CN112546007A - Oral solid tablet containing montelukast sodium and preparation method thereof - Google Patents
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Abstract
The invention provides an oral solid tablet containing montelukast sodium and a preparation method thereof, wherein the oral solid tablet is prepared from ambroxol hydrochloride crystals, montelukast sodium and auxiliary materials, wherein the auxiliary materials comprise a filling agent, a disintegrating agent, a flavoring agent, a wetting agent and a lubricating agent; according to the weight percentage, the ambroxol hydrochloride crystal is 5-30%, and the montelukast sodium is 5-15%. The disintegrating tablet is obtained by spraying a coating solution on ambroxol hydrochloride crystals and montelukast sodium powder to obtain coated particles, mixing with the rest auxiliary materials, and tabletting. The oral solid tablet prepared by the invention has the advantages of high disintegration speed, good taste, small side effect, obvious curative effect on pulmonary fibrosis, suitability for the old and the children, wide audience and good popularization prospect.
Description
Technical Field
The invention relates to an oral solid tablet (orally disintegrating tablet) containing montelukast sodium and a preparation method thereof, belonging to the technical field of medicines.
Background
The chemical name of ambroxol hydrochloride is trans-4- [ (2-amino-3, 5-dibromo benzyl) amino ] cyclohexanol hydrochloride: the molecular formula is as follows: c13h18br2n2o.hcl, molecular weight: 414.57, ambroxol is an active metabolite of bromhexine, is a new phlegm-resolving drug, has the functions of dissolving and secreting mucus and promoting mucus discharge, can promote the secretion of lung surfactant (such as PS), can promote the emptying movement of bronchus cilia, is beneficial to discharge of airway secretions, achieves the effects of obvious sputum discharge, anti-inflammation and improvement of respiratory conditions, and has the effect of improving pulmonary fibrosis caused by Acute Respiratory Distress Syndrome (ARDS). It has been occasionally reported to have minor upper gastrointestinal side effects (mainly heartburn, dyspepsia and occasionally nausea and vomiting) after oral administration. Allergic reactions, mainly rashes, occur very rarely, and severe acute allergic reactions are reported in few cases. Montelukast sodium, an oral leukotriene receptor antagonist, is a non-hormonal anti-inflammatory drug that specifically inhibits the cysteinyl leukotriene (CysLT1) receptor in the airway, which is an important bronchogenic substance and inflammatory mediator. The pharmacological action of the montelukast sodium is realized by preventing cysteine leukotriene (CysLT) mediated bronchoconstriction, increase of vascular permeability and aggregation of airway inflammatory cells, the montelukast sodium can also inhibit the mesenchymal transformation and fibrosis of bronchial epithelial cells and inhibit the generation of matrix metalloproteinase and collagen in fibroblasts, and the montelukast sodium is suitable for the prevention and long-term treatment of asthma and the treatment of allergic rhinitis of adults and children over 1 year old, so that the airway inflammation is improved, and the asthma symptom is effectively controlled.
The Chinese patent of application No. CN201910546930.X discloses an ambroxol hydrochloride tablet and a preparation method thereof, and the preparation method comprises the steps of mixing the raw materials of the ambroxol hydrochloride tablet for 11-35min at the rotating speed of 10-18r/min, and directly tabletting; the ambroxol hydrochloride tablet is prepared from raw materials including ambroxol hydrochloride, lactose, pregelatinized starch, colloidal silicon dioxide and magnesium stearate, the raw materials of the ambroxol hydrochloride tablet are mixed for 11-35min at a low rotating speed (10-18r/min), and the pregelatinized starch and the colloidal silicon dioxide are selected for matching, so that the flowability and tabletting performance of the raw materials can be improved, the powder can be conveniently directly tabletted, and the prepared ambroxol hydrochloride tablet has better stability.
Oral liquid, tablets, capsules, sustained-release pellets and injection varieties of ambroxol hydrochloride or montelukast sodium exist in domestic and foreign markets, the common tablets have long disintegration time, and patients with dysphagia of children and old people have inconvenience in taking, poor compliance and the like, so that the effective exertion of the treatment effect is influenced.
Disclosure of Invention
In order to solve the problems of poor compliance of ambroxol hydrochloride and montelukast sodium administration and poor treatment effect in the prior art, the invention provides an oral solid tablet containing montelukast sodium and a preparation method thereof.
In order to achieve the purpose, the invention provides the following technical scheme: an oral solid tablet containing montelukast sodium comprises ambroxol hydrochloride crystals, montelukast sodium and auxiliary materials, wherein the auxiliary materials comprise a filling agent, a disintegrating agent, a flavoring agent, a wetting agent and a lubricating agent;
wherein, according to the weight percentage,
0.01 to 40 percent of ambroxol hydrochloride crystal;
0.01 to 20 percent of montelukast sodium;
40.35-93.52% of filler;
5 to 25 percent of disintegrating agent;
0.001 to 5 percent of flavoring agent;
0.01-5% of a wetting agent;
0.5 to 5 percent of lubricant.
Preferably, the ambroxol hydrochloride crystal accounts for 5-30% by weight, and the montelukast sodium accounts for 5-15% by weight.
Preferably, the filler comprises at least one of lactose, sucrose, mannitol, sorbitol, and xylitol; the disintegrant comprises at least one of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl methylcellulose, and crospovidone.
As another aspect of the present invention, the present invention provides a method for preparing an oral solid tablet containing montelukast sodium, comprising the steps of: (1) dissolving the disintegrating agent in ethanol, adding correctant, and stirring to obtain coating solution; (2) ultrasonically crushing ambroxol hydrochloride crystals and montelukast sodium into powder, and spraying the coating solution into a fluidized bed to prepare coated particles; (3) and mixing the coated granules with the rest auxiliary materials, and tabletting to obtain the ambroxol hydrochloride orally disintegrating tablet.
Preferably, in the step (2), the air inlet is controlled at 40 +/-5 ℃ and the atomization pressure is 1.8-2pa when the coating liquid is sprayed.
Preferably, in the step (3), the compression pressure during tabletting is 15-25N.
Preferably, in the step (3), the mixing time is 10-30 min.
Preferably, the purity of the ambroxol hydrochloride crystal is more than 95%.
The invention has the beneficial effects that:
1. the invention improves the crystal form of ambroxol hydrochloride, has sharp main crystal peak without steamed bread peak, has good stability and ensures good dissolution effect;
2. the orally disintegrating tablet containing montelukast sodium prepared by the invention has obvious improvement effect on pulmonary fibrosis,
3. the invention uses sweet fillers such as mannitol, lactose, xylitol and the like, can well cover the unpleasant smell of the medicine, and in addition, the obtained disintegrating tablet is quick to disintegrate and absorb, and improves the medication effect.
Drawings
FIG. 1 is a diffraction pattern of ambroxol hydrochloride crystals obtained in example 1 of the present invention;
FIG. 2 is a diffraction pattern of ambroxol hydrochloride crystals obtained in example 2 of the present invention;
FIG. 3 is a graph of the staining results of the product of example 4 for treatment of pulmonary fibrosis in rats, where A is the result of IPF treatment and B is the result of ARDS treatment;
FIG. 4 is a graph of the staining results of rats treated with pulmonary fibrosis according to example 5, where A is the result of IPF treatment and B is the result of ARDS treatment.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below.
The ambroxol hydrochloride and the montelukast sodium are produced by Shaanxi Hanjiang pharmaceutical industry, namely, the company Limited, and auxiliary material suppliers are Carlekang pharmacy, Degussa pharmacy, Lejiawen pharmacy, Qufutianli pharmacy, namely, the company Limited and Huainan Shanhe pharmacy, namely, the company Limited.
Example i:
(1) ultrasonically crushing ambroxol hydrochloride solid for 5min at the ultrasonic power of 35W to obtain powder;
under a sound field with the frequency of 15KHz and the output power of 60W, adding a mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile into the ambroxol hydrochloride powder while stirring, wherein the volume ratio of the methanol to the 2-methyltetrahydrofuran to the acetonitrile in the mixed solvent is 8:4:2, and the volume of the mixed solvent is 5 times of the weight of the ambroxol hydrochloride;
(2) controlling the temperature at 40 ℃, adding a mixed solvent of ethanol and ethyl acetate into the solution obtained in the step (1) while stirring under a sound field with the frequency of 15KHz and the output power of 40W, wherein the volume of the mixed solvent is 10 times of the weight of ambroxol hydrochloride, and the volume ratio of the ethanol to the ethyl acetate in the mixed solvent is 5: 3;
(3) cooling to-10 ℃ at the speed of 4.5 ℃/min, standing for 5 hours for crystallization, separating out crystals, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain the ambroxol hydrochloride compound.
The X-ray powder diffraction pattern of the prepared ambroxol hydrochloride crystal obtained by Cu-Kalpha ray measurement is shown in figure 1, the main peak is sharp, and the purity of the ambroxol hydrochloride crystal is 97.3% by high performance liquid chromatography.
Example 2:
(1) ultrasonically crushing ambroxol hydrochloride solid for 5min at the ultrasonic power of 35W to obtain powder;
under a sound field with the frequency of 15KHz and the output power of 60W, adding a mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile into the ambroxol hydrochloride powder while stirring, wherein the volume ratio of the methanol to the 2-methyltetrahydrofuran to the acetonitrile in the mixed solvent is 8:5:3, and the volume of the mixed solvent is 5 times of the weight of the ambroxol hydrochloride;
(2) controlling the temperature at 40 ℃, adding a mixed solvent of ethanol and ethyl acetate into the solution obtained in the step (1) while stirring under a sound field with the frequency of 15KHz and the output power of 40W, wherein the volume of the mixed solvent is 10 times of the weight of ambroxol hydrochloride, and the volume ratio of the ethanol to the ethyl acetate in the mixed solvent is 2: 1;
(3) cooling to 0 ℃ at the speed of 2.5 ℃/min, standing for 5 hours for crystallization, separating out crystals, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain the ambroxol hydrochloride compound.
The X-ray powder diffraction pattern of the prepared ambroxol hydrochloride crystal is shown in figure 2, the main peak is sharp, a small amount of impurity peaks exist, and the purity of the ambroxol hydrochloride crystal is 95.8% by high performance liquid chromatography.
Example 3:
(1) ultrasonically crushing ambroxol hydrochloride solid for 5min at the ultrasonic power of 35W to obtain powder;
under a sound field with the frequency of 15KHz and the output power of 45W, adding a mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile into the ambroxol hydrochloride powder while stirring, wherein the volume ratio of the methanol to the 2-methyltetrahydrofuran to the acetonitrile in the mixed solvent is 8:5:3, and the volume of the mixed solvent is 5 times of the weight of the ambroxol hydrochloride;
(2) controlling the temperature at 40 ℃, adding a mixed solvent of ethanol and ethyl acetate into the solution obtained in the step (1) while stirring under a sound field with the frequency of 15KHz and the output power of 20W, wherein the volume of the mixed solvent is 10 times of the weight of ambroxol hydrochloride, and the volume ratio of the ethanol to the ethyl acetate in the mixed solvent is 2: 1;
(3) cooling to 0 ℃ at the speed of 2.5 ℃/min, standing for crystallization for 3 hours, cooling to-15 ℃ at the speed of 1.5 ℃/min, standing for crystallization for 3 hours, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain the ambroxol hydrochloride compound. The prepared ambroxol hydrochloride crystal has the purity of 99.2 percent as determined by high performance liquid chromatography.
Example 4:
the raw materials of the disintegrating tablet are weighed according to the following proportion and prepared into 1000 tablets.
1) Taking the hydroxypropyl methylcellulose with the formula amount, adding 80ml of 50% ethanol water solution until the hydroxypropyl methylcellulose is completely dissolved to prepare 8% hydroxypropyl methylcellulose ethanol water solution, adding orange essence, and fully stirring for dissolving to prepare taste-masking coating solution;
2) grinding 60g of ambroxol hydrochloride crystals and 10g of montelukast sodium, placing the ground crystals into a fluidized bed, uniformly spraying the coating solution prepared in the step 1) onto the surfaces of ambroxol hydrochloride and montelukast sodium powder by using a bottom spraying spray gun, controlling the inlet air at 40 +/-5 ℃ and the atomization pressure at 1.8-2pa, and preparing coated particles by using the fluidized bed;
3) mixing the coated particles prepared in the step 2) with other auxiliary materials in a mixer according to the formula amount, wherein the mixing time is 10min, tabletting the total mixed particles, controlling the tabletting hardness to be 20N, and preparing 1000 orally disintegrating tablets, wherein the effective content of ambroxol hydrochloride in each tablet is 60mg, the content of montelukast sodium is 16mg, the tablet weight is 163.67mg, the time limit of disintegration in vitro is 40 seconds, and the dissolution rate is 99.5%.
Meanwhile, 8 healthy volunteers are subjected to taste investigation, and the 8 subjects are comprehensively fed back to have no gravel feeling and slightly bitter sweet taste, disappear after lasting for 34 seconds on average, and have an average disintegration time limit of 30 seconds in the oral cavity.
Example 5:
the raw materials of the disintegrating tablet are weighed according to the following proportion and prepared into 1000 tablets.
1) Taking the hydroxypropyl methylcellulose with the formula amount, adding 80ml of 80% ethanol water solution until the hydroxypropyl methylcellulose is completely dissolved to prepare 8% hydroxypropyl methylcellulose ethanol water solution, adding orange essence, and fully stirring for dissolving to prepare the taste-masking coating solution;
2) grinding 60g of ambroxol hydrochloride crystals and 21g of montelukast sodium, placing the ground mixture into a fluidized bed, uniformly spraying the coating solution prepared in the step 1) onto the surfaces of the ambroxol hydrochloride crystals and the montelukast sodium powder by using a bottom spraying spray gun, controlling the inlet air at 40 +/-5 ℃ and the atomization pressure at 1.8-2pa, and preparing coated particles by using the fluidized bed;
3) mixing the coated particles prepared in the step 2) with other auxiliary materials in a mixer according to the formula amount, wherein the mixing time is 10min, tabletting the total mixed particles, controlling the tabletting hardness to be 25N, and preparing 1000 ambroxol hydrochloride orally disintegrating tablets, wherein the effective content of ambroxol hydrochloride in each tablet is 60mg, the content of montelukast sodium is 21mg, the tablet weight is 222.11mg, the time limit of disintegration in vitro is 36 seconds, and the dissolution rate is 99.6%.
Meanwhile, 8 healthy volunteers are subjected to taste investigation, and the 8 subjects are comprehensively fed back to have no gravel feeling and slightly bitter sweet taste, disappear after lasting for 29 seconds on average, and the average disintegration time limit in the oral cavity is 23 seconds.
Example 6:
respectively selecting 60 idiopathic pulmonary interstitial fibrosis (IPF) rat groups and acute respiratory distress syndrome pulmonary fibrosis (ARDS) rat groups, and dividing the rat groups into 3 groups, wherein each group comprises 60 rats; the orally disintegrating tablets prepared in examples 4 and 5 were dissolved and subjected to gavage treatment 3 times per day for 2 weeks at a ratio of 30 mg/kg of low dose, 60 mg/kg of medium dose and 90 mg/kg of high dose per day.
After treatment, rat samples were removed and venous blood was taken for White Blood Cells (WBC), neutrophils (PMN)) Ratio and arterial partial pressure of blood oxygen (PaO)2) Level, lung tissue samples were collected and Masson stained for pulmonary fibrosis and the results are shown in fig. 3 and 4.
As can be seen from the treatment results, the products obtained in examples 4 and 5 have good treatment effects on idiopathic pulmonary interstitial fibrosis and acute respiratory distress syndrome pulmonary fibrosis, and each dose group can well regulate the proportion of White Blood Cells (WBC), neutrophils (PMN) and arterial blood oxygen partial pressure (PaO)2) And (4) level, and relieving symptoms. In addition, Masson staining results under an optical microscope show that compared with a normal group, the model group has obvious collagen deposition, the alveolar wall interval is enlarged, and pulmonary fibrosis is generated; the collagen deposition of the low-dose group, the medium-dose group and the high-dose group is reduced, the fibrosis of lung tissues is obviously improved, particularly, the treatment effect of the fibrosis of the lung of the medium-dose group and the high-dose group is more obvious, and the synergistic effect of the ambroxol hydrochloride and the montelukast sodium is enhanced.
The invention contains the auxiliary materials besides the main medicine, and the main materials comprise 0.01-40% of ambroxol hydrochloride and 0.01-20% of montelukast sodium in percentage by weight, and the rest 40-99.98% of the auxiliary materials. The adjuvants are any available adjuvants suitable for making orally disintegrating tablets, and they may include fillers, flavoring or taste masking agents, colorants, lubricants, etc. The orally disintegrating tablet is required to be swallowed after being rapidly dissolved in the oral cavity, has good taste and no irritation to oral mucosa, so the selection of the types and the performances of the auxiliary materials is also the key for preparing the effervescent tablet. The invention determines the pharmaceutical excipients which are suitable for the oral tablets of montelukast sodium and ambroxol hydrochloride through selection, wherein the filler is selected to increase the weight and the volume of the disintegrating tablet so as to facilitate the forming and the dose division of the preparation. The fillers of the invention, such as lactose, sucrose, mannitol, xylitol, and the like, have the important function of flavoring; disintegrating agents commonly added include croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl methylcellulose, and crospovidone; meanwhile, a proper amount of flavoring agent with stronger taste masking effect is added, and the flavoring agent is preferably at least one of glycyrrhizin, grape, disodium glycyrrhizinate, trisodium glycyrrhizinate, mint, orange, kudzu, banana, aspartame, sucrose, aspartame and stevioside, so that the bad strange taste of ambroxol hydrochloride and the like is further masked, and the mouthfeel of the disintegrating tablet is improved.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. All equivalent changes and modifications made according to the disclosure of the present invention are covered by the scope of the claims of the present invention.
Claims (8)
1. An oral solid tablet comprising montelukast sodium, characterized in that: the raw materials comprise ambroxol hydrochloride crystals, montelukast sodium and auxiliary materials, wherein the auxiliary materials comprise a filling agent, a disintegrating agent, a flavoring agent, a wetting agent and a lubricating agent;
wherein, according to the weight percentage,
0.01 to 40 percent of ambroxol hydrochloride crystal;
0.01 to 20 percent of montelukast sodium;
40.35-93.52% of filler;
5 to 25 percent of disintegrating agent;
0.001 to 5 percent of flavoring agent;
0.01-5% of a wetting agent;
0.5 to 5 percent of lubricant.
2. The oral solid tablet of claim 1, comprising montelukast sodium wherein: according to the weight percentage, the ambroxol hydrochloride crystal is 5-30%, and the montelukast sodium is 5-15%.
3. An oral solid tablet comprising montelukast sodium according to claim 1 or 2, wherein: the filler comprises at least one of lactose, sucrose, mannitol, sorbitol and xylitol; the disintegrant comprises at least one of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl methylcellulose, and crospovidone.
4. The process for preparing oral solid tablets containing montelukast sodium according to claim 1, wherein: the method comprises the following steps:
(1) dissolving the disintegrating agent in ethanol, adding correctant, and stirring to obtain coating solution;
(2) ultrasonically crushing ambroxol hydrochloride crystals and montelukast sodium into powder, placing the powder in a fluidized bed, and spraying the coating solution to prepare coated particles;
(3) and mixing the coated granules with the rest auxiliary materials, and tabletting to obtain the ambroxol hydrochloride orally disintegrating tablet.
5. The process for preparing a solid tablet for oral administration comprising montelukast sodium according to claim 4, wherein: in the step (2), when the coating liquid is sprayed, the inlet air is controlled at 40 +/-5 ℃, and the atomization pressure is 1.8-2 pa.
6. The process for preparing a solid tablet for oral administration comprising montelukast sodium according to claim 4, wherein: in the step (3), the pressure during tabletting is 15-25N.
7. The process for preparing a solid tablet for oral administration comprising montelukast sodium according to claim 4, wherein: in the step (3), the mixing time is 10-30 min.
8. The process for preparing a solid tablet for oral administration comprising montelukast sodium according to claim 4, wherein: the purity of the ambroxol hydrochloride crystal is more than 95 percent.
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| CN202011627383.7A CN112546007A (en) | 2020-12-31 | 2020-12-31 | Oral solid tablet containing montelukast sodium and preparation method thereof |
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| CN202011627383.7A CN112546007A (en) | 2020-12-31 | 2020-12-31 | Oral solid tablet containing montelukast sodium and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070202055A1 (en) * | 2006-02-09 | 2007-08-30 | Julianne Berry | Pharmaceutical Formulations |
| CN102716128A (en) * | 2012-07-03 | 2012-10-10 | *** | Pharmaceutical composition for treating asthma |
| CN104860832A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug ambroxol hydrochloride composition for treating respiratory system disease |
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- 2020-12-31 CN CN202011627383.7A patent/CN112546007A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070202055A1 (en) * | 2006-02-09 | 2007-08-30 | Julianne Berry | Pharmaceutical Formulations |
| CN102716128A (en) * | 2012-07-03 | 2012-10-10 | *** | Pharmaceutical composition for treating asthma |
| CN104860832A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug ambroxol hydrochloride composition for treating respiratory system disease |
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Application publication date: 20210326 |