CN105294563A - Superfine powder of COX-2 inhibitor and preparation method for superfine powder - Google Patents
Superfine powder of COX-2 inhibitor and preparation method for superfine powder Download PDFInfo
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Abstract
The present invention relates to superfine powder pf cyclooxygenase-2 (COX-2) inhibitor and a preparation method for the superfine powder. A COX-2 inhibitor is often used as one of anti-inflammatory drugs. As the bioavailability is low, which causes relatively great dosage, the toxic and side effects are relatively obvious. A method for preparing the superfine powder of the COX-2 inhibitor comprises: in a homogeneous solution containing the COX-2 inhibitor, by applying an ultrasound with frequency of 10kHz-500kHz, power of 1mW-5000W and acoustic intensity of 0.1mW/cm2-500W/cm2, quickly obtaining COX-2 inhibitor crystals; and then directly obtaining the superfine powder of the COX-2 inhibitor through normal operations such as solid collection, washing and drying and the like. The superfine powder prepared by the preparation method provided by the present invention does not contain a host material, and has the characteristics of high drug loading capacity, high dissolving speed, and easily implement of higher bioavailability, stability and safety, thereby satisfying the demands of increasing the drug bioavailability, reducing the drug dosage, reducing the toxic and side effects; and the superfine powder has a wide application prospect.
Description
Technical field
The present invention relates to medical art, particularly a kind of ultrafine powder and preparation method thereof of cox 2 inhibitor.
Background technology
Non-steroidal analgesic-antipyretic (NSAIDs) has the advantage such as clear curative effect, better tolerance and is widely used in osteoarthritis (OA) and rheumatoid arthritis (RA) and various light to moderate pain, but its serious gastrointestinal untoward reaction caused limits the further application of this type of medicine.COX-2 (COX-2) selective depressant is the novel non-steroidal anti-inflammatory drugs of the class (NSAID) that the nineties in 20th century, Later development got up, mechanism of action is Selective depression COX-2, produces anti-inflammatory action by blocking inflammatory mediator prostaglandin(PG) (PG) biosynthesizing.Typical case's cox 2 inhibitor is the adjacent biaryl substituted heterocycle compounds that a class contains benzsulfamide or phenmethyl sulfone; now clinical application have celecoxib (celecoxib), rofecoxib (mfecoxib), valdecoxib (valdecoxib), Etoricoxib (etoricoxib) and Parecoxib (parecoxib); this kind of medicine does not suppress COX-1 gastrointestinal mucosa to provide protection, has lower gastrointestinal side effect.But along with the popularization of application and going deep into cox 2 inhibitor research, increasing experiment finds that the side effect of cox 2 inhibitor can not be ignored.
The oral administration biaavailability of cox 2 inhibitor is lower, as: the oral absolute bioavailability of celecoxib is: solution 64-88%, capsule 22-44%, and main manifestations is: insoluble in water, bulk density is low, easily bonds, poor compressibility, very slow during oral absorption.Celecoxib bulk drug is crushed to less than D90200 μm by world patent WO0032189 (Chinese patent CN99802185.7), preferably 1 ~ 10 μm, most preferably 5 ~ 7 μm time, make preparation according to a conventional method, can reach in the short period of time and effectively treat blood concentration.World patent WO0141760 (CN00805974.8) discloses further, when celecoxib is crushed to less than 1 μm, can further improve its highest haemoconcentration (Cmax), shorten the time (Tmax) reaching the highest haemoconcentration.Which illustrate the granular size reducing bulk drug, drug absorption may be made to accelerate.
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.
Medicine and polymer materials were dissolved in organic solvent in 2012 by the people such as AdamBohr in " ParticleformationandcharacteristicsofCelecoxib-loadedpol y (lactic-co-glycolicacid) microparticlespreparedindifferentsolventsusingelectrospr aying ", particulate is prepared again by single nozzle electron spray(ES) equipment, obtain the 0 dimension particle of 2 ~ 7 μm, the rate of release of the controlled pharmacy of this particle; The method actual preparation be pharmaceutical preparation particle, and use degradable polymeric material, expensive, instrument consume high.
People such as MichaelMorgen 2012 are at " PolymericNanoparticlesforIncreasedOralBioavailabilityand RapidAbsorptionUsingCelecoxibasaModelofaLow-Solubility, High-PermeabilityDrug " in by medicine and auxiliary material mixing be dissolved in methylene dichloride, nano suspension is obtained after emulsification, rotation evaporate to dryness, now nano-scale is at 100-150nm, after spray-dried, become greatly to as shown in Figure 1 the 0 dimension particle of 5-20 μm; The method is also used to useful in preparing drug formulations particle, and the methylene dichloride wherein applied has larger toxicity, and emulsification and spin dry process are not all suitable for large production.
MohamedNasr is squeezed into rapidly in water by syringe after celecoxib being dissolved in methyl alcohol in 2013 in " InfluenceofMicrocrystalFormulationonInVivoAbsorptionofCe lecoxibinRats ", after stirring, drying prepares crystallite, improves dissolution rate and the bioavailability of celecoxib; The method belongs to anti-solvent (solvent that medicine is insoluble) recrystallization method, and because processing condition are harsh, be only applicable to laboratory applications at present, commercial production conditions is also imperfect.
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.
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.
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, uncontrollable due to crystal growth, causes product size difference large, and it is general all with high-speed stirring or high speed centrifugation or high-pressure homogeneous, production unit not easily configures, and operational hazards coefficient is large, and cost is high.
The various defects of above-mentioned ultrafine powder preparation method are the principal elements causing not having cox 2 inhibitor 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 cox 2 inhibitor ultrafine powder and preparation method thereof, concrete preparation method is: be in the homogeneous phase solution of-30 DEG C ~ 100 DEG C in a kind of temperature containing cox 2 inhibitor, 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 cox 2 inhibitor crystal, then through routine operations such as solid collection, washing, drying, directly acquisition cox 2 inhibitor ultrafine powder.
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 cox 2 inhibitor and solvent is: 1:1 ~ 1:300.
Cox 2 inhibitor ultrafine powder preparation method provided by the invention, 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.
Cox 2 inhibitor ultrafine powder preparation method provided by the invention, 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.
Cox 2 inhibitor ultrafine powder prepared by aforesaid method, 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, cox 2 inhibitor includes but not limited to celecoxib, rofecoxib, valdecoxib, Etoricoxib and Parecoxib, and has the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
Especially, when cox 2 inhibitor of the present invention is celecoxib, the one dimension of its ultrafine powder or two-dimensional are not more than 4 μm/3 μm/2 μm/1 μm/900nm/800nm/700nm/600nm/500nm.
The cox 2 inhibitor that the present invention relates to 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, emulsion, patch etc.
Cox 2 inhibitor ultrafine powder of the present invention, 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 cox 2 inhibitor ultrafine powder preparation method that the present invention relates to, 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 the dried particulate of prior art nano suspension 100 μm of Electronic Speculum figure;
Fig. 2 is ultrafine powder 1 μm of Electronic Speculum figure of embodiment 1;
Fig. 3 is ultrafine powder 2 μm of Electronic Speculum figure of embodiment 1;
Fig. 4 is ultrafine powder 50 μm of Electronic Speculum figure of embodiment 1;
Fig. 5 is ultrafine powder 2 μm of Electronic Speculum figure of embodiment 4;
Fig. 6 is ultrafine powder 2 μm of Electronic Speculum figure of embodiment 4;
Fig. 7 is ultrafine powder 50 μm of Electronic Speculum figure of embodiment 4;
Fig. 8 is ultrafine powder 1 μm of Electronic Speculum figure of embodiment 21;
Fig. 9 is ultrafine powder 2 μm of Electronic Speculum figure of embodiment 21;
Figure 10 is ultrafine powder 50 μm of Electronic Speculum figure of embodiment 21;
Figure 11 is ultrafine powder 2 μm of Electronic Speculum figure of embodiment 24;
Figure 12 is ultrafine powder 2 μm of Electronic Speculum figure of embodiment 24;
Figure 13 is ultrafine powder 2 μm of Electronic Speculum figure of embodiment 36;
Figure 14 is ultrafine powder 5 μm of Electronic Speculum figure of embodiment 36;
Figure 15 is ultrafine powder 50 μm of Electronic Speculum figure of embodiment 36;
Figure 16 is the dissolution rate comparison diagram of celecoxib raw material and ultrafine powder in embodiment 21;
Figure 17 is the dissolution rate comparison diagram of Etoricoxib raw material and ultrafine powder in embodiment 36.
Embodiment
Below by specific 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
Celecoxib raw material 2g, adds the dehydrated alcohol of 13mL, heating for dissolving, and under normal temperature, 20kHz200W is ultrasonic, obtains Sample crystals; The ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, is shown in accompanying drawing 2,3,4) that two-dimensional is about 100nm ~ 400nm is obtained after collection, washing, drying.
Embodiment 2
Rofecoxib raw material 3g, adds the Virahol of 20mL, heating for dissolving, and under normal temperature, 40kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 3
Valdecoxib raw material 2.2g, 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 4
Etoricoxib raw material 2g, adds the acetone of 6mL, heating for dissolving, and under normal temperature, 25kHz300W is ultrasonic, obtains Sample crystals; The ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, is shown in accompanying drawing 5,6,7) of one dimension size is obtained after collection, washing, drying.
Embodiment 5
Celecoxib 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 6
Rofecoxib 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 7
Valdecoxib 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 8
Etoricoxib 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 9
Celecoxib 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 10
Rofecoxib 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 11
Valdecoxib 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 12
Etoricoxib 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 13
Celecoxib 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 14
Rofecoxib 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 15
Valdecoxib 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 16
Etoricoxib 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 17
Celecoxib 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 18
Rofecoxib raw material 1g, adds the dehydrated alcohol of 5mL, 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 19
Valdecoxib 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 20
Etoricoxib raw material 8g, adds the Virahol of 15mL, 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 21
Celecoxib raw material 5g, adds the dehydrated alcohol of 50mL, heating for dissolving, adds sherwood oil 150ml, 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 8,9,10) of two-dimensional 100nm ~ about 200nm is obtained after collection, washing, drying.
Embodiment 22
Rofecoxib 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 23
Valdecoxib 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 24
Etoricoxib raw material 2g, adds the acetone of 12mL, heating for dissolving, adds sherwood oil 8ml, and ice bath is lowered the temperature, and 25kHz350W is ultrasonic, obtains Sample crystals; Collect, washing, obtain one dimension size after drying at the ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, is shown in accompanying drawing 11,12) of about 2 μm.
Embodiment 25
Celecoxib 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 26
Rofecoxib 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 27
Valdecoxib raw material 16g, adds the acetone of 39mL, heating for dissolving, adds sherwood oil 59ml, and ice bath is lowered the temperature, and 15kHz400W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 28
Etoricoxib 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 29
Celecoxib raw material 21g, adds the Virahol of 49mL, 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 30
Rofecoxib 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 31
Valdecoxib 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 32
Etoricoxib 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 33
Celecoxib raw material 50g, adds the methylene dichloride of 60mL, 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 34
Rofecoxib 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 35
Valdecoxib 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 36
Etoricoxib raw material 1g, adds the dehydrated alcohol of 23mL, heating for dissolving, adds sherwood oil 122ml, and ice bath is lowered the temperature, and 20kHz250W is ultrasonic, obtains Sample crystals; Collect, washing, obtain one dimension size after drying at the ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, is shown in accompanying drawing 13,14,15) of 2 μm ~ about 4 μm.
Embodiment 37
Celecoxib raw material 4g, adds the dehydrated alcohol of 6mL, 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 38
Rofecoxib 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 39
Valdecoxib 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 40
Etoricoxib 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 41
Celecoxib 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 42
Rofecoxib 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 150W40kHz is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 43
Valdecoxib 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 44
Etoricoxib 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 45
Celecoxib 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 46
Rofecoxib 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 47
Valdecoxib 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 48
Etoricoxib raw material 7g, 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 49
Celecoxib 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 50
Rofecoxib 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 51
Valdecoxib 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 52
Etoricoxib 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 53
Celecoxib raw material 40g, adds the ethyl acetate solution 200mL of 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 54
Rofecoxib raw material 40g, adds the aqueous isopropanol 300mL of 1%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 55
Valdecoxib raw material 40g, add the DMSO solution 100mL of 1%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 56
Etoricoxib raw material 40g, adds the ethanol solution 300mL of 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 57
Celecoxib 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 58
Rofecoxib raw material 7g, adds the dichloromethane solution 22mL of 1% 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 59
Valdecoxib 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 60
Etoricoxib 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 61
Celecoxib 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 62
Rofecoxib 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 63
Valdecoxib 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 64
Etoricoxib 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 65
Celecoxib 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 66
Rofecoxib 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 67
Valdecoxib 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 68
Etoricoxib 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 69
Celecoxib 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 70
Rofecoxib 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 71
Valdecoxib 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 72
Etoricoxib 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 73
Celecoxib 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 74
Rofecoxib 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 75
Valdecoxib 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 76
Etoricoxib 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 77
Celecoxib 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 78
Rofecoxib 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 the ultrasonic 22min of 30kHz200W, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 79
Valdecoxib 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 80
Etoricoxib 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 81
Celecoxib 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 82
Rofecoxib 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 83
Valdecoxib 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 84
Etoricoxib 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 85
Celecoxib 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 86
Rofecoxib 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 87
Valdecoxib 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 88
Etoricoxib 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 89
Celecoxib 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 90
Rofecoxib 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 91
Valdecoxib 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 20kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 92
Etoricoxib raw material 6g, adds Virahol/sherwood oil (70/30) solution of 0.5% sapn 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 93
Celecoxib raw material 5g, adds 10mL methyl alcohol, 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 94
Rofecoxib raw material 4g, adds 8mL dehydrated 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 95
Valdecoxib 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 96
Etoricoxib raw material 5g, adds 20mL Virahol, heating for dissolving, then adds the isopropyl acetate 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 97
Etoricoxib raw material 5g, adds 20mL ethanol, heating for dissolving, then adds the isopropyl acetate of 41ml, backflow, and ice bath is lowered the temperature, and 20kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 98
Etoricoxib raw material 5g, adds 20mL acetone, heating for dissolving, then adds the isopropyl acetate of 21ml, then adds normal heptane 10ml, backflow, and ice bath is lowered the temperature, and 20kHz200W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 99
Etoricoxib raw material 5g, adds 20mL ethanol, heating for dissolving, then adds the isopropyl acetate of 25ml, then adds normal hexane 8ml, backflow, and ice bath is lowered the temperature, and 20kHz300W is ultrasonic, obtains Sample crystals; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 100
The product 1g of embodiment 96 ~ embodiment 99, add 10ml isopropyl acetate, 20kHz300W is ultrasonic, and ultrasonic time is no more than 24h, and control temperature is no more than 60 DEG C.Then at ultrasound condition borehole cooling to 20 DEG C; Off-white color ultrafine powder is obtained after collection, washing, drying.
Dissolution rate in vitro is tested: each 10mg of ultrafine powder taking celecoxib raw material and embodiment 21 preparation, be added in pure water 900ml, with the test of RC-6 type digestion instrument under constant temperature 22 DEG C, 50rpm condition, respectively at 5,10,15,30,60,90min 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 with blank medium, through high performance liquid chromatograph (chromatographic column: C184.6mmx150mm5 μm; Column temperature: 40 DEG C; Moving phase: methanol/water-70/30; Flow velocity: 1ml/min; Wavelength: 254nm; Sample size: 20 μ l) detect, calculate the concentration of each time point and draw dissolution rate chart (accompanying drawing 16).
Dissolution rate in vitro is tested: the ultrafine powder 30mg taking Etoricoxib raw material and embodiment 36 preparation, be added in the distilled water 900ml of 0.3%SDS, with the test of RC-6 type digestion instrument under constant temperature 22 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, detect in 235nm place (doing with dissolve medium blank) with UV detector (TU-1901), calculate the concentration of each time point and draw dissolution rate chart (accompanying drawing 17).
Claims (6)
1. a ultrafine powder for cox 2 inhibitor, is characterized in that: the one dimension of described ultrafine powder or two-dimensional are 1nm ~ 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.
2. cox 2 inhibitor ultrafine powder according to claim 1, it is characterized in that: described cox 2 inhibitor includes but not limited to celecoxib, rofecoxib, valdecoxib, Etoricoxib and Parecoxib, and there is the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
3. cox 2 inhibitor ultrafine powder according to claim 2, it is characterized in that: described cox 2 inhibitor is celecoxib, the one dimension of described ultrafine powder or two-dimensional are not more than 4 μm/3 μm/2 μm/1 μm/900nm/800nm/700nm/600nm/500nm.
4. prepare a method for cox 2 inhibitor ultrafine powder, its step is as follows:
(1) prepare a kind of homogeneous phase solution containing cox 2 inhibitor, wherein the weightmeasurement ratio (w/v, g/mL) of cox 2 inhibitor 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 cox 2 inhibitor crystal;
(3) through operations such as solid collection, washing, dryings, obtain cox 2 inhibitor ultrafine powder, 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.
5. the preparation method of cox 2 inhibitor ultrafine powder according to claim 4, it is characterized in that: described cox 2 inhibitor includes but not limited to celecoxib, rofecoxib, valdecoxib, Etoricoxib and Parecoxib, and there is the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
6. the purposes of any one of claims 1 to 3 cox 2 inhibitor ultrafine powder in pharmaceutical compositions.
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|---|---|---|---|---|
| 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 |
-
2014
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Non-Patent Citations (1)
| Title |
|---|
| 李战军，等: "超声波法制备唑嘧璜草胺纳米粉体", 《声学技术》 * |
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|---|---|---|---|---|
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Application publication date: 20160203 |