CN113730365A - Olanzapine orally disintegrating tablet and preparation method thereof - Google Patents
Olanzapine orally disintegrating tablet and preparation method thereof Download PDFInfo
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- CN113730365A CN113730365A CN202110912878.2A CN202110912878A CN113730365A CN 113730365 A CN113730365 A CN 113730365A CN 202110912878 A CN202110912878 A CN 202110912878A CN 113730365 A CN113730365 A CN 113730365A
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- Prior art keywords
- olanzapine
- orally disintegrating
- mixing
- lubricant
- mixture
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- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229960005017 olanzapine Drugs 0.000 title claims abstract description 73
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 48
- 239000000463 material Substances 0.000 claims abstract description 28
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 23
- 229930195725 Mannitol Natural products 0.000 claims abstract description 23
- 239000000594 mannitol Substances 0.000 claims abstract description 23
- 235000010355 mannitol Nutrition 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 23
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 22
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 22
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 22
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 22
- 229960001855 mannitol Drugs 0.000 claims abstract description 20
- 239000000314 lubricant Substances 0.000 claims abstract description 17
- 239000005715 Fructose Substances 0.000 claims abstract description 15
- 229930091371 Fructose Natural products 0.000 claims abstract description 15
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 13
- 108010011485 Aspartame Proteins 0.000 claims abstract description 9
- 239000000605 aspartame Substances 0.000 claims abstract description 9
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims abstract description 9
- 235000010357 aspartame Nutrition 0.000 claims abstract description 9
- 229960003438 aspartame Drugs 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 229960002737 fructose Drugs 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims description 34
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 238000007873 sieving Methods 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 8
- 238000004806 packaging method and process Methods 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- 239000000796 flavoring agent Substances 0.000 claims description 7
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052782 aluminium Inorganic materials 0.000 claims description 6
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
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- 239000002245 particle Substances 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 4
- 235000013539 calcium stearate Nutrition 0.000 claims description 4
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 229940032147 starch Drugs 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 235000019634 flavors Nutrition 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
- 238000009472 formulation Methods 0.000 claims 2
- 239000003826 tablet Substances 0.000 abstract description 21
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- 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 description 4
- 239000004480 active ingredient Substances 0.000 description 4
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- 238000004090 dissolution Methods 0.000 description 2
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
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- 238000012216 screening Methods 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
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- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
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- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
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- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
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- 102000034337 acetylcholine receptors Human genes 0.000 description 1
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- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
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- 238000006243 chemical reaction Methods 0.000 description 1
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- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002706 dry binder Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
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- 235000013305 food 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
- 239000008103 glucose Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
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- 238000003825 pressing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
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- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
- PESXGULMKCKJCC-UHFFFAOYSA-M sodium;4-methoxycarbonylphenolate Chemical compound [Na+].COC(=O)C1=CC=C([O-])C=C1 PESXGULMKCKJCC-UHFFFAOYSA-M 0.000 description 1
- IXMINYBUNCWGER-UHFFFAOYSA-M sodium;4-propoxycarbonylphenolate Chemical compound [Na+].CCCOC(=O)C1=CC=C([O-])C=C1 IXMINYBUNCWGER-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/205—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
- A61K9/2095—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nutrition Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an olanzapine orally disintegrating tablet, which consists of olanzapine, microcrystalline cellulose, mannitol, fructose, colloidal silicon dioxide, a disintegrating agent and a lubricant, wherein the composition does not contain aspartame corrective; the olanzapine orally disintegrating tablet has low tablet weight (high drug loading amount of auxiliary materials), can reduce production processes and production cost, has good mechanical strength in a lower hardness range while realizing rapid disintegration and quick response, and can meet the requirements on hardness and friability in the processes of preparation, production, transportation, use and the like of the tablet.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to olanzapine orally disintegrating tablets and a preparation method thereof.
Background
Olanzapine (Olanzapine), chemically known as 2-methyl-10- (4-methyl-1-piperazine) -4H-thieno [2,3-b ] [1,5] benzodiazepine, is a novel atypical neuroleptic agent, which binds to dopamine receptors, 5-HT receptors and cholinergic receptors and has an antagonistic effect, antagonizing the D2 receptor being associated with the treatment of the positive symptoms of schizophrenia; antagonism of the 5-HT2A receptor is associated with the treatment of the negative symptoms of schizophrenia.
The orally disintegrating tablet is a novel medicinal preparation which can automatically disintegrate into countless particles within 30 seconds after being placed on the tongue surface and has fragrant and sweet taste. Because it is quick in disintegration speed and absorption, and does not need to drink water after being taken, it is very suitable for special patients (psychosis, senile dementia, epileptic, etc.), children, old people, bedridden patients and serious disabled patients to take. The mouthfeel of the tablets is therefore of great importance for clinical compliance. At present, the oral disintegrating tablets are prepared at home and abroad by a freeze-drying method, a molding method and a direct tabletting method.
Olanzapine orally disintegrating tablets were first developed and marketed by Eli Lilly using gelatin, mannitol, aspartame, sodium methyl paraben, sodium propyl paraben using freeze drying technology. The process has the advantages of being beneficial to oral disintegration and release, high single tablet drug loading, small using amount of auxiliary materials, complex production process and higher cost, and when the tablet is actually taken, the tablet is very soft and is easy to deform or remain in an aluminum foil blister. TEVA company prepares olanzapine orally disintegrating tablets by using a wet granule molding technology, and has the disadvantages of complex process and higher production cost, and the preparation methods of the two orally disintegrating tablets are not developed in a large scale at home so far.
World patent WO2006115770 discloses olanzapine orally disintegrating tablets which are prepared by a compression molding method by using 75-95% of mannitol as a diluent, 1-10% of a disintegrating agent and other auxiliary materials, wherein the olanzapine orally disintegrating tablets have the disintegration time of less than 20S and the friability of less than 2%. Mannitol is fast to dissolve in the oral cavity, tastes good, and is very suitable for serving as a diluent of orally disintegrating tablets, but in large-scale production, too large mannitol dosage in a prescription often causes sticking in a tabletting process, hardness formability is poor, so that the prepared orally disintegrating tablets are poor in friability, aluminum bags are seriously damaged in a transportation process, and finally, the orally disintegrating tablets are inconvenient for patients to take.
Chinese patent application No. 201310451237.7 discloses an olanzapine orally disintegrating tablet and a preparation method thereof, the invention adopts a composition of olanzapine, microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, aspartame and magnesium stearate, adopts a powder direct compression process, and is characterized in that the disintegration time limit is less than 10s, but the requirements on the dosage and the type of auxiliary materials are higher, the drug-loading rate of the auxiliary materials is lower, the clinical medication is not facilitated, and the production cost is increased.
Chinese patent 201610583234.2 discloses an olanzapine orally disintegrating tablet and a preparation method thereof, and the olanzapine orally disintegrating tablet is characterized in that a pharmaceutical composition comprises olanzapine granules and additives, wherein the olanzapine granules are obtained by granulating water bodies of olanzapine, mannitol, cross-linked polyvinylpyrrolidone and polyvinyl acetate, and then the water bodies are mixed with a diluent, a disintegrating agent, a flavoring agent and a lubricant for tabletting.
Chinese patent application No. CN200910016306.5 discloses an olanzapine orally disintegrating tablet preparation and a preparation method thereof, wherein the composition comprises olanzapine, mannitol, lactose, a dry binder, a disintegrating agent, a flavoring agent and a lubricant; the preparation process can adopt a dry direct tabletting technology and a dry granulation tabletting technology, and is characterized in that lactose and mannitol are adopted as filling agents, the risk of large-scale production and tablet cracking is reduced, but the requirements on the dosage and the type of auxiliary materials are high, the drug-loading rate of the auxiliary materials is low, the tablet weight is large, the clinical medication is not facilitated, and the production cost is increased.
Chinese patent application No. 201710382896.8 discloses an olanzapine orally disintegrating tablet and a preparation method thereof, the method comprises the steps of preparing composition granules by using lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then mixing the composition granules with olanzapine, lactose, low-substituted hydroxypropyl cellulose, a flavoring agent and a lubricant for tabletting, and the method is characterized in that the content uniformity of the product is improved.
Chinese patent application No. 202010020747.9 discloses olanzapine orally disintegrating tablets and a preparation process thereof, wherein the olanzapine orally disintegrating tablets mainly comprise olanzapine, a filling agent, a disintegrating agent, a flavoring agent, a flow aid, a lubricant and other components, and the gritty sense defect of the existing orally disintegrating tablets is eliminated by regulating and controlling the components of the orally disintegrating tablets and the preparation process of the tablets.
The orally disintegrating tablets prepared by the patent have the defects of special taking comfort of patients with different degrees of gritty feeling, poor mouthfeel and the like, and have the risks of poor quality such as slow dissolution, content uniformity, absorbability, friability, stability and the like, and also have the problems of high tablet weight and high cost caused by complex process.
Therefore, there is still a need to develop an olanzapine orally disintegrating tablet which has the advantages of simple preparation process, high production efficiency, strong mechanical strength, rapid disintegration, good taste, good stability and good economic benefit.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an olanzapine orally disintegrating tablet which is low in tablet weight (high in auxiliary material drug loading), not only can reduce production procedures and reduce production cost, but also has good mechanical strength in a lower hardness range while realizing rapid disintegration and quick response, and can meet the requirements on hardness and friability in the processes of preparation, production, transportation, use and the like of the tablet.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
an olanzapine orally disintegrating tablet comprising olanzapine, microcrystalline cellulose, mannitol, fructose, colloidal silicon dioxide, a disintegrant and a lubricant, wherein the composition does not contain aspartame flavor;
the dose of olanzapine orally disintegrating tablet is 50mg, wherein:
5mg of olanzapine, 25mg of microcrystalline cellulose, 9mg of mannitol, 7.5mg of fructose, 1mg of colloidal silicon dioxide, 2mg of a disintegrant and 0.5mg of a lubricant;
or 10mg of olanzapine, 20mg of microcrystalline cellulose, 9mg of mannitol, 7.5mg of fructose, 1mg of colloidal silicon dioxide, 2mg of a disintegrant and 0.5mg of a lubricant.
Further, the disintegrating agent is selected from one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose or low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, pulvis Talci, calcium stearate, zinc stearate or sodium fumarate stearate.
Preferably, the disintegrant is crospovidone, and the lubricant is magnesium stearate.
Preferably, the particle size of olanzapine is D90Is 4-100 μm; the grain diameter of the microcrystalline cellulose adopts D90Less than 70 μm.
The invention also aims to provide a preparation method of the olanzapine orally disintegrating tablet, which adopts the following technical scheme:
a preparation method of olanzapine orally disintegrating tablets comprises the following steps:
(1) weighing: weighing the raw materials and auxiliary materials according to the weight ratio;
(2) sieving: taking fructose, colloidal silicon dioxide, mannitol, a disintegrating agent and microcrystalline cellulose according to the formula amount, respectively, sieving with a 60-mesh sieve, and mixing in a mixer to obtain a mixture;
(3) mixing olanzapine with a formula amount and the mixture obtained in the step (2) with the formula amount equal to that of olanzapine by an incremental mixing method, and sieving the mixture by a sieve of 80 meshes; continuously adding the mixture obtained in the step (2) in an amount which is 2 times of the formula amount of olanzapine, mixing the mixture, and sieving the mixture by a sieve of 80 meshes to obtain a material;
(4) mixing: adding the material obtained in the step (3) into a mixer, and continuously adding the rest mixture obtained in the step (2) into the mixer for mixing;
(5) lubrication: adding a lubricant into the mixture obtained in the step (4), mixing, and sampling to detect the content of the intermediate;
(6) tabletting: installing the intermediate obtained in the step (5) into a circular die with the diameter of 5mm, calculating the weight to be pressed according to the content result of the intermediate, controlling the difference of the weight of the pressed piece to be +/-3%, and controlling the hardness to be 30N-70N;
(7) packaging: and packaging with aluminum.
Preferably, when the amount of the mixture obtained in the step (2) is more than 4 times of the formula amount of olanzapine after 2 times of mixing in the step (3), the mixture obtained in the step (2) with the amount of 4 times of the formula amount of olanzapine is added and mixed together, and then the mixture is sieved by a 80-mesh sieve to obtain a material.
Preferably, the number of revolutions of the mixer in the step (2) and the step (4) is 10 to 20 revolutions per minute, and the mixing time is 10 to 30 minutes.
The olanzapine orally disintegrating tablet disclosed by the invention has the advantages that 5mg of olanzapine serving as an active ingredient, 45mg of other auxiliary materials or 10mg of olanzapine serving as an active ingredient, 40mg of other auxiliary materials, 8mg of olanzapine serving as an active ingredient in example 3 of patent publication No. CN101904824A, 92mg of other auxiliary materials, 5mg of olanzapine serving as an active ingredient in example 1 of patent publication No. CN 106265559B and 98.3mg of other auxiliary materials are adopted, and the effects of the existing marketed products can be achieved by using small amount of the auxiliary materials, which is shown in experiments 1 to 3.
The invention adopts microcrystalline cellulose as a filler, the microcrystalline cellulose is an excellent filler of the tablet, the invention adopts cellulose with D90 less than 50 mu m, and the defect of gritty feel of the conventional orally disintegrating tablet can be effectively eliminated by controlling the dosage of the microcrystalline cellulose and the weight of the composition tablet.
Fructose is an excellent flavoring agent that tastes sweeter than mannitol and sorbitol, and responds much faster in the mouth than sucrose and glucose. Although aspartame is widely used as an intense sweetener in oral pharmaceutical preparations, beverages and foods, according to published data ([1] r.c. roc, p.j. sertraline, p.j. weler. pharmaceutical excipients handbook [ M ] beijing: chemical industry press, 2005.), aspartame has incompatibility with calcium hydrogen phosphate and magnesium stearate, aspartame and sugar alcohol also have mutual reaction, and olanzapine compositions undergo significant degradation under stable conditions. Therefore, the invention does not adopt aspartame corrective, but adopts mannitol and fructose for flavoring, and can also achieve the characteristics of moderate sweetness and excellent taste, thereby not only enhancing the clinical compliance of patients, but also reducing the potential stability risk of the product.
The method for preparing the orally disintegrating tablet disclosed by the invention is mainly embodied in that 60-80% of the material in the mixer can reduce the adsorption loss of the raw materials, improve the mixing uniformity of the product and ensure the dose uniformity of the product. Olanzapine bulk drug is easy to adsorb and agglomerate, product dosage uniformity is the biggest challenge of production, layering phenomenon not only appears in the mixing stage but also appears in the preparation forming stage, and the inventor improves the uniformity of auxiliary materials through the screening and premixing pretreatment of auxiliary materials, so that the surface of a mixer is covered by the mixed auxiliary materials, and adsorption loss caused by direct feeding of raw materials is avoided. The progressive screening and mixing method is adopted in the mixing process, so that the mixing uniformity of the powder is improved, the dosage uniformity of the preparation is improved, the layering phenomenon of the medicine in the powder direct-pressing preparation process is improved, and the finished tablet product has good taste, and better content uniformity, absorption and stability.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A method for preparing olanzapine composition, which comprises the following steps when 10,000 tablets are produced:
(1) weighing: weighing 50g of olanzapine and the raw materials and auxiliary materials according to the weight ratio. 250g of microcrystalline cellulose, 90g of mannitol, 75g of fructose, 10g of colloidal silicon dioxide, 20g of cross-linked polyvinylpyrrolidone and 5g of magnesium stearate; wherein the particle size of olanzapine adopts D90Is 4-100 μm; the grain diameter of the microcrystalline cellulose adopts D90Less than 50 μm.
(2) Sieving: taking fructose, colloidal silicon dioxide, mannitol, cross-linked polyvinylpyrrolidone and microcrystalline cellulose in the formula amount, sequentially sieving with a 60-mesh sieve, placing in a mixer, mixing at 15 rpm for 30 minutes, and discharging.
(3) Mixing the olanzapine with the prescription amount and 50g of the mixture (2), and sieving the mixture by a sieve with 80 meshes; continuously adding 100g of the mixture (2), mixing, and sieving by a 80-mesh sieve; 200g of the mixture (2) was further added and mixed together, followed by sieving with an 80-mesh sieve.
(4) Mixing: adding the material obtained in the step (3) into a mixer, continuously adding the rest mixture obtained in the step (2) into the mixer, mixing at 10 revolutions per minute for 20 minutes, and discharging.
(5) Lubrication: adding magnesium stearate into the mixture obtained in the step (4), mixing, sampling and detecting the content of the intermediate;
(6) tabletting: installing the intermediate obtained in the step (5) into a circular die with the diameter of 5mm, calculating the weight to be pressed according to the content result of the intermediate, controlling the difference of the weight of the pressed piece to be +/-3%, and controlling the hardness to be 30N-70N;
(7) packaging: and packaging with aluminum.
The crospovidone in example 1 can be replaced with one or more of sodium carboxymethyl starch, croscarmellose sodium or low substituted hydroxypropyl cellulose; magnesium stearate can be replaced by one or more of talc, calcium stearate, zinc stearate or sodium stearyl fumarate.
Example 2
A method for preparing olanzapine composition, which comprises the following steps when 10,000 tablets are produced:
(1) weighing: weighing 100g of olanzapine and 100g of raw materials and auxiliary materials according to the weight ratio. 200g of microcrystalline cellulose, 90g of mannitol, 75g of fructose, 10g of colloidal silicon dioxide, 20g of cross-linked polyvinylpyrrolidone and 5g of magnesium stearate; wherein the particle size of olanzapine adopts D90Is 4-100 μm; the grain diameter of the microcrystalline cellulose adopts D90Less than 50 μm.
(2) Sieving: taking the fructose, the colloidal silicon dioxide, the mannitol, the cross-linked polyvinylpyrrolidone and the microcrystalline cellulose according to the prescription amount, sequentially sieving the mixture by a 60-mesh sieve, placing the mixture in a mixer, mixing the mixture for 20 minutes at a speed of 20 revolutions per minute, and discharging the mixture.
(3) Mixing the olanzapine with the prescription amount and 100g of the mixture (2), and sieving the mixture by a sieve with 80 meshes; 200g of (2) are added, mixed together and sieved by a 80-mesh sieve.
(4) Mixing: adding the material obtained in the step (3) into a mixer, continuously adding the rest mixture obtained in the step (2) into the mixer, mixing at 15 revolutions per minute for 30 minutes, and discharging.
(5) Lubrication: adding magnesium stearate into the mixture obtained in the step (4), mixing, sampling and detecting the content of the intermediate;
(6) tabletting: installing the intermediate obtained in the step (5) into a circular die with the diameter of 5mm, calculating the weight to be pressed according to the content result of the intermediate, controlling the difference of the weight of the pressed piece to be +/-3%, and controlling the hardness to be 30N-70N;
(7) packaging: and packaging with aluminum.
The crospovidone in example 1 can be replaced with one or more of sodium carboxymethyl starch, croscarmellose sodium or low substituted hydroxypropyl cellulose; magnesium stearate can be replaced by one or more of talc, calcium stearate, zinc stearate or sodium stearyl fumarate.
Test 1
The results of physicochemical tests performed on the samples obtained in examples 1 and 2 and on the original drug product 1722819A batch number are shown in the following table:
from the above measured data, it can be known that: the disintegration time of the orally disintegrating tablet prepared by the method is less than 10 seconds, and is similar to that of the original medicine; the hardness is 20N-50N, the friability is less than 0.5%, the formability is better than that of the original ground medicament, and the dissolution rate in 0.1M hydrochloric acid solution for 5min is more than 95%.
Test 2
Stability tests were performed on the samples obtained in examples 1 and 2 and on the original drug product 1722819A batch, and the results of the stability, accelerated stability and long-term stability of the specific influencing factors are compared (10 days and 6 months for the influencing factors) in the following table:
wherein the limit of each impurity (ketolactam is less than or equal to 0.5 percent, impurity I is less than or equal to 0.5 percent, ketothiolactam is less than or equal to 0.5 percent, impurity D is less than or equal to 0.5 percent, unknown single impurity is less than or equal to 0.2 percent, and total impurity is less than or equal to 1.5 percent).
The quality of the self-grinding product meets the requirements of the standard draft, and the self-grinding product is similar to the original grinding product and has good stability, and the stability of the self-preparation is superior to that of the original grinding product under various stability test conditions (such as high temperature, high humidity, illumination, acceleration and the like).
Test 3
After placing the tablet in the middle of the tongue of healthy volunteers, the tongue was allowed to move properly, and the disintegration time of 15 seconds of holding the tablet, the taste of the tablet, the presence of gritty sensation on the surface of the tongue, the presence of residue on the surface of the tongue, and the like were recorded. Results the healthy volunteers of example 1 and example 2 had good compliance. See table below:
Claims (7)
1. an olanzapine orally disintegrating tablet characterized by consisting of olanzapine, microcrystalline cellulose, mannitol, fructose, colloidal silicon dioxide, a disintegrant and a lubricant, the composition being free of aspartame flavor,
the dose of olanzapine orally disintegrating tablet is 50mg, wherein:
5mg of olanzapine, 25mg of microcrystalline cellulose, 9mg of mannitol, 7.5mg of fructose, 1mg of colloidal silicon dioxide, 2mg of a disintegrant and 0.5mg of a lubricant;
or 10mg of olanzapine, 20mg of microcrystalline cellulose, 9mg of mannitol, 7.5mg of fructose, 1mg of colloidal silicon dioxide, 2mg of a disintegrant and 0.5mg of a lubricant.
2. Olanzapine orally disintegrating tablet according to claim 1, characterized in that the disintegrating agent is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium or low substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, pulvis Talci, calcium stearate, zinc stearate or sodium fumarate stearate.
3. Olanzapine orally disintegrating tablet according to claim 2, characterized in that the disintegrant is crospovidone and the lubricant is magnesium stearate.
4. Olanzapine orally disintegrating tablet according to any of claims 1 to 3, characterized in that the particle size of olanzapine is taken as D90Is 4-100 μm; the grain diameter of the microcrystalline cellulose adopts D90Less than 50 μm.
5. The process for preparing olanzapine orally disintegrating tablets according to claim 1, characterized by comprising the steps of:
(1) weighing: weighing the raw materials and auxiliary materials according to the weight ratio;
(2) sieving: taking fructose, colloidal silicon dioxide, mannitol, a disintegrating agent and microcrystalline cellulose according to the formula amount, respectively, sieving with a 60-mesh sieve, and placing in a mixer to obtain a mixture;
(3) adopting an incremental mixing method, mixing olanzapine with a formula amount and the mixture obtained in the step (2) with the formula amount equal to that of the olanzapine, and sieving the mixture by a sieve of 80 meshes; continuously adding the mixture obtained in the step (2) in an amount which is 2 times of the formula amount of olanzapine, mixing the mixture, and sieving the mixture by a sieve of 80 meshes to obtain a material;
(4) mixing: adding the material obtained in the step (3) into a mixer, and continuously adding the rest mixture obtained in the step (2) into the mixer for mixing;
(5) lubrication: adding a lubricant into the mixture obtained in the step (4), mixing, and sampling to detect the content of the intermediate;
(6) tabletting: installing the intermediate obtained in the step (5) into a circular die with the diameter of 5mm, calculating the weight to be pressed according to the content result of the intermediate, controlling the difference of the weight of the pressed piece to be +/-3%, and controlling the hardness to be 30N-70N;
(7) packaging: and packaging with aluminum.
6. The process for preparing olanzapine orally disintegrating tablets according to claim 5, characterized in that after 2 times of mixing in step (3), when the amount of the mixture obtained in step (2) is more than 4 times of the amount of olanzapine formulation, the mixture obtained in step (2) is further added in 4 times of the amount of olanzapine formulation and mixed together, and then sieved through a 80-mesh sieve to obtain a mass.
7. The process for preparing olanzapine orally disintegrating tablets according to claim 5, wherein the number of revolutions of the mixer in the step (2) and the step (4) is 10 to 20 revolutions per minute, and the mixing time is 10 to 30 minutes.
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