CN102973530A - Febuxostat double-layer enteric-coated tablet and preparation method thereof - Google Patents
Febuxostat double-layer enteric-coated tablet and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a febuxostat double-layer enteric-coated tablet and a preparation method thereof. The tablet comprises the following components in parts by weight: 50 to 90 parts of febuxostat, 10 to 50 parts of non-steroidal anti-inflammatory drugs and proper medical auxiliary materials. Compared with the prior art, after the interaction of drugs and medicament adverse response pathogenetic mechanism are investigated, febuxostat and non-steroidal anti-inflammatory drugs are adopted, and pains of a patient in the treatment process can be effectively reduced while the drug effect of removing uric acid is not influenced in the combined action of ibuprofen, ketoprofen, aspirin and the like; and the enteric-coated tablet prepared from febuxostat is advantages to prevention of first pass effect, so that the bioavailability is improved, the maximum drug effect can be produced with minimum dosage, infection, nausea, diarrhea and other adverse responses of a human body caused by high-dosage febuxostat can be avoided, and the adaptability of the patient to medicaments can be improved.
Description
Technical field
The present invention relates to double-deck enteric coated tablet of a kind of Febuxostat and preparation method thereof, belong to the technical field of medicine.
Background technology
Febuxostat (febuxostat), chemistry 2-[3-cyano group by name-4-(2-methyl propoxyl group) phenyl]-the 4-methyl-5-thiazole formic acid, be fragrant thiazole derivative, can suppress XO active (the XO enzyme to oxidized form and reduced form all has significant inhibitory action) by selectivity, and have the therapeutic effect that reduces serum uric acid.In traditional uric acid resisting medicine, a class mainly is the medicine that uricopoiesis is reduced by suppressing xanthine oxidase, is applicable to the medicine of intractable chalky gout treatment; And another kind of be the medicine that promotes urate excretion, such as probenecid, sulphinpyrazone and benzbromarone, but how (creatinine clearance rate＜50mL/min) is unsuitable for treating intractable chalky gout because the patient exists a large amount of tophuses or more serious renal insufficiency.Allopurinol is a unique medicine that be used for to suppress uricopoiesis clinically, and be widely used in clinical as the gold medicine of gout, but because allopurinol only has inhibitory action to the XOR of reduced form, need to repeat heavy dose of administration and keep higher levels of drugs, many patients maybe can not tolerate allopurinol is irritated, invalid.But not Bu Suotan (febuxostat) then is a species specificity xanthine oxidase inhibitor, compares with allopurinol, and the curative effect of Febuxostat prevention gout outbreak and the incidence rate of adverse effect are similar, but it is higher to suppress uricopoiesis intensity.
CLINICAL PHARMACOKINETIS STUDY ON, animal pharmacodynamic study, human body pharmacodynamic study and toxicology test research surface, oral being easy to of Febuxostat absorbs, 1-1.5 hour can absorb more than 95%, protein binding rate in vivo higher (mainly being albumin), plasma half-life 5 ~ 8 hours, have higher drug effect, and toxicity is not obvious.But still exist some shortcomings.Febuxostat can't be by the oxidation of XO institute, thus in vivo action time relatively long, increase the weight of easily liver and renal metabolism burden.Experiment shows, gives the Consciousness dog oral 40 times of giving Febuxostat 100mg/kg(human body maximum exposure amount) after, the motion activity that demonstrates slightly descends; Give in addition mice 30mg/kg, also demonstrate the effect of identical inhibition motion activity, prove that Febuxostat has certain impact to the central nervous system.Experimentation confirms that the xanthic excretion of kidney presents dose dependent, and it has influence on the formation of xanthine crystallization/calculus in the renal tubules.Xanthic excretion is higher, and the probability that forms xanthic calculus is larger.Xanthic calculus can cause damage and causes the generation of bladder cancer kidney.In ongoing clinical trial, the common untoward reaction of Febuxostat mainly comprises: the S﹠S of upper respiratory tract infection, skeletal muscle and connective tissue, diarrhoea, nauseating.Take the Febuxostat initial stage because the serum uric acid concentration fast-descending can impel the uric acid that deposits in the tissue to be mobilized, similar gout outbreak symptom therefore very easily occurs, hurt like hell increases added burden to the patient.
Therefore, in view of drug effect and the untoward reaction of Febuxostat, the good dosage form that exploitation improves the Febuxostat bioavailability and eliminates untoward reaction, raising patient's the medication suitability has higher market value.
Summary of the invention
The object of the invention is to, provide a kind of Febuxostat double-deck enteric coated tablet, the present invention can effectively alleviate the pain of patient in the intractable chalky gout process for the treatment of when not affecting removing uric acid drug effect; Simultaneously Febuxostat is made enteric coatel tablets, remain on and produce maximum drug action in the smaller dose, the untoward reaction of having avoided the high dose Febuxostat that human body is produced.
The present invention is achieved by the following technical solutions: the double-deck enteric coated tablet of a kind of Febuxostat, calculate by weight, and be the double-deck enteric coated tablet of being made by 50～90 parts of Febuxostats, 10～50 parts of NSAID (non-steroidal anti-inflammatory drug) and an amount of pharmaceutic adjuvant.
In the double-deck enteric coated tablet of aforesaid Febuxostat, the pharmaceutic adjuvant of Febuxostat layer comprises microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose and magnesium stearate.
In the double-deck enteric coated tablet of aforesaid Febuxostat, calculate by weight, the Febuxostat layer is made by 50～90 parts of Febuxostats, 95～165 parts of microcrystalline Cellulose, 20～60 parts of lactose, 10～27 parts of cross-linking sodium carboxymethyl celluloses and 1～3 part of magnesium stearate.
In the double-deck enteric coated tablet of aforesaid Febuxostat, the pharmaceutic adjuvant of NSAID (non-steroidal anti-inflammatory drug) layer comprises starch and micropowder silica gel.
In the double-deck enteric coated tablet of aforesaid Febuxostat, calculate by weight, the NSAID (non-steroidal anti-inflammatory drug) layer is made by 10～50 parts of NSAID (non-steroidal anti-inflammatory drug), 10～60 parts of starch, 1～4 part of micropowder silica gel.
In the double-deck enteric coated tablet of aforesaid Febuxostat, NSAID (non-steroidal anti-inflammatory drug) is one or more in ibuprofen, ibuprofen pharmaceutically acceptable salt, ketoprofen, the aspirin.
In the double-deck enteric coated tablet of aforesaid Febuxostat, calculate by weight, preferred tablet is the double-deck enteric coated tablet that 60 parts of Febuxostats, 40 parts of ibuprofen and an amount of pharmaceutic adjuvant are made.
The preparation method of the double-deck enteric coated tablet of aforementioned Febuxostat may further comprise the steps:
(1) Febuxostat granulate: Febuxostat is crossed 80 mesh sieves, with microcrystalline Cellulose, lactose, partial cross-linked sodium carboxymethyl cellulose mix homogeneously, add in right amount soft material processed of purified water, crossing 18 eye mesh screens granulates, 70 ℃ of dryings, cross 18 mesh sieve granulate, add the cross-linked carboxymethyl fiber sodium of magnesium stearate and surplus, mix homogeneously;
(2) NSAID (non-steroidal anti-inflammatory drug) granulate: get NSAID (non-steroidal anti-inflammatory drug) and starch, micropowder silica gel mixing, add starch slurry and make soft material, cross 18 mesh sieves and granulate, granule takes out in 60～65 ℃ of dryings, is cooled to room temperature, crosses 18 mesh sieve granulate, adds micropowder silica gel;
(3) tabletting: the mixture that adopts bi-layer tablet press that (1), (2) are obtained carries out tabletting, gets double-deck plain sheet;
(4) coating: with EudragitⅡ with the dissolving of spending the night of 85% alcohol solution dipping, adding diethyl phthalate, Oleum Ricini and tween 80 grinds evenly, to cross in addition the Pulvis Talci of 120 mesh sieves, the titanium dioxide of crossing 120 mesh sieves and an amount of lemon yellow and add the mentioned solution grinding evenly, namely get coating solution; Getting in (3) double-deck plain sheet puts in the coating pan, the sheet bed tempertaure is controlled at 40～50 ℃, rotating speed is 30～40 rev/mins, the coating solution for preparing is sparged continuously the sheet sub-surface of rotation with spray gun, making the coated tablet weightening finish is 2%～4%, the enteric coated tablet of wrapping was put 30～40 ℃ of baking oven inner dryings 3～4 hours, and get final product.
In order to ensure prescription and preparation technology's science, reasonable, feasible of the double-deck enteric coated tablet of Febuxostat of the present invention, the applicant has carried out series of experimental research and investigation.
One, prescription research:
1, Febuxostat layer
(1) crude drug character
Febuxostat is white or off-white color crystalline powder; Insoluble in water.Therefore, when drafting the prescription of tablet, the dissolution of medicine is an aspect of considering emphatically.
(2) character of adjuvant and selection
As can be known, the adjuvant that uses among the ADENURIC is lactose, microcrystalline Cellulose, magnesium stearate etc. from the relevant information of the ADENURIC of European Union approval.
The lactose compact property is good, and uses lactose unilateral more smooth as filler, and outward appearance is better.
Microcrystalline Cellulose has good flowability and compressibility as filler, the rapid disintegrate of imbibition, and granule is very thin after the disintegrate.
Cross-linking sodium carboxymethyl cellulose has extremely strong disintegrate ability.Especially applicable for the medicine that hydrophobicity is strong.
Magnesium stearate is lubricant, is easy to the granule mixing, makes unilateral smooth.
(3) prescription screening
Because Febuxostat is water-soluble hardly, therefore, when carrying out prescription screening mainly take disintegration of tablet, dissolution etc. for main investigation index, the results are shown in Table 1.
Table 1 prescription screening result
| The supplementary material title | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| Febuxostat | 6g | 6g | 6g | 6g |
| Microcrystalline Cellulose | 14g | 12.5g | 12g | 12g |
| Lactose | -- | 2.5g | 3.5g | 3.5g |
| Cross-linking sodium carboxymethyl cellulose | 1g (outward) | (1.2g outward) | (1.6g outward) | (0.9g outward) 0.7g (interior) |
| Magnesium stearate | 0.2g | 0.2g | 0.2g | 0.2g |
| Appearance character | Unilateral slightly rough | Unilateral slightly rough | Unilateral bright and clean | Unilateral bright and clean attractive in appearance |
| Disintegration (min) | 20 | 14 | 8 | 7 |
| Dissolution is surveyed (%) | ---- | ---- | 81.3 | 88.6 |
The result: design sheet weight average does not add lactose at 0.25g in four prescriptions in prescription 1, and unilateral some is coarse, and the disintegrate of tablet and stripping are not ideal; Strengthened the consumption of lactose and disintegrating agent in prescription 2, disintegration time and stripping make moderate progress, but undesirable; Strengthened the consumption of disintegrating agent in 3 at prescription, strengthened behind the lactose consumption unilateral bright and clean attractive in appearance, but in disintegrating procedue the granule of accidental not disintegrate.Have in 4 half disintegrating agent to add in changing into so will write out a prescription, disintegration and stripping meet the requirements, and be comparatively desirable.
2, NSAID (non-steroidal anti-inflammatory drug) layer
Ibuprofen, ibuprofen pharmaceutically acceptable salt are can be simultaneous in pharmacy component ratio claimed range, make soft material with starch slurry as binding agent, avoided ibuprofen salt in preparation process, to meet water decomposition, ibuprofen salt is hydrolyzed in small intestinal and can discharges rapidly the former medicine of ibuprofen simultaneously, and is similar to direct oral ibuprofen drug effect.
The ibuprofen pharmaceutically acceptable salt can be ibuprofen arginine salt, Ibuproben-Lysiante etc., and its pharmacodynamic study shows that this salt has significantly analgesic, analgesia, antiinflammatory action, and drug effect and ibuprofen are suitable.
Two, Study of operational conditions
1, the selection of Febuxostat layer binding agent
Because the Febuxostat material is more puckery, its flowability is not good enough, therefore adopts wet granule compression tablet technique, and binding agent is screened.
According to prescription 4 preparation mixed powders, adopting respectively 50% alcoholic solution, purified water, 2%PVP-k30 aqueous solution is that binding agent is granulated, observing effect, the row filter of going forward side by side.The results are shown in Table 2.
Table 2 binding agent the selection result
Annotate: the above 18 mesh sieve granulating process that all adopt.
Conclusion: adopt 50% ethanol as binding agent, material viscosity is larger, can't granulate; Adopt water and 2%PVP-k30 aqueous solution as binding agent, uniform particles, complete, good fluidity, tablet weight variation is little, and both consider from simple process and economic angle without obviously difference, directly adopt purified water as binding agent.
2, NSAID (non-steroidal anti-inflammatory drug) layer
Take ibuprofen as the basis, select respectively the raw materials such as starch, lactose, dextrin, microcrystalline Cellulose, micropowder silica gel, starch slurry to carry out optimization, investigate with 100 tablet recipe amounts, investigate respectively the indexs such as mouldability, disintegration, compressibility.
Conclusion: when selecting starch as filler, micropowder silica gel during as fluidizer, the stripping of tablet discharges, all reach best, the tabletting superior performance disintegration.
Three, pharmacological research
1, the clinical treatment gout observation of curative effect of the double-deck enteric coated tablet of Febuxostat
Contrast at random in the clinical research 1.1 take separately Febuxostat sheet (commercially available), surpass the recommended dose that 100 patients have taken 80mg or 120mg and treat (research and 50 experimenters that 53 experimenters participated in for 3 weeks have participated in the research in 5 weeks).The order of severity of the adverse events relevant with treatment mostly is greatly light to moderate, the most common adverse events (by the researcher evaluation) and is diarrhoea, headache, feels sick, and the results are shown in Table 3.
Table 3 is taken separately the common adverse reactions of Febuxostat
1.2 taking the double-deck enteric coated tablet of Febuxostat contrasts in the clinical research at random, contrast at random and take the above-mentioned dosage (recommended dose of 80mg or 120mg is treated) of Denging in the clinical research, treat equally (research and 50 experimenters that 53 experimenters participated in for 3 weeks have participated in the research in 5 weeks), the order of severity of the adverse events relevant with treatment obviously alleviates, and the results are shown in Table 4.
Table 4 is taken the double-deck enteric coated tablet of Febuxostat to the improvement of untoward reaction
Summary, above-mentioned clinical research result shows, the double-deck enteric coated tablet of Febuxostat can obviously improve takes separately the related reactions that Febuxostat brings,, gastrointestinal function imbalance disorderly to nervous function improves significantly, and reduces that patient takes Febuxostat separately and the headache that produces, dizziness, diarrhoea, nauseating symptom.
2, the bioavailability study of the double-deck enteric coated tablet of Febuxostat
2.1 zoopery process: employing the present invention tests the double-deck enteric coated tablet of resulting Febuxostat and commercially available Febuxostat sheet compares, adopt same dose (every content of Febuxostat is identical), with beasle dog as object of study, be divided at random reference group and tested group, every group 6, the oral Febuxostat sheet of reference group (adjusting dosage to 80mg), the tested group of double-deck enteric coatel tablets (dosage is 80mg) of oral Febuxostat, fasting 12h before the administration, the single oral dose administration, after administration 0,1,2,3,4,5,6,7,8,10,12,24h gets blood, preparation blood plasma.
2.2 blood sample is processed: get blood plasma 0.5mL and add 1.0mL methanol, protein precipitation, vibration mixes 3min, and the centrifugal 5min of 10 000r/min gets supernatant 20L sample introduction.
2.3 chromatographic condition: chromatographic column is Cosmosil ODS C18 post, (4.6mm * 250 mm); Mobile phase is methanol-0.4% phosphoric acid (70:30); Flow velocity is 1 mL/min; Detecting wavelength is 290 nm; Column temperature is 25 ℃; Sample size is 20L.
Process blood plasma with the methanol extraction method, obtain sample feeding, take naproxen as interior mark, Febuxostat is as standard substance; The method adaptability is better, and the plasma endogenous material can interference measurement.
2.4 the range of linearity: precision takes by weighing Febuxostat standard substance 21 mg in the 100mL measuring bottle, the dissolve with methanol standardize solution obtains 210 μ g/mL Febuxostat storing solutions, gets naproxen 50mg and places the 100mL measuring bottle, the dissolve with methanol standardize solution obtains mark storing solution in the 500 μ g/mL.
Preliminary experiment shows, compares with the Febuxostat sheet after the double-deck enteric coatel tablets administration of Febuxostat, and blood drug level is higher, therefore, makes respectively two standard curves of low concentration group and high concentration group, and blood drug level is fallen into respectively in two standard curve range.
High concentration group standard curve: blank blood 0.3mL, mark storing solution 20L in adding; Precision pipettes the adding of 10,15,20,25,30 μ L mark product storing solution respectively, adds 1mL methanol, protein precipitation, and vibration mixes 3min, and the centrifugal 5min of 10 000r/min gets supernatant 20L sample introduction.
Low concentration group standard curve: blank blood 0.3mL, mark storing solution 20L in adding; Label taking product storing solution 1mL places the 100mL measuring bottle; The dissolve with methanol standardize solution, the accurate mark product storing solution that pipettes after 30,50,70,90,100 μ L dilute adds respectively; Add 1mL methanol, protein precipitation, vibration mixes 3min, and the centrifugal 5min of 10 000r/min gets supernatant 20L sample introduction.
With the interior mark storing solution mass concentration ρ that adds Febuxostat and the interior mark naproxen peak area ratio T that measures carried out linear regression, obtain standard curve.
High concentration group: T=166.6700 ρ+0.0158, r=0.9998; Low concentration group: T=166.1000 ρ+0.0055, r=0.9946.
The result shows that Febuxostat is at high concentration group (7～21 μ g.mL
-1) and low quality concentration group (0.21～0.70 μ g.mL
-1) linear relationship good, detect and to be limited to 100ng.mL
-1, quantitatively be limited to 200n g.mL
-1
2.5 relative bioavailability result
The main pharmacokinetic parameters n=6 of the double-deck enteric coatel tablets of table 5 Febuxostat and Febuxostat sheet (commercially available), x ± s
| Parameter (unit) | The double-deck enteric coatel tablets of Febuxostat | The Febuxostat sheet |
| AUC0-24h（g.h.mL -1） | 74.17±28.30 | 5.37±3.42 |
| Tmax（h） | 1.66±0.28 | 2.33±0.43 |
| Cmax（g.mL -1） | 8.97±5.80 | 0.40±0.09 |
As shown in Table 5, the AUC(area under the drug-time curve of the double-deck enteric coatel tablets of Febuxostat) and the Cmax(peak concentration of drug) all far above the Febuxostat sheet; As shown in Figure 1, between 6～12h, the double-deck enteric coatel tablets of Febuxostat can be kept a metastable concentration, this shows that also this medicine has obvious slow releasing function in Beagle dog body, and reach the time advance of Cmax peak value, the stripping behavior that shows this medicine is improved, and can reach rapidly onset concentration.
Compared with prior art, the present invention is after the interaction of having investigated medicine and adverse effect mechanism, adopt Febuxostat and NSAID (non-steroidal anti-inflammatory drug), such as combineds effect such as ibuprofen, ketoprofen, aspirin, when not affecting the drug effect of removing uric acid, can effectively alleviate the pain in the patient process; And Febuxostat made enteric coatel tablets, be conducive to avoid first pass effect, improve bioavailability, remain on and produce maximum drug action in the smaller dose, the infection that the Febuxostat of having avoided high dose produces human body, feel sick, a series of untoward reaction such as diarrhoea, increase patient to the adaptability of medicine.
Description of drawings
Fig. 1 is drug-time curve figure (n=6, the x ± s) behind the dog oral administration.
The present invention is further illustrated below in conjunction with the specific embodiment.
The specific embodiment
Embodiment 1: described double-deck enteric coated tablet comprises Febuxostat 60g, ibuprofen 40g, microcrystalline Cellulose 120g, lactose 35g, cross-linking sodium carboxymethyl cellulose 16g, magnesium stearate 2g, starch 45g and micropowder silica gel 3g.The 60g Febuxostat is crossed 80 mesh sieves, with 120g microcrystalline Cellulose, 35g lactose, 7g cross-linking sodium carboxymethyl cellulose mix homogeneously, add in right amount soft material processed of purified water, crossing 18 eye mesh screens granulates, 70 ℃ of dryings, cross 18 mesh sieve granulate, add 2g magnesium stearate and 9g cross-linked carboxymethyl fiber sodium, mix homogeneously; Get 40g ibuprofen and 45g starch, 2g micropowder silica gel mixing, add starch slurry and make soft material, cross 18 mesh sieves and granulate, granule takes out in 60～65 ℃ of dryings, is cooled to room temperature, crosses 18 mesh sieve granulate, adds the 1g micropowder silica gel; Adopt bi-layer tablet press mixture obtained above to carry out tabletting, get double-deck plain sheet; With 10g acrylic resin I number with the dissolving of spending the night of 230mL85% alcohol solution dipping, adding 6mL diethyl phthalate, 6mL Oleum Ricini and 5mL tween 80 grinds evenly, to cross in addition the Pulvis Talci of 120 mesh sieves, the titanium dioxide of crossing 120 mesh sieves and an amount of lemon yellow and add the mentioned solution grinding evenly, namely get coating solution; Getting double-deck plain sheet puts in the coating pan, the sheet bed tempertaure is controlled at 40～50 ℃, rotating speed is 30～40 rev/mins, the coating solution for preparing is sparged continuously the sheet sub-surface of rotation with spray gun, making the coated tablet weightening finish is 2%～4%, the enteric coated tablet of wrapping was put 30～40 ℃ of baking oven inner dryings 3～4 hours, and get final product.
Embodiment 2: described double-deck enteric coated tablet comprises Febuxostat 90g, ibuprofen and pharmaceutically acceptable salt 10g thereof, microcrystalline Cellulose 165g, lactose 60g, cross-linking sodium carboxymethyl cellulose 27g, magnesium stearate 3g, starch 10g and micropowder silica gel 1g.The 90g Febuxostat is crossed 80 mesh sieves, with 165g microcrystalline Cellulose, 60g lactose, 12g cross-linking sodium carboxymethyl cellulose mix homogeneously, add in right amount soft material processed of purified water, crossing 18 eye mesh screens granulates, 70 ℃ of dryings, cross 18 mesh sieve granulate, add 3g magnesium stearate and 15g cross-linked carboxymethyl fiber sodium, mix homogeneously; Get 10g ibuprofen and pharmaceutically acceptable salt thereof and 10g starch, 0.5g micropowder silica gel mixing, add starch slurry and make soft material, cross 18 mesh sieves and granulate, granule takes out in 60～65 ℃ of dryings, is cooled to room temperature, crosses 18 mesh sieve granulate, adds the 0.5g micropowder silica gel; Adopt bi-layer tablet press mixture obtained above to carry out tabletting, get double-deck plain sheet; With the 20g EudragitⅡ with the dissolving of spending the night of 460mL85% alcohol solution dipping, adding 12mL diethyl phthalate, 12mL Oleum Ricini and 10mL tween 80 grinds evenly, to cross in addition the Pulvis Talci of 120 mesh sieves, the titanium dioxide of crossing 120 mesh sieves and an amount of lemon yellow and add the mentioned solution grinding evenly, namely get coating solution; Getting double-deck plain sheet puts in the coating pan, the sheet bed tempertaure is controlled at 40～50 ℃, rotating speed is 30～40 rev/mins, the coating solution for preparing is sparged continuously the sheet sub-surface of rotation with spray gun, making the coated tablet weightening finish is 2%～4%, the enteric coated tablet of wrapping was put 30～40 ℃ of baking oven inner dryings 3～4 hours, and get final product.
Embodiment 3: described double-deck enteric coated tablet comprises Febuxostat 50g, ketoprofen 25g, aspirin 25g, microcrystalline Cellulose 95g, lactose 20g, cross-linking sodium carboxymethyl cellulose 10g, magnesium stearate 1g, starch 60g and micropowder silica gel 4g.The 50g Febuxostat is crossed 80 mesh sieves, with 95g microcrystalline Cellulose, 20g lactose, 4g cross-linking sodium carboxymethyl cellulose mix homogeneously, add in right amount soft material processed of purified water, crossing 18 eye mesh screens granulates, 70 ℃ of dryings, cross 18 mesh sieve granulate, add 1g magnesium stearate and 6g cross-linked carboxymethyl fiber sodium, mix homogeneously; Get 25g ketoprofen, 25g aspirin and 60g starch, 2g micropowder silica gel mixing, add starch slurry and make soft material, cross 18 mesh sieves and granulate, granule takes out in 60～65 ℃ of dryings, is cooled to room temperature, crosses 18 mesh sieve granulate, adds the 2g micropowder silica gel; Adopt bi-layer tablet press mixture obtained above to carry out tabletting, get double-deck plain sheet; With the dissolving of spending the night of II number 85% alcohol solution dipping with 120mL of 5g acrylic resin, adding 3mL diethyl phthalate, 3mL Oleum Ricini and 2.5mL tween 80 grinds evenly, to cross in addition the Pulvis Talci of 120 mesh sieves, the titanium dioxide of crossing 120 mesh sieves and an amount of lemon yellow and add the mentioned solution grinding evenly, namely get coating solution; Getting double-deck plain sheet puts in the coating pan, the sheet bed tempertaure is controlled at 40～50 ℃, rotating speed is 30～40 rev/mins, the coating solution for preparing is sparged continuously the sheet sub-surface of rotation with spray gun, making the coated tablet weightening finish is 2%～4%, the enteric coated tablet of wrapping was put 30～40 ℃ of baking oven inner dryings 3～4 hours, and get final product.
Claims (8)
1. the double-deck enteric coated tablet of a Febuxostat, it is characterized in that: calculating by weight, is the double-deck enteric coated tablet of being made by 50～90 parts of Febuxostats, 10～50 parts of NSAID (non-steroidal anti-inflammatory drug) and an amount of pharmaceutic adjuvant.
2. the double-deck enteric coated tablet of a kind of Febuxostat according to claim 1, it is characterized in that: the pharmaceutic adjuvant of Febuxostat layer comprises microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose and magnesium stearate.
3. the double-deck enteric coated tablet of a kind of Febuxostat according to claim 2, it is characterized in that: calculate by weight, the Febuxostat layer is made by 50～90 parts of Febuxostats, 95～165 parts of microcrystalline Cellulose, 20～60 parts of lactose, 10～27 parts of cross-linking sodium carboxymethyl celluloses and 1～3 part of magnesium stearate.
4. the double-deck enteric coated tablet of a kind of Febuxostat according to claim 1, it is characterized in that: the pharmaceutic adjuvant of NSAID (non-steroidal anti-inflammatory drug) layer comprises starch and micropowder silica gel.
5. the double-deck enteric coated tablet of a kind of Febuxostat according to claim 4, it is characterized in that: calculate by weight, the NSAID (non-steroidal anti-inflammatory drug) layer is made by 10～50 parts of NSAID (non-steroidal anti-inflammatory drug), 10～60 parts of starch, 1～4 part of micropowder silica gel.
6. according to claim 4 or the double-deck enteric coated tablets of 5 described a kind of Febuxostats, it is characterized in that: NSAID (non-steroidal anti-inflammatory drug) is one or more in ibuprofen, ibuprofen pharmaceutically acceptable salt, ketoprofen, the aspirin.
7. the double-deck enteric coated tablet of a kind of Febuxostat according to claim 6, it is characterized in that: calculate by weight, preferred tablet is the double-deck enteric coated tablet that 60 parts of Febuxostats, 40 parts of ibuprofen and an amount of pharmaceutic adjuvant are made.
8. such as the preparation method of the double-deck enteric coated tablet of each described Febuxostat in the claim 1～7, it is characterized in that, may further comprise the steps:
(1) Febuxostat granulate: Febuxostat is crossed 80 mesh sieves, with microcrystalline Cellulose, lactose, partial cross-linked sodium carboxymethyl cellulose mix homogeneously, add in right amount soft material processed of purified water, crossing 18 eye mesh screens granulates, 70 ℃ of dryings, cross 18 mesh sieve granulate, add the cross-linked carboxymethyl fiber sodium of magnesium stearate and surplus, mix homogeneously;
(2) NSAID (non-steroidal anti-inflammatory drug) granulate: get NSAID (non-steroidal anti-inflammatory drug) and starch, micropowder silica gel mixing, add starch slurry and make soft material, cross 18 mesh sieves and granulate, granule takes out in 60～65 ℃ of dryings, is cooled to room temperature, crosses 18 mesh sieve granulate, adds micropowder silica gel again;
(3) tabletting: the mixture that adopts bi-layer tablet press that (1), (2) are obtained carries out tabletting, gets double-deck plain sheet;
(4) coating: with EudragitⅡ with the dissolving of spending the night of 85% alcohol solution dipping, adding diethyl phthalate, Oleum Ricini and tween 80 grinds evenly, to cross in addition the Pulvis Talci of 120 mesh sieves, the titanium dioxide of crossing 120 mesh sieves and an amount of lemon yellow and add the mentioned solution grinding evenly, namely get coating solution; Getting in (3) double-deck plain sheet puts in the coating pan, the sheet bed tempertaure is controlled at 40～50 ℃, rotating speed is 30～40 rev/mins, the coating solution for preparing is sparged continuously the sheet sub-surface of rotation with spray gun, making the coated tablet weightening finish is 2%～4%, the enteric coated tablet of wrapping was put 30～40 ℃ of baking oven inner dryings 3～4 hours, and get final product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108096367A (en) * | 2017-12-19 | 2018-06-01 | 海南葫芦娃药业集团股份有限公司 | A kind of nourishing blood and tranquilization enteric coatel tablets and preparation method thereof |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009041798A1 (en) * | 2007-09-26 | 2009-04-02 | Espinosa Abdala Leopoldo De Jesus | Pharmaceutical compositions combining a nonsteroidal anti-inflammatory agent and a xanthine oxidase inhibiting agent, which can be used to control and treat gout, gouty arthritis and related diseases |
| CN101646440A (en) * | 2007-01-19 | 2010-02-10 | 武田制药北美公司 | Methods for preventing or reducing the number of gout flares using xanthine oxidoreductase inhibitors and anti-inflammatory agents |
| CN101658505A (en) * | 2009-09-29 | 2010-03-03 | 北京华禧联合科技发展有限公司 | Sustained-release preparation of uloric and preparation method thereof |
| CN101716132A (en) * | 2008-10-09 | 2010-06-02 | 北京方策方程医药科技有限公司 | Febuxostat enteric preparation |
| WO2010135536A2 (en) * | 2009-05-20 | 2010-11-25 | Ardea Biosciences, Inc. | Methods of modulating uric acid levels |
| CN101918377A (en) * | 2007-11-27 | 2010-12-15 | 亚德生化公司 | Novel compounds and compositions and methods of use |
| WO2011159745A1 (en) * | 2010-06-16 | 2011-12-22 | Takeda Pharmaceuticals North America, Inc. | Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors |
| WO2012073259A1 (en) * | 2010-12-02 | 2012-06-07 | Indoco Remedies Limited | Novel process for the preparation of febuxostat |
| CN102552197A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Tablet containing febuxostat and preparation method of the tablet |
-
2012
- 2012-12-14 CN CN201210545323.XA patent/CN102973530B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101646440A (en) * | 2007-01-19 | 2010-02-10 | 武田制药北美公司 | Methods for preventing or reducing the number of gout flares using xanthine oxidoreductase inhibitors and anti-inflammatory agents |
| WO2009041798A1 (en) * | 2007-09-26 | 2009-04-02 | Espinosa Abdala Leopoldo De Jesus | Pharmaceutical compositions combining a nonsteroidal anti-inflammatory agent and a xanthine oxidase inhibiting agent, which can be used to control and treat gout, gouty arthritis and related diseases |
| CN101918377A (en) * | 2007-11-27 | 2010-12-15 | 亚德生化公司 | Novel compounds and compositions and methods of use |
| CN101716132A (en) * | 2008-10-09 | 2010-06-02 | 北京方策方程医药科技有限公司 | Febuxostat enteric preparation |
| WO2010135536A2 (en) * | 2009-05-20 | 2010-11-25 | Ardea Biosciences, Inc. | Methods of modulating uric acid levels |
| CN101658505A (en) * | 2009-09-29 | 2010-03-03 | 北京华禧联合科技发展有限公司 | Sustained-release preparation of uloric and preparation method thereof |
| WO2011159745A1 (en) * | 2010-06-16 | 2011-12-22 | Takeda Pharmaceuticals North America, Inc. | Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors |
| WO2012073259A1 (en) * | 2010-12-02 | 2012-06-07 | Indoco Remedies Limited | Novel process for the preparation of febuxostat |
| CN102552197A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Tablet containing febuxostat and preparation method of the tablet |
Non-Patent Citations (1)
| Title |
|---|
| REZA KHOSRAVAN ET AL.: "Pharmacokinetic Interactions of Concomitant Administration of Febuxostat and NSAIDs", 《J CLIN PHARMACOL》, vol. 46, 31 December 2006 (2006-12-31), pages 855 - 866, XP003017258, DOI: 10.1177/0091270006289848 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108096367A (en) * | 2017-12-19 | 2018-06-01 | 海南葫芦娃药业集团股份有限公司 | A kind of nourishing blood and tranquilization enteric coatel tablets and preparation method thereof |
| CN108096367B (en) * | 2017-12-19 | 2021-02-19 | 海南葫芦娃药业集团股份有限公司 | Blood-nourishing and nerve-calming enteric-coated tablet and preparation method thereof |
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| CN102973530B (en) | 2016-08-03 |
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