CN104127390B - A kind of Domperidone Tablets and preparation technology thereof - Google Patents
A kind of Domperidone Tablets and preparation technology thereof Download PDFInfo
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- CN104127390B CN104127390B CN201410382676.1A CN201410382676A CN104127390B CN 104127390 B CN104127390 B CN 104127390B CN 201410382676 A CN201410382676 A CN 201410382676A CN 104127390 B CN104127390 B CN 104127390B
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- domperidone
- pastille
- polacrilin potassium
- preparation technology
- adsorbate
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- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 229960001253 domperidone Drugs 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 238000005516 engineering process Methods 0.000 title claims abstract description 32
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 235000010603 pastilles Nutrition 0.000 claims abstract description 39
- 229960000540 polacrilin potassium Drugs 0.000 claims abstract description 26
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 claims abstract description 26
- 239000007787 solid Substances 0.000 claims abstract description 20
- 235000013409 condiments Nutrition 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 12
- 239000000725 suspension Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 6
- 239000002156 adsorbate Substances 0.000 claims description 24
- 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 23
- 239000008101 lactose Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 15
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 239000007962 solid dispersion Substances 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- -1 flavouring Substances 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 1
- 229960003511 macrogol Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 42
- 238000004090 dissolution Methods 0.000 description 26
- 239000003814 drug Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 9
- 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 7
- 230000000052 comparative effect Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229960004268 domperidone maleate Drugs 0.000 description 2
- OAUUYDZHCOULIO-BTJKTKAUSA-N domperidone maleate Chemical compound [O-]C(=O)\C=C/C([O-])=O.O=C1[NH2+]C2=CC=CC=C2N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2[NH2+]C1=O OAUUYDZHCOULIO-BTJKTKAUSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000010148 water-pollination Effects 0.000 description 2
- SDTHIDMOBRXVOQ-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]-6-methyl-1h-pyrimidine-2,4-dione Chemical compound CC=1NC(=O)NC(=O)C=1N(CCCl)CCCl SDTHIDMOBRXVOQ-UHFFFAOYSA-N 0.000 description 1
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 108091008690 chemoreceptors Proteins 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229960005455 polacrilin Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- FYKDNWHPKQOZOT-UHFFFAOYSA-M sodium;dihydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].OP(O)([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FYKDNWHPKQOZOT-UHFFFAOYSA-M 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of Domperidone Tablets and preparation technology thereof, this tablet is that domperidone is dissolved in ethanol, add hydrophilicity condiment, make to disperse, drying under reduced pressure is removed ethanol, adds in the tert-butyl alcohol suspension of polacrilin potassium, and volatilization is except the tert-butyl alcohol, obtain pastille solid deposits, and form with other pharmaceutically acceptable auxiliary materials and mixing compressing tablet. The stripping of preparation of the present invention is rapid, and preparation technology is simple, is applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of tablet that contains domperidone andIts preparation technology.
Background technology
Domperidone is a Drags for Digestive Diseases of Belgian Janssen Pharmaceutica exploitation, and chemistry is by nameThe chloro-1-[1-[3-of 5-(2,3-dihydro-2-oxo--1H-benzimidazole-1-yl) propyl group] piperidin-4-yl]-1,3-dihydro-2H-benzeneAnd imidazoles-2-ketone, structural formula is as follows:
Domperidone is a kind of dopamine-receptor antagonist with emesis effect, is difficult for entering by blood-brain barrierEnter brain. Domperidone acts on the chemoreceptor trigger region outside blood-brain barrier, therefore acts on hardly maincenterNervous system; Domperidone selective exclusion dopamine 2 (DA2) acceptor, Main Function is in peripheral nerveSystem. Because DA2 acceptor is GI major receptors too, therefore DA2 receptor antagonist can subtractThe pipe smooth muscle of few DA Mediated is lax. In intestines and stomach, domperidone, as a kind of dynamics-promoting medicine, can increaseAdd gastral power, can be used for preventing stomach-esophageal reflux, promote gastric emptying, improve gastroduodenalSports coordination, prevents biliary regurgitation, regulates and recover the motion of upper gastro-intestinal tract; Suppress to feel sick, vomit.The domperidone formulation of listing has at present: ordinary tablet, supensoid agent, dispersing tablet, oral disnitegration tablet, capsule etc.
Domperidone is water-soluble poor, and the solubility in water is less than 0.1mg/ml, the preparation that gone on the market externalStripping behavior has bigger difference. The new drug that State Food and Drug Administration the promulgates dissolution rate inspection in standard of becoming a full memberLooking into sample time is 45min, and limit is 75%. Periodical literature (Wu Zhimin, Ding Weijiao, Li Yiqun. inconsiderateProducer's Domperidone Tablets dissolution rate comparative studies, Strait Pharmaceutical Journal .2008,20 (3): 30-32.) compare 5The producer's In Vitro Dissolution curve of preparation in pH1.2 hydrochloric acid solution that gone on the market, result 45min dissolution rate all can accord withStandardization requirement, but the dissolution rate of 5min has obvious difference, and the 5min of part producer dissolution rate is 94%What have above, is only 25% left and right. In the In Vitro Dissolution behavior of medicine and the body of medicine, bioavilability is directRelevant, be to evaluate the solid orally ingestible important method of bioavilability in vivo, direct relation product qualityQuality.
Patent CN101152156A discloses domperidone orally disintegrating tablet and preparation method thereof, by effective doseDomperidone with can be in oral cavity rapidly disintegration discharge the pharmaceutic adjuvant composition of medicine. This invention adopts former auxiliaryMaterial equivalent progressively increase mix after direct tablet compressing be prepared, compressing tablet hardness is 20-40N. This invention is during only from disintegrationBetween aspect investigate, and do not pay close attention to and affect the dissolution in vitro of preparation curative effect.
Patent CN101804036A discloses domperidone orally disintegrating tablet and preparation method thereof, in this inventionContain the auxiliary elements such as domperidone principal component and disintegrant, filler, flavouring. This invention adopts wet method systemGrain is prepared, and the oral disnitegration tablet disintegration of preparation is rapid, with reference to Ministry of Health of the People's Republic of China's standardIn (WS1-(X-185)-97Z), dissolution determination method detects, and dissolution rate is greater than 96%.
Patent CN101394850B discloses Orodispersible domperidone tablets, relates to a kind of by following weight ratioThe oral cavity dispersing tablet of composition: maximum 15% low dosage, have the material of therapeutic activity; 55% to 70% grainFootpath is at the sweet mellow wine of 30 μ m to 300 μ m; At least 2% maltodextrin; 3.5% to 8% crosslinked carboxylic firstBase sodium cellulosate; 10% to 20% microcrystalline cellulose; 0.5% to 1.5% dolomol, and 1% to5% spices and sweetener. The disintegration time of the preparation of this invention in 37 DEG C of water is less than 1 minute, pressure resistanceSpend average 20-30N.
The more than domperidone oral disintegrating tablet of invention preparation, disintegration of tablet is rapid, but does not examine from dissolution rateConsider the effect of invention. Domperidone poorly water-soluble, the quality of the preparation that gone on the market is also uneven, causes its bodyInterior bioavilability is different. Therefore, can not only consider the quality of preparation from disintegration speed, and tackle, it is externalDetailed investigation is carried out in stripping behavior.
Patent CN103006596A discloses a kind of domperidone maleate sheet and preparation technology thereof, this inventionActive component domperidone maleate is disclosed, be selected from microcrystalline cellulose and starch diluent, be selected from carboxymethylThe disintegrant of Starch Sodium, be selected from PVP adhesive, be selected from the glidant of silica and be selected from lubricantDolomol composition. The embodiment dissolution determination result that this patent provides shows, although 45min dissolution rate is93%, meet the requirement of Chinese pharmacopoeia, but 5min stripping is only 32%, stripping is too slow, has a strong impact in bodyBioavilability.
Patent CN103893130A discloses domperidone particulate, domperidone preparation and preparation method, itsPreparation method comprises the steps: domperidone and dispersion aids to be scattered in solvent, and acid adding, to dissolving, obtainsSolution I; Under stirring condition, in solution I, add alkali lye, obtain the mixture that contains domperidone particulate; PointFrom domperidone particulate. The average grain diameter of gained particulate is less than 20 μ m, has the common dopan of suitable particle diameter2 times of above specific areas of vertical ketone particulate, dissolution rate is high. This invention also discloses one and has contained this domperidoneThe preparation method of the preparation of particulate. This invention, by adopting recrystallization technology, reduces the particle diameter of medicine, increases medicineThe specific area of thing, thus reach the object that improves drug dissolution. But also there is following defect in this invention: (1)For domperidone is dissolved completely in solvent, this invention is by adding the method for acidic materials, due to manyIn Pan Li ketone molecule, contain lactams structure, be easy to hydrolysis, acid, alkali add the hydrolysis that membership causes medicine, shadowRing the stability of medicine; (2), for drug microparticles is better disperseed, in preparation process, added pool Lip river sandThe surfactants such as nurse, tween, Emulsifier EL-60, sucrose ester and s6, can increaseAdd GI excitant; (3) this invented technology complexity, auxiliary material is various, and manufacturing cycle is long, is unfavorable forReduce costs.
Find by careful retrieval document both domestic and external, prior art all fails to provide that a kind of dissolution rate is good, preparationThe simple domperidone preparation of technique.
Summary of the invention
In view of the deficiencies in the prior art, the object of the present invention is to provide that a kind of dissolution rate is good, preparation technology is simpleDomperidone Tablets.
According to Noyes-Whitney equation, improving drug dissolution comparison effective method is to improve its specific surfaceLong-pending. Generally, the method for increase specific area is to reduce its particle diameter. The conventional drug particles particle diameter that reducesMethod mainly contain comminution by gas stream, ball-milling method, solid dispersions method etc. First the inventor attempts using air-flowComminuting method improves drug-eluting. Test demonstration, when domperidone granularity is less than 10 μ m, stripping is significantly improved.But because granularity is too thin, free energy increases, and medicine aggregation tendency is obvious, causes between each batch stripping difference brightAobvious; And because electrostatic interaction strengthens, medicine is more difficult to be mixed, and causes the formulation content uniformity poor.
Subsequently, inventor attempts again medicine to mix with hydrophilicity condiment, then in grinding in ball grinder one timingBetween can obtain the powder of suitable particle size. The method can increase the hydrophily of medicine, improves to a certain extent its dissolution rate,But general effect is poor. And, because medicine is poor with the rear powder flowbility of a large amount of hydrophilicity condiments grindings, needAfter granulation, carry out compressing tablet, cause disintegration of tablet slack-off, further affected dissolution rate.
Solid dispersion technology is by medicine and certain carrier material, as PVP K30, hydroxypropyl cellulose,Hydroxypropyl methylcelluloses etc. are dissolved in solvent removed by evaporation at reduced pressure after appropriate organic solvent, obtain solid after pulverizing and sievingDispersion, thus drug dissolution improved. Inventor has attempted a large amount of conventional carrier material, does not all reach fullThe effect of meaning. For this reason, inventor creatively attempts introducing hydrophilicity condiment in the time preparing solid dispersions, orderPeople is pleasantly surprised, and the dissolution in vitro of prepared domperidone tablet has had significantly to be increased, and finally realizesObject of the present invention.
Based on above result of study, the concrete technical scheme of the present invention is summarized as:
A kind of Domperidone Tablets, wherein said Domperidone Tablets is mainly by domperidone, hydrophilicity condiment, rippleAfter clarke woods potassium is prepared solid dispersions, compressing tablet forms.
It should be noted that, in the time of preparation Domperidone Tablets as above, the polacrilin potassium that wherein adoptedSpecification be IRP-88.
The present invention also provides the preparation technology of above-mentioned Domperidone Tablets, adopts this technique can prepare dissolution rateGood Domperidone Tablets. Particularly, this preparation technology comprises the steps:
(1) domperidone is dissolved in ethanol, adds hydrophilicity condiment, make to disperse, drying under reduced pressure is removed secondAlcohol, obtains pastille adsorbate;
(2) described pastille adsorbate is added in the tert-butyl alcohol suspension of polacrilin potassium, stir, waveSend out and remove the tert-butyl alcohol, pastille adsorbate is deposited in to polacrilin potassium surface, obtain pastille solid deposits;
(3) described pastille solid deposits is mixed to compressing tablet with other pharmaceutically acceptable auxiliary material.
Preferably, the preparation technology of Domperidone Tablets as above, wherein the weight of domperidone and lactose is usedAmount is than being 1 ︰ 2-10.
Further preferably, the preparation technology of Domperidone Tablets as above, wherein domperidone and lactoseWeight consumption ratio is 1 ︰ 3.8-5.0.
Preferably, the preparation technology of Domperidone Tablets as above, wherein said pastille adsorbate and Andrea PollackThe weight consumption ratio of woods potassium is 1 ︰ 2-4.
Preferably, the preparation technology of Domperidone Tablets as above, wherein said other is pharmaceutically acceptableAuxiliary material comprise filler, disintegrant and lubricant.
Further, in order to improve the mouthfeel of preparation, increase patient's compliance, in preparation, added a certain amount ofFlavouring, it has no significant effect evidence stripping.
Preferably, the preparation technology of Domperidone Tablets as above, wherein said other is pharmaceutically acceptableAuxiliary material formed by lubricant.
Further preferably, the preparation technology of Domperidone Tablets as above, wherein said lubricant is selected fromFollowing one or more: sodium stearyl fumarate, dolomol, zinc stearate, hydrogenated vegetable oil, poly-secondGlycol 6000.
Again further preferably, the preparation technology of Domperidone Tablets as above, wherein said hydrophily is auxiliaryMaterial is lactose.
Compared with prior art, first the present invention is dissolved in domperidone in organic solvent, adds lactose to make pointLoose, stir, drying under reduced pressure is removed solvent, and along with the volatilization of ethanol, domperidone is slowly separated out and is adsorbedOn lactose surface, obtain pastille adsorbate; Then add the tert-butyl alcohol suspension of polacrilin potassium IRP-88,Stir, the tert-butyl alcohol is removed in volatilization, and the adsorbate of domperidone and lactose is deposited in to polacrilin potassiumIRP-88 surface, obtains pastille solid deposits; Last and mix lubricant, compressing tablet, gained domperidoneThe drug-eluting of sheet is rapid, and the complete stripping of 5min is analyzed reason and may be disperseed with microcrystalline state for domperidoneIn polacrilin potassium IRP-88 surface, because polacrilin potassium IRP-88 is loose structure, domperidone reaches againDisperse to greatest extent and be conducive to stripping. In addition, this preparation technology is simple, is easy to industrialized production,There is obvious advantage compared with prior art.
Detailed description of the invention
Now further describe preparation process of the present invention and implementation result by following examples, embodiment only usesIn the object of illustration, do not limit the scope of the invention, those of ordinary skill in the art do according to the present invention simultaneouslyApparent change and within modification is also contained in the scope of the invention.
Embodiment 1
Preparation technology:
(1) domperidone is dissolved in 150mL ethanol, adds lactose, make to disperse, stir, 50 DEG CDrying under reduced pressure is removed ethanol, and along with the volatilization of ethanol, domperidone is slowly separated out and is adsorbed on lactose surface, obtainsPastille adsorbate;
(2) in above-mentioned pastille adsorbate, add the tert-butyl alcohol suspension of polacrilin potassium IRP-88, stir allEven, the tert-butyl alcohol is removed in 70 DEG C of decompression volatilizations, and the pastille adsorbate of domperidone and lactose is deposited in to polacrilinPotassium IRP-88 surface, obtains pastille solid deposits;
(3) pastille solid deposits is mixed to compressing tablet with sodium stearyl fumarate.
Embodiment 2
Preparation technology:
(1) domperidone is dissolved in 100mL ethanol, adds lactose, make to disperse, stir, 55 DEG CDrying under reduced pressure is removed ethanol, and along with the volatilization of ethanol, domperidone is slowly separated out and is adsorbed on lactose surface, obtainsPastille adsorbate;
(2) in above-mentioned pastille adsorbate, add the tert-butyl alcohol suspension of polacrilin potassium IRP-88, stir allEven, the tert-butyl alcohol is removed in 74 DEG C of decompression volatilizations, and the pastille adsorbate of domperidone and lactose is deposited in to polacrilinPotassium IRP-88 surface, obtains pastille solid deposits;
(3) pastille solid deposits is mixed to compressing tablet with dolomol.
Embodiment 3
Preparation technology:
(1) domperidone is dissolved in 120mL ethanol, adds lactose, make to disperse, stir, 50 DEG CDrying under reduced pressure is removed ethanol, and along with the volatilization of ethanol, domperidone is slowly separated out and is adsorbed on lactose surface, obtainsPastille adsorbate;
(2) in above-mentioned pastille adsorbate, add the tert-butyl alcohol suspension of polacrilin potassium IRP-88, stir allEven, the tert-butyl alcohol is removed in 70 DEG C of decompression volatilizations, and the pastille adsorbate of domperidone and lactose is deposited in to polacrilinPotassium IRP-88 surface, obtains pastille solid deposits;
(3) pastille solid deposits is mixed to compressing tablet with dolomol.
Comparative example 1
Preparation technology: domperidone is dissolved in 250mL ethanol, adds polacrilin potassium IRP-88 to stir allEven; Drying under reduced pressure is removed ethanol, obtains pastille solid deposits; By pastille solid deposits and lactose, stearic acidMagnesium mixes, and compressing tablet to obtain final product.
Comparative example 2
Preparation technology:
(1) domperidone is dissolved in 120mL ethanol, adds lactose, make to disperse, stir, 50 DEG CDrying under reduced pressure is removed ethanol, and along with the volatilization of ethanol, domperidone is slowly separated out and is adsorbed on lactose surface, obtainsPastille adsorbate;
(2) in above-mentioned pastille adsorbate, add the tert-butyl alcohol suspension of PVPP, stir, 70 DEG CThe tert-butyl alcohol is removed in decompression volatilization, and the pastille adsorbate of domperidone and lactose is deposited in to PVPP surface,Obtain pastille solid deposits;
(3) pastille solid deposits is mixed to compressing tablet with dolomol.
Comparative example 3
Preparation technology:
Domperidone, lactose, polacrilin potassium IRP-88 are all crossed to 100 mesh sieves, and recipe quantity takes, and stirsEvenly, add recipe quantity dolomol, mix compressing tablet.
The dissolution determination of embodiment 4 Domperidone Tablets
Chromatographic condition and system suitability be taking octadecylsilane chemically bonded silica as filler, with0.02mol/L potassium dihydrogen phosphate (with 0.231% phosphorus acid for adjusting pH value to 3.5)-methyl alcohol (1:4) is for flowingPhase, detection wavelength is 287nm, setting column temperature is 25 DEG C, adjusts flow velocity and makes domperidone peak retention time approximatelyBe 5 minutes, number of theoretical plate calculates and should be not less than 1500 by domperidone peak, and tailing factor should be not more than 2.0.
Get this product, according to dissolution method (paddle board method), with sodium hydrogen phosphate-citrate buffer (pH6.0)900ml is solvent, and rotating speed is per minute 50 to turn, and operation in accordance with the law, respectively at 5,10,15,30,45 pointsZhong Shi, gets solution and filters in right amount, discards at least just filtrate of 10ml, and precision measures subsequent filtrate 2ml, and precision addsMethyl alcohol 2ml, shakes up, as need testing solution. Another precision takes vertical through 105 DEG C of dopans of dry 4 hours in advanceKetone reference substance 50mg, puts in 200ml measuring bottle, adds methyl alcohol and dissolves and be diluted to scale, shakes up, and precision measures5ml, puts in 100ml measuring bottle, adds methyl alcohol and is diluted to scale, shake up, then precision measures 2ml, accurate solubilizationGo out medium 2ml, shake up, in contrast product solution. Precision measures the each 20 μ l of above-mentioned two kinds of solution, injection liquidChromatography, records chromatogram; Stripping quantity by external standard method with every of calculated by peak area, limit is labelled amount75%, should conform with the regulations.
Table 1 Domperidone Tablets dissolution determination result (%)
From the result of the test of table 1, Domperidone Tablets prepared by embodiment of the present invention 1-3 is several in 5minStripping completely; And comparative example 1 does not add hydrophilicity condiment in the time preparing solid dispersions, therefore its preparationDissolution of Tablet lower; Comparative example 2 changes polacrilin potassium IRP-88 into PVPP, 5min strippingObviously reduce; Comparative example 6 adopts common mixed pressuring plate technique, and 5min dissolution rate is 5% left and right only, and this entersOne step has proved the progressive of technique of the present invention.
Claims (6)
1. a Domperidone Tablets, is characterized in that, described Domperidone Tablets is mainly by domperidone, hydrophilicity condiment, rippleAfter clarke woods potassium is prepared solid dispersions, compressing tablet forms, and method is: domperidone is dissolved in ethanol, adds hydrophilicity condiment,Make to disperse, drying under reduced pressure is removed ethanol, obtains pastille adsorbate; Add the tert-butyl alcohol of polacrilin potassium mixed described pastille adsorbateIn suspension, stir, the tert-butyl alcohol is removed in volatilization, and pastille adsorbate is deposited in to polacrilin potassium surface, obtains pastille solid heavyLong-pending thing; Described pastille solid deposits is mixed to compressing tablet with other pharmaceutically acceptable auxiliary material;
Described polacrilin potassium is polacrilin potassium IRP-88; Described hydrophilicity condiment is lactose; Domperidone and lactoseWeight consumption ratio be 1 ︰ 2-10; Described pastille adsorbate is 1 ︰ 2-4 with the weight consumption ratio of polacrilin potassium.
2. a preparation technology for Domperidone Tablets, is characterized in that this technique comprises the steps:
(1) domperidone is dissolved in ethanol, adds hydrophilicity condiment, make to disperse, drying under reduced pressure is removed ethanol, obtains pastille absorptionThing;
(2) described pastille adsorbate is added in the tert-butyl alcohol suspension of polacrilin potassium, stir, tertiary fourth is removed in volatilizationAlcohol, is deposited in polacrilin potassium surface by pastille adsorbate, obtains pastille solid deposits;
(3) described pastille solid deposits is mixed to compressing tablet with other pharmaceutically acceptable auxiliary material;
Described polacrilin potassium is polacrilin potassium IRP-88; Described hydrophilicity condiment is lactose; Domperidone and lactoseWeight consumption ratio be 1 ︰ 2-10; Described pastille adsorbate is 1 ︰ 2-4 with the weight consumption ratio of polacrilin potassium.
3. the preparation technology of Domperidone Tablets according to claim 2, is characterized in that, the weight of domperidone and lactoseAmount ratio is 1 ︰ 3.8-5.0.
4. the preparation technology of Domperidone Tablets according to claim 2, is characterized in that, described other pharmaceutically can connectThe auxiliary material being subject to comprises filler, flavouring, disintegrant and lubricant.
5. the preparation technology of Domperidone Tablets according to claim 2, is characterized in that, described other pharmaceutically can connectThe auxiliary material being subject to is made up of lubricant.
6. the preparation technology of Domperidone Tablets according to claim 5, is characterized in that, described lubricant is selected from as followsOne or more: sodium stearyl fumarate, dolomol, zinc stearate, hydrogenated vegetable oil, Macrogol 6000.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1634586A1 (en) * | 2004-09-09 | 2006-03-15 | Laboratorio Medinfar-Produtos Farmaceuticos, S.A. | Fast water-dispersible domperidone tablets |
| CN1850080A (en) * | 2006-03-08 | 2006-10-25 | 北京大学 | Oral dispersion domperidone coutrolled-release gel and its preparing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2898492B1 (en) * | 2006-03-15 | 2008-06-06 | Pierre Fabre Medicament Sa | ORODISPERSIBLE TABLETS OF DOMPERIDONE |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1634586A1 (en) * | 2004-09-09 | 2006-03-15 | Laboratorio Medinfar-Produtos Farmaceuticos, S.A. | Fast water-dispersible domperidone tablets |
| CN1850080A (en) * | 2006-03-08 | 2006-10-25 | 北京大学 | Oral dispersion domperidone coutrolled-release gel and its preparing method |
Non-Patent Citations (2)
| Title |
|---|
| 口服固体速释制剂的研究进展;沈岚等;《中国中药杂志》;20050131;第30卷(第2期);第89－92页 * |
| 重压法干法制粒工艺及设备应用研究;候有明等;《中国制药装备》;20120630;6－9页 * |
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