CN103156877B - A kind of capecitabine fast release micropill and preparation method thereof - Google Patents
A kind of capecitabine fast release micropill and preparation method thereof Download PDFInfo
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- CN103156877B CN103156877B CN201110415055.5A CN201110415055A CN103156877B CN 103156877 B CN103156877 B CN 103156877B CN 201110415055 A CN201110415055 A CN 201110415055A CN 103156877 B CN103156877 B CN 103156877B
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Abstract
The present invention relates to a kind of capecitabine fast release micropill and preparation method thereof, the composition of described capecitabine fast release micropill comprises capecitabine, excipient, disintegrating agent and binding agent, and described micropill particle diameter is 0.1-10mm; The present invention uses extruded type granulating technique to prepare capecitabine fast release micropill and direct encapsulating capsule, and enormously simplify production process, described method is simple and reliable, and the capecitabine fast release micropill favorable reproducibility prepared by method of the present invention, yield are high.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of capecitabine fast release micropill and preparation method thereof.
Background technology
Capecitabine (capecitabine) is a kind of oral '-fluoropyrimidine nucleosides class prodrug with targeting effect chemically fluorouracil (fluorouracil, FU) being carried out chemical constitution transformation.Its chemical name is: the fluoro-N-of 5 '-deoxidation-5-[(amoxy) carbonyl]-born of the same parents (pyrimidine core) glycosides, and its structural formula is:
Capecitabine is developed by Roche Holding Ag, and commodity are called " xeloda ", and in April, 1998 gets permission listing in the U.S., subsequently successively in state's listings such as Switzerland.Intactly gastrointestinal wall is passed through after it is oral, be 5 '-deoxidation-5-fluorine cytidine (5 '-DFCR) through liver carboxy-lesterase catalyze metabolic, then the cytidine deaminase in liver and tumor cell is catalytically conveted to 5 '-deoxidation-fluorouracil (5 '-DFUR), FU is catalytically conveted to finally by thymidine phosphorylase (TP, this enzyme concentration in tumor tissues is higher).Capecitabine and metabolite 5 '-DFCR5-DFUR thereof do not have cell killing, and the most lifelong FU of this metabolic process produces selecting cell toxic action to tumor cell.Because it has the ability of tumor cell and ordinary cells, can optionally concentrate in tumor cell, thus can effective killing off tumor cells, little to normal surrounding tissue harmful effect.Modal untoward reaction is reversibility gastrointestinal reaction clinically, and as diarrhoea, Nausea and vomiting, stomachache, stomatitis etc., hand-foot syndrome is also more common.
Capecitabine is used for combination chemotherapy late period or metastatic colorectal carcinoma, late period or metastatic gastric carcinoma.Also the further treatment of advanced primary that paclitaxel and chemotherapy regimen fail to respond to any medical treatment or metastatic breast cancer is applicable to.Recommended dose is 1250mg/m
2, oral (each 1 time sooner or later of every day 2 times; Equal every TDD 2500mg/m
2), treating rear drug withdrawal in 2 weeks a week, 3 weeks is a course for the treatment of.Capecitabine sheet should be swallowed with water in 30 minutes after the meal.When with Docetaxel conbined usage, the recommended dose 1250mg/m of capecitabine
2, every day 2 times, the Docetaxel recommended dose for the treatment of coupling with it after 2 weeks is 75mg/m
2, every 3 weeks 1 time, intravenous drip 1 hour.According to the description of Docetaxel, before Docetaxel is used to the patient accepting capecitabine and Docetaxel combined chemotherapy, should conventional some chemotherapy ancillary drugs of application.
In use capecitabine dosage may need adjustment, to reach the demand adapting to individual.Closely should monitor untoward reaction in using, and dosage enables patient's tolerate treatment as required.Untoward reaction caused by capecitabine is by mode process such as symptomatic treatment, drug withdrawal and adjustment dosage.
Capecitabine sheet commercially available is at present respectively: the capecitabine pale pink color film coating tablet of 150mg specification and the capecitabine colored film coated tablet of 500mg specification.Two kinds of specification collocation are needed to use when taking medicine clinically.But these two kinds of specifications still can not meet the demand of all individuations completely, occur more untoward reaction.
Grind the display of medicine (specification 500mg/ sheet) description according to capecitabine sheet is former, the former capecitabine label pharmaceutic adjuvant that grinds comprises Lactis Anhydrous, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, hypromellose, magnesium stearate; Film-coat composition comprises hypromellose, Pulvis Talci, titanium dioxide, synthetic iron oxide red and iron oxide yellow.In tablet, supplementary product kind is many and proportion is little, and again because capecitabine crude drug viscosity is large, poor fluidity, easily occurs in preparation process that supplementary material mixes uneven problem, larger on quality of the pharmaceutical preparations impact.And then affect the treatment and increase the incidence rate of untoward reaction.Therefore uniformity of dosage units test item is ordered into quality standard by Yuan Yan producer, monitors it.
The preparation technology of commercially available capecitabine sheet is wet granulation, and its preparation technology is: mixing → soft material → granulation → drying → granulate processed → always mixed → tabletting → coating.Whole preparation section is more loaded down with trivial details, and equipment needed thereby is many, needs strictly to control well each link, just can guarantee that preparation has good repeatability.
China Patent Publication No. CN101522168 discloses the patent of invention that a kind of name is called " capecitabine pediatric sheet ", a kind of quickly disintegrated film coating capecitabine pharmaceutical dosage form, described tablet in 37 DEG C of water being less than disintegrate in 2 minutes (USP disintegrate test).But the constituent of said preparation prescription is many, also easily occur mixing non-uniform phenomenon, and conventional tablet price is higher relatively; In addition, before capecitabine pediatric sheet is oral in water after fater disintegration, orally enter in body, directly absorb, vivo medicine concentration can be caused to increase sharply, easily cause more untoward reaction, larger harm is produced to human body, there is certain clinical risk.
Summary of the invention
An object of the present invention is to provide a kind of novel form of capecitabine, i.e. capecitabine fast release micropill.Described capecitabine fast release micropill, compares with commercial preparation, simplifies prescription and technique, and supplementary product kind used is few, and decrease the quality of the pharmaceutical preparations problem that in preparation process, supplementary material mixing is uneven caused, and preparation technology is simple, the quality of the pharmaceutical preparations is stablized controlled.Be particularly suitable for the adjustment of clinical medicine dose, adapt to the demand of individual, reduce the generation of untoward reaction.
Described capecitabine fast release micropill, comprises following component by weight percentage:
Wherein, described excipient is selected from the one in microcrystalline Cellulose, lactose, mannitol, starch, Icing Sugar, dextrin, calcium hydrogen phosphate, calcium carbonate;
Wherein, described disintegrating agent is selected from the one in carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose;
Wherein, described binding agent is selected from the one in cellulose derivative, the polyvinylpyrrolidones such as ethanol, propyl methocel, hydroxypropyl cellulose;
Wherein, described micropill diameter is 0.1-10mm.
Preferably, wherein, micropill diameter is 0.1-5mm.
More preferably, wherein, micropill diameter is 0.1-2mm.
Capecitabine fast release micropill of the present invention is compared with capecitabine ordinary tablet and is had the following advantages: 1) micropill can extensively be evenly distributed in gastrointestinal tract after taking, and medicine increases at gastrointestinal tract surface distributed area, makes drug bioavailability high.Effectively avoid local drug concentration excessive, reducing medicine stimulates gastrointestinal simultaneously.Uniform absorption, individual bioavailability difference is little.2) micropill size is even, and roundness is good, smooth surface.Pellet capsule can be opened and administered in divided doses, is more suitable for old man, the crowd of child and dysphagia uses.Be particularly suitable for this used in amounts of capecitabine to calculate according to body surface area, to reach the demand adapting to individual, untoward reaction at any time caused by capecitabine can carry out dose titration, reach optimum therapeutic effect, reduce the generation of untoward reaction; 3) load capsule, improve medicine stability.
Another object of the present invention is to provide a kind of method of capecitabine fast release micropill processed, said method comprising the steps of:
1) capecitabine, excipient and/or disintegrating agent are crossed 100 mesh sieves respectively, abundant mix homogeneously;
2) by step 1) homogeneous material of gained adds appropriate binding agent and makes soft material;
3) by step 2) soft material of gained drops in extruder and is squeezed into strip extrudate;
4) by step 3) extrudate of gained is added in spheronizator and takes out after round as a ball 5-8min and obtain micropill;
5) by step 4) obtained micropill dries 12h in 55 ~ 60 DEG C and namely obtains dry micropill;
6) by step 5) gained micropill screening 18-32 order, and use filling machine fill capsule, i.e. get Ka Pei
His shore fast release micropill;
Wherein, described excipient is selected from the one in microcrystalline Cellulose, lactose, mannitol, starch, Icing Sugar, dextrin, calcium hydrogen phosphate, calcium carbonate;
Wherein, described disintegrating agent is selected from the one in carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose;
Wherein, described binding agent is selected from the one in cellulose derivative, the polyvinylpyrrolidones such as ethanol, propyl methocel, hydroxypropyl cellulose.
The capecitabine fast release micropill dissolution prepared by method of the present invention is high, good stability, easily divided dose, is applicable to the adjustment of clinical medicine dose and preparation technology is simple, effectively can enhance productivity, energy savings, to reduce costs.
Preparation method of the present invention is compared with the preparation method of commercially available capecitabine sheet, and preparation section is simple, and equipment needed thereby is few, and effectively can enhance productivity, energy savings, to reduce costs, preparation repeatability is good.
Accompanying drawing explanation
Fig. 1 commercially available capecitabine sheet stripping curve
Fig. 2 embodiment 1 capecitabine micropill stripping curve (prescription one)
Fig. 3 embodiment 2 capecitabine micropill stripping curve (prescription two)
Fig. 4 embodiment 3 capecitabine micropill stripping curve (prescription three)
Fig. 5 embodiment 4 capecitabine micropill stripping curve (prescription four)
Detailed description of the invention
Supplementary material involved in concrete enforcement and device fabrication business information as follows:
Capecitabine: Suzhou Lixin Pharmacy Co., Ltd./lot number: 20110401
Microcrystalline Cellulose: Japanese Asahi Kasei Corporation/model: PH301
Lactose: German U.S. agent pleasure/model 200
Cross-linking sodium carboxymethyl cellulose: FMC Corp. of the U.S.
Polyvinylpyrrolidone: American I SP company/model: K-30
Calcium hydrogen phosphate: Huzhou Zhanwang Pharmaceutical Co., Ltd.
Hydroxypropyl methylcellulose: Huzhou Zhanwang Pharmaceutical Co., Ltd./E15
Polyvinylpolypyrrolidone: American I SP company/model: XL-10
Extruded type comminutor: Kexu Pharmaceutic Machinery Mfg. Co., Ltd., Chongqing City/LJ-50
[embodiment 1]
(1) prescription 1
(2) preparation method
Supplementary material crosses 100 mesh sieves respectively, abundant mix homogeneously; The material of mixing is added polyvinylpyrrolidone (K30) 220ml and make soft material; Then add extruder, be squeezed into bar; Bar is placed in spheronizator round as a ball, and the round as a ball time is 5min, 55 ~ 60 DEG C of dry 12h, and the micropill of collection 18 ~ 32 order particle diameter that sieves, obtains micropill.
[embodiment 2]
(1) prescription 2
(2) preparation method
Supplementary material crosses 100 mesh sieves respectively, abundant mix homogeneously; The material of mixing is added hydroxypropyl methylcellulose 180ml and makes soft material; Then add extruder, be squeezed into bar; Bar is placed in spheronizator round as a ball, and the round as a ball time is 5min, 55 ~ 60 DEG C of dry 12h, and the micropill of collection 18 ~ 32 order particle diameter that sieves, obtains micropill.
[embodiment 3]
(1) prescription 3
(2) preparation method
Supplementary material crosses 100 mesh sieves respectively, abundant mix homogeneously; The material of mixing is added hydroxypropyl methylcellulose 165ml and makes soft material; Then add extruder, be squeezed into bar; Bar is placed in spheronizator round as a ball, and the round as a ball time is 6min, 55 ~ 60 DEG C of dry 12h, and the micropill of collection 18 ~ 32 order particle diameter that sieves, obtains micropill.
[embodiment 4]
(1) prescription 4
(2) preparation method
Supplementary material crosses 100 mesh sieves respectively, abundant mix homogeneously; The material of mixing is added hydroxypropyl methylcellulose 140ml and makes soft material; Then add extruder, be squeezed into bar; Bar is placed in spheronizator round as a ball, and the round as a ball time is 8min, 55 ~ 60 DEG C of dry 12h, and the micropill of collection 18 ~ 32 order particle diameter that sieves, obtains micropill.
Claims (4)
1. a capecitabine fast release micropill, is characterized in that, described capecitabine fast release micropill is made up of following component:
2. a capecitabine fast release micropill, is characterized in that, described capecitabine fast release micropill is made up of following component:
3. a capecitabine fast release micropill, is characterized in that, described capecitabine fast release micropill is made up of following component:
4. a capecitabine fast release micropill, is characterized in that, described capecitabine fast release micropill is made up of following component:
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| CN201110415055.5A CN103156877B (en) | 2011-12-13 | 2011-12-13 | A kind of capecitabine fast release micropill and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433546A (en) * | 2007-11-13 | 2009-05-20 | 上海医药工业研究院 | Capecitabine sustained and controlled release oral formulation and preparation method thereof |
| CN101522168A (en) * | 2006-10-06 | 2009-09-02 | 霍夫曼-拉罗奇有限公司 | Capecitabine pediatric tablets |
| CN102166361A (en) * | 2011-04-19 | 2011-08-31 | 杭州高成生物营养技术有限公司 | Quick-collapsed type pellet core and preparation method thereof |
-
2011
- 2011-12-13 CN CN201110415055.5A patent/CN103156877B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101522168A (en) * | 2006-10-06 | 2009-09-02 | 霍夫曼-拉罗奇有限公司 | Capecitabine pediatric tablets |
| CN101433546A (en) * | 2007-11-13 | 2009-05-20 | 上海医药工业研究院 | Capecitabine sustained and controlled release oral formulation and preparation method thereof |
| CN102166361A (en) * | 2011-04-19 | 2011-08-31 | 杭州高成生物营养技术有限公司 | Quick-collapsed type pellet core and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 挤出-滚圆法制备微丸的研究进展;刘耀 等;《中国药学杂志》;20080331;第43卷(第6期);401-405 * |
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Effective date of registration: 20170413 Address after: Two road 518000 Guangdong city of Shenzhen province Nanshan District science and Technology Park, Xili Street North Long Road No. 16 Building 1 Neptune research Patentee after: Shenzhen Neptune medical science and Technology Research Institute Co., Ltd. Address before: 518057 Guangdong city of Shenzhen province Nanshan District high-tech road two North Long Hill Haiwang industrial city Patentee before: Haiwang Pharmaceutical Industry Co., Ltd., Shenzhen |
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