CN117064860A - Preparation method of riocigua tablet - Google Patents
Preparation method of riocigua tablet Download PDFInfo
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- CN117064860A CN117064860A CN202311201913.5A CN202311201913A CN117064860A CN 117064860 A CN117064860 A CN 117064860A CN 202311201913 A CN202311201913 A CN 202311201913A CN 117064860 A CN117064860 A CN 117064860A
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- riocidine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 53
- 239000002245 particle Substances 0.000 claims abstract description 47
- 238000000576 coating method Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000011248 coating agent Substances 0.000 claims abstract description 26
- 238000002156 mixing Methods 0.000 claims abstract description 21
- 238000001035 drying Methods 0.000 claims abstract description 18
- 239000000945 filler Substances 0.000 claims abstract description 11
- 239000007779 soft material Substances 0.000 claims abstract description 11
- 239000000853 adhesive Substances 0.000 claims abstract description 10
- 230000001070 adhesive effect Effects 0.000 claims abstract description 10
- 238000009835 boiling Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000000314 lubricant Substances 0.000 claims abstract description 6
- 239000000843 powder Substances 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims description 24
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 239000007888 film coating Substances 0.000 claims description 7
- 238000009501 film coating Methods 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 229940069328 povidone Drugs 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 6
- 229960003943 hypromellose Drugs 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 229910001220 stainless steel Inorganic materials 0.000 claims description 5
- 239000010935 stainless steel Substances 0.000 claims description 5
- 230000004584 weight gain Effects 0.000 claims description 5
- 235000019786 weight gain Nutrition 0.000 claims description 5
- 102220042174 rs141655687 Human genes 0.000 claims description 3
- 102220043159 rs587780996 Human genes 0.000 claims description 3
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 abstract description 41
- 238000004090 dissolution Methods 0.000 abstract description 22
- 229940079593 drug Drugs 0.000 abstract description 15
- 239000008187 granular material Substances 0.000 abstract description 12
- 239000008363 phosphate buffer Substances 0.000 abstract description 6
- 238000007873 sieving Methods 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 239000007941 film coated tablet Substances 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 7
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 description 5
- 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 description 4
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 4
- 229940081664 adempas Drugs 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 208000002815 pulmonary hypertension Diseases 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 238000004080 punching Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000000556 agonist Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 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 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000009817 primary granulation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
Classifications
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- 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)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The application relates to the technical field of medicine preparation, in particular to a preparation method of riocigua tablets. The preparation method comprises the following specific steps: s1, micronizing main medicines into different particle sizes and uniformly mixing for later use; s2, uniformly mixing the micronized main medicine, the filler, the disintegrating agent and the adhesive, and granulating by a wet method by using a solubilizer to prepare a soft material; s3, passing the soft material through a screen to obtain wet granules, drying the wet granules in a boiling drying granulator, and sieving the dry granules to obtain dry granules; s4, adding a lubricant into the dry particles and uniformly mixing to obtain total mixed particles; s5, putting the total mixed particles into a tablet press for tabletting to obtain tablet cores; s6, coating the tablet core with coating powder to obtain film coated tablets, and preparing Li Aoxi Gua tablets. The prepared sample and the reference preparation have similar dissolution curves in phosphate buffer medium with pH of 6.8, have similar speed, and are favorable for quality control of medicines and have better reproducibility.
Description
Technical Field
The application relates to the technical field of medicine preparation, in particular to a preparation method of riocigua tablets.
Background
The medicine for treating pulmonary arterial hypertension mainly comprises: prostacyclin-based drugs, endothelin receptor antagonists, calcium channel blockers, phosphodiesterase-5 inhibitors, anticoagulants, diuretics, others, and the like.
Riocidine (Adempas) was the first new class of Soluble Guanylate Cyclase (SGC) agonists developed and marketed by Bayer corporation, the first drug approved worldwide for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), and the only drug currently available is Pulmonary Arterial Hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).
Riocidine has chemical name of 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazole [3,4-b ]]Pyridin-3-yl]-methyl 5-pyrimidine (methyl) carbamate of formula C 20 H 19 FN 8 O 2 The molecular weight is 422.42, the CAS number is 625115-55-1, and the structural formula is as follows:
riocidine serves as a novel Soluble Guanylate Cyclase (SGC) agonist, has a dual action mode, can increase sensitivity of the Soluble Guanylate Cyclase (SGC) to endogenous Nitric Oxide (NO) on one hand, and can directly stimulate the SGC independently of NO on the other hand, so that the yield of Cyclic Guanylate (CGMP) is increased.
The Chinese patent literature publication No. CN105596311A, the patent name is "Riocidine oral solid preparation method", discloses a preparation method of Riocidine tablet: the main medicine and the filler are mixed and ground, so that the main solubility is improved. The main medicine in the grinding process may have adsorption phenomenon, the specification of the product is lower, the adsorption of the main medicine easily causes the condition of lower sample content, mannitol is added in the prescription, and the addition of the material can change the permeability of the active ingredients of the medicine, thereby affecting the medication safety of patients.
The Chinese patent literature publication No. CN104434845A, the patent name is "solid pharmaceutical preparation containing riocigua", discloses a preparation method of riocigua tablets: 1) Weighing prescribed amount of water-soluble polymer, and heating and melting the water-soluble polymer at 65 ℃ to obtain a molten liquid; 2) Slowly stirring the melt obtained in the step 1), slowly adding the prescription amount of riocigua, and after the riocigua is completely added, vigorously stirring the melt for 30 minutes to uniformly disperse the medicine; 3) Rapidly cooling the melt obtained in the step 2) at the temperature of minus 20 ℃ and solidifying for 2 to 3 hours to obtain a solidified substance; 4) Crushing the solidified material obtained in the step 3) at 4-8 ℃, sieving with a 80-mesh sieve, drying under reduced pressure for 4 hours to obtain a solid dispersion, 5) uniformly mixing the solid dispersion obtained in the step 4 with a prescribed amount of diluent and disintegrating agent, compressing the mixture by using a dry granulator, and performing primary granulation; 6) Sieving the granules obtained in the step 5) with a 20-mesh sieve; 7) Tabletting the materials obtained by blending the lubricant and the materials obtained in the step 6) by using a high-speed tabletting machine to obtain tablet cores; 8) And (3) coating the tablet core obtained in the step 7) to obtain the film-coated tablet. The preparation method is difficult to realize in the actual production process, and has the advantages of high labor and time consumption and high preparation cost.
The Chinese patent literature of the application discloses a preparation process of the riocigua tablet with the publication number of CN106913554A and the patent name of the riocigua tablet is a preparation method of a preparation for treating pulmonary arterial hypertension: pretreating raw materials, and micronizing riocido to the required granularity; preparing a liquid medicine, namely dispersing the micronized riociquone into an aqueous solution of an adhesive and a solubilizer; and granulating, namely adding granulating auxiliary materials into a fluidized bed, spraying the liquid medicine into the fluidized bed, and granulating by the fluidized bed in one step. The preparation method disperses the micronized raw material medicine into the adhesive, which can cause precipitation phenomenon and has poor process reproducibility.
Disclosure of Invention
The application aims at solving at least one of the technical problems existing in the prior art, and therefore, one aspect of the application aims at providing a preparation method of riocidine tablets, which comprises the following specific steps:
s1, micronizing main medicines into different particle sizes and uniformly mixing for later use;
s2, uniformly mixing the micronized main medicine, the filler, the disintegrating agent and the adhesive in the S1, and performing wet granulation by using a solubilizer to prepare a soft material;
s3, passing the soft material obtained in the step S2 through a screen to obtain wet particles, and placing the wet particles in a boiling drying granulator for drying, and passing the dried materials through the screen to carry out granulation to obtain dry particles;
s4, adding a lubricant into the dry particles obtained in the step S3, and uniformly mixing to obtain total mixed particles;
s5, putting the total mixed particles obtained in the step S4 into a tablet press for tabletting to obtain tablet cores;
s6, coating the tablet cores obtained in the step S5 with coating powder to obtain Li Aoxi Gua tablets.
Preferably, 70% of the main drug in S1 is micronized into particles with a diameter d90=5 μm to 10 μm and d50=2 μm to 4 μm;30% of the main medicine is micronized into particles with the diameter D90 smaller than 5 μm and the diameter D50 smaller than 2 μm.
Preferably, the main medicine in the S2 is riocigua, the filler is lactose and microcrystalline cellulose, the disintegrating agent is cross-linked povidone, the adhesive is hypromellose, the solubilizer is sodium dodecyl sulfate and water, and the water consumption accounts for 30-40% of the total medicine.
Preferably, the main medicine and the auxiliary materials in the S2 account for 0.5 to 3.0 percent of the total weight of the medicine, 40 to 50 percent of filler lactose, 40 to 50 percent of filler microcrystalline cellulose, 5 to 7 percent of disintegrant crosslinked povidone, 3 to 4 percent of adhesive hydroxypropyl methylcellulose and 0.1 to 0.5 percent of solubilizer sodium dodecyl sulfate.
Preferably, the soft material in the step S3 is sieved by a 24-mesh screen to obtain wet particles.
Preferably, the frequency of a fan in the multifunctional boiling granulator in the step S3 is controlled to be 20-40 HZ, the air inlet temperature is 60+/-5 ℃, the material temperature is 38+/-2 ℃, the drying time is 10-40 min, and the moisture is less than 3.0%; the granules are sized by a 1.2mm stainless steel screen mesh through a granulator with the rotating speed of 500rpm.
Preferably, the lubricant in S4 is magnesium stearate, accounting for 0.25-1% of the total weight of the medicine.
Preferably, the standard of tabletting in the step S5 is 0.085g of tabletting by using phi 6mm shallow concave punch, the main pressure of a tabletting machine is 10 KN-50 KN, and the hardness is controlled to be 30N-80N.
Preferably, the coating powder in the step S6 is a film coating premix, and is prepared into a film coating premix aqueous solution with a solid content of 12%.
Preferably, the air inlet temperature is controlled to be 60+/-5 ℃ in the coating process in the step S6, the material temperature is controlled to be 35 ℃ -45 ℃, the coating time is 2-6 h, and the coating weight gain is 2% -5%.
The application has the following beneficial effects:
the riocigua tablet prepared by the application only contains main medicines and conventional auxiliary materials, is safe to use and does not increase the burden of patients. Riocidine has extremely poor solubility and slow dissolution rate, and is unfavorable for drug absorption. Therefore, the development of a simple process and a reproducible preparation process is particularly important for the development of the product. In order to improve the dissolution rate of the riocidine in the preparation, the preparation is prepared by micronizing the raw materials, mixing the different particle sizes and controlling the release of the materials, so that the dissolution of the insoluble medicine is similar to that of a reference preparation.
The preparation process is simple and convenient to operate, the riociycycline is micronized into different particle sizes, the riociycycline is mixed with the filler, the disintegrating agent and the adhesive, and then a wet granulation process is adopted to prepare a tablet core, and a sample is obtained through coating. The prepared sample has the same weight and property as those of the reference preparation, and the dissolution curve in the phosphate buffer medium with the pH value of 6.8 is similar to that of the reference preparation. The preparation process has low cost and simple process, is favorable for quality control of medicines, has better reproducibility, and has similar dissolution behavior with the reference preparation.
The method has the advantages of short process steps, simpler and more convenient operation, improves the product yield, reduces the production cost and is suitable for industrial mass production.
Additional aspects and advantages of the application will become apparent in the following description or may be learned by practice of the application.
Drawings
Additional aspects and advantages of the present application will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings, in which:
FIG. 1 is a graphical representation of the comparative dissolution profiles of phosphate buffer at pH6.8 for inventive example 1, example 2, example 3 and reference formulation.
Detailed Description
In order that the above-recited objects, features and advantages of the present application will be more clearly understood, a more particular description of the application will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. It should be noted that, without conflict, the embodiments of the present application and features in the embodiments may be combined with each other.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application, however, the present application may be practiced otherwise than as described, and therefore the scope of the present application is not limited to the specific embodiments disclosed below.
Example 1
1. Prescription of prescription
2. Preparation
(1) And (3) main medicine treatment: pulverizing Riocidine with jet mill (D90 < 5 μm, D50 < 2 μm);
(2) Preparing a sodium dodecyl sulfate aqueous solution: weighing sodium dodecyl sulfate until purified water is dissolved;
(3) Premixing: weighing and evenly mixing the riocigua, lactose, microcrystalline cellulose, crosslinked povidone and hypromellose after crushing;
(4) Granulating: adding the premixed material in the step (3) into the aqueous solution of sodium dodecyl sulfate in the step (2) for wet granulation to obtain a soft material, and preparing wet granules through a 24-mesh sieve;
(5) And (3) drying: placing the prepared wet granules into a boiling drying granulator, controlling the frequency of a fan to be 20-40 HZ, the air inlet temperature to be 60+/-5 ℃, the material temperature to be 38+/-2 ℃, the drying time to be 10-40 min, and the moisture to be less than 3.0%;
(6) Finishing: finishing the dry particles by a stainless steel screen with the diameter of 1.2mm, wherein the rotating speed is 500rpm, so as to obtain dry particles;
(7) Total mixing: uniformly mixing the dry particles and the prescription amount of magnesium stearate to obtain total mixed particles;
(8) Tabletting: taking total mixed particlesThe tablet is subjected to shallow concave punching, the main pressure of the tablet press is 10 KN-50 KN, the hardness is controlled to be 30N-80N, and each tablet is 0.085g, so that a tablet core is obtained;
(9) Coating: coating the tablet core with a film coating premix aqueous solution with the solid content of 12%, wherein the air inlet temperature is controlled to be 60+/-5 ℃ in the coating process, the material temperature is controlled to be 35-45 ℃, the coating time is 2-6 h, and the coating weight gain is 2-5%, so as to obtain Li Aoxi Gua tablet.
3. Dissolution Curve determination
Referring to the second method of dissolution measurement of the second 0931 part of the chinese pharmacopoeia of 2020 edition, the tablet prepared in example 1 was subjected to dissolution test in phosphate buffer dissolution medium at ph6.8, and compared with the reference preparation (trade name Adempas (An Jiao), lot number BXJERX1, national drug standard of HJ20170360, manufacturer bayera). The elution profile is shown in FIG. 1, and the results are shown in Table 1 below.
TABLE 1 dissolution profile test results for 2.5mg of example 1 and reference formulations
Example 2
1. Prescription of prescription
2. Preparation
(1) And (3) main medicine treatment: pulverizing Riocidine by an air flow pulverizer (50% of main medicine micronization particle size is D90=5-10 μm, D50=2-4 μm;50% of main medicine micronization particle size is D90 < 5 μm, D50 < 2 μm);
(2) Preparing a sodium dodecyl sulfate aqueous solution: weighing sodium dodecyl sulfate until purified water is dissolved;
(3) Premixing: weighing and evenly mixing the riocigua, lactose, microcrystalline cellulose, crosslinked povidone and hypromellose after crushing;
(4) Granulating: adding the premixed material in the step (3) into the aqueous solution of sodium dodecyl sulfate in the step (2) for wet granulation to obtain a soft material, and preparing wet granules through a 24-mesh sieve;
(5) And (3) drying: placing the prepared wet granules into a boiling drying granulator, controlling the frequency of a fan to be 20-40 HZ, the air inlet temperature to be 60+/-5 ℃, the material temperature to be 38+/-2 ℃, the drying time to be 10-40 min, and the moisture to be less than 3.0%;
(6) Finishing: finishing the dry particles by a stainless steel screen with the diameter of 1.2mm, wherein the rotating speed is 500rpm, so as to obtain dry particles;
(7) Total mixing: uniformly mixing the dry particles and the prescription amount of magnesium stearate to obtain total mixed particles;
(8) Tabletting: taking total mixed particlesThe tablet is subjected to shallow concave punching, the main pressure of the tablet press is 10 KN-50 KN, the hardness is controlled to be 30N-80N, and each tablet is 0.085g, so that a tablet core is obtained;
(9) Coating: coating the tablet core with a film coating premix aqueous solution with the solid content of 12%, wherein the air inlet temperature is controlled to be 60+/-5 ℃ in the coating process, the material temperature is controlled to be 35-45 ℃, the coating time is 2-6 h, and the coating weight gain is 2-5%, so as to obtain Li Aoxi Gua tablet.
3. Dissolution Curve determination
In vitro dissolution experiments refer to the second method of dissolution measurement of the second 0931 part of the Chinese pharmacopoeia of 2020 edition, the tablet prepared in example 2 was placed in a phosphate buffer dissolution medium of pH6.8 for dissolution test, and compared with the reference preparation (commercial name Adempas (An Jiao), lot number BXJERX1, national drug standard of HJ20170360, manufacturer of BayerAG). The elution profile is shown in FIG. 1, and the results are shown in Table 2 below.
Table 2 results of the reference formulation dissolution profile test of example 2
Example 3
1. Prescription of prescription
2. Preparation
(1) And (3) main medicine treatment: pulverizing Riocidine by an air flow pulverizer (70% of main medicine micronization particle size is D90=5μm-10μm, D50=2μm-4μm;30% of main medicine micronization particle size is D90 < 5 μm, D50 < 2 μm);
(2) Preparing a sodium dodecyl sulfate aqueous solution: weighing sodium dodecyl sulfate until purified water is dissolved;
(3) Premixing: weighing and evenly mixing the riocigua, lactose, microcrystalline cellulose, crosslinked povidone and hypromellose after crushing;
(4) Granulating: adding the premixed material in the step (3) into the aqueous solution of sodium dodecyl sulfate in the step (2) for wet granulation to obtain a soft material, and preparing wet granules through a 24-mesh sieve;
(5) And (3) drying: placing the prepared wet granules into a boiling drying granulator, controlling the frequency of a fan to be 20-40 HZ, the air inlet temperature to be 60+/-5 ℃, the material temperature to be 38+/-2 ℃, the drying time to be 10-40 min, and the moisture to be less than 3.0%;
(6) Finishing: finishing the dry particles by a stainless steel screen with the diameter of 1.2mm, wherein the rotating speed is 500rpm, so as to obtain dry particles;
(7) Total mixing: uniformly mixing the dry particles and the prescription amount of magnesium stearate to obtain total mixed particles;
(8) Tabletting: taking total mixed particlesThe tablet is subjected to shallow concave punching, the main pressure of the tablet press is 10 KN-50 KN, the hardness is controlled to be 30N-80N, and each tablet is 0.085g, so that a tablet core is obtained;
(9) Coating: coating the tablet core with a film coating premix aqueous solution with the solid content of 12%, wherein the air inlet temperature is controlled to be 60+/-5 ℃ in the coating process, the material temperature is controlled to be 35-45 ℃, the coating time is 2-6 h, and the coating weight gain is 2-5%, so as to obtain Li Aoxi Gua tablet.
3. Dissolution Curve determination
In vitro dissolution experiments refer to the second method of dissolution measurement of the second 0931 part of the Chinese pharmacopoeia of 2020 edition, the tablet prepared in example 3 was placed in a phosphate buffer dissolution medium of pH6.8 for dissolution test, and compared with the reference preparation (commercial name Adempas (An Jiao), lot number BXJERX1, national drug standard of HJ20170360, manufacturer of BayerAG). The elution profile is shown in FIG. 1, and the results are shown in Table 3 below.
TABLE 3 dissolution profile test results for example 3 and reference formulation
The dissolution behavior between the two is compared with a similarity factor f2 to see whether the dissolution behavior is consistent.
Calculated example 1, example 2, example 3 and reference formulation similarity factor f 2 The values of 53, 67 and 89 > 50 in this order are similar to the dissolution profile of the reference formulation but example 3 is similarThe factor is higher.
From the above, the particle size of 70% of the main drug is controlled to d90=5-10 μm and d50=2-4 μm by using a jet mill; the dissolution curve of the prepared sample and the reference preparation is most similar when the particle size of 30% of the main medicine is controlled to be D90 < 5 mu m and D50 < 2 mu m.
The above description is only of the preferred embodiments of the present application, and is not intended to limit the present application, but various modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. A preparation method of Riocigua tablets is characterized in that: the preparation method comprises the following specific steps:
s1, micronizing a main medicine into different particle sizes, and uniformly mixing for later use;
s2, uniformly mixing the main medicine micronized in the step S1, the filler, the disintegrating agent and the adhesive, and performing wet granulation by using a solubilizer to prepare a soft material;
s3, passing the soft material obtained in the step S2 through a screen to obtain wet particles, and placing the wet particles in a boiling drying granulator for drying, and passing the dried materials through the screen to carry out granulation to obtain dry particles;
s4, adding a lubricant into the dry particles obtained in the step S3, and uniformly mixing to obtain total mixed particles;
s5, putting the total mixed particles obtained in the step S4 into a tablet press for tabletting to obtain tablet cores;
s6, coating the tablet cores obtained in the step S5 with coating powder to obtain Li Aoxi Gua tablets.
2. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: 70% of the main medicine in S1 is micronized into particles with the diameter of D90=5-10 mu m and D50=2-4 mu m;30% of the main medicine is micronized into particles with the diameter D90 smaller than 5 μm and the diameter D50 smaller than 2 μm.
3. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: the main medicine in S2 is riociquone, the filler is lactose and microcrystalline cellulose, the disintegrating agent is crospovidone, the adhesive is hypromellose, the solubilizer is sodium dodecyl sulfate solution water, and the water consumption accounts for 30-40% of the total medicine.
4. The method for preparing riocidine tablet according to claim 2, characterized in that: in the S2, the main medicine and auxiliary materials account for 0.5 to 3.0 percent of the total weight of the medicine, the main medicine riocigua accounts for 40 to 50 percent of filler lactose, the filler microcrystalline cellulose accounts for 40 to 50 percent, the disintegrating agent crosslinked povidone accounts for 5 to 7 percent, the adhesive hydroxypropyl methylcellulose accounts for 3 to 4 percent, and the solubilizer sodium dodecyl sulfate accounts for 0.1 to 0.5 percent.
5. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: the soft material in the step S3 is sieved by a 24-mesh screen to prepare wet particles.
6. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: the frequency of a fan in the multifunctional boiling granulator in the step S3 is controlled to be 20-40 HZ, the air inlet temperature is 60+/-5 ℃, the material temperature is 38+/-2 ℃, the drying time is 10-40 min, and the moisture is less than 3.0%; dry-granulating with a granulator with a stainless steel screen of 1.2mm at 500rpm.
7. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: the lubricant in the S4 is magnesium stearate, and accounts for 0.25-1% of the total weight of the medicine.
8. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: and the standard of tabletting in the step S5 is 0.085g of tablets, the tablets are stamped by using a phi 6mm shallow concave, the main pressure of a tablet press is 10 KN-50 KN, and the hardness is controlled to be 30N-80N.
9. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: the coating powder in the step S6 is a film coating premix, and is prepared into a film coating premix aqueous solution with the solid content of 12%.
10. The method for preparing riocidine tablet as defined in claim 1, wherein the method comprises the following steps: the air inlet temperature is controlled to be 60+/-5 ℃ in the coating process in the step S6, the material temperature is controlled to be 35 ℃ -45 ℃, the coating time is 2-6 h, and the coating weight gain is 2% -5%.
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| CN202311201913.5A CN117064860A (en) | 2023-09-18 | 2023-09-18 | Preparation method of riocigua tablet |
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| CN202311201913.5A CN117064860A (en) | 2023-09-18 | 2023-09-18 | Preparation method of riocigua tablet |
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