CN102274222B - High-bioavailability roflumilast medicinal composition and preparation method thereof - Google Patents
High-bioavailability roflumilast medicinal composition and preparation method thereof Download PDFInfo
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- CN102274222B CN102274222B CN 201110238135 CN201110238135A CN102274222B CN 102274222 B CN102274222 B CN 102274222B CN 201110238135 CN201110238135 CN 201110238135 CN 201110238135 A CN201110238135 A CN 201110238135A CN 102274222 B CN102274222 B CN 102274222B
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Abstract
The invention discloses a high-bioavailability roflumilast medicinal composition, which consists of roflumilast, betacyclodextrin, lactobiose, microcrystalline cellulose and magnesium stearate. The medicinal composition is characterized in that: a weight ratio of the roflumilast to the betacyclodextrin to the lactobiose is 1:2:20; the roflumilast medicinal composition has the advantages of improving yield, reducing cost, realizing industrialization, along with high stability; and the composition is better applied clinically, and the dissolution rate and bioavailability can be improved effectively; and the high-bioavailability roflumilast medicinal composition can be used for treating chronic obstructive pulmonary diseases.
Description
Technical field
The invention belongs to medical technical field, be specifically related to roflumilast medicinal composition and preparation method thereof.
Background technology
The nearly forty-two million asthma patient in the whole world and 2,800 ten thousand COPD (chronic obstructive pulmonary disease) patients.Over past ten years, along with the air pollution in the global range and ecological deterioration, the M ﹠ M of asthma is in rising trend, has every year 180000 people of surpassing to die from asthma.Other has the demonstration of analysis, and to the year two thousand twenty, COPD will rise to the 3rd from the 6th of the present global cause of the death.Conservative estimation, the annual number because of COPD death in the whole world will reach more than 3,500,000 till that time.At home, by the Epidemiological study result demonstration that Zhong Nanshan academician presides over, the overall prevalence of present Chinese COPD is 8.2%, and wherein the male sicken rate is 12.4%, and women's prevalence is 5.1%.COPD patient surpasses 4,000 ten thousand in China, estimates that China will have 6,500 ten thousand people and die from COPD during 2003～2033 years.
Huge patient group has achieved the pharmaceutical market that has a high potential.2005, the market sales revenue of global treating asthma medicine was up to 17,000,000,000 dollars.Wherein the Advair of GlaxoSmithKline PLC company is first ICS/LABA class medicine, it from 1999 first after U.S. listing just always in occupation of market bellwether's status.2005, this product was created 54.65 hundred million dollars sale good result with 21.4% rate of increase, was sure to occupy the position of the world's three large best-selling drugses., and in the sales volume of the whole world seven large main medical markets also above 4,900,000,000 dollars.After 2 years, AstraZeneca has been released therapeutic alliance medicine Symbicort, and this product went on the market in Europe first in calendar year 2001.Occupy global best-selling drugs with 10.06 hundred million dollars global marketing volume in 2005 and be ranked first 00.The therapeutic alliance medicine of the 3rd listing in the whole world is that the beclometasone+formoterol of Chiesi company goes on the market in Germany first in JIUYUE, 2007.Its global marketing volume was expected to reach 3,300 hundred million dollars in 2015 according to estimates.Although COPD treatment market will be doubled above from 2004 by 2014, but with regard to the drug development merchant, because the medicament research and development scale for the treatment of COPD is smaller, and lack some real new way of innovations and solve outstanding demand, improving curative effect of medication and the effective antiinflammatory of exploitation for disease, thus in the urgent need to the medicine of researching and developing new treatment COPD with satisfying the market to dissimilar and different demands for the treatment of machine-processed medicine.
Roflumilast
English name: Roflumilast;
Chemical name: N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-difluoromethoxybenzoamine amine;
Structural formula:
Molecular formula: C
17H
14C
L2F
2N
2O
3
Molecular weight: 403.21;
Physicochemical property: this product be white to the off-white color crystalline powder, be soluble in acetone, slightly soluble in methanol and ethanol, almost insoluble in water.
Pharmacology type: phosphodiesterase 4 (PDE-4) inhibitor.
Mechanism of action: process-N-oxidation generates roflumilast-N-oxide.Roflumilast and roflumilast-N-oxide optionally establishment PDE4 is active.Leukotriene B4, interleukin (IL-2, IL-4, IL-5), interferon and tumor necrosis factor synthetic, and the formation of active oxygen in the human leucocyte all reduce because of two kinds of chemical compounds.Except anti-inflammatory activity, roflumilast can also make the CBF in near-end and the far-end air flue increase external, shows that it has the latent effect that promotes lung mucociliary clearance rate.Roflumilast also can significantly reduce neutrophilic granulocyte, eosinophilic granulocyte, reach the absolute quantity that whole cell migration enter air flue, thereby reduces the stimulation to respiratory tract.
Indication: be used for following the chronic bronchitis history of frequent outbreak severe chronic obstructive pulmonary disease (COPD) (give after the bronchodilator the not enough desired value of FEV1 50%) adult patient keep treatment.
Usage and dosage: oral.Once a day, each a slice.
The former producer of grinding of roflumilast is German company Nycomed GmbH(trade name: Daxas; Specification: 500 μ g; Dosage form: tablet).In July, 2010 European Union's approval listing.Be the PDE-4 inhibitor, its effect is extremely strong, have characteristics of high selectivity, oral administration.It can be used for the treatment of asthma, COPD and chronic obstructive bronchitis.Clinically, the research of selectivity PDE-4 inhibitor for treating asthma and COPD is carried out for many years.Enter the 1st generation selectivity PDE-4 inhibitor in clinical research stage such as rolipram (rolipram) and interrupted research owing to obvious gastrointestinal side effect.2nd generation selectivity PDE-4 inhibitor, such as cilomilast (cilomilast), roflumilast (roflumilast), but cilomilast part test result all occur aspect curative effect of medication and the safety from the expection different, cause this medicine to stop further research and development.And several clinical test results of roflumilast are managed aspect curative effect of medication, safety and toleration.So in April, 2010, European Union ratified its list marketing.Test in the model in experiment, after PDE-4 is subject to the roflumilast inhibition, cause cAMP level rising in the cell, alleviated the leukocyte relevant with COPD, air flue and pulmonary arterial smooth muscle cell, endothelium and human airway epithelial cells and fibroblastic malfunction.In human neutrophil, mononuclear cell, macrophage or the test of lymphocytic stimulated in vitro, roflumilast and roflumilast-N-oxide has suppressed the release of inflammatory mediator (for example leukotriene B4, active oxygen, tumor necrosis factor α, interferon gamma and Cytotoxic cell proteinase-1).In the patient of suffering from copd, roflumilast has also reduced the neutrophilic granulocyte quantity in the sputum.In addition, in the healthy volunteer that endotoxin excites, it has reduced neutrophilic granulocyte and eosinophilic granulocyte converging in the air flue, thereby alleviates respiratory disorder.
Because at present treatment COPD Drug therapy lacks breakthrough always, be proved without any medicine now and can stop progression of disease or reduce mortality.Roflumilast is as a kind of anti-inflammatory drug, the pulmonary function of patients of severe COPD in can effectively improving, it is as the supplement therapy of bronchodilator, be used for following frequent outbreak the chronic bronchitis history the COPD adult patient keep treatment, can improve to a certain extent Quality of Life, clinical safety is effective.Roflumilast provides new selection for the COPD patient of doctor and different ill characteristics, farthest satisfies the needs to asthma and chronic obstructive pulmonary disease treatment.
Application number is that the derivant that PDE4 inhibitor and BH4 or BH4 have been described in the invention of CN200680014828.6 is united be used to the purposes that prevents and/or treats respiratory disorder, in an embodiment prescription and the preparation technology of relevant roflumilast tablet, the bed spray that adopt dry more, flour mill carries out the mode of micronizing control roflumilast particle diameter, improve the bioavailability of its preparation, the industrialized implementation cost is high, and equipment requirements is high, is difficult for implementing industrialization.
Application number is the pharmaceutical preparation that is suitable for local application of CN03812406.8, it comprises active pharmaceutical ingredient and one or more are suitable for pharmaceutical carriers and/or the excipient of topical, wherein said active pharmaceutical ingredient is the salt that is selected from roflumilast, roflumilast, the N-oxide of roflumilast pyridine residue or the chemical compound of its salt, the described pharmaceutical preparation that is suitable for local application is semisolid pharmaceutical formulation, and one of its excipient is Polyethylene Glycol.
The roflumilast medicinal composition that prior art is produced is little owing to its specification, thus high to the production equipment requirement, mostly adopting import equipment, expense is high, is not easy to this project of industrialized implementation.
The inventor is through studying for a long period of time, and unexpected the discovery used special adjuvant, the roflumilast medicinal composition of special process preparation, reliable in quality, dissolution rate is fast, has not only successfully solved roflumilast and has been not easy to Industrialization, and reduce production costs, easy to implement, remarkable in economical benefits.
Summary of the invention
The first purpose of the present invention is to provide a kind of roflumilast medicinal composition, and this roflumilast medicinal composition is to good stability, to improving product yield, reduces cost, realizes industrialization, better is applied to clinically, has more obvious advantage.
The second purpose of the present invention is to provide the preparation method of roflumilast medicinal composition of the present invention, and the method is simple, prepared roflumilast medicinal composition, and steady quality is reliable.
For realizing the first purpose of the present invention, the present invention adopts following technical scheme:
A kind of roflumilast medicinal composition, per 1000 described roflumilast medicinal compositions, its prescription consists of:
Roflumilast 0.5g
Betacyclodextrin 1g
Lactose 10g
Microcrystalline Cellulose 12 70 g
Magnesium stearate 2g
Roflumilast medicinal composition of the present invention is to adopt following method preparation:
1) prepares: with microcrystalline Cellulose 12, lactose, magnesium stearate under 80 ℃ of conditions dry 4 hours, for subsequent use;
2) with betacyclodextrin and the roflumilast of recipe quantity, put in the container, behind the mix homogeneously, be ground to granularity at 80 ± 10um, for subsequent use;
3) with 2) with microcrystalline Cellulose 12, the magnesium stearate mix homogeneously of recipe quantity;
4) tabletting: regulate suitable hardness and sheet heavy, carry out tabletting;
5) packing: adopt aluminium-plastic bubble plate packing machine to pack;
6) warehouse-in.
For realizing the second purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of roflumilast medicinal composition of the present invention, wherein, the method comprises the steps:
1) prepares: with microcrystalline Cellulose 12, lactose, magnesium stearate under 80 ℃ of conditions dry 4 hours, for subsequent use;
2) with betacyclodextrin and the roflumilast of recipe quantity, put in the container, behind the mix homogeneously, be ground to granularity at 80 ± 10um, for subsequent use;
3) with 2) with microcrystalline Cellulose 12, the magnesium stearate mix homogeneously of recipe quantity;
4) tabletting: regulate suitable hardness and sheet heavy, carry out tabletting;
5) packing: adopt aluminium-plastic bubble plate packing machine to pack;
6) warehouse-in.
Below to the more detailed elaboration of the present invention:
One aspect of the present invention provides a kind of roflumilast medicinal composition, per 1000 described roflumilast medicinal compositions, and its prescription consists of:
Roflumilast 0.5g
Betacyclodextrin 1g
Lactose 10g
Microcrystalline Cellulose 12 70 g
Magnesium stearate 2g
The preparation method of roflumilast medicinal composition of the present invention, wherein, the method comprises the steps:
1) prepares: with microcrystalline Cellulose 12, lactose, magnesium stearate under 80 ℃ of conditions dry 4 hours, for subsequent use;
2) with betacyclodextrin and the roflumilast of recipe quantity, put in the container, behind the mix homogeneously, be ground to granularity at 80 ± 10um, for subsequent use;
3) with 2) with microcrystalline Cellulose 12, the magnesium stearate mix homogeneously of recipe quantity;
4) tabletting: regulate suitable hardness and sheet heavy, carry out tabletting;
5) packing: adopt aluminium-plastic bubble plate packing machine to pack;
6) warehouse-in.
Traditional roflumilast medicinal composition, high to the production equipment requirement, the uniformity of dosage units diversity is large, and quality can't guarantee.
Cyclodextrin is starch derivatives, mainly as oral and injection medicine preparation, and the most frequently used is α-, β-, gamma-cyclodextrin has respectively 6,7,8 glucose units.Cyclodextrin is the ring molecule of the cavity by rigid structure and center thereof " tubbiness " or " coniform " that consist of, its size is according to the difference of the type of cyclodextrin and difference, the cavity inner surface is hydrophobicity, and the outside of ring is hydrophilic, this is by due to the arrangement in the polyhydroxylated molecule, this arrangement makes cyclodextrin hold enclosed molecule in the cavity again, forms clathrate.Cyclodextrin can be used to prepare the clathrate of multi-medicament molecule, mainly plays and improves the effect that improves release and bioavailability, and this is attributable to the increase of dissolubility, and the raising of chemistry and physical stability.The clathrate of cyclodextrin also is used for covering the disagreeable taste of active substance and liquid substance is converted into solid material.
It is oral nontoxic that beta-schardinger dextrin-is considered to, so safety when using in solid preparation.
Following Formulation and optimization Test are used for explanation the present invention:
Follow the general preparation principle of tablet, we have designed pre-prescription:
(1) prescription
| Prescription forms | Pre-prescription |
| Roflumilast | 1g |
| Lactose | 60g |
| Pregelatinized Starch | 20g |
| Crospovidone | 20g |
| 5% polyvidone, 50% ethanol solution | In right amount |
| Magnesium stearate | 1g |
(2) preparation method
1) roflumilast is pulverized, sieved, for subsequent use; With lactose, crospovidone, pregelatinized Starch, magnesium stearate is sieved respectively, and is for subsequent use;
2) take by weighing supplementary material by recipe quantity respectively, for subsequent use;
3) getting the mix homogeneously supplementary material adopts 5% polyvidone, 50% alcoholic solution to granulate 50 ℃ of dryings, 20 with 20 eye mesh screens
The eye mesh screen granulate;
4) adjust the loading amount tabletting according to content.
To write out a prescription in advance and carry out stripping curve mensuration:
| Time | 5min | 10min | 30min | 45min |
| Pre-prescription | 8.5% | 15.7% | 25.8% | 45.8% |
Shown by above result of the test: the stripping of said preparation prescription did not reach maximum stripping in 45 minutes, and we consider that adjusting process and prescription further screen:
| Prescription forms | 1 | 2 | 3 |
| Roflumilast | 0.5g | 0.25g | 1g |
| Betacyclodextrin | 1g | 0.5g | 2g |
| Lactose | 10g | 5g | 20g |
| Microcrystalline Cellulose 12 | 70g | 70g | 140g |
| Magnesium stearate | 2g | 2g | 2g |
Technique:
1) prepares: with microcrystalline Cellulose 12, lactose, magnesium stearate under 80 ℃ of conditions dry 4 hours, for subsequent use;
2) with betacyclodextrin and the roflumilast of recipe quantity, put in the container, behind the mix homogeneously, be ground to granularity at 80 ± 10um, for subsequent use;
3) with 2) with microcrystalline Cellulose 12, the magnesium stearate mix homogeneously of recipe quantity;
4) tabletting: regulate suitable hardness and sheet heavy, carry out tabletting;
5) packing: adopt aluminium-plastic bubble plate packing machine to pack;
6) warehouse-in.
Result of the test shows, the prescription of prescription 1-prescription 3 usefulness clathrate process preparation without the sticking problem, obtains good outward appearance and hardness, and dissolution is determined best prescription and technique also all near 100%.
The inventor is through a large amount of experimental study discoveries, and when roflumilast medicinal composition was above-mentioned prescription and preparation technology, described pharmaceutical composition uniformity of dosage units diversity was little, and quality is effectively guaranteed.
Compared with prior art, the present invention has following advantage:
1) new roflumilast compositions provided by the present invention has thoroughly solved in the roflumilast production process uniformity of dosage units problem that differs greatly.
2) roflumilast medicinal composition provided by the present invention is for the yield that improves this product, reduction production cost, and better being applied to clinical treatment has very large help.
3) new roflumilast compositions provided by the present invention proves constant product quality, through pharmacology, toxicological test through industrialized great production and study on the stability, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body without injury.
4) preparation method of new roflumilast compositions provided by the present invention, the method is simple, prepared roflumilast medicinal composition reliable in quality.
5) new roflumilast compositions provided by the present invention, stripping is fast, has higher bioavailability, and reaching rapidly needs concentration.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail
Embodiment 1
Per 1000 described roflumilast medicinal compositions, its prescription consists of:
Roflumilast 0.5g
Betacyclodextrin 1g
Lactose 10g
Microcrystalline Cellulose 12 70 g
Magnesium stearate 2g
Preparation technology:
1) prepares: with microcrystalline Cellulose 12, lactose, magnesium stearate under 80 ℃ of conditions dry 4 hours, for subsequent use;
2) with betacyclodextrin and the roflumilast of recipe quantity, put in the container, behind the mix homogeneously, be ground to granularity at 80 ± 10um, for subsequent use;
3) with 2) with microcrystalline Cellulose 12, the magnesium stearate mix homogeneously of recipe quantity;
4) tabletting: regulate suitable hardness and sheet heavy, carry out tabletting;
5) packing: adopt aluminium-plastic bubble plate packing machine to pack;
6) warehouse-in.
Embodiment 2
Per 1000 described roflumilast medicinal compositions, its prescription consists of:
Roflumilast 0.25g
Betacyclodextrin 0.5g
Lactose 5g
Microcrystalline Cellulose 12 70 g
Magnesium stearate 2g
Preparation technology: with embodiment 1.
Embodiment 3
Per 1000 described roflumilast medicinal compositions, its prescription consists of:
Roflumilast 1g
Betacyclodextrin 2g
Lactose 20g
Microcrystalline Cellulose 12 140 g
Magnesium stearate 2g
Preparation technology: with embodiment 1.
Comparing embodiment 1
CN200680014828.6 patent working example 4
The production of roflumilast Formulation
A) based on the weight of the tablet that contains the 0.125mg roflumilast
1. roflumilast 0.125mg
2. lactose monohydrate 49.660mg
3. corn starch 13.390mg
4.polyvidoneK90 1.300mg
5. magnesium stearate (plant) 0.650mg
65.125mg altogether
Produce: mix with the part of (3) (1), and produce trituration in planetary flour mill.This trituration concentrates in the product container of fluid bed granulation system with the remainder of (2) and (3), and the granulation solution (in purified water) of 5% (4) sprays under suitable condition and drying.(5) are joined in this granule, and be compressed in the tablet forcing press at the mixture that mixing obtains afterwards and have the tablet that average weight is 65.125mg.
B) based on the weight of the tablet that contains the 0.25mg roflumilast
1. roflumilast 0.250mg
2. microcrystalline Cellulose 33.900mg
3. corn starch 2.500mg
4.polyvidoneK90 2.250mg
5. carboxymethyl starch sodium (A type) 20.000mg
6. magnesium stearate (plant) 0.600mg
59.500mg altogether
Produce: mix with the part of (3) (1), and produce trituration in planetary flour mill.This trituration concentrates in the product container of fluid bed granulation system with the remainder of (2), (5) and (3), and the granulation solution (in purified water) of 5% (4) sprays under suitable condition and drying.(6) are joined in this granule, and be compressed in the tablet forcing press at the mixture that mixing obtains afterwards and have the tablet that average weight is 59.5mg.
C) based on the weight of the tablet that contains the 0.5mg roflumilast
1. roflumilast (micronization) 0.500mg
2. lactose monohydrate 49.660mg
3. corn starch 13.390mg
4.polyvidoneK90 1.300mg
5. magnesium stearate (plant) 0.650mg
65.500mg altogether
The granulation solution (in pure water) of (4) of preparation 5%.(1) is suspended in this solution.(2) be filled in the product container of fluid bed granulation system with (3).This suspension sprays under suitable condition and is dry.(5) are added in this granule, and the mixture that obtains after mixing is compressed in the tablet forcing press and has the tablet that average weight is 65.5mg.
Test example 1
This test example is to investigate the stability of roflumilast compositions provided by the present invention.
The accelerated test of roflumilast medicinal composition
Method according to the embodiment of the invention 1 prepares three batches of roflumilast medicinal compositions (lot number is respectively 1005001,1005002,1005003) according to commercially available back, at 40 ℃ ± 2 ℃, the condition of RH75% ± 5% was placed 6 months, during this time respectively at sampling in the 1st, 2,3,6 month, detect according to stable inspection item, and compare with 0 day data.
1, investigation project
High spot reviews: character, related substance and content.
2, accelerated test result
Above conclusion (of pressure testing) can be found out: this product is placed 6 months every detection indexs and was compared no significant difference, good stability with 0 month under the accelerated test condition.
Comparative test example 1
Comparative test example 1-b, comparative test example 1-c and embodiment 1 are placed respectively the calorstat 10 days of the illumination of 4500LX ± 500LX, 60 ℃ ± 2 ℃ of high temperature, respectively at 0 day, 10 days its character, related substance, content are checked.The results are shown in following table:
According to result of the test as can be known, embodiment 1 and comparative test example 1-b, comparative test example 1-c placed 10 days in the calorstat of the illumination of 4500LX ± 500LX, 60 ℃ ± 2 ℃ of high temperature, embodiment 1 is under different condition, each check item has no significant change, dissolution rate shows that embodiment 1 quality is better than comparative test example 1-b, comparative test example 1-c, has higher bioavailability.
Claims (7)
1. a roflumilast medicinal composition is comprised of roflumilast, betacyclodextrin, lactose, microcrystalline Cellulose 12, magnesium stearate, it is characterized in that, wherein roflumilast: betacyclodextrin: the weight ratio of lactose is 1:2:20.
2. pharmaceutical composition according to claim 1 is characterized in that, the weight range of described roflumilast is selected from every and contains roflumilast 0.25mg, 0.5mg, 1mg.
3. each described pharmaceutical composition is characterized in that according to claim 1-2, its described roflumilast medicinal composition, and per 1000 its prescriptions consist of:
Roflumilast 0.25-1g
Betacyclodextrin 0.5-2g
Lactose 5-20g
Microcrystalline Cellulose 12 70-140g
Magnesium stearate 2g.
4. pharmaceutical composition according to claim 3 is characterized in that, its described roflumilast medicinal composition, and per 1000 its prescriptions consist of:
Roflumilast 0.5g
Betacyclodextrin 1g
Lactose 10g
Microcrystalline Cellulose 12 70 g
Magnesium stearate 2g.
5. pharmaceutical composition according to claim 3 is characterized in that, its described roflumilast medicinal composition, and per 1000 its prescriptions consist of:
Roflumilast 0.25g
Betacyclodextrin 0.5g
Lactose 5g
Microcrystalline Cellulose 12 70 g
Magnesium stearate 2g.
6. pharmaceutical composition according to claim 3 is characterized in that, its described roflumilast medicinal composition, and per 1000 its prescriptions consist of:
Roflumilast 1g
Betacyclodextrin 2g
Lactose 20g
Microcrystalline Cellulose 12 140 g
Magnesium stearate 2g.
7. the preparation method of roflumilast medicinal composition according to claim 1 is characterized in that, the method comprises the steps:
1)Prepare: with microcrystalline Cellulose 12, lactose, magnesium stearate under 80 ℃ of conditions dry 4 hours, for subsequent use;
2)With betacyclodextrin and the roflumilast of recipe quantity, put in the container, behind the mix homogeneously, be ground to granularity at 80 ± 10um, for subsequent use;
3)With 2) with microcrystalline Cellulose 12, the magnesium stearate mix homogeneously of recipe quantity;
4)Tabletting: regulate suitable hardness and sheet heavy, carry out tabletting;
5)Packing: adopt aluminium-plastic bubble plate packing machine to pack;
6)Warehouse-in.
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| CN104644635A (en) * | 2013-11-25 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Vortioxetine pharmaceutical composition 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1635909A (en) * | 2002-02-20 | 2005-07-06 | 奥坦纳医药公司 | Oral dosage form comprising a PDE4 inhibitor as active ingredient and polyvinylpyrrolidone as excipient |
| CN101171005A (en) * | 2005-05-11 | 2008-04-30 | 尼科梅德有限责任公司 | Combination of a PDE4 inhibitor roflumilast with a tetrahydrobiopterin derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1635909A (en) * | 2002-02-20 | 2005-07-06 | 奥坦纳医药公司 | Oral dosage form comprising a PDE4 inhibitor as active ingredient and polyvinylpyrrolidone as excipient |
| CN101171005A (en) * | 2005-05-11 | 2008-04-30 | 尼科梅德有限责任公司 | Combination of a PDE4 inhibitor roflumilast with a tetrahydrobiopterin derivative |
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