CN104546831A - Medicine composition containing apremilast - Google Patents
Medicine composition containing apremilast Download PDFInfo
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- CN104546831A CN104546831A CN201410839155.4A CN201410839155A CN104546831A CN 104546831 A CN104546831 A CN 104546831A CN 201410839155 A CN201410839155 A CN 201410839155A CN 104546831 A CN104546831 A CN 104546831A
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- cyclodextrin
- apremilast
- pharmaceutical composition
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Abstract
The invention relates to medicine composition containing apremilast. The composition comprises apremilast and cyclodextrin or a cyclodextrin derivative. An inclusion complex is prepared from apremilast and cyclodextrin or the cyclodextrin derivative, so that the dissolving performance of apremilast is improved, and the product stability is improved.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of pharmaceutical composition containing Apremilast.
Background technology
Apremilast (apremilast), chemistry S-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-diketone by name, its chemical structural formula is:
Apremilast obtains U.S. FDA approval listing on March 25th, 2014, and commodity are called Otezla, are used for the treatment of psoriasis and psoriatic arthritis.
Due to the poorly water-soluble of Apremilast, the approximate saturation solubility in water is less than 0.03mg/ml.Therefore there is following problems in its formulation properties: (a) stripping in the medium not using surfactant is slow, cannot stripping completely; B () has the tendency that stripping postpones; (c) poor stability etc.Research has been had to attempt to increase dissolubility and the bioavailability of Apremilast.WO2013119607A2 reports the Apremilast pharmaceutical preparation of modifying excipient containing slow release.CN103442698A has prepared the controlled release oral dosage form of Apremilast, improves the bioavailability of insoluble drug by increasing medicine release time in the gastrointestinal tract.
As phosphodiesterase (PDE4) the inhibitor class new small molecule oral medicine of first granted listing, the application prospect of Apremilast is good.Known Apremilast is disclosed in TNF alpha levels unknown in the reduction mammal in US Patent No. 6011050A, suppresses the medicine of the PED4 in mammal.Chinese patent CN 100427085C and CN1965823B also individually discloses it and may be used for treatment asthma, chronic obstructive pulmonary disease and rheumatoid arthritis, psoriasis etc. by suppressing PDE4.
Summary of the invention
The object of this invention is to provide a kind of dissolubility good, stable Apremilast pharmaceutical composition.The present invention, by Apremilast and cyclodextrin or cyclodextrin derivative are prepared into clathrate and improve the solubility property of Apremilast, improves the stability of product.
The object of the invention is to be achieved through the following technical solutions:
Containing the pharmaceutical composition of Apremilast, Apremilast and cyclodextrin or cyclodextrin derivative, containing Apremilast and cyclodextrin or cyclodextrin derivative, are specifically prepared into clathrate by described pharmaceutical pack.The mol ratio of described Apremilast and cyclodextrin or cyclodextrin derivative is 1:0.01-20, preferred 1:0.1-10, more preferably 1:0.2-5.
Wherein said cyclodextrin or cyclodextrin derivative are be selected from least one in cyclodextrin, hydroxypropyl cyclodextrin, glucityl cyclodextrin, malt-base cyclodextrin and sulphur hydrocarbyl ether cyclodextrin and salt thereof.
Preferably, described cyclodextrin or cyclodextrin derivative are β
-cyclodextrin or hydroxypropyl
-beta-schardinger dextrin-.
Containing the pharmaceutical composition of Apremilast, it also comprises the acceptable material of pharmacy be selected from diluent, disintegrating agent, binding agent, fluidizer and lubricant.
Pharmaceutical composition containing Apremilast of the present invention can be used for various types of oral drugs.Various types of medicine is tablet, capsule, granule and dry suspension.
Cyclodextrin of the present invention or cyclodextrin derivative and active component Apremilast can be buied by business.
The preparation of Apremilast and cyclodextrin or cyclodextrin derivant clathrate can prepare (Shandong journal of Chinese medicine by known method, 2000,19(4): 241-243), as saturated water solution method (recrystallization or the sedimentation method), supercritical ultrasonics technology, polishing, freeze-drying and spray drying method.
Accompanying drawing explanation
Fig. 1 carries out the Apremilast tablet of cyclodextrin or cyclodextrin derivative enclose and the In Vitro Dissolution result of the test schematic diagram of Apremilast reference sheet.
Detailed description of the invention
The present invention explains in more detail can with reference to the following example.These embodiments do not limit the present invention.
Embodiment 1
By Apremilast (5g) and β
-cyclodextrin (25g) adds in water (400ml), uses high-shear emulsion machine (10000rpm) to mix 2 hours under 60 DEG C of insulations, filters the pharmaceutical composition that rear 60 DEG C of dry removing moisture obtain containing Apremilast.
Embodiment 2
By Apremilast (2g) and hydroxypropyl
-beta-schardinger dextrin-(15g) adds in water (100ml), ultrasonic disperse 1 hour, and the isolated by filtration supernatant also uses vacuum freeze-drying to obtain containing the pharmaceutical composition of Apremilast.
Embodiment 3: the preparation of tablet
Tablet formulation form, every 50 composed as follows:
| Component | Percentage ratio |
| Apremilast/β -Cyclodextrin clathrate | 24.0% |
| Lactose monohydrate | 50.5% |
| Microcrystalline Cellulose | 20.0% |
| Cross-linking sodium carboxymethyl cellulose | 2.0% |
| Polyvinylpyrrolidone | 3.0% |
| Purified water | / |
| Magnesium stearate | 0.5% |
Preparation technology: the Apremilast that 3.595g embodiment 1 is prepared and β
-cyclodextrin clathrate (A Pusite HPLC content 0.4172mg/mg) joins in wet mixing pelletizer, and mixes with lactose monohydrate (7.58g), microcrystalline Cellulose (PH101) (3.0g), cross-linking sodium carboxymethyl cellulose (0.15g), polyvinylpyrrolidone (PVP K30) (0.45g).Add purified water (3.6ml) soft material processed again, 18 orders are granulated.60 DEG C of dry 1-2 hour, add cross-linking sodium carboxymethyl cellulose (0.15g) after 24 mesh sieve granulate and magnesium stearate (0.075g) mix homogeneously obtains granule.300mg granule to be placed in sheet mould (Φ 9mm) and with 6-8KN pressure tabletted, to obtain 50 A Pusite sheets (every sheet is containing 30mg A Pusite).
Embodiment 4: the preparation of tablet
| Component | Percentage ratio |
| Apremilast/hydroxypropyl -β -Cyclodextrin clathrate | 49.3% |
| Lactose monohydrate | 25.2% |
| Microcrystalline Cellulose | 20.0% |
| Cross-linking sodium carboxymethyl cellulose | 2.0% |
| Polyvinylpyrrolidone | 3.0% |
| Purified water | / |
| Magnesium stearate | 0.5% |
Preparation technology: the Apremilast that 7.4g embodiment 2 is prepared and hydroxypropyl
-β
-cyclodextrin clathrate (Apremilast HPLC content 0.2035mg/mg) joins in wet mixing pelletizer, and mixes with lactose monohydrate (3.78g), microcrystalline Cellulose (PH101) (3.0g), cross-linking sodium carboxymethyl cellulose (0.15g), polyvinylpyrrolidone (PVP K30) (0.45g).Add purified water (3.6ml) soft material processed again, 18 orders are granulated.60 DEG C of dry 1-2 hour, add cross-linking sodium carboxymethyl cellulose (0.15g) after 24 mesh sieve granulate and magnesium stearate (0.075g) mix homogeneously obtains granule.300mg granule to be placed in sheet mould (Φ 9mm) and with 6-8KN pressure tabletted, to obtain 50 A Pusite sheets (every sheet is containing 30mg A Pusite).
Test example 1: deliquescent mensuration
Apremilast composition dissolves Apremilast, embodiment 1 and embodiment 2 prepared respectively, in water, is prepared saturated solution, is detected its dissolubility.Result is as shown in table 1.
In table 1 water, approximate saturation solubility compares
| Approximate saturation solubility mg/ml | |
| Do not carry out the Apremilast of cyclodextrin or cyclodextrin derivative enclose | 0.0170 |
| Embodiment 1 | 0.7121 |
| Embodiment 2 | 1.4311 |
As shown in table 1, compared with not carrying out the Apremilast of cyclodextrin or cyclodextrin derivative enclose, add β
-cyclodextrin and hydroxypropyl
-β
-cyclodextrin significantly increases the water solubility of Apremilast.
Test example 2: the mensuration of stability
Comparative example 3, embodiment 4 and Apremilast reference sheet (Otezla
?30mg, lot number F0002A, Celgene company of the U.S.) degradation product HPLC assay result.
Degradation product HPLC content assaying method: according to Chinese Pharmacopoeia two annex XIX C crude drug and the requirement of pharmaceutical preparation stability test guideline, to the Apremilast tablet obtained respectively in embodiment in the present invention 3, embodiment 4 and Apremilast reference sheet (Otezla
?30mg, lot number F0002A, Celgene company of the U.S.), carry out super-humid conditions stability test respectively.Sample exposed placement under the condition of relative humidity 75% sampled after 30 days, measured the total amount of the degradation product of Apremilast in each preparation with HPLC.HPLC analysis condition is as follows:
Chromatographic column: Agilent Eclipse XDB-C18(4.6mm × 250mm, 5 μm)
Column temperature: 30 DEG C
Eluting solvent: methanol: water (containing 0.5% triethylamine, adjusting pH to 2.4 with phosphoric acid)=60:40
The flow of eluting solvent: 1.0ml/min
Detector: UV-detector (determined wavelength: 230nm)
The result of stability test is as shown in table 2.
Table 2 stability test result
| Embodiment 3 | Embodiment 4 | Apremilast reference sheet | |
| Apremilast degradation impurity growing amount (%) | 0.012 | 0.015 | 0.113 |
Above measurement result shows, carries out cyclodextrin or hydroxypropyl
-β
-the Apremilast tablet of cyclodextrin inclusion compound is compared with common Apremilast tablet, and the generation of Apremilast degradation impurity is significantly suppressed.
Test example 3: Their Dissolution Test in vitro
Comparative example 3, embodiment 4 and Apremilast reference sheet (Otezla
?30mg, lot number F0002A, Celgene company of the U.S.) vitro release.
Vitro release assay method: according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods), using 900ml 25mM pH6.8 sodium phosphate buffer as medium, rotating speed is 75 turns per minute, operates in accordance with the law, in 5,10,15,20,30,45,60min samples 10ml, adds isothermal same volume medium in time.Get supernatant after sample centrifugal (15000rpm, 5min), measure the stripping quantity from the Apremilast respective tablet with high performance liquid chromatography (HPLC) analysis.HPLC analysis condition is identical with the condition shown in test example 2.The result of dissolution test is as shown in Fig. 1 and table 3.
Table 3 dissolution test result
Visible, carry out cyclodextrin or hydroxypropyl
-β
-the Apremilast of cyclodextrin inclusion compound can stripping rapidly in the medium not adding surfactant.
As mentioned above, the present invention can increase dissolubility and the dissolution velocity of insoluble drug Apremilast, and the pharmaceutical composition stability containing Apremilast of gained is better.
Claims (8)
1., containing the pharmaceutical composition of Apremilast, described pharmaceutical composition contains Apremilast and cyclodextrin or cyclodextrin derivative.
2. the pharmaceutical composition according to claim 1, wherein, described compositions is that Apremilast and cyclodextrin or cyclodextrin derivative are prepared into clathrate.
3. the pharmaceutical composition according to claim 1, wherein, the mol ratio of described Apremilast and cyclodextrin or cyclodextrin derivative is 1:0.01-20.
4. the pharmaceutical composition according to claim 1, wherein, the mol ratio of described Apremilast and cyclodextrin or cyclodextrin derivative is 1:0.1-10.
5. the pharmaceutical composition according to claim 1, wherein, the mol ratio of described Apremilast and cyclodextrin or cyclodextrin derivative is 1:0.2-5.
6. pharmaceutical composition according to claim 1, wherein said cyclodextrin or cyclodextrin derivative are be selected from least one in cyclodextrin, hydroxypropyl cyclodextrin, glucityl cyclodextrin, malt-base cyclodextrin and sulphur hydrocarbyl ether cyclodextrin and salt thereof.
7. pharmaceutical composition according to claim 6, wherein said cyclodextrin or cyclodextrin derivative are β
-cyclodextrin or hydroxypropyl
-beta-schardinger dextrin-.
8. the pharmaceutical composition according to claim 1-7, it also comprises the acceptable material of pharmacy be selected from diluent, disintegrating agent, binding agent, fluidizer and lubricant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410839155.4A CN104546831A (en) | 2014-12-30 | 2014-12-30 | Medicine composition containing apremilast |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410839155.4A CN104546831A (en) | 2014-12-30 | 2014-12-30 | Medicine composition containing apremilast |
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| Publication Number | Publication Date |
|---|---|
| CN104546831A true CN104546831A (en) | 2015-04-29 |
Family
ID=53064613
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410839155.4A Pending CN104546831A (en) | 2014-12-30 | 2014-12-30 | Medicine composition containing apremilast |
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|---|---|
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105343025A (en) * | 2015-11-08 | 2016-02-24 | 长沙佰顺生物科技有限公司 | Apremilast oral preparation and preparation method thereof |
| CN105919927A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Apremilast oral liquid and preparation method thereof |
| CN105935350A (en) * | 2015-12-18 | 2016-09-14 | 重庆两江药物研发中心有限公司 | Apremilast sustained-release implant and preparation method thereof |
| WO2017076987A1 (en) * | 2015-11-03 | 2017-05-11 | Ratiopharm Gmbh | Composition comprising apremilast in amorphous form |
| CN106667953A (en) * | 2017-02-14 | 2017-05-17 | 佛山市腾瑞医药科技有限公司 | Apremilast soft capsule preparation and preparation process thereof |
| CN106727395A (en) * | 2017-02-15 | 2017-05-31 | 佛山市腾瑞医药科技有限公司 | A kind of Apremilast fast release micropill preparation, preparation method |
| CN106727354A (en) * | 2017-01-02 | 2017-05-31 | 佛山市腾瑞医药科技有限公司 | A kind of Apremilast solid dispersion preparation and preparation method thereof |
| CN106822048A (en) * | 2017-02-16 | 2017-06-13 | 佛山市腾瑞医药科技有限公司 | A kind of microporous barrier controlled release coat Apremilast micropill and preparation method thereof |
| CN107115310A (en) * | 2017-04-12 | 2017-09-01 | 广州艾格生物科技有限公司 | A kind of Apremilast oral solid formulation and preparation method thereof |
| CN107405311A (en) * | 2015-12-24 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | Apremilast sustained release preparation |
| CN108283620A (en) * | 2018-03-13 | 2018-07-17 | 兆科药业（广州）有限公司 | A kind of local medicine composition of inhibitors of phosphodiesterase-4 and preparation method thereof |
| CN113960208A (en) * | 2021-10-28 | 2022-01-21 | 济南良福精合医药科技有限公司 | Method for measuring content of active ingredients in preparation containing apremilast |
-
2014
- 2014-12-30 CN CN201410839155.4A patent/CN104546831A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017076987A1 (en) * | 2015-11-03 | 2017-05-11 | Ratiopharm Gmbh | Composition comprising apremilast in amorphous form |
| CN105343025A (en) * | 2015-11-08 | 2016-02-24 | 长沙佰顺生物科技有限公司 | Apremilast oral preparation and preparation method thereof |
| CN105919927A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Apremilast oral liquid and preparation method thereof |
| CN105935350A (en) * | 2015-12-18 | 2016-09-14 | 重庆两江药物研发中心有限公司 | Apremilast sustained-release implant and preparation method thereof |
| CN105919927B (en) * | 2015-12-18 | 2019-01-22 | 重庆两江药物研发中心有限公司 | A kind of Apremilast oral solution and preparation method thereof |
| CN105935350B (en) * | 2015-12-18 | 2018-11-16 | 重庆两江药物研发中心有限公司 | A kind of Apremilast sustained-release implant and preparation method thereof |
| CN107405311A (en) * | 2015-12-24 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | Apremilast sustained release preparation |
| CN107405311B (en) * | 2015-12-24 | 2021-10-08 | 江苏恒瑞医药股份有限公司 | Apremilast sustained release preparation |
| CN106727354A (en) * | 2017-01-02 | 2017-05-31 | 佛山市腾瑞医药科技有限公司 | A kind of Apremilast solid dispersion preparation and preparation method thereof |
| CN106667953A (en) * | 2017-02-14 | 2017-05-17 | 佛山市腾瑞医药科技有限公司 | Apremilast soft capsule preparation and preparation process thereof |
| CN106727395A (en) * | 2017-02-15 | 2017-05-31 | 佛山市腾瑞医药科技有限公司 | A kind of Apremilast fast release micropill preparation, preparation method |
| CN106822048A (en) * | 2017-02-16 | 2017-06-13 | 佛山市腾瑞医药科技有限公司 | A kind of microporous barrier controlled release coat Apremilast micropill and preparation method thereof |
| CN107115310A (en) * | 2017-04-12 | 2017-09-01 | 广州艾格生物科技有限公司 | A kind of Apremilast oral solid formulation and preparation method thereof |
| CN108283620A (en) * | 2018-03-13 | 2018-07-17 | 兆科药业（广州）有限公司 | A kind of local medicine composition of inhibitors of phosphodiesterase-4 and preparation method thereof |
| CN113960208A (en) * | 2021-10-28 | 2022-01-21 | 济南良福精合医药科技有限公司 | Method for measuring content of active ingredients in preparation containing apremilast |
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Application publication date: 20150429 |