CN106667935A - Roflumilast tablet and preparation method thereof - Google Patents
Roflumilast tablet and preparation method thereof Download PDFInfo
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- CN106667935A CN106667935A CN201510766396.5A CN201510766396A CN106667935A CN 106667935 A CN106667935 A CN 106667935A CN 201510766396 A CN201510766396 A CN 201510766396A CN 106667935 A CN106667935 A CN 106667935A
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- roflumilast tablet
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Abstract
The invention provides a roflumilast tablet which comprises 0.15-0.25 wt% of roflumilast and 2-10 wt% of copovidone. The invention further discloses a preparation method of the roflumilast tablet. The method aims at defects of the prior art, a developed wet granulation process is adopted, process steps are simplified, the equipment cost is lowered, and the roflumilast tablet is applicable to industrial large-scale production.
Description
Technical field
The present invention relates to pharmaceutical preparations technology field, more particularly to a kind of roflumilast tablet and preparation method thereof.
Background technology
Chronic obstructive pulmonary disease (COPD) is one of common old respiratory system disease, in addition be also cause it is disabled and
One of dead Important cause of disease.Show according to WHO statistics, the current whole world there are about 600,000,000 people with chronic obstructive pulmonary
Disease, averagely just had a people dead because of COPD per 10 seconds, occupied the 4th of the global cause of death.Expect
The year two thousand twenty, annual COPD will cause global more than 600 ten thousand people dead.Due to course of disease delay, Relapse rate,
And in recent years in ascendant trend year by year, COPD causes heavy burden to personal, family and society.
Chemical entitled N- (3,5- dichloropyridine -4- the bases) -3- of roflumilast (roflumilast, formula I)
Ring the third methoxyl group -4- difluoromethoxybenzoamine amines, are researched and developed by German Anda (Altana) company, Switzerland
Metrizamide company (Nycomed Pharma GmbH) completes the phosphodiesterase 4 (PDE4) of III clinical trial phase
Inhibitor, gets the Green Light in July, 2010 in Europe, subsequently in the listing of Germany, Britain and Spain,
Trade name Daxas.Roflumilast obtains U.S. FDA approval within 2 months 2011, in U.S.'s listing, business
Name of an article DALIRESP.The medicine is the first treatment chronic obstructive pulmonary disease (COPD) for getting the Green Light during the last ten years
Medicine.This product can pass through the release for suppressing PDE4 to reduce inflammatory mediator, and then reduction COPD and asthma etc. are exhaled
Inhale the damage that tract disease is caused to lung tissue.
Roflumilast is practically insoluble in water, is described in WO95/01338, and at 21 DEG C, roflumilast is in water
In dissolubility be only 0.53mg/L.Belong to low-solubility, height in Biopharmaceutics Classification system (BCS)
Infiltrative II classes medicine.For this class medicine, the bioavailability of medicine substantially depend on medicine from
Release in formulation products, faster release and dissolving mean that it absorbs faster to medicine from preparation.For
The sl. sol. medicine in water, bioavailability is generally limited by dissolubility or dissolution rate, and this makes it difficult to life
Produce suitable dosage form.
A kind of roflumilast tablet and preparation method thereof is disclosed in the embodiment of Chinese patent CN1635909B,
Wherein component be roflumilast, lactose monohydrate, corn starch, polyvidone and magnesium stearate, traded commodity
DALIRESP compositions are identical with the tablet.In addition, CN1635909B employs bed spray drying and granulating
Technology, the method is high to equipment requirements, and energy consumption is larger, and said preparation technique is also significantly improved space.
Carry out stability to traded commodity DALIRESP to keep sample, result of the test show DALIRESP for high humidity because
Element is more sensitive, easy moisture absorption.Therefore be conducive to improving roflumilast preparation using the lower adjuvant of hygroscopicity
Stability.Copolyvidone is water-soluble organic macromolecule compound, be NVP (NVP) with
The linear copolymer of vinylacetate (VA).The polyvidone adjuvant tool that Copolyvidone is used relative to listing prescription
There are relatively much lower water absorption and more broad solubility property.
However, because Copolyvidone and polyvidone have different chemical constitutions, the solubilizing effect to roflumilast
Also it is different, it is difficult to find the Copolyvidone preparation that a kind of and traded commodity has identical result of extraction.
CN104644575A discloses a kind of roflumilast Solide dispersion tablets and preparation method thereof, the dispersible tablet by
Roflumilast, Copolyvidone, sodium stearyl fumarate and pharmaceutically acceptable adjuvant composition.Prepared by the invention
The disintegrate of roflumilast dispersible tablet is rapid, and in 5min, dissolution is more than 85%, and commercialized product DALIRESP
In 5min, the dissolution of sample is below 35%；In 30min, the inventive embodiments sample dissolution is equal
More than 97%, and DALIRESP sample dissolutions are respectively less than 90%.Therefore, the Solide dispersion tablets grind product with original
The dissolution releasing effect of product is inconsistent, the result of extraction and bioavailability of medicine is changed dramatically in, so as to cause
To drug effectiveness and the worry of untoward reaction.
CN104473862 discloses a kind of Roflumilast solid dispersion containing Copolyvidone carrier, the dispersion
Body is equally existed and discharges too fast, and original grinds the different problem of product result of extraction.Meanwhile, CN104473862
Also disclose in the case of roflumilast and Copolyvidone physical mixed, the solid preparation is molten at 30 minutes
Out-degree only has 44.3%, and result of extraction grinds product far below original.
The content of the invention
The invention provides a kind of roflumilast tablet and preparation method thereof.The roflumilast tablet is using water suction
Property lower Copolyvidone adjuvant, there is more preferably preparation sucting wet stability than listing like product.
By lot of experiments, inventor is it was unexpectedly found that a kind of and former product that grinds has identical result of extraction
Roflumilast tablet.
The invention provides a kind of Roflumilast tablet, containing the roflumilast of percentage by weight 0.15%～0.25%,
2%～10% Copolyvidone, 0.25%～2% lubricant, 60%～80% Lactose, 15%～30% starch.
The roflumilast can cover powder by hammer crusher, vibromill, turbine grinder, ball mill, thunder
The equipment such as broken machine, Universalpulverizer, jet mill are crushed to raw material and are prepared micronization roflumilast.
Roflumilast particle diameter distribution D90 is 5-20 μm.
The K values of the Copolyvidone are preferably 20～40, more preferably S630, VA64 or its combination.
Lubricant is selected from stearoylketene Fumaric acid sodium, magnesium stearate, calcium stearate, stearic acid, Talcum and colloidal state
Anhydride silica or its combination, lubricant is preferably 0.25%～2% magnesium stearate.
In embodiments of the invention, the invention provides a kind of Roflumilast tablet, the group of its percentage by weight
It is divided into：
In a kind of preferred embodiment of the present invention, the invention provides a kind of Roflumilast tablet, its weight hundred
The component of point ratio is：
In a kind of preferred embodiment of the present invention, the invention provides a kind of Roflumilast tablet, its weight hundred
The component of point ratio is：
In a kind of preferred embodiment of the present invention, the invention provides a kind of Roflumilast tablet, its weight hundred
The component of point ratio is：
In a kind of preferred embodiment of the present invention, the invention provides a kind of Roflumilast tablet, its weight hundred
The component of point ratio is：
In a kind of preferred embodiment of the present invention, the invention provides a kind of Roflumilast tablet, its weight hundred
The component of point ratio is：
In a kind of preferred embodiment of the present invention, the invention provides a kind of Roflumilast tablet, its weight hundred
The component of point ratio is：
The supplementary product kind of the present invention and the selection of consumption are particularly important, will affect the dissolved corrosion of Roflumilast tablet,
Substantial amounts of research work has been done in selection of the inventor to adjuvant.Copolyvidone has pyrrolidone ring and ethylene vinyl acetate
Ester group, is all the receptor of hydrogen bond, by the interaction of hydrogen bond, can improve the dissolution of insoluble drug.
Also, Copolyvidone has lower hygroscopicity relative to polyvidone, thus preparation stability is more preferably.Lactose
It is filler with starch, adds water miscible Lactose to contribute to the dissolution of product in tablet formulation, and starch shadow
Ring hardness and the disintegrate of preparation.Magnesium stearate is lubricant.The ratio of each composition in adjustment prescription, so that piece
Agent dissolution grinds consistent with original.
The invention provides the qualified roflumilast tablet of a kind of dissolution and uniformity of dosage units.
On the other hand, the invention provides the preparation method of the Roflumilast tablet, comprises the steps：Claim
Take the starch of recipe quantity, Lactose, micronization roflumilast and sequentially add in wet granulation pot and mix, then weigh place
The Copolyvidone of side's amount, with water the solution that concentration is 5%～20% is configured to, and is added into above-mentioned granulation pot and is stirred
Mixing grain, drying adds the magnesium stearate mix homogeneously of recipe quantity, determines the content of mixture, calculates piece weight,
Tabletting, obtains final product.
The tablet can also be put in high-efficiency coating machine and be coated.
Inventor it was unexpectedly found that by the control of roflumilast particle diameter distribution D90 at 5-20 μm, preparation
Roflumilast tablet and original are ground product and have identical result of extraction.
Inventor is 5%～20% by controlling the concentration of Copolyvidone aqueous solution in wet-granulation process, is affected
The granulating efficiency of tablet and the compressibility of granule, and finally affect the stripping curve of finished product.
The low tablet of active component content would ordinarily be encountered the not good problem of the finished product content uniformity.But it is of the invention
The high speed wet granulation method for using, has been surprisingly found that finished tablet uniformity of dosage units is qualified, and process simple and fast.
The roflumilast tablet preparation method is directed to the deficiencies in the prior art, using the wet method that production technology is ripe
Granulating process, simplifies processing step, reduces equipment cost, is adapted to industrialized great production.
Description of the drawings
Fig. 1, each embodiment sample is with original triturate Daxas in pH6.8 phosphate buffers (containing 0.1%SDS)
Stripping curve.
Specific embodiment
By the following examples the specific embodiment of form, makees further detailed to the above of the present invention
Describe in detail bright.But this scope for being interpreted as above-mentioned theme of the invention should not be only limitted to following examples.
Embodiment 1
1. roflumilast is crushed, by particle diameter distribution D90Control is at 5～20 μm.
2. Copolyvidone is slowly added in purified water, stirs to clarify Copolyvidone aqueous solution, solution concentration is about
5%～20%, use as binder solution.
3. starch, Lactose, micronization roflumilast are sequentially added in wet mixing pelletizer, unlatching stirring paddle,
Cutter, carry out premixing, and incorporation time is 15 minutes.
4. stirring and the cut state of wet mixing pelletizer, constant speed is kept to add the Copolyvidone in step 2 water-soluble
Liquid.
5. the soft material for making is added in oscillating granulator, makes wet granular.
6. wet granular is put in heated-air circulation oven, sets 80 DEG C of baking temperature, particle drying is existed to moisture value
Less than 4%.
7. by dried granule by carrying out dry granulate in pelletizing machine.
8. dry particl is added in Mixers with Multi-direction Movement, additional adjuvant magnesium stearate is added, set engine speed
20 revs/min, start mixer, 4～10min of incorporation time, rewinding.
9. tabletting is carried out with the circular shallow concave punch of Φ 9mm, piece Hardness Control is in 50-100N.
Embodiment 2
Recipe quantity active component and adjuvant are weighed by prescription 1, formulation preparation method is with embodiment 1.
Table 1, prescription 1
Embodiment 3
Recipe quantity active component and adjuvant are weighed by prescription 2, formulation preparation method is with embodiment 1.
Table 2, prescription 2
Embodiment 4
Recipe quantity active component and adjuvant are weighed by prescription 3, formulation preparation method is with embodiment 1.
Table 3, prescription 3
Embodiment 5
Recipe quantity active component and adjuvant are weighed by prescription 4, formulation preparation method is with embodiment 1.
Table 4, prescription 4
Embodiment 6
Recipe quantity active component and adjuvant are weighed by prescription 5, formulation preparation method is with embodiment 1.
Table 5, prescription 5
Embodiment 7
Solide dispersion tablets reference substance is prepared by CN104644575A methods.Prescription 6 is specially pressed by recipe quantity
Roflumilast is 1 with Mannitol in mass ratio：10 common micronizations, sieve to obtain micronizing materials, standby, will locate
The Copolyvidone of side's amount is configured to the aqueous solution of 10% (w/w), standby；By the Mannitol of surpluses, micropowder
The Lactose of compound material and recipe quantity, polyvinylpolypyrrolidone are sequentially added in mixed-hopper and mixed, and obtain roflumilast point
Discrete piece pre-mix powder；Roflumilast dispersible tablet pre-mix powder is placed in granulator, Copolyvidone aqueous solution is added
Make wet granular；Wet granular is dried；Add the sodium stearyl fumarate of recipe quantity；It is total mixed；Tabletting, i.e.,
.
Table 6, prescription 6
Embodiment 8
Dissolution assay method：This product is taken, is shone《Chinese Pharmacopoeia》Dissolution is examined with the second method of release detection method
Survey, dissolution medium volume 1000ml, rotating speed is 50 turns per minute, 5,10,15,30,45,60 points of Jing
Solution is taken during clock appropriate, filtration takes subsequent filtrate as need testing solution；Separately take roflumilast reference substance appropriate,
It is accurately weighed, in putting 50ml volumetric flasks, plus after a small amount of acetonitrile dissolving, with dissolution medium dilution every 1ml is made
In solution containing about 0.5 μ g, as reference substance solution.With octadecylsilane chemically bonded silica as filler,
With acetonitrile-water (with phosphorus acid for adjusting pH value to 3.5) (63:37) it is mobile phase；Flow velocity is 1ml/min, detection
Wavelength 215nm.Respectively precision measures need testing solution and reference substance solution 100ul, injects chromatographic column, record
Chromatogram, the stripping quantity by external standard method with calculated by peak area per piece.
Embodiment 9
The sample of prescription 1～6 is contrasted with original triturate Daxas stripping curves in pH6.8 media.As a result
Show that sample similar factors F2 of prescription of the present invention 1～5 are all higher than 50, the i.e. sample of prescription 1～5 and former triturate
Dissolved corrosion it is consistent.Tablets are respectively less than 40%, 30min dissolutions with the 5min dissolutions of former triturate
Degree is all higher than 80%.And the solid dispersion reference substance of prescription 6 is more than 80%, and former development in 5min dissolutions
The dissolved corrosion of agent is substantially inconsistent.
Daxas is purchased from Metrizamide company (Nycomed Pharma GmbH) traded commodity.
Claims (10)
1. a kind of Roflumilast tablet, ties up containing the roflumilast of percentage by weight 0.15%～0.25%, 2%～10% copolymerization
Ketone, 0.25%～2% lubricant, 60%～80% Lactose, 15%～30% starch.
2. Roflumilast tablet according to claim 1, the K values of the Copolyvidone are preferably 20～40.
3. Roflumilast tablet according to claim 2, the Copolyvidone selected from S630, VA64 or its group
Close.
4. Roflumilast tablet according to claim 1, the lubricant is selected from stearoylketene Fumaric acid sodium, hard
Fatty acid magnesium, calcium stearate, stearic acid, Talcum and colloidal anhydrous silicon dioxide or its combination.
5. Roflumilast tablet according to claim 4, the lubricant is weight percentage 0.25%～2%
Magnesium stearate.
6. Roflumilast tablet according to claim 1, the component of its percentage by weight is：
7. Roflumilast tablet according to claim 1, the component of its percentage by weight is：
8. Roflumilast tablet according to claim 1, the component of its percentage by weight is：
Or
Or
Or
Or
9. the preparation method of the Roflumilast tablet according to any one of claim 1～8, comprises the steps：
Weigh the starch of recipe quantity, Lactose, micronization roflumilast and sequentially add in wet granulation pot and mix, then weigh
The Copolyvidone of recipe quantity, with water the solution that concentration is 5%～20% is configured to, and is added into above-mentioned granulation pot simultaneously
Stirring granulation, drying adds the magnesium stearate mix homogeneously of recipe quantity, determines the content of mixture, calculates piece
Weight, tabletting is obtained final product.
10. the preparation method of Roflumilast tablet according to claim 9, the tablet is put in high-efficiency coating machine and carries out
Coating.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510766396.5A CN106667935A (en) | 2015-11-11 | 2015-11-11 | Roflumilast tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510766396.5A CN106667935A (en) | 2015-11-11 | 2015-11-11 | Roflumilast tablet and preparation method thereof |
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| Publication Number | Publication Date |
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| CN106667935A true CN106667935A (en) | 2017-05-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510766396.5A Pending CN106667935A (en) | 2015-11-11 | 2015-11-11 | Roflumilast tablet and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111643469A (en) * | 2020-04-30 | 2020-09-11 | 山东希尔康泰药业有限公司 | Roflumilast raw material medicine, prescription development method and preparation treatment method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104473862A (en) * | 2014-11-18 | 2015-04-01 | 北京科莱博医药开发有限责任公司 | Roflumilast solid dispersoid and preparation method thereof as well as roflumilast preparation |
| CN104644575A (en) * | 2013-11-21 | 2015-05-27 | 成都苑东药业有限公司 | Roflumilast dispersible tablet composition and preparation method thereof |
-
2015
- 2015-11-11 CN CN201510766396.5A patent/CN106667935A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104644575A (en) * | 2013-11-21 | 2015-05-27 | 成都苑东药业有限公司 | Roflumilast dispersible tablet composition and preparation method thereof |
| CN104473862A (en) * | 2014-11-18 | 2015-04-01 | 北京科莱博医药开发有限责任公司 | Roflumilast solid dispersoid and preparation method thereof as well as roflumilast preparation |
Non-Patent Citations (4)
| Title |
|---|
| ANONYMOUS: "Unit dosage form, useful for treating asthma or airway obstruction, comprises roflumilast, copovidone as a binder and at least one excipient which is at least one filler and at least one lubricant or release agent", 《RESEARCH DISCLOSURE》 * |
| 孟胜男: "《药剂学》", 31 January 2012 * |
| 方亮: "《药用高分子材料学 第4版》", 31 August 2015 * |
| 郑俊民: "《药用高分子材料学 第三版》", 31 January 2009 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111643469A (en) * | 2020-04-30 | 2020-09-11 | 山东希尔康泰药业有限公司 | Roflumilast raw material medicine, prescription development method and preparation treatment method thereof |
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Application publication date: 20170517 |