CN117731620A - High-stability montelukast sodium granule preparation and preparation method thereof - Google Patents
High-stability montelukast sodium granule preparation and preparation method thereof Download PDFInfo
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- CN117731620A CN117731620A CN202311766827.9A CN202311766827A CN117731620A CN 117731620 A CN117731620 A CN 117731620A CN 202311766827 A CN202311766827 A CN 202311766827A CN 117731620 A CN117731620 A CN 117731620A
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- montelukast sodium
- sodium
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- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 103
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 103
- 239000008187 granular material Substances 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 238000001035 drying Methods 0.000 claims abstract description 51
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims abstract description 24
- 229960000878 docusate sodium Drugs 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 239000011734 sodium Substances 0.000 claims abstract description 13
- 239000003223 protective agent Substances 0.000 claims abstract description 10
- 239000006260 foam Substances 0.000 claims abstract description 4
- 239000000853 adhesive Substances 0.000 claims abstract description 3
- 230000001070 adhesive effect Effects 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims description 47
- 239000000463 material Substances 0.000 claims description 42
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- 239000002245 particle Substances 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 26
- 229930195725 Mannitol Natural products 0.000 claims description 26
- 239000000594 mannitol Substances 0.000 claims description 26
- 235000010355 mannitol Nutrition 0.000 claims description 26
- 239000007779 soft material Substances 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 19
- 238000004806 packaging method and process Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 238000005520 cutting process Methods 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 14
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 13
- 238000005303 weighing Methods 0.000 claims description 11
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 10
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 9
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000011068 loading method Methods 0.000 claims description 9
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 9
- 229910000831 Steel Inorganic materials 0.000 claims description 7
- 238000007664 blowing Methods 0.000 claims description 7
- 238000010008 shearing Methods 0.000 claims description 7
- 239000010959 steel Substances 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 abstract description 21
- 239000012535 impurity Substances 0.000 abstract description 16
- 238000013112 stability test Methods 0.000 abstract description 10
- 238000005550 wet granulation Methods 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 33
- 230000000052 comparative effect Effects 0.000 description 23
- 239000000047 product Substances 0.000 description 15
- 239000008186 active pharmaceutical agent Substances 0.000 description 14
- 239000011248 coating agent Substances 0.000 description 12
- 238000000576 coating method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- 238000007873 sieving Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- SYELZBGXAIXKHU-UHFFFAOYSA-N dodecyldimethylamine N-oxide Chemical compound CCCCCCCCCCCC[N+](C)(C)[O-] SYELZBGXAIXKHU-UHFFFAOYSA-N 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 229960005127 montelukast Drugs 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229940068682 chewable tablet Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- 125000006018 1-methyl-ethenyl group Chemical group 0.000 description 1
- GWNVDXQDILPJIG-CCHJCNDSSA-N 11-trans-Leukotriene C4 Chemical compound CCCCC\C=C/C\C=C\C=C\C=C\[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-CCHJCNDSSA-N 0.000 description 1
- UCHDWCPVSPXUMX-LNMNGANESA-N 2-[1-[[(1r)-1-[3-[(z)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C/C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-LNMNGANESA-N 0.000 description 1
- QFTNWCBEAVHLQA-XNTDXEJSSA-N 2-[1-[[1-[3-[(e)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfinylmethyl]cyclopropyl]acetic acid Chemical compound CC(C)(O)C1=CC=CC=C1CCC(S(=O)CC1(CC(O)=O)CC1)C1=CC=CC(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)=C1 QFTNWCBEAVHLQA-XNTDXEJSSA-N 0.000 description 1
- DYLOVNSFPNMSRY-NTEUORMPSA-N 2-[1-[[3-(2-acetylphenyl)-1-[3-[(e)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid Chemical compound CC(=O)C1=CC=CC=C1CCC(C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 DYLOVNSFPNMSRY-NTEUORMPSA-N 0.000 description 1
- -1 7-chloro-2-quinolinyl Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000033309 Analgesic asthma syndrome Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 102000010918 Cysteinyl leukotriene receptors Human genes 0.000 description 1
- 108050001116 Cysteinyl leukotriene receptors Proteins 0.000 description 1
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 208000024744 aspirin-induced respiratory disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000024695 exercise-induced bronchoconstriction Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 239000008202 granule composition Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and discloses a high-stability montelukast sodium granule preparation and a preparation method thereof. The preparation method adopts a preparation process of drying after wet granulation, firstly adding a protective agent docusate sodium to dissolve completely, standing to remove foam, then continuously adding montelukast sodium to dissolve in a dark operation, and finally adding an adhesive CMC-Na to dissolve completely by continuous stirring. According to the invention, the protective agent with a specific proportion to the bulk drug is added in a specific sequence in the granulating process, so that the impurity level of various impurities is reduced, and the problem of reduced dissolution rate of the granules under the stability test condition is solved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, relates to an antiasthmatic montelukast sodium granule, and particularly relates to a high-stability montelukast sodium granule preparation and a preparation method thereof.
Background
Montelukast sodium granule is an antiasthmatic, and has main ingredient of Montelukast sodium and molecular formula C 35 H 35 ClNNaO 3 S has high affinity and selectivity to the I-type cysteinyl leukotriene receptor, can effectively inhibit the cysteinyl leukotriene (CysLT 1) receptor in the airway, thereby improving airway inflammation and effectively controlling asthma symptoms. Is suitable for preventing and treating asthma in adults and children for a long period of time, including daytime and nighttimeAsthma symptoms, treating patients with aspirin-sensitive asthma, and preventing exercise-induced bronchoconstriction.
At present, the preparation time of the conventional fluidized bed process is longer because the main medicine of the montelukast sodium in the montelukast sodium particles is lower. And the montelukast sodium has poor stability and is unstable to light, humidity and heat, so that the uniformity of the particle content and related substances are poor. For example, the publication WO2009153305A2 adopts nitrogen gas as carrier gas in the fluidized bed process, but cannot be realized in China due to the severe equipment cost condition. The montelukast sodium granule of the published patent CN02821212.6 has no study on the impurity level of the product, and the impurity (montelukast cis isomer) produced after 15 minutes of oral administration has certain toxicity, which has an influence on the health of patients. Meanwhile, montelukast sodium particles also have a problem of reduced dissolution rate as the time during storage is prolonged.
As disclosed in patent CN202111483337.9, a method for preparing montelukast sodium granule is provided, and a fluidized bed granulation process is also adopted, firstly, slowly adding hydroxypropyl cellulose into water, dissolving, adding montelukast sodium, stirring until dissolving, then adding magnesium stearate, and dispersing; and coating the coating suspension on mannitol, drying and granulating. However, the process has the problems that the dissolution rate RSD of the montelukast sodium particles is large, and the dissolution rate of the particles is reduced along with the extension of the storage time.
As disclosed in the publication patent No. cn202111035149.X, a montelukast sodium granule and a method for preparing the same are provided, wherein mannitol blank granules are prepared first, then the prepared mannitol blank granules are added into a fluidized bed granulating and coating machine, and a montelukast sodium ethanol solution is sprayed into the fluidized bed granulating and coating machine. However, the granulating and drying time of the process is still longer than that of the traditional process, the time for contacting the montelukast sodium with damp and hot is increased, and the preparation cost of the montelukast sodium granules is further increased due to the ethanol used in the granulating solution.
According to the disclosed patent CN202010012196.1, the montelukast sodium chewable tablet and the preparation method thereof are provided, and the montelukast sodium chewable tablet is prepared by mixing a mixed solution of montelukast sodium, a first binder and water with a medicinal auxiliary material, granulating and drying. However, the process is dried under severe conditions at 80℃and it is possible to further increase the content of the substances of interest in the finished product. And the trend of the increase of the substances of interest in the finished product and the substances of interest in the stability samples thereof was not studied.
In addition, it has been found through investigation that the published patent CN201510747141.4 discloses a montelukast sodium granule composition and a preparation method thereof, which adopts dodecyl dimethyl amine oxide and ammonium glycyrrhetate as protective agents, and the dodecyl dimethyl amine oxide has solubilization effect on main drugs and has low physiological toxicity, but the dodecyl dimethyl amine oxide still has potential safety hazard as an artificially synthesized surfactant for human bodies, especially gastrointestinal tracts of children.
Disclosure of Invention
The invention provides a high-stability montelukast sodium granule preparation and a preparation method thereof, which are used for solving the problems of reduced impurity level of the current montelukast sodium granule, reduced dissolution rate in the stability test process and the like.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the first aspect of the invention provides a preparation method of a high-stability montelukast sodium granule preparation, which comprises the following steps:
(1) Pretreatment: micronizing mannitol and low-substituted hydroxypropyl cellulose for later use:
(2) Preparing a granulating solution: under the dark operation, firstly, the docusate sodium is dissolved in purified water, then the montelukast sodium is added and stirred until the docusate sodium is dissolved, and finally, the sodium carboxymethylcellulose (CMC-Na) is slowly added until the sodium carboxymethylcellulose is completely dissolved, so as to obtain a granulating solution;
(3) Mixing granulating auxiliary materials: adding the mannitol, the low-substituted hydroxypropyl cellulose and the red ferric oxide pretreated in the step (1) into a wet mixing granulator, and fully mixing to obtain granulating auxiliary materials;
(4) Preparing a soft material: adjusting the rotating speed of a wet mixing granulator, and adding the granulating solution prepared in the step (2) to prepare a soft material;
(5) Wet finishing: granulating the soft material prepared in the step (4) by a swinging granulator with a 16-mesh steel wire sieve to prepare Montelukast sodium wet granules;
(6) And (3) drying: transferring the wet particles prepared in the step (5) into a fluidized bed or an electrothermal blowing drying oven for drying, wherein the drying temperature is 60 ℃ until the water content of the dry particles is less than 0.5%, and preparing the dry particles of the montelukast sodium;
(7) And (3) dry finishing: the dry granular material after the drying treatment in the step (6) is granulated by a mobile dry-wet granulator with a screen mesh of 1.5 mm;
(8) Total mixing: weighing materials, calculating the yield and converting the content of additional auxiliary materials, adding the materials subjected to the granule finishing in the step (7) and magnesium stearate into a hopper mixer, and mixing at 15rpm for 10min to obtain montelukast sodium particles;
(9) Content detection: detecting the content of a main drug in the montelukast sodium particles after the step (8) is totally mixed;
(10) And (3) packaging: and (3) calculating the loading amount according to the content detected in the step (9) and sub-packaging to obtain a finished product.
Preferably, in step (1), the mannitol is sieved through a 60 mesh sieve and the low substituted hydroxypropylcellulose is sieved through a 40 mesh sieve.
Preferably, in the step (2), the mass ratio of the docusate sodium to the montelukast sodium is (0.8 to 0.9): (0.4-1.8).
Preferably, in step (2), the particular sequence of formulating the granulation solution is:
adding the protecting agent docusate sodium, completely dissolving, standing to remove foam, continuously adding the montelukast sodium under the condition of light shielding, performing light shielding operation to dissolve, and finally adding the adhesive CMC-Na, continuously stirring and completely dissolving.
Preferably, in the step (3), the stirring rotation speed of the wet mixing granulator is 50-500 rpm, and the cutting speed is 50-500 rpm.
Preferably, in the step (3), the mass ratio of the mannitol, the low-substituted hydroxypropyl cellulose and the red ferric oxide is (90-92): (3-5): (0.1-0.6).
Preferably, in the step (4), the stirring rotation speed of the wet mixing granulator after adjustment is 50-500 rpm, and the cutting speed is 1000-2000 rpm.
Preferably, in the step (4), the solution adding time of the granulating solution is controlled to be 1-3 min, and the shearing time is controlled to be 1-3 min.
The second aspect of the invention provides a high-stability montelukast sodium granule preparation prepared by the method, which comprises the following components in percentage by mass:
preferably, the composition comprises the following components in percentage by weight:
compared with the prior art, the invention has the following technical effects:
the method adopts a preparation process of drying after wet granulation, not only remarkably reduces the dosage of the wetting agent in the granulating solution in the granulating process, but also remarkably reduces the contact time of the medicine and unstable conditions by adjusting the adding sequence and the proportion of the protective agent to prepare the granulating solution, not only can reduce the impurity level increasing trend of the finished product in the stability test process, but also can improve the problem of dissolution reduction in the stability test process.
Detailed Description
The present invention will be described in detail and in detail by way of the following examples, which are not intended to limit the scope of the invention, for better understanding of the invention.
Example 1
A high-stability montelukast sodium granule preparation, wherein the dosage ratio of montelukast sodium API to the solubilizer docusate sodium is 1:1, the specific prescription proportions are shown in table 1 below.
Table 1: EXAMPLE 1 Montelukast sodium prescription 4mg/500mg (API: solubiliser 1:1)
Note that: purified water was removed during the drying process without taking into account the weight of the recipe.
Based on the prescription proportion shown in table 1, the preparation method of the high-stability montelukast sodium granule specifically comprises the following steps:
(1) Pretreatment: sieving mannitol with 60 mesh sieve, sieving low substituted hydroxypropyl cellulose with 40 mesh sieve;
(2) Preparing a granulating solution: the operation in dark is carried out, the docusate sodium is dissolved in purified water, the montelukast sodium is continuously added and stirred until the docusate sodium is dissolved, and finally, the sodium carboxymethylcellulose (CMC-Na) is slowly added and completely dissolved to prepare a granulating solution;
(3) Mixing granulating auxiliary materials: adding the pretreated material in the step (1) and red ferric oxide into a wet mixing granulator for mixing (stirring rotation speed is 50-500 rpm, cutting speed is 50-500 rpm);
(4) Preparing a soft material: adjusting the rotation speed of a wet mixing granulator (50-500 rpm, 1000-2000 rpm of cutting speed), and adding the granulating solution prepared in the step (2) to prepare a soft material (1-3 min of liquid adding time and 1-3 min of shearing time);
(5) Wet finishing: granulating the soft material prepared in the step (4) by a swinging granulator with a 16-mesh steel wire screen;
(6) And (3) drying: transferring the wet particles prepared in the step (5) into a fluidized bed or an electrothermal blowing drying oven for drying, wherein the drying temperature is 60 ℃ until the water content of the dry particles is less than 0.5%;
(7) And (3) dry finishing: finishing the materials after the drying treatment in the step (6) by a mobile dry-wet finishing machine with a screen mesh of 1.5 mm;
(8) Total mixing: weighing the materials, calculating the yield and converting the content of the added auxiliary materials; adding the dried and granulated material and magnesium stearate into a hopper mixer, and mixing for 15rpm and 10min;
(9) Content detection: detecting the content of a main drug in the montelukast sodium particles after the step (8) is totally mixed;
(10) And (3) packaging: and (3) calculating the loading amount according to the content detected in the step (9) and sub-packaging to obtain a finished product.
Example 2
A high-stability montelukast sodium granule preparation, wherein the dosage ratio of montelukast sodium API to the solubilizer docusate sodium is 1:2, the specific prescription proportions are shown in table 2 below.
Table 2: example 2 Montelukast sodium recipe 4mg/500mg (API: solubiliser ratio 1:2)
Note that: purified water was removed during the drying process without taking into account the weight of the recipe.
Based on the prescription proportion shown in table 2, the preparation method of the high-stability montelukast sodium granule specifically comprises the following steps:
(1) Pretreatment: sieving mannitol with 60 mesh sieve, sieving low substituted hydroxypropyl cellulose with 40 mesh sieve;
(2) Preparing a granulating solution: operating in dark, adding montelukast sodium, stirring until the montelukast sodium is dissolved, and finally slowly adding sodium carboxymethylcellulose (CMC-Na) for complete dissolution to prepare a granulating solution;
(3) Mixing granulating auxiliary materials: adding the pretreated material in the step (1) and red ferric oxide into a wet mixing granulator for mixing (stirring rotation speed is 50-500 rpm, cutting speed is 50-500 rpm);
(4) Preparing a soft material: adjusting the rotation speed of a wet mixing granulator (50-500 rpm, 1000-2000 rpm of cutting speed), and adding the granulating solution prepared in the step (2) to prepare a soft material (1-3 min of liquid adding time and 1-3 min of shearing time);
(5) Wet finishing: granulating the soft material prepared in the step (4) by a swinging granulator with a 16-mesh steel wire screen;
(6) And (3) drying: transferring the wet particles prepared in the step (5) into a fluidized bed or an electrothermal blowing drying oven for drying, wherein the drying temperature is 60 ℃ until the water content of the dry particles is less than 0.5%;
(7) And (3) dry finishing: finishing the dried material in the step (6) by a mobile dry-wet finishing machine with a screen mesh of 1.5mm to obtain montelukast sodium particles;
(8) Total mixing: weighing the materials, calculating the yield and converting the content of the added auxiliary materials; adding the dried and granulated material obtained in the step (7) and magnesium stearate into a hopper mixer for mixing at 15rpm for 10min;
(9) Content detection: detecting the content of a main drug in the montelukast sodium particles after the step (8) is totally mixed;
(10) And (3) packaging: and (3) calculating the loading amount according to the content detected in the step (9) and sub-packaging to obtain a finished product.
Example 3
A high-stability montelukast sodium granule preparation, wherein the dosage ratio of montelukast sodium API to the solubilizer docusate sodium is 1:1, the specific prescription proportions are shown in table 3 below.
Table 3: example 3 Montelukast sodium recipe 4mg/500mg (API: solubilizer ratio 2:1)
| Product name | Weight of (E) | Prescription dose ratio (%) |
| Montelukast sodium | 4.16 | 0.832 |
| Docusate sodium | 2.08 | 0.416 |
| Mannitol (mannitol) | 457.26 | 91.452 |
| CMC-Na | 10 | 2 |
| L-HPC | 20 | 4 |
| Red iron oxide | 1.5 | 0.3 |
| Magnesium stearate | 5 | 1 |
| Sum total | 500 | 100 |
| Purified water | 150 | N/A |
Note that: purified water was removed during the drying process without taking into account the weight of the recipe.
Based on the prescription proportion shown in table 3, the preparation method of the high-stability montelukast sodium granule specifically comprises the following steps:
(1) Pretreatment: mannitol is sieved by a 60-mesh sieve, and low-substituted hydroxypropyl cellulose is sieved by a 40-mesh sieve:
(2) Preparing a granulating solution: operating in dark, adding montelukast sodium, stirring until the montelukast sodium is dissolved, and finally slowly adding sodium carboxymethylcellulose (CMC-Na) for complete dissolution to prepare a granulating solution;
(3) Mixing granulating auxiliary materials: adding the pretreated material in the step (1) and red ferric oxide into a wet mixing granulator for mixing (stirring rotation speed is 50-500 rpm, cutting speed is 50-500 rpm);
(4) Preparing a soft material: adjusting the rotation speed of a wet mixing granulator (50-500 rpm, 1000-2000 rpm of cutting speed), and adding the granulating solution prepared in the step (2) to prepare a soft material (1-3 min of liquid adding time and 1-3 min of shearing time);
(5) Wet finishing: granulating the soft material prepared in the step (4) by a swinging granulator with a 16-mesh steel wire screen;
(6) And (3) drying: transferring the wet particles prepared in the step (5) into a fluidized bed or an electrothermal blowing drying oven for drying, wherein the drying temperature is 60 ℃ until the water content of the dry particles is less than 0.5%;
(7) And (3) dry finishing: finishing the materials after the drying treatment in the step (6) by a mobile dry-wet finishing machine with a screen mesh of 1.5 mm;
(8) Total mixing: weighing the materials, calculating the yield and converting the content of the added auxiliary materials; adding the dried and granulated material and magnesium stearate into a hopper mixer, and mixing for 15rpm and 10min;
(9) Content detection: detecting the content of a main drug in the montelukast sodium particles after the step (8) is totally mixed;
(10) And (3) packaging: and (3) calculating the loading amount according to the content detected in the step (9) and sub-packaging to obtain a finished product.
Comparative example 1
The specific prescription proportions of the Montelukast sodium granule preparation are shown in the table 4 below.
Table 4: comparative example 1 Montelukast sodium prescription 4mg/500mg
| Name of the name | Dosage unit of preparation (mg/g) | Unit formulation ratio (%) |
| Montelukast sodium | 4.16 | 0.83 |
| Mannitol (mannitol) | 482.19 | 96.44 |
| Hydroxypropyl cellulose | 12.4 | 2.48 |
| Magnesium stearate (external) | 1.25 | 0.25 |
| Purified water | 250 | Removal during drying |
| Total amount of | 500 | 100％ |
Note that: purified water was removed during the drying process without taking into account the weight of the recipe.
Based on the prescription proportion shown in table 4, the preparation method of the montelukast sodium granule comprises the following steps:
(1) Pretreatment: sieving mannitol with 40 mesh sieve to remove blocks;
(2) Weighing: respectively weighing raw materials and auxiliary materials in a prescription amount, and preparing purified water;
(3) Preparing a coating suspension: slowly adding the prescription amount of hydroxypropyl cellulose into the prescription amount of purified water for dissolution, adding montelukast sodium after dissolution, stirring until dissolution, and defoaming for later use;
(4) Drug coating: placing mannitol into a fluidized bed, and coating the coating suspension onto mannitol in the fluidized bed by using a peristaltic pump;
(5) And (3) drying: drying in a fluidized bed, and stopping drying after controlling the moisture to be 0.5%;
(6) Finishing: sieving the dried granules with a 20-mesh oscillating screen;
(7) Total mixing: weighing the materials, calculating the yield and the dosage of the additional auxiliary materials (magnesium stearate), and uniformly mixing the dried materials with the magnesium stearate by using a hopper mixer (15 rpm,10 min);
(8) Content detection: detecting the content of a main drug in the total mixed montelukast sodium particles;
(9) And (3) packaging: and calculating the loading amount according to the detected content, and sub-packaging to obtain a finished product.
Comparative example 2
The specific prescription proportions of the Montelukast sodium granule preparation are shown in the table 5 below.
Table 5: comparative example 1 Montelukast sodium prescription 4mg/500mg
Note that: purified water was removed during the drying process without taking into account the weight of the recipe.
Based on the prescription proportion shown in table 5, the preparation method of the montelukast sodium granule comprises the following steps:
(1) Pretreatment: sieving mannitol with 40 mesh sieve to remove blocks;
(2) Weighing: respectively weighing raw materials and auxiliary materials in a prescription amount, and preparing purified water;
(3) Preparing a coating suspension: slowly adding the prescription amount of hydroxypropyl cellulose into the prescription amount of purified water for dissolution, adding montelukast sodium after dissolution, stirring until dissolution, and defoaming for later use;
(4) Drug coating: placing mannitol into a fluidized bed, and coating the coating suspension onto mannitol in the fluidized bed by using a peristaltic pump;
(5) And (3) drying: drying in a fluidized bed, and stopping drying after controlling the moisture to be 0.5%;
(6) Finishing: sieving the dried granules with a 20-mesh oscillating screen;
(7) Total mixing: weighing the materials, calculating the yield and the dosage of the additional auxiliary materials (magnesium stearate), and uniformly mixing the dried materials with the magnesium stearate by using a hopper mixer (15 rpm,10 min);
(8) Content detection: detecting the content of a main drug in the total mixed montelukast sodium particles;
(9) And (3) packaging: and calculating the loading amount according to the detected content, and sub-packaging to obtain a finished product.
Comparative example 3
A montelukast sodium granule formulation having a montelukast API to solubiliser docusate sodium dosage ratio of 1:1, the order of addition of the granulation solutions was changed and the specific formulations were as shown in table 6 below.
Table 6: comparative example 3 Montelukast sodium recipe 4mg/500mg (API: solubilizer 1:1, change order of addition)
Note that: purified water was removed during the drying process without taking into account the weight of the recipe.
Based on the prescription proportion shown in table 6, the preparation method of the montelukast sodium granule comprises the following steps:
(1) Pretreatment: mannitol is sieved by a 60-mesh sieve, and low-substituted hydroxypropyl cellulose is sieved by a 40-mesh sieve:
(2) Preparing a granulating solution: and (3) performing light-shielding operation, dissolving docusate sodium in purified water, then continuously slowly adding sodium carboxymethylcellulose (CMC-Na) and dissolving, and finally adding montelukast sodium and stirring until the sodium carboxymethylcellulose and the CMC-Na are completely dissolved to prepare a granulating solution.
(3) And (3) adding the pretreated material in the step (1) and red ferric oxide into a wet mixing granulator for mixing (stirring speed is 50-500 rpm, and cutting speed is 50-500 rpm).
(4) Preparing a soft material: the rotation speed of the wet mixing granulator is regulated (stirring rotation speed is 50-500 rpm, cutting speed is 1000-2000 rpm), and the solution prepared in the step (2) is added to prepare soft materials (liquid adding time is 1-3 min, and shearing time is 1-3 min).
(5) Wet finishing: granulating the soft material prepared in the step (4) by a swinging granulator with a 16-mesh steel wire sieve.
(6) And (3) drying: transferring the wet granules prepared in the step (5) into a fluidized bed or an electrothermal blowing drying oven for drying, wherein the drying temperature is 60 ℃ until the water content of the dry granules is less than 0.5%.
(7) And (3) dry finishing: the material was sized by a moving dry-wet granulator fitted with a 1.5mm screen.
(8) Total mixing: weigh the material, calculate the yield and convert the content of the additional auxiliary materials. The dried and granulated material was mixed with magnesium stearate in a hopper mixer at 15rpm for 10min.
(9) Content detection: detecting the content of a main drug in the total mixed montelukast sodium particles;
(10) And (3) packaging: and calculating the loading amount according to the detected content, and sub-packaging to obtain a finished product.
Comparative example 3 the order of addition of the three solutes was changed only when the granulating solution was prepared as in example 1.
Comparative example 4
A montelukast sodium granule formulation having a montelukast API to solubiliser docusate sodium dosage ratio of 1:1, the adding sequence of the granulating solution is changed, and the specific prescription proportion is shown in the following table 7.
Table 7: comparative example 4 Montelukast sodium prescription 4mg/500mg (API: solubilizer 1:1, change order of addition)
Note that: purified water was removed during the drying process without taking into account the weight of the recipe.
Based on the prescription proportion shown in table 7, the preparation method of the montelukast sodium granule comprises the following steps:
(1) Pretreatment: mannitol is sieved by a 60-mesh sieve, and low-substituted hydroxypropyl cellulose is sieved by a 40-mesh sieve:
(2) Preparing a granulating solution: and (3) operating in a dark place, slowly adding sodium carboxymethylcellulose (CMC-Na) into purified water, continuously adding sodium docusate to dissolve the sodium docusate, and finally adding montelukast sodium, continuously stirring until the sodium docusate is completely dissolved to prepare a granulating solution.
(3) And (3) adding the pretreated material in the step (1) and red ferric oxide into a wet mixing granulator for mixing (stirring speed is 50-500 rpm, and cutting speed is 50-500 rpm).
(4) Preparing a soft material: the rotation speed of the wet mixing granulator is regulated (stirring rotation speed is 50-500 rpm, cutting speed is 1000-2000 rpm), and the solution prepared in the steps (1) and (2) is added to prepare soft materials (liquid adding time is 1-3 min, and shearing time is 1-3 min).
(5) Wet finishing: granulating the soft material prepared in the step (4) by a swinging granulator with a 16-mesh steel wire sieve.
(6) And (3) drying: transferring the wet granules prepared in the step (5) into a fluidized bed or an electrothermal blowing drying oven for drying, wherein the drying temperature is 60 ℃ until the water content of the dry granules is less than 0.5%.
(7) And (3) dry finishing: the material was sized by a moving dry-wet granulator fitted with a 1.5mm screen.
(8) Total mixing: weigh the material, calculate the yield and convert the content of the additional auxiliary materials. The dried and granulated material was mixed with magnesium stearate in a hopper mixer at 15rpm for 10min.
(9) Content detection: detecting the content of a main drug in the total mixed montelukast sodium particles;
(10) And (3) packaging: and calculating the loading amount according to the detected content, and sub-packaging to obtain a finished product.
Comparative example 4 the order of addition of the three solutes was changed only when the granulating solution was prepared as in example 1.
Stability test method:
the final product is tested by a key item in 0 days and the test is accelerated (the accelerated test is a commercial package-aluminum plastic composite film package, and the package is placed for 6 months under the conditions of 40+/-2 ℃ and 75+/-5% RH, the equipment can control the temperature to +/-2 ℃ and the humidity to +/-5% and can detect the real temperature and the real humidity, and the test 1, the test 2, the test 3 and the test 6 months are sampled and the test is carried out according to the stability key investigation item
The known impurity information is shown below:
(1) Impurity B
C 35 H 34 ClNO 2 S 568.17
[1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinolinyl) -vinyl ] phenyl ] -3- [2- (1-methylethenyl) phenyl ] propenyl ] thio ] methyl ] cyclopropyl ] acetic acid
(2) Impurity C
C 35 H 36 ClNO 4 S 602.19
[1- [ [ [1- [3- [ (1E) -2- (7-chloro-2-quinolinyl) -vinyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] sulfinyl ] methyl ] cyclopropyl ] acetic acid
(3) Impurity G
C 35 H 36 ClNO 3 S 586.18
[1- [ [ [ (1R) -1- [3- [ (Z) -2- (7-chloro-2-quinolinyl) -vinyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropyl ] acetic acid
(4) Montelukast ketone impurity
C 29 H 26 ClNO 2 455.98
[1- [3- [ (1E) -2- (7-chloro-2-quinolinolato) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1 methylethyl) phenyl ] -1-propanone
Table 8: results of the product tests in examples 1 to 3 and comparative examples 1 to 4
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Summary of stability test results:
examples 1 to 3 are API: the protectant ratios were (1:1/1:2/2:1), respectively, and comparative examples 1 and 2 were conventional fluidized bed one-step granulation processes (varying ratios of magnesium stearate). Comparative example 3, comparative example 4, however, was identical to the formulation of example 1, except that the order of addition of the API with the protectant and binder was changed when the wet granulation solution was added.
From the above table, it is evident that comparative example 1 and comparative example 2 do not contain opacifying agent (red iron oxide) in the increasing trend of impurity G, so that the final impurity G basal level (0 days) is higher than other batches, eventually exceeding the limit > 0.1% during the stability test. Whereas for impurity C, the levels of example 1, example 2 and example 3 were significantly lower than for comparative examples 1, 2, 3 and 4, with comparative example 1 and comparative example 2 having exceeded and comparative example 3 and comparative example 4, although not already exceeded, caused a total impurity exceeding of > 1.7% because the impurity C level was close to the limit > 1.0%. Whereas for impurity B, the acceleration of comparative example 3 and comparative example 4 during the stability test had exceeded > 0.3% for 6 months, example 3 has also approached the limit. From the dissolution rate trend, examples 1 and 2 decreased slightly during the stability test, while the other batches decreased significantly, with a final acceleration of less than 90% for 6 months.
From the above summary of data, the API: the protective agent is in the range of (1:1-1:2). The preparation of the wet granulation solution requires a specific sequence: firstly, adding a protective agent (sodium docusate) to dissolve completely, standing to remove foam, continuously adding an API (montelukast sodium) under a light-shielding condition, performing light-shielding operation to dissolve, and finally, adding a binder (CMC-Na), continuously stirring to dissolve completely to prepare a granulating solution, wherein the finished product prepared by the granulating solution has the advantages of low impurity levels, no reduction of dissolution rate along with the storage time in the stability test process, and the like.
In summary, unlike the prior art which adopts dodecyl dimethyl amine oxide and ammonium glycyrrhizate as protective agents, the technology of the invention adopts docusate sodium as the protective agent, and the principle of protection mainly comprises the following two points. First, amorphous docusate sodium is first dissolved in purified water and then amorphous montelukast sodium is dissolved. The rate of dissolution of montelukast sodium is related to its crystalline form and wettability in the formulation. The docusate sodium maintains the amorphous state of the montelukast sodium by wrapping the montelukast sodium to generate a crystal inhibition effect when the docusate sodium is dried, and the drug is prevented from being aggregated again so as to be beneficial to dissolution. Secondly, there is a wetting effect of docusate sodium, and dissolution of docusate sodium in the gastrointestinal tract increases the wetting effect of montelukast sodium and may correspondingly increase the dissolution rate and absorption rate of montelukast sodium. At the same time, the impurity level of the montelukast sodium particles is further reduced in this way, and the dissolution rate is not reduced with the storage time.
The above description of the specific embodiments of the present invention has been given by way of example only, and the present invention is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for the present invention will occur to those skilled in the art, and are also within the scope of the present invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (10)
1. The preparation method of the high-stability montelukast sodium granule preparation is characterized by comprising the following steps of:
(1) Pretreatment: micronizing mannitol and low-substituted hydroxypropyl cellulose for later use:
(2) Preparing a granulating solution: under the dark operation, firstly, the docusate sodium is dissolved in purified water, then the montelukast sodium is added and stirred until the docusate sodium is dissolved, and finally, the sodium carboxymethylcellulose (CMC-Na) is slowly added until the sodium carboxymethylcellulose is completely dissolved, so as to obtain a granulating solution;
(3) Mixing granulating auxiliary materials: adding the mannitol, the low-substituted hydroxypropyl cellulose and the red ferric oxide pretreated in the step (1) into a wet mixing granulator, and fully mixing to obtain granulating auxiliary materials;
(4) Preparing a soft material: adjusting the rotating speed of a wet mixing granulator, and adding the granulating solution prepared in the step (2) to prepare a soft material;
(5) Wet finishing: granulating the soft material prepared in the step (4) by a swinging granulator with a 16-mesh steel wire sieve to prepare Montelukast sodium wet granules;
(6) And (3) drying: transferring the wet particles prepared in the step (5) into a fluidized bed or an electrothermal blowing drying oven for drying, wherein the drying temperature is 60 ℃ until the water content of the dry particles is less than 0.5%, and preparing the dry particles of the montelukast sodium;
(7) And (3) dry finishing: the dry granular material after the drying treatment in the step (6) is granulated by a mobile dry-wet granulator with a screen mesh of 1.5 mm;
(8) Total mixing: weighing materials, calculating the yield and converting the content of additional auxiliary materials, adding the materials subjected to the granule finishing in the step (7) and magnesium stearate into a hopper mixer, and mixing at 15rpm for 10min to obtain montelukast sodium particles;
(9) Content detection: detecting the content of a main drug in the montelukast sodium particles after the step (8) is totally mixed;
(10) And (3) packaging: and (3) calculating the loading amount according to the content detected in the step (9) and sub-packaging to obtain a finished product.
2. The method for preparing the high-stability montelukast sodium granule formulation of claim 1, wherein in the step (1), the mannitol is sieved through a 60 mesh sieve, and the low-substituted hydroxypropylcellulose is sieved through a 40 mesh sieve.
3. The method for preparing the high-stability montelukast sodium granule formulation according to claim 1, wherein in the step (2), the mass ratio of the docusate sodium to the montelukast sodium is (0.8 to 0.9): (0.4-1.8).
4. The method for preparing the high-stability montelukast sodium granule formulation of claim 1, wherein in step (2), the specific order of preparing the granulating solution is:
adding the protecting agent docusate sodium, completely dissolving, standing to remove foam, continuously adding the montelukast sodium under the condition of light shielding, performing light shielding operation to dissolve, and finally adding the adhesive CMC-Na, continuously stirring and completely dissolving.
5. The method for preparing the high-stability montelukast sodium granule formulation according to claim 1, wherein in the step (3), the stirring rotation speed of the wet mixing granulator is 50 to 500rpm, and the cutting speed is 50 to 500rpm.
6. The preparation method of the high-stability montelukast sodium granule preparation according to claim 1, wherein in the step (3), the mass ratio of mannitol, low-substituted hydroxypropyl cellulose to red ferric oxide is (90-92): (3-5): (0.1-0.6).
7. The method for preparing the high-stability montelukast sodium granule formulation according to claim 1, wherein in the step (4), the stirring rotation speed after the adjustment of the wet mixing granulator is 50-500 rpm, and the cutting speed is 1000-2000 rpm.
8. The method for preparing the high-stability montelukast sodium granule formulation according to claim 1, wherein in the step (4), the granulating solution is controlled to be fed for 1 to 3 minutes in response to the feeding time and the shearing time is controlled to be 1 to 3 minutes.
9. A high stability montelukast sodium granule formulation prepared by the process of any one of claims 1 to 8, comprising, in mass percent:
10. the high stability montelukast sodium granule formulation of claim 9, wherein the composition comprises, in weight percent, the following components:
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