CN103520130B - Montelukast sodium time-selective controlled-release tablet and preparation method thereof - Google Patents
Montelukast sodium time-selective controlled-release tablet and preparation method thereof Download PDFInfo
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- CN103520130B CN103520130B CN201310482964.XA CN201310482964A CN103520130B CN 103520130 B CN103520130 B CN 103520130B CN 201310482964 A CN201310482964 A CN 201310482964A CN 103520130 B CN103520130 B CN 103520130B
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Abstract
The invention discloses a Montelukast sodium time-selective controlled-release tablet and a preparation method thereof. The montelukast sodium controlled-release tablet consists of a quick-release tablet core and a slow-release outer layer. The tablet core consists of active pharmaceutical ingredients, a diluent, a disintegrating agent and a lubricant; the outer layer is composed of medicine, diluent, slow-release high molecular material and lubricant. The time-selective controlled release tablet is a chrono-therapeutic drug for asthma, and a patient only needs to take the drug once before sleeping at night, and the safety and the effectiveness of the drug can be improved.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of a montelukast sodium time-selective controlled release tablet.
Background
In recent years, studies show that physiological characteristics of human body such as blood pressure, heart rate, gastric secretion and the like have circadian rhythmicity, and occurrence of many diseases has similar laws, such as hypertension, arthritis, angina pectoris and the like. With the development of an hourly pathology study, it was found that asthma and related diseases usually occurred in the early morning and were relieved during the day. Asthma is a paroxysmal wheeze and cough with dyspnea, and the patient has difficulty in breathing rapidly during the attack, even cannot lie flat. In asthma attacks, aerosols, if used, although they act rapidly, but interfere with patient rest; the common preparation can not ensure enough blood concentration at 3-4 am; although the sustained-release preparation can keep the blood concentration stable for a long time, the high-concentration medicament can also improve the toxic and side effects of the preparation and reduce the safety of medication.
The montelukast sodium can also regulate CD4+ and CD5+ T cells in peripheral blood, further regulate inflammatory response, reduce histamine release of cells, and is mainly used for preventing and treating adult and child asthma clinically and for a long term, and can be used together with hormones and antihistamines to enhance clinical effects.
The patent CN102688238A discloses a compound granule of montelukast sodium and calcium citrate, which is used for treating allergic asthma and allergic rhinitis, the patent CN102085187B discloses a montelukast sodium liposome solid preparation which is stable to light and heat, the patent CN101773481B discloses a montelukast sodium chewable tablet, the patent CN102552921A discloses a composition consisting of montelukast sodium and polyacrylic resin L100-55, the stability of montelukast sodium can be obviously improved, and the risk of oxidizing montelukast sodium into montelukast ketone is reduced, and the patent CN1287792 discloses a dispersible tablet of montelukast sodium.
Foreign patents on formulation of montelukast sodium are: US20110189274 discloses stable mixtures of montelukast and its salts and the like with microcrystalline cellulose, flavoring agents and the like. US20030096840 discloses a method for the preparation of oral granules of montelukast sodium. European patent EP2540298a1 discloses a coated solid formulation of montelukast which is capable of improving the stability of the drug against moisture. World patent WO2012121461 discloses a montelukast oral film formulation that is rapidly soluble in water.
Domestic patents on chronogenesis pulse preparations include: CN102764243A discloses a preparation method of aspirin pulse release pellets, which can reduce the local concentration of the drug in the gastrointestinal tract and improve the stability of the drug. CN102429892A adopts styrene sulfonic acid-methacrylic acid copolymer as pulse controlled release material to prepare the levalbuterol sulfate pulse capsule, which is clinically used as antitussive. CN102100680A discloses a pulsatile formulation of benazepril, an antihypertensive drug, which employs a coating method to release the drug in a controlled manner and at a predetermined time.
Foreign patents on chronotropic pulse formulations include: US6627222 and US6991807 report the use of pulsatile delivery systems for antibiotic drugs, the delivery systems comprising a single immediate release portion and a plurality of delayed release portions, which are better able to reduce the incidence of microbial resistance.
According to the search, although some common dosage forms of the montelukast sodium have been developed at present, the montelukast sodium pulse-release tablets designed according to the rhythmicity of asthma attack are not reported in the patent.
Disclosure of Invention
The invention aims at the time characteristic of asthma attack and aims at designing a time-selecting drug-releasing oral tablet of montelukast sodium for taking medicine before sleep. After the oral administration of a patient, the medicine is quickly released and reaches the effective concentration, and the sustained-release part reaches the peak value of blood concentration at midnight, so that the attack of asthma is reduced, the sleep time of the patient is prolonged, and the safety and the effectiveness of the medicine are improved. Aiming at the defects of the existing preparation, the invention carries out a great deal of related researches according to the physicochemical properties of the Montelukast sodium and develops the oral pulse tablet with the time-selective controlled release characteristic.
The technical scheme of the montelukast sodium time-selective controlled-release tablet comprises the following steps:
the invention is characterized in that the prepared Montelukast sodium time-selecting controlled-release tablet consists of a controlled-release outer layer and a quick-release core, the medicine is released at a 0-level speed in a specific time after the medicine is taken, and the medicine of the core is released suddenly when the peak period of asthma attack is reached, so that higher blood concentration is generated, and the attack of asthma is better inhibited.
The invention is characterized in that the preparation technology of the press coating is adopted, and a part of montelukast sodium raw material and other auxiliary materials are prepared into a tablet core with quick release capability; then, part of the Montelukast sodium raw material and auxiliary materials including high polymer materials for controlling drug release are granulated and then tableted.
In the quick release tablet core in the embodiment of the invention, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl starch, pregelatinized starch and the like are preferably used as disintegrants, lactose, microcrystalline cellulose, corn starch, polyhydric alcohol and pregelatinized starch are used as fillers, polyhydric sugar alcohol is preferably used as a filler, part of the montelukast sodium raw material and the above filler disintegrant are subjected to dry granulation and then mixed with a lubricant to be tabletted, the montelukast sodium raw material and the filler disintegrant are premixed and then added with the lubricant to be tabletted directly to prepare the tablet core, the tablet core prepared by the traditional wet granulation process can be pressed, and the tablet core is required to be completely dissolved within 10 minutes by adopting a paddle method of 500 rpm500m L0.1.1N HCl.
In the immediate release tablet core in the embodiments of the present invention, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), Methylcellulose (MC), hydroxyethyl cellulose (HEC), or mixtures thereof are preferably used,
FS series,
R L series,
RS series,
NE series,
NM series and
SR, ethyl cellulose with various viscosity specifications and aqueous dispersions thereof are used as polymer materials for controlling drug release. Mixing the montelukast sodium and the filling agent, and mixing the mixture into the partial high polymer materialAnd then granulating. A wet granulation process and a fluidized bed one-step granulation process can be adopted; is preferably used in granulation
NE30D and
SR30D, can be used alone, can also use in combination.
The montelukast sodium time-selective controlled-release tablet provided by the invention can be taken before sleeping and then releases the drug at level 0 to maintain a specific blood concentration, and the drug in the quick-release part is released suddenly before the peak period of the early asthma attack in the morning to achieve a higher blood concentration, so that the attack of asthma can be better controlled.
Drawings
FIG. 1 is a schematic structural diagram of the time-selecting controlled-release tablet of the present invention, which comprises a controlled-release outer layer and an immediate-release core.
Figure 2 is a graph of the release profile of the formulation of example 1.
Figure 3 is a graph of the release profile of the formulation of example 2.
Detailed Description
Example 1:
taking hydroxypropyl cellulose EF20g, preparing a 5% solution with water, adding 25g of montelukast sodium raw material, and uniformly stirring for later use; taking 337.5g of mannitol powder and 101100g of microcrystalline cellulose, preheating and boiling the mannitol powder and the microcrystalline cellulose in a fluidized bed for 10 minutes, spraying the materials, drying the materials to 40 ℃, then adding 15g of croscarmellose sodium, drying the materials to 50-55 ℃, discharging the materials, and finishing granules by a 0.6mm conical sieve; transferring to a hopper mixer, adding 2.5g of magnesium stearate, and mixing for 5 minutes at 20 rpm; punching the tablet by using a 5mm shallow arc circle, controlling the weight of the tablet to be 50mg +/-1 mg and controlling the hardness to be 15-50N, thus obtaining the quick-release tablet core.
Taking 25g of montelukast sodium and 50g of lactose, uniformly mixing for later use, taking 102900g of microcrystalline cellulose, L XF150g of hydroxypropyl cellulose, MXF300g of hydroxypropyl cellulose, K4M600g of hydroxypropyl methyl cellulose and 51g of lactose, placing the mixture in a wet granulator, starting a stirring paddle and a cutting knife to mix for 3 minutes, adding the mixture of montelukast sodium and lactose, mixing for 3 minutes according to the same parameters, continuing to start the stirring paddle and the cutting knife to add water for granulation, transferring the material after the granulation to a fluidized bed, drying the material at L OD <3%, passing through a 0.8mm conical sieve, transferring the material to a hopper mixer, adding 15g of magnesium stearate, mixing for 5 minutes at 20rpm, and pressing core-spun tablets, wherein the hardness is controlled between 45N and 100N to obtain the core-spun tablets.
Example 2:
taking hydroxypropyl cellulose EF20g, preparing a 5% solution with water, adding 35g of montelukast sodium raw material, and uniformly stirring for later use; taking 337.5g of mannitol powder and 101100g of microcrystalline cellulose, preheating and boiling the mannitol powder and the microcrystalline cellulose in a fluidized bed for 10 minutes, spraying the materials, drying the materials to 40 ℃, then adding 15g of croscarmellose sodium, drying the materials to 50-55 ℃, discharging the materials, and finishing granules by a 0.6mm conical sieve; transferring to a hopper mixer, adding 2.5g of magnesium stearate, and mixing for 5 minutes at 20 rpm; punching the tablet by using a 5mm shallow arc circle, controlling the weight of the tablet to be 50mg +/-1 mg and controlling the hardness to be 15-50N, thus obtaining the quick-release tablet core.
The preparation method comprises the steps of sequentially taking 1010g of lactose, 15g of Montelukast sodium, 102900g of microcrystalline cellulose, 102900g of hydroxypropyl methyl cellulose K100L V600g and K4M30g, placing the materials in a fluidized bed, starting a fan, heating, mixing and preheating for 10 minutes, taking Kollicoat SR30D500g, adding 250g of water, uniformly stirring, spraying the materials into the fluidized bed, maintaining the temperature of the materials between 20 and 40 ℃, drying until the OD of L is less than 3 percent after spraying, sieving the materials through a 0.8mm conical sieve, transferring the materials into a hopper mixer, adding 15g of magnesium stearate, mixing for 5 minutes at 20rpm, pressing core-spun tablets, and controlling the hardness to be 45N to 100N to obtain the core-spun tablets.
Claims (2)
1. A Montelukast sodium time-selecting controlled-release tablet is characterized in that the tablet consists of a quick-release tablet core and a controlled-release outer layer,
the montelukast sodium time-selective controlled-release tablet is prepared by the following preparation method: under the condition of 25g of the Montelukast sodium raw material, 20g of hydroxypropyl cellulose EF is prepared into a 5% solution by using water, 25g of the Montelukast sodium raw material is added, and the mixture is uniformly stirred for later use; taking 337.5g of mannitol powder and 100g of microcrystalline cellulose 101, preheating and boiling in a fluidized bed for 10 minutes, spraying the materials, drying to the material temperature of 40 ℃, adding 15g of croscarmellose sodium, drying to the material temperature of 50-55 ℃, discharging, and sieving with a 0.6mm conical sieve to complete granules; transferring to a hopper mixer, adding 2.5g of magnesium stearate, and mixing for 5 minutes at 20 rpm; punching the tablet by using a 5mm shallow arc circle, controlling the weight of the tablet to be 50mg +/-1 mg and controlling the hardness to be 15-50N, thus obtaining the quick-release tablet core;
taking 25g of montelukast sodium and 50g of lactose, uniformly mixing for later use, taking 900g of microcrystalline cellulose 102, L XF150g of hydroxypropyl cellulose MXF, 300g of hydroxypropyl methyl cellulose K4M600g and 51g of lactose, placing the mixture in a wet granulator, starting a stirring paddle and a cutting knife to mix for 3 minutes, adding the mixture of montelukast sodium and lactose, mixing for 3 minutes according to the same parameters, continuing to start the stirring paddle and the cutting knife to add water for granulation, transferring the material after the granulation is finished to a fluidized bed, drying the material at L OD <3%, passing through a 0.8mm conical sieve, transferring the material to a hopper mixer, adding 15g of magnesium stearate, mixing for 5 minutes at 20rpm, and pressing core-spun tablets, wherein the hardness is controlled between 45N and 100N to obtain the core-spun tablets.
2. A Montelukast sodium time-selecting controlled-release tablet is characterized in that the tablet consists of a quick-release tablet core and a controlled-release outer layer,
the preparation method of the montelukast sodium time-selective controlled release tablet comprises the following steps:
under the condition that the Montelukast sodium raw material is 35g, 20g of hydroxypropyl cellulose EF is prepared into a 5% solution by using water, 35g of the Montelukast sodium raw material is added, and the mixture is uniformly stirred for later use; taking 337.5g of mannitol powder and 100g of microcrystalline cellulose 101, preheating and boiling in a fluidized bed for 10 minutes, spraying the materials, drying to the material temperature of 40 ℃, adding 15g of croscarmellose sodium, drying to the material temperature of 50-55 ℃, discharging, and sieving with a 0.6mm conical sieve for finishing; transferring to a hopper mixer, adding 2.5g of magnesium stearate, and mixing for 5 minutes at 20 rpm; punching the tablet by using a 5mm shallow arc circle, controlling the weight of the tablet to be 50mg +/-1 mg and controlling the hardness to be 15-50N, thus obtaining the quick-release tablet core;
1010g of lactose, 15g of Montelukast sodium, 900g of microcrystalline cellulose 102, 100g of hydroxypropyl methyl cellulose K100L V600g and 4 g of hydroxypropyl methyl cellulose K4M30 are sequentially put into a fluidized bed, a fan is started, heating, mixing and preheating are carried out for 10 minutes, 250g of water is added into 30g of Kollicoat SR30D500, the mixture is uniformly stirred and sprayed into the fluidized bed, the temperature of the material is maintained between 20 ℃ and 40 ℃, the spraying is finished, the drying is carried out until L OD is less than 3%, the material is sieved by a conical screen of 0.8mm, the material is transferred into a hopper mixer, 15g of magnesium stearate is added, the mixture is mixed for 5 minutes at 20rpm, the core-spun tablets are pressed, and the hardness is controlled between 45N and.
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| CN105456213B (en) * | 2015-12-31 | 2017-03-01 | 鲁南贝特制药有限公司 | A kind of montelukast sodium tablet |
| CN105616368B (en) * | 2016-01-22 | 2017-02-22 | 山东新时代药业有限公司 | Montelukast sodium 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575163A (en) * | 2001-10-26 | 2005-02-02 | 麦克弗罗斯特(加拿大)公司 | Granule formulation |
| US20060147482A1 (en) * | 2005-01-04 | 2006-07-06 | Center Laboratories, Inc. | Oral liquid pharmaceutical composition of leukotriene antagonists |
| CN1961867A (en) * | 2006-11-16 | 2007-05-16 | 徐英权 | Granule formulation of montelukast sodium |
| CN101773481A (en) * | 2010-01-09 | 2010-07-14 | 鲁南制药集团股份有限公司 | Chewable tablet containing montelukast sodium |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575163A (en) * | 2001-10-26 | 2005-02-02 | 麦克弗罗斯特(加拿大)公司 | Granule formulation |
| US20060147482A1 (en) * | 2005-01-04 | 2006-07-06 | Center Laboratories, Inc. | Oral liquid pharmaceutical composition of leukotriene antagonists |
| CN1961867A (en) * | 2006-11-16 | 2007-05-16 | 徐英权 | Granule formulation of montelukast sodium |
| CN101773481A (en) * | 2010-01-09 | 2010-07-14 | 鲁南制药集团股份有限公司 | Chewable tablet containing montelukast sodium |
Non-Patent Citations (1)
| Title |
|---|
| 茶碱的时辰给药系统及其在犬体内的药物动力学;毕岳琦等;《华西药学杂志》;20071231;第22卷(第5期);516-519 * |
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