CN105198886A - Ultra-micro powder of nucleoside antiviral drugs and preparation method thereof - Google Patents
Ultra-micro powder of nucleoside antiviral drugs and preparation method thereof Download PDFInfo
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- CN105198886A CN105198886A CN201410256477.6A CN201410256477A CN105198886A CN 105198886 A CN105198886 A CN 105198886A CN 201410256477 A CN201410256477 A CN 201410256477A CN 105198886 A CN105198886 A CN 105198886A
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Abstract
The invention relates to ultra-micro powder of nucleotide antiviral drugs and a preparation method thereof. The nucleotide antiviral drugs are main treatment drugs for virus diseases, but most drugs are poor in water solubility, and internal absorption is severely affected. The preparation method of the ultra-micro powder of the nucleotide antiviral drugs includes the steps that in a homogeneous solution containing the nucleotide antiviral drugs, ultrasonic waves are exerted to rapidly obtain nucleotide antiviral drug crystals, and then through solid collecting, rinsing, drying and other normal operations, the ultra-micro powder of the nucleotide antiviral drugs is directly obtained, wherein the frequency of the ultrasonic waves is 10 kHz-500 kHz, the power of the ultrasonic waves is 1 mW-5000 W, and the sound intensity of the ultrasonic waves is 0.1 mW/cm<2>-500 W/cm<2>. The prepared ultra-micro powder improves the bioavailability and solubility of the drugs, can improve drug absorption and is wider in application range.
Description
Technical field
The present invention relates to medical art, particularly a kind of ultrafine powder and preparation method thereof of uncleosides as antiviral agents.
Background technology
Viral infectious diseases is the transmissible disease of serious harm people ' s health in recent years, and according to incompletely statistics, in human body communicable disease, virus disease occupies about 60 ~ 65%.The common disease caused by virus has influenza, viral hepatitis, acquired immune deficiency syndrome (AIDS), bleb, measles, poliomyelitis etc.Therefore Devoting Major Efforts To Developing develops antiviral is safely and effectively a difficult task, is also necessary very much simultaneously.
Nucleoside medicine is as the curative effect medicine of viral diseases, extensively concerned in recent years.Its Main Function mechanism is directed acting in viral DNA reversed transcriptive enzyme or archaeal dna polymerase, mixes in the DNA chain synthesized, stops constantly copying of its DNA, thus suppresses the growth of virus, and then plays antiviral effect.
Ganciclovir is slightly soluble in water, almost insoluble in methyl alcohol, insoluble in methylene dichloride; Slightly molten in hydrochloric acid soln or sodium hydroxide solution.The Major excretion routes of ganciclovir with proto-drug through renal excretion, oral administration biaavailability only 6% ~ 9%.
Tynofovir is hardly through gastrointestinal absorption, and bioavailability is also lower than 10%, and after oral or drug administration by injection, major part is drained with prototype.
Acyclovir is slightly molten in Glacial acetic acid or hot water, slightly soluble in cold water, in ethanol soluble,very slightly, almost insoluble in ether or chloroform, easily molten in dilute alkaline soln, also easily molten in dilute hydrochloric acid, is also soluble in ammonia solution and methyl-sulphoxide.
This kind of medicine is most water-soluble poor, has a strong impact on its body absorption.Poorly water-soluble limits absorption and the bioavailability of existing medicine, past 10 years, water-insoluble active substance nanometer engineering has caused increasing concern, nanocrystal technology is in recent years as a kind of novel preparation technique, solubleness and the bioavailability of medicine can be improved, be not only applicable to slightly water-soluble compound, be applicable to be insoluble in the compound of water and oil simultaneously, thus provide more broad prospect for the exploitation of medicine.
Superfine powder (superfinepowder), also known as ultrafine powder, generally includes micron order (1 ~ 30 μm), submicron order (0.1 ~ 1 μm) and nano level (1 ~ 100nm).At present a strict definition be there is no for ultrafine powder, be referred to as ultrafine powder from the powder of a few nanometer to tens micron.To the definition of nano material can broad sense be interpreted as to have the material that one dimension is in nanoscale scope or is made up of as unit them in three dimensions at least.1. 0 dimension nano material can be divided into: scantling is nanoscale at three-dimensional space according to the concept of dimension; 2. 1 dimension nano material: material has two dimension in space for nanoscale; 3. 2 dimension nano materials: material has one dimension to be nanoscale in space; 4. 3 dimension nano materials: the bulk in three dimensions containing above-mentioned nano material.Conventional ultrafine powder MATERIALS METHODS of preparing has low-temperature airflow pulverizing, ball milling, the mechanical crushing method such as high-pressure homogeneous, and the physico-chemical process such as solvent diffusion, solvent evaporation, supercritical fluid technology, solvent deposition, lyophilize, spraying dry.Zhao Gaiqing etc. are in June, 2006 report in " spray drying technology is in the application prepared in ultra micro and nano-powder and prospect ", under the theoretical basis of mechanical crushing method is based on given stress condition, cause the fracture of particle, fragmentation and intergranular collision etc., produce the ultrafine powder (three-dimensional space) of 0 dimension particle; And adopting the physico-chemical processes such as spray drying technology can prepare the spherical powder that quality is homogeneous, repeatability is good, its ultrafine powder produced also belongs to 0 dimension particle.In sum, the ultrafine powder that current published preparation method obtains mostly is 0 dimension particle.
The people such as Rong Xinyu were referred to a kind of method preparing Azythromycin nanocrystal in 2012 in " it is nanocrystalline that media milling process prepares Azythromycin ", i.e. media milling process.Using zirconium white as grinding bead, constantly grinding Azithromycin mix suspension liquid, namely obtains the Azythromycin nanocrystalline (as shown in Figure 1) that median size is 165nm after freeze-drying.Media milling process is simple to operate, is most widely used in current ultrastructurepower technology, but 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, thus cause the pollution of product.
The people such as Liu Yun were referred to the colloidal solution of applying high voltage homogeneous legal system for meloxicam nano-lipid carrier in 2013 in " preparation and characterization of meloxicam nano-lipid carrier ", and the lipid carrier nano particle diameter containing meloxicam obtained after freeze-drying is at 154nm.Although high pressure homogenization method 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.
Comminution by gas stream makes crushing material by micronizer mill, and do not need medium not easily to 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.
The people such as Zhang Qiuju in " preparation technology of baicalin nanometer crystal " literary composition, prepared baicalin nanosuspension by the precipitator method in 2014, and the nano particle diameter of the suspensoid as shown in Figure 2 obtained is at about 280.6nm; Thank to pure as jade people such as grade in " anti-solvent recrystallization method prepares Artemisinin superfine powder " literary composition, by anti-solvent legal system for Artemisinin superfine powder, wherein Artemisinin is dissolved in dehydrated alcohol, under certain stirring velocity, Artemisinin ethanolic soln is fully mixed fast with deionized water, after the drug slurries having a large amount of crystal to separate out instantaneously is spray-dried, obtain the spherical particle of 2 ~ 3um; The people such as AvneshKumari in 2010 in " Developmentofbiodegradablenanoparticlesfordeliveryofquer cetin " literary composition, the quercetin nano carrier that utilized solvent evaporated method to prepare, the nano-carrier particle diameter wherein obtained is at about 130nm.The methods such as the evaporation of anti-solvent recrystallization, solvent diffusion, solvent, reaction precipitation, spraying dry, due to the uncontrollability of crystal growth, cause product size difference large, and it is general all with high-speed stirring or high speed centrifugation or high-pressure homogeneous, suitability for industrialized production equipment not easily configures, operational hazards coefficient is large, and cost is high.
Not about the report preparing uncleosides as antiviral agents ultrafine powder in current published document, and the various defects of above-mentioned ultrafine powder preparation method, be also the principal element causing not having uncleosides as antiviral agents 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 uncleosides as antiviral agents 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 uncleosides as antiviral agents, 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 uncleosides as antiviral agents crystal, then through routine operations such as solid collection, washing, drying, directly acquisition uncleosides as antiviral agents 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 uncleosides as antiviral agents and solvent is: 1:1 ~ 1:300.
Uncleosides as antiviral agents 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.
Uncleosides as antiviral agents 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.
Uncleosides as antiviral agents 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, uncleosides as antiviral agents includes but not limited to acyclovir, ganciclovir, Penciclovir, Famciclovir, valacyclovir, tynofovir, Adefovir, cidofovir, and they have the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
The uncleosides as antiviral agents 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, suspension solution agent etc., also can be used for making other formulations as lozenge, patch, breast (cream) agent, eye drops etc.
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 uncleosides as antiviral agents 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 azithromycin particles electromicroscopic photograph prepared by media milling process;
Fig. 2 prepares baicalin nanoparticle electromicroscopic photograph by the precipitator method;
Fig. 3 is 2 μm of electromicroscopic photographs of embodiment 3 ultrafine powder;
Fig. 4 is 2 μm of electromicroscopic photographs of embodiment 3 ultrafine powder;
Fig. 5 is 50 μm of electromicroscopic photographs of embodiment 3 ultrafine powder;
Fig. 6 is 2 μm of electromicroscopic photographs of embodiment 11 ultrafine powder;
Fig. 7 is 50 μm of electromicroscopic photographs of embodiment 11 ultrafine powder;
Fig. 8 is 1 μm of electromicroscopic photograph of embodiment 18 ultrafine powder;
Fig. 9 is 2 μm of electromicroscopic photographs of embodiment 18 ultrafine powder;
Figure 10 is 50 μm of electromicroscopic photographs of embodiment 18 ultrafine powder;
Figure 11 is 1 μm of electromicroscopic photograph of embodiment 40 ultrafine powder;
Figure 12 is 2 μm of electromicroscopic photographs of embodiment 40 ultrafine powder;
Figure 13 is 50 μm of electromicroscopic photographs of embodiment 40 ultrafine powder;
Figure 14 is the X-ray powder diffraction (PHILIPSX'PertPROX x ray diffractometer x) of tynofovir raw material;
Figure 15 is the X-ray powder diffraction of embodiment 18.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail.Should be appreciated that the restriction of following embodiment not to the technology 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
Ganciclovir 10g, adds 500ml dilute hydrochloric acid, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 2
Ganciclovir 15g, adds 578ml water, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 3
Ganciclovir 20g, adds 802ml water, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 200W are ultrasonic, obtain white crystal; The ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 3,4,5) of ganciclovir one dimension size 200nm ~ 300nm is obtained after collection, washing, drying.
Embodiment 4
Ganciclovir 10g, adds 306ml dilute sodium hydroxide, heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 300W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 5
Ganciclovir 100g, adds 4000ml water, heating for dissolving; Ice bath is lowered the temperature, and 60kHz, 800W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 6
Ganciclovir 10g, adds 400ml water, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 350W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 7
Ganciclovir 10g, adds 400ml water, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 8
Ganciclovir 10g, adds 400ml water, heating for dissolving, adds acetone 21ml under equality of temperature; Ice bath is lowered the temperature, and 40kHz, 100W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 9
Ganciclovir 20g, adds 790ml water, heating for dissolving, adds methyl alcohol 34ml under equality of temperature; Ice bath is lowered the temperature, and 20kHz, 1000W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 10
Ganciclovir 50g, adds 1900ml0.5% lauryl sodium sulfate aqueous solution, heating for dissolving; Ice bath is lowered the temperature, and 50kHz, 500W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 11
Ganciclovir 10g, adds the 402ml0.2% poloxamer aqueous solution, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 300W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 6,7) is obtained after collection, washing, drying.
Embodiment 12
Ganciclovir 10g, adds 400ml1.0% aqueous glycerin solution, heating for dissolving; Be cooled to room temperature, 10kHz, 250W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 13
Ganciclovir 20g, adds 820ml water/Virahol (90/10), heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 14
Ganciclovir 10g, adds 400ml water, heating for dissolving, adds acetone 2ml under equality of temperature; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, and ultrasonic limit, limit drips acetone to starting crystallization, stops dripping, continues ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 15
Ganciclovir 10g, adds 400ml0.4% methylated cellulose aqueous solution, heating for dissolving, adds the methyl alcohol 2ml containing 0.4% methylcellulose gum under equality of temperature; Ice bath is lowered the temperature, and 30kHz, 300W are ultrasonic, and limit ultrasonic limit dropping contains the methyl alcohol of 0.4% methylcellulose gum to starting crystallization, stops dripping, continues ultrasonic, obtain white crystal; Ganciclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 16
For promise Fu Wei 20g, add 46ml methyl alcohol, heating for dissolving; Ice bath is lowered the temperature, and 10kHz, 200W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 17
For promise Fu Wei 100g, add 520ml ethanol, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 400W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 18
For promise Fu Wei 10g, add 400ml water, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 500W are ultrasonic, obtain white crystal; The ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 8,9,10) (X-ray powder diffraction, accompanying drawing 15) of tynofovir one dimension size 100nm ~ 200nm is obtained after collection, washing, drying.
Embodiment 19
For promise Fu Wei 10g, add 50ml acetone, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 20
For promise Fu Wei 5g, add 75ml acetonitrile, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 21
For promise Fu Wei 20g, add 254ml acetic acid, heating for dissolving; Ice bath is lowered the temperature, and 10kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 22
For promise Fu Wei 10g, add 85ml Virahol, heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 300W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 23
For promise Fu Wei 10g, add 25mlN, dinethylformamide, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 24
For promise Fu Wei 50g, add 1540ml ethyl acetate, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 400W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 25
For promise Fu Wei 10g, add 25ml methyl alcohol, heating for dissolving, under equality of temperature, add 5ml water; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 26
For promise Fu Wei 100g, add 497ml acetone, heating for dissolving, under equality of temperature, add 27ml water; Ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 27
For promise Fu Wei 10g, add 50ml ethanol, heating for dissolving, under equality of temperature, add 11ml water; Ice bath is lowered the temperature, and 40kHz, 200W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 28
For promise Fu Wei 10g, add 80ml Virahol, heating for dissolving, under equality of temperature, add 14ml water; Ice bath is lowered the temperature, and 50kHz, 250W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 29
For promise Fu Wei 20g, add 80ml methyl-sulphoxide, heating for dissolving; Ice bath is lowered the temperature, and 10kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 30
For promise Fu Wei 30g, add 223ml tetrahydrofuran (THF), heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 31
For promise Fu Wei 10g, add 78ml tetrahydrofuran (THF)/water (83/17), heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 32
For promise Fu Wei 10g, add 300ml ethyl acetate, heating for dissolving, under equality of temperature, add 32ml sherwood oil; Ice bath is lowered the temperature, and 10kHz, 400W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 33
For promise Fu Wei 20g, add 592ml ethyl acetate, heating for dissolving, under equality of temperature, add 29ml ether; Ice bath is lowered the temperature, and 60kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 34
For promise Fu Wei 100g, add 254ml methyl alcohol, heating for dissolving, under equality of temperature, add 23ml sherwood oil; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 35
For promise Fu Wei 10g, add 50ml acetone, heating for dissolving, under equality of temperature, add 8ml sherwood oil; Ice bath is lowered the temperature, and 30kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 36
For promise Fu Wei 10g, add 80ml Virahol, heating for dissolving, add 35mlN under equality of temperature, dinethylformamide; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 37
For promise Fu Wei 10g, add 44ml methyl-sulphoxide, heating for dissolving, add 12mlN under equality of temperature, dinethylformamide; Ice bath is lowered the temperature, and 20kHz, 200W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 38
For promise Fu Wei 20g, adding 599ml ethyl acetate, heating for dissolving, adding sherwood oil under equality of temperature to producing muddiness, add ethyl acetate to dissolving, then add sherwood oil, move in circles, add ethyl acetate 606ml altogether, sherwood oil 59ml; Ice bath is lowered the temperature, and 70kHz, 250W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 39
For promise Fu Wei 5g, add the ethyl acetate/petroleum ether (88/12) of 167ml containing 0.5% Viscotrol C, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 100W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 40
For promise Fu Wei 10g, add the 404ml0.2% poloxamer aqueous solution, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; The ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 11,12,13) of tynofovir one dimension size 180nm ~ 260nm is obtained after collection, washing, drying.
Embodiment 41
For promise Fu Wei 10g, add 55ml acetone/diethyl ether (87/13), heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 42
For promise Fu Wei 10g, add 400ml0.1% benzalkonium chloride in water, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 200W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 43
For promise Fu Wei 100g, add 4007ml containing the 0.3% polyvidone aqueous solution, heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 250W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 44
For promise Fu Wei 10g, add 400ml1.5% Aqueous Solutions of Polyethylene Glycol, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 45
For promise Fu Wei 20g, add 77ml Virahol, heating for dissolving, under equality of temperature, add DMF 2ml; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, and ultrasonic limit, limit drips DMF to only starting crystallization, stops dripping, continues ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 46
For promise Fu Wei 50g, add the Virahol/sherwood oil (87/13) of 445ml containing 0.8% tween, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 300W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 47
For promise Fu Wei 10g, add the acetonitrile/sherwood oil (92/8) of 102ml containing 0.2% soybean oil, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 100W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 48
For promise Fu Wei 10g, add 90ml isopropanol/water (95/5), heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Tynofovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 49
Acyclovir 10g, adds 450ml water, heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 500W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 50
Acyclovir 10g, adds 55ml acetic acid, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 51
Acyclovir 20g, adds 79ml methyl-sulphoxide, heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 52
Acyclovir 10g, adds 51ml tetrahydrofuran (THF), heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 53
Acyclovir 10g, adds 130ml dilute hydrochloric acid, heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 100W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 54
Acyclovir 10g, adds 450ml water, heating for dissolving, adds 32ml ethanol under equality of temperature; Ice bath is lowered the temperature, and 50kHz, 250W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 55
Acyclovir 10g, adds 40ml methyl-sulphoxide, heating for dissolving, adds 5ml water under equality of temperature; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 56
Acyclovir 20g, adds 877ml water, heating for dissolving, adds 45ml methyl alcohol under equality of temperature; Ice bath is lowered the temperature, and 60kHz, 350W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 57
Acyclovir 10g, adds 40ml methyl-sulphoxide, heating for dissolving, adds 7ml ether under equality of temperature; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 58
Acyclovir 10g, adds 40ml methyl-sulphoxide, heating for dissolving, adds 10ml ethanol under equality of temperature; Ice bath is lowered the temperature, and 20kHz, 200W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 59
Acyclovir 50g, adds 237ml methyl-sulphoxide/methyl alcohol (79/21), heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 60
Acyclovir 20g, adds 80ml methyl-sulphoxide, heating for dissolving, adds 23ml acetone under equality of temperature; Ice bath is lowered the temperature, and 40kHz, 350W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 61
Acyclovir 10g, adds 56ml methyl-sulphoxide/benzene (85/15), heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 100W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 62
Acyclovir 50g, adds 278ml acetic acid, heating for dissolving, adds 35ml benzene under equality of temperature; Ice bath is lowered the temperature, and 40kHz, 300W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 63
Acyclovir 20g, adds 146ml methyl-sulphoxide/methyl alcohol (79/21), heating for dissolving; Ice bath is lowered the temperature, and 30kHz, 250W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 64
Acyclovir 10g, adds 57ml acetic acid, heating for dissolving, adds 13ml chloroform under equality of temperature; Ice bath is lowered the temperature, and 30kHz, 200W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 65
Acyclovir 10g, adds 55ml acetic acid, heating for dissolving, adds 20mlN, dinethylformamide under equality of temperature; Ice bath is lowered the temperature, and 30kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 66
Acyclovir 10g, adds the 450ml0.2% ethyl cellulose aqueous solution, heating for dissolving; Ice bath is lowered the temperature, and 50kHz, 200W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 67
Acyclovir 15g, adds 667ml1.0% lauryl sodium sulfate aqueous solution, heating for dissolving; Ice bath is lowered the temperature, and 80kHz, 500W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 68
Acyclovir 30g, adds the methyl-sulphoxide/acetonitrile (88/12) of 173ml containing 0.5% glycerine, heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 69
Acyclovir 20g, add the methyl-sulphoxide of 88ml containing 1.5% medium chain triglyceride, heating for dissolving, adds the ethyl acetate 21ml containing 1.5% medium chain triglyceride under equality of temperature; Ice bath is lowered the temperature, and 30kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 70
Acyclovir 10g, adds 60ml acetic acid, heating for dissolving, adds Virahol 13ml under equality of temperature; Ice bath is lowered the temperature, and 20kHz, 100W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 71
Acyclovir 10g, add the methyl-sulphoxide/Virahol (75/25) of 82ml containing 0.2% poly-olein, heating for dissolving, ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 72
Acyclovir 50g, adds 245ml methyl-sulphoxide/water (69/31), heating for dissolving; Ice bath is lowered the temperature, and 40kHz, 250W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 73
Acyclovir 100g, adds 890ml water, heating for dissolving, adds acetic acid under equality of temperature, to producing muddiness, adding water to dissolving, then adding acetic acid, moving in circles, add water 899ml altogether, acetic acid 36ml; Ice bath is lowered the temperature, and 20kHz, 250W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Embodiment 74
Acyclovir 10g, adds 100ml acetic acid/DMF (90/10), heating for dissolving; Ice bath is lowered the temperature, and 20kHz, 150W are ultrasonic, obtain white crystal; Acyclovir ultrafine powder is obtained after collection, washing, drying.
Claims (5)
1. the ultrafine powder of a uncleosides as antiviral agents, it is characterized in that: the one dimension of described ultrafine powder or two-dimensional are 1nm ~ 30 μm, maximum dimension is not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1 with the ratio of smallest dimension size.
2. uncleosides as antiviral agents ultrafine powder according to claim 1, it is characterized in that: described uncleosides as antiviral agents includes but not limited to acyclovir, ganciclovir, Penciclovir, Famciclovir, valacyclovir, tynofovir, Adefovir, cidofovir, and they have the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
3. prepare a method for uncleosides as antiviral agents ultrafine powder, its step is as follows:
(1) prepare a kind of homogeneous phase solution containing uncleosides as antiviral agents, wherein the weightmeasurement ratio (w/v, g/mL) of uncleosides as antiviral agents 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 uncleosides as antiviral agents crystal;
(3) through operations such as solid collection, washing, dryings, obtain uncleosides as antiviral agents 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.
4. the preparation method of uncleosides as antiviral agents ultrafine powder according to claim 3, it is characterized in that: described uncleosides as antiviral agents includes but not limited to acyclovir, ganciclovir, Penciclovir, Famciclovir, valacyclovir, tynofovir, Adefovir, cidofovir, and they have the isomer of physiologically active, pharmacologically acceptable salts and cocrystallization.
5. the purposes of uncleosides as antiviral agents ultrafine powder in pharmaceutical compositions described in claim 1 or 2.
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