CN106913547A - A kind of pazopanib tablet and preparation method thereof - Google Patents

A kind of pazopanib tablet and preparation method thereof Download PDF

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Publication number
CN106913547A
CN106913547A CN201511003522.8A CN201511003522A CN106913547A CN 106913547 A CN106913547 A CN 106913547A CN 201511003522 A CN201511003522 A CN 201511003522A CN 106913547 A CN106913547 A CN 106913547A
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pazopanib
tablet according
preparation
acetic acid
tablet
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CN201511003522.8A
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CN106913547B (en
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张贵民
陈小伟
郑华
李姝影
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses a kind of pazopanib tablet and preparation method thereof, controls to obtain pazopanib meso-porous titanium dioxide silicon compound by Crystallization Process, then mixes with filler, disintegrant again, pelletizes, and dries, and adds lubricant, compressing tablet to form in dry particl.Compared with prior art, the tablet that prepared by present invention dissolution in water is rapid, and preparation process is simple is adapted to industrialized production.

Description

A kind of pazopanib tablet and preparation method thereof
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of pazopanib tablet and preparation method thereof.
Background technology
Pazopanib (Axitinib) is ratified to list in the FDA of on January 27th, 2012, for other systematic treatings invalid evening Phase kidney (Renal Cell Carcinoma, RCC).Pazopanib is developed by Pfizer companies, trade name Inlyta.With Another cancer therapy drug Sutent (Sunitinib) of Pfizer is similar to, and pazopanib is also Mutiple Targets tyrosine-kinase enzyme level Agent, can suppress vascular endothelial growth factor receptor VEGFR1, VEGFR2, VEGFR3, platelet derived growth factor and receive Body and c-KIT.
The entitled N- methyl -2- [[3- [(1E) -2- (2- pyridine radicals) vinyl] -1H- indazole -6- bases] of pazopanib chemistry It is thio]-benzamide, structural formula is as follows：
Molecular formula：C22H18N4OS, molecular weight：386.47
Pazopanib for white to micro-yellow powder, 218.4 DEG C of fusing point is slightly soluble in PEG400, be slightly soluble in methyl alcohol or Ethanol, it is atomic to be dissolved in acetonitrile, it is practically insoluble in water.Solubility is about 0.8mg/ml in 20 DEG C of pH1.2 aqueous hydrochloric acid solutions, Solubility is about 0.2 μ g/ml in pH6.8 phosphate buffers, is typical pH dependent drugs.
After oral solid formulation enters in vivo, it is both needed to by process in leaching, could be absorbed by organisms through biomembrane.But by It is insoluble drug in pazopanib, is practically insoluble in water, is often met in the actual production of pazopanib oral solid formulation To dissolution rate is low or even underproof problem.When clinic is in the urgent need to quick-acting, high-efficiency preparation, solve insoluble drug because Solubility is small, dissolution is slow and causes a great problem of the low problem of bioavilability always pharmaceuticals industry.
Patent CN104013589A is related to a kind of pazopanib oral disnitegration tablet and preparation method thereof, by pazopanib and parent Aqueous auxiliary material carries out the particle diameter of common micronizing, 90% volume of control or more particle at 1-50 microns.It is easy to there is medicine in the technology In reassembling, supplementary material mixing uniformity is poor, improve result of extraction it is not notable the problems such as.
In the prior art, not yet there is a kind of effective method for improving pazopanib piece dissolution rate.
The content of the invention
In view of the deficiencies in the prior art, a kind of side that can effectively improve pazopanib piece dissolution rate of inventor's plan offer Method.
According to Noyes-Whitney equations, it is to improve its specific surface area to improve the relatively effective method of drug dissolution.One As in the case of, increase specific surface area method be reduce its particle diameter.The method of conventional reduction drug particles particle diameter mainly has gas Stream comminuting method, ball-milling method etc..The present inventor attempts inventor and uses multiple micronization technology, as shown in comparative example 3, by grain Footpath is crushed to D90Be 450nm or so, but corresponding to preparation 10min dissolution rates be 85%, dissolution is still incomplete, still can not be quick Work.And because granularity is too thin, free energy increase, substantially, dissolution difference is obvious between causing each batch for drug accumulation trend, Simultaneously because electrostatic interaction strengthens, medicine is more difficult well mixed, causes the formulation content uniformity poor.
Usually, hydrophobic starting material and water soluble adjuvant being crushed altogether can improve the hydrophily of medicine, improve dissolution rate, but As shown in comparative example 2, the method effect is limited.
Surfactant can improve the wetability of medicine, increase the solubility of medicine.Inventor attempt by pazopanib with The common micronization processes of lauryl sodium sulfate (SDS), as shown in comparative example 4, implementation result is not notable.
Solid dispersion technology is to improve one of conventional means of insoluble drug, be by medicine and certain carrier material, Such as PVP K30, hydroxypropyl cellulose, Hydroxypropyl methylcellulose are dissolved in solvent removed by evaporation at reduced pressure after appropriate organic solvent, Solid dispersions are obtained final product after pulverizing and sieving, so as to improve drug dissolution.Inventor has attempted substantial amounts of carrier material and difference Preparation method, not up to satisfied effect.
Readily soluble in glacial acetic acid in view of pazopanib, inventor considers to be added in the glacial acetic acid solution of medicine Alkaline matter, using acid-base neutralization principle, medicine is separated out, filtering, the pazopanib of drying to obtain superfine powder, experimental result Measure, fine powder D90=120nm, fine powder is pelletized on auxiliary material, then re-dry, and mix lubricant, compressing tablet, as a result 10min Dissolution rate is 94%.Achieve preferable effect.But, in amplification test, fine powder particle diameter substantially increases, and inventor considers can Can be that drug accumulation causes the particle diameter to increase, therefore, inventor intends from a kind of carrier material to adsorb pazopanib fine powder, passes through Many experiments, inventor, as carrier material, has obtained the pazopanib tablet of Fast Stripping from mesoporous silicon oxide.
Specifically, the present invention is realized by following technology：
A kind of pazopanib tablet of the present invention, prepares by the following method, by pazopanib dissolving in glacial acetic acid, Add mesoporous silicon oxide, stir, sodium hydrate aqueous solution is added in this solution under agitation, pazopanib with Meso-porous titanium dioxide silicon compound is separated out, filtering, is dried, and is then mixed with filler, disintegrant again, is pelletized, and is dried, in dry particl Lubricant, compressing tablet is added to form.
Described pazopanib tablet, pazopanib is 1 with the weight ratio of glacial acetic acid:3-5；Preferably, weight ratio is 1: 4。
NaOH and amount ratio (mol ratio) of the material of glacial acetic acid are 1 in described sodium hydrate aqueous solution:1.
Described pazopanib tablet, pazopanib is 1 with the weight ratio of mesoporous silicon oxide:0.3-0.5；Preferably, Weight ratio is 1:0.4.
Described filler is in lactose, mannitol, microcrystalline cellulose, starch, pregelatinized starch, starch milk saccharide complex One or more.
Described disintegrant is sodium carboxymethyl starch, Ac-Di-Sol, PVPP, low substituted hydroxy-propyl One or more in cellulose.
Described lubricant is one or more in magnesium stearate, sodium stearyl fumarate, zinc stearate.
Compared with prior art, preparation process is simple of the present invention, drug-eluting is rapid, is adapted to industrialized production.
Specific embodiment
Following examples further describe beneficial effects of the present invention, and embodiment is only used for the purpose of illustration, and this is not limited The scope of invention, while those of ordinary skill in the art are also contained according to the obvious change made of the invention and modification Within the scope of the invention.
Embodiment 1
Preparation technology：
By pazopanib dissolving in glacial acetic acid, mesoporous silicon oxide is added, is stirred, under agitation by hydrogen-oxygen Change sodium water solution to add in this solution, pazopanib is separated out with meso-porous titanium dioxide silicon compound, filtering, 60 DEG C of dryings, Ran Houyu The mixed powder of microcrystalline cellulose and sodium carboxymethyl starch is well mixed, and adds magnesium stearate mixing, compressing tablet.
Embodiment 2
Pazopanib 5g
Glacial acetic acid 25g
Mesoporous silica gel 2.5g
5mol/L sodium hydrate aqueous solutions 83.4ml
Microcrystalline cellulose 150g
PVPP 5g
Magnesium stearate 1g
Preparation technology：
By pazopanib dissolving in glacial acetic acid, mesoporous silicon oxide is added, is stirred, under agitation by hydrogen-oxygen Change sodium water solution to add in this solution, pazopanib is separated out with meso-porous titanium dioxide silicon compound, filtering, 65 DEG C of dryings, Ran Houyu The mixed powder of microcrystalline cellulose and PVPP is well mixed, and adds magnesium stearate mixing, compressing tablet.
Embodiment 3
Preparation technology：
By pazopanib dissolving in glacial acetic acid, mesoporous silicon oxide is added, is stirred, under agitation by hydrogen-oxygen Change sodium water solution to add in this solution, pazopanib is separated out with meso-porous titanium dioxide silicon compound, filtering, 60 DEG C of dryings, Ran Houyu The mixed powder of microcrystalline cellulose and sodium carboxymethyl starch is well mixed, and adds magnesium stearate mixing, compressing tablet.
Comparative example 1
Preparation technology：
By pazopanib dissolving in glacial acetic acid, stir, sodium hydrate aqueous solution is added in this under agitation In solution, pazopanib is separated out with meso-porous titanium dioxide silicon compound, filtering, 60 DEG C of dryings, then with microcrystalline cellulose and carboxylic first The mixed powder of base sodium starch is well mixed, and adds magnesium stearate mixing, compressing tablet.
Comparative example 2
Preparation technology：
Axitinib and mannitol are pressed 1:It is micronized altogether after the mixing of 8 ratios, control particle diameter is at 1-50 microns.It is remaining sweet Dew alcohol, lactose, PVPP, Sucralose, mannitol cross 80 mesh sieves respectively.Micro powder article altogether is sweet with remaining Dew alcohol, lactose, PVPP are well mixed, sodium carboxymethyl cellulose solution wet granulation, and sieving is dried, Whole grain.Particle after whole grain adds Sucralose, menthol, silica, magnesium stearate and is well mixed, and compressing tablet is made 1000, every piece weight 80mg, wherein Axitinib contains 1mg, auxiliary material 79mg.
Comparative example 3
Preparation technology：
Pazopanib is micronized, control D90 is less than 450nm, recipe quantity is weighed and has been micronized pazopanib with crystallite fibre The mixed powder of dimension element and PVPP is well mixed, and adds magnesium stearate mixing, compressing tablet.
Comparative example 4
Preparation technology：
To be micronized after pazopanib and lauryl sodium sulfate co-blended, control D90 is less than 5 μm, and recipe quantity is weighed The mixed powder of micronizing pazopanib, lauryl sodium sulfate is well mixed with the mixed powder of microcrystalline cellulose and PVPP, adds Magnesium stearate mixes, compressing tablet.
Checking each embodiment measurement result of embodiment
Dissolution determination.Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler；With Ammonium dihydrogen phosphate-the acetonitrile (70: 30) of 0.02mol/L is mobile phase, and flow velocity 1.5ml/min, Detection wavelength is 260nm.
This product is taken, according to dissolution method (the first methods of C of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ), with phosphate-buffered Liquid (pH4.0) 900ml is dissolution medium, and rotating speed is 50 turns per minute, is operated in accordance with the law, during through 10min, solution is taken respectively in right amount, Filtration, discards 10ml just filtrates, takes subsequent filtrate as need testing solution；The another pazopanib reference substance that takes is appropriate, accurately weighed, plus Acetonitrile dissolves and quantifies dilution and is made in every 1ml solution containing about 5.55 μ g, used as reference substance solution.It is molten that precision measures test sample Liquid and each 20 μ l of reference substance solution, are injected separately into liquid chromatograph, record chromatogram.By external standard method with every bag of calculated by peak area Stripping quantity.Limit is the 80% of labelled amount, should meet regulation.
The embodiment measurement result (%) of table 1
Embodiment 0th day 40 DEG C of 75%RH accelerate 6 months
Embodiment 1 100.1 99.8
Embodiment 2 98.9 99.3
Embodiment 3 99.9 99.4
Comparative example 1 83.2 80.5
Comparative example 2 55.6 51.6
Comparative example 3 70.8 68.6
Comparative example 4 77.9 76.1
As can be known from Table 1, embodiment of the present invention drug-eluting is rapid, and the basic dissolutions of 10min are complete；Comparative example 1, no Addition mesoporous silica gel, dissolution rate effect is poor；Comparative example 2, using prior art, raw material are micronized, and control particle diameter is in 1- 50 microns, because drug solubility is poor, therefore dissolution is most slow；Comparative example 3, and raw material is micronized, and control particle diameter is less than 450nm, dissolution is slow compared with embodiment；Pazopanib and lauryl sodium sulfate (SDS) are total to micronization processes by comparative example 4, Dissolution is slow compared with embodiment.

Claims (10)

1. a kind of pazopanib tablet, it is characterised in that contain pazopanib, mesoporous silica gel and filler, disintegrant, lubrication Agent.
2. pazopanib tablet according to claim 1, it is characterised in that described filler is lactose, mannitol, micro- One or more in crystalline cellulose, starch, pregelatinized starch, starch milk saccharide complex.
3. pazopanib tablet according to claim 1, it is characterised in that described filler is microcrystalline cellulose.
4. pazopanib tablet according to claim 1, it is characterised in that described disintegrant be sodium carboxymethyl starch, One or more in Ac-Di-Sol, PVPP, low-substituted hydroxypropyl cellulose.
5. pazopanib tablet according to claim 1, it is characterised in that described lubricant is magnesium stearate, tristearin One or more in fumaric acid sodium, zinc stearate.
6. pazopanib tablet according to claim 1, it is characterised in that described pazopanib and mesoporous silicon oxide Weight ratio be 1:0.3-0.5.
7. the preparation method of the pazopanib tablet according to claim 1-6 any claims, it is characterised in that by such as It is prepared by lower section method：By pazopanib dissolving in glacial acetic acid, mesoporous silicon oxide is added, is stirred, under agitation will Sodium hydrate aqueous solution is added in this solution, and pazopanib is separated out with meso-porous titanium dioxide silicon compound, and filtering is dried, Ran Houzai Mix with filler, disintegrant, pelletize, dry, add lubricant, compressing tablet to form in dry particl.
8. the preparation method of pazopanib tablet according to claim 7, it is characterised in that described pazopanib and ice The weight ratio of acetic acid is 1:3-5.
9. the preparation method of pazopanib tablet according to claim 7, it is characterised in that described pazopanib and ice The weight ratio of acetic acid is 1:4.
10. the preparation method of pazopanib tablet according to claim 9, it is characterised in that described NaOH water NaOH and the amount ratio of the material of glacial acetic acid are 1 in solution:1.
CN201511003522.8A 2015-12-28 2015-12-28 Acixtinib tablet and preparation method thereof Active CN106913547B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999176A (en) * 2019-12-19 2021-06-22 鲁南制药集团股份有限公司 Acertinib tablet

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101259104A (en) * 2008-04-29 2008-09-10 中国科学院山西煤炭化学研究所 Functionalization mesoporous molecular sieve used in adsorption and sustained-release alkaline drug method
CN102349874A (en) * 2011-08-26 2012-02-15 石药集团中奇制药技术（石家庄）有限公司 Imatinib mesylate composition and preparation method thereof
CN103826618A (en) * 2011-09-30 2014-05-28 辉瑞大药厂 Pharmaceutical compositions of n-methyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl]-benzamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101259104A (en) * 2008-04-29 2008-09-10 中国科学院山西煤炭化学研究所 Functionalization mesoporous molecular sieve used in adsorption and sustained-release alkaline drug method
CN102349874A (en) * 2011-08-26 2012-02-15 石药集团中奇制药技术（石家庄）有限公司 Imatinib mesylate composition and preparation method thereof
CN103826618A (en) * 2011-09-30 2014-05-28 辉瑞大药厂 Pharmaceutical compositions of n-methyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl]-benzamide

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999176A (en) * 2019-12-19 2021-06-22 鲁南制药集团股份有限公司 Acertinib tablet
CN112999176B (en) * 2019-12-19 2022-09-13 鲁南制药集团股份有限公司 Acertinib tablet

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