) preparing a proper amount of coating liquid by using a formula amount of a film coating premix of the karekang YS-1-7-003-CN, and adding the plain tablets obtained in the step (5) into a coating machine for coating, wherein the weight of the coating is increased by 2.0-5.0%.
(7) And (3) packaging: the polyvinyl chloride/polyvinylidene chloride solid medical composite hard sheet and medical aluminum foil are adopted for packaging.
Comparative example 2
The granisetron hydrochloride bulk drug is crushed and then detected to have larger granularity than that of example 1, and when 10,00 tablets are produced, the preparation method comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: weighing 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of microcrystalline cellulose, 4 parts of carboxymethyl starch sodium, 2 parts of hydroxypropyl methylcellulose, 1 part of magnesium stearate and 3 parts of film coating premix according to the weight ratio. Wherein the lactose particle size is smaller than 90 mu m, the microcrystalline cellulose particle size is 40-60 mu m, and the hydroxypropyl methylcellulose viscosity is 4.9mP.s. The granisetron hydrochloride bulk drug is crushed into micro powder by a hammer crusher, the micro powder is sieved by a 60-mesh sieve, D90 is 40-60 mu m, D50 is more than 20 mu m, and the micro powder is mixed with lactose with the formula amount of 50% to obtain granisetron hydrochloride lactose premix. Magnesium stearate was sieved through a 60 mesh screen. Adhesive configuration: the formulated amount of hypromellose and purified water were placed in a beaker and formulated into a binder solution having a solids content (g/ml) of 7%.
(2) Mixing and granulating: and (3) taking the granisetron hydrochloride lactose premix rotary granulator in the step (1), sieving by a 30-mesh sieve, continuously putting the rest lactose into the rotary granulator, continuously repeatedly sieving for 3 times, putting microcrystalline cellulose into the rotary granulator again for granulating, and obtaining the granisetron hydrochloride lactose microcrystalline cellulose mixture at the rotating speed of 1000 rpm.
(3) Granulating: adding the granisetron hydrochloride microcrystalline cellulose mixture and carboxymethyl starch sodium in the step (2) into a wet granulator for premixing, wherein the rotation speed of a stirring knife is 100rpm, the rotation speed of a chopping knife is 900rpm, adding the adhesive solution prepared in the step (1) after premixing, preparing a soft material, wherein the rotation speed of the stirring knife is 130rpm, the rotation speed of the chopping knife is 1200rpm, and granulating for 15 minutes. Wet sizing is carried out by a mobile sizing machine through a 3mm screen, the wet sizing is carried out in a drying oven at 50 ℃ until the water content is less than 3%, and then dry sizing is carried out through a 1mm screen.
(4) Total mixing: and (3) adding the intermediate obtained in the step (3) into a total mixer, adding magnesium stearate with the formula amount, mixing for 2 minutes at 12rpm, and setting the charging coefficient to be 45% -70%.
(5) Tabletting: and (3) loading the intermediate obtained in the step (4) into a die for tabletting, wherein the ambient humidity is 55%, calculating the weight of the tablet according to the intermediate content result, controlling the weight difference of the tablet to be +/-5%, and controlling the hardness to be 3.0-6.0 kg/mm.
(6) Coating: and (3) preparing a proper amount of coating liquid by using a formula amount of a film coating premix of the karekang YS-1-7-003-CN, and adding the plain tablets obtained in the step (5) into a coating machine for coating, wherein the weight of the coating is increased by 2.0-5.0%.
(7) And (3) packaging: the polyvinyl chloride/polyvinylidene chloride solid medical composite hard sheet and medical aluminum foil are adopted for packaging.
Comparative example 3
Granisetron hydrochloride has a smaller particle size than the examples after comminution, and when it is produced in 10,00 tablets, it comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: weighing 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of microcrystalline cellulose, 4 parts of carboxymethyl starch sodium, 2 parts of hydroxypropyl methylcellulose, 1 part of magnesium stearate and 3 parts of film coating premix according to the weight ratio. Wherein the lactose particle size is smaller than 90 mu m, the microcrystalline cellulose particle size is 40-60 mu m, and the hydroxypropyl methylcellulose viscosity is 4.9mP.s. The granisetron hydrochloride bulk drug is crushed into micro powder by using a jet mill, and is sieved by a 60-mesh sieve, wherein D90 is smaller than 9 mu m, D50 is smaller than 5 mu m, and then the micro powder is mixed with lactose with the formula amount of 50% to obtain granisetron hydrochloride lactose premix. Magnesium stearate was sieved through a 60 mesh screen. Adhesive configuration: the formulated amount of hypromellose and purified water were placed in a beaker and formulated into a binder solution having a solids content (g/ml) of 7%.
(2) Mixing and granulating: and (3) taking the granisetron hydrochloride lactose premix rotary granulator in the step (1), sieving by a 30-mesh sieve, continuously putting the rest lactose into the rotary granulator, continuously repeatedly sieving for 3 times, putting microcrystalline cellulose into the rotary granulator again for granulating, and obtaining the granisetron hydrochloride lactose microcrystalline cellulose mixture at the rotating speed of 1000 rpm.
(3) Granulating: adding the granisetron hydrochloride microcrystalline cellulose mixture and carboxymethyl starch sodium in the step (2) into a wet granulator for premixing, wherein the rotation speed of a stirring knife is 100rpm, the rotation speed of a chopping knife is 900rpm, adding the adhesive solution prepared in the step (1) after premixing, preparing a soft material, wherein the rotation speed of the stirring knife is 130rpm, the rotation speed of the chopping knife is 1200rpm, and granulating for 15 minutes. Wet sizing is carried out by a mobile sizing machine through a 3mm screen, the wet sizing is carried out in a drying oven at 50 ℃ until the water content is less than 3%, and then dry sizing is carried out through a 1mm screen.
(4) Total mixing: and (3) adding the intermediate obtained in the step (3) into a total mixer, adding magnesium stearate with the formula amount, mixing for 2 minutes at 12rpm, and setting the charging coefficient to be 45% -70%.
(5) Tabletting: and (3) loading the intermediate obtained in the step (4) into a die for tabletting, wherein the ambient humidity is 54%, calculating the weight of the tablet according to the intermediate content result, controlling the weight difference of the tablet to be +/-5%, and controlling the hardness to be 3.0-6.0 kg/mm.
(6) Coating: and (3) preparing a proper amount of coating liquid by using a formula amount of a film coating premix of the karekang YS-1-7-003-CN, and adding the plain tablets obtained in the step (5) into a coating machine for coating, wherein the weight of the coating is increased by 2.0-5.0%.
(7) And (3) packaging: the polyvinyl chloride/polyvinylidene chloride solid medical composite hard sheet and medical aluminum foil are adopted for packaging.
Comparative example 4
The granisetron hydrochloride microcrystalline cellulose is replaced by corn starch, and when 10,00 tablets are produced, the preparation method comprises the following steps:
(1) Pretreatment of raw materials and auxiliary materials: weighing 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of corn starch, 4 parts of carboxymethyl starch sodium, 2 parts of hydroxypropyl methylcellulose, 1 part of magnesium stearate and 3 parts of film coating premix according to the weight ratio. Wherein, the grain diameter of lactose is smaller than 90 mu m, the grain diameter of corn starch is 40-80 mu m, and the viscosity of hypromellose is 4.9mP. The granisetron hydrochloride bulk drug is crushed into micro powder by a hammer crusher, the micro powder is sieved by a 60-mesh sieve, D90 is 10-20 mu m, D50 is more than 10 mu m, and the micro powder is mixed with lactose with the formula amount of 50% to obtain granisetron hydrochloride lactose premix. Magnesium stearate was sieved through a 60 mesh screen. Adhesive configuration: the formulated amount of hypromellose and purified water were placed in a beaker and formulated into a binder solution having a solids content (g/ml) of 7%.
(2) Mixing and granulating: and (3) taking the granisetron hydrochloride lactose premix rotary granulator in the step (1), sieving by a 30-mesh sieve, continuously putting the rest lactose into the rotary granulator, continuously repeatedly sieving for 3 times, putting the corn starch into the rotary granulator again for granulating, and obtaining the granisetron hydrochloride lactose corn starch mixture at the rotating speed of 1000 rpm.
(3) Granulating: adding the granisetron hydrochloride lactose corn starch mixture and carboxymethyl starch sodium in the step (2) into a wet granulator for premixing, wherein the rotation speed of a stirring knife is 100rpm, the rotation speed of a chopping knife is 900rpm, adding the adhesive solution prepared in the step (1) after premixing, preparing a soft material, wherein the rotation speed of the stirring knife is 130rpm when preparing the soft material, the rotation speed of the chopping knife is 1200rpm, and granulating for 15 minutes. Wet sizing is carried out by a mobile sizing machine through a 3mm screen, the wet sizing is carried out in a drying oven at 50 ℃ until the water content is less than 3%, and then dry sizing is carried out through a 1mm screen.
(4) Total mixing: and (3) adding the intermediate obtained in the step (3) into a total mixer, adding magnesium stearate with the formula amount, mixing for 2 minutes at 12rpm, and setting the charging coefficient to be 45% -70%.
(5) Tabletting: and (3) loading the intermediate obtained in the step (4) into a die for tabletting, wherein the ambient humidity is 59%, calculating the weight of the tablet according to the intermediate content result, controlling the weight difference of the tablet to be +/-5%, and controlling the hardness to be 3.0-6.0 kg/mm.
(6) Coating: and (3) preparing a proper amount of coating liquid by using a formula amount of a film coating premix of the karekang YS-1-7-003-CN, and adding the plain tablets obtained in the step (5) into a coating machine for coating, wherein the weight of the coating is increased by 2.0-5.0%.
(7) And (3) packaging: the polyvinyl chloride/polyvinylidene chloride solid medical composite hard sheet and medical aluminum foil are adopted for packaging.
Test 1
The content uniformity of the product in the example 1 is measured, the experimental results are shown in the following table, the RSD of the measurement results of three batches of samples with the content uniformity is less than 3.0%, and the content uniformity meets the regulations; the content uniformity measurement was performed in example 2 and example 3, and the experimental results showed that the RSD of the samples of example 2 and example 3 was 1.2% to 1.6%, and the content uniformity was in accordance with the regulations.
| Sample lot number | 01 | 02 | 03 |
| 1 | 101.80％ | 102.43％ | 102.11％ |
| 2 | 99.35％ | 101.36％ | 99.67％ |
| 3 | 99.23％ | 98.92％ | 99.17％ |
| 4 | 101.05％ | 102.30％ | 101.62％ |
| 5 | 99.17％ | 98.73％ | 101.67％ |
| 6 | 101.61％ | 100.73％ | 100.86％ |
| 7 | 99.54％ | 101.98％ | 99.29％ |
| 8 | 101.05％ | 98.67％ | 100.86％ |
| 9 | 98.86％ | 100.92％ | 98.92％ |
| 10 | 101.36％ | 98.29％ | 101.98％ |
| X bar | 100.30％ | 100.43％ | 100.62％ |
| RSD | 1.2％ | 1.6％ | 1.2％ |
Note that: x bar: average of 10 pieces content; RSD (%): and determining the uniformity of the powder content.
Test 2
The product of the above example 1 was subjected to a study of placing the product for 10 days at a high temperature of 40 ℃/60 ℃ under light of 4500.+ -.500 lux/h and a high humidity RH of 75%/RH of 92.5%), a test of accelerating stability (40 ℃/75%) for 6 months and a test of long-term stability (30 ℃/65%) for 24 months, and the properties, dissolution (measured by a paddle method of 50rpm, 900ml of phosphate buffer at pH6.8, and a dissolution rate apparatus 2 of Chinese pharmacopoeia at 37 ℃), and the comparison of the contents of the relevant substances. The characters and the content of each time point of the self-made product meet the regulations.
Test 3
The samples prepared in example 1 were subjected to a multi-medium dissolution profile assay using 900ml of phosphate buffer at 50rpm, pH6.8, and a Chinese pharmacopoeia dissolution apparatus 2 at 37 ℃. Experimental results show that the preparation provided by the invention has good dissolution uniformity, the dissolution is uniform, and the dissolution curves of three batches of samples are in accordance with the regulations.
The products obtained in comparative examples 1 to 4 were examined:
1. content uniformity was tested according to test 1 and the results were as follows:
| Lot number | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 |
| 1 | 93.06％ | 103.87％ | 102.23％ | 101.14％ |
| 2 | 105.40％ | 101.87％ | 102.50％ | 102.77％ |
| 3 | 108.48％ | 98.67％ | 100.08％ | 98.92％ |
| 4 | 101.21％ | 95.81％ | 98.44％ | 98.04％ |
| 5 | 98.31％ | 99.64％ | 97.07％ | 100.73％ |
| 6 | 106.65％ | 98.46％ | 99.14％ | 97.02％ |
| 7 | 107.08％ | 102.93％ | 98.04％ | 99.48％ |
| 8 | 104.75％ | 100.62％ | 98.73％ | 97.40％ |
| 9 | 100.27％ | 98.69％ | 98.48％ | 100.56％ |
| 10 | 106.79％ | 101.34％ | 102.29％ | 101.61％ |
| X bar | 103.20％ | 100.19％ | 99.70％ | 99.77％ |
| RSD | 4.7％ | 2.4％ | 2.0％ | 1.9％ |
2. The test was carried out according to test 2 (high temperature 40 ℃ C.), and the results were as follows:
3. the dissolution rate was measured according to test 3, and the result is shown in FIG. 1.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The granisetron hydrochloride tablet is characterized by being prepared from the following raw materials in parts by weight:
0.5-1.7 parts of granisetron hydrochloride
80.4-102.4 Parts of filler
2-7 Parts of disintegrating agent
1-5 Parts of adhesive
0.6-1.4 Parts of lubricant
The D 90 of the granisetron hydrochloride is 10-20 mu m, and the D 50 of the granisetron hydrochloride is more than 10 mu m;
The filler is lactose and microcrystalline cellulose;
the granisetron hydrochloride tablet is prepared by the following method:
(1) Mixing the granisetron hydrochloride bulk drug with part of lactose to obtain a premix; the partial lactose accounts for 40% -60% of the total mass of lactose;
(2) Mixing the residual lactose with other fillers, and the obtained premix, and granulating to obtain a mixture;
(3) Wet granulating the obtained mixture, a disintegrating agent and a binder solution to obtain an intermediate;
(4) Mixing the obtained intermediate with lubricant, and tabletting.
2. The granisetron hydrochloride tablet of claim 1, which is characterized by being prepared from the following raw materials in parts by weight:
0.8-1.4 parts of granisetron hydrochloride
85.4-97.4 Parts of filler
3-6 Parts of disintegrating agent
1.5-4 Parts of adhesive
0.8-1.2 Parts of lubricant.
3. The granisetron hydrochloride tablet of claim 1, which is characterized by being prepared from the following raw materials in parts by weight:
Granisetron hydrochloride 1.1 parts
90.4-92.4 Parts of filler
4-5 Parts of disintegrating agent
2-3 Parts of adhesive
1 Part of lubricant.
4. The granisetron hydrochloride tablet of claim 1, wherein the mass ratio of microcrystalline cellulose to lactose is 1:1.1-4.3; the particle size of lactose is below 90 mu m, and the particle size of microcrystalline cellulose is 40-80 mu m.
5. A granisetron hydrochloride tablet according to any one of claims 1 to 3 wherein the disintegrant is any one or a combination of more of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium;
The adhesive is any one or a combination of a plurality of hydroxypropyl cellulose, ethyl cellulose and hypromellose; the viscosity of the adhesive is 3-20 cPs;
The lubricant is any one or a combination of more of stearic acid, magnesium stearate and sodium stearate fumarate; the lubricant is a lubricant which is sieved by a 60-80 mesh sieve.
6. Granisetron hydrochloride according to claim 1, characterized in that in step (1) the fraction of lactose is 45% -55% of the total mass of lactose;
In the step (2), the premix is sieved by a sieve with 30 meshes in a granulator, the rest lactose is added for repeated sieving for 2-5 times, and the rest filler is added for granulating and sieving, so that a mixture is obtained.
7. The granisetron hydrochloride tablet of claim 1, wherein in step (3), the binder solution is an aqueous solution of a binder, and the binder has a solid content of 3%g to 13% g/ml.
8. Granisetron hydrochloride according to claim 1, characterized in that the wet granulation is carried out by premixing, soft material preparation, wet granulation, drying and dry granulation in a wet granulator; during premixing, the rotation speed of the stirring knife is 90-120 rpm, and the rotation speed of the chopping knife is 800-1000 rpm; when the soft material is prepared, the rotating speed of the stirring knife is 100-150 rpm, the rotating speed of the chopping knife is 1000-1500 rpm, and the mixing time is more than 10 min; the aperture of the screen mesh is 3mm during wet granulation; the aperture of the screen mesh is 1mm during dry granulation.
9. The granisetron hydrochloride tablet of claim 1, wherein in step (4), the mixing is performed 1-3 times in a mixer; the charging coefficient of the mixer is 45% -70%; during mixing, the rotating speed of the mixer is 10-20 rpm; the mixing time is 1-5 min; in the tabletting process, the ambient humidity is controlled below 65%.
10. The granisetron hydrochloride tablet of claim 1, further comprising a coating material, the coating material being a gastric-soluble film coating premix; the tablet obtained after tabletting is coated by a coating material, and the weight is increased by 2.0% -5.0%; after coating, the solid medicinal composite hard sheet of polyvinyl chloride/polyvinylidene chloride and medicinal aluminum foil are adopted for packaging.
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| CN202410886190.5A CN118787601B (en) | 2023-11-30 | 2023-11-30 | Preparation method of granisetron hydrochloride tablet with good uniformity |
| CN202311620709.7A CN117482057B (en) | 2023-11-30 | 2023-11-30 | Stable granisetron hydrochloride tablet and preparation method thereof |
| ZA2024/05654A ZA202405654B (en) | 2023-11-30 | 2024-07-22 | Stable granisetron hydrochloride tablet and preparation method therefor |
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| CN202311620709.7A CN117482057B (en) | 2023-11-30 | 2023-11-30 | Stable granisetron hydrochloride tablet and preparation method thereof |
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| CN202410886190.5A Division CN118787601B (en) | 2023-11-30 | 2023-11-30 | Preparation method of granisetron hydrochloride tablet with good uniformity |
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| CN202311620709.7A Active CN117482057B (en) | 2023-11-30 | 2023-11-30 | Stable granisetron hydrochloride tablet and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1695614A (en) * | 2005-05-09 | 2005-11-16 | 河南大学 | Granisetron hydrochloride orally disintegrating tablet and preparation method thereof |
| CN105193737A (en) * | 2015-09-21 | 2015-12-30 | 青岛华之草医药科技有限公司 | Medicinal tropisetron hydrochloride composition dry suspension for treating nausea and emesis |
| CN113577079A (en) * | 2021-07-28 | 2021-11-02 | 山东裕欣药业有限公司 | Preparation method and composition of phosphodiesterase inhibitor |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6863901B2 (en) * | 2001-11-30 | 2005-03-08 | Collegium Pharmaceutical, Inc. | Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration |
| CN1332664C (en) * | 2002-04-26 | 2007-08-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Snuff |
| CN1289085C (en) * | 2002-04-26 | 2006-12-13 | 中国人民解放军军事医学科学院毒物药物研究所 | Nasal spray agent |
| CN1197556C (en) * | 2003-02-12 | 2005-04-20 | 刘智 | Tablet disintegzated in mouth rapidly for preventing and curing vomit and preparing method |
| CN1621040A (en) * | 2003-11-26 | 2005-06-01 | 周宇 | Antemetic Granisetron Hydrochloride tablet and its preparation |
| CN1623545A (en) * | 2003-12-06 | 2005-06-08 | 江苏晨牌药业有限公司 | Granisetron hydrochloride orally disintegrating tablet and preparation method thereof |
| US20060105038A1 (en) * | 2004-11-12 | 2006-05-18 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions prepared by coacervation |
| US20080139609A1 (en) * | 2006-11-08 | 2008-06-12 | Bikash Kumar Sahoo | Granisetron compositions |
| CN101342149B (en) * | 2008-08-29 | 2010-12-08 | 南昌弘益科技有限公司 | Process for preparing granisetron hydrochloride orally disintegrating tablets |
| KR20110012608A (en) * | 2009-07-31 | 2011-02-09 | 하나제약 주식회사 | Oral disintegrating tablet of granisetron and preparation method thereof |
| CN102100673A (en) * | 2009-12-18 | 2011-06-22 | 重庆药友制药有限责任公司 | Method for improving direct tabletting content uniformity of medicines with low loading rate |
| KR101111534B1 (en) * | 2010-12-24 | 2012-02-15 | (주)비씨월드제약 | Oral fast disintegrating composition and preparation method thereof |
| CN102526740A (en) * | 2012-02-14 | 2012-07-04 | 北京阜康仁生物制药科技有限公司 | Novel high-efficiency antiemetic medicinal composition |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1695614A (en) * | 2005-05-09 | 2005-11-16 | 河南大学 | Granisetron hydrochloride orally disintegrating tablet and preparation method thereof |
| CN105193737A (en) * | 2015-09-21 | 2015-12-30 | 青岛华之草医药科技有限公司 | Medicinal tropisetron hydrochloride composition dry suspension for treating nausea and emesis |
| CN113577079A (en) * | 2021-07-28 | 2021-11-02 | 山东裕欣药业有限公司 | Preparation method and composition of phosphodiesterase inhibitor |
Also Published As
| Publication number | Publication date |
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| ZA202405654B (en) | 2024-09-25 |
| CN118787601A (en) | 2024-10-18 |
| CN118787601B (en) | 2025-03-04 |
| CN117482057A (en) | 2024-02-02 |
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