CN117084984B - Method for efficiently preparing dimetanidazole premix - Google Patents
Method for efficiently preparing dimetanidazole premix Download PDFInfo
- Publication number
- CN117084984B CN117084984B CN202311288050.XA CN202311288050A CN117084984B CN 117084984 B CN117084984 B CN 117084984B CN 202311288050 A CN202311288050 A CN 202311288050A CN 117084984 B CN117084984 B CN 117084984B
- Authority
- CN
- China
- Prior art keywords
- premix
- hydrosol
- polyethylene glycol
- glycol diacrylate
- dimetanidazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 238000003756 stirring Methods 0.000 claims abstract description 27
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 25
- 125000004386 diacrylate group Chemical group 0.000 claims abstract description 25
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000004108 freeze drying Methods 0.000 claims abstract description 17
- 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 abstract description 14
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 14
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims abstract description 14
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims abstract description 14
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 229960002089 ferrous chloride Drugs 0.000 claims abstract description 10
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 230000008014 freezing Effects 0.000 claims abstract description 9
- 238000007710 freezing Methods 0.000 claims abstract description 9
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 7
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 7
- 239000004094 surface-active agent Substances 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims description 29
- 238000000227 grinding Methods 0.000 claims description 28
- 239000007921 spray Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000007873 sieving Methods 0.000 claims description 13
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 10
- 235000003704 aspartic acid Nutrition 0.000 claims description 10
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 10
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 230000010355 oscillation Effects 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- SDIXRDNYIMOKSG-UHFFFAOYSA-L disodium methyl arsenate Chemical compound [Na+].[Na+].C[As]([O-])([O-])=O SDIXRDNYIMOKSG-UHFFFAOYSA-L 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- 244000248349 Citrus limon Species 0.000 claims description 5
- 235000005979 Citrus limon Nutrition 0.000 claims description 5
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 claims description 5
- 229930003944 flavone Natural products 0.000 claims description 5
- 150000002212 flavone derivatives Chemical class 0.000 claims description 5
- 235000011949 flavones Nutrition 0.000 claims description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 5
- 229940068968 polysorbate 80 Drugs 0.000 claims description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims description 5
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 5
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 229960001031 glucose Drugs 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 7
- 239000012752 auxiliary agent Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 2
- 238000000859 sublimation Methods 0.000 abstract description 2
- 230000008022 sublimation Effects 0.000 abstract description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 abstract 1
- 235000004279 alanine Nutrition 0.000 abstract 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 abstract 1
- 229960000282 metronidazole Drugs 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 12
- 239000002245 particle Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000010924 continuous production Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 241000223782 Ciliophora Species 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 241000224526 Trichomonas Species 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of veterinary medicine preparation, and discloses a method for efficiently preparing a dimetanidazole premix, which comprises the following preparation steps: pre-treating ground metronidazole, antioxidant and sodium carboxymethylcellulose, screening, adding the mixture and alanine into methanol solution, stirring for dissolving, adding 70% of polyethylene glycol diacrylate, uniformly mixing, ultrasonically oscillating 30% of polyethylene glycol diacrylate, ferrous chloride, auxiliary agent and surfactant to form hydrosol, freezing with liquid nitrogen, and spray-freeze-drying in a freeze dryer. Compared with the preparation method of high temperature or high shear force in the conventional process, the preparation method of the invention has mild preparation conditions, effectively avoids the problem of thermal sublimation of the dimetazole, and the sodium carboxymethyl cellulose and the polyethylene glycol diacrylate synergistically form a double-network structure, thereby not only improving the release rate of the dimetazole, but also better retaining the activity and the stability of the dimetazole and obviously improving the yield of the premix.
Description
Technical Field
The invention belongs to the technical field of veterinary medicine preparation, and particularly relates to a method for efficiently preparing dimet-dazole premix.
Background
Dimetanidazole is one kind of antibiotic medicine for clinical application, and belongs to the field of azacyclo medicine. It has broad-spectrum antibacterial activity, and has bactericidal or inhibitory effects on a number of gram-positive and gram-negative bacteria, protozoa and some anaerobic bacteria. In addition, dimetazole is equally effective against trichomonas, pig colon pouch ciliates, flagellates, eperythrozoons, and the like; the medicine is also effective on spirochetes between protozoa and bacteria, and is an effective medicine for treating swine bloody dysentery. The mechanism of action of dimnidazole is mainly related to interfering with the DNA synthesis process of bacteria and protozoa. Once dimnidazole enters the cell and is reduced, the active metabolites produced can bind to DNA within the cell, resulting in breakage and damage of the DNA strand, thereby inhibiting the growth and proliferation of bacteria and protozoa.
The dimnidazole raw material is white or yellowish powder, slightly dissolves in water, the water solubility is lower than 2000ppm, the dissolution rate is slow, the difficult complete dissolution under room temperature conditions is difficult, for insoluble drugs, the bioavailability often depends on the dissolution rate of solid drugs in the preparation, and the powder in a coarse dispersion state prepared by a general mixing method is often low in bioavailability due to low dissolution rate. In addition, dimetanidazole itself is alkaline, and has poor stability under alkaline conditions, and may undergo decomposition, oxidation, and other reactions, thereby resulting in reduced efficacy. When the dimnidazole premix is prepared by the traditional method, the production efficiency is lower due to the limitations of production equipment and process technology, so as to meet the requirement of large-scale industrial production.
Among the patents related to the preparation of the dimnidazole premix, chinese patent publication No. CN114601795A discloses a dimnidazole premix with high stability and a preparation method thereof, the dimnidazole premix with good water solubility and high stability is prepared through multiple mixing, grinding and other process treatments, but the method leads to different degrees of particle abrasion and particle size distribution change due to multiple grinding, thereby leading to unstable product quality, relatively low production efficiency and difficult continuous production. In addition, dimnidazole undergoes thermal sublimation at high temperatures, which can lead to reduced yields and affect the quality and stability of the product.
Therefore, aiming at a plurality of defects of the existing preparation of the dimnidazole premix, how to improve and perfect the preparation method of the dimnidazole premix, and then efficiently and stably prepare the dimnidazole premix is a worth exploring problem.
Disclosure of Invention
Based on the problems, the invention aims at overcoming the defects and shortcomings of the existing preparation method of the dimnidazole premix and providing a method for efficiently preparing the dimnidazole premix and ensuring the long-term stability of the dimnidazole premix.
A method for efficiently preparing dimetazole premix, comprising the following steps:
step one: adding dimetanidazole, an antioxidant and sodium carboxymethylcellulose into a grinder for grinding, using a grinding ball or a grinding wheel as a grinding tool, controlling the rotating speed to be 120-150 r/min, controlling the time to be 8-12 min, and sieving through a 60-80 mesh ISO standard screen to obtain a pretreated substance a;
step two: weighing a proper amount of aspartic acid and a pretreatment a, dissolving in methanol, adding into a reaction kettle, adding 15wt% hydrochloric acid to adjust the pH to 5.9-6.8, mixing and stirring at a speed of 100-150 r/min for 3-5 min to obtain a mixed solution b, weighing 70% of polyethylene glycol diacrylate with a prescription amount, adding into the mixed solution b, fully stirring for 180-240 r/min, mixing for 2-5 min uniformly, and filtering to obtain a mixed solution c;
step three: adding the mixed solution c, ferrous chloride and 30% of polyethylene glycol diacrylate with the prescription amount into deionized water, adding auxiliary preparation and surfactant for filling, and performing ultrasonic oscillation at the frequency of 35-50 kHz, the power of 350-500W and the time of 5-12 min to form hydrosol, adding the hydrosol into 2-3 times of liquid nitrogen, and performing vigorous stirring at the speed of 1300-1800 r/min and the time of 1-3 min to obtain frozen hydrosol d;
step four: and placing the frozen hydrosol d in a round bottom flask, hanging in a freeze dryer, spray freeze drying, and sieving with a 40-100 mesh ISO standard sieve in a vibrating manner to prepare the dimet pre-mixing agent.
The preparation method is mild in preparation condition, simple and efficient, and compared with other high-temperature or high-shear preparation methods, the method can better retain the activity of the medicine and improve the stability of the medicine, and in addition, the impurities filtered in the second step can be continuously used after washing and drying, so that the high-activity dimetanidazole premix can be continuously prepared in batches in a short time.
Preferably, in the first step, the antioxidant is one of lemon flavone and tea-fragrant phenol, and the mass ratio of the antioxidant is 0.5-1% of dimet.
Preferably, in the first step, the mass ratio of the sodium carboxymethyl cellulose is 5-8% of that of the dimetanidazole.
Preferably, in the second step, the concentration of the methanol is 95-99 wt%, and the ratio of the methanol to the pretreated material a is: (170-260) mL, 16g.
Preferably, in the second step, the mass ratio of the aspartic acid to the pretreated substance a is: (0.32-0.8): 1.
Preferably, in the second step, the mass ratio of the polyethylene glycol diacrylate to the pretreated object a is: (0.05-0.11): 1.
Preferably, in the third step, the auxiliary agent is one of hydroxypropyl- β -cyclodextrin and anhydrous glucose.
Preferably, in the third step, the surfactant is one of polysorbate-80 and sodium dodecyl sulfate.
Preferably, in the third step, the ratio of the dosage of the mixed solution c, ferrous chloride, auxiliary agent, surfactant and deionized water is as follows: 1mL (0.001-0.005) g (0.08-0.12) g (0.05-0.1) mL (1-2) mL.
Preferably, in the fourth step, the spray freeze drying is carried out at an external temperature of 25 ℃, a spray pressure of 0.35-0.5 MPa, a nozzle diameter of 10-15 um, and a spray freezing temperature of-25 to-21 ℃ for 3.5-4 h.
The invention has the following beneficial effects:
experiments prove that the dissolution rate of the dimetazole premix prepared by the invention is improved by 5 times compared with that of dimetazole, in addition, the active ingredients of the dimetazole premix prepared by the invention have no obvious change when the dimetazole premix is placed for 6 months under an acceleration condition, the solubility is basically unchanged when the dimetazole premix is stored for 24 months under a room temperature condition, the product quality is stable, the transportation is convenient, and the cost is greatly reduced;
according to the invention, sodium carboxymethyl cellulose is added into dimetazole for co-grinding and pretreatment, so that fineness and grinding efficiency of dimetazole and stability in the storage and use processes are effectively improved, and the sodium carboxymethyl cellulose can be added into polyethylene glycol diacrylate to synergistically act as a premix carrier in the subsequent steps, so that the preparation viscosity is reduced, the solubility and release rate of dimetazole are improved, and when hydrosol is prepared, sodium carboxymethyl cellulose and polyethylene glycol diacrylate interact in the hydrosol to form an interlocked netlike small crystallization area through crosslinking, so that the stability of the carrier is improved, and further, the stability of dimetazole premix is improved, and in addition, aspartic acid and polyethylene glycol diacrylate form a polyethylene glycol diacrylate polymerization block, so that the stability of dimetazole is further improved;
according to the invention, deionized water is added into the solution as an antisolvent, an ultrasonic oscillation technology is adopted, so that no residual dissolved solid or ions remain in the hydrosol process, the surface tension is reduced, fine liquid drops are formed, the contact area of the solution and the material is increased, and the mixing of the substrate material and the solution is remarkably accelerated;
the invention adopts mild preparation conditions, does not need repeated grinding and high-temperature heating treatment, reduces the loss in the preparation process of the dimnidazole premix, better maintains the activity and stability of the medicine, and meanwhile, compared with the finished product rate of the dimnidazole premix prepared by the general preparation process, which is about 80 percent, the finished product rate of the dimnidazole premix prepared by the invention is obviously improved to more than 95 percent;
the invention provides a high-efficiency preparation method of dimetanidazole premix, which can realize an automatic and continuous production mode to further improve the production efficiency and save the cost.
Drawings
In order to more clearly illustrate the invention or the technical solutions of the prior art, it will be apparent that the figures in the following description are only the invention, and that other figures can be obtained from these figures without inventive effort for a person skilled in the art, in a clearly understandable way.
FIG. 1 is a flow chart of a preparation method according to an embodiment of the present invention;
FIG. 2 is a graph showing a comparison of drug dissolution profiles of the dimetazole premix prepared in accordance with the present invention;
FIG. 3 is a graph showing the weight loss measurements of the dimetanidazole premix prepared according to the present invention;
FIG. 4 is a raw powder scanning electron microscope image of the dimetizole premix prepared and obtained by the invention;
fig. 5 is a graph showing the infrared spectrum comparison of the dimet azole premix prepared and obtained by the invention and dimet azole.
Detailed Description
In order to facilitate the understanding of the present invention by those skilled in the art, the present invention provides the following specific embodiments for further describing the preparation method of the dimnidazole premix.
Example 1: the embodiment provides a method for efficiently preparing a dimetazole premix, which comprises the following steps:
step one: adding 100g of dimnidazole, 0.5g of lemon flavone and 5g of sodium carboxymethylcellulose into a grinder, using a grinding ball as a grinding tool for grinding, controlling the rotating speed to be 120r/min, controlling the time to be 8min, and sieving through a 60-mesh ISO standard screen to obtain a pretreated substance a;
step two: adding 33.6g of aspartic acid, a pretreatment a and 1115mL of 95wt% methanol into a stirring reaction kettle, adding 15wt% hydrochloric acid to adjust the pH to 5.9, stirring at a speed of 100r/min for 3min to obtain a mixed solution b, adding 3.7g of polyethylene glycol diacrylate into the mixed solution b, stirring at a speed of 180r/min for 2min, uniformly mixing, and filtering to obtain a mixed solution c;
step three: adding the mixed solution c, 1.3g of ferrous chloride and 1.6g of polyethylene glycol diacrylate into 1170mL of deionized water, adding 93.6g of hydroxypropyl-beta-cyclodextrin and 59mL of polysorbate-80 for filling and carrying out ultrasonic oscillation, controlling the frequency to be 35kHz, the power to be 350W, and the time to be 5min to form hydrosol, adding the hydrosol into 2 times of liquid nitrogen, and vigorously stirring for 1300r/min for 1min to obtain frozen hydrosol d;
step four: placing the frozen hydrosol d in a round bottom flask, hanging in a freeze dryer, spray freeze drying, wherein the spray freeze drying keeps the external temperature of 25 ℃, the spray pressure of 0.35MPa, the nozzle diameter of 10um, the spray freezing temperature of-25 ℃ and the time of 3.5h, and sieving the obtained particles by a 40-100 mesh ISO standard screen vibration sieve to obtain the finished product of the dimetanidazole premix, wherein the finished product rate is 95%.
Example 2: the embodiment provides a method for efficiently preparing a dimetazole premix, which comprises the following steps:
step one: adding 100g of dimnidazole, 0.6g of lemon flavone and 6g of sodium carboxymethylcellulose into a grinder, using a grinding ball as a grinding tool for grinding, controlling the rotating speed to be 130r/min, controlling the time to be 9min, and sieving through a 70-mesh ISO standard screen to obtain a pretreated substance a;
step two: adding 40g of aspartic acid, a pretreatment a and 1260mL of 95wt% methanol into a stirring reaction kettle, adding 15wt% hydrochloric acid to adjust the pH to 6.1, stirring at a speed of 120r/min for 3min to obtain a mixed solution b, adding 4.5g of polyethylene glycol diacrylate into the mixed solution b, stirring at a speed of 200r/min for 3min, uniformly mixing, and filtering to obtain a mixed solution c;
step three: adding mixed solution c, 2.7g of ferrous chloride and 1.9g of polyethylene glycol diacrylate into 1840mL of deionized water, adding 121g of anhydrous glucose and 94mL of polysorbate-80 for filling, carrying out ultrasonic oscillation, controlling the frequency to be 40kHz, controlling the power to be 400W, and carrying out time to 8min to form hydrosol, adding the hydrosol into 2 times of liquid nitrogen, and carrying out vigorous stirring for 1500r/min for 2min to obtain frozen hydrosol d;
step four: and placing the frozen water-soluble d glue in a round bottom flask, hanging in a freeze dryer, spray freeze drying, wherein the spray freeze drying keeps the external temperature of 25 ℃, the spray pressure of 0.4MPa, the nozzle diameter of 10um, the spray freezing temperature of-21 ℃ and the time of 3.5h, and sieving the obtained particles by a 40-100 mesh ISO standard screen vibration sieve to obtain the finished product of the dimetanidazole premix, wherein the finished product rate is 96%.
Example 3: the embodiment provides a method for efficiently preparing a dimetazole premix, which comprises the following steps:
step one: adding 100g of dimnidazole, 0.7g of tea-phenol and 6g of sodium carboxymethylcellulose into a grinder, using a grinding ball as a grinding tool for grinding, controlling the rotating speed to 140r/min, and the time to 10min, and sieving with a 70-mesh ISO standard sieve to obtain a pretreated substance a;
step two: 53g of aspartic acid, a pretreated matter a and 1325mL of 99wt% methanol are added into a stirring reaction kettle, 15wt% hydrochloric acid is added to adjust the pH to 6.5, the stirring speed is 130r/min, the time is 4min, a mixed solution b is obtained, 6.7g of polyethylene glycol diacrylate is added into the mixed solution b, the stirring speed is 200r/min, the time is 4min, the mixture is uniformly mixed, and the mixture is filtered, so that a mixed solution c is obtained;
step three: adding the mixed solution c, 4.4g of ferrous chloride and 2.9g of polyethylene glycol diacrylate into 2420mL of deionized water, adding 142g of hydroxypropyl-beta-cyclodextrin and 118mL of sodium dodecyl sulfate for filling, and carrying out ultrasonic oscillation, controlling the frequency to be 45kHz, the power to be 400W, and the time to be 10min to form hydrosol, adding the hydrosol into 3 times of liquid nitrogen, and vigorously stirring for 1500r/min for 2min to obtain frozen hydrosol d;
step four: placing the frozen hydrosol d in a round bottom flask, hanging in a freeze dryer, spray freeze drying, wherein the spray freeze drying keeps the external temperature of 25 ℃, the spray pressure of 0.4MPa, the diameter of a nozzle of 15um, the spray freezing temperature of-25 ℃ and the time of 4h, and sieving the obtained particles by a 40-100 mesh ISO standard screen cloth vibration sieve to obtain the finished product of the dimetanidazole premix, wherein the yield is 97%.
Example 4: the embodiment provides a method for efficiently preparing a dimetazole premix, which comprises the following steps:
step one: adding 100g of dimnidazole, 0.8g of lemon flavone and 7g of sodium carboxymethylcellulose into a grinder, using a grinding ball as a grinding tool for grinding, controlling the rotating speed to 140r/min, and the time to 10min, and sieving with a 80-mesh ISO standard screen to obtain a pretreated substance a;
step two: adding 75.5g of aspartic acid, a pretreated matter a and 1620mL of 99wt% methanol into a stirring reaction kettle, adding 15wt% hydrochloric acid to adjust the pH to 6.5, stirring at a speed of 140r/min for 5min to obtain a mixed solution b, adding 6.8g of polyethylene glycol diacrylate into the mixed solution b, stirring at a speed of 220r/min for 4min, uniformly mixing, and filtering to obtain a mixed solution c;
step three: adding the mixed solution c, 7.6g of ferrous chloride and 2.9g of polyethylene glycol diacrylate into 3200mL of deionized water, adding 178g of anhydrous glucose and 135mL of sodium dodecyl sulfate for filling, and carrying out ultrasonic oscillation, controlling the frequency to be 40kHz, the power to be 450W, and the time to be 10min to form hydrosol, adding the hydrosol into 2 times of liquid nitrogen, and vigorously stirring for 1600r/min for 2min to obtain frozen hydrosol d;
step four: placing the frozen hydrosol d in a round bottom flask, hanging in a freeze dryer, spray freeze drying, wherein the spray freeze drying keeps the external temperature of 25 ℃, the spray pressure of 0.45MPa, the diameter of a nozzle of 15um, the spray freezing temperature of-25 ℃ and the time of 4h, and sieving the obtained particles by a 40-100 mesh ISO standard screen cloth vibration sieve to obtain the finished product of the dimetanidazole premix, wherein the yield is 97%.
Example 5: the embodiment provides a method for efficiently preparing a dimetazole premix, which comprises the following steps:
step one: adding 100g of dimetanidazole, 1g of tea-phenol and 8g of sodium carboxymethylcellulose into a grinder, using a grinding ball as a grinding tool for grinding, controlling the rotating speed to be 150r/min, controlling the time to be 12min, and sieving through an 80-mesh ISO standard screen to obtain a pretreated substance a;
step two: adding 87.2g of aspartic acid, a pretreatment a and 1770mL of 99wt% methanol into a stirring reaction kettle, adding 15wt% hydrochloric acid to adjust the pH to 6.8, stirring at a speed of 150r/min for 5min to obtain a mixed solution b, adding 8.4g of polyethylene glycol diacrylate into the mixed solution b, stirring at a speed of 240r/min for 5min, uniformly mixing, and filtering to obtain a mixed solution c;
step three: adding the mixed solution c, 9.6g of ferrous chloride and 3.6g of polyethylene glycol diacrylate into 3800mL of deionized water, adding 227.9g of hydroxypropyl-beta-cyclodextrin and 190mL of polysorbate-80 for filling and carrying out ultrasonic oscillation, controlling the frequency to be 50kHz, the power to be 500W, and the time to be 12min, forming hydrosol, adding the hydrosol into 3 times of liquid nitrogen, and vigorously stirring for 1800r/min for 3min to obtain frozen hydrosol d;
step four: and placing the frozen hydrosol d in a round bottom flask, hanging in a freeze dryer, spray freeze drying, wherein the spray freeze drying keeps the external temperature of 25 ℃, the spray pressure of 0.5MPa, the diameter of a nozzle of 15um, the spray freezing temperature of-21 ℃ and the time of 4h, and the particles obtained by vibration screening of an ISO standard screen mesh with 40-100 meshes are the finished product of the dimetanidazole premix, and the yield is 95%.
Comparative example 1 is the same as example 2 except that polyethylene glycol diacrylate is not added to comparative example 1.
Comparative example 2 is the same as example 3 except that the methanol solution in the second step is replaced with an ethanol solution in comparative example 2.
Comparative example 3 the same as example 4, except that in comparative example 3, the frozen hydrosol was prepared without using liquid nitrogen in step three, and the hydrosol was directly spray-freeze-dried.
And (3) performance detection:
and (3) drying weight loss detection: taking the dimetanidazole premix prepared in the examples and the comparative examples, drying to constant weight at 105 ℃, measuring and calculating the weight before and after weight loss, and calculating the loss rate according to the following formula:
loss ratio (%) = (weight of product after weight loss-weight of product before measurement)/weight of product before measurement×100%.
And (3) dissolution detection: taking 6 parts of the dimetanidazole premix prepared in the examples and the comparative examples, respectively dissolving in 900mL of water, sampling at 5min, 10min, 20min, 30min, 40min and 60min respectively, sampling 10mL of each sampling point, then supplementing 10mL of liquid, measuring the dissolution, and calculating the dissolution according to the following formula:
X n ’ =X n +(X 1 +X 2 +X n-1 )V 2 /V 1 ；
wherein X is n For the relative percent dissolution, X, determined after the nth calibration n ’ For the n-th actual measured relative percent dissolution, V 1 To dissolve the volume of the medium, V 2 The number of volumes replenished after each sampling.
Stability test: stability accelerated stability test was performed according to the related regulations of the chinese veterinary pharmacopoeia, the dimetazole premix prepared in examples and comparative examples was stored in a commercially available package, left for 6 months at a temperature of 40±2 ℃ and a relative humidity of 75% ±5%, and sampled once at 1, 2, 3 and 6 months of the test period, and stability was calculated from the following formula:
stability (%) = (weight of sample before test-weight of sample on day n of test)/weight of sample before test×100%.
The results of the measurements are shown in tables 1, 2 and 3.
TABLE 1 loss on drying results (%)
TABLE 2 dissolution results (%)
TABLE 3 stability test (%)
Table 1 shows the results of examples 1-5 and the results of comparative experiments, and shows that the water content of the dimetazole premix prepared by the method is lower than 2%, the weight loss is not more than 3% according to the measurement marking of a dry weight loss method, and the preparation result of the method is stable and reliable, and the water content of the product is well controlled; the results of the examples in Table 2 show that the dimetanidazole premix prepared by the method has a high dissolution rate, the solubility of the dimetanidazole premix reaches over 90% in 20min, and the dimetanidazole premix is basically and completely dissolved in 60min, which indicates that the premix prepared by the method has a high quality and can be quickly dissolved, and the drug effect is improved. By comparing the results of the loss on weight and loss on drying rates of comparative example 1 and example 2, it was found that polyethylene glycol diacrylate had a smaller effect on the water content of the dimnidazole premix, but had a certain effect on the dissolution rate of the dimnidazole premix. The dissolution results of comparative examples 2 and 3 in Table 2 show that they are the same as those of examples 3 and 4 before 20min, but that a certain difference occurs in the dissolution results after 20 min. The effect of freeze drying after preparing frozen hydrosol by liquid nitrogen rapid freezing is better than that of direct freeze drying after preparing hydrosol by ethanol as solvent. This suggests that the solvent and frozen hydrosol sequence has an effect on the dissolution rate of the product, but that this effect does not manifest itself until a certain time. As can be seen from the results of the examples in Table 3, the dimetanidazole premix prepared by the method has good stability and is easy to store for a long time. In general, the water content, the dissolution and the stability of the dimetanidazole premix prepared by the process are well controlled, and the dimetanidazole premix has good performance. As can be seen from the results of FIG. 5, the obtained product has no change in molecular structure of the drug, and the obtained product has a substantially identical infrared absorption spectrum peak position with that of the original powder. Thus, the method is a reliable and effective method for preparing the dimetanidazole premix.
Those of ordinary skill in the art will appreciate that: the discussion of any of the embodiments above is merely exemplary and is not intended to suggest that the scope of the invention (including the claims) is limited to these examples; the technical features of the above embodiments or in the different embodiments may also be combined within the idea of the invention, the steps may be implemented in any order and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.
The present invention is intended to embrace all such alternatives, modifications and variances which fall within the broad scope of the appended claims. Therefore, any omission, modification, equivalent replacement, improvement, etc. of the present invention should be included in the scope of the present invention.
Claims (1)
1. A method for efficiently preparing dimet azole premix, which is characterized by comprising the following steps:
step one: adding dimetanidazole, an antioxidant and sodium carboxymethylcellulose into a grinder for grinding, using a grinding ball or a grinding wheel as a grinding tool, controlling the rotating speed to be 120-150 r/min, controlling the time to be 8-12 min, and sieving through a 60-80 mesh ISO standard screen to obtain a pretreated substance a;
step two: weighing a proper amount of aspartic acid and a pretreatment a, dissolving in methanol, adding into a reaction kettle, adding 15wt% hydrochloric acid to adjust the pH to 5.9-6.8, mixing and stirring at a speed of 100-150 r/min for 3-5 min to obtain a mixed solution b, weighing 70% of polyethylene glycol diacrylate with a prescription amount, adding into the mixed solution b, fully stirring for 180-240 r/min, and uniformly mixing for 2-5 min to obtain a mixed solution c;
step three: adding the mixed solution c, ferrous chloride and 30% of polyethylene glycol diacrylate with the prescription amount into deionized water, adding auxiliary preparation and surfactant for filling, and performing ultrasonic oscillation at the frequency of 35-50 kHz, the power of 350-500W and the time of 5-12 min to form hydrosol, adding the hydrosol into 2-3 times of liquid nitrogen, and performing vigorous stirring at the speed of 1300-1800 r/min and the time of 1-3 min to obtain frozen hydrosol d;
step four: placing the frozen hydrosol d in a round bottom flask, hanging in a freeze dryer, spray freeze drying, and sieving with a 40-100 mesh ISO standard sieve in a vibrating manner to prepare the dimetanidazole premix;
the antioxidant in the first step is lemon flavone, and the mass ratio of the antioxidant is 0.5-1% of dimet;
in the first step, the mass ratio of the sodium carboxymethyl cellulose is 5-8% of that of the dimet;
in the second step, the concentration of the methanol is 95-99 wt percent, and the ratio of the methanol to the pretreated material a is as follows: 170-260 mL/16 g;
the mass ratio of aspartic acid to pretreated matter a in the second step is as follows: 0.32-0.8:1;
the mass ratio of the polyethylene glycol diacrylate to the pretreated object a in the second step is as follows: 0.05-0.11:1;
the auxiliary preparation in the step three is one of hydroxypropyl-beta-cyclodextrin and anhydrous glucose;
the surfactant in the third step is one of polysorbate-80 and sodium dodecyl sulfate;
in the third step, the mixing solution c, ferrous chloride, auxiliary preparation, surfactant and deionized water are used in the following ratio: 1mL of 0.001-0.005 g of 0.08-0.12 g of 0.05-0.1 mL of 1-2 mL;
in the fourth step, spray freeze drying is carried out at the outside temperature of 25 ℃, the spray pressure of 0.35-0.5 MPa, the diameter of a nozzle of 10-15 um, and the spray freezing temperature of-25 to-21 ℃ for 3.5-4 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311288050.XA CN117084984B (en) | 2023-10-08 | 2023-10-08 | Method for efficiently preparing dimetanidazole premix |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311288050.XA CN117084984B (en) | 2023-10-08 | 2023-10-08 | Method for efficiently preparing dimetanidazole premix |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117084984A CN117084984A (en) | 2023-11-21 |
| CN117084984B true CN117084984B (en) | 2024-03-29 |
Family
ID=88777537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311288050.XA Active CN117084984B (en) | 2023-10-08 | 2023-10-08 | Method for efficiently preparing dimetanidazole premix |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117084984B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118178336A (en) * | 2024-04-03 | 2024-06-14 | 上海同仁药业股份有限公司 | Method for preparing efficient tilmicosin premix |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919942A (en) * | 2016-07-07 | 2016-09-07 | 杭州爱力迈动物药业有限公司 | Dimetridazole soluble powder and preparation method thereof |
| CN106074514A (en) * | 2016-08-31 | 2016-11-09 | 上海邦森生物科技有限公司 | A kind of water solublity dimetridazole pre-mixing agent and preparation method thereof |
| CN109260158A (en) * | 2018-09-28 | 2019-01-25 | 青岛康地恩动物药业有限公司 | A kind of Dimetridazole pre-mixing agent of highly-water-soluble high stability |
| CN113425686A (en) * | 2021-07-29 | 2021-09-24 | 四川伴农动保生物技术有限公司 | Dimetridazole soluble powder and preparation method thereof |
| CN114601795A (en) * | 2022-04-02 | 2022-06-10 | 江西利德菲生物药业有限公司 | High-stability dimetridazole premix and preparation method thereof |
-
2023
- 2023-10-08 CN CN202311288050.XA patent/CN117084984B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919942A (en) * | 2016-07-07 | 2016-09-07 | 杭州爱力迈动物药业有限公司 | Dimetridazole soluble powder and preparation method thereof |
| CN106074514A (en) * | 2016-08-31 | 2016-11-09 | 上海邦森生物科技有限公司 | A kind of water solublity dimetridazole pre-mixing agent and preparation method thereof |
| CN109260158A (en) * | 2018-09-28 | 2019-01-25 | 青岛康地恩动物药业有限公司 | A kind of Dimetridazole pre-mixing agent of highly-water-soluble high stability |
| CN113425686A (en) * | 2021-07-29 | 2021-09-24 | 四川伴农动保生物技术有限公司 | Dimetridazole soluble powder and preparation method thereof |
| CN114601795A (en) * | 2022-04-02 | 2022-06-10 | 江西利德菲生物药业有限公司 | High-stability dimetridazole premix and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117084984A (en) | 2023-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN117084984B (en) | Method for efficiently preparing dimetanidazole premix | |
| EP2836517B1 (en) | Melt-extruded composition comprising a cellulose ether | |
| CN102134281A (en) | Method for producing high-flowability pregelatinized starch | |
| CN109531857A (en) | The preparation method and products obtained therefrom of a kind of hyaluronic acid or its salt particle | |
| EP1919959B1 (en) | A method for preparing polyanhydroglucuronic acid and/or salts thereof | |
| JP2001199902A (en) | Method for forming hydroxypropylcellulose particle with low substitution degree | |
| HU194050B (en) | Process for loading of swelling, not poluable in water polimers with medroxi-progresteron acetat | |
| CN103977009B (en) | Composition for oral liquid containing cefdinir and preparation method thereof | |
| CN102973519A (en) | Amoxicillin granules and preparation technology of same | |
| CN105535018A (en) | Calcium carbonate D3 granules and preparation method thereof | |
| US10174128B2 (en) | Method for producing purified low-substituted hydroxypropyl cellulose | |
| CN108175752A (en) | Breviscapinun nano particle and preparation method thereof | |
| CN104688743B (en) | Cefprozil suspension and preparation method thereof | |
| JPH01152104A (en) | Preparation of water-soluble chitosan salt powder | |
| CN109730970A (en) | De Lamani quick releasing formulation and preparation method thereof | |
| JP4051431B2 (en) | Colloidal gold solution and method for producing the same | |
| EP2474559B1 (en) | Hydroxypropyl cellulose particles | |
| CN112618543B (en) | Everolimus-containing composition and preparation method thereof | |
| CN104530489A (en) | Water-soluble starch film-forming composition | |
| CN102499909B (en) | Itraconazole dispersible tablets and preparation method thereof | |
| WO2004006945A1 (en) | Tablet composition containing chinese orthodox medicine extract and process for producing the same | |
| KR100396440B1 (en) | Manufacturing method of natural dyes | |
| CN110218267A (en) | A kind of Preparation method and use of iron-dextrin | |
| CN106310286B (en) | Tosufloxacin tosylate composition | |
| CN101157472B (en) | Method for preparing nano alkaline-earth metal sulfate powder with different crystal morphology |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |