CN103610654B - Micronized tinidazole powder injection - Google Patents
Micronized tinidazole powder injection Download PDFInfo
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- CN103610654B CN103610654B CN201310661656.3A CN201310661656A CN103610654B CN 103610654 B CN103610654 B CN 103610654B CN 201310661656 A CN201310661656 A CN 201310661656A CN 103610654 B CN103610654 B CN 103610654B
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- tinidazole
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Abstract
The invention relates to a micronized tinidazole powder injection, which is prepared by the following steps: firstly, carrying out large-tray freeze-dried aseptic treatment on tinidazole and auxiliary materials, then micronizing by adopting a superfine grinding technology, so as to prepare fine powder, and carrying out aseptic packaging; or firstly, micronizing the tinidazole by adopting the superfine grinding technology, so as to prepare fine powder, carrying out large-tray freeze-dried aseptic treatment on the fine powder and the auxiliary materials, and carrying out aseptic packaging. By adopting the micronized tinidazole powder injection prepared by adopting the superfine grinding technology, the water solubility of the tinidazole is improved, the bioavailability is improved, and the clinical treatment effect of a medicament preparation is improved.
Description
Technical field
The present invention relates to tinidazole powder injection formulation, be specifically related to a kind of micronized tinidazole powder injection formulation adopting superfine communication technique to make, belong to medical art.
Background technology
Tinidazole has greater activity to protozoon and anaerobe.To tool antibacterial activities such as the Bacteroidess such as bacteroides fragilis, Fusobacterium, fusobacterium, dyspepsiacoccus, peptostreptococcus, Wei Rong Coccus and Jia get Na bacterium, the concentration of 2 ~ 4mg/L can suppress most of anaerobe; Microaerobe, helicobacter pylori are responsive to it; To the MIC of trichomonas vaginitis and metronidazole similar, its metabolite to the activity of Jia get Na bacterium comparatively tinidazole be strong.
The mechanism of action of tinidazole is illustrated not yet completely, and the nitroreductase of anaerobe plays an important role in the energy metabolism of sensitive strain.The nitro of tinidazole is reduced into a kind of cell toxicant, thus acts on the DNA metabolic process of antibacterial, impels bacterial death.Fastbacteria often lacks nitroreductase and to this product drug resistance.The mechanism of the anti-ameba of tinidazole, for suppressing its redox reaction, makes the nitrogen chain of protozoon rupture, thus kills protozoon.
The dissolubility of tinidazole is poor, causes bioavailability lower, utilizes existing preparation technique to improve its bioavailability, becomes a present popular problem.
Micronizing is nearly new and high technology developed rapidly for 20 years, raw material can be processed into the even nano level micropowder of micron, be widely used in every profession and trade.Air-flow superfine communication technique is the one of superfine communication technique, it utilizes material under the effect of high velocity air, obtain huge kinetic energy, the high velocity impact between material particles, severe friction is caused in pulverizing chamber, high velocity air produces shear action to material simultaneously, thus reaching the object of comminuting matter, Raw material processing can be become superfine powder (< 10 μm) by it.But at present, superfine communication technique is mainly applied to Chinese medicine by the technical staff of drug world, up to now, almost superfine communication technique is not applied to chemical drugs Western medicine aspect, with the application of defect existing for the preparation aspect improving chemical drugs.
Generally speaking, by pulverizing that there is less particle diameter to medical compounds crystallization, contribute to the dissolubility improving medicament, but for tinidazole and preparation thereof, predict and need the drug microparticles of how particle diameter so that it is difficult for controlling dissolubility for this skilled artisan.
In fact, the particle size distribution of drug microparticles and the bioavailability not linear change of medicament.Although prior art teaches some compound can be carried out micronization, but, find the pharmaceutical formulations with the micronization tinidazole of gratifying biological utilisation being suitable for Clinical practice become Present clinical treatment in the urgent need to.
Powder ampoule agent for injection is a kind of dosage form prepared for medicine unstable in water.Prepared by its conventional freeze-drying that adopts, be about to need dry drug solution to be frozen into solid in advance, then, under low-temp low-pressure condition, from frozen state without the dewatered a kind of drying means of distillation, it is applicable to for thermo-responsive and unstable in aqueous medicine.But conventional adopt prepare injectable sterile powder as freeze-dried powder exists following shortcoming: freeze-dried powder is uneven, color and luster is poor, pure loading amount there are differences, clarity has problems, the product purity of preparation is lower, the stability problem of material is not solved completely, still not easily preserve for a long time, and freeze-dried powder technics comparing is complicated, cost is higher.
Common sterile packaged preparation for injection, grain diameter is comparatively large, and redissolve slow, and after redissolving, clarity is poor, in point process of assembling, content uniformity is larger.
For the problems referred to above that injectable sterile powder exists, the present inventor is through research conscientious for a long time, find in the preparation of injectable sterile powder superfine communication technique being applied to tinidazole, the above-mentioned series of problems existing for regular injection sterilized powder can be solved, create beyond thought effect, obtain have that purity is high, the injectable sterile powder of more excellent more stable, the advantage such as clarity is better of quality, thus complete the present invention.
Summary of the invention
For the problems referred to above that tinidazole exists, the present inventor is through research conscientious for a long time, find that tinidazole compound particle particle diameter is not directly proportional little to its pharmacokinetics effect, superfine communication technique is applied in the preparation of tinidazole compound, obtain the granule of the micronization tinidazole compound being in specified particle diameter, the dissolubility in its water can be significantly improved, create beyond thought effect, substantially improve bioavailability, thus complete the present invention.
The object of the present invention is to provide a kind of micronized tinidazole powder injection formulation, namely first tinidazole and adjuvant are carried out deep bid lyophilizing aseptic process, then precomminution, makes coarse granule, then adopts superfine communication technique to carry out micronization, makes fine powder, aseptic subpackaged.
The object of the present invention is to provide a kind of micronized tinidazole powder injection formulation, namely first by tinidazole precomminution, make coarse granule, then adopt superfine communication technique to carry out micronization, make fine powder, then carry out deep bid lyophilizing aseptic process with adjuvant, aseptic subpackaged.
Wherein, described adjuvant can be selected from HP-β-CD, PEG400, propylene glycol, mannitol, one or more in citric acid etc.
In preferred specific embodiments, the micronized tinidazole powder injection formulation of one of the present invention, primarily of based on the micronized tinidazole 1 part of parts by weight, HP-β-CD 0-7 part, PEG400 is 0-4 part, propylene glycol 0-4 part, mannitol 3-8 part and citric acid 0.2 part are made.
In preferred specific embodiments, the micronized tinidazole powder injection formulation of one of the present invention, make primarily of the micronized following composition based on parts by weight, tinidazole 1 part, HP-β-CD 0-7 part, PEG400 is 0-4 part, propylene glycol 0-4 part, mannitol 3-8 part and citric acid 0.2 part.
As the present invention one preferred embodiment, it is 70-150 μm that coarse grained particle diameter is made in the first precomminution of described tinidazole, then by the particle diameter that superfine communication technique micronization is made be 2-10 μm be suitable for micronization tinidazole of the present invention.
As the present invention one preferred embodiment, it is 70-150 μm that coarse grained particle diameter is made in described tinidazole and the first precomminution of adjuvant, then is 2-10 μm by the particle diameter that superfine communication technique micronization is made.
As the present invention one preferred embodiment, precomminution adopts the conventional crushing technology in this area to carry out, and described technology comprises, but be not limited to grinding, extruding, collision, cutting, reducing mechanism used includes, but are not limited to mortar, ball mill, fluid energy mill, preferably adopts the fluid energy mill of impacting technology.
As the present invention one preferred embodiment, superfine communication technique is selected from mechanical activation comminution, vibrant pulverization, comminution by gas stream, Ultrasonic Pulverization, high pressure abrasive, preferred airflow pulverization.Superfine communication technique equipment therefor is selected from QWJ-5 air-flow vortex pulverizer, QWJ-15 air-flow vortex pulverizer, CWM-80 super vortex mill, CWM-120 super vortex mill, CWJ-30 super micron mill, CWJ-45 super micron mill, preferred CWJ-30 type super micron mill.
Preferred, the concrete operation step that described airflow pulverization adopts is as follows: be that coarse grained tinidazole injects super micron mill jointly with the noble gas after lyophilization by precomminution, high velocity air is adopted to pulverize, preferably, noble gas after lyophilization, preferred air or nitrogen, temperature is 0-15 DEG C, preferably 5 DEG C-10 DEG C, water content≤1%, during air Injection super micron mill, pressure is 0.8-1.5MPa, preferred 1.1-1.2MPa, the operating pressure of super micron mill is 0.8-1.5MPa, preferred 1.1-1.2MPa, internal operating temperature is 0-8 DEG C, preferably 2 DEG C-6 DEG C, grinding time is 30-200min, preferred 50-150min.
Micronized tinidazole powder injection formulation of the present invention, its preparation method comprises the steps:
(1) tinidazole and some adjuvants are dissolved, deep bid lyophilizing, obtains injection tinidazole aseptic powder;
(2) precomminution injection tinidazole aseptic powder, makes coarse granule;
(3) adopt superfine communication technique to pulverize coarse granule, make fine powder;
(4) aseptically carry out subpackage, obtain powder ampoule agent for injection.
In preparation method described above, adjuvant can be selected from HP-β-CD, PEG400, propylene glycol, mannitol, one or more in citric acid etc.
The present invention's adopt superfine communication technique to prepare injection tinidazole aseptic powder that particle diameter is 2-7 μm, improves the water-soluble of tinidazole, redissolves faster, improve bioavailability, add the clinical efficacy of pharmaceutical preparation.
In the present invention, if do not have specified otherwise, the technology adopted, technique, unit, test etc. are all that this area is conventional known.
Accompanying drawing explanation
Fig. 1 describes blood drug level and the relation curve of time of four groups of injection tinidazole injectable powder.
Detailed description of the invention
Provide the specific embodiment of the present invention as follows, be to be understood that the present invention is not limited to these concrete embodiments, those skilled in the art can not deviate under the spirit and scope of the present invention, can carry out various modification and change to the present invention, but such improvement is considered to all be included in the scope of the application's claims.The preparation of embodiment 1 micronized injection tinidazole powder injection formulation
(1) by 100g tinidazole and 700g HP-β-CD, 300g mannitol, 20g citric acid mixed dissolution, deep bid lyophilizing, obtains injection tinidazole aseptic powder;
(2) adopt the fluid energy mill precomminution injection tinidazole aseptic powder of impacting technology, making particle diameter is 150 μm of coarse granules;
(3) adopt CWJ-30 type super micron mill to carry out micronizing to above-mentioned coarse granule, be ground into 2-10 μm of fine powder;
Pulverization conditions: the air themperature after lyophilization is 10 DEG C, water content 0.4%, during injection super micron mill, pressure is 1.1MPa, and the operating pressure of super micron mill is 1.2MPa, and internal operating temperature is 5 DEG C, and grinding time is 60min.
(4) aseptically carry out subpackage, obtain powder ampoule agent for injection.
The preparation of embodiment 2 micronized injection tinidazole powder injection formulation
(1) by 100g tinidazole and 300g PEG400,600g mannitol, 20g citric acid mixed dissolution, deep bid lyophilizing, obtains injection tinidazole aseptic powder;
(2) adopt the fluid energy mill precomminution injection tinidazole aseptic powder of impacting technology, making particle diameter is 70 μm of coarse granules;
(3) adopt CWJ-30 type super micron mill to carry out micronizing to above-mentioned coarse granule, be ground into 2-10 μm of fine powder;
Pulverization conditions: the air themperature after lyophilization is 5 DEG C, water content 0.5%, during injection super micron mill, pressure is 1.2MPa, and the operating pressure of super micron mill is 1.0MPa, and internal operating temperature is 3 DEG C, and grinding time is 120min.
(4) aseptically carry out subpackage, obtain powder ampoule agent for injection.
The preparation of embodiment 3 micronized injection tinidazole powder injection formulation
(1) by 100g tinidazole and 400g propylene glycol, 700g mannitol, 20g citric acid mixed dissolution, deep bid lyophilizing, obtains injection tinidazole aseptic powder;
(2) adopt the fluid energy mill precomminution injection tinidazole aseptic powder of impacting technology, making particle diameter is 100 μm of coarse granules;
(3) adopt CWJ-30 type super micron mill to carry out micronizing to above-mentioned coarse granule, be ground into 2-10 μm of fine powder;
Pulverization conditions: the air themperature after lyophilization is 8 DEG C, water content 0.4%, during injection super micron mill, pressure is 1.0MPa, and the operating pressure of super micron mill is 1.2MPa, and internal operating temperature is 6 DEG C, and grinding time is 150min.
(4) aseptically carry out subpackage, obtain powder ampoule agent for injection.
The preparation of embodiment 4 micronized injection tinidazole powder injection formulation
(1) 100g tinidazole is adopted the fluid energy mill precomminution injection tinidazole aseptic powder of impacting technology, making particle diameter is 120 μm of coarse granules;
(2) adopt CWJ-30 type super micron mill to carry out micronizing to above-mentioned coarse granule, be ground into 2-10 μm of fine powder;
Pulverization conditions: the air themperature after lyophilization is 7 DEG C, water content 0.7%, during injection super micron mill, pressure is 0.9MPa, and the operating pressure of super micron mill is 1.3MPa, and internal operating temperature is 4 DEG C, and grinding time is 70min.
(3) by micronized tinidazole and 200g PEG400,300g propylene glycol, 800g mannitol, 20g citric acid mixed dissolution, deep bid lyophilizing, obtains injection tinidazole aseptic powder;
(4) aseptically carry out subpackage, obtain powder ampoule agent for injection.
The preparation of comparative example 1 sample
Adopt the prescription identical with embodiment 1 and technique, difference is not carry out micronization processes to injection tinidazole aseptic powder (tinidazole and adjuvant).
Embodiment 5 solubility test
The micronized injection tinidazole powder injection formulation prepared by embodiment 1-4 is soluble in water, makes supersaturated solution, calculates the dissolubility of tinidazole in water by detection level, and contrasts with sample prepared by comparative example 1, and result is as follows:
| Material | Comparative example 1 | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Tinidazole | 12.3mg/ml | 21.5mg/ml | 22.3mg/ml | 20.9mg/ml | 18.35mg/ml |
Embodiment 6 bioavailability study
Get 40 rats, body weight 203 ± 10g, be divided into four groups at random, the wherein injection tinidazole injectable powder of first group of injection embodiment 1 preparation, injection tinidazole injectable powder prepared by second group of injection embodiment 2, injection tinidazole injectable powder prepared by the 3rd group of injection embodiment 4, injection tinidazole injectable powder prepared by the 4th group of inject contrast example 1.Dosage is injection tinidazole 0.4g and adds glucose injection 250ml, and injected dose is 5ml/kg body weight.Respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h blood sampling after administration, blood sample after treatment, adopts the blood drug level of high effective liquid chromatography for measuring tinidazole.Be specially:
Be filler with octadecylsilane chemically bonded silica; With 0.05%mol/L potassium dihydrogen phosphate (by phosphoric acid adjust ph to 3.5)-methanol (80:20) for mobile phase, determined wavelength 310nm, number of theoretical plate calculates by tinidazole peak and is not less than 2000, and the separating degree at tinidazole peak and other impurities peak should meet the requirements.
Precision measures blood sample 1ml and puts in 10ml measuring bottle, adds mobile phase and is diluted to scale, shake up, and as need testing solution, precision measures 20 μ l, injection liquid chromatography, record chromatogram; Separately get tinidazole reference substance appropriate, accurately weighed, add mobile phase and dissolve and quantitatively dilute the solution made about containing 120 μ g in every 1ml, be measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Draw blood drug level and the relation curve of time of four groups of injections, be shown in accompanying drawing 1.
As shown in Figure 1, in four groups, first group and second group injection after have the following advantages: the peak plasma concentrations of tinidazole is high, and release rate in vivo slows down, body circulation in distribution time extend, reach the delayed release effect of improvement, bioavailability increase.3rd group is taken second place, and the data of the 4th group are the poorest.
Claims (4)
1. a micronized tinidazole powder injection formulation, it is characterized in that being made up of the micronized following composition based on parts by weight, tinidazole 1 part, HP-β-CD 0-7 part, PEG400 is 0-4 part, propylene glycol 0-4 part, mannitol 3-8 part and citric acid 0.2 part, it is 70-150 μm that coarse grained particle diameter is made in wherein said tinidazole and the first precomminution of adjuvant, then is 2-10 μm by the particle diameter that superfine communication technique micronization is made.
2. a micronized tinidazole powder injection formulation, it is characterized in that making by based on the following composition of parts by weight, micronized tinidazole 1 part, HP-β-CD 0-7 part, PEG400 is 0-4 part, propylene glycol 0-4 part, mannitol 3-8 part and citric acid 0.2 part, it is 70-150 μm that coarse grained particle diameter is made in the first precomminution of described tinidazole, then is 2-10 μm by the particle diameter that superfine communication technique micronization is made.
3. prepare a method for micronized tinidazole powder injection formulation according to claim 1, it is characterized in that preparation method is specially:
(1) tinidazole and adjuvant are dissolved, deep bid lyophilizing, obtains injection tinidazole aseptic powder;
(2) precomminution injection tinidazole aseptic powder, makes coarse granule;
(3) adopt superfine communication technique to pulverize coarse granule, make fine powder;
(4) aseptically carry out subpackage, obtain powder ampoule agent for injection.
4. prepare a method for micronized tinidazole powder injection formulation according to claim 2, it is characterized in that preparation method is specially:
(1) by the precomminution of injection tinidazole, coarse granule is made;
(2) adopt superfine communication technique to pulverize coarse granule, make fine powder;
(3) dissolve with adjuvant, deep bid lyophilizing, obtains injection tinidazole aseptic powder again;
(4) aseptically carry out subpackage, obtain powder ampoule agent for injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310661656.3A CN103610654B (en) | 2013-12-09 | 2013-12-09 | Micronized tinidazole powder injection |
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| CN201310661656.3A CN103610654B (en) | 2013-12-09 | 2013-12-09 | Micronized tinidazole powder injection |
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| CN103610654B true CN103610654B (en) | 2015-03-11 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1704053A (en) * | 2004-06-02 | 2005-12-07 | 魏秀华 | Aseptic subpackage preparation of tindazole for injection |
| CN101332188A (en) * | 2008-07-11 | 2008-12-31 | 海南数尔药物研究有限公司 | Method for preparing powder injection using superfine communication technique and prepared products |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1704053A (en) * | 2004-06-02 | 2005-12-07 | 魏秀华 | Aseptic subpackage preparation of tindazole for injection |
| CN101332188A (en) * | 2008-07-11 | 2008-12-31 | 海南数尔药物研究有限公司 | Method for preparing powder injection using superfine communication technique and prepared products |
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