CN103191065A - Celecoxib new formulation and preparation method thereof - Google Patents
Celecoxib new formulation and preparation method thereof Download PDFInfo
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- CN103191065A CN103191065A CN2013101338379A CN201310133837A CN103191065A CN 103191065 A CN103191065 A CN 103191065A CN 2013101338379 A CN2013101338379 A CN 2013101338379A CN 201310133837 A CN201310133837 A CN 201310133837A CN 103191065 A CN103191065 A CN 103191065A
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Abstract
The invention discloses a celecoxib pellet preparation, which is used for treating rheumatic arthritis, osteoarthritis and ankylosing spondylitis, and also can be used for treating acute pain, dysmenorrheal, colorectal polyps, post-operation analgesia, low back pain, periarthritis of shoulder and tenosynovitis. According to the celecoxib new formulation and the preparation method thereof, the pellet preparation technology and the controlled-release pellet upper covering technology are adopted and microcrystalline cellulose pills are selected for dissolving the celecoxib material medicines in adhesive povidone solution, the medicine materials are uniformly sprayed on the surface of the pills and covered with isolating layers, so that the pellet is pressed and capsule. When the disintegration time limit of the celecoxib pellet preparation is remarkably shortened and the bioavailability is remarkably improved.
Description
[technical field]
The present invention relates to novel form of a kind of celecoxib and preparation method thereof.Specifically, relate to a kind of slow release of celecoxib or enteric coated pellets formulation and preparation method thereof.
[background technology]
It is a cookle medicine of Pfizer's development and sale that match comes former times cloth, is mainly used in treating rheumatic arthritis, osteoarthritis and ankylosing spondylitis, also is used for the treatment of to ease pain after acute pain, dysmenorrhea, colorectal polyp and the operation etc.Celecoxib was approved for back pain, scapulohumeral periarthritis and tenosynovitis again in 2007.Celecoxib is used for traumatic pain, the back pain that gets a tooth pulled out is just clinical in the III phase, is used for the treatment of various tumors and comprises that breast carcinoma, pulmonary carcinoma and cancer of pancreas etc. are also among research.Up-to-date domestic and international epidemiology, clinical and experimentation show that celecoxib also has prevention and suppresses the effect of tumor.Because its targeting is strong, side effect is little, in kinds of tumors prevention and treatment, play a significant role.
The celecoxib mechanism of action be selectively acting in cyclooxygenase 2 (COX-2), belong to selective COX-2-inhibitor 2.It is generally acknowledged selectivity cyclooxygenase inhibitor 2, owing to do not act on COX-1, do not influence PGI2 synthetic that gastrointestinal tract and kidney is had protective effect, gastrointestinal side effect and nephrotoxicity are all little than general NSAID (non-steroidal anti-inflammatory drug).
The celecoxib annual sales amount is above 2,500,000,000 dollars.Along with the indication after the approval in 2007 enlarges, bigger market, bigger demand will be had.Domestic granted import first of in August, 2000, the indication of approval is osteoarthritis, rheumatoid arthritis and adult's acute pain at present, in October, 2012, approval was used for China patient's ankylosing spondylitis indication.Crude drug and capsule only have Pfizer, Searle two families to obtain SFDA approval of import sale at present.Domestic do not have producer to go on the market.
Match comes the chemical essential information of former times cloth as follows:
Chinese common name: celecoxib
Trade name: celecoxib
English common name: Celecoxib
Chemical name: 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1-pyrazol-1-yl] benzene sulfanilamide
CAS numbering: 169590-42-5
Molecular formula: C
17H
14F
3N
3O
2S
Molecular weight: 381.37
Chemical structural formula:
Celecoxib dissolubility in water is extremely low, and condenses in bulk easily, can not direct compression.In order to improve bioavailability, the celecoxib preparation that preparation is satisfied, Chinese patent 99802185.7 adopts micronized method, a kind of oral celecoxib pharmaceutical composition is provided, each dosage unit contains celecoxib granule and one or more excipient, wherein the celecoxib granule D of the 10-1000mg that has an appointment
90Less than 200 μ m, can make dosage forms such as tablet, capsule.
Chinese patent 201210259149.2 provides a kind of celecoxib solid composite of tool high-dissolution, by celecoxib being dissolved in the suitable solvent (for example ethanol), after using adjuvant (for example micropowder silica gel) to carry out adsorption dry then, obtain the amorphous compositions of celecoxib.According to actual demand, further be prepared into various solid preparation forms such as tablet, capsule, granule.
Micropill is a kind of dosage decentralized, and diameter is generally the oral formulations of sphere or the class sphere of 0.25-1.5mm, in the capsulae vacuus of can packing into or be pressed into tablet and use.The advantage that micropill has in preparation process, pharmacological action is that other dosage forms can't realize.In recent years, micropill is subject to people's attention day by day, becomes a main trend of preparation process development.The advantage of micropill: 1. take the back extensively, be evenly distributed in gastrointestinal tract, big at gastrointestinal surface distributed area, thus improve bioavailability, reduce or eliminate medicine gastrointestinal is stimulated; 2. pellet is in the influence of the gastrointestinal transhipment unable to take food thing conveying rhythm and pace of moving things, gastric emptying; 3. the release rule of slow controlled release micro pill is than the tablet favorable reproducibility, and indivedual micropills are to the not serious influence of the drug release behavior of whole preparation; 4. the micropill of different rate of releasing drug can be dressed up capsule in proportion, to satisfy different needs; 5. the compound capsule of being made up of different micropills has stability preferably, reduces the interaction between the medicine; 6. micropill is better mobile, is conducive to preparation packing or further molding.
Pellet preparations can adopt celphere to prepare, and pharmaceutical pack is wrapped in the ball wicking surface, for example pharmaceutical pack is rolled in the surface of microcrystalline Cellulose celphere.Most of micropills need carry out isolation coat on the medicine layer surface; On contagion gown, can also enteric coated or extended release coatings.Can adopt the granulating coated legal system of ebullated bed to be equipped with micropill, also be fluid bed pill method, equipment is made up of air compression system, power heating system, spraying system and control system.Celphere is placed in the fluidising chamber, and the air of uniform temperature enters fluidising chamber by the bottom through screen cloth, sprays into atomized adhesive then, when granular size reaches the regulation requirement, stop spraying, wrap contagion gown, enteric coating or extended release coatings then, the granule of formation is directly at fluidising chamber's inner drying.
[summary of the invention]
The technical problem to be solved in the present invention is to overcome the prior art deficiency, and the celecoxib that a kind of disintegration is short, bioavailability is high novel formulation is provided.
The present invention realizes by following technical solution.Select the microcrystalline Cellulose ball heart for use, adopt microcapsule technology of preparing and controlled release micro pill medicine-feeding packaging technique, Sai Laixibu crude drug, binding agent polyvidone (PVP) are dissolved in the alcoholic solution, then gained solution evenly is sprayed on ball heart surface, wrap one deck sealing coat again, the microcapsule that will contain crude drug further is processed into dosage forms such as capsule, tablet, injection, suspensoid, lotion, ointment, suppository, preferably capsule and tablet.
Specifically, technical solution of the present invention is: a kind of celecoxib pellet preparations, with microcrystalline Cellulose as fine pellet core, the ball wicking surface is surrounded by medicine layer, medicine layer comprises active component celecoxib and binding agent polyvidone, the two weight ratio is 3～15: 1, preferred weight ratio 4～6: 1, and preferred especially 5: 1.The medicine layer surface is surrounded by sealing coat.Sustained release coating or enteric coating be can also be surrounded by on the sealing coat, slow-release micro-pill and enteric coated micropill made respectively.Celecoxib pellet preparations of the present invention adopts the preparation of following method: celecoxib, binding agent polyvidone are dissolved in alcoholic solution, then gained solution evenly are sprayed on the surface of the blank pill heart, wrap dry getting final product behind one deck sealing coat again.The micropill that makes can further be processed into capsule or tablet.Preferred version is after wrapping one deck sustained release coating or enteric coat layer again on the micropill sealing coat, again micropill further to be processed into capsule or tablet.
In a preferred version of the present invention, select the 30-40 order microcrystalline Cellulose blank pill heart for use.
In another preferred version of the present invention, can in alcoholic solution, add proper amount of surfactant, for example add 0.3-1.5% (w/v) sodium lauryl sulphate (SDS) as solubilizing agent.
In another preferred version of the present invention, sustained release coating micropill and enteric coated-pellet are mixed in proportion, incapsulate, make capsule.As canonical reference, determine mixed proportion with brand medicine release profiles.For example, sustained release coating micropill and enteric coated-pellet are in 1～5: 1 ratio is mixed, and preferably according to 2～4: 1 ratio is mixed.
Adopt fluid bed to prepare celecoxib preparation of the present invention.Specifically, the preparation technology of celecoxib preparation of the present invention in turn includes the following steps:
1, Sai Laixibu crude drug, polyvidone are dissolved in the alcoholic solution, are mixed with medicine carrying solution, prepare isolation coat liquid, sustained release coating liquid simultaneously, standby;
During concrete enforcement, be the PVP alcoholic solution of 5-11% with 95% ethanol preparation mass concentration, the ethanol volume according to 5: 1～3: celecoxib weight adds the celecoxib raw material, namely adds 1～3g celecoxib raw material, stirring and dissolving in the alcoholic solution of every 5ml.Preferred proportion is the ethanol volume: celecoxib weight=5: 2.Determine PVP concentration preferably by the brightness of observing medicine-feeding back micropill: film-coat is more bright, illustrates that the concentration of PVP is more suitable.
The molecular weight of PVP can characterize with the viscosity of its aqueous solution with respect to water, represent with the K value, the K value between 10-120, K value Fikentscher ' s Equation for Calculating.Preferred K value=about 30 are for example selected pvp K30 for use among the present invention.
Isolation coat liquid, sustained release coating liquid: adopt existing conventional formulation.
2, celphere preheating: get the MCC celphere, put in the fluid bed, the preheating celphere;
3, medicine-feeding: after the preheating of MCC celphere finished, medicine was sprayed at the end;
4, bag contagion gown: medicine-feeding finishes the end, back spray bag sealing coat;
5, bag extended release coatings or enteric coating: the enteric coated or extended release coatings of end spray.
6, drying: it is dry that coating finishes the back, treats that the arrival of coated micropill water content gets final product below 3.0%.
After finishing, drying preferably carries out post processing, for example antiseized operation, heat treatment etc.
The inventor finds that by test of many times the key parameter of fluid bed is inlet temperature and material (the ball heart) temperature, and has determined the scope of these parameters.In celphere preheating, medicine-feeding, bag contagion gown and bag extended release coatings, enteric coating, dry this several steps, inlet temperature is controlled at 30 to 48 degrees centigrade, and temperature of charge is 25 to 38 degrees centigrade.In addition, the inventor finds that the guide cylinder height also is an important parameter, and determines that by testing the guide cylinder height is 11-13mm (being applicable to above each step), for example 11mm, 12mm or 13mm.
The invention has the beneficial effects as follows: content and release all can reach requirement, have solved the low problem of celecoxib raw material dissolution; The dispersion of having accelerated medicine absorbs, and has improved bioavailability, thereby has increased drug effect, has reduced side effect and untoward reaction; Increased the quality stability of medicine, the release repeatability is good; Because the micropill good fluidity, content uniformity is littler, has guaranteed the medicine uniformity.
[specific embodiment]
Embodiment 1 (slow-release micro-pill)
It is as follows to write out a prescription
A. according to the prescription obtain solution
A-1 preparation medicine carrying solution
Take by weighing plug by prescription and seek cloth crude drug, sodium lauryl sulphate in beaker, add 95% ethanol of recipe quantity again, stir and dissolve fully until the celecoxib crude drug.Beaker is shifted out water-bath, leave standstill, be cooled to room temperature.Pressing at last writes out a prescription slowly adds pvpK30, leaves standstill after the stirring, dissolves fully until pvpK30 to get final product.
A-2 preparation isolation coat liquid
Take by weighing 50% hydroxypropyl methylcellulose HPMC (5mPa.s) by prescription, get an amount of purified water, HPMC is slowly added in the water, the limit edged stirs, and leaves standstill, and gets final product to the HPMC complete swelling.
A-3 preparation sustained release coating liquid
Remaining HPMC (5mPa.s) is swollen in an amount of purified water, standby;
Get Pulvis Talci (Talc, 800 orders) by prescription, add an amount of purified water, stir, through high speed shear (10000rpm) 10 minutes, get A;
Get NE30D by prescription, slowly add among the A, the limit edged stirs, and gets B;
The HPMC solution for preparing before is mixed among the B, stirs, mixing adds the residue purified water, gets C;
Slowly stir C with dasher, face and it is crossed 40 mesh sieves before the coating, continue mixing time before the coating and must not be less than 40 minutes, continue to stir coating solution in the coating process.
B. coating
Main use equipment: the multi-functional coating machine of DPL-1 type (fluid bed)
The preheating of B-1MCC celphere
Warm-up phase fluidized bed process parameter
The B-2 medicine-feeding
Treat that celphere reaches 30 ℃, medicine is sprayed at the lasting end that begins after 5 minutes.
This process fluid bed is wiped operating parameter
B-3 wraps sealing coat
Treat that medicine-feeding finishes to wrap the HPMC sealing coat immediately, flow velocity strengthens gradually.Need the tight whether adhesion of ball core of noting in this process, as finding the adhesion of ball core, can suitably reduce flow velocity or temporarily stop coating.The fluidized bed process parameter is as follows
B-4 wraps extended release coatings
After bag HPMC sealing coat finishes, adjust the fluid bed parameter, treat that temperature of charge begins coating when reaching this process setting value.Parameter is as follows
The B-5 drying
After treating that coating finishes, fluid bed inner drying coated micropill.The fluid bed parameter is as follows
In the coating process, should guarantee the normal fluid bed state of micropill, avoid occurring adhesion phenomenon.Require from content and release, should guarantee certain medicine-feeding yield, control is about 90%, and release should be able to satisfy the reproduction requirement.
The B-6 post processing
Antiseized operation: treat that the coated micropill drying finishes, discharging is weighed.Get an amount of Pulvis Talci (coated micropill gross weight 0.5%), with the micropill mixing, prevent micropill adhesion in follow-up heat treatment process.
Heat treatment: different coated micropill heat treatment modes are different.The sustained release coating micropill: 40 ℃ were worn out 24 hours in the baking oven.Enteric coated-pellet: 40 ℃ got final product in dry 1-2 hour in the baking oven.
C. make finished product
With the slow-release micro-pill capsule of packing into No. two, make 1000 capsules (200mg specification).
Embodiment 2 (enteric coated micropill)
Prescription is seen embodiment 1 form, and processing step is with embodiment 1, and difference is:
A-3 prepares enteric coating liquid
Remaining HPMC (5mPa.s) is swollen in an amount of purified water, standby;
Take by weighing triethyl citrate (TEC) by prescription, add an amount of purified water, stir, add recipe quantity Pulvis Talci (Talc, 800 orders) again, stir, through high speed shear (10000rpm) 10 minutes, get A;
Take by weighing L30D-55 by prescription, slowly add among the A, the limit edged stirs, and gets B;
The HPMC solution for preparing before is mixed among the B, stirs, mixing adds the residue purified water, gets C;
Stir slowly stirring C with dasher, face preceding 40 mesh sieves of crossing of coating, continue mixing time before the coating and must not be less than 40 minutes, the lasting stirring of coating process coating solution.
B-4 is enteric coated
After bag HPMC sealing coat finishes, adjust the fluid bed parameter, treat that temperature of charge begins coating when reaching this process setting value.Parameter is as follows
With the enteric coated micropill capsule of packing into No. two, make 1000 capsules (200mg specification).
Embodiment 3 (slow-release micro-pill+enteric coated micropill)
Embodiment 1 and 2 is made sustained release coating micropill and enteric coated-pellet in 3: 1 ratio mix homogeneously, No. two capsules (200mg specification) of packing into.
Embodiment 4 (slow-release micro-pill)
It is as follows to write out a prescription
Preparation technology is with embodiment 1, and fluid bed control parameter sees Table 1.
Embodiment 5 (enteric coated micropill)
Prescription is seen embodiment 4 forms, and preparation technology is with embodiment 2, and fluid bed control parameter sees Table 2.
Embodiment 6 (slow-release micro-pill+enteric coated micropill)
Embodiment 4 and 5 is made sustained release coating micropill and enteric coated-pellet in 1: 1 ratio mix homogeneously, No. two capsules (200mg specification) of packing into.
Embodiment 7 (slow-release micro-pill)
It is as follows to write out a prescription
Preparation technology is with embodiment 1, and fluid bed control parameter sees Table 3.
Embodiment 8 (enteric coated micropill)
Prescription is seen embodiment 7 forms, and preparation technology is with embodiment 2, and fluid bed control parameter sees Table 3.
Embodiment 9 (slow-release micro-pill+enteric coated micropill)
Embodiment 7 and 8 is made sustained release coating micropill and enteric coated-pellet in 5: 1 ratio mix homogeneously, No. two capsules (200mg specification) of packing into.
Embodiment 10
According to embodiment 3 preparation samples.According to the content detection value, adorn capsule (lot number: RD08005164) No. two by the 100mg loading amount.
Change the basket method according to 2010 editions two appendix X of Chinese Pharmacopoeia and measure release, the result sees following table for details:
| Time (h) | RD08005164 | Standard | Contrast |
| 0 | 0 | 0 | 0 |
| 1(h) | 6.21％ | - | 4.58％ |
| 2(h) | 25.56％ | 12-39 | 16.06％ |
| 3(h) | 57.90％ | 44-70 | 50.99％ |
| 5(h) | 76.18％ | ＞70 | 77.37％ |
| 8(h) | 86.06％ | - | 91.48％ |
Embodiment 11
Study on the stability
Get the RD08005164 batch sample and be positioned in the stability test case, temperature is set under 40 ℃, relative humidity 75%RH condition, carries out accelerating in three months to investigate.
1) release changes
| Time (h) | The 0th day | Accelerated one month | Accelerated two months | Accelerated three months |
| 0 | 0％ | 0％ | 0％ | 0％ |
| 1 | 8％ | 8％ | 9％ | 5％ |
| 2 | 31％ | 29％ | 31％ | 30％ |
| 3 | 63％ | 62％ | 66％ | 67％ |
| 5 | 81％ | 79％ | 84％ | 82％ |
[conclusion] rate of release does not have significant change
2) content
| ? | The 0th day | Accelerated one month | Accelerated two months | Accelerated three months |
| Content | 100％ | 96.6％ | 100.4％ | 99.6％ |
[conclusion] content does not have remarkable decline
3) relative substance
Claims (11)
1. celecoxib pellet preparations, as fine pellet core, the ball wicking surface is surrounded by medicine layer with microcrystalline Cellulose, and medicine layer comprises celecoxib and polyvidone, and the two weight ratio is 3～15:1, and the medicine layer surface is surrounded by sealing coat.
2. celecoxib pellet preparations according to claim 1, the two weight ratio of celecoxib and polyvidone is 4～6:1.
3. celecoxib pellet preparations according to claim 1 also is surrounded by sustained release coating or enteric coat layer on the sealing coat, makes slow-release micro-pill and enteric coated micropill respectively.
4. celecoxib pellet preparations according to claim 1, wherein microcrystalline Cellulose ball heart 30-40 order.
5. the celecoxib pellt capsule contains the described celecoxib slow-release micro-pill of claim 3 and enteric coated micropill.
6. celecoxib pellt capsule according to claim 5, wherein sustained release coating micropill and enteric coated-pellet ratio 1～5:1.
7. celecoxib pellt capsule according to claim 6, wherein sustained release coating micropill and enteric coated-pellet ratio 2～4:1.
8. the preparation method of the described celecoxib pellet preparations of claim 1 is dissolved in alcoholic solution with celecoxib, polyvidone, then gained solution evenly is sprayed on the surface of the microcrystalline Cellulose ball heart, wraps dry getting final product behind one deck sealing coat again.
9. the preparation method of celecoxib pellet preparations according to claim 8 adds sodium lauryl sulphate in alcoholic solution.
10. the preparation method of the described celecoxib pellet preparations of claim 3 adopts the fluid bed preparation, in turn includes the following steps:
A, Sai Laixibu, polyvidone are dissolved in the alcoholic solution, are mixed with medicine carrying solution, prepare isolation coat liquid, sustained release coating liquid simultaneously, standby;
B, the preheating of microcrystalline Cellulose celphere;
C, medicine-feeding: after the preheating of microcrystalline Cellulose ball core finished, medicine was sprayed at the end;
D, bag contagion gown: medicine-feeding finishes the end, back spray bag sealing coat;
E, bag extended release coatings or enteric coating: the enteric coated or extended release coatings of end spray.
F, drying: be dried to the micropill water content after coating finishes and arrive below 3.0%.
11. the preparation method of celecoxib pellet preparations according to claim 10, wherein:
In the steps A, be the pvp K30 alcoholic solution of 5-11% with 95% ethanol preparation mass concentration, according to the ethanol volume of 5:1～3: celecoxib weight adds celecoxib, stirring and dissolving;
Among step B～F, the fluid bed inlet temperature is controlled at 30 to 48 degrees centigrade, and temperature of charge is 25 to 38 degrees centigrade, and the guide cylinder height is 11-13mm.
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| CN2013101338379A CN103191065A (en) | 2013-04-17 | 2013-04-17 | Celecoxib new formulation and preparation method thereof |
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| CN2013101338379A CN103191065A (en) | 2013-04-17 | 2013-04-17 | Celecoxib new formulation and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721146A (en) * | 2015-04-03 | 2015-06-24 | 海南海力制药有限公司 | Celecoxib solvent dispersoid, pellet capsule and preparation methods of celecoxib solvent dispersoid and pellet capsule |
| CN106806353A (en) * | 2015-12-02 | 2017-06-09 | 江苏先声药业有限公司 | Ailamode spansule and preparation method thereof |
| CN110215460A (en) * | 2019-06-18 | 2019-09-10 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | A kind of antitumor combination composition of medicine |
| CN113413371A (en) * | 2021-07-05 | 2021-09-21 | 艾美科健（中国）生物医药有限公司 | Celecoxib capsule and preparation method thereof |
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| WO2008069546A1 (en) * | 2006-12-07 | 2008-06-12 | Boryung Pharmaceutical Co., Ltd | Oral administrative preparation for treating cardiovascular system disease |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721146A (en) * | 2015-04-03 | 2015-06-24 | 海南海力制药有限公司 | Celecoxib solvent dispersoid, pellet capsule and preparation methods of celecoxib solvent dispersoid and pellet capsule |
| CN106806353A (en) * | 2015-12-02 | 2017-06-09 | 江苏先声药业有限公司 | Ailamode spansule and preparation method thereof |
| CN110215460A (en) * | 2019-06-18 | 2019-09-10 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | A kind of antitumor combination composition of medicine |
| CN110215460B (en) * | 2019-06-18 | 2022-03-04 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | Combined drug for resisting tumors |
| CN113413371A (en) * | 2021-07-05 | 2021-09-21 | 艾美科健（中国）生物医药有限公司 | Celecoxib capsule and preparation method thereof |
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Application publication date: 20130710 |