CN110876731A - Preparation method of ambrisentan tablet - Google Patents
Preparation method of ambrisentan tablet Download PDFInfo
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- CN110876731A CN110876731A CN201811039700.6A CN201811039700A CN110876731A CN 110876731 A CN110876731 A CN 110876731A CN 201811039700 A CN201811039700 A CN 201811039700A CN 110876731 A CN110876731 A CN 110876731A
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- Prior art keywords
- ambrisentan
- lactose
- filler
- hopper mixer
- tabletting
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- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 title claims abstract description 61
- 229960002414 ambrisentan Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000002156 mixing Methods 0.000 claims description 44
- 239000011248 coating agent Substances 0.000 claims description 41
- 238000000576 coating method Methods 0.000 claims description 41
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 34
- 239000008101 lactose Substances 0.000 claims description 31
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 239000000463 material Substances 0.000 claims description 28
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 25
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 25
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 25
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 17
- 239000000945 filler Substances 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 13
- 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 13
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 13
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 13
- 238000007873 sieving Methods 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 11
- 238000005469 granulation Methods 0.000 claims description 11
- 230000003179 granulation Effects 0.000 claims description 11
- 239000002245 particle Substances 0.000 claims description 9
- 239000000314 lubricant Substances 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229940032147 starch Drugs 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 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 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 28
- 238000001727 in vivo Methods 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 5
- 239000008351 acetate buffer Substances 0.000 description 5
- 239000002308 endothelin receptor antagonist Substances 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 239000007916 tablet composition Substances 0.000 description 5
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 208000002815 pulmonary hypertension Diseases 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229940126656 GS-4224 Drugs 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 208000020875 Idiopathic pulmonary arterial hypertension Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010039163 Right ventricular failure Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000009475 tablet pressing Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
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- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of an ambrisentan tablet, which has the advantages of simple preparation process, easy operation, low cost, good reproducibility and suitability for industrial large-scale production, and the obtained ambrisentan tablet has smooth surface, good content uniformity, high dissolution rate, small dissolution difference among batches and high in-vivo bioavailability.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a production method of an ambrisentan tablet.
Background
Pulmonary Arterial Hypertension (PAH) is a disease characterized pathologically by abnormally elevated pulmonary arterial blood vessel pressure and progressive occlusion of the pulmonary vascular bed, including idiopathic PAH (ipah), PAH caused by pulmonary widespread lesions, PAH caused by pulmonary arteriolar hypoxic spasm, left ventricular disease association, hypoxia and pulmonary disease, chronic thrombotic embolism, and the like, which ultimately leads to progressive vascular resistance increase and right heart failure. Currently, pulmonary hypertension drugs are mainly classified into phosphodiesterase-5 (PDE-5) inhibitors, prostacyclins, and endothelin receptor antagonists according to the mechanism of action. Wherein, the endothelin receptor antagonist can be completely combined with endothelin receptor, thereby achieving the purpose of delaying disease deterioration, therefore, the research on the pulmonary hypertension drug in recent years tends to be Endothelin Receptor Antagonist (ERA).
Ambrisentan was originally developed as an endothelin receptor antagonist by BASF Pharma, 12 months 2000, and Myogen (now Gilead Colorado) developed this product in conjunction with BASF Pharma (now Abbott GmbH & Co KG) under the agreement, 11 months 2001, the agreement was modified, and Myogen acquired exclusive rights to develop this product. Subsequently, the U.S. Kuransu Schker (GlaxoSmithKline plc) agreed with Myogen and acquired production rights for ambrisentan outside the U.S. Myogen was purchased as a subsidiary by 17 japanese girlidd Science corporation (Gilead Science) on 11.2006, and acquired ownership of ambrisentan. The drug is approved by the U.S. FDA in 6-15 th in 2007 and Chinese CFDA in 19 th in 2010, and is orally taken for treating pulmonary hypertension, and ambrisentan has the advantages of good treatment effect and safety data and no significant drug interaction and is a leading sheep in the arterial hypertension market.
The chemical name of ambrisentan is (+) - (2S) -2- [ (4, 6-dimethyl pyrimidine-2-yl) oxy]-3-methoxy-3, 3-diphenylpropanoic acid of formula C22H22N2O4The molecular weight is 378.42, and the structure is shown in formula (I).
AmbrisentanThe drug is insoluble in water and 0.1mol/L-1The hydrochloric acid solution is almost insoluble, and the problem of low dissolution rate or even unqualified dissolution rate is often encountered in the actual production of the tablets; moreover, because the content of ambrisentan in the preparation is low, the ambrisentan is difficult to be fully mixed in the preparation process, so that the problems of high and low content and large dissolution difference among tablets exist frequently in the dissolution rate detection process, and particularly, the dissolution difference of each batch is larger in the process of expanding the production, so that the safety and the effectiveness of the medicine are directly influenced. Even though the original production of the original product of the kakkiso, the problem of large batch dissolution difference exists, so that the development of a process which meets the requirement of dissolution of a product, has small dissolution difference among all batches of tablets and can be used for producing ambrisentan tablets in an industrialized and large-scale manner is a technical problem which needs to be solved urgently at present.
Disclosure of Invention
The invention aims to provide a method for industrially producing an ambrisentan tablet on a large scale, and the obtained ambrisentan tablet has smooth surface, good content uniformity, high dissolution rate, small dissolution difference among batches and high in-vivo bioavailability.
Specifically, the invention is realized by the following technical scheme:
a method for industrially producing ambrisentan tablets in large scale comprises the following steps:
(1) micronizing ambrisentan, and controlling the particle size of d (0.9) to be not less than 20um and not more than 50 um;
(2) uniformly mixing the micronized ambrisentan and the first filler in a hopper mixer, and then adding the mixture into a granulator for granulation.
(3) Uniformly mixing the granules obtained in the step (2) with a second filler, a disintegrating agent and a lubricating agent in a hopper mixer in sequence;
(4) adding the intermediate material obtained in the step (3) into a tabletting machine for tabletting, and controlling the hardness of the plain tablets to be 5.00kg/cm2～10.00kg/cm2；
(5) And (4) coating.
In one embodiment of the present invention, the micronization treatment may be pulverization with a pulverizer. Generally, the raw material can be pulverized by a universal pulverizer, a micro pulverizer, a turbo pulverizer, a ball mill, a jet mill, or the like, and preferably pulverized by a micro pulverizer.
In one embodiment of the invention, the ambrisentan has a particle size of 20 um. ltoreq. d (0.9). ltoreq.35 um, for example 25 um. ltoreq. d (0.9). ltoreq.35 um.
In one embodiment of the invention, the bulking agent is first pre-treated by sieving through a 50-80 mesh sieve, for example, through a 60 mesh sieve, for example, through a 70 mesh sieve.
In one embodiment of the invention, the granulator pore size screen is from 0.25mm to 2.00mm, such as from 0.85mm to 1.40mm, such as from 1.0mm to 1.40 mm.
In one embodiment of the invention, the speed of the granulator is between 200rpm and 450rpm, for example between 300rpm and 400 rpm.
In one embodiment of the invention, the rotational speed of the hopper mixer is between 8rpm and 20rpm, for example between 10rpm and 12 rpm.
In one embodiment of the invention, the mixing time of each adjuvant is 5min to 20min, for example 5min to 15 min.
In one embodiment of the present invention, in step (4), the tablet pressing speed of the tablet press is 50.0-120.0 kp/hr, such as 60.0-100.0 kp/hr, such as 80.0-100.0 kp/hr.
In one embodiment of the invention, in step (4), the mean value of the main pressure of the tablet press is 4.00 to 20.00KN, for example 6.00 to 10.00 KN.
In one embodiment of the present invention, in the step (4), the hardness of the obtained plain sheet is 6.00kg/cm2～8.00kg/cm2。
In one embodiment of the present invention, the first filler and the second filler are independently selected from the group consisting of lactose, microcrystalline cellulose, mannitol, corn starch, and pregelatinized starch.
In one embodiment of the invention, the first filler is lactose and the second filler is microcrystalline cellulose.
In one embodiment of the present invention, the first filler is lactose and the second filler is microcrystalline cellulose, wherein the weight ratio of lactose to microcrystalline cellulose is 2-4: 1, for example, the weight ratio of lactose to microcrystalline cellulose is 2.5-3: 1.
in one embodiment of the invention, the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl cellulose, microcrystalline cellulose, crospovidone.
In one embodiment of the invention, the disintegrant is croscarmellose sodium.
In one embodiment of the invention, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, talc, aerosil.
In one embodiment of the invention, the lubricant is magnesium stearate.
In one embodiment of the invention, the coating material used for the coating is a gastric coating material, for example
In one embodiment of the invention, the ambrisentan is present in an amount of 1% to 10% by weight, for example 2.5% to 7.5% by weight, based on the total weight of the composition.
In one embodiment of the invention, the total weight of ambrisentan is 3.6% of the total weight of the composition.
In one embodiment of the invention, the total weight of ambrisentan is 7.1% of the total weight of the composition.
In one embodiment of the invention, the filler is present in an amount of 60% to 80% by weight, for example 65% to 70% by weight, based on the total weight of the composition.
In one embodiment of the invention, the total weight of the disintegrant is 1% to 5% of the total weight of the composition, for example 2.5% to 3% of the total weight of the composition.
In one embodiment of the invention, the total weight of the lubricant is 0.1% to 2% of the total weight of the composition, for example 0.5% to 1% of the total weight of the composition.
In one embodiment of the invention, the coating weight gain is 1% to 6% of the total weight of the composition, preferably 3% to 5% of the total weight of the composition.
In one embodiment of the invention, the method for industrially producing the ambrisentan tablet in large scale comprises the following steps:
(1) micronizing ambrisentan, and controlling the particle size of d (0.9) to be less than or equal to 20um and less than or equal to 35 um;
(2) uniformly mixing the micronized ambrisentan and lactose in a hopper mixer, and then adding the mixture into a granulator for granulation.
(3) Uniformly mixing the granules obtained in the step (2) with microcrystalline cellulose, croscarmellose sodium and magnesium stearate in a hopper mixer in sequence;
(4) adding the intermediate material obtained in the step (3) into a tabletting machine for tabletting, and controlling the hardness of the plain tablets to be 5.00kg/cm2～10.00kg/cm2；
(5) And (4) coating.
In one embodiment of the invention, the method for industrially producing the ambrisentan tablet in large scale comprises the following steps:
(1) micronizing ambrisentan, and controlling the particle size of d (0.9) to be less than or equal to 20um and less than or equal to 35 um;
(2) in a hopper mixer, uniformly mixing the micronized ambrisentan with half of the prescription amount of lactose, and then adding the mixture into a granulator for granulation.
(3) Uniformly mixing the granules obtained in the step (2) with the lactose in the other half formula amount in a hopper mixer, then uniformly mixing the granules with microcrystalline cellulose and croscarmellose sodium, and finally uniformly mixing the granules with magnesium stearate;
(4) adding the intermediate material obtained in the step (3) into a tabletting machine for tabletting, and controlling the hardness of the plain tablets to be 5.00kg/cm2～10.00kg/cm2；
(5) And adding the plain tablets into a coating pan for coating.
In one embodiment of the invention, the method for industrially producing the ambrisentan tablet in large scale comprises the following steps:
(1) micronizing ambrisentan, and controlling the granularity of d (0.9) to be less than or equal to 25um and less than or equal to 35 um;
(2) the preparation method comprises the steps of firstly sieving lactose and microcrystalline cellulose by a 60-70-mesh sieve for pretreatment, then mixing the micronized ambrisentan and half of formula amount of lactose for 5-15 min in a hopper mixer, adding the mixture into a granulator for granulation, setting a pore-size screen of the granulator to be 0.25-2.00 mm, and setting the rotation speed of the granulator to be 200-450 rpm;
(3) mixing the granules obtained in the step (2) with the lactose in the other half formula amount for 5-15 min in a hopper mixer, then mixing with microcrystalline cellulose and croscarmellose sodium for 10-15 min, and finally mixing with magnesium stearate for 5-15 min;
(4) adding the intermediate material obtained in the step (2) into a tablet press for tabletting, and controlling the tabletting speed to be 50.0-120.0 kilo tablets/hour, the average value of the main pressure to be 4.00-20.00 KN and the hardness of plain tablets to be 6.00kg/cm2～8.00kg/cm2；
(5) And (3) adding the plain tablets into a coating pan for coating, controlling the temperature of a tablet bed to be 35-45 ℃, and stopping coating after all coating liquid is used up.
The ambrisentan tablet is prepared by a direct powder tabletting method, the production process is simple, the operation is easy, the cost is low, the reproducibility is good, the obtained ambrisentan tablet has high dissolution rate, high bioavailability and good stability, after the large-scale production, the dissolution difference among batches is very small, the ambrisentan tablet is particularly suitable for industrial large-scale production, and the market prospect is wide.
Drawings
FIG. 1 is a comparison of the dissolution curves of the tablets of examples 3 to 5 in water
FIG. 2 is a comparison of the dissolution profiles of the tablets of examples 3 to 5 in 0.1mol/L hydrochloric acid
FIG. 3 is a comparison of the dissolution profiles of the tablets of examples 3-5 in acetate buffer at pH4.5
FIG. 4 is a comparison of the dissolution profiles of the tablets of examples 3-5 in acetate buffer solution at pH5.0
FIG. 5 is a comparison of the dissolution profiles of the tablets of examples 3-5 in acetate buffer at pH6.8
FIG. 6 is a comparison of the dissolution profiles of the tablets of examples 6-7 in 5 media
Detailed Description
To further illustrate the present invention, the present invention will be specifically described with reference to specific examples, but the scope of the present invention is not limited to the specific examples.
Example 1 ambrisentan particle size study
TABLE 1
And (4) conclusion: by investigating angle of repose, tablet weight difference, mixing uniformity, plain tablet content uniformity, plain tablet dissolution rate and the like, when the granularity of ambrisentan is 20um or more and d (0.9) or more and 50um or less, the obtained plain tablet has small tablet weight difference and has good content uniformity, mixing uniformity and drug dissolution rate.
Example 2 hardness examination
TABLE 2
And (4) conclusion: by inspecting the appearance, friability, dissolution rate and the like of the ambrisentan tablet, when the hardness range of the ambrisentan tablet is 5.00-10.00 kg/cm2The obtained tablet is complete, smooth, uniform in color, free of unfilled corners and breakage, and quick in drug dissolution.
Example 3
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: sieving the ambrisentan micro powder, controlling d (0.9) to be 33.3um, and sieving lactose and microcrystalline cellulose by a 60-mesh sieve;
(2) putting prescribed amount of ambrisentan and half prescribed amount of lactose into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(3) adding the intermediate material obtained in the step (2) into a granulator for granulation, setting a mesh with a pore diameter of 1.0mm for the granulator, and setting the rotating speed of a rotary cutter to be 300-400 rpm;
(4) adding the sized intermediate material and the other half of the prescribed amount of lactose into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 5 min;
(5) adding the microcrystalline cellulose and the croscarmellose sodium in the formula amount into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 15 min;
(6) adding the magnesium stearate with the prescription amount into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(7) adding the material obtained in the step (6) into a rotary tablet press for tabletting, setting the tabletting speed of the rotary tablet press to be 80.0 kilotablets/hour, the rotating speed of a filling device to be 50rpm, the average main pressure to be 7.5KN, and setting the hardness of the obtained plain tablets to be 6.75kg/cm2。
(8) Coating: and (3) adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after all the coating liquid is used up.
Example 4
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: sieving the ambrisentan micro powder, controlling d (0.9) to be 25.8um, and sieving lactose and microcrystalline cellulose by a 70-mesh sieve;
(2) putting prescribed amount of ambrisentan and half prescribed amount of lactose into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(3) adding the intermediate material obtained in the step (2) into a granulator for granulation, setting a mesh with a pore diameter of 1.4mm for the granulator, and setting the rotating speed of a rotary cutter to be 300-400 rpm;
(4) adding the sized intermediate material and the other half of the prescribed amount of lactose into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 5 min;
(5) adding the microcrystalline cellulose and the croscarmellose sodium in the formula amount into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 15 min;
(6) adding the magnesium stearate with the prescription amount into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(7) adding the material obtained in the step (6) into a rotary tablet press for tabletting, setting the tabletting speed of the rotary tablet press to be 80 thousand tablets/h, the rotating speed of a filling device to be 80rpm, the average main pressure to be 8.0KN, and setting the hardness of the obtained plain tablets to be 6.02kg/cm2。
(8) Coating: and (3) adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after all the coating liquid is used up.
Example 5
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: sieving the ambrisentan micro powder, controlling d (0.9) to be 19.6um, and sieving lactose and microcrystalline cellulose by a 70-mesh sieve;
(2) putting prescribed amount of ambrisentan and half prescribed amount of lactose into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(3) adding the intermediate material obtained in the step (2) into a granulator for granulation, setting a mesh with a pore diameter of 1.0mm for the granulator, and setting the rotating speed of a rotary cutter to be 300-400 rpm;
(4) adding the sized intermediate material and the other half of the prescribed amount of lactose into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 5 min;
(5) adding the microcrystalline cellulose and the sodium carboxymethyl starch in the formula amount into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 15 min;
(6) adding the magnesium stearate with the prescription amount into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(7) adding the material obtained in the step (6) into a rotary tablet press for tabletting, setting the tabletting speed of the rotary tablet press to be 70 thousand tablets/h, the rotating speed of a filling device to be 80rpm, the average main pressure to be 8.7KN, and setting the hardness of the obtained plain tablets to be 12.25kg/cm2。
(8) Coating: and (3) adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after all the coating liquid is used up.
Example 6
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: sieving the ambrisentan micro powder, controlling d (0.9) to be 26.5um, and sieving lactose and microcrystalline cellulose by a 60-mesh sieve;
(2) putting prescribed amount of ambrisentan and half prescribed amount of lactose into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(3) adding the intermediate material obtained in the step (2) into a granulator for granulation, setting a mesh with a pore diameter of 1.4mm for the granulator, and setting the rotating speed of a rotary cutter to be 300-400 rpm;
(4) adding the sized intermediate material and the other half of the prescribed amount of lactose into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 5 min;
(5) adding the microcrystalline cellulose and the croscarmellose sodium in the formula amount into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 15 min;
(6) adding the magnesium stearate with the prescription amount into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(7) tabletting, setting the tabletting speed of the rotary tablet press to be 100 thousand tablets/h, the rotating speed of a filling device to be 45rpm and the average main pressure to be 8.0KN, soThe hardness of the obtained plain tablet is 7.64kg/cm2。
(8) Coating: and (3) adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after all the coating liquid is used up.
Example 7
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: sieving the ambrisentan micro powder, controlling d (0.9) to be 31.6um, and sieving lactose and microcrystalline cellulose by a 60-mesh sieve;
(2) putting prescribed amount of ambrisentan and half prescribed amount of lactose into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(3) adding the intermediate material obtained in the step (2) into a granulator for granulation, setting a mesh with a pore diameter of 1.0mm for the granulator, and setting the rotating speed of a rotary cutter to be 300-400 rpm;
(4) adding the sized intermediate material and the other half of the prescribed amount of lactose into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 5 min;
(5) adding the microcrystalline cellulose and the croscarmellose sodium in the formula amount into a hopper mixer, setting the rotating speed to 10rpm, and mixing for 15 min;
(6) adding the magnesium stearate with the prescription amount into a hopper mixer, setting the rotating speed to be 10rpm, and mixing for 5 min;
(7) adding the material obtained in the step (6) into a rotary tablet press for tabletting, setting the tabletting speed of the rotary tablet press to be 100 kilotablets/hour, the rotating speed of a filling device to be 45rpm, the average value of main pressure to be 7.5KN, and setting the hardness of the obtained plain tablets to be 6.77kg/cm2。
(8) Coating: and (3) adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after all the coating liquid is used up.
Example 8 drug dissolution study
Dissolution medium: 900ml of 0.1mol/L hydrochloric acid, pH4.5 acetate buffer solution, pH5.0 acetate buffer solution, pH6.8 phosphate buffer solution and water;
the dissolution method comprises the following steps: paddle method, 50 rpm;
temperature of the medium: 37.0 +/-0.5 ℃;
sampling: sampling 5ml after 5min, 10min, 15min, 30min and 45min respectively, filtering by a mixed cellulose membrane, and simultaneously supplementing isothermal same medium;
sample preparation: in the ambrisentan tablets provided in examples 3 to 7, 30 tablets were randomly sampled from each batch, and the dissolution of each batch in different dissolution media was examined.
The results are shown in FIGS. 1 to 5.
As can be seen from the comparison of the dissolution curves of the self-made preparations in different batches, the dissolution difference of the self-made preparations in different batches is small, and the method is suitable for industrial mass production.
Example 9 in vivo pharmacokinetic Studies
Determining the concentration of ambrisentan in plasma of the subject after the administration by adopting liquid chromatography-tandem mass spectrometry (LC/MS/MS).
The linear range of the analysis method is 1-2000 ng/mL, and the lower limit of the quantification is 1 ng/mL. The concentrations of the low, medium and high Quality Control (QC) samples were: 3. 100 and 1500 ng/mL.
After a single oral administration of the ambrisentan tablet prepared in example 3 on an empty stomach of healthy subjects, the mean pharmacokinetic parameters of ambrisentan in vivo are shown in table 3.
TABLE 3
| Parameter (Unit) | Arithmetic mean + -SD |
| Tmax(h) | 1.39 |
| Cmax(ng/mL) | 562.0±77.0 |
| AUC0-t(h*ng/mL) | 3928±660 |
| AUC0-∞(h*ng/mL) | 4071±701 |
| λz(1/h) | 0.035±0.009 |
| t1/2(h) | 20.8±4.7 |
Claims (10)
1. A preparation method of an ambrisentan tablet comprises the following steps:
1) micronizing ambrisentan, and controlling the particle size of d (0.9) to be not less than 20um and not more than 50 um;
2) uniformly mixing the micronized ambrisentan and a first filler in a hopper mixer, and then adding the mixture into a granulator for granulation;
3) uniformly mixing the granules obtained in the step 2) with a second filler, a disintegrating agent and a lubricating agent in a hopper mixer in sequence;
4) adding the intermediate material obtained in the step 3) into a tablet press for tabletting, wherein the hardness of the plain tablets is controlled to be 5.00kg/cm2～10.00kg/cm2Preferably, the hardness of the plain sheet is 6.00kg/cm2～8.00kg/cm2；
5) And (4) coating.
2. The method according to claim 1, characterized in that the particle size of ambrisentan is 20 um. ltoreq. d (0.9). ltoreq.35 um, preferably 25 um. ltoreq. d (0.9). ltoreq.35 um.
3. A method according to claim 1, wherein the filler is pre-treated by sieving through a 50-80 mesh sieve, preferably through a 60 mesh sieve, more preferably through a 70 mesh sieve, prior to mixing.
4. A method according to claim 1, characterised in that the rotational speed of the hopper mixer is 8-20 rpm, preferably 10-12 rpm.
5. The method according to claim 1, wherein the tabletting speed of the tabletting machine is 50.0 to 120.0 kp/hr, preferably 60.0 to 100.0 kp/hr, more preferably 80.0 to 100.0 kp/hr.
6. A method according to claim 1, characterized in that the mean value of the main pressure of the tablet press is 4.00 to 20.00KN, preferably 6.00 to 10.00 KN.
7. The method according to claim 1, characterized in that the granulator aperture screen is from 0.25mm to 2.00mm, preferably from 0.85mm to 1.40mm, more preferably from 1.0mm to 1.40 mm; the rotational speed of the granulator is 200 to 450rpm, preferably 300 to 400 rpm.
8. The method of claim 1, wherein the first filler and the second filler are independently selected from one or more of lactose, microcrystalline cellulose, mannitol, corn starch, and pregelatinized starch, preferably the first filler is lactose and the second filler is microcrystalline cellulose; the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl cellulose, microcrystalline cellulose and crospovidone, preferably the croscarmellose sodium and the sodium carboxymethyl starch; the lubricant is selected from magnesium stearate, sodium stearyl fumarate, talcum powder and silica gel micropowder, and preferably magnesium stearate.
9. The method of claim 8, comprising the steps of:
1) micronizing ambrisentan, and controlling the particle size of d (0.9) to be less than or equal to 20um and less than or equal to 35 um;
2) uniformly mixing the micronized ambrisentan and lactose in a hopper mixer, and then adding the mixture into a granulating machine for granulating;
3) mixing the granules obtained in the step 2) with microcrystalline cellulose, croscarmellose sodium and magnesium stearate in a hopper mixer in sequence;
4) adding the intermediate material obtained in the step 3) into a tablet press for tabletting, wherein the hardness of the plain tablets is controlled to be 5.00kg/cm2～10.00kg/cm2；
5) And (4) coating.
10. The method of claim 9, comprising the steps of:
1) micronizing ambrisentan, and controlling the particle size of d (0.9) to be less than or equal to 20um and less than or equal to 35 um;
2) uniformly mixing the micronized ambrisentan with half of formula amount of lactose in a hopper mixer, and then adding the mixture into a granulator for granulation;
3) uniformly mixing the granules obtained in the step 2) with the lactose in the other half formula amount in a hopper mixer, then uniformly mixing the granules with microcrystalline cellulose and croscarmellose sodium, and finally uniformly mixing the granules with magnesium stearate;
4) adding the intermediate material obtained in the step 3) into a tablet press for tabletting, wherein the hardness of the plain tablets is controlled to be 5.00kg/cm2～10.00kg/cm2；
5) And adding the plain tablets into a coating pan for coating.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110025587A (en) * | 2019-04-28 | 2019-07-19 | 常州恒邦药业有限公司 | Ambrisentan oral tablet and preparation method thereof |
| EP4014968A1 (en) * | 2020-12-16 | 2022-06-22 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A film coated tablet comprising micronized ambrisentan |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105581990A (en) * | 2014-08-27 | 2016-05-18 | 人福医药集团股份公司 | Ambrisentan tablet and preparation method thereof |
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2018
- 2018-09-06 CN CN201811039700.6A patent/CN110876731A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105581990A (en) * | 2014-08-27 | 2016-05-18 | 人福医药集团股份公司 | Ambrisentan tablet and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110025587A (en) * | 2019-04-28 | 2019-07-19 | 常州恒邦药业有限公司 | Ambrisentan oral tablet and preparation method thereof |
| EP4014968A1 (en) * | 2020-12-16 | 2022-06-22 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A film coated tablet comprising micronized ambrisentan |
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