CN104146975A - Montelukast sodium chewable tablet, preparation method and determination method of dissolution rate - Google Patents
Montelukast sodium chewable tablet, preparation method and determination method of dissolution rate Download PDFInfo
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Abstract
The invention relates to the field of medicinal preparations and particularly relates to a montelukast sodium chewable tablet, apreparation method and a determination method of a dissolution rate. Raw materials of the montelukast sodium chewable tablet comprise montelukast sodium, mannitol, microcrystalline cellulose, hydroxy propyl cellulose, crosslinking sodium carboxymethylcellulose, aspartame, ferric oxide, magnesium stearate and cherry essence. The hydroxy propyl cellulose is prepared into a solution with a mass percentage content being 6-8% through water being a solvent and a disintegrating agent is prepared through a wet process of an internal addition method. The montelukast sodium chewable tablet is significantly increased in disintegrating speed and in-vitro dissolution rate. By means of a dissolution curve detection method, quality differences among products in each batch can be effectively distinguished. Differences between products in each batch can be reduced better and a quality risk of the products can be controlled in a controllable range.
Description
Technical field
The present invention relates to field of medicaments, particularly a kind of Menglusitena chewable tablet and preparation method thereof and dissolving-out method.
Background technology
Montelukast is nonsteroidal anti-inflammatory drug of new generation, is a kind of selectivity LTRA.This product has affinity and the selectivity of height to CysLT1 receptor (Leukotrienes sputum receptor 1), the proinflammatory effect Control of asthma outbreak of blocking-up leukotriene and without any receptor agonist activity, its Clinical efficacy and safety for the treatment of childhood asthma is confirmed.
Menglusitena is the sodium-salt form of montelukast, and less stable is unstable to strong acid, illumination, easily decompose, and meets oxidant oxidizable.Menglusitena is one of best-selling treating asthma medicine in the world at present, and over 1998, in the listing of a plurality of countries and regions, existing dosage form has Film coated tablets, chewable tablet, oral cavity disintegration tablet, granule.In technique, take direct powder compression and wet granulation as main.Though direct powder compression can be simplified production technology, shorten the production cycle.But the mobile phase of powder is poor, very high to the requirement of adjuvant, under the condition without additives in prescription, easily cause content to decline, many drawbacks such as related substance increase.And the stripping of finished product is on the low side compared with wet granulation.Current wet granulations that adopt, slice, thin piece external form that this method is produced is better, compressibility is high, stripping good, bioavailability is high, adds the stability that applicable additives improve product more.But mainly there is at present following problem: 1) Menglusitena is shown in that light easily produces photodegradative cis-isomer impurity, has relatively high expectations to production environment.2) part wet granulation technology adopts ethanol as adhesive solvent, because Menglusitena is very easily dissolved in the decline that alcohols solvent causes main content, affects quality and the curative effect of product.
CN101732268A (CN201010003871.0) discloses a kind of montelukast sodium tablet, it is comprised of Menglusitena, microcrystalline Cellulose, carboxymethyl starch sodium, iron oxide red, lubricant, fluidizer and binding agent, and wherein lubricant is magnesium stearate or zinc stearate; Fluidizer is micropowder silica gel, talcous a kind of or two kinds; Binding agent is selected from one or more in polyvinylpyrrolidone-vinyl acetate co-polymer, sodium carboxymethyl cellulose and polyvinylpyrrolidone.This invention adopts iron oxide red coloring agent and dry method polyvinyl pyrrolidone-vinyl acetate co-polymer to solve the problem that in preparation process, Menglusitena is shown in photo-labile, direct compression after employing dry granulation.
CN101773481A (CN201010003886.7) discloses a kind of Menglusitena chewable tablet, it is characterized in that it is composed of the following components: Menglusitena, microcrystalline Cellulose, mannitol, 4%PVPK30 alcoholic solution, zinc stearate and opacifier, described opacifier is iron oxide red, iron oxide yellow or titanium dioxide.
CN1961867A (CN200610151038.4) discloses a kind of montelukast sodium granules type, wherein contains: (1) Menglusitena, (2) auxiliary additive is the additive of preparing the pharmaceutically acceptable granule dosage form of granule dosage form.
Application for a patent for invention prospectus CN101365450A discloses the stabilised pharmaceutical preparation of Menglusitena, the chewable tablet that contains Menglusitena is wherein disclosed, disclosed chewable tablet comprises Menglusitena, hydroxypropyl cellulose, sodium starch glycolate, mannitol, coloring agent (as ferrum oxide), additional sweeting agent, flavouring agent and magnesium stearate, does not contain microcrystalline Cellulose.
Publication number is the patent of CN103239450A, by adding the additives such as sodium hydroxide, sodium carbonate to improve stability and the dissolubility of tablet in prescription.This patent is thought Menglusitena indissoluble in gastrointestinal sour environment, can improve the alkaline microenvironment of oral solid formulation by additives, to improve the dissolution rate of medicine, promotes medicine absorption in vivo.
The most patents that retrieved, that mode by the adjuvant of Menglusitena chewable tablet being adjusted or being added additives is to improve preparation stability or stripping, do not relate to the improvement to disintegration rate, and do not relate to the improvement of Menglusitena chewable tablet dissolving-out method.
Summary of the invention
The object of this invention is to provide a kind of Menglusitena chewable tablet and preparation method thereof
Another object of the present invention is to provide a kind of assay method of Menglusitena chewable tablet dissolution.
In order to realize object of the present invention, the present invention adopts following technical scheme: a kind of Menglusitena chewable tablet, is prepared from by the raw material that comprises following weight portion:
It is that solvent is mixed with the solution that quality percentage composition is 6-8% that described hydroxypropyl cellulose adopts water.
In order to realize better tabletting and result of extraction, the present invention preferably adopts following technical scheme, and a kind of Menglusitena chewable tablet, is prepared from by the raw material that comprises following weight portion:
The present invention finds after deliberation, only need by 95% ethanol, change the solvent of preparation binding agent into water, and the disintegration rate of Menglusitena chewable tablet and dissolution in vitro just can significantly improve.And MK chewable tablet of the present invention all can be realized with former and grind the similar stripping behavior of medicine Singulair that contrasts in 0.4-0.6% (mass volume ratio) sodium lauryl sulphate phosphate buffered solution, and can effectively distinguish that production technology changes and formulation and technology changes the stripping impact that product is caused, stability and former bioequivalence of grinding product between having guaranteed batch.
Another technical scheme of the present invention, the preparation method that Menglusitena of the present invention is chewed, comprises the following steps:
(1), under the condition of lucifuge, Menglusitena crude drug, magnesium stearate, red ferric oxide, mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, aspartame, cherry essence are sieved respectively;
(2) take hyprolose and add purified water, be stirred to and dissolve completely, being mixed with quality percentage composition is 6-8% aqueous solution;
(3) by the Menglusitena having sieved, mannitol, microcrystalline Cellulose, partial cross-linked sodium carboxymethyl cellulose, red ferric oxide mix homogeneously in wet granulation equipment, the hyprolose aqueous solution that adds step (2) to be mixed with, wet granulation, granulate;
(4) wet granular step (3) being made, through fluidized drying, makes moisture Control below 1.5%, granulate;
(5) add cross-linking sodium carboxymethyl cellulose, cherry essence, the A Siba of surplus sweet, magnesium stearate mix after tabletting.
Preparation method disintegrating agent of the present invention (cross-linking sodium carboxymethyl cellulose) adopts and in step (3) and (5) two steps of step, adds respectively, and this kind of preparation method can effectively improve the dissolution of medicine.
Concrete, step (1) is crossed 80-100 mesh sieve by Menglusitena crude drug, magnesium stearate, red ferric oxide; Mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, A Siba are sweet, cherry essence is crossed 60-80 mesh sieve.
Concrete, the 40-60% that the addition of the described cross-linking sodium carboxymethyl cellulose of step (3) is all cross-linking sodium carboxymethyl celluloses, preferably 50%.
Concrete, 30 mesh sieve granulate for step (3); 20 mesh sieve granulate for step (4); Step (5) is mixed 15-20min in three-dimensional motion mixer.
Concrete, in step (4), wet granular is put to fluidized drying and can be selected the arbitrary scheme in prior art scheme, preferably adopt following technical scheme: in fluidization drying apparatus, 40 ℃ of-45 ℃ of fluidized drying 30min-40min.
Concrete, the described mixing of step (5) can be selected the arbitrary scheme in prior art scheme, preferably adopts following technical scheme: in three-dimensional motion mixer, mix 15-20min.
Concrete, the described tabletting of step (5) can be selected the arbitrary scheme in prior art scheme, preferably adopts following technical scheme: adopt high speed rotating tablet machine tabletting, the heavily about 0.3g of sheet, pressure 60-75N, diameter 10mm.
In addition, even if experimenter of the present invention finds that in prescription research process existing dissolving-out method still can show good stripping curve and stripping behavior under the condition of change prescription, processing parameter.Such dissolving-out method has brought certain risk to the control of the control of product quality and production technology.The present invention, according to experiment experience in the past, on existing methodical basis, has made improvement to dissolving-out method, has improved selectivity and the differentiation power of dissolving-out method.
Another technical scheme of the present invention, the assay method of Menglusitena chewable tablet dissolution, according to two appendix XC dissolution method the second methods of Chinese Pharmacopoeia version in 2010, the sodium lauryl sulphate phosphate buffered solution that the mass volume ratio of take is 0.4-0.6% is dissolution medium.Mass volume ratio herein refers to the mass volume ratio of sodium lauryl sulphate and phosphate buffer.
Concrete, the assay method of Menglusitena chewable tablet dissolution of the present invention comprises the following steps:
(1) getting 5mg chewable tablet, to take the sodium lauryl sulphate phosphate buffered solution that 900ml mass volume ratio is 0.4-0.6% be dissolution medium, rotating speed is per minute 50 to turn, during respectively at 5min, 10min, 15min, 20min, 30min, sample 10ml, filter, get subsequent filtrate as need testing solution; Separately get reference substance 15mg, add dissolve with methanol and be diluted to 50ml, shake up, after shaking up, get 2ml solution, add mass volume ratio 0.4-0.6% sodium lauryl sulphate phosphate buffered saline(PBS) dissolved dilution to 100ml, in contrast product solution;
(2) get need testing solution and the reference substance solution employing high performance liquid chromatography of step (1) gained, take phenyl bonded silica gel as filler, take 0.2% trifluoroacetic acid aqueous solution (mass volume ratio) and 0.2% trifluoroacetic acid acetonitrile solution (mass volume ratio) by volume as the mixed solution of 1: 1 is mobile phase, by external standard method with calculated by peak area dissolution.
Preferably, step (1) is got 5mg chewable tablet, and to take the sodium lauryl sulphate phosphate buffered solution that 900ml mass volume ratio is 0.5% be dissolution medium, rotating speed is per minute 50 to turn, during respectively at 5min, 10min, 15min, 20min, 30min, sample 10ml, filter, get subsequent filtrate as need testing solution; Separately get reference substance 15mg, add dissolve with methanol and be diluted to 50ml, after shaking up, get 2ml solution, add mass volume ratio 0.5% sodium lauryl sulphate phosphate buffered saline(PBS) dissolved dilution to 100ml, in contrast product solution.
The described reference substance of step (1) is chosen a kind of in montelukast hexanamine salt, montelukast acid, Menglusitena, preferably montelukast hexanamine salt.
Concrete, when step (2) adopts high performance liquid chromatography, flow velocity is 0.8-1.0ml/min; Column temperature is 48-52 ℃, and sampling volume is 48-52 μ l.
Dissolving-out method of the present invention can show good stripping curve and stripping behavior, thereby can control the quality of product at change prescription, the equal of processing parameter all existing products.Under poor prescription and technological parameter, stripping curve and behavior performance are poor, and under normal process and parameter, stripping curve and behavior show up to specification, and the dissolving-out method of existing standard can not be distinguished.
The assay method of Menglusitena chewable tablet dissolution provided by the invention can also be for measuring tablet and the granule containing montelukast sodium raw materials.
Accompanying drawing explanation
Fig. 1 is the stripping curve that Singulair and embodiment 4 utilize dissolution determination method of the present invention to measure;
Fig. 2 is the stripping curve of measuring with dissolution determination method of the present invention at different disintegrating agent consumption prescription condition diarrhea;
Fig. 3 is the stripping curve comparison of measuring with dissolution determination method of the present invention at different-grain diameter raw material prescription condition diarrhea;
Fig. 4 is Singulair and embodiment 4 stripping curve under standard leaching condition abroad;
Fig. 5 is the stripping curve under standard leaching condition abroad under different disintegrating agent consumption prescription conditions;
Fig. 6 is the stripping curve under standard leaching condition abroad under different-grain diameter raw material prescription condition.
The specific embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
Embodiment 1-embodiment 3
In embodiment 1-embodiment 3, Menglusitena chewable tablet comprises that raw material is as follows:
| Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Menglusitena 3g | Menglusitena 2g | Menglusitena 1g |
| Mannitol 128g | Mannitol 75.25g | Mannitol 42.6g |
| Microcrystalline Cellulose 22g | Microcrystalline Cellulose 14.75 | Microcrystalline Cellulose 7.5g |
| Hydroxypropyl cellulose 2.33g | Hydroxypropyl cellulose 1.5g | Hydroxypropyl cellulose 0.8g |
| Cross-linking sodium carboxymethyl cellulose 9g | Cross-linking sodium carboxymethyl cellulose 6g | Cross-linking sodium carboxymethyl cellulose 3g |
| The sweet 0.3g of A Siba | The sweet 0.2g of A Siba | The sweet 0.1g of A Siba |
| Red ferric oxide 0.9g | Red ferric oxide 0.9g | Red ferric oxide 0.3g |
| Magnesium stearate 0.6g | Magnesium stearate 0.6g | Magnesium stearate 0.2g |
| Cherry essence 0.45g | Cherry essence 0.45g | Cherry essence 0.15g |
The preparation method of embodiment 1 Menglusitena chewable tablet comprises the following steps:
(1), under the condition of lucifuge, Menglusitena crude drug, magnesium stearate, red ferric oxide are crossed to 100 mesh sieves; Mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, A Siba are sweet, cherry essence is crossed 80 mesh sieves;
(2) take hyprolose and add purified water, be stirred to and dissolve completely, be mixed with 8% hyprolose adhesive aqueous solution;
(3) by the Menglusitena having sieved, mannitol, microcrystalline Cellulose, partial cross-linked sodium carboxymethyl cellulose (in mass ratio, account for all cross-linking sodium carboxymethyl celluloses 60%), red ferric oxide mix homogeneously in wet granulation equipment, the 8% hyprolose aqueous solution that adds step (2) to be mixed with, wet granulation, with 30 mesh sieve granulate;
(4) wet granular step (3) being made is put into fluidized bed drying equipment, and dry 30min, makes moisture Control below 1.5%, 20 mesh sieve granulate for dried particles at 40 ℃;
(5) add that surplus cross-linking sodium carboxymethyl cellulose, cherry essence, A Siba are sweet, magnesium stearate is mixed 15min in three-dimensional motion mixer, with Highspeedrotarytabletpress, be pressed into tablet.
The preparation method of embodiment 2 MK chewable tablet is compared with embodiment 1, and difference is: step (2) takes hyprolose and adds purified water, is stirred to and dissolves completely, and being mixed with quality percentage composition is 6% aqueous solution.
The preparation method of embodiment 3 MK chewable tablet is compared with embodiment 1, and difference is: the addition of the described cross-linking sodium carboxymethyl cellulose of step (3) is all cross-linking sodium carboxymethyl celluloses 40%.
Experimental example 1:
This experimental example is according to dissolution determination method of the present invention, and the Menglusitena chewable tablet of embodiment 1-embodiment 3 preparations is carried out to the research of stripping curve.
The dissolution determination method of embodiment 1, comprises the following steps:
(1) according to two appendix XC dissolution method the second methods of Chinese Pharmacopoeia version in 2010, getting chewable tablet a slice (5mg/ sheet), to take 0.4% (mass volume ratio) sodium lauryl sulphate phosphate buffered solution (pH=6.8) 900ml be dissolution medium, rotating speed is per minute 50 to turn, during respectively at 5min, 10min, 15min, 20min, 30min, sample 10ml, filter, get subsequent filtrate as need testing solution, equivalent is supplemented synthermal fresh dissolution medium; Separately get montelukast hexanamine salt 15mg, add dissolve with methanol and be diluted to 50ml, shake up, get above-mentioned solution 2ml, add 0.5% sodium lauryl sulphate phosphate buffered solution dissolved dilution to 100ml, in contrast product solution;
(2) according to two appendix VD of Chinese Pharmacopoeia version in 2010, get step (1) need testing solution and reference substance solution and adopt high performance liquid chromatography, take phenyl bonded silica gel as filler, the mixed solution that 0.2% trifluoroacetic acid aqueous solution and 0.2% trifluoroacetic acid acetonitrile solution are 1: 1 by volume of take is mobile phase, and flow velocity is 0.9ml/min; Column temperature is 50 ℃, and sampling volume is 50 μ l, by external standard method with calculated by peak area dissolution.
The assay method of embodiment 2 dissolutions is compared with embodiment 1, and difference is: by mass volume ratio, take containing 0.6% sodium lauryl sulphate phosphate buffered solution is dissolution medium.
The assay method of embodiment 3 dissolutions is compared with embodiment 1, and difference is: by mass volume ratio, take containing 0.5% sodium lauryl sulphate phosphate buffered solution is dissolution medium.
The dissolution of table 1 embodiment 1-embodiment 3 Menglusitena chewable tablet
The disintegration rate of table 2 embodiment 1-embodiment 3 Menglusitena chewable tablet
| Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Disintegration | ＜3min | ＜3min | ＜4min |
Embodiment 4
In the present embodiment, Menglusitena chewable tablet comprises the raw material of following weight:
In the present embodiment, the preparation method of Menglusitena chewable tablet comprises the following steps:
(1), under the condition of lucifuge, Menglusitena crude drug, magnesium stearate, red ferric oxide are crossed to 100 mesh sieves; Mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, A Siba are sweet, cherry essence is crossed 80 mesh sieves;
(2) take hyprolose and add purified water, be stirred to and dissolve completely, be mixed with 8% hyprolose adhesive aqueous solution;
(3) by the Menglusitena having sieved, mannitol, microcrystalline Cellulose, 9.6g cross-linking sodium carboxymethyl cellulose, red ferric oxide mix homogeneously in wet granulation equipment, the 8% hyprolose aqueous solution that adds step (2) to be mixed with, wet granulation, with 30 mesh sieve granulate;
(4) wet granular step (3) being made is put into fluidized bed drying equipment, and dry 30min, makes moisture Control below 1.5%, 20 mesh sieve granulate for dried particles at 40 ℃;
(5) add cross-linking sodium carboxymethyl cellulose, cherry essence, the A Siba of surplus 9.6g sweet, magnesium stearate mixes 15min in three-dimensional motion mixer, with Highspeedrotarytabletpress, is pressed into tablet.
Embodiment 5
In the raw material of the present embodiment chewable tablet, except the consumption of cross-linking sodium carboxymethyl cellulose is different from embodiment 1, the composition of remainder and consumption are all identical with embodiment 4.The consumption of cross-linking sodium carboxymethyl cellulose is 4.8g in the present embodiment.The prescription sample that departs from scope that this embodiment designs for experimenter is checking dissolving-out method.
The preparation method that the present embodiment is concrete, except adding cross-linking sodium carboxymethyl cellulose 2.4g in step (3), step (5) adds outside cross-linking sodium carboxymethyl cellulose 2.4g, and all the other steps are also identical with embodiment 1.
Embodiment 6
In the raw material of the present embodiment chewable tablet, except the consumption of cross-linking sodium carboxymethyl cellulose is different from embodiment 1, the composition of remainder and consumption are all identical with embodiment 4.The consumption of cross-linking sodium carboxymethyl cellulose is 9.6g in the present embodiment.
The preparation method that the present embodiment is concrete, except adding cross-linking sodium carboxymethyl cellulose 4.8g in step (3), step (5) adds outside cross-linking sodium carboxymethyl cellulose 4.8g, and all the other steps are also identical with embodiment 1.
Embodiment 7
The raw material of the present embodiment chewable tablet forms with embodiment 1.
The preparation method of the present embodiment, except the Menglusitena mean diameter of using is 30 μ m, is about to Menglusitena and crosses outside 380 mesh sieves, and all the other preparation process are consistent with embodiment 4.
Embodiment 8
The raw material of the present embodiment chewable tablet forms with embodiment 1.
The preparation method of the present embodiment, except the Menglusitena mean diameter of using is 150 μ m, is about to Menglusitena and crosses outside 80 mesh sieves, and all the other preparation process are consistent with embodiment 4.
Experimental example 2
The present embodiment has been measured the dissolution of the chewable tablet of embodiment 4-embodiment 8 preparations.Wherein the Singulair in table 1 and Fig. 1 is commercially available Menglusitena chewable tablet, and manufacturer is MerckSharp & Dohme Ltd. (U.K.), specification 5mg/ sheet; Embodiment 4 is Menglusitena chewable tablet provided by the invention, and Singulair and embodiment 4 dissolutions the results are shown in Table 3 and Fig. 1; Embodiment 5 and embodiment 6 are the dissolution of crucial adjuvant (cross-linking sodium carboxymethyl cellulose) consumption Menglusitena chewable tablet while changing, and it the results are shown in Table 4 and Fig. 2; Menglusitena chewable tablet dissolution when embodiment 7 and embodiment 8 change for Menglusitena particle diameter, it the results are shown in Table 5 and Fig. 3.
Table 3 Singulair and the dissolution of embodiment 4 under leaching condition of the present invention
Dissolution under the chewable tablet of the different disintegrating agent consumptions of table 4 under leaching condition of the present invention
The dissolution of the chewable tablet of table 5 different material particle diameter under leaching condition of the present invention
Table 6 Singulair and embodiment comparison 4 disintegration
| Sample title | Singulair | Embodiment 1 sample |
| Complete disintegration | ＜5min | ＜3min |
By table 3 and Fig. 1, can be found out, under identical condition determination, the dissolution of Menglusitena chewable tablet provided by the invention is greater than Singulair, and in 15min, Menglusitena chewable tablet dissolution of the present invention is greater than 85%, meets the requirement of chewable tablet correlation technique.
, in the process that the dissolution of Menglusitena chewable tablet and Singulair is measured, find meanwhile, the disintegrate completely in 3 minutes of embodiment 4 samples, disintegration rate is faster than Singulair.
Again, from table 3-table 5 and Fig. 1-Fig. 3, dissolution determination method of the present invention can be distinguished different prescriptions preferably and technique causes the mass discrepancy between product, can better control product quality attribute.
Comparative example
This comparative example is the dissolution in vitro experimental technique with reference to existing external report, carries out the research of the Menglusitena chewable tablet In Vitro Dissolution curve of embodiment 4-embodiment 8 preparations.
Concrete, in this comparative example, Menglusitena chewable tablet dissolution in vitro experimental technique is as follows:
(1) lucifuge operation, get Menglusitena chewable tablet a slice (5mg/ sheet) of embodiment 4-embodiment 8 preparations according to dissolution method (two appendix XC dissolution method the second methods of Chinese Pharmacopoeia version in 2010), take respectively that to contain 0.5% (mass volume ratio) lauryl sodium sulfate aqueous solution 900ml be dissolution medium, rotating speed is per minute 50 to turn, respectively at 5min, 10min, 15min, 20min, during 30min, sample 10ml, filter, get subsequent filtrate as need testing solution, equivalent is supplemented synthermal fresh dissolution medium, i.e. 0.5% lauryl sodium sulfate aqueous solution, separately get montelukast hexanamine salt 15mg, add dissolve with methanol and be diluted to 50ml, shake up, get above-mentioned solution 2ml, add 0.5% lauryl sodium sulfate aqueous solution and be diluted to 100ml, in contrast product solution,
(2) according to two appendix V D of Chinese Pharmacopoeia version in 2010, get step (1) need testing solution and reference substance solution and adopt high performance liquid chromatography, take phenyl bonded silica gel as filler, the mixed solution that 0.2% trifluoroacetic acid aqueous solution and 0.2% trifluoroacetic acid acetonitrile solution are 1: 1 by volume of take is mobile phase, and flow velocity is 0.9ml/min; Column temperature is 50 ℃, and sampling volume is 50 μ l, by external standard method with calculated by peak area dissolution.
This comparative example has been measured the dissolution of the chewable tablet of embodiment 4-embodiment 8 preparations, wherein the Singulair in table 7 and Fig. 4 is commercially available Menglusitena chewable tablet, manufacturer is Merck Sharp & Dohme Ltd. (U.K.), specification 5mg/ sheet, embodiment 4 is Menglusitena chewable tablet provided by the invention, and its dissolution the results are shown in Table 7 and Fig. 4; Embodiment 5 and embodiment 6 are the dissolution of crucial adjuvant (cross-linking sodium carboxymethyl cellulose) consumption chewable tablet while changing, and it the results are shown in Table 8 and Fig. 5; Dissolution when embodiment 7 and embodiment 8 change for Menglusitena particle diameter, its result is table 9 and Fig. 6.
Table 7 Singulair and embodiment 4 be the dissolution under standard leaching condition abroad
Dissolution under standard leaching condition abroad under the chewable tablet of the different disintegrating agent consumptions of table 8
The chewable tablet of table 9 different material particle diameter is the dissolution under standard leaching condition abroad
In oral solid formulation preparation process, the particle diameter of raw material, granularity, crystal formation, the disintegrating agent consumption in prescription can cause the change of final sample dissolution.For the such crude drug of Menglusitena, disintegrating agent consumption, raw material particle size in its prescription affect preparation stripping behavior, and the present invention selects different-grain diameter, different disintegrating agent consumption to make preparation, investigates the difference of these preparation stripping behaviors.
From table 7-table 9 and Fig. 4-Fig. 6, existing dissolution determination method is the in the situation that of raw material particle size change and the change of crucial supplementary product consumption, and prepared sample still shows similar stripping behavior, and dissolving-out method does not have certain differentiation power.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a Menglusitena chewable tablet, is characterized in that: by the raw material that comprises following weight portion, be prepared from:
It is that solvent is mixed with the solution that quality percentage composition is 6-8% that described hydroxypropyl cellulose adopts water.
2. Menglusitena chewable tablet according to claim 1, is characterized in that: by the raw material that comprises following weight portion, be prepared from:
3. the preparation method of the Menglusitena chewable tablet described in claim 1 or 2, is characterized in that, comprises the following steps:
(1), under the condition of lucifuge, Menglusitena, magnesium stearate, red ferric oxide, mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, A Siba is sweet, cherry essence sieves respectively;
(2) take hyprolose and add purified water, be stirred to and dissolve completely, being mixed with quality percentage composition is 6-8% aqueous solution;
(3) by the Menglusitena having sieved, mannitol, microcrystalline Cellulose, partial cross-linked sodium carboxymethyl cellulose, red ferric oxide mix homogeneously in wet granulation equipment, the hyprolose aqueous solution that adds step (2) to be mixed with, wet granulation, granulate;
(4) wet granular step (3) being made, through fluidized drying, makes moisture Control below 1.5%, granulate;
(5) add cross-linking sodium carboxymethyl cellulose, cherry essence, the A Siba of surplus sweet, magnesium stearate mix after tabletting.
4. preparation method according to claim 4, is characterized in that: the 40-60% that the addition of the described cross-linking sodium carboxymethyl cellulose of step (3) is all cross-linking sodium carboxymethyl celluloses, preferably 50%.
5. the assay method of Menglusitena chewable tablet dissolution described in claim 1 or 2, according to two appendix XC dissolution method the second methods of Chinese Pharmacopoeia version in 2010, it is characterized in that: the sodium lauryl sulphate phosphate buffered solution of mass volume ratio 0.4-0.6% of take is dissolution medium.
6. the assay method of dissolution according to claim 5, is characterized in that, comprises the following steps:
(1) getting 5mg chewable tablet, to take the sodium lauryl sulphate phosphate buffered solution that 900ml mass volume ratio is 0.4-0.6% be dissolution medium, rotating speed is per minute 50 to turn, during respectively at 5min, 10min, 15min, 20min, 30min, sample 10ml, filter, get subsequent filtrate as need testing solution; Separately get reference substance 15mg, add dissolve with methanol and be diluted to 50ml, after shaking up, get 2ml solution, add mass volume ratio 0.4-0.6% sodium lauryl sulphate phosphate buffered saline(PBS) dissolved dilution to 100ml, in contrast product solution;
(2) get need testing solution and the reference substance solution employing high performance liquid chromatography of step (1) gained, take phenyl bonded silica gel as filler, take 0.2% trifluoroacetic acid aqueous solution and 0.2% trifluoroacetic acid acetonitrile solution by volume as the mixed solution of 1: 1 is mobile phase, by external standard method with calculated by peak area dissolution.
7. the assay method of dissolution according to claim 6, it is characterized in that: step (1) is got 5mg chewable tablet, and to take the sodium lauryl sulphate phosphate buffered solution that 900ml mass volume ratio is 0.5% be dissolution medium, rotating speed is per minute 50 to turn, during respectively at 5min, 10min, 15min, 20min, 30min, sample 10ml, filter, get subsequent filtrate as need testing solution; Separately get reference substance 15mg, add dissolve with methanol and be diluted to 50ml, after shaking up, get 2ml solution, add mass volume ratio 0.5% sodium lauryl sulphate phosphate buffered saline(PBS) dissolved dilution to 100ml, in contrast product solution.
8. the assay method of dissolution according to claim 6, is characterized in that: the described reference substance of step (1) is chosen a kind of in montelukast hexanamine salt, montelukast acid, Menglusitena.
9. the assay method of dissolution according to claim 6, is characterized in that: when step (2) adopts high performance liquid chromatography, flow velocity is 0.8-1.0ml/min; Column temperature is 48-52 ℃, and sampling volume is 48-52 μ l.
10. the application of the assay method of dissolution described in claim 5-9 any one.
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Cited By (8)
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| CN105287413A (en) * | 2015-10-23 | 2016-02-03 | 南京泽恒医药技术开发有限公司 | Chewable tablet containing montelukast sodium and preparation method of chewable 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 |
| CN108186594A (en) * | 2018-03-09 | 2018-06-22 | 上海安必生制药技术有限公司 | A kind of Montelukast sodium chewable tablet and preparation method thereof |
| CN109833302A (en) * | 2017-11-29 | 2019-06-04 | 扬子江药业集团有限公司 | A kind of stable Montelukast sodium chewable tablet and preparation method thereof |
| CN109900823A (en) * | 2019-03-12 | 2019-06-18 | 康诚科瑞医药研发（武汉）有限公司 | The quantitative detecting method of montelukast in a kind of human plasma |
| CN111000813A (en) * | 2020-01-06 | 2020-04-14 | 国药集团致君（深圳）坪山制药有限公司 | Montelukast sodium chewable tablet and preparation method thereof |
| CN112034118A (en) * | 2020-07-29 | 2020-12-04 | 北京诺康达医药科技股份有限公司 | Method for rapidly detecting dissolution rate of solid preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105287413A (en) * | 2015-10-23 | 2016-02-03 | 南京泽恒医药技术开发有限公司 | Chewable tablet containing montelukast sodium and preparation method of chewable 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 |
| CN109833302A (en) * | 2017-11-29 | 2019-06-04 | 扬子江药业集团有限公司 | A kind of stable Montelukast sodium chewable tablet and preparation method thereof |
| CN108186594A (en) * | 2018-03-09 | 2018-06-22 | 上海安必生制药技术有限公司 | A kind of Montelukast sodium chewable tablet and preparation method thereof |
| CN108186594B (en) * | 2018-03-09 | 2021-08-13 | 上海安必生制药技术有限公司 | Montelukast sodium chewable tablet and preparation method thereof |
| CN109900823A (en) * | 2019-03-12 | 2019-06-18 | 康诚科瑞医药研发（武汉）有限公司 | The quantitative detecting method of montelukast in a kind of human plasma |
| CN111000813A (en) * | 2020-01-06 | 2020-04-14 | 国药集团致君（深圳）坪山制药有限公司 | Montelukast sodium chewable tablet and preparation method thereof |
| CN112034118A (en) * | 2020-07-29 | 2020-12-04 | 北京诺康达医药科技股份有限公司 | Method for rapidly detecting dissolution rate of solid preparation |
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Application publication date: 20141119 |