CN103520136B - Montelukast sodium pulse capsule and preparation method thereof - Google Patents
Montelukast sodium pulse capsule and preparation method thereof Download PDFInfo
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- CN103520136B CN103520136B CN201310483443.6A CN201310483443A CN103520136B CN 103520136 B CN103520136 B CN 103520136B CN 201310483443 A CN201310483443 A CN 201310483443A CN 103520136 B CN103520136 B CN 103520136B
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Abstract
The invention discloses a Montelukast sodium pulse capsule capable of releasing medicine at a specific time. The montelukast sodium pulse capsule consists of a quick release part and a modified release part, wherein the quick release part consists of quick release powder or quick release granules, and the powder or the granules of the quick release part are prepared from hydrophilic auxiliary materials; the release-regulating part consists of release-regulating particles, and the release-regulating particles are coated with an outer coating consisting of one or more pH-dependent polymers. Compared with the common preparation, the pulse release capsule of the invention reaches the peak value of blood concentration at the time when asthma is easy to attack in the morning, can meet the aim of hour treatment, and improves the effectiveness and safety of the medicine for asthma patients.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a Montelukast sodium time-selecting pulse-release capsule and a preparation method thereof.
Background
The Montelukast sodium is a potent cysteinyl leukotriene 1 receptor antagonist drug, can block the combination of leukotriene and receptor, and block the inflammatory action of leukotriene, regulates the vascular permeability by selectively inhibiting the activity of leukotriene polypeptide in airway smooth muscle, reducing the expression of vascular endothelial growth factor, improves airway edema, effectively prevents and inhibits the infiltration of airway eosinophilic granulocyte and bronchospasm.
Asthma is a global disease, and according to epidemiological statistics, 3 hundred million asthma patients exist in the world at present, and the number of asthma patients in China is up to 3000 thousands. Ancient Chinese medicine found that the attack of asthma is in the law of light day and heavy night, and the attack in the latter half of the night is more than that in the former half of the night, so there is a saying that "Bai Bian, Dan Hui Luan, and xi Jia Shi Ji Shi" in Ling Shu, divided into four seasons in one day. With the development of chronophysiology in recent years, a timing administration concept is provided aiming at the pathological characteristic that asthma is most likely to attack at 3-4 points in the morning. If the montelukast sodium for treating asthma is prepared into a time-selective pulse administration capsule, a quick-release part (quick-release powder or quick-release granules) can quickly take effect, and a release-regulating part (release-regulating granules or release-regulating pellets) reaches the peak value of blood concentration at the middle night, so that the aim of time-based treatment is fulfilled, the safety and compliance of administration of a patient are improved, and the attack of asthma can be more effectively prevented and treated.
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. US20030096840a1 discloses a process 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.
In search, although some common Montelukast sodium dosage forms have been developed, no patent report has been found on Montelukast sodium pulse capsule dosage forms designed according to the rhythmicity of asthma attack.
Disclosure of Invention
The invention aims to overcome the defects of the conventional montelukast sodium common preparation by a preparation means, and provides a montelukast sodium pulse capsule which can ensure effective blood concentration and remarkably improve the safety and compliance of medicine taking of an asthma patient according to the rhythmicity characteristic of asthma attack. The preparation is firstly released from the quick-release part into the blood, so that the patient can fall asleep safely; then the modified release part reaches the peak value of blood concentration at 3-4 hours in the morning, and the possibility of attack of asthma patients in the middle of the night is reduced. Therefore, the invention can improve the life quality of asthma patients and improve the safety and effectiveness of medication.
The Montelukast sodium pulse capsule comprises: an immediate release portion and a modified release portion. Wherein the quick-release part can be quick-release powder or quick-release granules, and the quick-release part comprises main drug, filler, disintegrating agent, adhesive, and lubricant; the release regulating part comprises main medicine, filler, adhesive and lubricant, and enteric coating is coated on the powder or granule, and the coating layer comprises enteric coating material, antisticking agent, plasticizer and other adjuvants.
The filler of the invention is: one or more of lactose, mannitol, sorbitol and other polyhydric sugar alcohols.
The adhesive of the invention is as follows: one or more of hypromellose, hydroxypropyl methylcellulose, and polyvidone.
Hair brushThe enteric material is sold under the trade name of
L100、
L100-55、，
L30D-55, and having the trade name
And shellac.
The slow-release high polymer material is preferably ethyl cellulose or aqueous dispersion thereof, and the trade name of the slow-release high polymer material is ethyl cellulose
R L type resin and its aqueous dispersion,
RS type resin and its aqueous dispersion,
MAE30D and
one or more of SR 30D.
The disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.
The anti-sticking agent can be selected from one or more of liver transplantation monostearate, hydrogenated vegetable oil, calcium stearate or talcum powder.
The plasticizer of the invention can be selected from the following components: one or more of triethyl citrate, dibutyl sebacate, PEG and the like.
The preparation method of the quick release and modified release granules comprises the following steps: placing the raw and auxiliary materials into a wet granulator according to a prescription, adding water to prepare soft materials, granulating by using a granulator or a swing granulator, or extruding, rounding and granulating by using an extruding and rounding machine, and drying to obtain quick-release granules; coating the quick-release granules with enteric coating material or enteric slow-release compound coating material to obtain the release-regulated granules.
The preparation method of the quick release and modified release pellet comprises the following steps: placing the blank pellet core in proper equipment such as a fluidized bed or a centrifugal granulation coating machine, adding a surfactant, an adhesive and montelukast sodium into a proper amount of water, uniformly stirring, spraying the pellet for carrying the medicine, and drying to obtain a quick-release pellet; drying, and coating with enteric-coated material or enteric-coated sustained-release compound material to obtain the controlled-release pellet.
The drug release curve is drawn by dissolving the drug in artificial gastric juice for 2 hours at 50rpm according to USP II method and then dissolving the drug in artificial intestinal juice for 12 hours. The experimental result shows that compared with the prior art, the Montelukast sodium pulse capsule provided by the invention can release the medicine according to the preset time compared with the existing Montelukast sodium preparation.
Drawings
Figure 1 is a graph of the release profile of the formulation of example 1.
Figure 2 is a graph of the release profile of the formulation of example 2.
Detailed Description
Example 1
Taking 20g of montelukast sodium, 880g of lactose (200 meshes), 50g of hydroxypropyl methylcellulose (EF) and 50g of croscarmellose sodium, dissolving the hydroxypropyl methylcellulose in a proper amount of water, adding the montelukast sodium, uniformly stirring, placing the lactose and the croscarmellose sodium into a 4L wet method, firstly stirring at 500rpm, cutting and mixing at 1000rpm for 180 seconds, then adding the adhesive solution containing the main drug under the same parameters, granulating for a proper time after the addition is finished, discharging, granulating by using a 26-mesh swing granulator, and drying until the OD of L is less than 3.0%, thus obtaining the quick-release granules.
Preparing 30g of montelukast sodium, 690g of lactose (200 meshes), 40g of hydroxypropyl methylcellulose (EF) and 40g of croscarmellose sodium, dissolving the hydroxypropyl methylcellulose in a proper amount of water, adding the montelukast sodium, uniformly stirring, placing the lactose and the croscarmellose sodium in a 4L wet method, stirring at 500rpm, cutting and mixing at 1000rpm for 180 seconds, adding the adhesive solution containing the main drug under the same parameters, granulating for a proper time after the addition is finished, discharging, granulating by using a 26-mesh swing granulator, drying until L OD is less than 3.0%, weighing and preparing Eudragit L100 and 55135g, ethyl cellulose N745 and 745g, 20g of triethyl citrate, dissolving the mixture by using 2300g of 95% ethanol, and transferring the prepared granules into a fluidized bed and spraying the coating solution to obtain the modified release granules.
Filling the quick-release granules 100mg and the release-regulating granules 100mg into capsules respectively to obtain the capsule. The drug release is shown in figure 1.
Example 2
Taking 20g of montelukast sodium, 150g of microcrystalline cellulose 101, 730g of lactose (200 meshes), 50g of hydroxypropyl methylcellulose (EF) and 50g of low-substituted hydroxypropyl cellulose, dissolving the hydroxypropyl methylcellulose in proper amount of water, adding the montelukast sodium, uniformly stirring, putting the microcrystalline cellulose, the lactose and the low-substituted hydroxypropyl cellulose in a 4L wet method, stirring at 500rpm, cutting and mixing at 1000rpm for 180 seconds, adding the main drug-containing adhesive solution under the same parameters, granulating for proper time after the addition is finished, discharging, extruding by using a 1.0mm sieve, rounding, drying until L OD is less than 3.0%, obtaining a quick-release pellet, dissolving the montelukast sodium in proper amount of 30g, stirring uniformly, putting the microcrystalline cellulose 101 in 120g, 570g of lactose (200 meshes), 40g of hydroxypropyl methylcellulose (EF), 40g of cross-linked sodium carboxymethylcellulose, dissolving the hydroxypropyl methylcellulose in proper amount of water, adding the montelukast sodium, stirring for uniform release, putting the microcrystalline cellulose, cross-linked sodium carboxymethylcellulose in a 4-mesh pill, stirring for 40g of the hydroxypropyl methylcellulose (EF), adding the cross-linked sodium cellulose, granulating by using a 20.95 rpm, adding the obtained pellet, stirring, adding the obtained by using a 20.0% centrifugal drying machine, adding the obtained adhesive solution, adding the obtained by using a 20g of ethyl cellulose, stirring, adding the obtained by using a 20g of 10.0 mm-100 rpm, adding the obtained dry eye drop of 100 g of the obtained eye drop, grinding, stirring, adding the obtained eye drop of the obtained eye.
Filling the quick-release pellets 100mg and the release-regulating pellets 100mg into capsules respectively to obtain the capsule. The drug release is shown in figure 2.
Claims (2)
1. A Montelukast sodium pulse release capsule is characterized in that the capsule consists of a quick release part and a modified release part,
the montelukast sodium pulse release capsule is prepared by the following preparation method:
taking 20g of Montelukast sodium, adding 880g of 200-mesh lactose, 50g of hydroxypropyl methylcellulose EF and 50g of croscarmellose sodium to prepare quick-release granules;
dissolving hydroxypropyl methylcellulose EF in a proper amount of water, adding Montelukast sodium, uniformly stirring, placing lactose and croscarmellose sodium into a 4L wet granulator, stirring at 500rpm, cutting and mixing at 1000rpm for 180 seconds, adding the adhesive solution containing the main drug under the same parameters, granulating for a proper time after the addition is finished, discharging, granulating by using a 26-mesh swing granulator, and drying until the OD of L is less than 3.0%, thus obtaining quick-release granules;
under the condition of taking 30g of Montelukast sodium, 690g of lactose with 200 meshes, 40g of hydroxypropyl methylcellulose EF and 40g of croscarmellose sodium are added to prepare release-regulating granules;
dissolving hydroxypropyl methylcellulose EF in appropriate amount of water, adding Montelukast sodium, stirring, adding lactose and croscarmellose sodium into 4L wet granulator, stirring at 500rpm, cutting at 1000rpm, mixing for 180 s, adding the above binder solution containing principal drug under the same parameters, granulating for appropriate time, discharging, grading with 26 mesh swing granulator, and drying to L OD<3.0 percent for standby; weighing 135g of Eudragit®L100-55 g, 45g ethyl cellulose N7 g and 20g triethyl citrate, which are dissolved by 2300g of 95 percent ethanol to obtain coating liquid, and then the standby particles are transferred into a fluidized bed and sprayed into the coating liquid to obtain the release-regulating particles;
and respectively filling the quick-release granules and the modified-release granules into capsules according to the mass ratio of 1:1 to obtain the montelukast sodium pulse release capsules.
2. A Montelukast sodium pulse release capsule is characterized in that the capsule consists of a quick release part and a modified release part,
the montelukast sodium pulse release capsule is prepared by the following preparation method:
taking 20g of Montelukast sodium, adding 150g of microcrystalline cellulose 101, 730g of lactose of 200 meshes, 50g of hydroxypropyl methylcellulose EF and 50g of low-substituted hydroxypropyl cellulose to prepare a quick-release pellet;
dissolving hydroxypropyl methylcellulose EF in a proper amount of water, adding Montelukast sodium, uniformly stirring, placing microcrystalline cellulose 101, lactose and low-substituted hydroxypropyl cellulose in a 4L wet granulator, stirring at 500rpm, cutting and mixing at 1000rpm for 180 seconds, adding the adhesive solution containing the main drug under the same parameters, granulating for a proper time after the addition is finished, discharging, extruding by using a 1.0mm screen, rounding, and drying until the OD of L is less than 3.0%, thus obtaining the quick-release pellets;
under the condition of taking 30g of Montelukast sodium, 120g of microcrystalline cellulose 101 type, 570g of lactose of 200 meshes, 40g of hydroxypropyl methylcellulose EF and 40g of croscarmellose sodium are added to prepare a release-regulating pellet;
dissolving hydroxypropyl methylcellulose EF with appropriate amount of water, adding Montelukast sodium, stirring, placing microcrystalline cellulose 101, lactose and croscarmellose sodium into a 4L wet granulator, stirring at 500rpm, cutting at 1000rpm, mixing for 180 s, adding the above binder solution containing main ingredients under the same parameters, granulating for appropriate time after adding, discharging, extruding with 1.0mm screen, rolling, and drying to L OD<2.0 percent for standby; weighing 135g of Eudragit®L100, 45g of 20cps ethyl cellulose and 20g of triethyl citrate, which are dissolved by 2300g of 95 percent ethanol to obtain coating solution, and then the standby particles are transferred to a centrifugal granulation coating machine to be sprayed into the coating solution to obtain the release-regulating pellets;
and respectively taking the quick-release pellets and the release-regulating pellets to fill the capsule according to the mass ratio of 1:1, thus obtaining the montelukast sodium pulse release capsule.
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| CN106491556A (en) * | 2016-10-21 | 2017-03-15 | 江苏阿尔法药业有限公司 | A kind of stable montelukast sodium enteric-coated pellet |
| CN110368369B (en) * | 2019-08-30 | 2021-11-05 | 广州新济药业科技有限公司 | Calcium supplement and method of making same |
| CN115919806A (en) * | 2022-12-22 | 2023-04-07 | 南京乐韬生物科技有限公司 | Preparation method of GABA (Gamma-aminobutyric acid) sustained-release capsule |
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| 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 |
| CN102309468A (en) * | 2011-09-23 | 2012-01-11 | 深圳市嘉轩医药科技发展有限公司 | Levalbuterol hydrochloride oral controlled release tablet capsule and preparation method thereof |
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| 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 |
| CN102309468A (en) * | 2011-09-23 | 2012-01-11 | 深圳市嘉轩医药科技发展有限公司 | Levalbuterol hydrochloride oral controlled release tablet capsule and preparation method thereof |
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