CN103127011B - Roflumilast tablet and preparation method thereof - Google Patents
Roflumilast tablet and preparation method thereof Download PDFInfo
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- CN103127011B CN103127011B CN201210593342.XA CN201210593342A CN103127011B CN 103127011 B CN103127011 B CN 103127011B CN 201210593342 A CN201210593342 A CN 201210593342A CN 103127011 B CN103127011 B CN 103127011B
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Abstract
The present invention provides a Roflumilast tablet and a preparation method of the Roflumilast tablet. The method adopts a direct powder tabletting method, production process is easy, production cycle is shortened, equipment cost and operation cost are reduced, the prepared and obtained Roflumilast tablet is good in appearance, technical process is smooth, the method possesses good operability, product dissolution rate is high, content uniformity is qualified, the Roflumilast tablet can achieve good bioavailability in human body, and therefore good curative effects is produced.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of chronic obstructive pulmonary disease (COPD) inhibitor roflumilast sheet and preparation method thereof.
Background technology
Roflumilast (Roflumilast) is to be developed by German Nycomed company, a new oral medicine that is used for the treatment of asthma and chronic obstructive pulmonary disease, in 2011, obtain U.S. FDA approval and be used for the treatment of chronic obstructive pulmonary disease, listing dosage form is tablet, and commodity are by name
, specification is 0.5mg.
Roflumilast chemistry 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) Benzoylamide by name, molecular formula is C
17h
14cl
2f
2n
2o
3, molecular weight: 403.207, structural formula is as follows:
Roflumilast with and body in active metabolite roflumilast nitrogen oxide be the selective depressant of 4 type phosphodiesterases (PDE4).Cyclic nucleotide cAMP and cGMP are important second message,second messengers in cell, at various extracellular signals, comprise in the biologically that hormone, autologous active substance and neurotransmitter cause and playing an important role.Phosphodiesterase (PDE) has the function of the interior cAMP of hydrolysis cell or cGMP, makes its key enzyme that changes deactivated mononucleotide into, is the only approach of cAMP and cGMP hydrolysis.PDE4 is the main moderator of cAMP metabolism, is the main PDE isozyme of inflammation and immunocyte, is also the main PDE isozyme that is distributed in pulmonary, a group of maximum in ShiPDE family.Roflumilast selectivity suppresses PDE4, because cAMP can cause the lax and pneumonia reaction of bronchial smooth muscle, therefore suppresses the release that PDE4 can reduce inflammatory mediator, and then suppresses the damage that lung tissue caused as respiratory tract diseases such as COPD and asthma.Roflumilast is current unique phosphate-4 inhibitor that can oral medication COPD.
Roflumilast raw material be white to pale powder, hardly water-soluble and and normal hexane, slightly soluble and ethanol, be slightly dissolved in acetone.Therefore, as insoluble drug, it is prepared into the dissolution problem that the oral solid formulations such as tablet need to solve formulation products roflumilast, and need meet other tablet quality index requests such as uniformity of dosage units.
CN102274222A discloses roflumilast medicinal composition of a kind of high bioavailability and preparation method thereof, said composition is comprised of roflumilast, betacyclodextrin, lactose, microcrystalline Cellulose, magnesium stearate, adopt the method preparation of direct compression, the unexposed and former product that grinds
stripping result contrast.After repeating the method, find, the roflumilast sheet dissolution that the method prepares and the former medicine that grinds have larger gap.
CN102743353A discloses a kind of roflumilast tablet and preparation method thereof, and the method adopts and the former product that grinds
the same drug component, i.e. roflumilast, starch, lactose, PVP, through wet granulation, tabletting, obtain grinding the more consistent stripping behavior of medicine with former.
Component and the preparation method of the roflumilast sheet that to disclose specification in the embodiment of the CN101171005A of Yuan Yan company application be 0.5mg, wherein component is roflumilast (micronization), lactose monohydrate, corn starch, polyvidoneK90, magnesium stearate, adopts bed spray drying and granulating, tabletting, the method is high to equipment requirements.
In said method, except the disclosed method of CN102274222A is direct powder compression, other is the wet granulation method of tabletting again.But the roflumilast sheet stripping result that the method for CN102274222A prepares is undesirable, and bioavailability is not high, and curative effect cannot guarantee.Those skilled in the art are known, the dissolution of the medicine that dissolubility is little is subject to the impact of its specific surface area and medicine finished surface character larger, the disintegration of tablet of preparing by direct powder compression is very fast, after disintegrate, medicine directly discharges from powder, dispersion increases, stripping is accelerated, and relative bioavailability improves.And the sheet disintegrate that adopts wet granulation to prepare is slower, drug release is slower to the speed of dissolution medium.And direct powder compression (direct comPression method) directly carries out the mixture of medicine and adjuvant the method for tabletting without pelletization, saved granulation step, simplify technique.In order further to make the dissolution of roflumilast sheet meet the requirements, prepare bioavailability high, there is definite curative effect, and the satisfactory roflumilast sheet of quality, be necessary the method for direct powder compression to study.
Summary of the invention
The invention provides a kind of roflumilast sheet and preparation method thereof, the method adopts the method for direct powder compression, has simplified processing step, shortens life cycle of the product, and the roflumilast sheet dissolution preparing is high, and uniformity of dosage units is qualified.
The invention provides a kind of roflumilast sheet and preparation method thereof, it is characterized in that, comprise following component:
Preparation method is: roflumilast crude drug is pulverized with jet mill, taken the roflumilast raw material for standby of recipe quantity; The method that adopts equivalent to progressively increase, first roflumilast raw material is fully mixed with cross-linking sodium carboxymethyl cellulose, the carboxymethyl starch sodium of recipe quantity, fully mix with pregelatinized Starch, microcrystalline Cellulose, vertical compression lactose, the magnesium stearate of recipe quantity successively afterwards; After the material detection level mixing, according to content, tabletting weight is answered in conversion, carries out tabletting, regulates the hardness 2～3kg of tablet, and content uniformity ± 5.0%, carries out tabletting.
Preferred roflumilast sheet comprises following component:
Preparation method is: roflumilast crude drug is pulverized with jet mill, taken the roflumilast raw material for standby of recipe quantity; The method that adopts equivalent to progressively increase, first fully mixes roflumilast raw material with cross-linking sodium carboxymethyl cellulose, the carboxymethyl starch sodium of recipe quantity, fully mixes successively afterwards with recipe quantity pregelatinized Starch, microcrystalline Cellulose, vertical compression lactose, magnesium stearate; After the material detection level mixing, according to content, tabletting weight is answered in conversion, carries out tabletting, regulates the hardness 2～3kg of tablet, and content uniformity ± 5.0%, carries out tabletting.
Roflumilast raw material poorly water-soluble, the particle diameter of raw material is less, and its specific surface area of the roflumilast of equal in quality is larger, and its area contacting with dissolution medium is larger, thus the stripping that is more conducive to improve medicine.Through inventor, study discovery, preparation method of the present invention, when the particle diameter of roflumilast 90% particle is less than 20um, can reach qualified dissolution rate.As a rule, can cover the equipment such as pulverizer, Universalpulverizer, jet mill raw material is pulverized by hammer crusher, vibromill, turbine grinder, ball mill, thunder, inventor is through contrasting multiple disintegrating apparatus crushing effect, raw material particle size after discovery employing jet mill is pulverized is all below 20um, can save the step of sieving like this, and improve raw material availability.Thereby the pre-treatment of this product raw material adopts jet mill to carry out micronization processes.
Technique of direct powder compression has higher requirement for compressibility, mouldability and the mobility of mixed-powder, because bulk density and the mobility of each adjuvant is not quite similar, thereby the prepared various physical parameters of mixed-powder of adjuvant of variety classes, different proportionings can exist certain difference, these differences can affect tablet compact property and uniformity of dosage units.The adjuvant that direct powder compression is conventional comprises that microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol are as filler, magnesium stearate, silicon dioxide, Pulvis Talci are as lubricant, also can add as required cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, hyprolose, carboxymethyl starch sodium etc. as disintegrating agent, in the method for the invention, due to crude drug roflumilast indissoluble, therefore added disintegrating agent, to promote the stripping of roflumilast sheet.
Because roflumilast crude drug of the present invention is through micronization processes, below particle diameter 20um, the non-constant of mobility, and roflumilast sheet specification of the present invention is 0.5mg, and in prescription, proportion is less, therefore, the kind of adjuvant and the selection of consumption become particularly important, otherwise will affect tabletting success, or the underproof problem of uniformity of dosage units, the stripping behavior of prepared roflumilast sheet also can be affected in addition.Inventor has done a large amount of research work to the selection of adjuvant.
Because roflumilast raw material is insoluble in water, in vertical compression prescription, add hydrophilic adjuvant to contribute to the stripping of product.Vertical compression lactose and vertical compression mannitol are water soluble adjuvant, but experiment discovery adopts these two kinds of water solublity vertical compression adjuvants to carry out powder vertical compression process exploitation, there will be sticking phenomenon, and tablet weight variation is larger in tabletting process.For solving sticking problem, the amount of magnesium stearate in prescription need be improved.When in prescription, the ratio of magnesium stearate brings up to 0.8%, we find the not improvement of sticking phenomenon, when this ratio brings up to 1.0%, sticking phenomenon is resolved, but magnesium stearate is lyophobic dust, when it is when proportion is 1.0% in prescription, can obviously reduce the stripping of product.Therefore in prescription, the amount of magnesium stearate should not surpass 1.0% of recipe quantity.
We select the pharmaceutical lactose series of products of German MEGGLE company vertical compression lactose, in experimentation, attempted the vertical compression lactose of Tablettose80, Tablettose100, tri-models of FlowLac100, we find to adopt the sample size uniformity, mobility, the compressibility prepared by FlowLac100 all to show well in prescription.In prescription, adopt the RSD value of the sample size uniformity prepared by Tablettose80 bigger than normal; And the prescription of employing Tablettose100, the mobility of its mixed-powder, the performance of compressibility are all not as FlowLac100.
Common microcrystalline Cellulose particle diameter is less, poor fluidity, and be not suitable for the exploitation of vertical compression technique.Microcrystalline Cellulose we select the microcrystalline Cellulose of Japanese Asahi Chemical Industry to study, and finds that the performance of pH-102 type product is better than pH-301 model and other models in experiment, is more suitable for direct powder compression and prepares roflumilast sheet.
Therefore, in technical scheme of the present invention, the preferred model of vertical compression lactose is FlowLac100, and the preferred model of microcrystalline Cellulose is pH-102.
Through the repeated screening to supplementary product kind and proportioning, obtain preferably tetra-technical schemes of embodiment 1-4 of result, each technical scheme comprises that prescription forms and preparation method, the roflumilast sheet good appearance obtaining, technical process is smooth, have good operability, uniformity of dosage units is qualified, and product dissolution is with former to grind product more consistent.Meanwhile, pleasantly surprised discovery, the stripping behavior of the roflumilast sheet that in above-mentioned four technical schemes, embodiment 4 makes is even better than the former product that grinds.
The invention provides a kind of roflumilast sheet and preparation method thereof, the method adopts direct powder compression preparation, and production technology is simple, has shortened the production cycle, reduced the cost of equipment and running, the roflumilast sheet good appearance preparing, technical process is smooth, has good operability, product dissolution is high, uniformity of dosage units is qualified, can reach good bioavailability at human body, thus the curative effect having produced.
Below in conjunction with the embodiment of the specific embodiment and Figure of description, the present invention will be further described.
Figure of description
Accompanying drawing 1 embodiment 2, embodiment 4 products and the former stripping comparison diagram that grinds commercially available prod
The specific embodiment
Embodiment 1
Preparation method: roflumilast raw material is pulverized with jet mill, taken the roflumilast raw material of 1000 tablet recipe amounts, standby; The method that adopts equivalent to progressively increase, first fully mixes roflumilast raw material with the cross-linking sodium carboxymethyl cellulose of recipe quantity, fully mixes successively afterwards with microcrystalline Cellulose, vertical compression lactose, the magnesium stearate of recipe quantity; The powder mixing detects bulk density, and angle of repose, according to content, tabletting weight is answered in conversion, carries out tabletting, regulates the hardness 2～3kg of tablet, content uniformity ± 5.0%.
Embodiment 2
Preparation method: roflumilast raw material is pulverized with jet mill, taken the roflumilast raw material of 1000 tablet recipe amounts, standby; The method that adopts equivalent to progressively increase, first fully mixes roflumilast raw material with the cross-linking sodium carboxymethyl cellulose of recipe quantity, fully mixes successively afterwards with pregelatinized Starch, microcrystalline Cellulose, vertical compression lactose, the magnesium stearate of recipe quantity; After the material detection level mixing, according to content, tabletting weight is answered in conversion, carries out tabletting, regulates the hardness 2～3kg of tablet, content uniformity ± 5.0%.
Embodiment 3
Preparation method: roflumilast raw material is pulverized with jet mill, taken the roflumilast raw material of 1000 tablet recipe amounts, standby; The method that adopts equivalent to progressively increase, first fully mixes roflumilast raw material with the carboxymethyl starch sodium of recipe quantity, fully mixes successively afterwards with pregelatinized Starch, microcrystalline Cellulose, vertical compression lactose, the magnesium stearate of recipe quantity; The powder mixing detects after angle of repose, bulk density content, and according to content, tabletting weight is answered in conversion, carries out tabletting, regulates the hardness 2～3kg of tablet, content uniformity ± 5.0%.
Embodiment 4
Preparation method: roflumilast raw material is pulverized with jet mill, taken the roflumilast raw material of 1000 tablet recipe amounts, standby; The method that adopts equivalent to progressively increase, first roflumilast raw material is fully mixed with cross-linking sodium carboxymethyl cellulose, the carboxymethyl starch sodium of recipe quantity, fully mix with pregelatinized Starch, microcrystalline Cellulose, vertical compression lactose, the magnesium stearate of recipe quantity successively afterwards; After the material detection level mixing, according to content, tabletting weight is answered in conversion, carries out tabletting, regulates the hardness 2～3kg of tablet, content uniformity ± 5.0%.
Above embodiment is measured respectively to bulk density, angle of repose, the uniformity of dosage units of mixed powder, and the friability of tablet, the projects such as uniformity of dosage units, tablet weight variation, result is as follows.
The mensuration of embodiment 5 dissolutions
Assay method: get this product, make dissolution medium according to dissolution method with 0.3% lauryl sodium sulfate aqueous solution 500ml, rotating speed is per minute 50 to turn, and gets solution appropriate through 30 minutes, filters, and gets subsequent filtrate as need testing solution; It is appropriate that another precision takes roflumilast reference substance, with after a small amount of dissolve with ethanol, adds 0.4% sodium dodecyl sulfate solution to make every 1ml and approximately contain the solution of 1ug roflumilast, in contrast product solution.With octadecylsilane chemically bonded silica, as filler, using 0.3% phosphate as mobile phase, flow velocity is 1ml/min, and detection wavelength is 216nm.For several times, the relative standard deviation of its area should be not more than 2.0% to reference substance solution continuous sample introduction, and precision measures need testing solution and reference substance solution 20ul respectively, injects chromatographic column, records chromatogram, the stripping quantity by external standard method with every of calculated by peak area.Its result is as shown in the table:
Roflumilast sheet dissolution testing result
Above result demonstration, the dissolution of the sample 30min of embodiment 2 and embodiment 4 preparations is more approaching in former triturate.
Choose embodiment 2 and in 0.4% lauryl sodium sulfate aqueous solution, carry out the mensuration of stripping curve with the roflumilast sheet of embodiment 4 preparations, in 5min, 10min, 15min, 20min, 30min, 45min, 60min sampling, detect respectively the stripping quantity of sample, record data are also compared with the stripping curve of listing product, and result is as shown in the table:
Above result shows, embodiment 2 and embodiment 4 are preferred technical scheme, and the In Vitro Dissolution situation of itself and commercially available product has higher similarity, embodiment 4 more preferably wherein, and stripping behavior is better than the former commercially available prod (seeing accompanying drawing 1) of grinding.
Comparative example 1 (wet granulation method)
Preparation method: roflumilast raw material is pulverized with jet mill, standby; Take each supplementary material mix homogeneously of recipe quantity, add appropriate 4.0% hyprolose solution soft material processed, wet stock is crossed to 30 mesh sieves and granulate, wet granular is placed under 60 ℃ of conditions and is dried, after dry materials, according to the weight of dry granule, add magnesium stearate mix homogeneously, after the material detection level mixing, according to content, tabletting weight is answered in conversion, carries out tabletting, regulate the hardness 2～3kg of tablet, content uniformity ± 5.0%.
This product is carried out in 500ml0.3% lauryl sodium sulfate aqueous solution to dissolution detection:
Above result shows, the sample stripping that adopts wet granulation to prepare is partially slow, and its stripping f2 value is less than 50, can judge that the In Vitro Dissolution behavior of itself and former triturate does not have concordance.
Comparative example 2 (wet granulation method)
Preparation method: roflumilast raw material is pulverized with jet mill, standby; Take each supplementary material mix homogeneously of recipe quantity, add appropriate 5% PVP K-90 solution soft material processed, wet stock is crossed to 30 mesh sieves and granulate, wet granular is placed under 60 ℃ of conditions and is dried, after dry materials, according to the weight of dry granule, add magnesium stearate mix homogeneously, after the material detection level mixing, according to content, tabletting weight is answered in conversion, carries out tabletting, regulate the hardness 2～3kg of tablet, content uniformity ± 5.0%.
Stripping curve is measured:
Get this product, make dissolution medium according to dissolution method with 0.3% lauryl sodium sulfate aqueous solution 500ml, rotating speed is per minute 50 to turn, and measures respectively it at the dissolution of 5min, 10min, 15min, 20min, 30min, 45min, 60min.
Above result shows, the sample stripping that adopts above-mentioned wet granulation to prepare is partially slow, and its f2 value is 17, when f2 value is less than 50, can judge that the In Vitro Dissolution behavior of itself and former triturate does not have concordance.Adopt sample prepared by above formulation and technology to meet after water, surface can form sticky floccule, causes roflumilast from tablet, to be discharged in dissolution medium, causes sample stripping partially slow.
Claims (1)
1. roflumilast sheet, is characterized in that, comprises following component:
Described microcrystalline Cellulose model is pH-102, and the model of described vertical compression lactose is F1owLac100;
Preparation method is: roflumilast crude drug is pulverized with jet mill, taken the roflumilast raw material for standby of recipe quantity; The method that adopts equivalent to progressively increase, first roflumilast raw material is fully mixed with cross-linking sodium carboxymethyl cellulose, the carboxymethyl starch sodium of recipe quantity, fully mix with recipe quantity pregelatinized Starch, microcrystalline Cellulose, vertical compression lactose, magnesium stearate successively respectively afterwards; After the material detection level mixing, according to content, tabletting weight is answered in conversion, carries out tabletting, regulates the hardness 2～3kg of tablet, and content uniformity ± 5.0%, carries out tabletting.
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| CN201210593342.XA CN103127011B (en) | 2012-12-27 | 2012-12-27 | Roflumilast tablet and preparation method thereof |
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| CN103830195A (en) * | 2014-03-11 | 2014-06-04 | 熊妲妮 | Indacaterol tablet and preparation method thereof |
| CN103976965A (en) * | 2014-05-20 | 2014-08-13 | 朱金强 | Etoncoxib tablet and preparation method thereof |
| CN104027318A (en) * | 2014-06-13 | 2014-09-10 | 青岛市市立医院 | Domperidone tablet and preparation method thereof |
| CN106139161A (en) * | 2016-08-12 | 2016-11-23 | 合肥久诺医药科技有限公司 | A kind of roflumilast clathrate and solid preparation thereof |
| CN111643470A (en) * | 2020-04-30 | 2020-09-11 | 山东希尔康泰药业有限公司 | Preparation process of roflumilast film-coated tablets |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| MY140561A (en) * | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| CN102274222B (en) * | 2011-08-18 | 2013-04-10 | 天津市汉康医药生物技术有限公司 | High-bioavailability roflumilast medicinal composition and preparation method thereof |
| CN102626410A (en) * | 2012-03-16 | 2012-08-08 | 北京万全阳光医学技术有限公司 | Pharmaceutical composition containing roflumilast |
| CN102743353A (en) * | 2012-07-27 | 2012-10-24 | 海南盛科生命科学研究院 | Roflumilast tablet preparation and preparation method thereof |
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