CN105218370A - Ultrafine powder of a kind of fibrate lipid-lowering drugs and preparation method thereof - Google Patents
Ultrafine powder of a kind of fibrate lipid-lowering drugs and preparation method thereof Download PDFInfo
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- CN105218370A CN105218370A CN201410255373.3A CN201410255373A CN105218370A CN 105218370 A CN105218370 A CN 105218370A CN 201410255373 A CN201410255373 A CN 201410255373A CN 105218370 A CN105218370 A CN 105218370A
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Abstract
The present invention relates to ultrafine powder of a kind of fibrate lipid-lowering drugs and preparation method thereof.Fibrate lipid-lowering drugs is the curative effect medicine of lipidemia, but due to the impact of the water-soluble factor such as poor, causes its bioavailability not high.The method preparing fibrate lipid-lowering drugs ultrafine powder provided by the invention: containing in the homogeneous phase solution of fibrate lipid-lowering drugs, be 10kHz ~ 500kHz by applying frequency, power is 1mW ~ 5000W, and the sound intensity is 0.1mW/cm
2~ 500W/cm
2ultrasonic wave, fast obtain fibrate lipid-lowering drugs crystal, then through routine operations such as solid collection, washing, drying, directly acquisition fibrate lipid-lowering drugs ultrafine powder.Ultrafine powder prepared by the present invention improve medicine bioavailability, reduce drug dose, improve drug solubility and can drug absorption be strengthened, apply more extensive.
Description
Technical field
The present invention relates to medical art, particularly a kind of ultrafine powder and preparation method thereof of fibrate lipid-lowering drugs.
Background technology
The whole world probably has 1,200 ten thousand people to die from cardiovascular diseases and cerebral apoplexy every year, and the atherosclerosis that hyperlipidaemia causes causes the major cause of coronary heart disease, hypertension and cerebrovascular disease.2002, only nearly 8,000,000,000 dollars of the global annual sales amount of atorvastatin (a kind of hypolipidemic) medicine, became the best-selling medicine in the world then.As can be seen here, research and develop blood lipid-lowering medicine and there are great social benefit and market outlook.
Fibrate lipid-lowering drugs is the part of the peroxisome proliferator activated receptor alpha (PPAR α) of a class synthetic, can effectively delay atherosclerotic development process.Wherein, fenofibrate, as typical fibrate, is one of choice drug reducing triglyceride level, also can reduces serum uric acid level simultaneously, also have good effect, good market prospects to the treatment of II-patients with type Ⅰ DM and metabolism syndrome.But water-soluble poor due to fenofibrate, oral administration biaavailability is low, limits giving full play to of its drug effect.
Find according to Noyes-Whitney equation, medicine is from the proportional relation of surface-area of the dissolution rate solid dosage and drug particle.The experimental study to Progesterone and medroxyprogesterone such as Alessi shows, the drug effect of these biosynthesizing medicines and medicine size and surface area relationship close; The micronization research to Ibuprofen BP/EP such as Yan Junfeng shows, Ibuprofen BP/EP is insoluble in water, so absorption and onset are slowly, greatly can improve its solubleness after being prepared into fine powder, thus improves drug effect and save the energy.The report of various document, material proves further, by reducing particle diameter, increasing medicine specific surface area, reducing thickness of diffusion layer, is conducive to improving drug-eluting and absorption.Ultra micro powdering techniques improves its bioavailability by reducing diameter of aspirin particle exactly.
Superfine powder (superfinepowder), also known as ultrafine powder, generally includes micron order (1 ~ 30 μm), submicron order (0.1 ~ 1 μm) and nano level (1 ~ 100nm).At present a strict definition be there is no for ultrafine powder, be referred to as ultrafine powder from the powder of a few nanometer to tens micron.To the definition of nano material can broad sense be interpreted as to have the material that one dimension is in nanoscale scope or is made up of as unit them in three dimensions at least.1. 0 dimension nano material can be divided into: scantling is nanoscale at three-dimensional space according to the concept of dimension; 2. 1 dimension nano material: material has two dimension in space for nanoscale; 3. 2 dimension nano materials: material has one dimension to be nanoscale in space; 4. 3 dimension nano materials: the bulk in three dimensions containing above-mentioned nano material.Conventional ultrafine powder MATERIALS METHODS of preparing has low-temperature airflow pulverizing, ball milling, the mechanical crushing method such as high-pressure homogeneous, and the physico-chemical process such as solvent diffusion, solvent evaporation, supercritical fluid technology, solvent deposition, lyophilize, spraying dry.Zhao Gaiqing etc. are in June, 2006 report in " spray drying technology is in the application prepared in ultra micro and nano-powder and prospect ", under the theoretical basis of mechanical crushing method is based on given stress condition, cause the fracture of particle, fragmentation and intergranular collision etc., produce the ultrafine powder (three-dimensional space) of 0 dimension particle; And adopting the physico-chemical processes such as spray drying technology can prepare the spherical powder that quality is homogeneous, repeatability is good, its ultrafine powder produced also belongs to 0 dimension particle.In sum, the ultrafine powder that current published preparation method obtains mostly is 0 dimension particle.
At present, research fibrate being reduced to size has no small progress, also has many disclosed documents and materials:
Disclosing in Chinese patent CN1668281A a kind of " the special Nano-particulate medicinal composition of shellfish " of high bioavailability, is adopt media milling process to prepare the special nanoparticle suspension of shellfish.Thick for medicine suspension is reduced diameter of aspirin particle by the mechanical effect of grinding medium (zirconium white or cross-linked polystyrene resin etc.) by this media milling process, and adsorb stablizer to prevent aggregation of particles, finally obtain the nanoparticle containing fibrate.
Disclose fenofibrate tablet and preparation method thereof in Chinese patent CN200480011341.3, the method by fenofibrate and tensio-active agent micronization altogether, then makes tablet by adding other auxiliary materials by jet-impingement technology.
Chinese patent CN101209239A discloses a kind of manufacture method containing fenofibrate nanometer particle, the method first mixes fenofibrate, organic solvent and promotor to form saturated solution, and then the spray-dired method of employing system obtains the nanoparticle containing fenofibrate.
Chinese patent CN101283982A discloses a kind of preparation method of fenofibrate nanometer suspension, and the method is by after fenofibrate and auxiliary material melting, and pre-emulsification is sheared in application, after high-pressure homogeneous, just can obtain fenofibrate nanometer suspension.The grain diameter of suspensoid is as shown in Figure 1 about 190-380nm.
Chinese patent CN03817270.4 discloses a kind of nanoparticle fenofibrate formulations, wherein use anti-solvent legal system for fenofibrate nanometer grain, namely first medicine is dissolved in suitable solvent, add in surface-stable agent solution again, apply non-suitable solvent to precipitate, eventually through the preparation obtained after drying containing nanoparticle.
Chinese patent CN103239401A discloses a kind of method preparing fenofibrate nanometer suspension, wherein by fenofibrate and copolyvidone PVPS630 dissolve with ethanol, slowly add the aqueous solution of polyvidone PVPK-90, fling to ethanol, obtain fenofibrate nanometer suspension, the mean particle size of this suspensoid is 100 ~ 500nm.
The people such as Luo Ning were referred to a kind of solvent diffusion method in 2011 and prepare fenofibrate nanometer grain in " bioavailability study of fenofibrate nanometer suspension "; wherein fenofibrate is dissolved in dehydrated alcohol; under high-speed stirring, organic phase is injected fast the water containing diffusing protection agent; continue to stir; removing organic solvent; namely obtain fenofibrate nanometer suspension, the nanoparticle median size of this suspensoid is at 333.9+50.2nm.
The people such as Pradum were referred to a kind of method of ultrasonic preparation fenofibrate nanometer crystal in 2013 in " Fabricationoffenofibratenanocrystalsbyprobesonicationmet hodforenhancementofdissolutionrateandoralbioavailability ", wherein fenofibrate is joined PLURONICS F87 and be made into suspension, finally obtain fenofibrate nanometer powder (accompanying drawing 2) by high-speed stirring, ultrasonic disperse, cryodesiccated mode.
At fenofibrate nanometer preparation (tablet) TriCor (2004) and the Triglide (2005) of U.S.'s listing, be respectively SkyePharma company and prepared by high pressure homogenization technique (Dissocubes) by media mill technology (NanoCrystals) and ParPharmaceuticalCompaniesInc..And from microscopic dimensions, prepared by it, be 0 dimension particle preparation.
The preparation method of above-mentioned ultrafine powder comprises medium milling, high pressure homogenization method, jet-impingement technology, spraying dry, anti-solvent recrystallization, solvent diffusion, solvent evaporation, freeze-drying method.In addition micronized preparation method also has comminution by gas stream, acid-base reaction precipitation etc.
Media milling process is the technology be most widely used in ultrafine powder preparation at present, although have device and the simple feature of preparation process, single batch of cycle of producing is long, and production efficiency is not high; And due to particle encounter and mechanical movement and discharge amount of heat, the preparation of inapplicable low melting point substance in process of lapping; Simultaneously because the wearing and tearing of dielectric material in process of lapping also can produce mechanical impurity, thus cause the pollution of product.
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 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 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.
The various defects of above-mentioned ultrafine powder preparation method are the principal elements causing rarely having fibrate lipid-lowering drugs 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 fibrate lipid-lowering drugs 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 fibrate lipid-lowering drugs, 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 fibrate lipid-lowering drugs crystal, then through routine operations such as solid collection, washing, drying, directly acquisition fibrate lipid-lowering drugs 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 fibrate lipid-lowering drugs and solvent is: 1:1 ~ 1:300.
Fibrate lipid-lowering drugs 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.
Fibrate lipid-lowering drugs 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.
Fibrate lipid-lowering drugs 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, fibrate lipid-lowering drugs includes but not limited to fenofibrate, lifibrate, gemfibrozil, bezafibrate, Win-35833, and they have the isomer of physiologically active or pharmacologically acceptable salts and cocrystallization.Wherein, the pharmaceutically acceptable salt of fenofibrate comprises choline salt, ethanolamine salt, diethanolamine salt, piperazine salt, piperidinium salt, morpholine salt, calcium salt and tromethamine salt etc.
The fibrate lipid-lowering drugs 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, patch etc.
Fibrate lipid-lowering drugs ultrafine powder of the present invention, the meltage in appropriate medium in (15 ~ 25 DEG C) 5min be non-ultrafine powder material dissolution amount 115% 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 fibrate lipid-lowering drugs 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 particle Electronic Speculum figure prepared by high pressure homogenization method;
Fig. 2 is the fenofibrate nanometer crystal Electronic Speculum figure of ultrasonic preparation;
Fig. 3 is fenofibrate bulk drug 50 μm of Electronic Speculum figure;
Fig. 4 is fenofibrate bulk drug 100 μm of Electronic Speculum figure;
Fig. 5 is 10 μm of Electronic Speculum figure of embodiment 22 ultrafine powder;
Fig. 6 is 50 μm of Electronic Speculum figure of embodiment 22 ultrafine powder;
Fig. 7 is 5 μm of Electronic Speculum figure of embodiment 34 ultrafine powder;
Fig. 8 is 50 μm of Electronic Speculum figure of embodiment 34 ultrafine powder;
Fig. 9 is 5 μm of Electronic Speculum figure of embodiment 42 ultrafine powder;
Figure 10 is 50 μm of Electronic Speculum figure of embodiment 42 ultrafine powder;
Figure 11 is the dissolution rate in vitro curve of fenofibrate raw material and embodiment 22 ultrafine powder;
Figure 12 is the X-ray powder diffraction (PHILIPSX'PertPROX x ray diffractometer x) of fenofibrate raw material;
Figure 13 is the X-ray powder diffraction of embodiment 22 ultrafine powder.
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
Gemfibrozil raw material 4g, adds the methyl alcohol of 50mL, heating for dissolving, and also 20kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 2
Fenofibrate raw material 5g, adds the dehydrated alcohol of 60mL, heating for dissolving, and also 30kHZ, 400W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 3
Bezafibrate raw material 3g, adds the methyl alcohol of 30mL, heating for dissolving, and also 20kHZ, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 4
Lifibrate raw material 5g, adds the acetone of 15mL, heating for dissolving, and also 20kHZ, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 5
Gemfibrozil raw material 5g, adds the acetone of 20mL, heating for dissolving, and also 30kHZ, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 6
Fenofibrate raw material 8g, adds the methyl alcohol of 100mL, heating for dissolving, and also 40kHZ, 400W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 7
Bezafibrate raw material 10g, adds the DMF of 50mL, heating for dissolving, and also 30kHZ, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 8
Lifibrate raw material 6g, adds the ethyl acetate of 40mL, heating for dissolving, and also 35kHZ, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 9
Gemfibrozil raw material 5g, adds the acetonitrile of 20mL, heating for dissolving, and also 30kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 10
Fenofibrate raw material 3g, adds the Virahol of 60mL, heating for dissolving, and also 30kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 11
Bezafibrate raw material 20g, adds the acetone of 50mL, heating for dissolving, and also 50kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 12
Lifibrate raw material 4g, adds the sherwood oil of 70mL, heating for dissolving, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 13
Gemfibrozil raw material 8g, adds the DMF of 80mL, heating for dissolving, and also 40kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 14
Fenofibrate raw material 4g, adds the ethyl acetate of 20mL, heating for dissolving, and also 20kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 15
Bezafibrate raw material 9g, adds the dehydrated alcohol of 120mL, heating for dissolving, and also 25kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 16
Lifibrate raw material 5g, adds the methyl alcohol of 90mL, heating for dissolving, and also 40kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 17
Gemfibrozil raw material 10g, adds the acetone of 24mL, heating for dissolving, and the 6ml that adds water continues backflow, and also 20kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 18
Fenofibrate raw material 4g, adds the methyl alcohol of 50mL, heating for dissolving, and the 20ml that adds water continues backflow, and also 300kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 19
Bezafibrate raw material 4g, adds the Virahol of 80mL, heating for dissolving, and the 8ml that adds water continues backflow, and also 40kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 20
Lifibrate raw material 5g, adds the DMF of 20mL, heating for dissolving, and the 8ml that adds water continues backflow, and also 15kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 21
Gemfibrozil raw material 6g, adds the acetonitrile of 18mL, heating for dissolving, and the 12ml that adds water continues backflow, and also 30kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 22
Fenofibrate raw material 2g, adds the dehydrated alcohol of 80mL, heating for dissolving, and the 43ml that adds water continues backflow, and also 40kHz, 350W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; The fenofibrate ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 5,6, and the X-ray powder diffraction shown in accompanying drawing 13) of two-dimensional is obtained after collection, washing, drying.
Embodiment 23
Bezafibrate raw material 5g, adds the acetone of 40mL, heating for dissolving, and the 40ml that adds water continues backflow, and also 25kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 24
Lifibrate raw material 4g, adds the acetonitrile of 22mL, heating for dissolving, and the 10ml that adds water continues backflow, and also 20kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 25
Gemfibrozil raw material 7g, adds the DMF of 30mL, heating for dissolving, and the 15ml that adds water continues backflow, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 26
Fenofibrate raw material 5g, adds the Virahol of 25mL, heating for dissolving, and the 18ml that adds water continues backflow, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 27
Bezafibrate raw material 3g, adds the methyl alcohol of 50mL, heating for dissolving, and the 20ml that adds water continues backflow, and also 25kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 28
Lifibrate raw material 8g, adds the dehydrated alcohol of 120mL, heating for dissolving, and the 120ml that adds water continues backflow, and also 40kHz, 450W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 29
Gemfibrozil raw material 10g, adds the ethyl acetate of 50mL, heating for dissolving, and the 30ml that adds water continues backflow, and also 30kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 30
Fenofibrate raw material 6g, adds the acetone of 35mL, heating for dissolving, and the 25ml that adds water continues backflow, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 31
Bezafibrate raw material 5g, adds the DMF of 55mL, heating for dissolving, and the 50ml that adds water continues backflow, and also 20kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 32
Lifibrate raw material 5g, adds the Virahol of 100mL, heating for dissolving, and the 15ml that adds water continues backflow, and also 30kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 33
Gemfibrozil raw material 4g, adds the dehydrated alcohol of 60mL, heating for dissolving, and the 40ml that adds water continues backflow, and also 25kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 34
Fenofibrate raw material 2g, adds the dehydrated alcohol of 120mL, heating for dissolving, and the 120ml that adds water continues backflow, and also 40kHz, 400W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 7,8) is obtained after collection, washing, drying.
Embodiment 35
Bezafibrate raw material 2g, adds the ethyl acetate of 30mL, heating for dissolving, and the 20ml that adds water continues backflow, and also 20kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 36
Lifibrate raw material 7g, adds the acetone of 50mL, heating for dissolving, and the 35ml that adds water continues backflow, and also 25kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 37
Gemfibrozil raw material 5g, adds the methyl alcohol of 60mL, heating for dissolving, and the 20ml that adds water continues backflow, and also 20kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 38
Fenofibrate raw material 5g, adds the DMF of 100mL, heating for dissolving, and the 68ml that adds water continues backflow, and also 30kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 39
Bezafibrate raw material 9g, adds the acetonitrile of 90mL, heating for dissolving, and the 56ml that adds water continues backflow, and also 35kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 40
Lifibrate raw material 4g, adds the methyl alcohol of 60mL, heating for dissolving, and the 30ml that adds water continues backflow, and also 20kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 41
Gemfibrozil raw material 5g, adds the ethyl acetate of 30mL, heating for dissolving, adds 0.5% poloxamer aqueous solution 20ml and continues backflow, and also 20kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 42
Fenofibrate raw material 3g, adds the dehydrated alcohol of 180mL, heating for dissolving, adds 0.5% lauryl sodium sulfate aqueous solution 180ml and continues backflow, and also 40kHz, 500W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder (U.S. FEISirion200 field scan Electronic Speculum, accompanying drawing 9,10) is obtained after collection, washing, drying.
Embodiment 43
Bezafibrate raw material 7g, adds the methyl alcohol of 100mL, heating for dissolving, adds 0.5% Aqueous Solutions of Polyethylene Glycol 30ml and continues backflow, and also 35kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 44
Lifibrate raw material 4g, adds the acetonitrile of 40mL, heating for dissolving, adds 0.5% sapn aqueous solution 20ml and continues backflow, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 45
Gemfibrozil raw material 5g, adds the acetone of 60mL, heating for dissolving, adds 0.5% poloxamer aqueous solution 40ml and continues backflow, and also 20kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 46
Fenofibrate raw material 6g, adds the Virahol of 120mL, heating for dissolving, adds 0.5% Aqueous Solutions of Polyethylene Glycol 20ml and continues backflow, and also 25kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 47
Bezafibrate raw material 3g, adds the methyl alcohol of 60mL, heating for dissolving, adds 0.5% sapn aqueous solution 20ml and continues backflow, and also 20kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 48
Lifibrate raw material 10g, adds the acetone of 50mL, heating for dissolving, adds 0.5% lauryl sodium sulfate aqueous solution 30ml and continues backflow, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 49
Gemfibrozil raw material 4g, adds the dehydrated alcohol of 100mL, heating for dissolving, adds 0.5% lauryl sodium sulfate aqueous solution 60ml and continues backflow, and also 35kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 50
Fenofibrate raw material 5g, adds the ethyl acetate of 60mL, heating for dissolving, adds 0.5% sapn aqueous solution 10ml and continues backflow, and also 20kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 51
Bezafibrate raw material 5g, adds the acetone of 70mL, heating for dissolving, adds 0.5% poloxamer aqueous solution 40ml and continues backflow, and also 30kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 52
Lifibrate raw material 7g, adds the Virahol of 120mL, heating for dissolving, adds 0.5% Aqueous Solutions of Polyethylene Glycol 25ml and continues backflow, and also 40kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 53
Gemfibrozil raw material 4g, adds the methanol/water (60/40) of 80ml, heating for dissolving, and also 20kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 54
Fenofibrate raw material 5g, adds the dehydrated alcohol/water (50/50) of 120ml, heating for dissolving, and also 25kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 55
Bezafibrate raw material 4g, adds the acetone/water (30/70) of 100ml, heating for dissolving, and also 20kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 56
Lifibrate raw material 6g, adds the ethyl acetate/water (55/45) of 85ml, heating for dissolving, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 57
Gemfibrozil raw material 5g, adds the DMF/water (70/30) of 120ml, heating for dissolving, and also 35kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 58
Fenofibrate raw material 4g, adds the isopropanol/water (60/40) of 80ml, heating for dissolving, and also 20kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 59
Bezafibrate raw material 6g, adds the dehydrated alcohol/water (50/50) of 240ml, heating for dissolving, and also 40kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 60
Lifibrate raw material 5g, adds the methanol/water (75/25) of 110ml, heating for dissolving, and also 25kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 61
Gemfibrozil raw material 10g, adds the acetone/water (65/35) of 300ml, heating for dissolving, and also 40kHz, 350W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 62
Fenofibrate raw material 8g, adds the acetonitrile/water (55/45) of 360ml, heating for dissolving, and also 50kHz, 450W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 63
Bezafibrate raw material 4g, adds the ethyl acetate/water (90/10) of 60ml, heating for dissolving, and also 20kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 64
Lifibrate raw material 7g, adds the dimethyl formamide/water (80/20) of 90ml, heating for dissolving, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 65
Gemfibrozil raw material 5g, adds the dehydrated alcohol/water (70/30) of 140ml, heating for dissolving, and also 30kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 66
Fenofibrate raw material 13g, adds the acetone/water (75/25) of 80ml, heating for dissolving, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 67
Bezafibrate raw material 4g, adds the methanol/water (55/45) of 250ml, heating for dissolving, and also 35kHz, 400W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 68
Lifibrate raw material 8g, adds the acetonitrile/water (50/50) of 120ml, heating for dissolving, and also 25kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 69
Gemfibrozil raw material 2g, adds the dehydrated alcohol alcohol/sherwood oil (50/50) of 20ml, heating for dissolving, and also 20kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 70
Fenofibrate raw material 4g, adds the ethyl acetate/petroleum ether (30/70) of 25ml, heating for dissolving, and also 20kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 71
Bezafibrate raw material 5g, adds the DMF alcohol/water (60/40) of 20ml, heating for dissolving, and also 30kHz, 100W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 72
Lifibrate raw material 10g, adds the methyl alcohol/sherwood oil (80/20) of 120ml, heating for dissolving, and also 40kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 73
Gemfibrozil raw material 9g, adds the Virahol/sherwood oil (66/34) of 0.5% poloxamer of 300ml, heating for dissolving, and also 50kHz, 350W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 74
Fenofibrate raw material 5g, adds the dehydrated alcohol/sherwood oil (55/45) of 0.5% sapn of 210ml, heating for dissolving, and also 45kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 75
Bezafibrate raw material 8g, adds the acetone/sherwood oil (40/60) of 0.5% polyoxyethylene glycol of 120ml, heating for dissolving, and also 25kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 76
Lifibrate raw material 20g, adds the ethyl acetate/petroleum ether (33/67) of 0.5% sodium lauryl sulphate of 350ml, heating for dissolving, and also 50kHz, 450W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 77
Gemfibrozil raw material 12g, adds the acetonitrile/sherwood oil (30/70) of 0.5% polyoxyethylene glycol of 100ml, heating for dissolving, and also 20kHz, 150W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 78
Fenofibrate raw material 15g, adds the DMF/sherwood oil (10/90) of 0.5% sodium lauryl sulphate of 150ml, heating for dissolving, and also 35kHz, 250W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 79
Bezafibrate raw material 4g, adds the methyl alcohol/sherwood oil (70/30) of 0.5% sodium lauryl sulphate of 100ml, heating for dissolving, and also 40kHz, 350W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 80
Lifibrate raw material 9g, adds the Virahol/sherwood oil (54/46) of 0.5% sodium lauryl sulphate of 220ml, heating for dissolving, and also 50kHz, 350W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 81
Gemfibrozil raw material 30g, adds the methanol/isopropanol (50/50) of 0.5% sapn of 500ml, heating for dissolving, and also 50kHz, 500W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Gemfibrozil ultrafine powder is obtained after collection, washing, drying.
Embodiment 82
Fenofibrate raw material 22g, adds the acetone/dehydrated alcohol (20/80) of 0.5% poloxamer of 150ml, heating for dissolving, and also 35kHz, 200W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Fenofibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 83
Bezafibrate raw material 20g, adds the acetonitrile/Virahol (10/90) of 0.5% polyoxyethylene glycol of 200ml, heating for dissolving, and also 35kHz, 300W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Bezafibrate ultrafine powder is obtained after collection, washing, drying.
Embodiment 84
Lifibrate raw material 30g, adds the methyl alcohol/dehydrated alcohol (50/50) of 0.5% poloxamer of 320ml, heating for dissolving, and also 40kHz, 400W are ultrasonic simultaneously in ice bath cooling, obtain white crystal; Lifibrate ultrafine powder is obtained after collection, washing, drying.
Dissolution rate in vitro is tested: each 50mg of ultrafine powder taking fenofibrate bulk drug and embodiment 22 preparation, be placed in the stripping rotor containing 900ml0.5%SDS solution, constant temperature 37 DEG C, 100rpm stir with the test of RC-6 type digestion instrument, respectively at 5,10,20,30,45,60,75,90min samples 5ml and supplements blank solution 5ml, 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 red laser telltale.After filtrate is diluted to suitable concn by blank solvent, detects in 289nm place (doing with dissolution solvent blank) with TU-1901 type ultraviolet spectrophotometer, calculate each time point concentration and draw dissolution rate chart (accompanying drawing 11).
Claims (5)
1. a ultrafine powder for fibrate lipid-lowering drugs, is characterized in that: the one dimension of described ultrafine powder or two-dimensional are 1nm ~ 30 μm, and maximum dimension is not less than 2:1/3:1/4:1/5:1/6:1/7:1/8:1/9:1/10:1 with the ratio of smallest dimension size.
2. fibrate lipid-lowering drugs ultrafine powder according to claim 1, it is characterized in that: described fibrate lipid-lowering drugs includes but not limited to fenofibrate, lifibrate, gemfibrozil, bezafibrate, Win-35833, and they have the isomer of physiologically active or pharmacologically acceptable salts and cocrystallization; Wherein, the pharmaceutically acceptable salt of fenofibrate comprises choline salt, ethanolamine salt, diethanolamine salt, piperazine salt, piperidinium salt, morpholine salt, calcium salt and tromethamine salt etc.
3. prepare a method for fibrate lipid-lowering drugs ultrafine powder, its step is as follows:
(1) prepare a kind of homogeneous phase solution containing fibrate lipid-lowering drugs, wherein the weightmeasurement ratio (w/v, g/mL) of fibrate lipid-lowering drugs 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 fibrate lipid-lowering drugs crystal;
(3) through operations such as solid collection, washing, dryings, obtain fibrate lipid-lowering drugs 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 fibrate lipid-lowering drugs ultrafine powder according to claim 3, it is characterized in that: described fibrate lipid-lowering drugs includes but not limited to fenofibrate, lifibrate, gemfibrozil, bezafibrate, Win-35833, and they have the isomer of physiologically active or pharmacologically acceptable salts and cocrystallization; Wherein, the pharmaceutically acceptable salt of fenofibrate comprises choline salt, ethanolamine salt, diethanolamine salt, piperazine salt, piperidinium salt, morpholine salt, calcium salt and tromethamine salt etc.
5. the purposes of the ultrafine powder of fibrate lipid-lowering drugs described in claim 1 or 2 in pharmaceutical compositions.
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| CN108558654A (en) * | 2018-06-02 | 2018-09-21 | 浙江精进药业有限公司 | The preparation method of Gemfibrozil Capsules crystal form I |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108558654A (en) * | 2018-06-02 | 2018-09-21 | 浙江精进药业有限公司 | The preparation method of Gemfibrozil Capsules crystal form I |
| CN108558654B (en) * | 2018-06-02 | 2021-09-07 | 浙江精进药业有限公司 | Preparation method of gemfibrozil crystal form I |
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