CN107693494B - Montelukast sodium particle composition and preparation method thereof - Google Patents
Montelukast sodium particle composition and preparation method thereof Download PDFInfo
- Publication number
- CN107693494B CN107693494B CN201710762772.2A CN201710762772A CN107693494B CN 107693494 B CN107693494 B CN 107693494B CN 201710762772 A CN201710762772 A CN 201710762772A CN 107693494 B CN107693494 B CN 107693494B
- Authority
- CN
- China
- Prior art keywords
- montelukast sodium
- granules
- parts
- copovidone
- crospovidone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a montelukast sodium particle composition and a preparation method thereof, wherein the particles are prepared from montelukast sodium, a filling agent, crospovidone, copovidone, magnesium stearate and purified water.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, and in particular relates to a montelukast sodium particle composition and a preparation method thereof.
Background
Montelukast (Montelukast) is an anti-asthmatic developed by the company Merck, usa as a selective leukotriene receptor antagonist, marketed by the FDA in the united states at 2 months 1998 under the trade name "Singulair" in the form of film-coated tablets, chewable tablets and granules in the size of 10mg, 5mg, 4mg, respectively, and subsequently marketed in 71 countries, canada, italy, spain, sweden, switzerland, germany, france, etc. At the end of the 90 s of the 20 th century, montelukast tablets from the company moendong began to enter the market of China under the trade name "cis-ning", and then oral granules (the national standard of medicine J20120044) and chewable tablets thereof were continuously marketed in China, and 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 asthmatic patients and the prevention of exercise-induced bronchoconstriction.
Montelukast sodium belongs to class ii, classified according to BCS, as a poorly soluble, hypertonic drug; international Journal of pharmaceuticals 134(1996)59-70 reported that the solubility-pH curve of montelukast sodium is shown in FIG. 3.
As shown in FIG. 3, the solubility of the montelukast sodium in the drug is low at pH 3.0-6.8. From the description of the commercially available samples, it is known that clinical studies in healthy adolescents show that montelukast sodium has a half-life of 2.7-5.5h, the main site of absorption is in the intestinal tract, and the pH in the intestinal tract is in the range of 3.0-6.8, so that it is critical to ensure the bioavailability of montelukast sodium to ensure the solubility of montelukast sodium in the absorption site.
Patent WO2003035036A1 discloses a formula and a preparation process of a commercially available montelukast sodium granule, a fluidized bed granulation mode is adopted, the prepared granule is loose, the dissolution speed of montelukast sodium is further improved, the bioavailability in vivo is ensured, but the montelukast sodium is easy to react with oxygen at high temperature, and the increase of oxidized impurities (sulfoxide) is obvious; in order to reduce the oxidation impurities, the patent WO2009153305A2 adopts nitrogen as the carrier gas of the fluidized bed, avoids the contact of particles and oxygen, has less oxidation impurities, but has higher requirements on equipment, and is difficult to realize by the prior art in China.
Patent CN201510747141.4 discloses a montelukast sodium granule composition and a preparation method thereof, wherein dodecyl dimethyl amine oxide and ammonium glycyrrhetate are used as protective agents, and although dodecyl dimethyl amine oxide can perform a solubilizing effect on a main drug and has low physiological toxicity, the dodecyl dimethyl amine oxide serving as an artificially synthesized surfactant still has potential safety hazards to human bodies, particularly gastrointestinal tracts of children.
Patent CN201310598573.4 discloses a montelukast sodium particle composition and a preparation method thereof, wherein hydroxypropyl cellulose and hydroxypropyl methylcellulose are used as adhesives, and the fact that unknown impurities can be introduced into montelukast sodium particles by the aid of the hydroxypropyl cellulose is verified, and the montelukast sodium particle composition changes along with the change of a preparation process and is highly dependent on the process.
The dissolution and crystallization of the drug are a pair of reversible reactions, and because the crystallization speed of the insoluble drug is high, the two reactions reach equilibrium when a small amount of the drug is dissolved, so that the insoluble drug shows low dissolution rate. The improvement of the dissolution rate of the slightly soluble medicament can be started from two aspects, namely the improvement of the dissolution rate of the medicament on the one hand and the reduction of the crystallization rate on the other hand. The hydrogen bond association technology can inhibit the recrystallization of the insoluble drug, maintain the supersaturation state of the insoluble drug, namely reduce the crystallization rate of the drug and improve the dissolution rate of the drug. The copovidone is a polymer formed by vinylpyrrolidone and vinyl acetate according to a certain proportion, and the structural formula of the copovidone is shown as the following formula:
the crospovidone contains a pyrrolidone ring and is a hydrogen bond receptor; copovidone contains pyrrolidone ring and vinyl acetate group, which are hydrogen bond receptors. The dissolution rate of the insoluble drug can be improved by the interaction of hydrogen bonds, and the hydrogen bonds can inhibit the recrystallization of the insoluble drug and maintain the supersaturated state of the insoluble drug, namely the crystallization rate of the drug is reduced and the dissolution rate of the drug is improved.
Based on the problems, the invention provides a wet granulation process, which avoids the increase of oxidized impurities caused by a fluidized bed process under a high temperature condition, and simultaneously adopts crospovidone and copovidone as a disintegrating agent and an adhesive respectively, and utilizes the interaction of hydrogen bonds to perform a solubilization function on montelukast sodium, thereby ensuring that montelukast sodium particles are quickly dissolved out under different pH values, improving the bioavailability of the montelukast sodium particles, and ensuring that unknown impurities introduced by hydroxypropyl cellulose are not generated. And the preparation method is simple and is suitable for industrial production.
Disclosure of Invention
The invention aims to provide montelukast sodium particles with high bioavailability and better safety and stability and a preparation process thereof. The montelukast powder is characterized by comprising montelukast sodium, a filling agent, copovidone, crospovidone and magnesium stearate. Wherein the filler is mannitol or lactose, preferably mannitol; copovidone as a binder, preferably, hypnaglyne copovidone S-630; crospovidone as disintegrant selected from Polyplasdone of HimalayanTMXL, Kollidon CL from BASF, crospovidone from Anhui mountain river, preferably Polyplasdone from HimalayanTMXL; magnesium stearate serves as a lubricant.
The montelukast sodium granules comprise the following components in parts by weight:
further, the montelukast sodium granules comprise the following components in parts by weight:
the montelukast sodium granules of the invention have a specification of 0.5g:4mg (based on montelukast), and a preferred formulation composition is as follows:
more preferred formulations are as follows:
the most preferred formulation consists of:
the montelukast sodium granules comprise the following steps:
(1) adding montelukast sodium into water to dissolve;
(2) adding filler, copovidone, and crospovidone to obtain mixture;
(3) adding the raw material solution into the mixture, making soft mass, and granulating;
(4) the granules were dried and then sized.
(5) Adding magnesium stearate into the granules after finishing the granules, and mixing to prepare the montelukast sodium granules.
Further, the preparation method of the montelukast sodium granules comprises the following steps:
(1) sieving the auxiliary materials for later use, weighing montelukast sodium according to a prescription, adding the montelukast sodium into water, and dissolving the montelukast sodium into the water until the montelukast sodium is transparent for later use;
(2) adding filler, copovidone, and crospovidone into wet granulating machine, and mixing for 5min to obtain mixture;
(3) adding the raw material solution into the mixture, adopting a wet granulation machine to prepare a soft material, and adopting a swing type granulator to granulate in 24 meshes;
(4) the granules are added into a vacuum drying oven for drying at 60 ℃ for 2h, and then the granules are sized.
(5) Adding magnesium stearate into the finished granules, placing the granules into a multi-item motion mixer, mixing for 20min at a speed of 30r/min, and discharging to obtain the montelukast sodium granules.
According to the montelukast sodium granules, the synergistic effect of the crospovidone and the copovidone is fully utilized in the prescription, the dissolution and release behaviors are effectively guaranteed under the action of hydrogen bonds in vitro and in vivo, and the bioavailability of the montelukast sodium granules is increased; the montelukast sodium granules disclosed by the invention take copovidone as an adhesive, so that the introduction of unknown impurities in a finished product is controlled, and the safety of clinical administration is ensured; meanwhile, the preparation process of the montelukast sodium particles is simple, and the montelukast sodium particles are more suitable for industrial production.
Drawings
FIG. 1 in vitro release of Montelukast sodium particles in pH6.8 medium
FIG. 2 in vitro release of Montelukast sodium particles in pH4.5 medium
FIG. 3 Montelukast sodium solubility-pH Curve
Detailed Description
For a better understanding of the present invention, the following examples are set forth to illustrate, but are not to be construed to limit the present invention.
Example 1
The process comprises the following steps:
(1) preparing materials according to the prescription of example 1, sieving mannitol with a 80-mesh sieve for later use, adding the Montelukast sodium with the prescription amount into purified water, and dissolving until the Montelukast sodium is transparent for later use;
(2) adding mannitol, crospovidone and copovidone into wet granulating machine, and mixing for 5min to obtain mixture;
(3) adding the raw material solution into the mixture, adopting a wet granulation machine to prepare a soft material, and adopting a swing type granulator to granulate in 24 meshes;
(4) the granules are added into a vacuum drying oven for drying at 60 ℃ for 2h, and then the granules are sized.
(5) Adding magnesium stearate into the finished granules, placing the granules into a multi-item motion mixer, mixing for 20min at a speed of 30r/min, and discharging to obtain the montelukast sodium granules.
Example 2
The same preparation as in example 1 was carried out according to the above formulation, thus obtaining finished product 2.
Example 3
The same preparation as in example 1 was carried out according to the above formulation, thus obtaining finished product 3.
Example 4
According to the above formulation, the same preparation method as in example 1 was employed, thereby obtaining a finished product 4.
According to the guiding principle of dissolution, the dissolution curve of the product with distinguishing force under different pH conditions is screened out, and the Montelukast sodium is compared with the commercial samples in two mediums of pH4.5 and pH6.8 which have large in-vitro correlation in vivo and in vivo by referring to the main absorption site in vivo: according to the invention, the solubility of montelukast sodium is increased by utilizing the hydrogen bond effect of the crospovidone and the copovidone, and the in-vitro dissolution curve of the preferable prescription example 1 is consistent with that of a reference preparation; the co-povidone and the crospovidone are used cooperatively to obviously improve the dissolution of the insoluble drug. The results of the experiment are shown in FIGS. 1 and 2.
The results of examining the present invention and the commercial samples for the substances under 0 day and accelerated conditions (accelerated conditions of 40 ℃ C. and 75% + -5% humidity) are shown in the following table:
from the results, according to the original open prescription, hydroxypropyl cellulose is used as an adhesive, unknown impurities are introduced into the finished product, the unknown impurities are 0.09% at the acceleration of 6 months, and the product prepared by using hydroxypropyl cellulose as the adhesive is stored for a period of time and then taken, so that certain potential safety hazards are brought to the human body, and the safety is poor; compared with the samples sold in the market, the prescription of the invention has better stability and higher safety in taking in the process of accelerating investigation.
Claims (8)
1. The montelukast sodium granules are characterized in that the montelukast sodium granules comprise montelukast sodium, a filler, a disintegrant, a binder and a lubricant; the disintegrant is crospovidone, and the binder is copovidone; the filler is selected from one or the combination of any two of mannitol, sucrose and lactose; the components are as follows according to parts by weight:
2-8 parts of montelukast sodium
Filler 250-600 parts
1-10 parts of cross-linked polyvidone
5-25 parts of copovidone
1-5 parts of a lubricant;
the preparation method of the montelukast sodium granules comprises the following steps:
1) adding montelukast sodium into water to dissolve;
2) preparing mixture of filler, copovidone and crospovidone;
3) adding the raw material solution into the mixture, making soft mass, and granulating;
4) drying the granules, and then finishing the granules;
5) adding lubricant magnesium stearate into the granules after finishing the granules, and mixing to prepare the montelukast sodium granules.
2. The montelukast sodium granules according to claim 1, wherein the bulking agent is selected from mannitol.
3. The montelukast sodium granules according to any of claims 1 to 2, characterized in that the components consist of, in parts by weight:
4-5 parts of montelukast sodium
500 portions of filler 350-
5-10 parts of cross-linked polyvidone
5-15 parts of copovidone
1-3 parts of a lubricant.
4. Montelukast sodium granules according to any of claims 1 to 2, characterized in that the copovidone is selected from the group consisting of ashiran copovidone S-630; the crospovidone is Polyplasdone from HimalayanTMXL, Kollidon CL from Pasteur, or crospovidone from Anhui mountain river.
5. The montelukast sodium granules according to any of claims 1-2, the formulation consisting of:
6. the montelukast sodium granules according to any of claims 1-2, the formulation consisting of:
7. the method for preparing montelukast sodium granules according to any one of claims 1 to 6, wherein the step of preparing the montelukast sodium granules comprises:
1) adding montelukast sodium into water to dissolve;
2) preparing mixture of filler, copovidone and crospovidone;
3) adding the raw material solution into the mixture, making soft mass, and granulating;
4) drying the granules, and then finishing the granules;
5) adding lubricant magnesium stearate into the granules after finishing the granules, and mixing to prepare the montelukast sodium granules.
8. The method for preparing montelukast sodium granules according to claim 7, wherein the step of preparing the montelukast sodium granules comprises:
1) sieving the auxiliary materials for later use, weighing montelukast sodium according to a prescription, adding the montelukast sodium into water, and dissolving the montelukast sodium into the water until the montelukast sodium is transparent for later use;
2) adding filler, copovidone, and crospovidone into wet granulating machine, and mixing for 5min to obtain mixture;
3) adding the raw material solution into the mixture, adopting a wet granulation machine to prepare a soft material, and adopting a swing type granulator to granulate in 24 meshes;
4) adding the granules into a vacuum drying oven, drying at 60 deg.C for 2h, and grading;
5) and adding magnesium stearate into the finished granules, putting the granules into a multidirectional motion mixer, mixing for 20min at a speed of 30r/min, and discharging to obtain the montelukast sodium granules.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710762772.2A CN107693494B (en) | 2017-08-31 | 2017-08-31 | Montelukast sodium particle composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710762772.2A CN107693494B (en) | 2017-08-31 | 2017-08-31 | Montelukast sodium particle composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107693494A CN107693494A (en) | 2018-02-16 |
| CN107693494B true CN107693494B (en) | 2021-02-09 |
Family
ID=61169984
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710762772.2A Active CN107693494B (en) | 2017-08-31 | 2017-08-31 | Montelukast sodium particle composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107693494B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113476415A (en) * | 2021-07-26 | 2021-10-08 | 北京丰科睿泰医药科技有限公司 | Lurasidone hydrochloride tablet and preparation method thereof |
| CN117064857A (en) * | 2023-08-31 | 2023-11-17 | 博济医药科技股份有限公司 | Montelukast sodium granule preparation and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732268A (en) * | 2010-01-09 | 2010-06-16 | 鲁南制药集团股份有限公司 | Montelukast sodium tablet and preparation method thereof |
| CN103502236A (en) * | 2011-03-07 | 2014-01-08 | 阿托佩斯治疗有限公司 | Amorphous (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid |
| CN104840427A (en) * | 2014-02-13 | 2015-08-19 | 长春海悦药业有限公司 | Pharmaceutical composition containing montelukast sodium |
-
2017
- 2017-08-31 CN CN201710762772.2A patent/CN107693494B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732268A (en) * | 2010-01-09 | 2010-06-16 | 鲁南制药集团股份有限公司 | Montelukast sodium tablet and preparation method thereof |
| CN103502236A (en) * | 2011-03-07 | 2014-01-08 | 阿托佩斯治疗有限公司 | Amorphous (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid |
| CN104840427A (en) * | 2014-02-13 | 2015-08-19 | 长春海悦药业有限公司 | Pharmaceutical composition containing montelukast sodium |
Non-Patent Citations (1)
| Title |
|---|
| 共聚维酮对交联聚维酮改善溶出度作用的影响;王如意等;《中国现代应用药学》;20150131;第32卷(第01期);第44-45页第3节 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107693494A (en) | 2018-02-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6764959B2 (en) | Pharmaceutical composition | |
| JP3180350B2 (en) | β-lactam antibiotic-containing tablet and method for producing the same | |
| EP3417861B1 (en) | Pharmaceutical composition containing jak kinase inhibitor or pharmaceutically acceptable salt thereof | |
| JP6339089B2 (en) | Oral suspension containing amorphous tolvaptan | |
| WO2008018371A1 (en) | Oral disintegrating tablet having masked bitter taste and method for production thereof | |
| SI23290A (en) | New forms of ivabradine hydrochloride | |
| JPS63165318A (en) | Light-stable nifedipin concentrate and manufacture | |
| TW200902089A (en) | Solid pharmaceutical composition | |
| TW202112376A (en) | Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor | |
| CN107693494B (en) | Montelukast sodium particle composition and preparation method thereof | |
| TWI299994B (en) | Anti-allergic agent pharmaceutical composition and production method therefor | |
| JP2022507562A (en) | Pharmaceutical composition containing PARP inhibita | |
| WO2010059038A2 (en) | Wet granulation of tenofovir, emtricitabine and efavirenz | |
| CN104473862A (en) | Roflumilast solid dispersoid and preparation method thereof as well as roflumilast preparation | |
| US20090017122A1 (en) | Drug Forms Having Controlled Bioavailability | |
| JP2004131393A (en) | Readily eluting pharmaceutical preparation | |
| CN102552168A (en) | Pharmaceutical composition containing orlistat and its preparation method | |
| CA3079567A1 (en) | Lenalidomide immediate release formulations | |
| JPS58109412A (en) | Nifedipine solid preparation | |
| JP3037393B2 (en) | Method for producing solid drug for oral administration | |
| CN106913537B (en) | Abiraterone acetate sublingual tablet and preparation method thereof | |
| CN109481437B (en) | Losartan potassium pharmaceutical preparation | |
| JPH1121236A (en) | Loxoprofen-sodium solid preparation | |
| KR100267525B1 (en) | Cytarabine ocfosfate hard capsule | |
| CN106913538B (en) | Abiraterone acetate sublingual tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |