CN104721169B - A kind of Celebret preparation compositions - Google Patents
A kind of Celebret preparation compositions Download PDFInfo
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- CN104721169B CN104721169B CN201510139945.6A CN201510139945A CN104721169B CN 104721169 B CN104721169 B CN 104721169B CN 201510139945 A CN201510139945 A CN 201510139945A CN 104721169 B CN104721169 B CN 104721169B
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Abstract
The invention provides a kind of Celebret and preparation method thereof.The Celebret of the present invention includes active component celecoxib and the pharmaceutic adjuvant such as organic acid, calcium carbonate or sodium acid carbonate, lactose.The Celebret of the present invention has preparation technology simple, and dissolving out capability is excellent, and relevant content of material is low, the advantages of stability is high.
Description
Technical field
The present invention relates to pharmaceutical field, and in particular to a kind of Celebret and preparation method thereof.
Background technology
Celecoxib (Celecoxib), i.e. 4- [hydrogen -1- pyrazol-1-yls of 5- (4- tolyls) -3- (trifluoromethyl) -1] benzene
Sulfonamide, is first Selective COX-2 inhibitor, is also the maximum non_steroidal anti_inflammatory drug of current global recipe quantity, no
Only there is notable analgesia effect, can significantly mitigate joint tenderness/pain and arthroncus, and with superior intestines and stomach safety
Property, according to《JAMA》The SUCCESS research reports delivered for 2006,39 national 13274 are related at one
In the comparative study of patient, symptomatic ulcer occurs for celecoxib group patient and the probability of ulcer complication is more anti-than traditional non-steroidal
The patient of scorching antalgesic group is low by 87.5%.
But, celecoxib dissolubility is extremely low, and solubility is about 0.007mg/ml in water at 25 DEG C, in conventional dissolution medium
Middle dissolution is slow, and its quality standard uses pH12 sodium radio-phosphate,P-32 solution.It is well known that the dissolution of medicine is to play therapeutic action
How premise, promote celecoxib quick and complete dissolution, be the problem of those skilled in the art need to put forth effort to solve.
In order to improve the dissolution of celecoxib, technical staff employs different solutions, raw material is made unformed
Structure or solid dispersions are conventional methods.Pharmacia Corp's patent (application number 00805635.8) " improves biological profit
With the solid-state form of the celecoxil of rate ", including two kinds of techniques, the first technique is by taking high temperature melting-quickly cooling mode to be made
Undefined structure, second of technique is that undefined structure is made with drying after crystallization inhibitor dissolving.The fusing point of celecoxib is
160 DEG C~165 DEG C, the first technique needs high temperature and liquid nitrogen frozen, and process conditions are harsh, and degraded production is easily caused under high temperature
The increase of thing；Second of technique is removed using heating after organic solvent such as isopropanol dissolving by the way of solvent re-dry, process
Complexity, and a large amount of organic solvents are consumed, environment is influenceed, increases cost.(the application of Hengrui Medicine Co., Ltd., Jiangsu Prov.'s patent
Number:201210003999.6) " Celecoxib solid dispersion and preparation method thereof ", Hangzhou Heze Pharmaceutical Technology Co., Ltd. is special
Sharp (application number：201210259149.2) " a kind of Celecoxib solid composition, preparation method and application for having high-dissolution ",
Substantially it is also a kind of solid dispersions, is also prepared using solvent method.Ningbo Institute of Technology, Zhejiang University patent (application number:
201010301422.4) " a kind of solid dispersion containing celecoxib and its preparation method and application ", with celecoxib and poly-
Solid dispersion is made in ethylene glycol.Ningbo Institute of Technology, Zhejiang University patent (application number:201210124986.4) " one kind is containing plug
Carry out solid dispersion of former times cloth and preparation method thereof ", solid dispersion is prepared with celecoxib and copolyvidone, squeezed using melting
The production technology gone out, temperature is up to 70-140 DEG C, it is necessary to special equipment, and the problem of equally have high temperature degradation.Beijing star sky
Medical limited company's patent (application number:201210362698) " a kind of Celecoxib solid dispersion and preparation method thereof
And application ", using PLURONICS F87 as carrier, Celecoxib solid dispersion is prepared using fusion method, solvent method.No matter use
Which kind of mode, it is inevitable the need for special installation and increase process, and the undefined structure or solid dispersions of medicine
There is crystallization trend in storage process, how to suppress is a problem.
Tianjin Inst. of Materia Medica patent (application number:201110243045.8) " a kind of celecoxib composition and preparation side
Method and purposes ", celecoxib is micronized.It is to improve the conventional technical measures of dissolution by drug micronization, but carrys out former times for filling in
Cloth, the effect of micronizing is unsatisfactory, especially in conventional dissolution medium such as simulated gastric fluid (pH1.2 hydrochloric acid solutions), manually
In intestinal juice (pH6.8 phosphate buffers, pH4.5 acetate buffers).
Jiangsu ZhengDa QingJiang Pharmaceutical Co., Ltd's patent (application number:201310382316.7) " a kind of containing celecoxib
Inclusion compound and preparation method thereof ", containing celecoxib and inclusion material, preparation method is by inclusion material and celecoxib difference
It is dissolved in water and organic solvent and is included, celecoxib inclusion compound is obtained by the way of vacuum drying or freeze-drying.
Yellow China's patent (application number:201310137516.6) " a kind of new celecoxib composition and its preparation technology ", former times is carried out containing plug
Cloth and inclusion material glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin.Bulk drug is without crushing during inclusion, but is wrapped
The limitation of condensation material is, it is necessary to add substantial amounts of inclusion material, and loading capsule has certain difficulty.
Beijing Jingwei Yankang Pharmaceuticals Research Inst., Co., Ltd's application number:201210124793.9 it is a kind of containing celecoxib
Solid composite medicament, is prepared using the formula for adding a small amount of liquid macrogol, and makes liquid curing with auxiliary material absorption.Liquid
Polyethylene glycol has good dissolution to celecoxib, but influence is brought on pelletization, and the improvement to dissolution is limited.
Hainan Herui Pharmaceutical Co., Ltd.'s patent (application number:201310551574.3) " a kind of dissolution rate is increased
Celecoxib solid composition and its preparation method and application ", is made up of celecoxib, dispersion enhancing agents and alkali compounds,
Wherein alkali compounds is one kind in sodium carbonate, sodium acetate, sodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or sodium hydroxide
Or several, preferably two kinds of mixing, and celecoxib, dispersion enhancing agents and alkali compounds ground to form under nitrogen protection micro-
Powder.It is lower in the basic conditions to grind, influence is inevitably brought on the stability of celecoxib, it is therefore desirable to be filled with nitrogen simultaneously
It is 15-30 DEG C to control temperature, is made troubles to production.
By the analysis of above-mentioned prior art, capsule is very important as conventional solid dosage forms, its dissolution
Quality index, but bulk drug is micronized, selected or increased pharmaceutic adjuvant, hand is handled using special equipment or preparation technology etc.
Section, on the premise of general pharmaceutical preparation requirement is met, this is inevitably brought, and preparation technology is complicated or relevant material increases
Plus, medicine stability reduction etc. defect.Therefore, a kind of preparation technology how is provided simple, dissolving out capability is excellent, and relevant thing
The Celebret that matter content is low, stability is high, this needs those skilled in the art to put forth effort solution.
The content of the invention
By numerous studies, it has been surprisingly found that adding organic acid and calcium carbonate in Celebret prescription
Or sodium acid carbonate, and by the control of its content in particular range, Celebret produced by the present invention have dissolution quick and
Complete characteristic, and with good quality and stability, and preparation technology is simple, it is not necessary to special installation.Based on this, we
It is prepared for technique simple, dissolving out capability is excellent, relevant content of material is low, the high Celebret of stability, and then completes this
Invention.
Specifically, the invention provides a kind of Celebret, including：
Wherein, the weight ratio of celecoxib, organic acid and calcium carbonate or sodium acid carbonate is 10：1：1, wherein described is organic
Acid is selected from citric acid, tartaric acid or its mixture.
Wherein, the Celebret can also include glidant 1-5 parts by weight, lubricant 0.5-1 parts by weight, wherein
The preferred silica of described glidant, the preferred magnesium stearate of described lubricant.
More specifically, the invention provides following Celebret：
(1) a kind of Celebret, is constituted as follows：
(2) a kind of Celebret, is constituted as follows：
(3) a kind of Celebret, is constituted as follows：
Celebret of the present invention can be prepared using the conventional method of field of pharmaceutical preparations.For example：
(1) in addition to glidant, lubricant, remaining supplementary material is mixed, dry granulation, is optionally added glidant, lubrication
Agent is mixed, encapsulated, is produced；
(2) in addition to glidant, lubricant, remaining supplementary material is mixed, and wetting agent softwood is done with ethanol, is pelletized, and is dried, whole
Grain, is optionally added glidant, lubricant and mixes, encapsulated, produces；
Or,
(3) in addition to glidant, lubricant, organic acid or sodium acid carbonate/calcium carbonate, remaining supplementary material is mixed, with purified water
Or hydrous ethanol does wetting agent softwood, pelletize, dry, whole grain, add organic acid or sodium acid carbonate/calcium carbonate, and it is optional
Add glidant, lubricant with selecting, mix, it is encapsulated, produce.
The dosage of Celebret of the present invention is needed depending on the judgement according to clinician, for example, daily dose can
To be 100-800mg.
The present invention is based on scientific and rational Celebret prescription, compared with prior art, achieves significant technology
It is progressive.What the present invention was obtained has the beneficial effect that：Although supplementary material constituent is more, preparation is listed with Celebret
(Celebrex) is compared, and Celebret of the invention not only drastically increases the dissolution rate of celecoxib, and preparation is steady
Qualitative high, relevant content of material is extremely low.Moreover, with the reference examples (weight of celecoxib, organic acid and calcium carbonate or sodium acid carbonate
Amount is than non-10：1：1) compare, the dissolution rate of Celebret of the invention, stability are significantly improved.In addition, of the invention
Special installation need not be used, preparation technology is simple, is especially suitable for industrialization production.
Embodiment
Embodiment is only that the present invention is further explained and described, and is not necessarily to be construed as limitation of the present invention.
Supplementary material in embodiment is purchased in market.
(the weight ratio of celecoxib, citric acid and calcium carbonate is 10 to the Celebret of the present invention of embodiment 1：1：1)
Prescription：
Preparation technology：
In addition to silica, magnesium stearate, remaining supplementary material is mixed, dry granulation, add silica, stearic acid
Magnesium, is mixed, encapsulated, is produced (100mg/).
(the weight ratio of celecoxib, citric acid and calcium carbonate is 10 to the Celebret of the present invention of embodiment 2：1：1)
Prescription：
Preparation technology：
In addition to silica, magnesium stearate, remaining supplementary material is mixed, wetting agent softwood is done with ethanol, is pelletized, is done
Dry, whole grain adds silica, magnesium stearate and mixed, encapsulated, produces (100mg/).
(the weight ratio of celecoxib, tartaric acid and sodium acid carbonate is 10 to the Celebret of the present invention of embodiment 3：1：
1)
Prescription：
Preparation technology：
In addition to tartaric acid, silica, magnesium stearate, remaining supplementary material is mixed, it is soft to do wetting agent system with 75% ethanol
Material, pelletizes, and dries, whole grain, adds tartaric acid, silica, magnesium stearate, mixes, encapsulated, produces (200mg/).
(the weight ratio of celecoxib, citric acid and calcium carbonate is 5 to the Celebret of the present invention of reference examples 1：1：1)
Prescription：
Preparation technology：
In addition to silica, magnesium stearate, remaining supplementary material is mixed, dry granulation, add silica, stearic acid
Magnesium, is mixed, encapsulated, is produced (100mg/).
(the weight ratio of celecoxib, citric acid and calcium carbonate is 30 to the Celebret of reference examples 2：3：5)
Prescription：
Preparation technology：
In addition to silica, magnesium stearate, remaining supplementary material is mixed, wetting agent softwood is done with ethanol, is pelletized, is done
Dry, whole grain adds silica, magnesium stearate and mixed, encapsulated, produces (100mg/).
(the weight ratio of celecoxib, tartaric acid and sodium acid carbonate is 8 to the Celebret of reference examples 3：2：1)
Prescription：
Preparation technology：
In addition to tartaric acid, silica, magnesium stearate, remaining supplementary material is mixed, it is soft to do wetting agent system with 75% ethanol
Material, pelletizes, and dries, whole grain, adds tartaric acid, silica, magnesium stearate, mixes, encapsulated, produces (200mg/).
The dissolution study of the Celebret of experimental example 1
Celebret made from Example 1~3, is pressed《Chinese Pharmacopoeia》Two methods of annex XC second of version in 2010 are surveyed
Determine dissolution rate.Leaching condition：Respectively with 0.1mol/L hydrochloric acid solutions (including 0.5% lauryl sodium sulfate), pH4.5 phosphate
Buffer solution (including 0.5% lauryl sodium sulfate), pH6.8 phosphate buffers (including 0.5% lauryl sodium sulfate) are
Dissolution medium, volume 1000ml, 75 turns/min of rotating speed, took dissolution fluid, according to high performance liquid chromatography (Chinese Pharmacopoeia through 30 minutes
Two D of annex V of version in 2010) experiment, it is filler (SUPELCOSIL LC-DP 250*4.6mm) with phenyl bonded silica,
Potassium dihydrogen phosphate 2.7g (is taken, the 1000ml that adds water dissolvings, with phosphorus acid for adjusting pH to 3.0)-methanol-acetonitrile with phosphate buffer
(6:6:1) it is mobile phase；60 DEG C of column temperature；Detection wavelength is 215nm；Flow velocity is 1.5ml per minute.By external standard method in terms of peak area
Cumulative defaultlogic is calculated, it is as a result as follows：
| 0.1mol/L hydrochloric acid solutions | PH4.5 phosphate buffers | PH6.8 phosphate buffers | |
| Embodiment 1 | 100.1% | 98.7% | 94.9% |
| Embodiment 2 | 99.9% | 99.0% | 92.8% |
| Embodiment 3 | 99.8% | 98.9% | 90.4% |
| Reference examples 1 | 81.3% | 85.6% | 68.7% |
| Reference examples 2 | 79.4% | 88.2% | 73.6% |
| Reference examples 3 | 75.2% | 82.87% | 70.1% |
| List preparation | 70.4% | 83.9% | 76.2% |
The stability study of the Celebret of experimental example 2
According to two annex XIX C stability tests guideline requirements of Chinese Pharmacopoeia 2010 edition, embodiment 1~3 is investigated
Obtained Celebret, is determined about material and content using HPLC methods, and chromatographic condition is to fill out with phenyl bonded silica
Fill agent (SUPELCOSIL LC-DP 250*4.6mm)；Potassium dihydrogen phosphate 2.7g (is taken, the 1000ml that adds water is molten with phosphate buffer
Solution, with phosphorus acid for adjusting pH to 3.0)-methanol-acetonitrile (60:30:10) it is mobile phase；60 DEG C of column temperature；Detection wavelength is 215nm；Stream
Speed is 1.5ml per minute.As a result it is as follows：
| Relevant material % | Content % | |
| Embodiment 1 | 0.05 | 99.9 |
| Embodiment 2 | 0.03 | 100.0 |
| Embodiment 3 | 0.06 | 99.8 |
| Reference examples 1 | 0.18 | 100.1 |
| Reference examples 2 | 0.21 | 100.2 |
| Reference examples 3 | 0.25 | 99.8 |
| List preparation | 0.23 | 100.1 |
Claims (8)
1. a kind of Celebret, including：
Wherein, the weight ratio of the celecoxib, organic acid and calcium carbonate or sodium acid carbonate is 10：1：1.
2. Celebret according to claim 1, wherein described organic acid is selected from citric acid, tartaric acid or it is mixed
Compound.
3. Celebret according to claim 1 or 2, in addition to：
Glidant 1-5 parts by weight,
Lubricant 0.5-1 parts by weight.
4. Celebret according to claim 3, wherein described glidant is silica.
5. Celebret according to claim 3, wherein described lubricant is magnesium stearate.
6. Celebret according to claim 1, is constituted as follows：
7. Celebret according to claim 1, is constituted as follows：
8. Celebret according to claim 1, is constituted as follows：
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838542A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form I of celecoxib, preparation method and purpose thereof |
| CN103230382A (en) * | 2013-04-17 | 2013-08-07 | 贵州联盛药业有限公司 | Celecoxib effervescent tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102838542A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form I of celecoxib, preparation method and purpose thereof |
| CN103230382A (en) * | 2013-04-17 | 2013-08-07 | 贵州联盛药业有限公司 | Celecoxib effervescent tablet and preparation method thereof |
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Address after: 051500 Haixing Road, Zhaoxian County Industrial Park, Shijiazhuang, Hebei Patentee after: HEBEI RENHE YIKANG PHARMACEUTICAL Co.,Ltd. Address before: 053411 Hengshui City, Hebei, Wuyi County, Qing Liang store town Patentee before: HEBEI RENHE YIKANG PHARMACEUTICAL Co.,Ltd. |
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