CN111249238A - Preparation method of montelukast sodium granules - Google Patents
Preparation method of montelukast sodium granules Download PDFInfo
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- CN111249238A CN111249238A CN202010062432.0A CN202010062432A CN111249238A CN 111249238 A CN111249238 A CN 111249238A CN 202010062432 A CN202010062432 A CN 202010062432A CN 111249238 A CN111249238 A CN 111249238A
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- montelukast sodium
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- preparing
- mannitol
- granules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
Abstract
The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a preparation method of montelukast sodium granules, which comprises the steps of weighing mannitol in a prescription amount, adding the mannitol into a wet granulating machine, sieving the mannitol by a 60-mesh sieve, drying to obtain a granule base material, weighing hydroxypropyl cellulose in the prescription amount, adding deionized water, stirring to dissolve the hydroxypropyl cellulose to prepare a 3.0% adhesive aqueous solution, weighing montelukast sodium in the prescription amount, adding the montelukast sodium into a grinding machine to grind, sieving the montelukast sodium by a 300-mesh sieve to obtain medicinal powder, placing the granule base material processed by S1 on a fluidized bed, spraying the adhesive and the medicinal powder onto the surface of the granule base material by adopting a fluidized bed side spraying technology, drying after spraying to obtain dry granules, adding magnesium stearate into the dry granules, and mixing uniformly to obtain the montelukast. The invention overcomes the defects of the prior art, has short preparation period and lower cost, controls the introduction of unknown impurities in the finished product, ensures the safety of clinical administration and meets the requirements of industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, and particularly belongs to a preparation method of montelukast sodium granules.
Background
Montelukast sodium is an oral selective leukotriene receptor antagonist that specifically inhibits the cysteinyl leukotriene (CysLT1) receptor.
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are mediators of inflammation, released by a variety of cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to the cysteinyl leukotriene (CysLT) receptor. Type I cysteinyl leukotriene (CysLT1) receptors are distributed in the airways of humans (including airway smooth muscle cells and airway macrophages) and other proinflammatory cells (including eosinophils and certain bone marrow stem cells). CysLTs are associated with pathophysiological processes in asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a series of airway responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil aggregation. In allergic rhinitis, both in the immediate and delayed phase reactions following allergen exposure, the nasal mucosa releases CysLTs associated with the symptoms of allergic rhinitis. Intranasal CysLTs challenge increases the symptoms of nasal airway resistance and nasal obstruction. Montelukast sodium can improve the inflammation index of asthma. Montelukast sodium has high affinity and selectivity on CysLT1 receptor, and can effectively inhibit the physiological effect generated by the combination of LTC4, LTD4 and LTE4 and CysLT1 receptor without any receptor agonistic activity.
The montelukast sodium granules are suitable for the prevention and long-term treatment of childhood asthma, including the prevention of daytime and nighttime asthma symptoms, the treatment of aspirin-sensitive asthmatics and the prevention of exercise-induced bronchoconstriction.
The invention patent with the publication number of CN100591329 discloses a method for preparing a montelukast sodium preparation, which is a commonly used method for the existing montelukast sodium preparation, and the method needs to spray a binder on mannitol and then spray the binder, so that the process flow is complex, the preparation period is long, and the operation difficulty is high.
Disclosure of Invention
The invention aims to provide a preparation method of montelukast sodium granules, which overcomes the defects of the prior art, has short preparation period and lower cost, controls the introduction of unknown impurities in a finished product, ensures the safety of clinical administration and meets the requirements of industrial production.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a method for preparing montelukast sodium granules, which comprises the following steps:
s1: granulating, namely weighing mannitol in a prescription amount, adding the mannitol into a wet granulator, sieving with a 60-mesh sieve, and drying to obtain a granular base material for later use;
s2: preparing a binding agent, weighing hydroxypropyl cellulose in a prescription amount, adding deionized water, stirring to dissolve, and preparing a 3.0% binding agent aqueous solution for later use;
s3: preparing medicinal powder, weighing montelukast sodium in a prescription amount, adding the montelukast sodium into a grinder for grinding, and sieving the montelukast sodium with a 300-mesh sieve to obtain medicinal powder for later use;
s4: loading medicine, namely placing the particle base material treated by the S1 on a fluidized bed, spraying an adhesive and medicinal powder on the surface of the particle base material by adopting a fluidized bed side spraying technology, and drying after spraying to obtain dry particles;
s5: and (4) totally mixing, namely adding magnesium stearate into the dry granules, and uniformly mixing to obtain the montelukast sodium granules.
Further, the montelukast sodium particles comprise the following components in parts by weight: 200-260 parts of mannitol, 10-18 parts of hydroxypropyl cellulose, 6-12 parts of montelukast sodium and 5-15 parts of magnesium stearate.
Further, the montelukast sodium particles comprise the following components in parts by weight: 250 parts of mannitol 210-containing material, 12-16 parts of hydroxypropyl cellulose, 7-11 parts of montelukast sodium and 6-14 parts of magnesium stearate.
Further, the montelukast sodium particles comprise the following components in parts by weight: 230 parts of mannitol, 14 parts of hydroxypropyl cellulose, 9 parts of montelukast sodium and 10 parts of magnesium stearate.
Further, the side spraying conditions of the fluidized bed are as follows: the spraying speed is 16-18g/min, and the atomizing pressure is 1.5 multiplied by 105PA, particle base, angle of repose 32.5 °, degree of compression 8%.
Further, the drying in S1 and S4 adopts a vacuum drying oven, the temperature is adjusted to be 80-95 ℃, and the drying time is 30-40 min.
Compared with the prior art, the invention has the following implementation effects:
according to the preparation method of the montelukast sodium granules, the adhesive and the montelukast sodium powder are sprayed on the surfaces of the mannitol granules by utilizing the fluidized bed side spraying technology, the used medicament types are few, the process flow is simple, the preparation period is short, the cost is low, the introduction of unknown impurities in finished products is controlled, the safety of clinical administration is ensured, and the requirement of industrial production is met.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples, and any modification is within the scope of the present invention without departing from the spirit of the present invention.
Example 1
The embodiment provides a method for preparing montelukast sodium granules, which comprises the following steps:
s1: granulating, namely weighing 200g of mannitol, adding into a wet granulator, sieving with a 60-mesh sieve, and drying to obtain a granular base material for later use;
s2: preparing a binding agent, namely weighing 10g of hydroxypropyl cellulose, adding deionized water, stirring to dissolve, and preparing a 3.0% binding agent aqueous solution for later use;
s3: preparing medicinal powder, weighing 6g of montelukast sodium, adding the montelukast sodium into a grinder for grinding, and sieving the montelukast sodium with a 300-mesh sieve to obtain medicinal powder for later use;
s4: loading medicine, namely placing the particle base material treated by the S1 on a fluidized bed, spraying an adhesive and medicinal powder on the surface of the particle base material by adopting a fluidized bed side spraying technology, and drying after spraying to obtain dry particles;
wherein, the conditions of the fluidized bed side spraying are as follows: the spraying speed is 16-18g/min, and the atomizing pressure is 1.5 multiplied by 105PA, angle of repose of the particle substrate is 32.5 degrees, degree of compression is 8%;
s5: and (4) totally mixing, namely adding 5-15g of magnesium stearate into the dry granules, and uniformly mixing to obtain the montelukast sodium granules.
And drying in S1 and S4 in a vacuum drying oven at 80-95 deg.C for 30-40 min.
Example 2
The embodiment provides a method for preparing montelukast sodium granules, which comprises the following steps:
s1: granulating, namely weighing 230g of mannitol, adding into a wet granulator, sieving with a 60-mesh sieve, and drying to obtain a granular base material for later use;
s2: preparing a binding agent, weighing 14g of hydroxypropyl cellulose, adding deionized water, stirring to dissolve, and preparing a 3.0% binding agent aqueous solution for later use;
s3: preparing medicinal powder, weighing 9g of montelukast sodium, adding the montelukast sodium into a grinder for grinding, and sieving the montelukast sodium with a 300-mesh sieve to obtain medicinal powder for later use;
s4: loading medicine, namely placing the particle base material treated by the S1 on a fluidized bed, spraying an adhesive and medicinal powder on the surface of the particle base material by adopting a fluidized bed side spraying technology, and drying after spraying to obtain dry particles;
wherein, the conditions of the fluidized bed side spraying are as follows: the spraying speed is 16-18g/min, and the atomizing pressure is 1.5 multiplied by 105PA, angle of repose of the particle substrate is 32.5 degrees, degree of compression is 8%;
s5: and (4) totally mixing, adding 10g of magnesium stearate into the dry granules, and uniformly mixing to obtain the montelukast sodium granules.
And drying in S1 and S4 in a vacuum drying oven at 80-95 deg.C for 30-40 min.
Example 3
The embodiment provides a method for preparing montelukast sodium granules, which comprises the following steps:
s1: granulating, namely weighing 260g of mannitol, adding into a wet granulator, sieving with a 60-mesh sieve, and drying to obtain a granular base material for later use;
s2: preparing a binding agent, weighing 18g of hydroxypropyl cellulose, adding deionized water, stirring to dissolve, and preparing a 3.0% binding agent aqueous solution for later use;
s3: preparing medicinal powder, weighing 12g of montelukast sodium, adding into a grinder for grinding, and sieving with a 300-mesh sieve to obtain medicinal powder for later use;
s4: loading medicine, namely placing the particle base material treated by the S1 on a fluidized bed, spraying an adhesive and medicinal powder on the surface of the particle base material by adopting a fluidized bed side spraying technology, and drying after spraying to obtain dry particles;
wherein, the conditions of the fluidized bed side spraying are as follows: the spraying speed is 16-18g/min, and the atomizing pressure is 1.5 multiplied by 105PA, angle of repose of the particle substrate is 32.5 degrees, degree of compression is 8%;
s5: and (4) totally mixing, adding 15g of magnesium stearate into the dry granules, and uniformly mixing to obtain the montelukast sodium granules.
And drying in S1 and S4 in a vacuum drying oven at 80-95 deg.C for 30-40 min.
Comparative example 1
The material and preparation process were substantially the same as those of example 3, except that hydroxypropyl cellulose was replaced with hydroxypropylmethyl cellulose.
Comparative example 2
The materials and preparation process were substantially the same as those of example 3, except that talc was used instead of magnesium stearate.
Comparative example 3
The preparation method provided by the embodiment of the invention patent CN100591329 is adopted.
Stability test
Six groups of montelukast sodium granules were prepared according to the formulation methods provided in examples 1 to 3 and comparative examples 1 to 3, and the six groups were separately placed in artificial gastric juice, and the release rates thereof at different times were respectively measured, and the specific measurement results are shown in table 1;
table 1 statistical table of the results of the release degree test
| Time of standing | Example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| 0 minute | 22.6％ | 21.3％ | 20.9％ | 23.8％ | 28.3％ | 26.1％ |
| 15 minutes | 42.1％ | 38.4％ | 35.7％ | 44.1％ | 42.8％ | 48.4％ |
| 30 minutes | 62.6％ | 63.7％ | 58.9％ | 66.1％ | 65.2％ | 68.9％ |
| 45 minutes | 81.4％ | 72.9％ | 73.7％ | 81.1％ | 83.4％ | 87.1％ |
| 60 minutes | 97.3％ | 91.7％ | 92.4％ | 98.4％ | 99.2％ | 98.3％ |
| 75 minutes | 100％ | 99.2％ | 98.4％ | 99.6％ | 100％ | 100％ |
| 90 minutes | 100％ | 100％ | 100％ | 100％ | 100％ | 100％ |
According to the result analysis of the table 1, the product produced by the method for preparing the montelukast sodium granules provided by the invention has good slow release performance and meets the clinical use standard; the side spraying technology of the fluidized bed is utilized to spray the adhesive and the Montelukast sodium powder on the surfaces of the mannitol particles, the used medicament types are few, the process flow is simple, the preparation period is short, the cost is low, the introduction of unknown impurities in finished products is controlled, the safety of clinical administration is guaranteed, and the requirement of industrial production is met.
The foregoing is merely exemplary and illustrative of the present inventive concept and various modifications, additions and substitutions of similar embodiments may be made to the specific embodiments described by those skilled in the art without departing from the inventive concept or exceeding the scope of the claims as defined in the accompanying claims.
Claims (6)
1. A preparation method of montelukast sodium granules is characterized in that: the method comprises the following steps:
s1: granulating, namely weighing mannitol in a prescription amount, adding the mannitol into a wet granulator, sieving with a 60-mesh sieve, and drying to obtain a granular base material for later use;
s2: preparing a binding agent, weighing hydroxypropyl cellulose in a prescription amount, adding deionized water, stirring to dissolve, and preparing a 3.0% binding agent aqueous solution for later use;
s3: preparing medicinal powder, weighing montelukast sodium in a prescription amount, adding the montelukast sodium into a grinder for grinding, and sieving the montelukast sodium with a 300-mesh sieve to obtain medicinal powder for later use;
s4: loading medicine, namely placing the particle base material treated by the S1 on a fluidized bed, spraying an adhesive and medicinal powder on the surface of the particle base material by adopting a fluidized bed side spraying technology, and drying after spraying to obtain dry particles;
s5: and (4) totally mixing, namely adding magnesium stearate into the dry granules, and uniformly mixing to obtain the montelukast sodium granules.
2. The method for preparing montelukast sodium granules according to claim 1, wherein: the montelukast sodium granules comprise the following components in parts by weight: 200-260 parts of mannitol, 10-18 parts of hydroxypropyl cellulose, 6-12 parts of montelukast sodium and 5-15 parts of magnesium stearate.
3. The method for preparing montelukast sodium granules according to claim 1, wherein: the montelukast sodium granules comprise the following components in parts by weight: 250 parts of mannitol 210-containing material, 12-16 parts of hydroxypropyl cellulose, 7-11 parts of montelukast sodium and 6-14 parts of magnesium stearate.
4. The method for preparing montelukast sodium granules according to claim 1, wherein: the montelukast sodium granules comprise the following components in parts by weight: 230 parts of mannitol, 14 parts of hydroxypropyl cellulose, 9 parts of montelukast sodium and 10 parts of magnesium stearate.
5. The method for preparing montelukast sodium granules according to claim 1, wherein: the conditions of the fluidized bed side spraying are as follows: the spraying speed is 16-18g/min, and the atomizing pressure is 1.5 multiplied by 105PA, particle base, angle of repose 32.5 °, degree of compression 8%.
6. The method for preparing montelukast sodium granules according to claim 1, wherein: and drying in a vacuum drying oven at 80-95 deg.C for 30-40min in S1 and S4.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010062432.0A CN111249238A (en) | 2020-01-19 | 2020-01-19 | Preparation method of montelukast sodium granules |
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| CN202010062432.0A CN111249238A (en) | 2020-01-19 | 2020-01-19 | Preparation method of montelukast sodium granules |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070184101A1 (en) * | 2006-02-09 | 2007-08-09 | Teva Pharmaceutical Industries Ltd. | Stable pharmaceutical formulations of montelukast sodium |
| CN100591329C (en) * | 2001-10-26 | 2010-02-24 | 默克弗罗斯特加拿大有限公司 | Montelukast granule formulation |
| CN103520129A (en) * | 2013-10-15 | 2014-01-22 | 天垚医药科技发展（上海）有限公司 | Montelukast sodium pulse release preparation |
| KR20140125492A (en) * | 2013-04-19 | 2014-10-29 | 주식회사 에스텍파마 | Granule composition containing sodium montelukast and its preparing method and chewable tablet |
| CN104644564A (en) * | 2013-11-25 | 2015-05-27 | 天津汉瑞药业有限公司 | Stable granular preparation containing montelukast 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 |
-
2020
- 2020-01-19 CN CN202010062432.0A patent/CN111249238A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100591329C (en) * | 2001-10-26 | 2010-02-24 | 默克弗罗斯特加拿大有限公司 | Montelukast granule formulation |
| US20070184101A1 (en) * | 2006-02-09 | 2007-08-09 | Teva Pharmaceutical Industries Ltd. | Stable pharmaceutical formulations of montelukast sodium |
| KR20140125492A (en) * | 2013-04-19 | 2014-10-29 | 주식회사 에스텍파마 | Granule composition containing sodium montelukast and its preparing method and chewable tablet |
| CN103520129A (en) * | 2013-10-15 | 2014-01-22 | 天垚医药科技发展（上海）有限公司 | Montelukast sodium pulse release preparation |
| CN104644564A (en) * | 2013-11-25 | 2015-05-27 | 天津汉瑞药业有限公司 | Stable granular preparation containing montelukast 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 |
Non-Patent Citations (1)
| Title |
|---|
| 朱永光，等: "孟鲁司特钠颗粒处方工艺及其稳定性研究", 《中国医院用药评价与分析》 * |
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