CN105218458A - Ultrafine powder of a kind of nitroimidazoles medicine and derivative thereof and preparation method thereof - Google Patents
Ultrafine powder of a kind of nitroimidazoles medicine and derivative thereof and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to ultrafine powder of a kind of nitroimidazoles medicine and derivative thereof and preparation method thereof.Nitroimidazoles medicine and derivative thereof are that a class has that sterilizing power is strong, has a broad antifungal spectrum, not easily produce the medicine of resistance and the advantage such as cheap.The method preparing nitroimidazoles medicine and derivative ultrafine powder thereof provided by the invention: in the homogeneous phase solution containing nitroimidazoles medicine and derivative thereof, be 10kHz ~ 500kHz by applying frequency, power is 1mW ~ 5000W, and the sound intensity is 0.1mW/cm
2~ 500W/cm
2ultrasonic wave, fast obtain nitroimidazoles medicine and derivative crystal thereof, then through routine operations such as solid collection, washing, drying, directly acquisition nitroimidazoles medicine and derivative ultrafine powder thereof.Ultrafine powder prepared by the present invention has that drug loading is high, dissolution rate is fast, easily realize the features such as higher bioavailability, stability and security, thus meet the bioavailability improving medicine, the demand reducing drug dose, reduce toxic side effect, be with a wide range of applications clinically.
Description
Technical field
The present invention relates to medical art, particularly the ultrafine powder and preparation method thereof of a kind of nitroimidazoles medicine and derivative thereof.
Background technology
Nitroimidazoles medicine and derivative thereof are that a class has that sterilizing power is strong, has a broad antifungal spectrum, not easily produce the medicine of resistance and the advantage such as cheap, are widely used clinically.Conventional nitroimidazoles medicine mainly contains metronidazole, tinidazole, ornidazole, secnidazole, and wherein metronidazole, tinidazole, ornidazole have unique killing action to anerobe and protozoon.At present, the common formulations of nitroimidazoles medicine has tablet and injection liquid, and wherein the common adverse effect of tablet is digestive tract reaction, as felt sick, and vomiting or diarrhoea etc.; And injection liquid can cause nerve and blood system reaction, as brought out epilepsy, reduce granulocyte etc.
The most large usage quantity of nitroimidazoles medicine, as: metronidazole is 0.6-1.4g/ days, and ornidazole is 0.5-1.0g/ days, and secnidazole is 1.5-2.0g/ days, easily causes untoward reaction.Little in the situation not affecting curative effect of medication, reduce dosage, international common method is by the particle size reduction of medicine.
Superfine powder (superfinepowder), also known as ultrafine powder, generally includes micron order (1 ~ 30 μm), submicron order (0.1 ~ 1 μm) and nano level (1 ~ 100nm).At present a strict definition be there is no for ultrafine powder, be referred to as ultrafine powder from the powder of a few nanometer to tens micron.To the definition of nano material can broad sense be interpreted as to have the material that one dimension is in nanoscale scope or is made up of as unit them in three dimensions at least.1. 0 dimension nano material can be divided into: scantling is nanoscale at three-dimensional space according to the concept of dimension; 2. 1 dimension nano material: material has two dimension in space for nanoscale; 3. 2 dimension nano materials: material has one dimension to be nanoscale in space; 4. 3 dimension nano materials: the bulk in three dimensions containing above-mentioned nano material.Conventional ultrafine powder MATERIALS METHODS of preparing has low-temperature airflow pulverizing, ball milling, the mechanical crushing method such as high-pressure homogeneous, and the physico-chemical process such as solvent diffusion, solvent evaporation, supercritical fluid technology, solvent deposition, lyophilize, spraying dry.Zhao Gaiqing etc. are in June, 2006 report in " spray drying technology is in the application prepared in ultra micro and nano-powder and prospect ", under the theoretical basis of mechanical crushing method is based on given stress condition, cause the fracture of particle, fragmentation and intergranular collision etc., produce the ultrafine powder (three-dimensional space) of 0 dimension particle; And adopting the physico-chemical processes such as spray drying technology can prepare the spherical powder that quality is homogeneous, repeatability is good, its ultrafine powder produced also belongs to 0 dimension particle.In sum, the ultrafine powder that current published preparation method obtains mostly is 0 dimension particle.
At present conventional ultrafine powder preparation method comprises medium milling, the mechanical crushing method such as high-pressure homogeneous, and the physico-chemical process such as supercritical fluid technology, anti-solvent (solvent that medicine is insoluble) recrystallization, solvent diffusion, solvent evaporation, spraying dry.
Media milling process is the technology be most widely used in ultrafine powder preparation at present, although have device and the simple feature of preparation process, single batch of cycle of producing is long, and production efficiency is not high; And due to particle encounter and mechanical movement and discharge amount of heat, the preparation of inapplicable low melting point substance in process of lapping; Simultaneously because the wearing and tearing of dielectric material in process of lapping also can produce mechanical impurity, may cause to medicine the pollution that cannot remove.The Azythromycin 0 that Rong Xinyu etc. adopt media milling process to obtain as shown in Figure 1 in 2012 in " it is nanocrystalline that media milling process prepares Azythromycin " ties up particle.
Although high pressure homogenization has the features such as technique circulation ratio is stable, because equipment is complicated, only have less medicine to be applicable to preparation that this equipment carries out ultra micro efflorescence; The method exist equally because of equipment part corrosion, come off the pollution problem caused medicine; The factors such as the high-frequency wearing and tearing of the parts such as homogeneous valve body and homogenizing valve simultaneously, production efficiency is low, energy consumption is high cause production cost to remain high.0 dimension nanocrystal micropill of the applying high voltage homogeneous method acquisition baicalin in " preparation of baicalin nanocrystal micropill and pharmacokinetics preliminary study thereof " in 2013 such as Jin Shiying, significantly improves the bioavailability of medicine.
Supercritical fluid technology, namely utilizes the feature of supercutical fluid, and realize gas phase or liquid phase recrystallization, make material grains miniaturization, particle size dispersion is even.This technology opens the new way preparing ultrafine powder, is particularly suitable for preparing the ultrafine powder that some has thermo-sensitivity, oxidisability, biologically active substance.But because the higher and Supercritical Conditions of the requirement of supercritical technology to equipment is very big by temperature, pressure influence, state is difficult to keep, the research of related application equipment still needs to be strengthened further.
The methods such as the evaporation of anti-solvent recrystallization, solvent diffusion, solvent, spraying dry are uncontrollable due to crystal growth, cause product size difference large, and general all with high-speed stirring or high speed centrifugation or high-pressure homogeneous, production unit not easily configures, operational hazards coefficient is large, and cost is high.The people such as Zu YuanGang in 2011, adopted anti-solvent recrystallization method to obtain Potenlini 0 and tie up particle in " response surface design method is optimized anti-solvent recrystallization and prepared Potenlini micro mist " literary composition.
Not about the report preparing nitroimidazoles medicine and derivative ultrafine powder thereof in current published document, and the various defects of above-mentioned ultrafine powder preparation method, be also the principal element causing not having nitroimidazoles medicine and derivative thereof to go on the market with super-fine powder form so far.
Summary of the invention
For the deficiency in prior art, the invention provides a kind of nitroimidazoles medicine and derivative ultrafine powder and preparation method thereof thereof, concrete preparation method is: be in the homogeneous phase solution of-30 DEG C ~ 100 DEG C in a kind of temperature containing nitroimidazoles medicine and derivative thereof, by apply ultrasonic frequency be 10kHz ~ 500kHz, power is 1mW ~ 5000W, and the sound intensity is 0.1mW/cm
2~ 500W/cm
2ultrasonic wave, fast obtain nitroimidazoles medicine and derivative crystal thereof, then through routine operations such as solid collection, washing, drying, directly acquisition nitroimidazoles medicine and derivative ultrafine powder thereof.
The solvent that in the present invention, homogeneous phase solution is used generally includes methyl alcohol, ethanol, Virahol, propyl carbinol, propylene glycol, acetone, DMF (DMF), N-Methyl pyrrolidone (NMP), tetrahydrofuran (THF), acetonitrile, ether, sherwood oil, t-butyl methyl ether, normal hexane, normal heptane, methylene dichloride, trichloromethane, methyl-sulphoxide (DMSO), methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, acetic acid, aceticanhydride, benzene at interior lower alcohol (C
1-6), lower ketones (C
3-12), rudimentary ether (C
2-12), lower acid (C
1-6), lower member ester (esterification products of lower alcohol and lower acid), the single solvent such as aromatic hydrocarbon, alkane, haloalkane and water, or the combination of two kinds and two or more solvent.In homogeneous phase solution, the weightmeasurement ratio (w/v, g/mL) of nitroimidazoles medicine and derivative and solvent is: 1:1 ~ 1:300.
Nitroimidazoles medicine provided by the invention and derivative ultrafine powder preparation method thereof, crystal seed can be added in homogeneous phase solution, suitable stablizer can be added, suitable mixing with solvent but the solvent (i.e. anti-solvent) that solubility property or solubility property are very little is not had to medicine can be added, can alr mode be applied.
Nitroimidazoles medicine provided by the invention and derivative ultrafine powder preparation method thereof, the amount that can add stablizer in homogeneous phase solution is 0 ~ 5% (percent weight in volume of relative system solution), described stablizer includes but are not limited to methylcellulose gum, ethyl cellulose, glycerine, Viscotrol C, soybean oil, medium chain triglyceride, polyglycerol monooleate, cyclodextrin, polyvidone and tensio-active agent are as tween, sapn, sell pool, Bian Ze, quaternary ammonium salt, poloxamer, olein, sodium lauryl sulphate, polyoxyethylene glycol, Yelkin TTS, stearic acid, Triton X-100 etc.
Nitroimidazoles medicine prepared by aforesaid method and derivative ultrafine powder thereof, from angle of statistics meter, 50% and above particle there is following characteristics: spatially have two-dimentional yardstick to be less than 30 μm, or have unidimensional scale to be less than 30 μm, its maximum dimension is not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1 with the ratio of smallest dimension size.
In the present invention, nitroimidazoles medicine and derivative thereof include but not limited to metronidazole, tinidazole, ornidazole and secnidazole, and have the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
The nitroimidazoles medicine that the present invention relates to and derivative thereof can be used for preparing various pharmaceutical composition, to manufacture pharmaceutical dosage form conventional clinically as oral solid formulation, suspensoid etc., also can be used for making other formulations as lozenge, patch, emulsion etc.
Nitroimidazoles medicine of the present invention and derivative ultrafine powder thereof, the meltage in appropriate medium in (15 ~ 25 DEG C) 5min be non-ultrafine powder material dissolution amount 110% and more than.Appropriate medium can be containing 0 ~ 5% tensio-active agent as the aqueous solution of sodium lauryl sulphate, tween, polyoxyethylene glycol, poloxamer etc., can be the buffer salt solution of pH value 1 ~ 10.
Medicine ultrafine powder prepared by the present invention is different from other nanometer formulation, as nano-emulsion, solid lipid nanoparticle, nano-micelle and polymer nanoparticle; Ultrafine powder containing substrate material, is not only made up of medicine, or only containing a small amount of stablizer, has the higher bioavailability of high, the easy realization of drug loading, stability and security, apply more extensive.
The nitroimidazoles medicine that the present invention relates to and derivative ultrafine powder preparation method thereof, operational path is simple, and processing condition are gentle, and single or multiple equipment can be utilized to combine, carry out continuous prodution, the technical process that can produce with pharmaceutical industriesization easily realizes seamless connection; Morphology microstructure is stablized: setting different technical parameters, can obtain the stable homogeneous powder of different size, production technique collimation is good, and products therefrom homogeneity is good, steady quality.Technology of the present invention can become the technology platform manufacturing various chemicals and biochemical drug ultrafine powder new formulation.
Accompanying drawing explanation
Fig. 1 is azithromycin particle 100 μm of Electronic Speculum figure that media milling process obtains;
Fig. 2 is ultrafine powder 5 μm of Electronic Speculum figure that embodiment 8 obtains;
Fig. 3 is ultrafine powder 50 μm of Electronic Speculum figure of embodiment 8;
Fig. 4 is ultrafine powder 5 μm of Electronic Speculum figure that embodiment 12 obtains;
Fig. 5 is ultrafine powder 50 μm of Electronic Speculum figure that embodiment 12 obtains;
Fig. 6 is the dissolution rate comparison diagram of tinidazole raw material and embodiment 8 ultrafine powder.
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention is described in further detail.Should be appreciated that following embodiment is not construed as limiting the present invention for illustration of the present invention, all equivalent variations done according to key problem in technology of the present invention, all fall into protection scope of the present invention.
Embodiment 1
Metronidazole raw material 5g, adds 10mL Virahol, heating for dissolving, then adds the acetone of 30ml, and ice bath is lowered the temperature, and 25kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 2
Secnidazole raw material 4g, adds 8mL methyl alcohol, heating for dissolving, then adds the acetone of 24ml, and ice bath is lowered the temperature, and 10kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 3
Ornidazole raw material 6g, adds 15mL ethyl acetate, heating for dissolving, then adds the acetone of 44ml, and ice bath is lowered the temperature, and 30kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 4
Tinidazole raw material 5g, adds 20mL dehydrated alcohol, heating for dissolving, then adds the acetone of 61ml, and ice bath is lowered the temperature, and 40kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 5
Ornidazole raw material 6g, adds the Virahol of 6mL, heating for dissolving, adds sherwood oil 24ml, and ice bath is lowered the temperature, and 30kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 6
Metronidazole raw material 6g, adds the dehydrated alcohol of 10mL, heating for dissolving, adds sherwood oil 20ml, and ice bath is lowered the temperature, and 30kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 7
Secnidazole raw material 5g, adds the ethyl acetate of 12mL, heating for dissolving, adds sherwood oil 20ml, and ice bath is lowered the temperature, and 40kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 8
Tinidazole raw material 2g, adds the acetone of 60mL, heating for dissolving, adds sherwood oil 40ml, and ice bath is lowered the temperature, and 20kHz250W is ultrasonic, obtains Sample crystals; The ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, is shown in accompanying drawing 2,3) of two-dimensional is obtained after collection, washing, drying.
Embodiment 9
Metronidazole raw material 3g, adds the ethyl acetate of 6mL, heating for dissolving, adds sherwood oil 12ml, and ice bath is lowered the temperature, and 30kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 10
Secnidazole raw material 4g, adds the Virahol of 8mL, heating for dissolving, adds sherwood oil 14ml, and ice bath is lowered the temperature, and 40kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 11
Tinidazole raw material 5g, adds the DMSO of 10mL, heating for dissolving, adds sherwood oil 21ml, and ice bath is lowered the temperature, and 20kHz350W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 12
Ornidazole raw material 16g, adds the methyl alcohol of 39mL, heating for dissolving, and add water 109ml, and ice bath is lowered the temperature, and 15kHz400W is ultrasonic, obtains Sample crystals; The ultrafine powder (accompanying drawing 4,5) of one dimension size is obtained after collection, washing, drying.
Embodiment 13
Metronidazole raw material 21g, adds the Virahol of 37mL, heating for dissolving, adds sherwood oil 120ml, and ice bath is lowered the temperature, and 15kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 14
Secnidazole raw material 23g, adds the acetone of 49mL, heating for dissolving, adds sherwood oil 135ml, and ice bath is lowered the temperature, and 20kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 15
Ornidazole raw material 24g, adds the DMSO of 79mL, heating for dissolving, adds sherwood oil 206ml, and ice bath is lowered the temperature, and 25kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 16
Metronidazole raw material 50g, adds the methylene dichloride of 40mL, heating for dissolving, adds sherwood oil 88ml, and ice bath is lowered the temperature, and 15kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 17
Tinidazole raw material 20g, adds the ethyl acetate of 89mL, heating for dissolving, adds sherwood oil 215ml, and ice bath is lowered the temperature, and 40kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 18
Ornidazole raw material 50g, adds the ethyl acetate of 80mL, heating for dissolving, adds sherwood oil 155ml, and ice bath is lowered the temperature, and 50kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 19
Secnidazole raw material 50g, adds the DMSO of 64mL, heating for dissolving, adds sherwood oil 126ml, and ice bath is lowered the temperature, and 25kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 20
Tinidazole raw material 50g, adds the Virahol of 90mL, heating for dissolving, adds sherwood oil 210ml, and ice bath is lowered the temperature, and 35kHz350W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 21
Metronidazole raw material 40g, adds the ethyl acetate solution 200mL of 0.1%PEG400, heating for dissolving, adds sherwood oil 300ml, and ice bath is lowered the temperature, and 40kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 22
Secnidazole raw material 40g, adds the aqueous isopropanol 300mL of 2%PEG400, heating for dissolving, adds sherwood oil 250ml, and ice bath is lowered the temperature, and 30kHz450W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 23
Ornidazole raw material 40g, add the DMSO solution 100mL of 0.5%PEG400, heating for dissolving, adds sherwood oil 400ml, and ice bath is lowered the temperature, and 45kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 24
Tinidazole raw material 40g, adds the ethanol solution 300mL of 0.1%PEG400, heating for dissolving, adds sherwood oil 200ml, and ice bath is lowered the temperature, and 15kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 25
Metronidazole raw material 60g, adds the aqueous isopropanol 180mL of 1% sapn, heating for dissolving, adds sherwood oil 550ml, and ice bath is lowered the temperature, and 30kHz5000W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 26
Secnidazole raw material 7g, adds the dichloromethane solution 22mL of 0.3% Viscotrol C, heating for dissolving, adds sherwood oil 78ml, and ice bath is lowered the temperature, and 40kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 27
Ornidazole raw material 3g, add 1% stearic ethanol solution 9mL, heating for dissolving, adds sherwood oil 21ml, and ice bath is lowered the temperature, and 25kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 28
Tinidazole raw material 2g, adds the acetone soln 5mL of 1% soybean oil, heating for dissolving, adds sherwood oil 15ml, and ice bath is lowered the temperature, and 15kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 29
Secnidazole raw material 3g, adds the dehydrated alcohol of 20mL, heating for dissolving, and under normal temperature, 40kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 30
Metronidazole raw material 2g, adds the ethyl acetate of 11mL, heating for dissolving, and under normal temperature, 20kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 31
Tinidazole raw material 1g, adds the acetone of 3mL, heating for dissolving, and under normal temperature, 15kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 32
Ornidazole raw material 22g, adds the methyl alcohol of 50mL, heating for dissolving, and under normal temperature, 30kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 33
Metronidazole raw material 7g, adds the Virahol of 13mL, heating for dissolving, and add water 8ml, and ice bath is lowered the temperature, and 40kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 34
Secnidazole raw material 4g, adds the methyl alcohol of 10mL, heating for dissolving, and add water 30ml, and ice bath is lowered the temperature, and 30kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 35
Ornidazole raw material 10g, adds the acetone of 24mL, heating for dissolving, and add water 8ml, and ice bath is lowered the temperature, and 50kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 36
Tinidazole raw material 15g, adds the N-METHYLFORMAMIDE of 8mL, heating for dissolving, and add water 8ml, and ice bath is lowered the temperature, and 15kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 37
Metronidazole raw material 7g, adds the DMSO of 21mL, heating for dissolving, and add water 25ml, and ice bath is lowered the temperature, and 25kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 38
Tinidazole raw material 4g, adds the DMSO of 12mL, heating for dissolving, and add water 12ml, and ice bath is lowered the temperature, and 25kHz350W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 39
Secnidazole raw material 5g, adds the DMSO of 8mL, heating for dissolving, and add water 21ml, and ice bath is lowered the temperature, and 30kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 40
Ornidazole raw material 6g, adds the dehydrated alcohol of 12mL, heating for dissolving, and add water 18ml, and ice bath is lowered the temperature, and 40kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 41
Metronidazole raw material 9g, adds the dehydrated alcohol of 16mL, heating for dissolving, and add water 10ml, and ice bath is lowered the temperature, and 40kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 42
Tinidazole raw material 10g, adds the acetone of 20mL, heating for dissolving, and add water 30ml, and ice bath is lowered the temperature, and 50kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 43
Secnidazole raw material 7g, adds the acetone of 9mL, heating for dissolving, and add water 21ml, and ice bath is lowered the temperature, and 30kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 44
Ornidazole raw material 6g, adds the DMSO of 10mL, heating for dissolving, and add water 10ml, and ice bath is lowered the temperature, and 35kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 45
Metronidazole raw material 5g, adds the Virahol of 5mL, heating for dissolving, and add water 15ml, and ice bath is lowered the temperature, and 20kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 46
Secnidazole raw material 10g, adds the dehydrated alcohol of 10mL, heating for dissolving, and add water 15ml, and ice bath is lowered the temperature, and 30kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 47
Ornidazole raw material 7g, adds the Virahol of 14mL, heating for dissolving, and add water 28ml, and ice bath is lowered the temperature, and 25kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 48
Tinidazole raw material 8g, adds the Virahol of 10mL, heating for dissolving, and add water 15ml, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 49
Secnidazole raw material 3g, adds the methyl alcohol of 7mL, heating for dissolving, adds the aqueous solution 34ml of 1%SDS, and ice bath is lowered the temperature, and 50kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 50
Ornidazole raw material 5g, adds the acetone of 11mL, heating for dissolving, adds the aqueous solution 54ml of 1%SLS, and ice bath is lowered the temperature, and 25kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 51
Metronidazole raw material 3g, adds the dehydrated alcohol of 5mL, heating for dissolving, adds the aqueous solution 44ml of 1%SDS, and ice bath is lowered the temperature, and 20kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 52
Tinidazole raw material 4g, adds the Virahol of 8mL, heating for dissolving, adds the aqueous solution 34ml of 1%PEG, and ice bath is lowered the temperature, and 30kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 53
Metronidazole raw material 1g, adds the methyl alcohol of 5mL, heating for dissolving, adds the aqueous solution 15ml of 1% tween 80, and ice bath is lowered the temperature, and 20kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 54
Ornidazole raw material 1g, adds the Virahol of 7mL, heating for dissolving, adds the aqueous solution 16ml of 1%PEG400, and ice bath is lowered the temperature, and 30kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 55
Tinidazole raw material 1g, adds the DMSO of 3mL, heating for dissolving, adds the aqueous solution 21ml of 1% tween 80, and ice bath is lowered the temperature, and 10kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 56
Secnidazole raw material 1g, adds the acetone of 4mL, heating for dissolving, adds the aqueous solution 14ml of 1%SLS, and ice bath is lowered the temperature, and 40kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 57
Metronidazole raw material 4g, adds the acetone of 11mL, heating for dissolving, adds the aqueous solution 35ml of 1%SDS, and ice bath is lowered the temperature, and 25kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 58
Secnidazole raw material 6g, adds the Virahol of 15mL, heating for dissolving, adds the aqueous solution 57ml of 1%PEG400, and ice bath is lowered the temperature, and 20kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 59
Ornidazole raw material 3g, adds the N-METHYLFORMAMIDE of 7mL, heating for dissolving, adds the aqueous solution 55ml of 1% poloxamer, and ice bath is lowered the temperature, and 30kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 60
Metronidazole raw material 5g, adds the N-METHYLFORMAMIDE of 15mL, heating for dissolving, adds the aqueous solution 23ml of 1% poloxamer, and ice bath is lowered the temperature, and 40kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 61
Tinidazole raw material 6g, adds the methyl alcohol of 13mL, heating for dissolving, adds the aqueous solution 75ml of 1%SLS, and ice bath is lowered the temperature, and 10kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 62
Secnidazole raw material 7g, adds the DMSO of 18mL, heating for dissolving, the aqueous solution 38ml of 1%SLS, and ice bath is lowered the temperature, and 50kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 63
Ornidazole raw material 4g, adds the dehydrated alcohol of 13mL, heating for dissolving, the aqueous solution 25ml of 1%PVC, and ice bath is lowered the temperature, and 20kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 64
Tinidazole raw material 8g, adds the methyl alcohol of 21mL, heating for dissolving, the aqueous solution 55ml of 1% tween 80, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 65
Ornidazole raw material 8g, adds ethyl acetate/petroleum ether (75/25) solution of 14mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 66
Metronidazole raw material 7g, adds ethyl acetate/petroleum ether (50/50) solution of 20mL, heating for dissolving, and ice bath is lowered the temperature, and 10kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 67
Tinidazole raw material 7g, adds ethyl acetate/petroleum ether (30/70) solution of 30mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 68
Secnidazole raw material 6g, adds ethyl acetate/petroleum ether (60/40) solution of 16mL, heating for dissolving, and ice bath is lowered the temperature, and 15kHz350W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 69
Ornidazole raw material 6g, adds DMSO/ sherwood oil (70/30) solution of 43mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 70
Metronidazole raw material 32g, adds DMSO/ sherwood oil (25/75) solution of 550mL, heating for dissolving, and ice bath is lowered the temperature, and 40kHz1500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 71
Secnidazole raw material 12g, adds DMSO/ sherwood oil (40/60) solution of 105mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 72
Tinidazole raw material 7g, adds DMSO/ sherwood oil (50/50) solution of 55mL, heating for dissolving, and ice bath is lowered the temperature, and 25kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 73
Metronidazole raw material 6g, adds methanol/water (25/75) solution of 0.5% poloxamer of 55mL, heating for dissolving, and ice bath is lowered the temperature, and 35kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 74
Secnidazole raw material 4g, adds methanol/water (40/60) solution of 0.5% poloxamer of 30mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 75
Ornidazole raw material 5g, adds methanol/water (50/50) solution of 0.5% poloxamer of 25mL, heating for dissolving, and ice bath is lowered the temperature, and 15kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 76
Tinidazole raw material 7g, adds methanol/water (70/30) solution of 0.5% poloxamer of 15mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 77
Metronidazole raw material 17g, adds isopropanol/water (40/60) solution of the 0.5%SDS of 62mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 78
Secnidazole raw material 15g, adds isopropanol/water (60/40) solution of the 0.5%SDS of 45mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 79
Ornidazole raw material 14g, adds isopropanol/water (30/70) solution of the 0.5%SDS of 78mL, heating for dissolving, and ice bath is lowered the temperature, and 40kHz350W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 80
Tinidazole raw material 15g, adds isopropanol/water (70/30) solution of the 0.5%SDS of 37mL, heating for dissolving, and ice bath is lowered the temperature, and 50kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 81
Metronidazole raw material 54g, adds N-METHYLFORMAMIDE/sherwood oil (50/50) solution of the 0.4%PEG400 of 450mL, heating for dissolving, and ice bath is lowered the temperature, and 40kHz5000W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 82
Secnidazole raw material 53g, adds N-METHYLFORMAMIDE/sherwood oil (65/35) solution of the 0.3%PEG400 of 400mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz1000W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 83
Ornidazole raw material 24g, adds N-METHYLFORMAMIDE/sherwood oil (30/70) solution of the 0.5%PEG400 of 150mL, heating for dissolving, and ice bath is lowered the temperature, and 10kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 84
Metronidazole raw material 7g, adds Virahol/sherwood oil (40/60) solution of 0.5% sapn of 30mL, heating for dissolving, and ice bath is lowered the temperature, and 25kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 85
Tinidazole raw material 16g, adds N-METHYLFORMAMIDE/sherwood oil (25/75) solution of the 0.4%PEG400 of 60mL, heating for dissolving, and ice bath is lowered the temperature, and 25kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 86
Secnidazole raw material 5g, adds Virahol/sherwood oil (35/65) solution of 0.5% sapn of 30mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 87
Ornidazole raw material 7g, adds Virahol/sherwood oil (50/50) solution of 0.5% sapn of 28mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 88
Tinidazole raw material 6g, adds Virahol/sherwood oil (70/30) solution of 0.5% Viscotrol C of 21mL, heating for dissolving, and ice bath is lowered the temperature, and 40kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 89
Tinidazole raw material 16g, adds DMSO/ sherwood oil (50/50) solution of 0.5% Viscotrol C of 60mL, heating for dissolving, and ice bath is lowered the temperature, and 25kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 90
Secnidazole raw material 5g, adds DMSO/ sherwood oil (40/60) solution of 0.1% Viscotrol C of 34mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 91
Ornidazole raw material 7g, adds DMSO/ sherwood oil (30/70) solution of 0.4% Viscotrol C of 33mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 92
Tinidazole raw material 6g, adds DMSO/ sherwood oil (70/30) solution of 0.2% Viscotrol C of 15mL, heating for dissolving, and ice bath is lowered the temperature, and 40kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 93
Ornidazole raw material 8g, adds dehydrated alcohol/water (70/30) solution of 26mL, heating for dissolving, and ice bath is lowered the temperature, and 30kHz350W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 94
Metronidazole raw material 10g, adds dehydrated alcohol/water (50/50) solution of 25mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz250W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 95
Secnidazole raw material 9g, adds dehydrated alcohol/water (40/60) solution of 30mL, heating for dissolving, and ice bath is lowered the temperature, and 40kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 96
Tinidazole raw material 11g, adds dehydrated alcohol/water (35/65) solution of 44mL, heating for dissolving, and ice bath is lowered the temperature, and 35kHz100W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 97
Metronidazole raw material 5g, adds acetone/water (80/20) solution of 13mL, heating for dissolving, and ice bath is lowered the temperature, and 10kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 98
Secnidazole raw material 5g, adds acetone/water (60/40) solution of 29mL, heating for dissolving, and ice bath is lowered the temperature, and 40kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 99
Ornidazole raw material 5g, adds acetone/water (30/70) solution of 35mL, heating for dissolving, and ice bath is lowered the temperature, and 35kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 100
Tinidazole raw material 25g, adds acetone/water (40/60) solution of 176mL, heating for dissolving, and ice bath is lowered the temperature, and 25kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 101
Metronidazole raw material 4g, adds isopropanol/water (35/65) solution of 27mL, heating for dissolving, and ice bath is lowered the temperature, and 15kHz150W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 102
Secnidazole raw material 5g, adds isopropanol/water (50/50) solution of 34mL, heating for dissolving, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 103
Ornidazole raw material 5g, adds isopropanol/water (45/55) solution of 55mL, heating for dissolving, and ice bath is lowered the temperature, and 10kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 104
Tinidazole raw material 25g, adds isopropanol/water (67/33) solution of 176mL, heating for dissolving, and ice bath is lowered the temperature, and 50kHz500W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Dissolution rate in vitro is tested: the ultrafine powder 30mg taking tinidazole raw material and embodiment 8 preparation, be added in 900ml0.3%SDS solution, with the test of RC-6 type digestion instrument under constant temperature 21 DEG C, 50rpm condition, respectively at 5,10,15,30,45,60min samples 5ml and supplements blank solution 5ml, sample liquid 0.22 μm of membrane filtration, filtrate is irradiated (if do not observe scattering, then this solution is not containing nano particle) with red laser telltale.After filtrate is diluted to suitable concn by blank solvent (doing blank with dissolution solvent), detect in 317nm place with UV detector (TU-1901), calculate each time point concentration and draw dissolution rate chart (accompanying drawing 6).
Claims (5)
1. the ultrafine powder of a nitroimidazoles medicine and derivative thereof, it is characterized in that: the one dimension of described ultrafine powder or two-dimensional are 1nm ~ 30 μm, maximum dimension is not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1 with the ratio of smallest dimension size.
2. nitroimidazoles medicine according to claim 1 and derivative ultrafine powder thereof, it is characterized in that: described nitroimidazoles medicine and derivative thereof include but not limited to metronidazole, tinidazole, ornidazole and secnidazole, and there is the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
3. prepare a method for nitroimidazoles medicine and derivative ultrafine powder thereof, its step is as follows:
(1) prepare a kind of homogeneous phase solution containing nitroimidazoles medicine and derivative thereof, wherein the weightmeasurement ratio (w/v, g/mL) of nitroimidazoles medicine and derivative and solvent is: 1:1 ~ 1:300; Solvent used is: methyl alcohol, ethanol, Virahol, propyl carbinol, propylene glycol, acetone, DMF (DMF), N-Methyl pyrrolidone (NMP), tetrahydrofuran (THF), acetonitrile, ether, sherwood oil, t-butyl methyl ether, normal hexane, normal heptane, methylene dichloride, trichloromethane, methyl-sulphoxide (DMSO), methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, acetic acid, aceticanhydride, benzene are at interior lower alcohol (C
1-6), lower ketones (C
3-12), rudimentary ether (C
2-12), lower acid (C
1-6), lower member ester (esterification products of lower alcohol and lower acid), one or more in aromatic hydrocarbon, alkane, haloalkane and water;
(2) when temperature is-30 DEG C ~ 100 DEG C, the homogeneous phase solution prepared by step (1) is applied to frequency is 10kHz ~ 500kHz, power is 1mW ~ 5000W, the sound intensity is 0.1mW/cm
2~ 500W/cm
2, obtain nitroimidazoles medicine and derivative crystal thereof;
(3) through operations such as solid collection, washing, dryings, obtain nitroimidazoles medicine and derivative ultrafine powder thereof, its one dimension or two-dimensional are less than 30 μm, and maximum dimension is not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1 with the ratio of smallest dimension size.
4. the preparation method of nitroimidazoles medicine and derivative ultrafine powder thereof according to claim 3, it is characterized in that: described nitroimidazoles medicine and derivative thereof include but not limited to metronidazole, tinidazole, ornidazole and secnidazole, and there is the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
5. nitroimidazoles medicine any one of claim 1 or 2 and the purposes of derivative ultrafine powder in pharmaceutical compositions thereof.
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Citations (2)
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|---|---|---|---|---|
| CN1437464A (en) * | 2000-04-20 | 2003-08-20 | 斯凯伊药品加拿大公司 | Improved water-insoluble drug particle process |
| CN102016814A (en) * | 2005-06-17 | 2011-04-13 | 北卡罗来纳大学查珀尔希尔分校 | Nanoparticle fabrication methods, systems, and materials |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1437464A (en) * | 2000-04-20 | 2003-08-20 | 斯凯伊药品加拿大公司 | Improved water-insoluble drug particle process |
| CN102016814A (en) * | 2005-06-17 | 2011-04-13 | 北卡罗来纳大学查珀尔希尔分校 | Nanoparticle fabrication methods, systems, and materials |
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Application publication date: 20160106 |