CN102302466A - Capecitabine medicinal composition capable of direct powder tableting, and application thereof - Google Patents
Capecitabine medicinal composition capable of direct powder tableting, and application thereof Download PDFInfo
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- CN102302466A CN102302466A CN201110267016A CN201110267016A CN102302466A CN 102302466 A CN102302466 A CN 102302466A CN 201110267016 A CN201110267016 A CN 201110267016A CN 201110267016 A CN201110267016 A CN 201110267016A CN 102302466 A CN102302466 A CN 102302466A
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Abstract
The present invention discloses a capecitabine medicinal composition capable of direct powder tableting, and an application thereof. The composition comprises capecitabine having an average particle size of 100-200 mum and a pharmaceutically-acceptable excipient. The capecitabine medicinal composition capable of direct powder tableting can be used for preparing solid capecitabine preparations, especially tablets. Compared to the prior art, with the present invention, the electrostatic interaction of the capecitabine medicinal composition is significantly reduced, the fluidity and the compressibility of the capecitabine medicinal composition are good, the sticking problem is solved, the preparation process for the solid capecitabine preparations is simplified, the dissolution rate and the stability of the capecitabine preparation meet the requirements so as to ensure the quality of the preparation, reduce the preparation cost, and meet the industrial production requirements.
Description
Technical field
The present invention relates to a kind of capecitabine Pharmaceutical composition and application thereof, specifically, but relate to a kind of capecitabine Pharmaceutical composition and application thereof of direct powder compression, belong to technical field of medicine.
Background technology
Capecitabine is first the oral fluorinated pyrimidine carbamate series antineoplastic medicament that has gone on the market, is the novel targeted medicine that is used to treat breast carcinoma, colorectal carcinoma.This medicine is by Roche Holding Ag (Roche) exploitation, and commodity are called " Xeloda ", and get permission listing in the U.S. in April, 1998, goes on the market in states such as Switzerland successively subsequently.Begin to register clinical trial in November, 1999, carry out clinical trial by 5 national antitumor drug clinical experimental study centers on ground such as Beijing, Shanghai, Guangzhou, and go on the market with trade name " xeloda " in China.
The chemistry of capecitabine is by name 5 '-deoxidation-5-fluoro-N-[(amoxy)-carbonyl]-cytidine, its chemical structural formula is following:
Capecitabine is a kind of to the selective active oral cell toxicant class preparation of tumor cell; Has the unique pharmacological mechanism that is different from traditional chemotherapeutics; When just having got in the body in oral back; Itself no cytotoxicity reaches liver and through a series of transformations, can generate effective metabolite with blood.At present existing capecitabine thin membrane coated tablet listing; And (application number is: 200710048137.4) disclose a kind of capecitabine oral sustained-release preparation and preparation method thereof, (application number is the Chinese patent document Chinese patent document: 200780036204.9) disclose a kind of capecitabine pediatric tablets.
Because capecitabine has low relatively bulk density, this character make its be difficult to high amount of drug processed have the weight unanimity, the ideal tablet of hardness.Capecitabine has static in addition, and the principal agent proportion is too big again, and raw material and adjuvant combine insecure; Can be adhered to the surface of tablet machine drift and mould; Even employing wet granulation, the granule that makes often flowability are also very poor, cause tablet weight variation bigger; And in the tabletting process, be easy to generate the bonding die phenomenon, influence carrying out smoothly of tabletting.Therefore prior art has mostly added a large amount of compressibility adjuvant preferably in prescription, to play dilution capecitabine raw material, adopts wet granulation technology simultaneously, improves material fluidity, solves the tabletting situation of difficult.This measure can effectively improve the problems referred to above really, but has also brought following drawback simultaneously: increased tablet weight 1..Usually oral tablet weight surpasses 800mg, can cause dysphagia, and the patient takes inconvenience, especially the child.2. owing in prescription, strengthened the consumption of adjuvant, also increased production cost virtually.
Therefore, be necessary to explore a kind of capecitabine pharmaceutical composition, to solve particulate flowability and compressibility and sticking problem; Reduce potential safety hazard, guarantee product quality, simplify production technology, reduce production costs, and suitable suitability for industrialized production requirement.
Technical scheme
To the above-mentioned defect problem of existing in prior technology; But the present invention provides a kind of capecitabine Pharmaceutical composition and application thereof of direct powder compression, to solve the particulate flowability of capecitabine and compressibility and sticking problem, reduces potential safety hazard; Guarantee product quality; Simplify production technology, reduce production costs, satisfy the suitability for industrialized production requirement.
But the capecitabine Pharmaceutical composition of a kind of direct powder compression of the present invention is that capecitabine and the pharmaceutically acceptable excipient of 100～200 μ m formed by mean diameter.
As preferred version, in the described compositions, the percentage by weight of capecitabine is 50～90%, and the percentage by weight of pharmaceutically acceptable excipient is 50～10%.
As further preferred version, in the described compositions, the percentage by weight of capecitabine is 75～85%, and the percentage by weight of pharmaceutically acceptable excipient is 25～15%.
Described pharmaceutically acceptable excipient comprises any one or the compositions more than two kinds in filler, disintegrating agent, binding agent, the lubricant.
But in the capecitabine Pharmaceutical composition of described direct powder compression, containing percentage by weight is the disintegrating agent of 1～10% (preferred 3～6%).
Described disintegrating agent is recommended as any one or the mixture more than two kinds in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, the carboxymethyl starch sodium; Be preferably cross-linking sodium carboxymethyl cellulose.
But do not contain surfactant in the capecitabine Pharmaceutical composition of described direct powder compression.
As optimal case, but the capecitabine Pharmaceutical composition of described direct powder compression is made up of following component as following weight percent:
The percentage by weight sum of said components is 100%; The mean diameter of said capecitabine is 100～200 μ m.
As further optimal case, but the capecitabine Pharmaceutical composition of described direct powder compression is made up of following component as following weight percent:
The percentage by weight sum of said components is 100%; The mean diameter of said capecitabine is 100～150 μ m.
Mean diameter described in the present invention is the capecitabine of 100～200 mu m ranges, can obtain through following treatment step:
A) with the capecitabine material dissolution in organic solvent, obtain settled solution;
B) distilling under reduced pressure becomes muddy slightly to solution;
C) add normal heptane, mix, obtain suspension;
D) be cooled to 0～5 ℃, centrifugalize is filtered, and drying promptly gets.
Crystal formation or amorphous products that described capecitabine raw material is an any known.
Described organic solvent be for dissolving the low boiling point organic solvent of capecitabine, can be selected from any one or the mixed solvent more than two kinds in the organic solvents such as dichloromethane, ethyl acetate, butyl acetate, methanol, is preferably butyl acetate.
The capecitabine raw material in the step a) and the proportioning of organic solvent are: 1g capecitabine raw material is with 3～40ml organic solvent.
Vacuum distillation temperature in the step b) is recommended as 10～40 ℃, is preferably 20～33 ℃.
Normal heptane consumption in the step c) is preferably 1～2 times of volume of the used organic solvent of step a).
The time of mixing in the step c) is recommended as 0.5～10 hour, is preferably 3～5 hours.
Preferably dropping mode of normal heptane in the step c) adds.
Dry preferred room temperature vacuum drying in the step d).
But the capecitabine Pharmaceutical composition of direct powder compression of the present invention can be used for the preparation of capecitabine solid preparation, especially can be used for the preparation of (comprising conventional tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow-release tablet agent etc.) of the various tablets of capecitabine.
Compared with prior art, but the capecitabine Pharmaceutical composition of direct powder compression of the present invention, and flowability and compressibility are good; Solved the sticking problem; Simplified the preparation technology of capecitabine solid preparation, and the dissolution of prepared preparation and stability meets the requirements all, guaranteed the quality of preparation; Reduce preparation cost, met the suitability for industrialized production requirement.
The specific embodiment
Below in conjunction with embodiment to the present invention do further in detail, intactly explanation.
Embodiment 1
Be equipped with in the four-hole boiling flask of mechanical agitator, condenser and thermometer at 1000ml, add capecitabine bullion (50g is with dry weight basis) and methanol (200ml), be stirred to dissolving fully, obtain settled solution.
With this settled solution 30 ℃ ,-carry out distilling under reduced pressure under the 0.085MPa condition, get muddy slightly until solution becomes.
Be added drop-wise in the above-mentioned turbid solution with 4 hours at 30 ℃ of normal heptane, obtain suspension, continued insulated and stirred 1 hour, slowly be cooled to 0～5 ℃ then 400ml.
Centrifugalize is filtered, and the room temperature vacuum drying obtains the 48g dry product.
Using the Malvern laser diffractometry to record mean diameter through Mastersizer 2000 laser particle analyzers is 100 μ m.
Embodiment 2
Be equipped with in the four-hole boiling flask of mechanical agitator, condenser and thermometer at 1000ml, add capecitabine bullion (50g is with dry weight basis) and butyl acetate (300ml), be stirred to dissolving fully, obtain settled solution.
With this settled solution 30 ℃ ,-carry out distilling under reduced pressure under the 0.085MPa condition, get muddy slightly until solution becomes.
Be added drop-wise in the above-mentioned turbid solution with 5 hours at 30 ℃ of normal heptane, obtain suspension, continued insulated and stirred 1 hour, slowly be cooled to 0～5 ℃ then 300ml.
Centrifugalize is filtered, and the room temperature vacuum drying obtains the 47.5g dry product.
Using the Malvem laser diffractometry to record mean diameter through Mastersizer 2000 laser particle analyzers is 150 μ m.
Embodiment 3
Be equipped with in the four-hole boiling flask of mechanical agitator, condenser and thermometer at 1000ml, add capecitabine bullion (50g is with dry weight basis) and butyl acetate (400ml), be stirred to dissolving fully, obtain settled solution.
With this settled solution 30 ℃ ,-carry out distilling under reduced pressure under the 0.08MPa condition, get muddy slightly until solution becomes.
Be added drop-wise in the above-mentioned turbid solution with 6 hours at 30 ℃ of normal heptane, obtain suspension, continued insulated and stirred 1 hour, slowly be cooled to 0～5 ℃ then 400ml.
Centrifugalize is filtered, and the room temperature vacuum drying obtains the 49g dry product.
Using the Malvern laser diffractometry to record mean diameter through Mastersizer 2000 laser particle analyzers is 200 μ m.
Embodiment 4
Press the formulation capecitabine Pharmaceutical composition shown in the table 1.
Table 1
The difference of above-mentioned 3 prescriptions only is that the size of used capecitabine raw material is different, and wherein: the mean diameter of the 1 used capecitabine raw material of filling a prescription is 40 μ m (can with reference to patent documentation: method described in the WO2008131062A2 obtains); The mean diameter of 2 used capecitabine raw materials of filling a prescription is 100 μ m (being obtained by method described in the embodiment 1); The mean diameter of 3 used capecitabine raw materials of filling a prescription is 200 μ m (being obtained by method described in the embodiment 3).
Preparation technology: capecitabine, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose elder generation mix homogeneously with formula ratio, add magnesium stearate then and make mix homogeneously, measure the angle of repose of mixed material.At last mixed material directly is pressed into 1000, measures the dissolution of compressed tablet.
Angle of repose and dissolution determination method are with reference to American Pharmacopeia USP34-NF29.
Measuring the result sees shown in the table 2.
Table 2
| Test item | Prescription 1 | Prescription 2 | Prescription 3 |
| Angle of repose | 57 | 35 | 37 |
| Dissolution (30 minutes) | 98.5％ | 98.2％ | 74.5％ |
Particulate flowability representes that angle of repose, numerical value was more little available angle of repose, explains that flowability is good more.Visible by table 2: the mean diameter size of used capecitabine raw material can obviously influence the flowability of prepared compositions and the dissolution of compressibility and compressed tablet; The mean diameter of used capecitabine raw material too little (as filling a prescription 1), the compositions of preparation mobile bad be prone to sticking, but stripping is complete; When the mean diameter of used capecitabine raw material 100～200 mu m ranges (as fill a prescription 2 with prescription 3); The flowability of the compositions of preparation is all better, and ability is tabletting smoothly, still; When the mean diameter increase of used capecitabine raw material, can delay the dissolution rate of capecitabine.
Embodiment 5
Press the formulation capecitabine Pharmaceutical composition shown in the table 3, wherein fill a prescription 4～mean diameter of the used capecitabine raw material of prescription 6 is 150 μ m (being obtained by method described in the embodiment 2).
Table 3
Described in preparation technology such as the embodiment 4.
According to measure described in the embodiment 4 prepared compositions angle of repose and the dissolution of compressed tablet, and measure the friability of compressed tablets with reference to Chinese Pharmacopoeia 2010.
Measuring the result sees shown in the table 4.
Table 4
| Test item | Prescription 4 | Prescription 5 | Prescription 6 |
| Angle of repose | 33 | 37 | 36 |
| Friability | 0.20％ | 0.22％ | 0.18％ |
| Dissolution (30 minutes) | 99.3％ | 101.2％ | 98.6％ |
Visible by table 4: capecitabine Pharmaceutical composition of the present invention has good flowability and compressibility, and the stripping that is pressed into behind the tablet is complete, and friability and hardness all meet the preparation requirement fully.
Embodiment 6
The tablet of prescription 4 compactings is carried out coating with Opadry by weightening finish 3%; Aluminum-plastic packagedly be placed on 40 ℃; Carry out accelerated test in the climatic chamber of 75% humidity; With reference to American Pharmacopeia USP34-NF29, respectively at detecting its content, dissolution and related substance in 0 day, 1 month, 2 months, 3 months and 6 months.Testing result is seen shown in the table 5.
Table 5
Visible by table 5: the coated tablet by capecitabine Pharmaceutical composition preparation of the present invention has reliable in quality, the obvious advantage that has good stability.
Be necessary to be pointed out that at this: above embodiment only is used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (20)
1. but the capecitabine Pharmaceutical composition of a direct powder compression is characterized in that: by mean diameter is that capecitabine and the pharmaceutically acceptable excipient of 100～200 μ m formed.
2. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 1, it is characterized in that: in the described compositions, the percentage by weight of capecitabine is 50～90%, and the percentage by weight of pharmaceutically acceptable excipient is 50～10%.
3. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 2, it is characterized in that: in the described compositions, the percentage by weight of capecitabine is 75～85%, and the percentage by weight of pharmaceutically acceptable excipient is 25～15%.
4. but according to the capecitabine Pharmaceutical composition of each described direct powder compression in the claim 1 to 3, it is characterized in that: described pharmaceutically acceptable excipient comprises any one or the compositions more than two kinds in filler, disintegrating agent, binding agent, the lubricant.
5. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 1 is characterized in that: contain percentage by weight in the described compositions and be 1～10% disintegrating agent.
6. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 5 is characterized in that: described disintegrating agent is any one or the mixture more than two kinds in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, the carboxymethyl starch sodium.
7. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 1 is characterized in that: do not contain surfactant in the described compositions.
But 8. the capecitabine Pharmaceutical composition of direct powder compression according to claim 1, it is characterized in that: described compositions is made up of following component as following weight percent:
The percentage by weight sum of said components is 100%; The mean diameter of said capecitabine is 100～200 μ m.
But 9. the capecitabine Pharmaceutical composition of direct powder compression according to claim 8, it is characterized in that: described compositions is made up of following component as following weight percent:
The percentage by weight sum of said components is 100%; The mean diameter of said capecitabine is 100～150 μ m.
10. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 1 is characterized in that, described mean diameter is that the capecitabine of 100～200 μ m is to obtain through following treatment step:
A) with the capecitabine material dissolution in organic solvent, obtain settled solution;
B) distilling under reduced pressure becomes muddy slightly to solution;
C) add normal heptane, mix, obtain suspension;
D) be cooled to 0～5 ℃, centrifugalize is filtered, and drying promptly gets.
But 11. the capecitabine Pharmaceutical composition of direct powder compression according to claim 10 is characterized in that: crystal formation or amorphous products that described capecitabine raw material is an any known.
But 12. the capecitabine Pharmaceutical composition of direct powder compression according to claim 10 is characterized in that: described organic solvent is for dissolving the low boiling point organic solvent of capecitabine.
But 13. the capecitabine Pharmaceutical composition of direct powder compression according to claim 12 is characterized in that: described organic solvent is any one or the mixed solvent more than two kinds in dichloromethane, ethyl acetate, butyl acetate, the methanol.
14. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 10 is characterized in that the capecitabine raw material in the step a) and the proportioning of organic solvent are: 1g capecitabine raw material is with 3～40ml organic solvent.
15. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 10 is characterized in that the vacuum distillation temperature in the step b) is 10～40 ℃.
16. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 10 is characterized in that the normal heptane consumption in the step c) is 1～2 times of volume of the used organic solvent of step a).
17. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 10 is characterized in that the time of mixing in the step c) is 0.5～10 hour.
18. but the capecitabine Pharmaceutical composition of direct powder compression according to claim 10 is characterized in that the normal heptane in the step c) adds with the dropping mode.
19. but the application of the capecitabine Pharmaceutical composition of the described direct powder compression of claim 1 is characterized in that: be used for the preparation of capecitabine solid preparation.
But 20. the application of the capecitabine Pharmaceutical composition of direct powder compression according to claim 19 is characterized in that: be used for the preparation of the various tablets of capecitabine.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013030602A1 (en) * | 2011-09-02 | 2013-03-07 | Slotervaart Participaties Bv | Solid extended release composition for oral administration comprising substantially amorphous capecitabine |
| CN103251569A (en) * | 2013-05-30 | 2013-08-21 | 成都苑东药业有限公司 | Capecitabine tablet composition and preparation method thereof |
| CN103509072A (en) * | 2012-06-19 | 2014-01-15 | 齐鲁制药有限公司 | Preparation method of micro-powder capecitabine |
| CN106496294A (en) * | 2016-09-21 | 2017-03-15 | 齐鲁天和惠世制药有限公司 | A kind of method for preparing micro powder type capecitabine |
| CN117229341A (en) * | 2023-11-07 | 2023-12-15 | 成都苑东生物制药股份有限公司 | Capecitabine crystal form I and preparation method thereof |
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| 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 |
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2011
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| 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 |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013030602A1 (en) * | 2011-09-02 | 2013-03-07 | Slotervaart Participaties Bv | Solid extended release composition for oral administration comprising substantially amorphous capecitabine |
| CN103509072A (en) * | 2012-06-19 | 2014-01-15 | 齐鲁制药有限公司 | Preparation method of micro-powder capecitabine |
| CN103509072B (en) * | 2012-06-19 | 2016-01-13 | 齐鲁制药有限公司 | A kind of preparation method of micro powder type capecitabine |
| CN103251569A (en) * | 2013-05-30 | 2013-08-21 | 成都苑东药业有限公司 | Capecitabine tablet composition and preparation method thereof |
| CN103251569B (en) * | 2013-05-30 | 2015-10-28 | 成都苑东药业有限公司 | Capecitabine tablet composition and preparation method thereof |
| CN106496294A (en) * | 2016-09-21 | 2017-03-15 | 齐鲁天和惠世制药有限公司 | A kind of method for preparing micro powder type capecitabine |
| CN106496294B (en) * | 2016-09-21 | 2018-10-30 | 齐鲁天和惠世制药有限公司 | A method of preparing micro powder type capecitabine |
| CN117229341A (en) * | 2023-11-07 | 2023-12-15 | 成都苑东生物制药股份有限公司 | Capecitabine crystal form I and preparation method thereof |
| CN117229341B (en) * | 2023-11-07 | 2024-02-09 | 成都苑东生物制药股份有限公司 | Capecitabine crystal form I and preparation method thereof |
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Application publication date: 20120104 |