CN103330689A - Orally disintegrating tablet comprising roflumilast - Google Patents
Orally disintegrating tablet comprising roflumilast Download PDFInfo
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- CN103330689A CN103330689A CN2013101076696A CN201310107669A CN103330689A CN 103330689 A CN103330689 A CN 103330689A CN 2013101076696 A CN2013101076696 A CN 2013101076696A CN 201310107669 A CN201310107669 A CN 201310107669A CN 103330689 A CN103330689 A CN 103330689A
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Abstract
The invention belongs to the field of medicine technology, and relates to an orally disintegrating tablet comprising roflumilast and a preparation method of the orally disintegrating tablet. The orally disintegrating tablet comprises roflumilast, a hydrophilic filler, a water-soluble polymer adhesive, a disintegrating agent, a flavouring agent, a lubricant, and the like. The objective of the invention is to provide the roflumilast orally disintegrating tablet that has advantages of simple preparation technology, taking convenience, rapid effect, rapid concentration peak and obvious curative effects.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of active component and be roflumilast disintegrate rapidly oral cavity disintegration tablet and produce the method for this dosage form.
Background technology
(Chronic obstructive pulmonary disease COPD) is a kind of disease that can prevent and treat with flow limitation feature to chronic obstructive pulmonary disease.Flow limitation is not exclusively reversible, be and carry out sexual development, and is relevant to the abnormal inflammatory reaction of harmful gas such as smoke from cigarette or deleterious particle with pulmonary.COPD is a kind of carrying out property and life-threatening pneumonopathy, is one of human health " killer ", and it makes the patient respiratory difficulty, LOM.This disease generally includes chronic bronchitis and emphysema.According to estimates, the whole world has 2.1 hundred million people to suffer from this disease approximately, expects the year two thousand twenty, and COPD will become the third-largest dead factor in the whole world.According to the graduate conclusion of American National heart, lung and blood, smoking is the main paathogenic factor of COPD.In the U.S. 1,200 ten thousand patients are arranged, may have 1,200 ten thousand people to suffer from this disease in addition and do not diagnosed.In the U.S., in numerous " healthy killers ", COPD ranks the 4th.
Roflumilast (roflumilast, 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) Benzoylamide), be a kind of oral selectivity phosphodiesterase 4 (PDE4) inhibitor, be proved to be able to suppress COPD dependency inflammation with a kind of novel binding mode.Roflumilast is tablet once a day, is first medicine at serious symptom COPD novel therapeutic.Also be to be the special first oral anti-inflammatory treatment medicine of developing of COPD patient.This medicine belongs to the long-acting inhibitor of selectivity 4 type phosphodiesterases (PDE-4), and antiinflammatory action is arranged, and is used for reducing COPD seizure frequency and sx.This class has the chemical compound of Benzoylamide structure and mentions as being described among the WO 95/01338 of cyclic nucleotide phosphodiesterase (PDE) inhibitor for treating disease with them.Also mention simultaneously: the roflumilast dissolubility is very little, and dissolubility only is 0.52-0.56mg/L(21 ℃-22 ℃).And the stripping of medicine from preparation determining bioavailability of medicament, and for sl. sol. medicine in water, therefore bioavailability often is subjected to the restriction of dissolubility or dissolution rate, and this makes and is difficult to produce suitable dosage form.Mention the solid oral dosage form that the preferred active component of peroral dosage form of roflumilast discharges immediately among the WO 03/070279, so that sl. sol. PDE-4 inhibitor plays quick, acceptable bioavailability.
US 5,286, and 494 have proposed control or the sustained release forms of sl. sol. PDE-4 inhibitor Rolipram, yet the production technology of this dosage form is comparatively complicated.
WO 03/070279 relates to a kind of PDE-4 of containing inhibitor as active component and the polyvinylpyrrolidone peroral dosage form as excipient.But disintegration time is longer, and drug releasing rate is comparatively slow.
FDA ratifies roflumilast in February, 2011 and is used for the treatment of chronic obstructive pulmonary disease, is to sell in European Union and American market with roflumilast Film coated tablets and conventional tablet form, but does not see that oral cavity disintegration tablet dosage form report is arranged.
Oral cavity disintegration tablet (orally disintegrating tablet) is emerging in recent years novel form, compare with conventional tablet, this dosage form need not water and also need not to chew, medicine places on the tongue, meet the rapid disintegrate of saliva and be dispersed into fine particle, borrow swallowing act to go into the stomach onset, also can place the Sublingual, medicine passes through the mucosa absorption onset after the disintegrate rapidly.The medicine stripping is accelerated, and is big in the gastrointestinal tract area distributions, have rapid-action, the characteristics that bioavailability is high.
Summary of the invention
The object of the invention provides the oral cavity disintegration tablet dosage form of roflumilast, the production of this dosage form does not need very high technical complexity, this dosage form is considered the low solubility of roflumilast, quick to produce, the acceptable bioavailability of characteristic of the rapid disintegrate by oral cavity disintegration tablet is in order to obtain the serum-concentration that needs and therefore obtain excellent clinical outcome fast.
Roflumilast oral cavity disintegration tablet of the present invention, this pharmaceutical composition contain just like the N-(3 shown in (1), 5-two chloro-pyridin-4-yls)-3-cyclo propyl methoxy-4-difluoro-methoxy Benzoylamide,
（1）
And hydrophilic filler, water-soluble copolymer adhesive, disintegrating agent, correctives and lubricant; Wherein crude drug and hydrophilicity condiment carry out common micronization, and its ratio is 1:1-1:1:150(w/w); The disintegration time that adopts static disintegration time mensuration method to measure is 10-60 second, is preferably 15-40s.
We find under study for action: with active component roflumilast and hydrophilicity condiment in 1:1-1:150(w/w) ratio carry out common micronization, the stripping of medicine is greatly improved, and is preferably 1:5-1:100(w/w especially).And the particle diameter at roflumilast behind the micronization is controlled in the 1-50 mu m range, is preferably especially in the 1-20 mu m range.And under these conditions, during 10min active component in aqueous medium dissolution greater than 75%.
Among the present invention with roflumilast altogether micronized hydrophilicity condiment comprise a kind of in mannitol, lactose, corn starch, the microcrystalline Cellulose, its ratio is 1:1-1:1:150(w/w), be preferably 1:5-1:60(w/w especially).If desired, also can use their mixture.
The content of the active component roflumilast among the present invention is 0.125%-1.25%, is preferably 0.1mg, 0.125mg, 0.25mg, 0.5mg, 1mg.
Hydrophilic filler among the present invention comprises can select in lactose, sucrose, mannitol, xylitol, sorbitol, microcrystalline Cellulose, dextrin, the starch one or more, consumption is the heavy 25%-90% of total sheet, be preferably in lactose, mannitol, xylitol, microcrystalline Cellulose, the starch one or several, consumption is preferably 40%-80%.
Water-soluble copolymer adhesive among the present invention can be selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone.Its ratio is 0.2%-10%, is preferably 0.5%-5%.Wherein hydroxypropyl emthylcellulose is to have more low viscously, is preferable over viscosity coefficient and is lower than 400mPa.s.
The disintegrating agent that the present invention relates to can be selected from a kind of of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, pregelatinized Starch or two kinds or more ofly unite use, consumption is the heavy 5%-70% of total sheet, is preferably 10%-60%.
Correctives among the present invention can be selected from one or several in acesulfame potassium, sucralose, aspartame, stevioside, Mentholum, cherry essence, Fructus Citri Limoniae essence, Herba Menthae essence, vanilla, Semen Maydis essence, flavoring banana essence, Fructus Ananadis comosi Fructus Musae, honey peach Fructus Musae, the Fructus Vitis viniferae Fructus Musae, consumption is the heavy 0.2%-6% of total sheet, is preferably 0.5%-5%.
The lubricant that the present invention relates to can be selected from one or several in magnesium stearate, Stepanol MG, micropowder silica gel, the Pulvis Talci, is preferably a kind of in magnesium stearate, the micropowder silica gel or two kinds and share, and consumption is preferably 0.2%-0.5%.
Roflumilast oral cavity disintegration tablet of the present invention, the heavy 60-200mg of sheet is preferably 80-160mg; Hardness 20-60N is preferably 25-40N.
Description of drawings Fig. 1 makes preparation by oneself and control formulation body giving drugs into nose contrasts for kinetic curve
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Specific embodiment 1 roflumilast oral cavity disintegration tablet (1000)
0.125g
Mannitol (being total to micronization with Ro) 12.5g
Mannitol 26.275
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
The user of magnesium stearate 0.5g[Microsoft 1]
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, brain and magnesium stearate.
5, measure granule content, it is heavy to calculate sheet, and tabletting is made 1000 altogether, control hardness 20-40N.
Specific embodiment 2 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.125g
Mannitol (being total to micronization with Ro) 0.625g
Mannitol 38.15
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, brain and magnesium stearate.
Specific embodiment 3 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.125g
Mannitol (being total to micronization with Ro) 6.25g
Mannitol 32.525
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 4 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.25g
Mannitol (being total to micronization with Ro) 25g
Mannitol 33.65
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 5 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.25g
Mannitol (being total to micronization with Ro) 1.25g
Mannitol 37.4g
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 6 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.5g
Mannitol (being total to micronization with Ro) 2.5g
Mannitol 35.9g
Microcrystalline Cellulose 30g
Crospolyvinylpyrrolidone 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 7 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.5g
Mannitol (being total to micronization with Ro) 25g
Mannitol 33.4g
Microcrystalline Cellulose 30g
Crospolyvinylpyrrolidone 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 8 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.5g
Mannitol (being total to micronization with Ro) 50g
Mannitol 28.4g
Microcrystalline Cellulose 30g
Crospolyvinylpyrrolidone 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 9 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 1.0g
Mannitol (being total to micronization with Ro) 5g
Mannitol 32.9g
Microcrystalline Cellulose 30g
Crospolyvinylpyrrolidone 8g
Hypromellose 0.6
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 10 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 1.0g
Mannitol (being total to micronization with Ro) 100g
Mannitol 8g
Microcrystalline Cellulose 30g
Crospolyvinylpyrrolidone 8g
Hypromellose 0.5
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
Specific embodiment 11 roflumilast oral cavity disintegration tablets (1000)
Roflumilast(Ro) 0.5g
Mannitol (being total to micronization with Ro) 25g
Mannitol 40.5
Starch 15g
Crospolyvinylpyrrolidone 16g
Hypromellose 0.5
Acesulfame potassium 1.0g
Herba Menthae essence 1.0g
Magnesium stearate 0.5g
Method for making: 1, will write out a prescription in active component Ro and mannitol carry out micronization processes in the prescription ratio.
2, with the Ro of recipe quantity and mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone mix homogeneously in blender.
3,60% alcoholic solution soft material processed that adds 2% hypromellose in the said mixture, granulation.
4, be dried to moisture L.O.D(90 ℃, 5min)＜3%, granulate, conversion adds consumption and the above-mentioned band medicine granule mixing of low-substituted hydroxypropyl cellulose, acesulfame potassium, Mentholum and magnesium stearate.
[user of Microsoft 2] investigated in the static slaking test of 1 roflumilast
Get 1 of roflumilast oral cavity disintegration tablet oral cavity disintegration tablet, put 10ml test tube (the test tube internal diameter is 13mm), in vitro fill 2ml water, water temperature is 37 ℃, tablet disintegrate in 1 minute, is dispersed in the water.Pour out and sieve, each water 2ml washes test tube and screen cloth at twice, can be all by 24 eye mesh screens.Check 6 (n=6) as stated above, the results are shown in following table:
The static disintegrate result of 11 kinds of embodiment of table 1
By above result as can be seen: according to the prepared oral cavity disintegration tablet of embodiment, all in 30s, disintegrate is very fast for static disintegration time, reaches requirement disintegration of oral cavity disintegration preparation.
Test example 2 crude drug and hydrophilicity condiment are pressed behind the common micronization of different proportion the influence to stripping
Get crude drug and carry out common micronization processes in the ratio in " claim 1 " and hydrophilicity condiment, prepare sample by the prescription among the embodiment and technology, the dissolution of active component when detecting 10min.
Carry out dissolution test according to 2010 editions two appendix of Chinese Pharmacopoeia " dissolution method ", second method.Measuring condition is: water, 0.05%SDS; Oar rotating speed: 50rpm; Liquor capacity: 1000ml.Stripping the results are shown in following table:
Stripping contrasted after table 2 RO and hydrophilicity condiment were pressed the common micronization of different proportion
| The ratio of RO and hydrophilicity condiment | RO | 1:1 | 1:5 | 1:20 | 1:40 | 1:100 |
| 10min dissolution/% | 32 | 34 | 78 | 82 | 80 | 81 |
By above dissolution result as can be seen: after the ratio in the by specification was carried out common micronization with crude drug roflumilast and hydrophilic adjuvant, the dissolution of active component when 10min had tangible improvement.Dosage form of the present invention and technology have significantly increased the dissolution rate of roflumilast.
The test of test example 3 roflumilast oral cavity disintegration tablet 10min dissolutions is investigated
The dissolution result of 11 kinds of embodiment of table 3
By above dissolution result as can be seen: according to the prepared oral cavity disintegration tablet of embodiment, its 10min dissolution is all greater than 75%, and rapider than the stripping of former triturate roflumilast sheet, brought into play the advantage of oral cavity disintegration tablet.
Embodiment 4 roflumilast oral cavity disintegration tablet stability tests are investigated
According to the listed investigation project of stability test in 2010 editions two appendix of Chinese Pharmacopoeia " medicine stability test guideline ", roflumilast oral cavity disintegration tablet oral cavity disintegration tablet of the present invention is carried out factors influencing.
Method according to the embodiment of the invention 1 prepares a collection of roflumilast oral cavity disintegration tablet oral cavity disintegration tablet by commercially available back, putting intensity of illumination 4500Lx ± 500Lx, 60 ℃ of high temperature and 25 ℃ of RH92.5% of high humidity ± 5% transfers and deposits 10 days, the 5th day and sampling detection in the 10th day, the results are shown in following table:
Table 4 roflumilast oral cavity disintegration tablet oral cavity disintegration tablet factors influencing result
Conclusion: this product is through factors influencing, and it is all qualified that every index was compared with 0 day, illustrates that this oral cavity disintegration tablet compositions and the stable preparation process that the present invention relates to are feasible.
The pharmacokinetics comparative study of embodiment 5 roflumilast oral cavity disintegration tablets and former triturate
Design: 24 patients of random choose, for each case, dosage is 0.5mg (1, every contains the 0.5mg roflumilast).Behind oral administration 0.5mg roflumilast oral cavity disintegration tablet, study the serum-concentration of itself and Comparative formulation roflumilast sheet:
The tablet of self-control preparation: embodiment 1
Control formulation: roflumilast sheet (American Forest pharmacy, trade name: Daliresp)
As seen from Figure 1, faster with former triturate roflumilast sheet contrast behind oral administration roflumilast oral cavity disintegration tablet, observed higher serum levels more significantly.Therefore, roflumilast oral disintegrated preparation of the present invention is compared infiltration rate and has been increased significantly with former grinding, brought into play oral disintegrated preparation rapid-action, reach the peak early, the curative effect remarkable advantages.
Preferably list with form, see a bit disorderly like this
Also can do Orally disintegrating test and the test of tablet friability, prove that intra-oral disintegration is fast, mouthfeel good, hardness meets the storage movement requirement.
Claims (10)
1. the roflumilast oral cavity disintegration tablet with good disintegrate effect is characterized in that containing in this oral cavity disintegration tablet the N-(3 just like shown in (1), 5-two chloro-pyridin-4-yls)-3-cyclo propyl methoxy-4-difluoro-methoxy Benzoylamide,
（1）
Wherein also comprise hydrophilic filler, water-soluble copolymer adhesive, disintegrating agent, correctives and lubricant, the disintegration time of this oral cavity disintegration tablet is 15-60 second, 10min in aqueous medium dissolution greater than 75%; Wherein crude drug and hydrophilicity condiment carry out common micronization, and its ratio is 1:1-1:150(w/w), described micronization control 90% volume or more the particle diameter of multiparticle at 1-50 μ m.
2. hydrophilicity condiment according to claim 1 comprises a kind of in mannitol, lactose, corn starch, potato starch, wheaten starch and the microcrystalline Cellulose, and its ratio is 1:5-1:60(w/w).
3. oral cavity disintegration tablet according to claim 1, wherein the content of roflumilast is 0.125%-1.25%.
4. oral cavity disintegration tablet according to claim 1, wherein the hydrophilic filler is one or more in lactose, sucrose, mannitol, xylitol, sorbitol, microcrystalline Cellulose, dextrin, the starch, consumption is the heavy 25%-98% of total sheet.
5. oral cavity disintegration tablet according to claim 1 is characterized in that described water-soluble copolymer adhesive is one or more in hydroxypropyl emthylcellulose, hydroxypropyl cellulose, the polyvinylpyrrolidone, and its ratio is 0.2%-10%.
6. follow according to the described water-soluble copolymer adhesive of claim 5, wherein hydroxypropyl emthylcellulose is to have more low viscously, is preferable over viscosity coefficient and is lower than 400mPa.s.
7. oral cavity disintegration tablet according to claim 1, wherein disintegrating agent is one or more in microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, the pregelatinized Starch, and consumption is the heavy 5%-70% of total sheet.
8. oral cavity disintegration tablet according to claim 1, wherein correctives can be selected from one or several in acesulfame potassium, sucralose, aspartame, stevioside, Mentholum, cherry essence, Fructus Citri Limoniae essence, Herba Menthae essence, vanilla, Semen Maydis essence, flavoring banana essence, Fructus Ananadis comosi Fructus Musae, honey peach Fructus Musae, the Fructus Vitis viniferae Fructus Musae, and consumption is the heavy 0.2%-6% of total sheet.
9. oral cavity disintegration tablet according to claim 1, wherein lubricant can be selected from one or several in magnesium stearate, Stepanol MG, micropowder silica gel, the Pulvis Talci, and consumption is the heavy 0.1%-2% of total sheet.
10. oral disintegrating tablet formulation according to claim 1; said preparation prepares by the following method, and described method comprises that the mixed-powder that utilizes water-soluble copolymer adhesive solution will contain roflumilast, filler, disintegrating agent, correctives, lubricant mixes granulation.
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| CN105878197A (en) * | 2016-03-31 | 2016-08-24 | 北京万全德众医药生物技术有限公司 | Riociguat orally disintegrating tablet and preparation method thereof |
| CN106880607A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of oral disnitegration tablet containing Rui Gefeini and preparation method thereof |
| CN106880601A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of oral disnitegration tablet containing teriflunomide and preparation method thereof |
| CN107898787A (en) * | 2017-12-15 | 2018-04-13 | 扬子江药业集团上海海尼药业有限公司 | A kind of pharmaceutical composition and its preparation and preparation method |
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| WO2003070279A1 (en) * | 2002-02-20 | 2003-08-28 | Altana Pharma Ag | Oral dosage form containing a pde 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
| WO2006097456A1 (en) * | 2005-03-16 | 2006-09-21 | Nycomed Gmbh | Taste masked dosage form containing roflumilast |
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| CN105287413A (en) * | 2015-10-23 | 2016-02-03 | 南京泽恒医药技术开发有限公司 | Chewable tablet containing montelukast sodium and preparation method of chewable tablet |
| CN106880607A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of oral disnitegration tablet containing Rui Gefeini and preparation method thereof |
| CN106880601A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of oral disnitegration tablet containing teriflunomide and preparation method thereof |
| CN105878197A (en) * | 2016-03-31 | 2016-08-24 | 北京万全德众医药生物技术有限公司 | Riociguat orally disintegrating tablet and preparation method thereof |
| CN107898787A (en) * | 2017-12-15 | 2018-04-13 | 扬子江药业集团上海海尼药业有限公司 | A kind of pharmaceutical composition and its preparation and preparation method |
| CN107898787B (en) * | 2017-12-15 | 2018-11-30 | 扬子江药业集团上海海尼药业有限公司 | A kind of pharmaceutical composition and its preparation and preparation method |
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