CN104644564A - Stable granular preparation containing montelukast and preparation method thereof - Google Patents
Stable granular preparation containing montelukast and preparation method thereof Download PDFInfo
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- CN104644564A CN104644564A CN201310598573.4A CN201310598573A CN104644564A CN 104644564 A CN104644564 A CN 104644564A CN 201310598573 A CN201310598573 A CN 201310598573A CN 104644564 A CN104644564 A CN 104644564A
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Abstract
The invention belongs to the technical field of medicines and specifically relates to a stable granular preparation containing montelukast and a preparation method of the preparation. As the montelukast raw material itself is not stable, has high hygroscopicity, is easy to degrade when exposed to light and is easy to cause transfinite related substances, content variation and other problems, environment and condition requirements during the production process are high. By adoption of a granular dosage form and with combination of properties of the montelukast raw materials and preparation characteristics, a prescription of an original research product is optimized, and addition amount and addition time of a diluent, an adhesive and a disintegrating agent are optimized so as to obtain stable montelukast granules. As the drug is mainly used for children, the granular dosage form is easy for children to take. The preparation has high stability and good compliance. The invention also relates to a preparation method of the montelukast granules in the production stage.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of stable Menglusitena granular preparation and preparation method thereof.
Background technology
Asthma comprises by various kinds of cell the chronic airway inflammation disease that the inflammatory cell of air flue and Constituent cell (as eosinophilic granulocyte, mastocyte, T lymphocyte, neutrophilic granulocyte, smooth muscle cell, human airway epithelial cells etc.) and cellular component (cellular elements) participate in.This chronic inflammatory disease causes airway hyperreactivity, the reversible airflow limitation that usual appearance is extensively changeable, and causing the symptoms such as the panting of repeated relapsing, out of breath, uncomfortable in chest or cough, be everlasting night and (or) outbreak in early morning, aggravation, most of patients can spontaneous remission or alleviate through treatment.Acute attack stage, chronic sustained phase and clinical relieving period can be divided into according to clinical manifestation asthma.Asthma in acute attack refer to pant, tachypnea, cough, the symptom such as uncomfortable in chest occur suddenly, or original symptom sharp deterioration, often have dyspnea, be reduced to its feature with expiratory gas flow, often because contact allergen, stimulus object or respiratory tract infection are brought out; The chronic sustained phase refers to weekly equal different frequency and (or) occurs symptom (pant, out of breath, uncomfortable in chest, cough etc.) to some extent; Clinical relieving period means and to disappear through treatment or untreated symptom, sign, and pulmonary function returns to level before acute attack, and maintains more than 3 months.If asthmatic patient occurs that serious acute shows effect, treatment not in time may be fatal.The not good routine work to patient of Asthma control and life all impact, and can cause delaying work, learning by mistake, and movable, limitation of movement, makes quality of life decline, and bring extra financial burden to family and society.
In recent years, in the world, asthma prevalence rises, especially in child with surprising rapidity in world's most area.Prevalence about asthma reports that difference is comparatively large both at home and abroad, but most data shows many areas adds 1 times at 10 ~ 20 years old asthma prevalence, and global childhood asthma prevalence is 3.3% ~ 29.0%, and Adults Asthma prevalence is 1.2% ~ 25.5%.The children asthma disease condition investigation in 0 ~ 14 years old of China city finds, nineteen ninety, prevalence was 0.91%, 2000 annuals add up prevalence up to 1.50%, and rise more than 64.84% between 10 years, above-mentioned statistical data illustrates that the childhood asthma prevalence of China has obvious ascendant trend.Adults in Liaoning province prevalence is 0.90%, with 0.92% of Yunnan Province, Guangdong Province 0.99%, 0.82% survey result in Henan Province all closely, but lacks the epidemiologic data of nationwide Adults Asthma disease condition at present.Find although the research (ISAAC) of childhood asthma and anaphylactic disease is middle internationally, the asthma prevalence of Britain, Australia and New Zealand is the highest, the asthma prevalence of developing country is relatively low, but existing asthma prevalence disease learns survey data display in China, the prevalence of Shanghai City asthmatic children is up to 4.52%, and west of Guangdong Province Yuexi Rural Adult asthma prevalence is also up to 6.0%.
Menglusitena absorbed following oral administration is rapid, and absolute bioavailability is about 70%.In the dosage range of research (≤200mg), the pharmacokinetic curve of Menglusitena linearly.Medicine time and sex are on there are no significant the impact of its pharmacokinetics.
Extracorporeal receptor binding tests result shows, and Menglusitena can be combined by the CysLT1 receptor-specific obtained in guinea pig trachea cell in Guinea pig lung cell, Pulmonis caprae seu ovis cell, mankind dU937 cell and Cavia porcellus body.
Results of pharmacodynamic test display in body, per os, vein or inhalation route give to excite after the Cavia porcellus of bronchoconstriction, Squirrel monkey and sheep Menglusitena through leukotriene D, its symptom obtains specificity and alleviates, and invalid to the broncho-constriction symptoms of the Cavia porcellus that other bronchoconstriction agent excite.
Results of pharmacodynamic test display in body, after peroral route gives the Squirrel monkey Menglusitena exciting the rat of respiration inhibition, the Squirrel monkey of ascaris bronchoconstriction, sheep and anaphylactic bronchoconstriction through monoclonal antibody, its symptom all can obtain remarkable alleviation.
Above-mentioned experimental result confirms, Menglusitena is a kind of potent oral formulations that significantly can improve inflammation of asthma index, CysLT1 receptor is had to affinity and the selectivity of height, its physiological effect that can effectively suppress cysteinyl leukotriene and CysLT1 receptors bind to produce and without any receptor agonist activity.
Menglusitena is developed by MSD Corp., and be current best-selling asthma medications in the world, multinational in the world have list marketing this product, and domestic existing dosage form has Film coated tablets, chewable tablet and granule.Because this medicine is mainly used in preventing chronic asthma, this disease is as the morbidity of a kind of child's height, the use of granule can improve the compliance of child patient, maintain decoction absorb very fast, act on feature rapidly, overcome again decoction face the used time decoct inconvenience, dose greatly, easily mouldly lose the shortcomings such as rotten; Preparation Technology of Granules is suitable for commercial production, and constant product quality; Because its dosage is less, take, carry, preserve, transport all more convenient.
In the face of the asthmatic patient that China is a large amount of, the Menglusitena medicine that existing market is sold can not meet the market demand of expanding day.My company's research worker is through experiment repeatedly, filter out optimum pharmaceutical adjunct, the basis that cost reduces also assures that quality, not only there is the curative effect suitable with import drugs, reasonable price simultaneously, especially be applicable to the child patient needing long-term prescription, provide a kind of selection newly to extensive patients, while meeting the need of market, also benefited extensive patients.
Summary of the invention
A kind of Menglusitena granular preparation provided by the invention, it is characterized in that, wherein containing Menglusitena, mannitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose and magnesium stearate composition, its mannitol is as diluent, hydroxypropyl cellulose and hydroxypropyl methylcellulose are as binding agent, magnesium stearate is as lubricant, and wherein magnesium stearate lubricant adopts additional mode to add in preparation.
Menglusitena granule provided by the invention is made up of Menglusitena, mannitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose and magnesium stearate.
In above-mentioned granule, described mannitol is diluent; Hydroxypropyl cellulose and hydroxypropyl methylcellulose are binding agent; Magnesium stearate is lubricant.
A kind of Menglusitena granule provided by the invention, its diluent mannitol accounts for the 5%-95% of supplementary material gross weight.
A kind of Menglusitena granule provided by the invention, its binding agent hydroxypropyl methylcellulose accounts for the 1%-4% of supplementary material gross weight.
A kind of Menglusitena granule provided by the invention, its binding agent hydroxypropyl cellulose accounts for the 1%-4% of supplementary material gross weight.
A kind of Menglusitena granule provided by the invention, its magnesium stearate lubricant accounts for the 0.25%-5% of supplementary material gross weight, and adopts additional mode to add in preparation.
Prescription adopts the adjuvants such as mannitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose and magnesium stearate; Mixed homogeneously with mannitol by the Menglusitena of recipe quantity, with 5% hydroxypropyl methylcellulose aqueous solution for adhesive, wet granulation, mixes after particle drying with magnesium stearate, to obtain final product.With mobility of particle, melting, granularity and stripping quantity for index, according to result of the test, the suitably each supplementary product consumption of adjustment, makes final prescription obtain preparation and former to grind the behavior of medicine release in vitro consistent, and quality is close, its preparation technology has repeatable and amplifies the feasibility of producing.
The pre-prescription of table 1 Menglusitena granule
Preparation technology: supplementary material crosses 80 mesh sieves respectively, get the Menglusitena of 500 bags of amounts, mannitol mixing, be adhesive soft material with 5% hydroxypropyl methylcellulose (60RT5) aqueous solution and 5% hydroxypropyl cellulose (60RT5) aqueous solution, 20 eye mesh screens are granulated, 60 DEG C of dryings 2 hours, dried particles mixes 1 minute and get final product with magnesium stearate.With obtained mobility of particle, granulating situation, moisture and stripping situation for index, investigate prescription compatibility of medicines.
Accompanying drawing explanation
The different adhesive consumption of Fig. 1 Menglusitena granule is on the impact of stripping;
Fig. 2 Menglusitena granule different wetting agent kind is on the impact of stripping.
Detailed description of the invention
embodiment 1
Regulate adhesive, the i.e. consumption of hydroxypropyl methylcellulose and hydroxy methocel, investigate adhesive consumption to the impact of obtained mobility of particle, sample stripping, prescription adjustment is as follows:
The optimization of table 2 Menglusitena granule prescription adhesive consumption
Preparation technology: supplementary material crosses 80 mesh sieves respectively, get the Menglusitena of 100 bags of amounts, mannitol mixing, prescription 2 is adhesive soft material with 3% hydroxypropyl methylcellulose (60RT5) aqueous solution, prescription 3 with 7% hydroxypropyl methylcellulose aqueous solution for adhesive soft material, 20 eye mesh screens are granulated, 60 DEG C of dryings 2 hours, dried particles mixes 1 minute with the magnesium stearate of recipe quantity and get final product.
Result shows, and along with the increase of adhesive consumption, mobility of particle and grain graininess change not quite, and moisture all conforms with the regulations.
Lucifuge operates, with 0.5% sodium dodecyl sulfate solution 900ml for dissolution medium, and rotating speed 50 revs/min, alr mode is paddle method, and investigate the stripping curve of above-mentioned prescription, result of the test is as follows, sees Fig. 1:
The different adhesive consumption of table 3 Menglusitena granule is on the impact of stripping
Result shows, and adhesive consumption increases, and granule stripping is substantially constant, and mobility of particle and grain graininess change not quite, therefore selects adhesive consumption placed in the middle, and namely prescription 1 carries out next step research.
embodiment 2
Usual water and ethanol all can be used as wetting agent, and prescription compatibility of medicines adopts prescription 1, be that wetting agent is granulated respectively, investigate granulating situation and mobility of particle with water, ethanol and 50% ethanol (w/w) solution.Result of the test is as follows:
The optimization of table 4 Menglusitena granule prescription lubricant quantity
Preparation technology: supplementary material crosses 80 mesh sieves respectively, get the Menglusitena of 100 bags of amounts, mannitol mixing, prescription 4 is adhesive soft material with the alcoholic solution of 5% hydroxypropyl methylcellulose (60RT5), prescription 5 is adhesive soft material with 50% ethanol (w/w) solution of 5% hydroxypropyl methylcellulose (60RT5), 20 eye mesh screens are granulated, 60 DEG C of dryings 2 hours, dried particles mixes 1 minute with the magnesium stearate of recipe quantity and get final product.
Result shows, granulates with different wetting agent, grain graininess no significant difference, and better with water granulation mobility of particle, pellet moisture all conforms with the regulations.
Lucifuge operates, with 0.5% sodium dodecyl sulfate solution 900ml for dissolution medium, and rotating speed 50 revs/min, alr mode is paddle method, and investigate the stripping curve of above-mentioned prescription, result of the test is as follows, sees Fig. 2:
The stripping curve of table 5 different wetting agent kind compares
Result of the test shows, different wetting agent on grain graininess and stripping substantially without affecting, but with water granulation mobility of particle better, therefore use prescription 1 as final prescription.
Claims (5)
1. a Menglusitena granule, it is characterized in that, wherein containing Menglusitena, mannitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose and magnesium stearate composition, its mannitol is as diluent, hydroxypropyl cellulose and hydroxypropyl methylcellulose are as binding agent, magnesium stearate is as lubricant, and wherein magnesium stearate lubricant adopts additional mode to add in preparation.
2. a kind of Menglusitena granule as claimed in claim 1, it is characterized in that, diluent mannitol accounts for the 5%-95% of supplementary material gross weight.
3. a kind of Menglusitena granule as claimed in claim 1, it is characterized in that, binding agent hydroxypropyl methylcellulose accounts for the 1%-4% of supplementary material gross weight.
4. a kind of Menglusitena granule as claimed in claim 1, it is characterized in that, binding agent hyprolose accounts for the 1%-4% of supplementary material gross weight.
5. a kind of Menglusitena granule as claimed in claim 1, it is characterized in that, magnesium stearate lubricant accounts for the 0.25%-5% of supplementary material gross weight, and adopts additional mode to add in preparation.
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| CN201310598573.4A CN104644564A (en) | 2013-11-25 | 2013-11-25 | Stable granular preparation containing montelukast and preparation method thereof |
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| CN201310598573.4A CN104644564A (en) | 2013-11-25 | 2013-11-25 | Stable granular preparation containing montelukast and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193743A (en) * | 2015-11-05 | 2015-12-30 | 石家庄市华新药业有限责任公司 | Montelukast sodium granular preparation and preparation method thereof |
| CN107595783A (en) * | 2017-06-01 | 2018-01-19 | 合肥远志医药科技开发有限公司 | A kind of Menglusitena particle and preparation method thereof |
| CN111110679A (en) * | 2018-10-31 | 2020-05-08 | 长春海悦药业股份有限公司 | Pharmaceutical composition containing montelukast sodium |
| CN111249238A (en) * | 2020-01-19 | 2020-06-09 | 安徽省先锋制药有限公司 | Preparation method of montelukast sodium granules |
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| CN1575163A (en) * | 2001-10-26 | 2005-02-02 | 麦克弗罗斯特(加拿大)公司 | Granule formulation |
| CN1813686A (en) * | 2005-12-08 | 2006-08-09 | 苏州东瑞制药有限公司 | Montelukast oral disintegrating tablet formulation and its preparing method |
| CN1961867A (en) * | 2006-11-16 | 2007-05-16 | 徐英权 | Granule formulation of montelukast sodium |
| WO2007077135A1 (en) * | 2005-12-30 | 2007-07-12 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition containing montelukast |
| CN103239450A (en) * | 2012-02-07 | 2013-08-14 | 齐鲁制药有限公司 | Rapidly-dissolving and stabile montelukast oral solid preparation and preparation method thereof |
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2013
- 2013-11-25 CN CN201310598573.4A patent/CN104644564A/en active Pending
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| CN1575163A (en) * | 2001-10-26 | 2005-02-02 | 麦克弗罗斯特(加拿大)公司 | Granule formulation |
| CN1813686A (en) * | 2005-12-08 | 2006-08-09 | 苏州东瑞制药有限公司 | Montelukast oral disintegrating tablet formulation and its preparing method |
| WO2007077135A1 (en) * | 2005-12-30 | 2007-07-12 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition containing montelukast |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193743A (en) * | 2015-11-05 | 2015-12-30 | 石家庄市华新药业有限责任公司 | Montelukast sodium granular preparation and preparation method thereof |
| CN105193743B (en) * | 2015-11-05 | 2018-05-08 | 石家庄市华新药业有限责任公司 | A kind of Montelukast Sodium granular preparation and preparation method thereof |
| CN107595783A (en) * | 2017-06-01 | 2018-01-19 | 合肥远志医药科技开发有限公司 | A kind of Menglusitena particle and preparation method thereof |
| CN111110679A (en) * | 2018-10-31 | 2020-05-08 | 长春海悦药业股份有限公司 | Pharmaceutical composition containing montelukast sodium |
| CN111249238A (en) * | 2020-01-19 | 2020-06-09 | 安徽省先锋制药有限公司 | Preparation method of montelukast sodium granules |
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Application publication date: 20150527 |