CN102988297A - Roflumilast solid dispersion and medicinal composition containing same - Google Patents
Roflumilast solid dispersion and medicinal composition containing same Download PDFInfo
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- CN102988297A CN102988297A CN2012105643249A CN201210564324A CN102988297A CN 102988297 A CN102988297 A CN 102988297A CN 2012105643249 A CN2012105643249 A CN 2012105643249A CN 201210564324 A CN201210564324 A CN 201210564324A CN 102988297 A CN102988297 A CN 102988297A
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Abstract
The invention discloses a roflumilast solid dispersion and a medicinal composition containing the same. The roflumilast solid dispersion comprises (1) roflumilast, (2) one or several of crosslinked polyvinylpyrrolidone, lactose, polyethylene glycol and microcrystalline cellulose, and (3) sodium dodecyl sulfate. The medicinal composition comprises the roflumilast solid dispersion and a pharmaceutically acceptable carrier. By preparing roflumilast into a solid dispersion, the solubility of a medicine is improved, the dissolution speed of the medicine is increased, and the dissolution rate of a medicinal composition containing the roflumilast solid dispersion in a dissolution medium is greatly improved; and in a grinding process, premixing of the medicine and some accessories is realized, and the problem in the content uniformity of a small dose of preparation is greatly reduced.
Description
Technical field
The present invention relates to a kind of roflumilast solid dispersion and contain its pharmaceutical composition, belong to field of medicaments.
Background technology
Chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD) be a kind of fatal pneumonopathy that hinders eupnea, the whole world estimates at 2.1 hundred million people's suffering from copd, there were 3,000,000 people of surpassing to die from COPD in 2005, be equivalent to 5% of then all death of the whole world, 90% COPD death nearly occurs in low income and middle income country.According to World Health Organization's prediction, will become the third-largest cause of the death in the whole world to the year two thousand thirty COPD.COPD is because its number of patients is many, and mortality rate is high, and social economical burden is heavy, has become an important public health problem.
The medicine that is used for the treatment of clinically COPD mainly contains bronchodilators and 17-hydroxy-11-dehydrocorticosterone etc., and roflumilast is under the jurisdiction of bronchodilators, but mechanism of action is all different from other bronchodilators, at effectiveness and safety significant advantage and characteristics is arranged.Roflumilast (English name: Roflumilast), be 1993 by the medicine of the treatment chronic obstructive pulmonary disease of Altana Pharma company research and development, be a kind of PED4 inhibitor, the at present former tablet that grinds is in European Union and U.S.'s approval listing.
The chemical constitution that depends on roflumilast, the roflumilast dissolubility in water is very low, belong to extremely difficult dissolved substance, and the medicine indissoluble will affect medicine release in vivo, just has inevitably the bioavailability problem.For the medicine of indissoluble in water, be difficult to directly produce suitable preparation.
Patent CN 1635909B disclose take the PDE4 inhibitor as active component and polyvinylpyrrolidone as the peroral dosage form of excipient; in an embodiment prescription and the preparation technology of relevant roflumilast tablet; adopt first with after active component and the partial supplementary material grinding more; adding other adjuvant carries out fluidized-bed spray granulation or active component and partial supplementary material is formed spray granulation behind the suspension again; improve the preparation dissolution rate; process is comparatively complicated; equipment requirements is higher, is unfavorable for the reduction of industrialization cost.
Patent CN102274222A discloses roflumilast medicinal composition of high bioavailability and preparation method thereof, roflumilast medicinal composition mainly is comprised of roflumilast and betacyclodextrin, lactose, microcrystalline Cellulose, grinds by roflumilast and betacyclodextrin to form clathrate and increase the roflumilast dissolution rate.
Solid dispersion refers to a kind of disperse system that exists with solid form that the medicine high degree of dispersion is formed in solid carrier.Little and the high degree of dispersion of medicine particle diameter in carrier, be mainly used in accelerating and increasing the stripping of insoluble drug, improve its bioavailability, the preparation method of solid dispersion is divided into fusion method, solvent method, melting-solvent method, solvent spray seasoning, polishing etc. usually.The fusion method preparation is complicated, suitability for industrialized production is relatively more difficult at present, solvent method contains organic solvent usually, be difficult to remove residual and the difficult control of production process safety, melting-solvent method more is difficult to realize, spray drying method is higher to equipment requirements, with an organic solvent then needs explosion precaution, has made aqueous solvent then to drug solubility certain requirement be arranged.
Analyze from the preparation method of solid dispersion, be the physical arrangement that fusion method, solvent method or polishing have all changed medicine, be generally molecule, amorphous or microstructure etc., from thermodynamics, these states all are unsettled, and the trend that is converted into stable drug crystallization is arranged.Solid dispersion reassemble crystallization or crystallization alligatoring, hardness of drug molecule or crystallite occurs and becomes the situation such as large, drug dissolution reduction and be called as aging after placement after a while.It is generally acknowledged the aging relevant with many-sided factors such as pharmaceutical properties, carrier and preparation methoies of solid dispersion.Problem of aging is to need the major issue that solves in solid dispersion and the preparation R﹠D process.
Summary of the invention
The purpose of this invention is to provide a kind of solid dispersion of roflumilast and contain the pharmaceutical composition of this solid dispersion.
Described roflumilast solid dispersion comprises: (1) roflumilast; (2) one or more in crospolyvinylpyrrolidone, lactose, Polyethylene Glycol, the microcrystalline Cellulose; (3) sodium lauryl sulphate.
Preferably, described roflumilast solid dispersion comprises roflumilast, Polyethylene Glycol and sodium lauryl sulphate.
Described Polyethylene Glycol is selected from Macrogol 4000, polyethylene glycol 6000, PEG 8000, Polyethylene Glycol 12000, PEG 20000 and composition thereof, preferred Macrogol 4000, polyethylene glycol 6000, PEG 8000 or its mixture.
In the described solid dispersion, the content of roflumilast is measured the excessive formation that then may affect solid dispersion, thereby is affected solubilizing effect for forming the amount of solid dispersion, and preferred amount is the 0.1%-20%(percentage by weight).
Preferably, in the described solid dispersion, the content of sodium lauryl sulphate is the 1.5%-15%(percentage by weight).
The preparation method of described roflumilast solid dispersion is after each composition is mixed, to adopt the polishing preparation.
Find in the research that above-mentioned roflumilast solid dispersion is compared with the physical mixture of same composition, and good solubilizing effect is arranged.The solid dispersion that does not contain component (3) sodium lauryl sulphate, solubilizing effect is suitable with the solid dispersion that contains component (3), but catabiosis has appearred in stability test, dissolution descends obviously, and the adding of component (3) sodium lauryl sulphate has suppressed the aging of solid dispersion effectively.
The present invention also provides the pharmaceutical composition that comprises above-mentioned roflumilast solid dispersion.
Described pharmaceutical composition comprises powder, granule, tablet, capsule, dry suspension etc., and component comprises roflumilast solid dispersion and the conventional adjuvant of preparation.
For example, the composition of powder, granule, tablet, capsule, dry suspension comprises (percentage by weight):
Described roflumilast solid dispersion, 2%-10%;
Starch, 0%-40%, described starch is selected from corn starch, potato starch and wheaten starch, and described starch is pregelatinized Starch or common starch, preferred pregelatinized corn starch;
Microcrystalline Cellulose, 0%-30%;
Saccharide, 50%-70%, described saccharide are selected from glucose, lactose, fructose, sucrose and dextrose and their mixture, and wherein said lactose is lactose monohydrate;
The disintegrating agent low-substituted hydroxypropyl cellulose, 0-10%;
Suspending agent, 0-10% is selected from hypromellose, sodium carboxymethyl cellulose, arabic gum, xanthan gum and methylcellulose, preferred hypromellose;
Lubricant or fluidizer, 0%-1% is selected from stearic acid, magnesium stearate, calcium stearate, Pulvis Talci and colloidal silica, preferred magnesium stearate;
Binding agent or wetting agent are selected from starch slurry and water, preferred water.
The preparation method of described pharmaceutical composition can adopt conventional method, can adopt following process steps such as the preparation of granule, tablet, capsule: 1) take by weighing adjuvant and the above-mentioned solid dispersion of recipe quantity, mix homogeneously; 2) add suitable amount of adhesive soft material processed, oven dry, granulate; 3) directly pack; Or adding lubricant or releasing agent, mixing, tabletting; Or fill capsule.
Beneficial effect of the present invention: by roflumilast is made as solid dispersion, increased the dissolubility of medicine, accelerated the dissolution rate of medicine, preparation dissolution rate in dissolution medium of preparation is improved greatly, and in process of lapping, realize the premixing of medicine and partial supplementary material, greatly reduced the uniformity of dosage units problem of low dose of preparation.
Description of drawings
Fig. 1 is the In Vitro Dissolution curve (n=6) of the solid dispersion that makes of roflumilast and different auxiliary material
Fig. 2 is the stripping curve (n=6) of adjuvant and roflumilast physical mixture and pure roflumilast powder
The specific embodiment
The present invention is described further below in conjunction with embodiment, but do not consist of limiting the scope of the invention.
The preparation of embodiment 1 roflumilast-crospolyvinylpyrrolidone-sodium lauryl sulphate solid dispersion
(1) roflumilast 0.1g(2) crospolyvinylpyrrolidone 0.5g(3) sodium lauryl sulphate 0.1g
Put into after (1) (2) (3) are mixed horizontal planetary formula ball mill (model QM-WX04, Shanghai Chu Bai laboratory equlpment company limited, lower with) in, add 10 of 10mm abrading-balls, 400 rev/mins were ground 1 hour, took out abrasive material and crossed 60 mesh sieves and get final product.
The preparation of embodiment 2 roflumilasts-polyethylene glycol 6000-sodium lauryl sulphate solid dispersion
(1) roflumilast 0.1g (2) polyethylene glycol 6000 1.9g (3) sodium lauryl sulphate 0.1g
(1) (2) (3) mixture is put into planetary ball mill, add 15 of 10mm abrading-balls, 400 rev/mins were ground 1 hour, and the taking-up abrasive material is crossed 60 mesh sieves and be get final product.
The preparation of embodiment 3 roflumilasts-lactose-sodium lauryl sulphate solid dispersion
(1) roflumilast 0.1g (2) lactose 0.9g (3) sodium lauryl sulphate 0.1g
(1) (2) (3) mixture is put into planetary ball mill, add 10 of 10mm abrading-balls, 400 rev/mins were ground 1 hour, and the taking-up abrasive material is crossed 60 mesh sieves and be get final product.
The preparation of embodiment 4 roflumilasts-microcrystalline Cellulose-sodium lauryl sulphate solid dispersion
(1) roflumilast 0.1g (2) microcrystalline Cellulose 4.9g (3) sodium lauryl sulphate 0.1g
(1) (2) (3) mixture is put into planetary ball mill, add 15 of 10mm abrading-balls, 400 rev/mins were ground 2 hours, and the taking-up abrasive material is crossed 60 mesh sieves and be get final product.
The preparation of embodiment 5 roflumilasts-microcrystalline Cellulose-crospolyvinylpyrrolidone-sodium lauryl sulphate solid dispersion
(1) roflumilast 0.1g (2) crospolyvinylpyrrolidone 0.2g (3) Macrogol 4000 2.9g(4) sodium lauryl sulphate 0.1g
(1) (2) (3) (4) mixture is put into planetary ball mill, add 15 of 10mm abrading-balls, 400 rev/mins were ground 2 hours, and the taking-up abrasive material is crossed 60 mesh sieves and be get final product.
Embodiment 6 solid dispersion and physical mixture dissolution are relatively
According to the prescription among the embodiment 1-5, prepare respectively physical mixture, do dissolution relatively with corresponding solid dispersion.
Dissolution determination method: sample thief, according to dissolution method (two appendix XC the second methods of Chinese Pharmacopoeia version in 2010), 900ml adds 0.1% sodium lauryl sulphate as dissolution medium with pH1 hydrochloric acid solution (9 → 1000), measure temperature and be (37 ± 0.5) ℃, rotating speed is that per minute 50 turns, and operates in accordance with the law, respectively at 15 minutes, get respectively solution 10ml in 30 minutes, through 0.45 μ m filtering with microporous membrane, add simultaneously the dissolution medium of equal volume, uniform temp.To measure filtrate an amount of for precision respectively, and according to high performance liquid chromatography (2010 editions two appendix VD of Chinese Pharmacopoeia), the place measures respectively trap at the 210nm wavelength, calculates stripping quantity by external standard method after suitable dilution.
The dissolution curve of gained solid dispersion as shown in Figure 1, the dissolution curve of respective physical mixture is as shown in Figure 2.As can be seen from Figure: the dissolution of solid dispersion is much larger than the dissolution of physical mixture.
The preliminary stripping stability test of embodiment 7 solid dispersion relatively
According to the prescription among the embodiment 1-5, remove the sodium lauryl sulphate that adds, adopt same grinding condition, the preparation solid dispersion is done the stripping stability test relatively with embodiment 1-5 gained sample.
Consider that the Polyethylene Glycol fusing point is lower than 60 ° of C, thus 40 ° of C adopted, 75%RH, setting-out is preliminary over ten days investigates the stability of the above-mentioned solid dispersion stripping of lateral comparison.
Table 1 dissolution comparative result
| Add the sodium lauryl sulphate sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| 0 |
99.10 | 98.12 | 92.64 | 90.32 | 94.50 |
| 10 |
96.33 | 97.02 | 90.08 | 88.91 | 91.47 |
| Remove the sodium lauryl sulphate sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| 0 |
98.53 | 97.48 | 91.83 | 90.99 | 95.29 |
| 10 |
86.33 | 88.02 | 80.08 | 78.91 | 81.47 |
As shown in Table 1, behind the removal sodium lauryl sulphate, the stripping of solid dispersion is not affected substantially, but rapid decline appears in stability, illustrates that sodium lauryl sulphate has mainly played the effect that prevents the solid dispersion stability decreases among prescription.
The preparation of embodiment 8 capsules
Get the solid dispersion of embodiment 4 preparations, be mixed in proportion with following pharmaceutical aids, the preparation capsule:
(1) roflumilast-microcrystalline Cellulose-sodium lauryl sulphate solid dispersion 25.5mg
(2) low-substituted hydroxypropyl cellulose 9mg
(3) lactose 90mg
Amount to 124.5mg
(1) with after evenly mix (2) (3), is granulated granulate after 40 ° of C oven dry, fill capsule after adding an amount of pure water moistening.
The preparation of embodiment 9 granules
Get the solid dispersion of embodiment 3 preparations, be mixed in proportion with following pharmaceutical aids, the preparation granule:
(1) roflumilast-lactose-sodium lauryl sulphate solid dispersion 5.5mg
(2) starch 30mg
(3) lactose 95mg
Amount to 130.5mg
(1) with after evenly mix (2) (3), is granulated packing behind 40 ° of C oven dry granulate after adding an amount of pure water moistening.
The preparation of embodiment 10 tablets
Get the solid dispersion of embodiment 2 preparations, be mixed in proportion with following pharmaceutical aids, the preparation tablet:
(1) roflumilast-polyethylene glycol 6000-sodium lauryl sulphate solid dispersion 10.5mg
(2) starch 35mg
(3) lactose 85mg
(4) magnesium stearate 1.3 mg
Amount to 131.8mg
(1) with after evenly mix (2) (3), is granulated after adding an amount of pure water moistening, add (4) mixings after 40 ° of C oven dry after, tabletting.
The preparation of embodiment 11 powders
Get the solid dispersion of embodiment 3 preparations, cross 120 mesh sieves after pulverizing, be mixed in proportion with following pharmaceutical aids, preparation powder:
(1) roflumilast-lactose-sodium lauryl sulphate solid dispersion 5.5mg
(2) starch 30mg
(3) lactose 95mg
Amount to 130.5mg
With (1) with after evenly mix (2) (3), packing.
The preparation of embodiment 12 dry suspension
Get the solid dispersion of embodiment 1 preparation, be mixed in proportion with following pharmaceutical aids, the preparation dry suspension
(1) roflumilast-crospolyvinylpyrrolidone-sodium lauryl sulphate solid dispersion 3.5mg
(2) starch 30mg
(3) lactose 90mg
(4) hypromellose 5mg
Amount to 128.5mg
(1) with after evenly mix (2) (3) (4), is granulated packing behind 40 ° of C oven dry granulate after adding an amount of pure water moistening.
Similarly, measure the dissolution of embodiment 8-12 gained sample, the result is as follows:
The dissolution comparative result of each embodiment goods of table 2
| Sample | Embodiment 8 | Embodiment 9 | |
Embodiment 11 | Embodiment 12 |
| 15 minutes dissolution rates (%) | 76.63 | 92.50 | 89.25 | 91.85 | 95.89 |
| 30 minutes dissolution rates (%) | 90.21 | 93.04 | 95.26 | 92.14 | 95.86 |
Conclusion: the dissolution rate of goods of the present invention is very fast and stripping is more complete, has realized purpose of the present invention.
Because the roflumilast preparation of selling in the market only has the roflumilast sheet, so we carry out stability relatively with the former tablet that grinds with the self-control tablet.With former sheet (the former sheet information of grinding: 500ug/ sheet roflumilast film-coated tablet of grinding of buying on the market, lot10635066, DAXAS, NYCOMED) and according to embodiment 10 homemade three batches of roflumilast sheet (lot numbers 2012011201,2012011202,2012011203) according to commercially available back, at 40 ° of C, the condition of RH75% was placed 3 months, sampling at the 3rd the end of month, detect the stripping data according to the described dissolution determination method in top, and compare with 0 day data.
Table 3 is former to be ground sheet and compares from film-making 0 day and 90 days stripping data
Conclusion: under the long term high temperature super-humid conditions, formerly grind sheet and from the film-making stripping decline is arranged all, but to grind sheet little than former from the stripping rate of descent of film-making, illustrates from film-making to have advantage aspect stable.
The present invention lays particular emphasis on the dissolubility that makes roflumilast and carrier form solid dispersion and increase medicine.Its major advantage is, the present invention adopts grinding technique, medicine is dispersed in the carrier, not only solved the problem that drug solubility is low, release is slow, but also solved the poor problem of the low dose of formulation content uniformity, conventional mixing can guarantee the uniformity of dosage units of preparation after grinding, simultaneously the good stability of products obtained therefrom.Solid dispersion of the present invention and to contain its pharmaceutical composition manufacturing process simple extremely is conducive to large realization of producing.
Claims (7)
1. a roflumilast solid dispersion is characterized in that comprising: (1) roflumilast; (2) one or more in crospolyvinylpyrrolidone, lactose, Polyethylene Glycol, the microcrystalline Cellulose; (3) sodium lauryl sulphate.
2. roflumilast solid dispersion according to claim 1 is characterized in that adopting the polishing preparation.
3. roflumilast solid dispersion according to claim 1 and 2, the content that it is characterized in that described roflumilast is the 0.1%-20%(percentage by weight).
4. roflumilast solid dispersion according to claim 1 and 2, the content that it is characterized in that described sodium lauryl sulphate is the 1.5%-15%(percentage by weight).
5. roflumilast solid dispersion according to claim 1 and 2 is characterized in that described Polyethylene Glycol is Macrogol 4000, polyethylene glycol 6000, PEG 8000 or its mixture.
6. a pharmaceutical composition is characterized in that it contains each described solid dispersion of claim 1-5 and pharmaceutically acceptable carrier.
7. pharmaceutical composition according to claim 6 is characterized in that described pharmaceutical composition is tablet, capsule, granule, dry suspension or powder.
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Cited By (4)
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| CN103830194A (en) * | 2014-03-11 | 2014-06-04 | 熊妲妮 | Indacaterol solid dispersion and pharmaceutical composition containing same |
| 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 |
| CN105434328A (en) * | 2014-09-01 | 2016-03-30 | 天津药物研究院有限公司 | Roflumilast solid dispersion-containing solid preparation and preparation method thereof |
| CN106176618A (en) * | 2016-09-18 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of Roflumilast solid dispersion preparation and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103830194A (en) * | 2014-03-11 | 2014-06-04 | 熊妲妮 | Indacaterol solid dispersion and pharmaceutical composition containing same |
| CN105434328A (en) * | 2014-09-01 | 2016-03-30 | 天津药物研究院有限公司 | Roflumilast solid dispersion-containing solid preparation 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 |
| CN104473862B (en) * | 2014-11-18 | 2017-09-29 | 北京科莱博医药开发有限责任公司 | A kind of Roflumilast solid dispersion and preparation method thereof and roflumilast preparation |
| CN106176618A (en) * | 2016-09-18 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of Roflumilast solid dispersion preparation and preparation method thereof |
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Application publication date: 20130327 |