CN103040784A - Montelukast tablet composition and preparation method thereof - Google Patents
Montelukast tablet composition and preparation method thereof Download PDFInfo
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- CN103040784A CN103040784A CN2012105743942A CN201210574394A CN103040784A CN 103040784 A CN103040784 A CN 103040784A CN 2012105743942 A CN2012105743942 A CN 2012105743942A CN 201210574394 A CN201210574394 A CN 201210574394A CN 103040784 A CN103040784 A CN 103040784A
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
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Abstract
The invention discloses a Montelukast tablet composition. The composition comprises Montelukast, porous filling agent, disintegrating agent, lubricant, opadry film coating premixing agent and purified water; and the stability of the Montelukast can be remarkably improved. The invention further discloses a preparation method for the Montelukast tablet composition; the powder is adopted to directly compress tablets, so that the operation is convenient, the influence to the product quality from the drying process and the hot and humid condition is avoided, the content of related substances is low, and the stability is remarkably improved.
Description
Technical field
The invention belongs to field of medicine preparations, be specifically related to a kind of Menglusitena tablet composition and preparation method thereof.
Background technology
Montelukast is the oral LTRA of a new generation, it is a kind of potent oral formulations that can significantly improve the inflammation of asthma index, biochemistry and pharmacological bioassay show, montelukast has high selectivity, the combination of energy competitive antagonism leukotriene D (LTD4) and Cys-LTl receptor has good curative effect to asthma; A large amount of clinical practice data show that the general toleration of montelukast is good, and untoward reaction is slight, usually do not need stopped treatment, and the total adverse reaction rate of this product is similar to placebo; Menglusitena becomes the anti-asthmatic medicament brand product with its highly conforming properties, good effect, characteristics that toxic and side effects is low.
Traditional Menglusitena tablet composition and preparation method thereof is tabletting behind the supplementary material wet granulation, and supplementary material is subjected to the impact of hygrothermal environment and illumination before tabletting, has increased the probability of decomposing, and related substance can increase.
Summary of the invention
The object of the invention is to solve the problem of above-mentioned Menglusitena tablet composition, improve stability and the operability of producing, in conjunction with the physicochemical property of Menglusitena, the invention provides a kind of Menglusitena tablet composition, said composition comprises following component by weight:
Wherein, described porous filler is porous mannitol, the porous lactose, porous starch milk saccharide complex, porous fiber element lactose complex, porous micro crystal cellulose milk sugar complex, porous lactose cross-linked carboxymethyl cellulose complex, porous lactose microcrystal cellulose composite, porous microcrystalline Cellulose mannitol complex, porous mannitol sodium carboxymethyl cellulose complex, porous lactose polyvidone polyvinylpolypyrrolidone complex, porous mannitol polyvinylpolypyrrolidone polyvinyl acetate polyvidone complex, the porous maltose alcohol, in porous xylitol and the porous sorbitol one or more;
Described mannitol can be selected from
Company provides by Merck KGaA; Described mannitol can be selected from
With
Provided by French Roquette Freres; Described lactose can be selected from
With
Provided by the Germany happy group of U.S. agent; Described lactose can be selected from
Company provides by Sheffield, GBR; Described lactose can be selected from
Provided by Dutch DMV company; Described starch milk saccharide complex can be selected from
Provided by French Roquette Freres; Described cellulose milk sugar complex can be selected from
Provided by the Germany happy group of U.S. agent; Described micro crystal cellulose milk sugar complex can be selected from
By the Germany happy group of U.S. agent provide, described lactose cross-linked carboxymethyl cellulose complex can be selected from Disintequik, company provides by Sheffield, GBR; Described lactose microcrystal cellulose composite can be selected from Disintequik MCC, and company provides by Sheffield, GBR; Described mannitol sodium carboxymethyl cellulose complex can be selected from
Company provides by Merck KGaA; Described lactose polyvidone polyvinylpolypyrrolidone complex can be selected from
Provided by BASF Aktiengesellschaft; Described mannitol polyvinylpolypyrrolidone polyvinyl acetate polyvidone complex can be selected from
Provided by BASF Aktiengesellschaft; Described sorbitol can be selected from
Company provides by Merck KGaA;
Described disintegrating agent is one or more in microcrystalline Cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and the hydroxypropyl cellulose;
Described Opadry film coating pre-mix dose is Opadry
Opadry
Opadry
Opadry
Opadry
With
In a kind of.
Described Opadry film coating pre-mix dose ingredient generally comprises polyvinyl alcohol, titanium dioxide, Pulvis Talci, Polyethylene Glycol, phospholipid or soybean phospholipid, hydroxypropyl emthylcellulose, yellow ferric oxide, red ferric oxide etc., and concrete model and product are provided by Shanghai Colorcon Coating Technology Co., Ltd.
Opadry film coating pre-mix dose in the above-mentioned Menglusitena tablet composition and the consumption of purified water are in right amount, are that this is that those skilled in the art all can control flexibly because can rule of thumb regulate in the production process.
Preferably, described component comprises following component by weight:
Preferably, described component comprises following component by weight:
Preferably, described component comprises following component by weight:
Preferably, described component comprises following component by weight:
The present invention also provides a kind of preparation method of Menglusitena tablet composition, may further comprise the steps:
(1) Menglusitena, porous filler and disintegrating agent are crossed 40～80 mesh sieves, lubricant is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing Menglusitena, porous filler, disintegrating agent and the lubricant of recipe quantity, drop in the mixer and mix 25～45 minutes, for subsequent use;
(3) pressed powder;
(4) configuration coating solution: the Opadry film coating pre-mix dose is joined in the purified water while stirring, and then stir the coating solution that was configured to 15%～20% concentration in 30～50 minutes, cross 80 mesh sieves, for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
Preferably, the incorporation time in the described step (2) is 30 minutes.
Preferably, the preparation method of the porous filler in the described step (1) makes through spray-drying after being the filler dissolving.
Preferably, after the preparation method of the porous filler in the described step (1) is the filler dissolving, behind the interpolation disintegrating agent Uniform Dispersion, make through spray-drying.Again preferably, described disintegrating agent is one or more in starch, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyvinylpolypyrrolidone.
The invention provides a kind of Menglusitena tablet composition, have following beneficial effect:
1. the present invention adopts the porous filler, and feasible process has preferably practicality;
2. the Menglusitena tablet composition its related substances of the present invention's preparation is low, has improved the stability of product;
3. the bright Menglusitena tablet composition of making of this law carries and stores conveniently, and disintegrate is fast, and is scattered, and dissolution is high;
4. coat again opaque film-coat behind the Menglusitena tablet composition that the present invention makes, avoid the illumination degrading of packaging process.
The present invention also provides a kind of preparation method of Menglusitena tablet composition, has following beneficial effect:
1. the present invention adopts direct powder compression, and feasible process has preferably practicality;
2. the present invention adopts direct powder compression, thereby has avoided dry run and damp and hot impact on product quality in the conventional wet granulating process, has improved the stability of product;
3. the present invention adopts direct powder compression, and is simple to operation, and production process is easy to control;
4. each batch of direct powder compression favorable reproducibility of the present invention, process stabilizing.
The specific embodiment
The above is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also are considered as protection scope of the present invention.
Embodiment one
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena,
Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, hyprolose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing recipe quantity Menglusitena,
Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, hyprolose and magnesium stearate drop in the mixer and mixed 25 minutes, and be for subsequent use;
(3) pressed powder;
(4) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
Embodiment two
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) preparation porous sorbitol: after the dissolving of water solublity sorbitol, be prepared into through spray-drying and have porous granule;
(2) Menglusitena, porous sorbitol, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(3) take by weighing Menglusitena, porous sorbitol, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the magnesium stearate of recipe quantity, drop in the mixer and mixed 45 minutes, for subsequent use;
(4) pressed powder;
(5) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(6) film coating namely gets the Menglusitena tablet composition.
Embodiment three
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing recipe quantity Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate drop in the mixer and mixed 30 minutes, and be for subsequent use;
(3) pressed powder;
(4) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 30 minutes, crosses 80 mesh sieves, and is for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
Embodiment four
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing recipe quantity Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate drop in the mixer and mixed 30 minutes, and be for subsequent use;
(3) pressed powder;
(4) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 50 minutes, crosses 80 mesh sieves, and is for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
Embodiment five
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena,
Microcrystalline Cellulose, carboxymethyl starch sodium are crossed 80 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing recipe quantity Menglusitena,
Microcrystalline Cellulose, carboxymethyl starch sodium and magnesium stearate drop in the mixer and mixed 30 minutes, and be for subsequent use;
(3) pressed powder;
(4) configuration coating solution: will
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
Embodiment six
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) preparation porous maltose alcohol: after the dissolving of water solublity maltose alcohol, add the polyvinylpolypyrrolidone Uniform Dispersion after, be prepared into through spray-drying and have porous granule;
(2) Menglusitena, porous maltose alcohol polyvinylpolypyrrolidone complex, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, lubricant is crossed 100 mesh sieves, mix homogeneously;
(3) take by weighing Menglusitena, porous maltose alcohol polyvinylpolypyrrolidone complex, low-substituted hydroxypropyl cellulose and the magnesium stearate of recipe quantity, drop in the mixer and mixed 30 minutes, for subsequent use;
(4) pressed powder;
(5) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 15% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(6) film coating namely gets the Menglusitena tablet composition.
Embodiment seven
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) preparation porous xylitol: after the dissolving of water solublity xylitol, add 5 parts of low-substituted hydroxypropyl cellulose Uniform Dispersions after, be prepared into through spray-drying and have porous granule;
(2) Menglusitena, porous xylitol low-substituted hydroxypropyl cellulose complex, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(3) take by weighing Menglusitena, porous xylitol low-substituted hydroxypropyl cellulose complex, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the magnesium stearate of recipe quantity, drop in the mixer and mixed 30 minutes, for subsequent use;
(4) pressed powder;
(5) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 20% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(6) film coating namely gets the Menglusitena tablet composition.
Embodiment eight
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing recipe quantity Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate drop in the mixer and mixed 30 minutes, and be for subsequent use;
(3) pressed powder;
(4) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
Embodiment nine
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing recipe quantity Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate drop in the mixer and mixed 30 minutes, and be for subsequent use;
(3) pressed powder;
(4) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
Embodiment ten
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing recipe quantity Menglusitena,
Cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate drop in the mixer and mixed 30 minutes, and be for subsequent use;
(3) pressed powder;
(4) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
The comparative example
For clearly setting forth beneficial effect of the present invention, provide Menglusitena tablet composition of the present invention and preparation method thereof embodiment and comparative example one, two contrast test as follows:
The comparative example one
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) with Menglusitena, spray-dried lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, as the hyprolose of binding agent cross 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, and is for subsequent use;
(2) hyprolose dissolving being made concentration is 2% aqueous solution, as binding agent;
(3) take by weighing Menglusitena, spray-dried lactose, microcrystalline Cellulose and the cross-linking sodium carboxymethyl cellulose of recipe quantity, drop in the efficient wet granulator and mixed 5 minutes, add binding agent soft material processed, 20 mesh sieves are granulated, 18 mesh sieve granulate are crossed in 50 ℃ of oven dry, namely get intermediate;
(4) intermediate after the assay was approved, tabletting;
(5) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(6) film coating namely gets the Menglusitena tablet composition.
The comparative example two
A kind of Menglusitena tablet composition comprises following component by weight:
A kind of preparation method of Menglusitena tablet composition may further comprise the steps:
(1) Menglusitena, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose are crossed 60 mesh sieves, magnesium stearate is crossed 100 mesh sieves, the crystallization lactose is crossed 200 mesh sieves, and is for subsequent use;
(2) hyprolose dissolving being made concentration is 2% aqueous solution, as binding agent;
(3) take by weighing Menglusitena, crystallization lactose, microcrystalline Cellulose and the cross-linking sodium carboxymethyl cellulose of recipe quantity, drop in the efficient wet granulator and mixed 5 minutes, add binding agent soft material processed, 20 mesh sieves are granulated, 18 mesh sieve granulate are crossed in 50 ℃ of oven dry, namely get intermediate;
(4) intermediate after the assay was approved, tabletting;
(5) configuration coating solution: with Opadry
Film coating pre-mix dose joins in the purified water while stirring, and then stirs the coating solution that was configured to 18% concentration in 45 minutes, crosses 80 mesh sieves, and is for subsequent use;
(6) film coating namely gets the Menglusitena tablet composition.Menglusitena tablet composition long-time stability are investigated
One, test objective: by to each embodiment study on the stability, measure each index, observe the quality stability situation of change.
Two, test method: embodiment 1～10 and comparative example 1,2 prepared Menglusitena tablet compositions, aluminum aluminum packing, respectively at 25 ℃ ± 2 ℃, place under RH60% ± 10% condition, take out in 0 month, June, December, 18 months, 24 months and to investigate as follows its character, related substance, dissolution, content and uniformity of dosage units, compare, the results are shown in Table 2.
1, character detection method visual method is observed the character situation of change.
2, determination of related substances method
The lucifuge operation.Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability are filler with the phenyl bonded silica gel, 50 ℃ of column temperatures; The detection wavelength is 255nm; Flow rate of mobile phase is 1.5ml/min; Sampling volume 20 μ l; Adopt linear gradient elution, mobile phase and elution program see Table 1:
Mobile phase A: 0.2% trifluoroacetic acid aqueous solution Mobile phase B: methanol-acetonitrile (60:40)
Table 1 mobile phase and elution program
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 48 | 52 |
| 5 | 45 | 55 |
| 12 | 45 | 55 |
| 22 | 25 | 75 |
| 23 | 25 | 75 |
| 25 | 48 | 52 |
| 30 | 48 | 52 |
Take off and state system suitability solution 20 μ l sample introductions, the relative retention time of catabolite sulfoxide, ketone group methanol, cis-isomer, methyl ketone is about 0.45,0.71,0.92,1.05, and the separating degree of cis-isomer and montelukast should be not less than 1.5; The theoretical cam curve of main peak should be not less than 5000, and the tailing factor of main peak should be not more than 2.5.
The about 41mg of Menglusitena reference substance is got in the preparation of reference substance solution, and is accurately weighed, puts in the brown measuring bottle of 100ml, adds the mixed solution 80ml of methanol-water (3:1), makes dissolving in ultrasonic 5 minutes, lets cool to room temperature, adds mixed solution to scale.
Reference substance solution 1ml is got in the preparation of 0.1% reference substance solution, with mixed solution dissolving and be diluted to 100ml, shakes up.Get mentioned solution 5ml, with mixed solution dissolving and be diluted to 50ml, shake up.
Reference substance solution 10ml is got in the preparation of system suitability solution, puts in the colourless measuring bottle of 10ml, adds 4 μ l hydrogen peroxide and shakes up.Measuring bottle was put natural light lower 1 hour.
8 of this product are got in the preparation of need testing solution, put in the brown measuring bottle of 100ml, add the mixed solution 80ml of methanol-water (3:1), made dissolving in ultrasonic 30 minutes, and let cool to room temperature, add mixed solution and be diluted to scale, with the membrane filtration of 0.45 μ m, discard just filtrate, get subsequent filtrate as sample solution.
Algoscopy is got 0.1% reference substance solution, 20 μ l sample introductions, and the sensitivity of regulating instrument makes the signal to noise ratio at montelukast peak be not less than 10; Difference extracting sample solution and reference substance solution 20 μ l sample introductions, the content of calculating degradation product (pressing montelukast calculates).Wherein the content of sulfoxide must not cross 1.5%; The content of cis-isomer must not cross 0.1%; The content of ketone group methanol (relative response factor is 1.7) must not cross 0.1%; The content of methyl ketone must not cross 0.1%; The content of other maximum single impurity must not cross 0.1%; Total impurities content must not cross 1.7%.
3, dissolution determination method
The lucifuge operation.Measure according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C the second method).
Sodium dodecyl sulfate solution 900ml take 0.5% is as dissolution medium, and rotating speed is 50 rev/mins, in accordance with the law operation.Get solution in the time of 20 minutes and filter, get subsequent filtrate as sample solution.Other gets the about 55mg of Menglusitena reference substance, and is accurately weighed, puts in the brown measuring bottle of 200ml, adds the about 150ml of methanol solution, makes dissolving in ultrasonic 5 minutes, lets cool to room temperature, adds methanol solution to scale.Get above-mentioned reference substance solution 1ml, with dissolution medium dissolving and be diluted to 50ml, shake up, in contrast product solution.Each 50 μ l of extracting sample solution and reference substance solution measure according to method under the Content uniformity test item, and limit is 85% of labelled amount.
4, content assaying method
Lucifuge operation according to the method under the related substance item, is got respectively sample introduction of need testing solution and reference substance solution, the record chromatogram, and external standard method is with calculated by peak area, and get final product.
5, uniformity of dosage units detection method
Instrument: Waters 2695-2489 type high performance liquid chromatograph; Intersil phenyl post (5 μ m, 4.6mm * 250mm); Electronic balance AL204; Electronic balance AB265-S
Mobile phase: the acetonitrile solution=50:50 of 0.2% trifluoroacetic acid aqueous solution-0.2% trifluoroacetic acid
Chromatographic condition: column temperature: 50 ℃; Detect wavelength: 389nm; Flow velocity: 0.9ml/min; Sampling volume: 10 μ l;
The sample preparation: the about 52mg of Menglusitena reference substance is got in the preparation of reference substance solution, and is accurately weighed.The mixed solution 150ml that adds methanol-water (3:1), the supersound process accelerate dissolution lets cool to room temperature, adds mixed solution to 200ml, shakes up, and gets mentioned solution 5ml, with the dissolving of the mixed solution of methanol-water (3:1) and be diluted to 50ml.
The preparation of need testing solution is got a slice and is put in the brown measuring bottle, add mixed solution, made dissolving in ultrasonic 30 minutes, let cool to room temperature, add mixed solution and be diluted to scale, be mixed with the solution that every 100ml contains the 2.5mg montelukast approximately, with the membrane filtration of 0.45 μ m, discard just filtrate, getting subsequent filtrate is sample solution.
Sample determination: get respectively reference substance solution and sample solution sample introduction, the record chromatogram, external standard method is asked its meansigma methods with the content X of every of calculated by peak area
And the absolute value A between standard deviation S and labelled amount and the average: such as A+1.8S≤15.0, represent that then the uniformity of dosage units of test sample is up to specification.
Table 2 long-term stable experiment comparative result
From above embodiment 1～10 and comparative example 1,2 table 2 relatively can be found out, the present invention is with embodiment 1～10 Menglusitena tablet composition of direct powder compression preparation with the comparative example 1 of wet granulation preparation, 2 Menglusitena tablet compositions are compared, in character, dissolution, content and uniformity of dosage units aspect do not have notable difference, but aspect related substance, then differ greatly, the amount of the related substance of 0 month Menglusitena tablet composition that embodiment 1～10 method is prepared is respectively: 0 month sulfoxide≤0.15 of embodiment 1～10, ketone group methanol≤0.00, cis-isomer≤0.05, methyl ketone≤0.08, other single maximum contaminant≤0.06, total impurities≤0.32; 0 month sulfoxide 0.29 of comparative example 1, ketone group methanol 0.05, cis-isomer 0.05, methyl ketone 0.08, other single maximum contaminant 0.08, total impurities 0.92; 0 month sulfoxide 0.36 of comparative example 2, ketone group methanol 0.06, cis-isomer 0.03, methyl ketone 0.04, other single maximum contaminant 0.08, total impurities 1.01, the amount of 0 month related substance of comparative example 1,2 preparations is apparently higher than 0 month Menglusitena tablet composition of embodiment 1～10 preparation.
Relatively it can also be seen that from above embodiment 1～10 and comparative example 1,2 table 2, long-time stability are investigated result's demonstration in 24 months under same package condition and same test conditions, the amount of the related substance of 0 month Menglusitena tablet composition of embodiment 1～10 preparation is respectively: 0 month sulfoxide≤0.30 of embodiment 1～10, ketone group methanol≤0.00, cis-isomer≤0.05, methyl ketone≤0.09, other single maximum contaminant≤0.07, total impurities≤0.54; The amount of the related substance ketone group methanol of embodiment 1～10 Menglusitena tablet composition, the isomer of taking advantage of a situation, methyl ketone is temporal evolution not substantially, the amount of related substance sulfoxide, other single maximum contaminant and total impurities only slightly increases, less than or the limit that requires much smaller than quality standard; Otherwise, 0 month sulfoxide 0.71 of comparative example 1, ketone group methanol 0.12, cis-isomer 0.06, methyl ketone 0.08, other single maximum contaminant 0.36, total impurities 1.41; 0 month sulfoxide 0.86 of comparative example 2, ketone group methanol 0.17, cis-isomer 0.08, methyl ketone 0.09, other single maximum contaminant 0.39, total impurities 1.64, the related substance basic temporal evolution not of amount of isomer, methyl ketone of taking advantage of a situation in comparative example 1, the 2 Menglusitena tablet compositions, the quantitative changeization of related substance sulfoxide, ketone group methanol, other single maximum contaminant and total impurities is more obvious, and related substance ketone group methanol, other single maximum contaminant have all exceeded the standard code limit at 24 months in the probation in comparative example 1 and 2.
Therefore, Menglusitena tablet composition of the present invention and be starkly lower than the Menglusitena tablet compositions of comparative example 1,2 preparations with the Menglusitena tablet composition related substance amount of preparation method of the present invention preparation, product stability is significantly improved.
Claims (10)
1. Menglusitena tablet composition, it is characterized in that: said composition comprises following component by weight:
Wherein, described porous filler is porous mannitol, the porous lactose, porous starch milk saccharide complex, porous fiber element lactose complex, porous micro crystal cellulose milk sugar complex, porous lactose cross-linked carboxymethyl cellulose complex, porous lactose microcrystal cellulose composite, porous microcrystalline Cellulose mannitol complex, porous mannitol sodium carboxymethyl cellulose complex, porous lactose polyvidone polyvinylpolypyrrolidone complex, porous mannitol polyvinylpolypyrrolidone polyvinyl acetate polyvidone complex, the porous maltose alcohol, in porous xylitol and the porous sorbitol one or more;
Described disintegrating agent is one or more in microcrystalline Cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and the low-substituted hydroxypropyl cellulose;
Described Opadry film coating pre-mix dose is Opadry
Opadry
Opadry
Opadry
Opadry
With
In a kind of.
2. compositions according to claim 1, it is characterized in that: described component comprises following component by weight:
3. compositions according to claim 1, it is characterized in that: described component comprises following component by weight:
4. compositions according to claim 1, it is characterized in that: described component comprises following component by weight:
5. compositions according to claim 1, it is characterized in that: described component comprises following component by weight:
6. the preparation method of each described Menglusitena tablet composition in 5 according to claim 1 is characterized in that: may further comprise the steps:
(1) Menglusitena, porous filler and disintegrating agent are crossed 40～80 mesh sieves, lubricant is crossed 100 mesh sieves, mix homogeneously;
(2) take by weighing Menglusitena, porous filler, disintegrating agent and the lubricant of recipe quantity, drop in the mixer and mix 25～45 minutes, for subsequent use;
(3) pressed powder;
(4) configuration coating solution: the Opadry film coating pre-mix dose is joined in the purified water while stirring, and then stir the coating solution that was configured to 15%～20% concentration in 30～50 minutes, cross 80 mesh sieves, for subsequent use;
(5) film coating namely gets the Menglusitena tablet composition.
7. preparation method according to claim 6, it is characterized in that: the incorporation time in the described step (2) is 30 minutes.
8. preparation method according to claim 6 is characterized in that: the preparation method of the porous filler in the described step (1) makes through spray-drying after being the filler dissolving.
9. preparation method according to claim 6 is characterized in that: after the preparation method of the porous filler in the described step (1) is the filler dissolving, behind the interpolation disintegrating agent Uniform Dispersion, make through spray-drying.
10. preparation method according to claim 9, it is characterized in that: described disintegrating agent is one or more in starch, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyvinylpolypyrrolidone.
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| CN2012105743942A CN103040784A (en) | 2012-12-26 | 2012-12-26 | Montelukast tablet composition and preparation method thereof |
| PCT/CN2012/087853 WO2014101115A1 (en) | 2012-12-26 | 2012-12-28 | Montelukast sodium tablet composition and preparation method thereof |
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| CN103655497A (en) * | 2013-12-18 | 2014-03-26 | 北京华禧联合科技发展有限公司 | Montelukast orally disintegrating tablet and preparation method thereof |
| CN103690508A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | Tablet composition containing pitavastatin calcium and preparation method of tablet |
| CN105456213A (en) * | 2015-12-31 | 2016-04-06 | 鲁南贝特制药有限公司 | Montelukast sodium tablet |
| CN105616368A (en) * | 2016-01-22 | 2016-06-01 | 山东新时代药业有限公司 | Montelukast sodium tablet and preparation method thereof |
| CN106474080A (en) * | 2016-09-24 | 2017-03-08 | 万特制药(海南)有限公司 | A kind of Montelukast receives oral disintegrating tablet and preparation method thereof |
| CN110575444A (en) * | 2019-10-08 | 2019-12-17 | 苏州弘森药业股份有限公司 | Preparation method of doxepin hydrochloride membrane controlled release preparation |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103655497A (en) * | 2013-12-18 | 2014-03-26 | 北京华禧联合科技发展有限公司 | Montelukast orally disintegrating tablet and preparation method thereof |
| CN103690508A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | Tablet composition containing pitavastatin calcium and preparation method of tablet |
| CN103655497B (en) * | 2013-12-18 | 2018-05-29 | 北京华禧联合科技发展有限公司 | A kind of Montelukast Sodium oral disnitegration tablet and preparation method thereof |
| CN105456213A (en) * | 2015-12-31 | 2016-04-06 | 鲁南贝特制药有限公司 | Montelukast sodium tablet |
| CN105616368A (en) * | 2016-01-22 | 2016-06-01 | 山东新时代药业有限公司 | Montelukast sodium tablet and preparation method thereof |
| CN106474080A (en) * | 2016-09-24 | 2017-03-08 | 万特制药(海南)有限公司 | A kind of Montelukast receives oral disintegrating tablet and preparation method thereof |
| CN110575444A (en) * | 2019-10-08 | 2019-12-17 | 苏州弘森药业股份有限公司 | Preparation method of doxepin hydrochloride membrane controlled release preparation |
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| WO2014101115A1 (en) | 2014-07-03 |
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