CN105198747A - Non-steroidal anti-inflammatory drug ultra-fine powder and preparation method thereof - Google Patents
Non-steroidal anti-inflammatory drug ultra-fine powder and preparation method thereof Download PDFInfo
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- CN105198747A CN105198747A CN201410257660.8A CN201410257660A CN105198747A CN 105198747 A CN105198747 A CN 105198747A CN 201410257660 A CN201410257660 A CN 201410257660A CN 105198747 A CN105198747 A CN 105198747A
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Abstract
The invention relates to non-steroidal anti-inflammatory drug ultra-fine powder and a preparation method thereof. A non-steroidal anti-inflammatory drug has the functions of resisting inflammations and rheumatism, relieving pain, bringing down a fever and resisting blood coagulation and is widely used for alleviating osteoarthritis, rheumatoid arthritis, various fevers and various painful symptoms in clinic. The method for preparing the non-steroidal anti-inflammatory drug ultra-fine powder comprises the steps that non-steroidal anti-inflammatory drug crystals are rapidly obtained by exerting ultrasonic waves with the frequency ranging from 10 kHz to 500 kHz, the power ranging from 1 mW to 5000 W and the sound intensity ranging from 0.1 mW/cm<2> to 500 w/cm<2> into a homogeneous solution containing the non-steroidal anti-inflammatory drug, and then the non-steroidal anti-inflammatory drug ultra-fine powder is directly obtained after normal operations such as solid collection, washing and drying are conducted. The non-steroidal anti-inflammatory drug ultra-fine powder is free of substrate materials and has the advantages that the drug-loading rate is high, the dissolution velocity is high, higher bioavailability is easy to achieve, and the stability and the safety are achieved, so that the requirements for improving the bioavailability of the drug, decreasing the drug dosage and reducing adverse reactions are met, and a wide application prospect in clinic is achieved.
Description
Technical field
The present invention relates to medical art, particularly a kind of ultrafine powder and preparation method thereof of NSAID (non-steroidal anti-inflammatory drug).
Background technology
NSAID (non-steroidal anti-inflammatory drug) is different from glucocorticoid steroids antiphlogiston (SAIDS) with anti-inflammatory mechanisms due to its chemical structure, therefore is called non-steroidal anti-inflammatory drugs (NSAIDs); There is anti-inflammatory, antipyretic, analgesic activity.Except formulations such as conventional oral, injections, also widely use in the local applications such as eye.Current NSAIDs is that the whole world uses one of maximum medicament categories, and there are 3,000 ten thousand people in the whole world in use about every day.
Acetylsalicylic acid, is slightly soluble in water, is soluble in ethanol.It is one of three large classical medicines in medical history, is most widely used antipyretic, analgesic anti-inflammatory drug clinically.If acetylsalicylic acid dosage is excessive, in blood, free drug concentration can sharply rise, and easily causes serious untoward reaction, even poisoning.
Diclofenac sodium, Giba-Geigy company of Switzerland in 1979 Initial Public Offering.The feature of diclofenac sodium is micro dissolution in water, dissolves, is slightly soluble in acetone, be insoluble to chloroform, ether in methyl alcohol, ethanol; Oral plasma half-life is short, has very strong hormesis under one's belt to gastric mucosa, greatly limit the clinical application of this medicine.
Indomethacin is white or micro-yellow crystalline powder, is soluble in acetone, is slightly dissolved in ethanol, chloroform, ether, water-soluble hardly.Ordinary preparation is as low in the bioavailability such as tablet, capsule, and easily causes the untoward reactions such as gastrointestinal lesions, hepatic injury, renal impairment and central nervous diseases.
One of on Ibuprofen BP/EP Shi Shi China's antipyretic and analgesic market four large pillar products, are recorded in China's " national basic medical Drug catalogue ".Ibuprofen BP/EP is a kind of white crystalline powder, water insoluble, is soluble in dehydrated alcohol, acetone, trichloromethane and ether; Usually there is absorption slow with onset, bioavailability is lower, and dosage used is excessive, easily causes the shortcomings such as untoward reaction.
Piroxicam is enolic acid derivative, is white or yellowish green crystalline powder.Piroxicam is easily molten in chloroform, slightly molten in acetone, slightly soluble in ethanol or ether, almost insoluble in water, dissolves in acid, slightly molten in alkali.
NSAIDs due to poorly water-soluble, absorb and bioavailability low, in prolonged application, easily there is the untoward reactions such as gi tract, blood system and kidney, its clinical application be restricted.
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.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.
US Patent No. 5843863 describes a kind of method of Ibuprofen BP/EP crystallization, object is to prepare a kind of Ibuprofen BP/EP crystallization to be had mean length and is greater than about 75 μm, length is greater than about 4:1 ~ about 5:1 with width ratio, preferred particle length about 100 ~ 200 μm, preferred length is from about 4.1:1 ~ 5:1 with the ratio of width.
Yan Junfeng in 2010 in " the micronized research of Ibuprofen BP/EP " literary composition, describe a kind of anti-solvent recrystallization method and prepare Ibuprofen BP/EP micro mist, first medicine is dissolved in the good solvent of a kind of solvability, then under condition that is ultrasonic or that stir, the poor solvent of another kind of medicine is added in this drug solution, medicine crystallization from mixing solutions obtains micro mist, and the grain diameter of gained is less.
The people such as Chen Xingquan in 2002 " using supercritical fluid quick expansion legal system is for material micro mist: I. the preparation of Ibuprofen BP/EP micro mist " in utilize using supercritical fluid quick expansion legal system for Ibuprofen BP/EP micro mist.Dissolved by Ibuprofen BP/EP and form solution, then by nozzle, within the extremely short time, rapid expansion is to vacuum, and solute is separated out because of supersaturation and obtained median size is 4 ~ 26 μm of particles.
The people such as Foster just mentioned in 2003 in " Applicationofdensegastechniquesfortheproductionoffinepar ticles ", use supercritical fluid technology to prepare Ibuprofen BP/EP micro mist, it is spherical that particle changes into as shown in Figure 1 from biconical.
The people such as Zhou Minyi are in 2003 in " recrystallization micronization improve ibuprofen dissolution " literary composition, and the micro mist of Ibuprofen BP/EP that utilized solvent Anti recrystallization method to prepare, obtains the cubes particle close to 0 dimension.
Chen Xi in 2009 in " research of Ibuprofen BP/EP micronization and solublization thereof ", have employed physical grinding, recrystallization, ultrasonic emulsification recrystallization method three kinds of methods prepare the research of Ibuprofen BP/EP micro mist and compare, final employing micropowder silica gel is as sorbent material, Poloxamer188 is stablizer, by ultrasonic emulsification solvent adsorption legal system for Ibuprofen BP/EP silica gel adsorption micro mist (Ibuprofen BP/EP G-micro mist).
Chinese patent CN103536926A describes a kind of Freeze Drying Technique and prepares oligochitosan-ibuprofen nanoparticle, preparation be the nanometer formulation of Ibuprofen BP/EP.It utilizes the hydrophobicity of Ibuprofen BP/EP and the wetting ability coupling of oligochitosan, and then obtain nanoparticle by centrifugal lyophilize, as Fig. 2, electric Microscopic observation shows rounded nanoparticle.
The people such as Wang Jianzhu adopt emulsion-solvent evaporation method in 2003 in " emulsification-evaporation method prepares acetylsalicylic acid ethyl cellulose micro-capsule " literary composition, ethyl cellulose are dissolved in ethanol, and as disperse phase, then stirring adds acetylsalicylic acid.Appropriate Span-80 is dispersed in whiteruss and forms external phase.By above-mentioned two kinds of liquid mix and blend in propeller stirrer, form thin dripping 40 DEG C of stirred in water bath emulsifications, the volatilization micro-capsule of organic solvent is cured, and forms spherical solid micro-capsule, makes the medicament-carried nano preparation of aspirin tablet.
The people such as ZhenHuang in 2005 in " Formationofultrafineaspirinparticlesthroughrapidexpansio nofsupercriticalsolutions (RESS) ", adopt using supercritical fluid quick expansion legal system for ultra-fine aspirin granule, the main spheroidal particle forming 0 dimension.
Wu Ying in 2009 in " micronization and solid dispersion technology are to the research of indomethacin dissolving out capability promoter action ", utilize the principle of recrystallization, adopt pH conversion reaction crystallization process, ultrasonic emulsification solvent diffusion method and disrupt red cell instrument method etc. to prepare the micro mist of indomethacin, compare research.
The people such as Kim are in 2000 at " Microcrystallizationofindome-thacinusingapH-shiftmethod " in literary composition, and the indomethacin micro mist using strong acid and strong base pH transformation approach to prepare, obtains median size at the particle of 10 μm.
Chinese patent CN102018674A describes a kind of preparation method possessing the diclofenac sodium hydrogel microsphere of PH susceptibility, and forming the inclusion compound containing diclofenac sodium by ionic bonding, gelation, is a kind of nanometer formulation.
What the diclofenac submicron capsule (Zorvolex) that the U.S. goes on the market adopted is iCeutica company proprietary SoluMatrix fine particle technology, it is actual is a kind of dry mill process: be about to the solid pharmaceutical raw material that need dry grind and mixed milling type grinds matrix, in common input shredder, through mechanical stirring, the grinding of enough time, prepare the fine particle (0 dimension particle) of medicine.
The preparation method of above-mentioned ultrafine powder comprises medium milling, supercritical fluid technology, anti-solvent recrystallization, solvent diffusion, acid-base reaction precipitation, freeze-drying method.In addition micronized preparation method also has comminution by gas stream, high-pressure homogeneous, solvent evaporation, spraying dry etc.
Media milling process is the technology be most widely used in the preparation of current ultrafine powder, has device and the simple feature of preparation process; But single batch of production cycle is long, production efficiency is not high, and particle encounter and mechanical movement discharge amount of heat in process of lapping, easily causes the rotten of low melting point substance; The simultaneously corrosion of dielectric material in process of lapping, come off generation mechanical impurity, may cause the pollution cannot removed medicine.
Stablize although high pressure homogenization has technique circulation ratio, be easy to the features such as amplification, equipment is complicated, only have less medicine to be suitable for 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, energy consumption height cause production cost to remain high.
Comminution by gas stream makes crushing material by micronizer mill, and do not need medium, not easily produce pollution, throughput is large; But this method is applicable to the medicine with certain degree of hardness, and namely slight change easily causes local disorders in high velocity air crushing process, and produce macrobead, technology stability is poor.
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, reaction precipitation, due to the uncontrollability of crystal growth, cause product size difference large, and general all with high-speed stirring or high speed centrifugation or high-pressure homogeneous, spraying dry and lyophilize be then as drying mode collect dry particle usually need with additive method coupling; These method suitability for industrialized production equipment not easily configure above, and operational hazards coefficient is large, and cost is high.
The various defects of above-mentioned ultrafine powder preparation method are the few principal elements of the medicament categories that causes current NSAID (non-steroidal anti-inflammatory drug) to be gone on the market with super-fine powder form and quantity.
Summary of the invention
For the deficiency in prior art, the invention provides a kind of NSAID (non-steroidal anti-inflammatory drug) 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 NSAID (non-steroidal anti-inflammatory drug), 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 NSAID (non-steroidal anti-inflammatory drug) crystal, then through routine operations such as solid collection, washing, drying, directly acquisition NSAID (non-steroidal anti-inflammatory drug) 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 NSAID (non-steroidal anti-inflammatory drug) and solvent is: 1:1 ~ 1:300.
NSAID (non-steroidal anti-inflammatory drug) 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.
NSAID (non-steroidal anti-inflammatory drug) 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.
NSAID (non-steroidal anti-inflammatory drug) 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, the ratio of its maximum dimension and smallest dimension size is for being not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1.
In the present invention, NSAID (non-steroidal anti-inflammatory drug) comprises following classification: acetylsalicylic acid salt, comprises acetylsalicylic acid; Non-acetylsalicyclic Barbiturates, comprises magnesium salicylate, sodium salicylate, choline salicylate magnesium, sasapyrin; Non-salicylic acid salt, comprise Ibuprofen BP/EP, indomethacin (INDOMETHACIN), fluorine than Ibuprofen BP/EP, Naproxen Base, nabumetone, Phenylbutazone, paracetamol, Fen Luofen, Ketoprofen BP 93, diclofenac sodium, sulindac, tolmetin, and there is isomer or the derivative of physiologically active.
Especially, when NSAID (non-steroidal anti-inflammatory drug) of the present invention is indomethacin, the one dimension of its ultrafine powder or two-dimensional are not more than 10 μm/9 μm/8 μm/7 μm/6 μm/5 μm/4 μm/3 μm/2 μm/1 μm.
The NSAID (non-steroidal anti-inflammatory drug) 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, patch, emulsion, aerosol etc.
NSAID (non-steroidal anti-inflammatory drug) 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 NSAID (non-steroidal anti-inflammatory drug) 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 Ibuprofen BP/EP micro mist 10 μm of Electronic Speculum figure prepared with supercritical fluid technology;
Fig. 2 prepares ibuprofen nanoparticle 250nm Electronic Speculum figure for utilizing Freeze Drying Technique;
Fig. 3 is acetylsalicylic acid raw material microscope figure (× 100);
Fig. 4 is the microscope figure (× 1000) of embodiment 1 ultrafine powder;
Fig. 5 is 5 μm of Electronic Speculum figure of embodiment 9 ultrafine powder;
Fig. 6 is 50 μm of Electronic Speculum figure of embodiment 9 ultrafine powder;
Fig. 7 is the microscope figure (× 1000) of embodiment 16 ultrafine powder;
Fig. 8 is 5 μm of Electronic Speculum figure of embodiment 42 ultrafine powder;
Fig. 9 is 50 μm of Electronic Speculum figure of embodiment 42 ultrafine powder;
Figure 10 is the dissolution rate graphic representation of embodiment 42 ultrafine powder and diclofenac sodium raw materials.
Embodiment
Further technical scheme of the present invention is specifically described below by specific embodiment.Should be appreciated that, the following examples just as illustrating, and do not limit the scope of the invention, and the apparent change made according to the present invention of those skilled in the art simultaneously and modification are also contained within the scope of the invention.
Embodiment 1
Acetylsalicylic acid raw material 10g, add 40ml methyl alcohol, heating for dissolving, room temperature, 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder (electron microscope XSP-BM-2C, accompanying drawing 4) is obtained after collection, washing, drying.
Embodiment 2
Acetylsalicylic acid raw material 100g, adds 397ml methyl alcohol, heating for dissolving, and add water 81ml, and ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 3
Diclofenac sodium raw materials 10g, adds 50ml methyl alcohol, heating for dissolving, and add water 10ml, and ice bath is lowered the temperature, and 20kHz, 200W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 4
Indomethacin raw material 10g, adds 30ml methyl alcohol, heating for dissolving, and add water 25ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 5
Acetylsalicylic acid raw material 100g, adds 380ml ethanol, heating for dissolving, and ice bath is lowered the temperature, and 60kHz, 200W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 6
Ibuprofen BP/EP raw material 10g, adds 55ml methyl alcohol, heating for dissolving, and add water 64ml, room temperature, and 20kHz, 350W are ultrasonic, obtains white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 7
Piroxicam raw material 20g, adds 40ml methyl alcohol, heating for dissolving, and add water 70ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 8
Acetylsalicylic acid raw material 10g, adds 85ml methyl alcohol: water (62%:38%), heating for dissolving, and ice bath is lowered the temperature, and 20kHz, 100W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 9
Diclofenac sodium raw materials 10g, adds 78ml methyl alcohol: water (57%:43%), heating for dissolving, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 5,6) is obtained after collection, washing, drying.
Embodiment 10
Ibuprofen BP/EP raw material 50g, adds 405ml methyl alcohol: water (32%:68%), heating for dissolving, and ice bath is lowered the temperature, and 30kHz, 350W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 11
Piroxicam raw material 10g, adds 30ml methyl alcohol, heating for dissolving, first adds ethyl acetate 2ml, and ice bath is lowered the temperature, and 20kHz, 300W are ultrasonic, and continue to add ethyl acetate, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 12
Acetylsalicylic acid raw material 10g, adds 40ml methyl alcohol, heating for dissolving, first adds ethyl acetate 2ml, and ice bath is lowered the temperature, and 10kHz, 250W are ultrasonic, and continue to add ethyl acetate, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 13
Diclofenac sodium raw materials 10g, adds 50ml methyl alcohol, heating for dissolving, and first add water 2ml, and ice bath is lowered the temperature, and 50kHz, 150W are ultrasonic, and continue to add water, and obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 14
Ibuprofen BP/EP raw material 20g, adds 106ml methyl alcohol, heating for dissolving, adds water, and to producing muddiness, add methyl alcohol to dissolving, then add water, move in circles, add methyl alcohol 108ml altogether, water 217ml, ice bath is lowered the temperature, and 10kHz, 500W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 15
Indomethacin raw material 100g, adds 300ml methyl alcohol, heating for dissolving, adds sherwood oil, to producing muddiness, add methyl alcohol to dissolving, then add sherwood oil, move in circles, add methyl alcohol 312ml altogether, sherwood oil 896ml, ice bath is lowered the temperature, and 20kHz, 1000W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 16
Acetylsalicylic acid raw material 10g, adds 36ml ethanol, heating for dissolving, and add water 20ml, room temperature, and 40kHz, 50W are ultrasonic, obtains white crystal; Ultrafine powder (electron microscope XSP-BM-2C, accompanying drawing 7) is obtained after collection, washing, drying.
Embodiment 17
Diclofenac sodium raw materials 10g, adds 37ml ethanol, heating for dissolving, and add water 15ml, and ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 18
Piroxicam raw material 10g, adds 35ml acetic acid, heating for dissolving, and ice bath is lowered the temperature, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 19
Magnesium salicylate raw material 10g, adds 40ml ethanol, heating for dissolving, and add water 10ml, and ice bath is lowered the temperature, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 20
Indomethacin raw material 20g, adds 65ml ethanol, heating for dissolving, and add water 20ml, and ice bath is lowered the temperature, and 30kHz, 300W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 21
Diclofenac sodium raw materials 50g, adds 186ml ethanol, heating for dissolving, adds water, and to producing muddiness, add ethanol to dissolving, then add water, move in circles, add ethanol 190ml altogether, water 244ml, ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 22
Acetylsalicylic acid raw material 20g, adds 50ml acetonitrile, heating for dissolving, and add water 23ml, and ice bath is lowered the temperature, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 23
Ibuprofen BP/EP raw material 10g, adds 50ml acetonitrile, heating for dissolving, and add water 11ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 24
Piroxicam raw material 10g, adds 47ml acetonitrile, heating for dissolving, and add water 29ml, and ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 25
Indomethacin raw material 5g, adds 42ml acetonitrile, heating for dissolving, and add water 30ml, and ice bath is lowered the temperature, and 40kHz, 200W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 26
Diclofenac sodium raw materials 10g, adds 65ml acetonitrile: water (55%:45%), heating for dissolving, and 40kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 27
Acetylsalicylic acid raw material 10g, adds 83ml acetonitrile: water (48%:52%), heating for dissolving, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 28
Ibuprofen BP/EP raw material 10g, adds 45ml Virahol, heating for dissolving, and first add water 3ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, and continue to add water, and obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 29
Piroxicam raw material 10g, adds 35ml acetic acid, heating for dissolving, and add water 13ml, and ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 30
Piroxicam raw material 10g, adds 70ml Virahol: water (40%:60%), heating for dissolving, and ice bath is lowered the temperature, and 20kHz, 100W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 31
Diclofenac sodium raw materials 10g, adds 42ml Virahol, heating for dissolving, and first add water 5ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, and continue to add water, and obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 32
Acetylsalicylic acid raw material 30g, add 94ml Virahol, heating for dissolving, room temperature, 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 33
Acetylsalicylic acid raw material 10g, adds 38ml acetone, heating for dissolving, and ice bath is lowered the temperature, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 34
Paracetamol raw material 5g, adds 30ml acetone, heating for dissolving, and add benzene 15ml, 60kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 35
Indomethacin raw material 10g, adds 44ml acetone, heating for dissolving, and add water 50ml, room temperature, and 40kHz, 150W are ultrasonic, obtains white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 36
Diclofenac sodium raw materials 10g, adds 29ml acetone, heating for dissolving, and add water 20ml, and ice bath is lowered the temperature, and 20kHz, 350W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 37
Piroxicam raw material 20g, adds 67ml acetone, heating for dissolving, and add water 84ml, and ice bath is lowered the temperature, and 80kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 38
Indomethacin raw material 400g, adds 3600ml methyl-sulphoxide, heating for dissolving, and add water 1815ml, 20kHz, 4000W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 39
Piroxicam raw material 10g, adds 33ml tetrahydrofuran (THF), heating for dissolving, and add water 51ml, and ice bath is lowered the temperature, and 20kHz, 350W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 40
Diclofenac sodium raw materials 10g, adds 39ml ethanol, heating for dissolving, first adds chloroform 2ml, and ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, and continue to add chloroform, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 41
Paracetamol raw material 5g, adds 26mlNMP, heating for dissolving, and add water 47ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 42
Diclofenac sodium raw materials 10g, adds 110ml water, heating for dissolving, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 8,9) is obtained after collection, washing, drying.
Embodiment 43
Acetylsalicylic acid raw material 10g, add 80ml water, heating for dissolving, 50kHz, 50W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 44
Indomethacin raw material 10g, adds 135ml water, heating for dissolving, and ice bath is lowered the temperature, and 20kHz, 100W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 45
Acetylsalicylic acid raw material 10g, adds 36ml acetone, heating for dissolving, adds sherwood oil 130ml, and ice bath is lowered the temperature, and 20kHz, 200W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 46
Diclofenac sodium raw materials 10g, adds 60ml acetone, heating for dissolving, adds sherwood oil 170ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 47
Ibuprofen BP/EP raw material 20g, adds 110ml acetone, heating for dissolving, and add sherwood oil 370ml, 10kHz, 650W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 48
Piroxicam raw material 10g, adds 40ml acetone, heating for dissolving, adds sherwood oil 143ml, and ice bath is lowered the temperature, and 40kHz, 400W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 49
Paracetamol raw material 10g, adds 50ml acetone, heating for dissolving, adds sherwood oil 110ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 50
Phenylbutazone raw material 10g, adds 40ml acetone, heating for dissolving, and add sherwood oil 290ml, room temperature, 10kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 51
Ibuprofen BP/EP raw material 5g, adds 200ml acetone: sherwood oil (43%:57%), heating for dissolving, and ice bath is lowered the temperature, and 70kHz, 100W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 52
Diclofenac sodium raw materials 20g, adds 370ml acetone: sherwood oil (60%:40%), heating for dissolving, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 53
Acetylsalicylic acid raw material 20g, add 69ml ethyl acetate, heating for dissolving, 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 54
Paracetamol raw material 20g, adds 100ml ethanol, heating for dissolving, adds benzene 150ml, and ice bath is lowered the temperature, and 20kHz, 200W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 55
Paracetamol raw material 10g, adds 50ml ethanol, heating for dissolving, adds sherwood oil 360ml, and with cooling, 40kHz, 300W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 56
Acetylsalicylic acid raw material 100g, adds 400ml ethanol, heating for dissolving, adds sherwood oil 2451ml, and ice bath is lowered the temperature, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 57
Ibuprofen BP/EP raw material 10g, adds 40ml ethanol, heating for dissolving, adds sherwood oil 350ml, and ice bath is lowered the temperature, and 40kHz, 300W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 58
Indomethacin raw material 10g, adds 45ml ethyl acetate, heating for dissolving, adds sherwood oil 412ml, and ice bath is lowered the temperature, and 40kHz, 300W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 59
Ibuprofen BP/EP raw material 10g, adds 60ml methyl acetate, heating for dissolving, adds sherwood oil 560ml, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 60
Acetylsalicylic acid raw material 10g, adds 45ml ethyl acetate, heating for dissolving, and add sherwood oil 440ml, 70kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 61
Acetylsalicylic acid raw material 10g, adds 500ml methyl acetate: sherwood oil (13%:87%), heating for dissolving, and 40kHz, 450W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 62
Diclofenac sodium raw materials 20g, adds 970ml ethyl acetate: sherwood oil (40%:60%), heating for dissolving, and ice bath is lowered the temperature, and obtains white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 63
Diclofenac sodium raw materials 20g, adds 59ml ethyl acetate, and reflux is dissolved, and first adds sherwood oil 20ml, cooling, and 60kHz, 150W are ultrasonic, and continue to add sherwood oil, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 64
Acetylsalicylic acid raw material 10g, adds the ethyl acetate of 70ml, heating for dissolving, adds sherwood oil, to producing muddiness, add ethyl acetate to dissolving, then add sherwood oil, move in circles, add ethyl acetate 77ml altogether, sherwood oil 590ml, ice bath is lowered the temperature, and 20kHz, 300W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 65
Diclofenac sodium raw materials 10g, adds 50ml Virahol, heating for dissolving, and add sherwood oil 244ml, room temperature, 20kHz, 200W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 66
Phenylbutazone raw material 10g, adds 50ml chloroform, heating for dissolving, and add sherwood oil 260ml under equality of temperature, room temperature, 30kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 67
Paracetamol raw material 10g, adds 323ml Virahol: sherwood oil (22%:78%), heating for dissolving, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 68
Diclofenac sodium raw materials 10g, adds 221ml ethyl acetate: ether (32%:68%), heating for dissolving, and ice bath is lowered the temperature, and 30kHz, 400W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 69
Acetylsalicylic acid raw material 20g, add the ethyl acetate of 88ml containing 0.1% soybean oil, heating for dissolving, add the sherwood oil 472ml containing 0.1% soybean oil, 20kHz, 350W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 70
Diclofenac sodium raw materials 10g, add the methyl acetate of 58ml containing 0.8% Viscotrol C, heating for dissolving, adds containing 0.8% Viscotrol C sherwood oil 340ml, and ice bath is lowered the temperature, and 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 71
Piroxicam raw material 10g, add the acetone of 430ml containing 1.5% Viscotrol C: sherwood oil (33%:67%), heating for dissolving, ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 72
Phenylbutazone raw material 10g, add the acetone of 70ml containing 0.5% medium chain triglyceride, heating for dissolving, add sherwood oil 160ml, 20kHz, 100W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 73
Ibuprofen BP/EP raw material 20g, add the ethanol of 124ml containing 0.2%PEG2000, heating for dissolving, adds the water 55ml containing 0.2%PEG2000, and ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 74
Phenylbutazone raw material 10g, add the ethanol of 52ml containing 2.0% ethyl cellulose, heating for dissolving, add the water 40ml containing 2.0% ethyl cellulose, 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 75
Paracetamol raw material 10g, add the ethanol of 62ml containing 0.02% polyglycerol monooleate, heating for dissolving, adds the benzene 30ml containing 0.02% polyglycerol monooleate, and ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 76
Diclofenac sodium raw materials 10g, add the acetone of 40ml containing 0.5%PEG400, heating for dissolving, add the water 10ml containing 0.5%PEG400,20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 77
Ibuprofen BP/EP raw material 10g, add the methyl-sulphoxide of 50ml containing 0.2% soybean oil, heating for dissolving, add the ethyl acetate 410ml containing 0.2% soybean oil, 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 78
Acetylsalicylic acid raw material 15g, add the water of 120ml containing 0.5% sodium lauryl sulphate, heating for dissolving, ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 79
Diclofenac sodium raw materials 10g, add the water of 100ml containing 0.2% methylcellulose gum, heating for dissolving, ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 80
Diclofenac sodium raw materials 10g, add the water of 100ml containing 0.1% benzalkonium chloride, heating for dissolving, ice bath is lowered the temperature, and 30kHz, 100W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 81
Diclofenac sodium raw materials 10g, add the water of 122ml containing 0.2% poloxamer188, heating for dissolving, room temperature, 40kHz, 250W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 82
Acetylsalicylic acid raw material 10g, add the methyl alcohol of 75ml containing 0.5% glycerine: water (62%:38%), heating for dissolving, 40kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Embodiment 83
Diclofenac sodium raw materials 10g, add the acetone of 83ml containing 1.1% PLURONICS F87: water (57%:43%), heating for dissolving, ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ultrafine powder is obtained after collection, washing, drying.
Dissolution rate in vitro: the product 80mg taking diclofenac sodium raw materials and embodiment 42 respectively, be placed in containing the stripping rotor of 900mlPH4.0 phosphate buffered saline buffer as dissolve medium, under constant temperature 22 DEG C, 50rpm condition, test with RC-6 type digestion instrument, respectively 5,10,15,30,45,60,90,120min sampling, every sub-sampling 5ml, supplements the fresh equality of temperature medium of 5ml simultaneously.Sample liquid through 0.22 μm of membrane filtration, filtrate is irradiated (if do not observe scattering, then this solution is not containing nano particle) with infrared laser telltale.After filtrate is diluted to suitable concn with blank medium, detects (using dissolution solvent as blank) with TU-1901 type ultraviolet spectrophotometer in 276nm place, calculate each time point concentration and draw dissolution rate chart (accompanying drawing 10).
Claims (6)
1. a ultrafine powder for NSAID (non-steroidal anti-inflammatory drug), is characterized in that: the one dimension of described ultrafine powder or two-dimensional are 1nm ~ 30 μm, and the ratio of maximum dimension and smallest dimension size is for being not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1.
2. NSAID (non-steroidal anti-inflammatory drug) ultrafine powder according to claim 1, is characterized in that: described NSAID (non-steroidal anti-inflammatory drug) comprises following classification: acetylsalicylic acid salt, comprises acetylsalicylic acid; Non-acetylsalicyclic Barbiturates, comprises magnesium salicylate, sodium salicylate, choline salicylate magnesium, sasapyrin; Non-salicylic acid salt, comprise Ibuprofen BP/EP, indomethacin (INDOMETHACIN), fluorine than Ibuprofen BP/EP, Naproxen Base, nabumetone, Phenylbutazone, paracetamol, Fen Luofen, Ketoprofen BP 93, diclofenac sodium, sulindac, tolmetin, and there is isomer or the derivative of physiologically active.
3. NSAID (non-steroidal anti-inflammatory drug) ultrafine powder according to claim 2, it is characterized in that: described NSAID (non-steroidal anti-inflammatory drug) is indomethacin, the one dimension of described ultrafine powder or two-dimensional are not more than 10 μm/9 μm/8 μm/7 μm/6 μm/5 μm/4 μm/3 μm/2 μm/1 μm.
4. prepare a method for NSAID (non-steroidal anti-inflammatory drug) ultrafine powder, its step is as follows:
(1) prepare a kind of homogeneous phase solution containing NSAID (non-steroidal anti-inflammatory drug), wherein the weightmeasurement ratio (w/v, g/mL) of NSAID (non-steroidal anti-inflammatory drug) 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 NSAID (non-steroidal anti-inflammatory drug) crystal;
(3) through operations such as solid collection, washing, dryings, obtain NSAID (non-steroidal anti-inflammatory drug) ultrafine powder, its one dimension or two-dimensional are less than 30 μm, and the ratio of maximum dimension and smallest dimension size is for being not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1.
5. the preparation method of NSAID (non-steroidal anti-inflammatory drug) ultrafine powder according to claim 4, is characterized in that: described NSAID (non-steroidal anti-inflammatory drug) comprises following classification: acetylsalicylic acid salt, comprises acetylsalicylic acid; Non-acetylsalicyclic Barbiturates, comprises magnesium salicylate, sodium salicylate, choline salicylate magnesium, sasapyrin; Non-salicylic acid salt, comprise Ibuprofen BP/EP, indomethacin (INDOMETHACIN), fluorine than Ibuprofen BP/EP, Naproxen Base, nabumetone, Phenylbutazone, paracetamol, Fen Luofen, Ketoprofen BP 93, diclofenac sodium, sulindac, tolmetin, and there is isomer or the derivative of physiologically active.
6. the purposes of any one of claims 1 to 3 NSAID (non-steroidal anti-inflammatory drug) ultrafine powder in pharmaceutical compositions.
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| CN109444054A (en) * | 2018-12-26 | 2019-03-08 | 北京倍肯恒业科技发展股份有限公司 | The detection card and method of piroxicam content in a kind of quick detection dispelling wind and eliminating dampness Chinese medicine |
| CN118370720A (en) * | 2024-06-21 | 2024-07-23 | 中润药业有限公司 | Dexketoprofen tromethamine injection and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109444054A (en) * | 2018-12-26 | 2019-03-08 | 北京倍肯恒业科技发展股份有限公司 | The detection card and method of piroxicam content in a kind of quick detection dispelling wind and eliminating dampness Chinese medicine |
| CN118370720A (en) * | 2024-06-21 | 2024-07-23 | 中润药业有限公司 | Dexketoprofen tromethamine injection and preparation method thereof |
| CN118370720B (en) * | 2024-06-21 | 2024-09-17 | 中润药业有限公司 | Dexketoprofen tromethamine injection and preparation method thereof |
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