CN103271886B - Pirfenidone tablet and preparation method thereof - Google Patents
Pirfenidone tablet and preparation method thereof Download PDFInfo
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- CN103271886B CN103271886B CN201310208519.4A CN201310208519A CN103271886B CN 103271886 B CN103271886 B CN 103271886B CN 201310208519 A CN201310208519 A CN 201310208519A CN 103271886 B CN103271886 B CN 103271886B
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- pirfenidone
- hydroxypropyl cellulose
- microgranule
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Abstract
The invention discloses a pirfenidone tablet and a preparation method thereof. The pirfenidone tablet is prepared by evenly mixing and tabletting medicine-containing microparticles, a disintegrating agent and a lubricant, wherein the medicine-containing microparticles are prepared by adopting the following method: dissolving pirfenidone and hydroxy propyl cellulose into ethanol, adding the obtained solution into liquid paraffin, carrying out reduced-pressure drying to remove ethanol, separating out the microparticles, and drying to obtain the medicine-containing microparticles. With the prepared medicine-containing microparticles, not only can the drug mobility be greatly improved, the types of auxiliary ingredients can be reduced, and the dissolution rate of the tablet can be better improved.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pirfenidone tablets and preparation method thereof.
Background technology
Pulmonary fibrosis is the disease of a class serious harm human health, and frequently-occurring disease is in the 40-50 women in year, and its main symptom is dyspnea, coughs, breathes hard.Dyspnea is the common sympton of pulmonary fibrosis.During slight pulmonary fibrosis, dyspnea only occurs when aggravating activities, so usually out in the cold or mistaken diagnosis is other diseases.When pulmonary fibrosis makes progress, dyspnea also occurs when tranquillization, and the whole course of disease is the process that carrying out property increases the weight of, mean survival time (MST) is 5-6, separately has minority acute case progress sharply, how dead in 6 months.Treatment to fibrotic disease at present, pay attention to control the risk factor aspect that causes organ dysfunction to worsen more, and be also confined to non-specific property anti-inflammatory agent, immunosuppressant and glucocorticoid etc. for the medicine that suppresses fibrotic processes, the untoward reaction of these medicines is more, and curative effect is also undesirable.The anti-fibrosis medicine of a kind of wide spectrum of pirfenidone (pirfenidone, PFD), by suppressing the synthetic anti-fibrosis effect with wide spectrum of collagen, can prevent and reverse the formation of fibrosis and cicatrix.Pirfenidone is good absorbing effect in vivo, and untoward reaction is low, and the clinical treatment for idiopathic pulmonary fibrosis, has good development prospect.
The Pirfenidone tablet of listing is to be developed by Japanese Shionogi Seiyaku Kabushiki Kaisha at present, its prescription comprises lactose hydrate, carboxymethylcellulose calcium, hyprolose, magnesium stearate, hypromellose, triethyl citrate, titanium dioxide, Pulvis Talci, yellow ferric oxide, and sheet is heavily about 300mg.Because the mobility of pirfenidone raw material itself is poor, while preparing large specification tablet according to this prescription and technique, compressibility and mouldability are all poor, are unfavorable for suitability for industrialized production.In addition, lactose, as a kind of conventional pharmaceutic adjuvant, is applicable to draw moist stronger medicine tabletting, but considers that this product is long term administration, adds lactose likely part lactose intolerance crowd to be brought to untoward reaction.CN102008446A discloses a kind of pirfenidone solid dispersion and contains the preparation of pirfenidone solid dispersion, and carrier is selected with Polyethylene Glycol, poloxamer or polyvinylpyrrolidone, to improve the bioavailability of pirfenidone.But because Polyethylene Glycol, poloxamer fusing point are low, easily cause the sticking problem in preparation production process.
Summary of the invention
In view of the deficiencies in the prior art, the object of the invention is to, by preparation prescription and technique are studied, provides pirfenidone tablets that a kind of compressibility is good and stripping is fast and preparation method thereof.
In order to realize object of the present invention, inventor studies by lot of experiments, has finally obtained following technical scheme:
A kind of pirfenidone tablets, by pastille microgranule and disintegrating agent and lubricant, mixing rear tabletting forms, described pastille microgranule is prepared from as follows: pirfenidone and hydroxypropyl cellulose are dissolved in to ethanol, gained solution adds in liquid paraffin, drying under reduced pressure is removed ethanol, and the microgranule drying of separating out obtains pastille microgranule.
Preferably, above-mentioned pirfenidone tablets, the model of wherein said hydroxypropyl cellulose is HPC-SL and/or HPC-SSL.
Further preferably, above-mentioned pirfenidone tablets, the model of wherein said hydroxypropyl cellulose is HPC-SSL.
Again further preferably, above-mentioned pirfenidone tablets, wherein pirfenidone is 1:0.2-0.6 with the weight consumption ratio of hydroxypropyl cellulose.
Again further preferably, above-mentioned pirfenidone tablets, wherein pirfenidone is 1:4 with the weight consumption ratio of hydroxypropyl cellulose.
Pirfenidone tablets of the present invention, wherein said disintegrating agent is one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose.Described disintegrating agent is preferably cross-linking sodium carboxymethyl cellulose.Described lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, castor oil hydrogenated and sodium stearyl fumarate.
Second object of the present invention is to provide a kind of according to the preparation method of above-mentioned pirfenidone tablets, described pirfenidone tablets preparation method and comprises the steps:
(1) pirfenidone and hydroxypropyl cellulose are dissolved in ethanol by the weight ratio of 1:0.2-0.6;
(2) above-mentioned solution is joined in liquid paraffin, drying under reduced pressure is removed ethanol, and pirfenidone and hydroxypropyl cellulose form microgranule and separate out, and the microgranule of separating out is dry;
(3) dried microgranule and disintegrating agent and mix lubricant are even, tabletting.
Preferably, the preparation method of above-mentioned pirfenidone tablets, wherein said disintegrating agent is one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose; Described lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, castor oil hydrogenated and sodium stearyl fumarate.
For pirfenidone tablets, key is to solve pirfenidone flowability problem.For this reason, the inventor is creatively dissolved in pirfenidone and hydroxypropyl cellulose in ethanol, utilizes the standby medicine carrying microgranule of solvent-nonsolvent legal system significantly to improve the mobility defect of pirfenidone raw material.In addition, in the present invention, do not add any filler, hydroxypropyl cellulose used is both as becoming capsule material, there is again the effect of porogen and binding agent, the medicine carrying microgranule of preparation has not only greatly improved drug flow, reduce the kind of adjuvant, more improved the dissolution of tablet, obtained beyond thought effect.
The specific embodiment
The specific embodiment of form, is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples.
Embodiment 1
Preparation technology:
(1) pirfenidone and HPC SL, SSL are dissolved in ethanol,
(2) above-mentioned solution is joined in liquid paraffin, drying under reduced pressure is removed ethanol, and pirfenidone and hydroxypropyl cellulose form microgranule and separate out, and 60 ℃ of the microgranules of separating out is dry;
(3) dried microgranule is mixed homogeneously with carboxymethyl starch sodium, polyvinylpolypyrrolidone and magnesium stearate, the micropowder silica gel of crossing 100 mesh sieves, and tabletting forms.
Embodiment 2
Preparation technology:
(1) pirfenidone and hydroxypropyl cellulose SSL are dissolved in ethanol,
(2) above-mentioned solution is joined in liquid paraffin, drying under reduced pressure is removed ethanol, and pirfenidone and hydroxypropyl cellulose form microgranule and separate out, and 55 ℃ of the microgranules of separating out is dry;
(3) dried microgranule is mixed homogeneously with polyvinylpolypyrrolidone and the magnesium stearate of crossing 100 mesh sieves, and tabletting forms.Embodiment 3
Preparation technology:
(1) pirfenidone and hydroxypropyl cellulose SSL are dissolved in ethanol,
(2) above-mentioned solution is joined in liquid paraffin, drying under reduced pressure is removed ethanol, and pirfenidone and hydroxypropyl cellulose form microgranule and separate out, and 50 ℃ of the microgranules of separating out is dry;
(3) dried microgranule is mixed homogeneously with cross-linking sodium carboxymethyl cellulose and the magnesium stearate of crossing 100 mesh sieves, and tabletting forms.
Comparative example 1
Preparation technology:
Pirfenidone, hydroxypropyl cellulose SSL, cross-linking sodium carboxymethyl cellulose are all crossed 100 mesh sieves, and recipe quantity takes rear and magnesium stearate mix homogeneously, and tabletting forms.
Comparative example 2
Preparation technology:
Pirfenidone, hydroxypropyl cellulose SSL, cross-linking sodium carboxymethyl cellulose are all crossed 100 mesh sieves, and mix homogeneously, adds appropriate amount of ethanol, granulate, and 20 mesh sieve granulate, 50 ℃ are dry, dried granule and magnesium stearate mix homogeneously, tabletting forms.
Comparative example 3
Preparation technology:
(1) pirfenidone and HPMC E5 are dissolved in ethanol,
(2) above-mentioned solution is joined in liquid paraffin, drying under reduced pressure, removes ethanol, and pirfenidone and hydroxypropyl cellulose form microgranule and separate out, and 50 ℃ of the microgranules of separating out is dry;
(3) dried microgranule is mixed homogeneously with cross-linking sodium carboxymethyl cellulose and the magnesium stearate of crossing 100 mesh sieves, and tabletting forms.
The mensuration of embodiment 4 medicine carrying mobility of particles and Pirfenidone tablet dissolution
1, mobility of particle.Get the powder before embodiment of the present invention 1-3 and comparative example 1-3 tabletting, adopt algoscopy angle of repose, by measuring height (H) and the rear calculating of disc radius (r) of powder layer, tan α=H/r, angle of repose is less, powder fluidity is better, if be less than 30 ° angle of repose, shows that powder fluidity is good; As being greater than 40 ° angle of repose, powder fluidity is poor.Concrete measurement result is in Table 1.
2, dissolution method.Get Pirfenidone tablet sample prepared by embodiment of the present invention 1-3 and comparative example 1-3, adopt the second method in 2010 editions two appendix X C dissolution methods of < < Chinese Pharmacopoeia > >, dissolution medium is that 900mL water, rotating speed are 50r/min, during 10min, sampling and measuring.The results are shown in Table 1.
Table 1 mobility of particle and dissolution determination result
| Embodiment | Angle of repose | Dissolution (%) |
| Embodiment 1 | 18.5° | 96.2 |
| Embodiment 2 | 20.1° | 97.8 |
| Embodiment 3 | 18.3° | 99.4 |
| Comparative example 1 | 65.2° | 90.2 |
| Comparative example 2 | 52.2° | 92.1 |
| Comparative example 3 | 23.5° | 55.2 |
From the experimental result of table 1, can find out: embodiment of the present invention 1-3 gained pastille microgranule is less angle of repose, show that microgranule mobility is better, tablet stripping is simultaneously rapid, the basic stripping completely of 10min; Comparative example 1 is directly by supplementary material mixed pressuring plate, although stripping is good, angle of repose is larger, shows that mobility of particle is poor, is difficult to meet the requirement of tabletting process to granule; Comparative example 2 adopts wet granulation, and stripping is good, but because material forming is poor, angle of repose is larger, and mobility of particle is bad; Comparative example 3 uses hypromellose instead as becoming capsule material, and mobility of particle is good, but because hydroxypropyl emthylcellulose encystation is finer and close, medicine is difficult to Fast Stripping, therefore stripping is slower.
Claims (7)
1. a pirfenidone tablets, it is characterized in that: by pastille microgranule and disintegrating agent and lubricant, mix rear tabletting and form, described pastille microgranule is prepared from as follows: pirfenidone and hydroxypropyl cellulose are dissolved in to ethanol, gained solution adds in liquid paraffin, drying under reduced pressure is removed ethanol, and the microgranule drying of separating out obtains pastille microgranule; Described hydroxypropyl cellulose is HPC-SL and/or HPC-SSL, and the weight ratio of pirfenidone and hydroxypropyl cellulose is 1:0.2-0.6.
2. pirfenidone tablets according to claim 1, is characterized in that: described hydroxypropyl cellulose is HPC-SSL.
3. pirfenidone tablets according to claim 1 and 2, is characterized in that: described disintegrating agent is one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose.
4. pirfenidone tablets according to claim 3, is characterized in that: described disintegrating agent is cross-linking sodium carboxymethyl cellulose.
5. pirfenidone tablets according to claim 1 and 2, is characterized in that: described lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, castor oil hydrogenated and sodium stearyl fumarate.
6. a preparation method for pirfenidone tablets according to claim 1 and 2, is characterized in that comprising the steps:
(1) pirfenidone and hydroxypropyl cellulose are dissolved in ethanol by the weight ratio of 1:0.2-0.6;
(2) above-mentioned solution is joined in liquid paraffin, drying under reduced pressure is removed ethanol, and pirfenidone and hydroxypropyl cellulose form microgranule and separate out, and the microgranule of separating out is dry;
(3) dried microgranule and disintegrating agent and mix lubricant are even, tabletting.
7. the preparation method of pirfenidone tablets according to claim 6, is characterized in that: described disintegrating agent is one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose; Described lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, castor oil hydrogenated and sodium stearyl fumarate.
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| CN201310208519.4A CN103271886B (en) | 2013-05-29 | 2013-05-29 | Pirfenidone tablet and preparation method thereof |
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| CA2937365C (en) | 2016-03-29 | 2018-09-18 | F. Hoffmann-La Roche Ag | Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same |
| KR20180100869A (en) * | 2017-03-02 | 2018-09-12 | 영진약품 주식회사 | Pharmaceutical composition of particle size controlled pirfenidone with improved compressibility and method for preparing the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008446A (en) * | 2010-12-22 | 2011-04-13 | 北京凯因科技股份有限公司 | Pirfenidone solid dispersion and preparation thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008446A (en) * | 2010-12-22 | 2011-04-13 | 北京凯因科技股份有限公司 | Pirfenidone solid dispersion and preparation thereof |
Non-Patent Citations (2)
| Title |
|---|
| 固体分散技术在药剂学中的研究进展;张惠平等;《中国药学杂志》;20070630;第42卷(第11期);第808页第1.1栏 * |
| 张惠平等.固体分散技术在药剂学中的研究进展.《中国药学杂志》.2007,第42卷(第11期),第808页第1.1栏. |
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