CN106727345A - A kind of pharmaceutical composition of montelukast sodium - Google Patents
A kind of pharmaceutical composition of montelukast sodium Download PDFInfo
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- CN106727345A CN106727345A CN201510811443.3A CN201510811443A CN106727345A CN 106727345 A CN106727345 A CN 106727345A CN 201510811443 A CN201510811443 A CN 201510811443A CN 106727345 A CN106727345 A CN 106727345A
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- pharmaceutical composition
- menglusitena
- methacrylic acid
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Abstract
The present invention relates to a kind of pharmaceutical composition of montelukast sodium, contain Menglusitena, mannitol, hydroxypropyl cellulose, methacrylic acid aminoalkyl ester copolymer in composition, said composition can reduce the growth of the impurity such as Menglusitena catabolite sulfoxide, significantly improve Menglusitena stability.Meanwhile, the invention provides a kind of preparation method of pharmaceutical composition of montelukast sodium, the method preparation process is simple facilitates feasible, and reproducible, low cost is suitable for industrialized large-scaled production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of pharmaceutical composition of montelukast sodium and preparation method thereof.
Background technology
Asthma is a kind of common respiratory disease of clinic, about have impact on the children in the whole world 10% and 5% adult, to the greatest extent
Pipe has further understanding to the pathogenesis of asthma at present, but asthma is generally popular still as chronic disease.
In asthma, the effect of leukotriene mediation is reacted including a series of air flue, such as bronchoconstriction, mucous secretion, vasopermeability
Increase and eosinophil accumulation.
Menglusitena was the antasthmatic developed by United States Merck company (Merck＆Co., Inc.U.S.A.), in 1998 2
Obtain U.S. FDA approval listing, trade name the moonMerck in 1999 obtains CFDA approvals and goes up at home
City, wherein granule enter domestic for 2005 in 2002 in U.S.'s listing, and the specification of granule is 0.5g：4mg is (with Meng
Lu Site is counted), Aluminum-plastic composite bag packaging.Menglusitena chemical structural formula is：
Menglusitena, can the specific cysteinyl suppressed in air flue used as strong selectivity LTRA of new generation
Leukotriene (CysLT) acceptor, so as to reach improvement airway inflammation, effective Control of asthma symptom, it is adaptable to 1 years old and 1 years old
Above children and the prevention and long-term treatment of Adults Asthma, it is convenient to take because its range of application is wider, obtain clinical doctor
The extensive approval and clinical practice of teacher.Menglusitena can not only improve the PFT of asthmatic patient, and in anti-inflammatory, immune
Also there is important application value etc. all many-sides.
Menglusitena during storage due to molecule in hydroxyl presence, because the change of temperature is easily oxidized into Meng Lusi
Special ketone, and with the generation of catabolite sulfoxide, montelukast ketone metabolic pathway in vivo and the basic phase of Menglusitena
Together, but in the presence of liver renal toxicity higher, the security risks in clinical practice are increased, therefore how to control Meng in Menglusitena
The content of the impurity such as Lu Site ketones and sulfoxide turns into a technical problem urgently to be resolved hurrily.
Original grinds the discovery of product analysis result, and preferably, impurity level is relatively low for product initial stage quality, in 60 DEG C of placements of influence factor,
Impurity increases larger, and impurity A (catabolite sulfoxide) has exceeded standard limits, and less stable illustrates that this is the main property of medicine
Caused by matter.
Patent document CN102552921 discloses a kind of montelukast sodium compositions, by Menglusitena and polyacrylic acid tree
Fat L100-55 constitutes to improve Menglusitena stability, reduces the risk that Menglusitena is oxidized to montelukast ketone, but
There are problems that following：1) experiment is carried out using the patent prescription to find to adopt described Menglusitena and polyacrylic resin
Sample impurity A (catabolite sulfoxide) prepared by L100-55 ratios is still higher, increases very fast in placement process, amplification
It is larger, easily beyond import registered standard scope；2) species and consumption of filler are not referred in the patent, and filler sweet dew
Alcohol need to meet minimum with the impurity content that the product compatibility is produced during certain model, and optimum is placed for a long time.
So, a kind of Menglusitena better stability of preparation how is obtained, it is readily transported and stores, adapts to industrialized production,
As a technical problem urgently to be resolved hurrily.
The content of the invention
It is an object of the invention to be directed to the deficiencies in the prior art, there is provided a kind of better stability of preparation, it is readily transported and stores up
Deposit, adapt to the pharmaceutical composition of montelukast sodium of industrialized production.The present invention mainly adds a certain proportion of methyl in prescription
Aminoalkyl acrylate copolymer and mannitol reduce the impurity contents such as montelukast ketone and sulfoxide, improve preparation stability.
Pharmaceutical composition of montelukast sodium of the invention is specific as follows：
A kind of pharmaceutical composition of montelukast sodium, it is characterised in that the pharmaceutical composition contain Menglusitena, hydroxypropyl cellulose,
Methacrylic acid aminoalkyl ester copolymer and mannitol.
The mass percent of Menglusitena is 0.7~1.2% in the described pharmaceutical composition.
The mass percent of hydroxypropyl cellulose is 0.5%~2.0%, preferably 1.0-1.5% in described pharmaceutical composition.
The mass percent of methacrylic acid aminoalkyl ester copolymer is 0.001%~0.05% in described pharmaceutical composition, preferably
0.001%~0.01%.
Further, methacrylic acid aminoalkyl ester copolymer is E types in described pharmaceutical composition.
Further, the mannitol is mannitol 160C.
Meanwhile, this application provides a kind of preparation method of aforementioned pharmaceutical compositions, step is as follows：
1) by the hydroxypropyl cellulose, methacrylic acid aminoalkyl ester copolymer, it is placed in solvent orange 2 A, mixed liquor I is obtained；
2) Menglusitena is placed in mixed liquor I under light protected environment, mixed liquor I I is obtained；
3) stirred to addition mixed liquor I I in mannitol；
4) pelletize；Dry；Whole grain；Screening, packing.
The solvent orange 2 A is water, absolute ethyl alcohol or hydrous ethanol.
The present invention first according to feedstock property, protected with reference to former triturate Patents and required, for diluent in original prescription, viscous
Mixture, stabilizer are studied, and granulating process is prepared to this product in a wet process for selection, and prescription screening formula table is shown in Table 1：
The prescription screening formula table of table 1
BHT：2,6 di tert butyl 4 methyl phenol
By above-mentioned prescription, 5% concentration hydroxypropyl cellulose binder solution is prepared, stabilizer and 4.15mg Menglusitenas is former
Material is added, and is configured to solution, separately mixes each auxiliary material of mannitol and recipe quantity, adds binder solution, prepares Menglusitena
Particle, detects its impurity situation, while sample is placed into 60 DEG C of influence factor experiments, in being detected after 10 days, concrete outcome is shown in
Table 2：
The prescription screening data summary table of table 2
Impurity A：Catabolite sulfoxide；Impurity B：Menglusitena cis-isomer；Impurity C+D：Process contaminants
Impurity E：Catabolite；Impurity F：Process contaminants methyl styrene
Result shows when a small amount of stabilizer BHT and sodium thiosulfate is added in prescription, have when the impurity of product is not added
Improved, i.e., impurity A is slightly reduced, it is always miscellaneous slightly to reduce, but it is former to add sodium thiosulfate to accelerate Menglusitena in prescription
The notable degraded of material, result in the generation of new unknown degradation impurity E；Drawn with the contrast of other prescriptions according to prescription 8, plus
Enter the prescription of a small amount of methacrylic acid aminoalkyl ester copolymer E types under normal temperature and hot conditions, relevant single miscellaneous and total miscellaneous content increases
Situation long makes moderate progress, and methacrylic acid aminoalkyl ester copolymer E types are acidic materials, are usually used in doing general thin or isolation
Layer dress material, Menglusitena is shown in that light is easily decomposed and is easily oxidized, and product stability is poor, and the present invention adds certain ratio in prescription
The methacrylic acid aminoalkyl ester copolymer of example can reduce the impurity contents such as montelukast ketone and sulfoxide, improve preparation stability,
Impurity is reduced to produce；Shown with the contrast of other prescriptions according to prescription 5, prescription 6 and prescription 8 simultaneously, use mannitol 160C
When compared with the product high temperature drawn using other model mannitol and long-term to place impurity content low.
Thereafter, the application is further studied the consumption of methacrylic acid aminoalkyl ester copolymer, and specific Formulation is shown in Table
3：
The formulation optimization formula table of table 3
By above-mentioned prescription, 5% concentration hydroxypropyl cellulose binder solution is prepared, by methacrylic acid aminoalkyl ester copolymer E
Type and montelukast sodium raw materials are added, and are configured to solution, separately mix mannitol 160C with each auxiliary material of recipe quantity, add bonding
Agent solution, prepares Menglusitena particle, detects its impurity situation, while sample is placed into 60 DEG C of influence factor experiments, in 10
Detected after it, concrete outcome is shown in Table 4：
The formulation optimization data summary table of table 4
Impurity A：Catabolite sulfoxide；Impurity B：Menglusitena cis-isomer；Impurity C+D：Process contaminants
Impurity E：Catabolite；Impurity F：Process contaminants methyl styrene
Result display prescription 12 (content 0.001%) to prescription 14 (content 0.01%) impurity content is relatively low, works as metering system
When sour aminoalkyl ester copolymer E types consumption increases, product impurities phase should increase, and illustrate methacrylic acid aminoalkyl ester copolymer E
Type can play inhibitory action in the less scope of content to Menglusitena granule foreign, therefore add recipe quantity
0.001%~0.01% methacrylic acid aminoalkyl ester copolymer E types can control product impurity in acceptability limit, to product impurity
Play inhibitory action.
Meanwhile, the present invention is studied the consumption of hydroxypropyl cellulose, respectively with recipe quantity 0.5%, 1.0%, 1.5%, 2.0%
Hydroxypropyl cellulose be adhesive preparation prescription sample, with fine powder rate, lump rate, particle yield, angle of repose as index, in detail
Carefully the results are shown in Table 5：
The binder dosage choice experiment result of table 5
Result display adhesive hydroxypropyl cellulose consumption be 0.5%-2.0% can pelletize, but consumption for 1.0%-1.5% when mobility
Suitably, particle yield is higher, therefore hydroxypropyl cellulose is adhesive preferably in the range of this.
In addition, the present invention is in preparation process, adhesive solvent is studied, water, 50% ethanol, 95% second is respectively adopted
Alcohol, absolute ethyl alcohol are that solvent prepares adhesive granulation, dry to moisture and are less than 0.5% (loss on drying), detect it about material
Situation, detailed results are shown in Table 6：
The adhesive solvent of table 6 screens impurity summary sheet
Impurity A：Catabolite sulfoxide；
Result shows that, with the rising of determining alcohol, drying time shortens, the impurity increasing degree reduction of product, wherein with high concentration
Ethanol prepares optimal, and preferably absolute ethyl alcohol is adhesive solvent.
Meanwhile, the invention provides a kind of preparation method of pharmaceutical composition of montelukast sodium, comparative study supplementary material directly mixes
Granulation and stabilizer add two methods of raw material granulation after being first dissolved in adhesive, respectively at different parts sampling, determine content,
Uniformity of dosage units is calculated, it is 1.83%, 1.01% that as a result RSD is respectively, and two kinds of hybrid modes can reach ideal effect, excellent
Select the latter.
The prepared montelukast sodium compositions product stabilization of the present invention, single miscellaneous and total miscellaneous content is relatively low, long-term to place and hot test
Middle impurity increases slow, and in the range of the limit of impurities, is suitable to long-term storage；Preparation process is simple of the present invention, facilitates feasible,
Reproducible, low cost is suitable for industrialized large-scaled production.
Specific embodiment
Specific embodiment is only to further explain and describe the present invention, is not necessarily to be construed as any limitation of the invention.
Embodiment 1-3：Pharmaceutical composition of montelukast sodium and its preparation
Preparation method：
1) adhesive hydroxypropyl cellulose, the stabilizer methacrylic acid aminoalkyl ester copolymer E types of recipe quantity are weighed, nothing is placed in
In water-ethanol, it is stirred to dissolve to clarification, mixed liquor I is obtained.
2) under lucifuge (red yellow colorama lighting) environment, the Menglusitena of recipe quantity is weighed, is placed in adhesive 1, stirred
Mix to raw material and be completely dissolved, solution clarification is obtained mixed liquor I I.
3) stirred to addition adhesives II in mannitol 160C.
4) 20 mesh stainless steel mesh granulation；Dry；14 mesh sieve whole grains；Screening, packing.
Embodiment 4-6：Pharmaceutical composition of montelukast sodium and its preparation
Preparation method：
1) adhesive hydroxypropyl cellulose, the stabilizer methacrylic acid aminoalkyl ester copolymer E types of recipe quantity are weighed, nothing is placed in
In water-ethanol, it is stirred to dissolve to clarification, mixed liquor I is obtained.
2) under lucifuge (red yellow colorama lighting) environment, the Menglusitena of recipe quantity is weighed, is placed in adhesive 1, stirred
Mix to raw material and be completely dissolved, solution clarification is obtained mixed liquor I I.
3) stirred to addition adhesives II in mannitol 160C.
4) 20 mesh stainless steel mesh granulation；Dry；14 mesh sieve whole grains；Screening, packing.
Stability experiment is studied：
Above-described embodiment and original are ground into product (0000179284A) while carrying out influence factor experiment, concrete outcome see the table below：
Impurity A：Catabolite sulfoxide；Impurity B：Menglusitena cis-isomer；Impurity C+D：Process contaminants
Impurity E：Catabolite；Impurity F：Process contaminants methyl styrene
When data in table can be seen that the 0 of the embodiment of the present application 1-6, its is steady for 60 DEG C of influence factorial experiments data displays on the 10th
It is qualitative to be significantly better than commercially available former triturate；And 40 DEG C of June and 25 DEG C of December influence factor examinations have been carried out to section Example
Test, as a result show that the application product impurity when 6 months, long-term 12 months are accelerated remains at reduced levels, its stability
It is substantially better than commercially available former triturate.
Claims (10)
1. a kind of pharmaceutical composition of montelukast sodium, it is characterised in that the pharmaceutical composition contains Menglusitena, hydroxy propyl cellulose
Element, methacrylic acid aminoalkyl ester copolymer and mannitol.
2. pharmaceutical composition according to claim 1, it is characterised in that the quality hundred of Menglusitena in the pharmaceutical composition
Divide than being 0.7~1.2%.
3. pharmaceutical composition according to claim 1, it is characterised in that the quality of hydroxypropyl cellulose in the pharmaceutical composition
Percentage is 0.5%~2.0%.
4. pharmaceutical composition according to claim 3, it is characterised in that the quality of hydroxypropyl cellulose in the pharmaceutical composition
Percentage is 1.0-1.5%.
5. pharmaceutical composition according to claim 1, it is characterised in that methacrylic acid aminoalkyl ester in the pharmaceutical composition
The mass percent of copolymer is 0.001%~0.05%.
6. pharmaceutical composition according to claim 5, it is characterised in that methacrylic acid aminoalkyl ester in the pharmaceutical composition
The mass percent of copolymer is 0.001%~0.01%.
7. the pharmaceutical composition according to claim 5 or 6, it is characterised in that methacrylic acid ammonia alkane in the pharmaceutical composition
Base ester copolymer is E types.
8. pharmaceutical composition according to claim 1, it is characterised in that the mannitol is mannitol 160C.
9. as any one of claim 1-8 pharmaceutical composition preparation method, it is characterised in that step is as follows：
1) by the hydroxypropyl cellulose, methacrylic acid aminoalkyl ester copolymer, it is placed in solvent orange 2 A, mixed liquor I is obtained；
2) Menglusitena is placed in mixed liquor I under light protected environment, mixed liquor I I is obtained；
3) stirred to addition mixed liquor I I in mannitol；
4) pelletize；Dry；Whole grain；Screening, packing.
10. preparation method according to claim 7, it is characterised in that the solvent orange 2 A is water, absolute ethyl alcohol or aqueous second
Alcohol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510811443.3A CN106727345B (en) | 2015-11-20 | 2015-11-20 | A kind of pharmaceutical composition of montelukast sodium |
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| CN201510811443.3A CN106727345B (en) | 2015-11-20 | 2015-11-20 | A kind of pharmaceutical composition of montelukast sodium |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108371654A (en) * | 2018-03-26 | 2018-08-07 | 南京正科医药股份有限公司 | A kind of Montelukast Sodium particle and preparation method thereof that light is stablized |
| CN109718214A (en) * | 2017-10-27 | 2019-05-07 | 南京长澳医药科技有限公司 | A kind of preparation method of calcium dobesilate |
| CN113662920A (en) * | 2021-09-28 | 2021-11-19 | 南京长澳医药科技有限公司 | Bilastine orally disintegrating tablet and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552921A (en) * | 2012-02-28 | 2012-07-11 | 南京正科制药有限公司 | Montelukast sodium composition |
-
2015
- 2015-11-20 CN CN201510811443.3A patent/CN106727345B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552921A (en) * | 2012-02-28 | 2012-07-11 | 南京正科制药有限公司 | Montelukast sodium composition |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109718214A (en) * | 2017-10-27 | 2019-05-07 | 南京长澳医药科技有限公司 | A kind of preparation method of calcium dobesilate |
| CN109718214B (en) * | 2017-10-27 | 2022-07-22 | 南京长澳医药科技有限公司 | Preparation method of calcium dobesilate tablets |
| CN108371654A (en) * | 2018-03-26 | 2018-08-07 | 南京正科医药股份有限公司 | A kind of Montelukast Sodium particle and preparation method thereof that light is stablized |
| CN113662920A (en) * | 2021-09-28 | 2021-11-19 | 南京长澳医药科技有限公司 | Bilastine orally disintegrating tablet and preparation method thereof |
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Address after: Nanxiang Road 224100 Jiangsu province Dafeng Yancheng City District No. 266 Applicant after: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd. Address before: Cheng Wei Road Nanjing city Jiangsu province 210046 No. 9 Jiangsu Xianlin University Life Science and Technology Innovation Park F6 8 storey building in Jiangsu Zhengda Fenghai Pharmaceutical Co. Ltd. Applicant before: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd. |
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