• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Enhancing the dissolution of phenylbutazone using Syloid?based mesoporous silicas for oral equine applications

    2018-06-20 05:50:50LurWtersJohnHnrhnJosephToinCtherineFinchGrethPrkesShmsuddeenAhmdFrjMohmmdMriSleem
    Journal of Pharmaceutical Analysis 2018年3期

    Lur J.Wters,John P.Hnrhn,Joseph M.Toin,Ctherine V.Finch,Greth M.B.Prkes,Shmsuddeen A.Ahmd,Frj Mohmmd,Mri Sleem

    aSchool of Applied Sciences,University of Hudders field,Queensgate,Hudders field HD1 3DH,UK

    bGlantreo Ltd,ERI Building,Lee Road,Cork City T23 XE10,Ireland

    1.Introduction

    Mesoporous silica has bee n shown to exhibit a great potential to aid in the formulation of pharmaceutical compounds with poor aqueous solubility,as reviewed by Choudhari et al.[1].As a drug carrier system,mesoporous silica can accommodate drugs that have been introduced through organic solvent immersion,incipient wetness impregnation or melted in[2].Specific advantages of using excipients such as mesoporous silicas are their nanoporous structures,high surface areas,clinical safety and large pore volumes[3].Current opinion is that substantial progress has been made in recent years in the characterisation and development of mesoporous drug delivery systems although more work is needed regarding dissolution enhancement potential and related physicochemical properties[4].There are several reasons for this need to continue exploring the possible use of mesoporous silica such as practical considerations such as manufacturability to large scale quantities(e.g.tonne)and regulation,as well as physicochemical considerations such as the possibility of re-adsorption onto the silica surface[4].Adsorption of small drug particles on the surface of large excipients has been a successful strategy for low-dose drugs,poorly water soluble drugs,targeted drug release[5],sustained drug delivery[6]and stability enhancement.This is mainly a result of improving the dissolution pro file by increasing drug surface area or transformation of the drug from a crystalline to amorphous form[7],and its ability to be retained within the silica pores[8].In many cases,the method of formulation can be critical in defining the properties of the resultant formulation.For example,silica-based drug delivery vehicleshavebeen investigated to avoid hydrolisation of the active compound using supercritical CO2[9,10],a formulation method known for its high drug-loading ability[11]amongst other advantages[12].Several other formulation methods have also been attempted,for example,to create liquid(also known as liquisolid)formulations[13]and pediatric(solvent free)formulations[14].The work within our group that has previously confirmed the application of microwave irradiation for mesoporous silicas[15].Furthermore,there is clearly an interest in developing mesoporous silica formulations as evidenced by recent work to predict in vivo performance,for example,using in silico techniques[16],to overcome multidrug resistance[17]as well as to ameliorate toxic side effects[18].

    One particular category of mesoporous silicas where only very limited studies have been conducted to date is regarding Syloid?silica based formulations.These forms of silica have a highly developed network of mesopores that provide access to the large surface area,i.e.a combination of a high adsorption capacity,along with a desirable pore size and surface morphology.For these reasons,these silicas tend to be used to improve the flow properties of pharmaceuticals where liquid ingredients can be converted into free- flowing powders.Although these properties are beneficial,their suitability to enhance dissolution has only briefly been considered(by publication)for two forms of Syloid?silica(244 and AL-1)with two model drugs,namely,indomethacin[19]and itraconazole[20].Interestingly,for both compounds,an enhancement in the rate and extent of dissolution was observed in both studies.Yet surprisingly,other forms of Syloid?silica have not yet been considered even though they may provide a plethora of advantages for drug-loading formulations.

    One specific drug renowned for having poor aqueous solubility∶0.05 mg/mL[21],and therefore problematic dissolution with potentially low bioavailability,is phenylbutazone.This particular compound is commonly used in equine environments as a nonsteroidal anti-inflammatory drug(NSAID)[22,23],often prescribed for pain control[24,25].Although drug solubility is significantly greater in ethanol and 1-octanol[26],the low level of aqueous solubility results in complications for formulators.One study has successfully enhanced the dissolution through the creation of a solid dispersion with polyethylene glycol 8000[27]and another with SBA-15[28],yet there is still a clear need for developing alternative formulations that can achieve an even greater enhancement in release of the active compound.Phenylbutazone is an excellent candidate for exploring the potential to enhance solubility through formulation with a dissolution-limiting low solubility yet incredibly significant usage within the equine community.This is because many of the present formulations available on the market tend to be unfavourable with issues surrounding drug delivery and poor palatability[29].Thus ways to enhance phenylbutazone-based formulations are highly desirable.

    This work investigates the suitability of using three types of Syloid?silica based excipients to quantify their potential to enhance the rate of dissolution of phenylbutazone and determine the causes of any enhancements observed.

    2.Materials and methods

    2.1.Materials

    Phenylbutazone,potassium phosphate dibasic,and potassium phosphate monobasic(all≥99%)were purchased from Sigma Aldrich(Dorset,UK)and used as received.Syloid?silicas(AL-1 FP,XDP 3050 and XDP 3150)were kindly donated by Glantreo Ltd,Cork,Ireland and W.R.Grace&Co,Maryland,USA.Table 1 provides a summary of the physicochemical properties of the Syloid?silicas,and the data presented were determined using nitrogen gas sorption isotherms.These were measured at 77K using a Micromeritics TriStar II surface area analyzer(Micromeritics,Norcross,GA,USA).Samples were pre-treated by heating at 200°C undernitrogen for 12 h.The surface area was measured using the Brunauer-Emmett-Teller(BET)method.The pore volume and pore diameter data was calculated using the Barrett,Joyner and Halenda(BJH)method[2].Specific surface areas were calculated from the measured relative pressure in the range of P/P0=0.01 to P/P0=0.3.Mesoporous volumes were estimated from the volume of nitrogen adsorbed after the micropores have been filled until after condensation into the mesopores was complete.Of particular interest is the range of surface areas and pore volumes exhibited by the three Syloid?silicas as based on previous research,such properties may influence dissolution.For example,pore size has been known to effect drug release pro files for other mesoporous systems[30].

    2.2.Methods

    2.2.1.Formulation methods

    200mg of Syloid?silica XDP 3050 was placed in a beaker whereupon 40mL of deionised water was gradually added,followed by 200mg of phenylbutazone to achieve a total drug and silica mass of 400mg.Over a period of 60min the solution was stirred and heated to a maximum of 90°C,cooled to room temperature,vacuum filtered and dried overnight at 60°C,and then sieved to remove agglomerates larger than 250μm.This process was repeated in triplicate and then with the replacement of XDP 3050 with XDP 3150 and AL-1 FP to produce a total of three unique drug-Syloid?silica formulations.A series of variable ratios of drug∶Syloid drug∶Syloid?silica formulations were also formulated but based on dissolution pro file data(not shown),no significant differences in release pro files were observed between the formulations;thus this paper only presents formulations at a 1∶1 ratio.A f i nal formulation was produced that involved phenylbutazone undergoing the formulation process(but without the presence of Syloid?silica)to determine if it was the processing that affected dissolution or the presence of each Syloid?silica itself.Water was used as a ‘carrier’to disperse the drug within the mixture,rather than dissolving the drug with organic solvent,followed by heating to help achieve maximum dispersion within the mixture.

    2.2.2.Characterisation methods

    Powder X-ray diffraction(XRD)data were collected on a Bruker D2-Phaser equipped with a Cu Kα1radiation source at 30 kV and 10 mA current.Particle size distribution of the formulated products was analysed using a Malvern Mastersizer 2000(Worcestershire,UK)using 5–10 mg of powder per sample with one drop of surfactant(IGEPAL?CA-630)at a stirring speed of 2000rpm.Triplicate data was subsequently analysed using Mastersizer 2000 software(V5.61).Drug loading was verified to be 100%in all formulated samples by UV analysis of the filtrates(λ=282 nm)with no residual drug detected(<1%),thus confirming all of the drug remained within the formulation(rather than washed away with the filtrate during the formulation process).For stability conf i rmation the infrared spectrum for the pure samples and their formulations was recorded using a Nicolet-380 Fourier Transform Infrared spectrometer(FT-IR)with an ATR crystal.Powder samples were placed directly onto the diamond crystal and the anvil was lowered to ensure that sample was in full contact with the diamond.Each spectrum was obtainedintherange of500–4000 cm-1with 2 cm-1resolution.In this study,the morphology of the prepared samples was characterised using scanning electron microscopy(SEM)(JEOL JSM-6060LV,Japan)with gold-plating using a sputter coater(SC7620)prior to imaging.

    2.2.3.In vitro phenylbutazone release

    Dissolution pro files were determined using a USP Type II(paddle method)PharmaTest DT70 system,with manual sampling for a period of 30 min.Formulated samples with a total drug content of 22.5 mg were placed in 900 mL of pH 7.0 phosphate buffer,stirred at 75 rpm and maintained at 37.0 ± 0.5°C,maintaining sink conditions throughout the duration of the experiment.Filtered samples were removed every 5 min,replaced with phosphate buffer,and analysed using UV spectroscopy(Cary 60,Agilent)set at a wavelength(λ)of 282 nm with conversion to percentage drug release using a standard calibration plot.Samples were analysed in triplicate to determine mean drug release percentages and associated error limits.

    3.Results and discussion

    3.1.Characterisation of formulations

    XRD patterns for samples of the three mesoporous silicas both with and without the presence of phenylbutazone are shown in Fig.1.Previous XRD studies using naproxen noted that the diminishment of peak intensities confirmed that the drug had loaded into channels of a mesoporous material[31],resulting in an amorphous formulation with an absence of characteristic peaks[15].A similar result was observed in this work whereby the purely crystalline phenylbutazone that could be seen in Fig.1A(and after processing in Fig.1B)was converted to the amorphous form following formulation with the three Syloid?silicas(Figs.1C-E).As discussed earlier,from analysing the filtrates and confirming all of the drug had remained within the formulation,the absence of peaks cannot be explained by a reduced concentration of drug and can only be explained by a transformation to the amorphous form.

    Particle size analysis confirmed that phenylbutazone(prior to formulation)exhibited an average particle sizes of 65–70μm.The sizes of the three Syloid?silicas prior to formulation are presented in Table 1 and were confirmed in this study to have average values of 10,50 and 110μm for AL-1 FP,XDP 3050 and XDP 3150,respectively.These three Syloid?silicas display an interesting range of particle sizes prior to formulation.Yet their subsequent dissolution pro files may actually be more dependent upon their size after formulation(through the formation of aggregates);therefore,it is this parameter that is of interest in this work.Firstly,AL-1 FP displayed an increase in the average particle size and a slightly broader distribution of sizes with the majority of particles between 5 and 100 μm after formulation.Secondly,a similar result was seen for XDP 3050 with the majority of particles between 40 and 100μm.An explanation for this increase in size and diversity of sizes for both Syloid?silicas is most likely a consequence of particle agglomeration as a result of drug incorporation and/or processing effects.Thirdly,Syloid?silica 3150 did not exhibit any significant increase in average particle size following formulation although there was an increase in the polydispersity of particle size.Again,this indicates agglomeration may have occurred to a limited extent but not to the same degree as that seen for the other Syloid?silicas.

    Fig.1.XRD patterns for(a)phenylbutazone,(b)processed phenylbutazone,(c)phenylbutazone and AL-1 FP,(d)phenylbutazone and XDP 3150,and(e)phenylbutazone and XDP 3050.

    Fig.2.FT-IR analysis of(a)phenylbutazone,(b)AL-1 FP,(c)XDP 3150,and(d)XDP 3050 silicas prior to formulation.

    FT-IR spectroscopy was used to monitor the presence of phenylbutazone and determine interactions with the three silicas(Figs.2 and 3).Analysis of spectra for phenylbutazone showed the expected absorption bands at wavenumbers(with corresponding functional groups)of 754 and 1483cm-1(C-H),1270cm-1(C-N)and 1720cm-1(C=O).Analysis of the spectra for phenylbutazone subjected to the processing method did not reveal any changes in the specific absorption bands for the drug,suggesting a lack of degradation as a result of the formulation process.The three Syloid?silicas were analysed using FT-IR spectroscopy and all displayed the expected intense Si-O absorption band at 1060–1070cm-1[32].For the three phenylbutazone-silica formulated products,the results indicated a significant disappearance of the drug,mainly displaying spectra corresponding to just each type of silica present.Furthermore,the spectra did not display any obvious additional peaks,thus indicating there had been no significant changes in the chemical structure or drug-silica interactions.

    Fig.3.FT-IR analysis of(a)phenylbutazone,(b)processed phenylbutazone,(c)phenylbutazone and AL-1 FP,(d)phenylbutazone and XDP 3150,and(e)phenylbutazone and XDP 3050 silicas after formulation.

    Fig.4.Scanning electron micrographs for particles of(A)phenylbutazone,(B)AL-1 FP,(C)XDP 3150,and(D)XDP 3050 silicas prior to formulation.

    Surface morphologies of the pure phenylbutazone and the three Syloid?silicas prior to formulation,processed phenylbutazone,and Syloid?silica-based formulations–XDP 3050,XDP 3150 and AL-1 FP are presented in Figs.4 and 5.The drug's crystalline state,along with the disordered irregular shapes of AL-1 FP,XDP 3150,and XDP 3050 silicas was evident by SEM(Fig.4).The SEM image confirmed the insignificant effect of processed phenylbutazone as the drug retained a crystalline structure.However,there was a uniform distribution of phenylbutazone on the surface of AL-1 FP due to a larger surface area,smaller pore volume and pore diameter.For Syloid?XDP 3150 and XDP 3050 based formulations,there was an even distribution of the former particles with phenylbutazone particles reduced in size while for the latter,more of the drug was con fined in the pores and on the surface,visible in the SEM images(Fig.5).

    3.2.In vitro phenylbutazone release

    Dissolution pro files of phenylbutazone loaded Syloid?silicas were investigated for a period of 30 min in pH 7.0 phosphate buffer.As can be seen in Fig.6,pure phenylbutazone that had not undergone the formulation process exhibited 7.2%(±1.4%)drug release after 5 min yet only increased to a maximum of 43.7%(±2.3%)release after 30 min.For many drugs,this low percentage of drug release after this time would be deemed unsuitably low and may limit bioavailability.Through undertaking the formulation process with the drug alone,i.e.hydration,heating, filtering,drying then sieving,the percentage of drug release,or more accurately in this case,dissolution after 30 min was 43.8%(±7.9%).Therefore,it has been confirmed that exposure of the drug to the formulation process did not affect the pro file observed,i.e.hydrating through sieving did not enhance the effects observed for phenylbutazone.AllthreeSyloid?silicabasedformulations exhibited a dramatic enhancement in percentage dissolution,confirming that the presence of Syloid?silica contributed to the increase.Firstly,XDP 3150 achieved a percentage release of 42.4%(±1.9%)after only 5 min,i.e.almost equal to that observed for drug alone after twice as long.After a period of 30 min,this value had increased to 78.3%(±2.2%),far higher than that seen for drug alone or drug that had undergone the formulation process.Secondly,Syloid?silicas AL-1 FP did not show such a promising percentage release after 5 min(30.2%(±1.2%))compared with XDP 3150,yet after a total of 30 min had exceeded the former Syloid?silica to reach a maximum percentage release of 86.0%(±4.2%).Finally,XDP 3050 was found to be the most successful Syloid?silica for enhancing percentage release with an impressive 49.4%(±0.8%)released after 5 min,i.e.greater than the total seen for pure drug after 30 min,increasing to a maximum of 99.6%(±3.0%)release after 30 min.

    When determining why all three Syloid?silicas enhanced the percentageofdissolution following astandard formulation method,it would appear that the transformation from the crystalline to amorphous form(as evidenced by XRD and dissolution pro files of processed samples)plays a key role.This has been the conclusion of other researchers,when investigating alternative mesoporous materials[31],and fits well with the results from this work.However,when considering why the three Syloid?silicas did not facilitate the same increase in percentage release,it is more appropriate to consider their relative physicochemical properties,specifically those identified in Table 1.For example,AL-1 FP and XDP 3050 pore sizes are very different,in that AL-1 FP has small mesopores,i.e.a smaller pore volume and diameter compared with XDP 3050.Based on the pattern of increasing percentage release,i.e.from XDP 3150 to AL-1 FP to XDP 3050,it would appear that two properties of the Syloid?silicas may play a key role in controlling the process,namely,surface area and/or pore diameter.Interestingly,pore volume does not appear to be an influential factor for the rate and extent of dissolution,yet pore diameter is.In this work it appears that a large pore diameter,with a small surface area,maximises the extent of dissolution,which again, fits well with the findings of other studies with mesoporous microspheres[30,33].As a consequence of this,it is not only possible to dramatically enhance the rate and extent of dissolution,but also to vary the percentage depending upon the type of Syloid?silica used.Another potentially influential factor is the formation of aggregates which may affect the drug release pro file through the creation of particle aggregation.If this is the case,then it can be proposed that there are two unique structures within the formulation∶drug within pores and aggregates between particles which can both contribute to drug release.

    Fig.5.Scanning electron microscope images(SEM)of(A)processed phenylbutazone,(B)phenylbutazone and AL-1 FP,(C)phenylbutazone and XDP 3150,and(D)phenylbutazone and XDP 3050 after formulations.

    Fig.6.Phenylbutazone release pro files for phenylbutazone(PhB),processed phenylbutazone,and Syloid? silica based formulations–XDP 3050,XDP 3150 and AL-1 FP.Each data point represents the mean of triplicate results(±SD).

    4.Conclusions

    In summary,it has been confirmed that it is possible to formulate Syloid?silica based formulations to enhance the dissolution of a poorly soluble drug,in this case,phenylbutazone.Characterisation data implies that this enhancement is a result of a change in crystallinity and the ability of the drug to enter pores within the Syloid?silica structure.All three Syloid?silicas analysed demonstrated a dramatic increase in percentage release with their final percentage values linked to the Syloid?silica pore diameter and/or surface area.This finding can be of benefit for not only phenylbutazone-based equine formulations but potentially a far wider range of compounds that exhibit poor aqueous solubility,which will help alleviate bioavailability issues.To ensure that longterm stability is not a limiting factor for formulation possibilities,it is the intended subject of future sample analysis,using techniques such as XRD and SEM.

    Conflicts of interest

    The authors declare that there are no conflicts of interest.

    [1]Y.Choudhari,H.Hoefer,C.Libanati,et al.,Mesoporous silica drug delivery systems.N.Shah,H.Sandhu,D.S.Choi,et al.(Eds.),Amorphous Solid Dispersions∶Theory and Practice,Springer,New York,2014∶665–693.

    [2]W.Xu,J.Riikonen,V.P.Lehto,Mesoporous systems for poorly soluble drugs,Int.J.Pharm.453(2012)181–197.

    [3]S.C.Shen,W.K.Ng,L.S.O.Chia,et al.,Applications of mesoporous materials as excipients for innovative drug delivery and formulation,Curr.Pharm.Des.19(2013)6270–6289.

    [4]C.A.McCarthy,R.J.Ahern,R.Dontireddy,et al.,Mesoporous silica formulation strategies for drug dissolution enhancement∶a review,Expert Opin.Drug Deliv.13(2016)93–108.

    [5]S.H.Cheng,W.N.Liao,L.M.Chen,et al.,pH-controllable release using functionalized mesoporous silica nanoparticles as an oral drug delivery system,J.Mater.Chem.21(2011)7130–7137.

    [6]Y.Hu,X.Dong,L.Ke,et al.,Polysaccharides/mesoporous silica nanoparticles hybrid composite hydrogel beads for sustained drug delivery,J.Mater.Sci.52(2017)3095–3109.

    [7]H.Wen,Y.Qiu,Adsorption of small drug particles at the surface of large excipients,Pharm.Technol.Eur.18(2006)39–44.

    [8]A.Kiwilsza,A.Pajzderska,J.Mielcarek,et al.,Dynamical properties of nimodipine molecules con fined in SBA-15 matrix,Chem.Phys.475(2016)126–130.

    [9]N.Murillo-Cremaes,A.M.López-Periago,J.Saurina,et al.,Nanostructured silica-based drug delivery vehicles for hydrophobic and moisture sensitive drugs,J.Supercrit.Fluids 73(2013)34–42.

    [10]A.Patil,U.N.Chirmade,V.Trivedi,et al.,Encapsulation of water insoluble drugs in mesoporous silica nanoparticles using supercritical carbon dioxide,J.Nanomed.Nanotechnol.2(2011)111–119.

    [11]R.J.Ahern,A.M.Crean,K.B.Ryan,The influence of supercritical carbon dioxide(SC-CO2)processing conditions on drug loading and physicochemical properties,Int.J.Pharm.439(2012)92–99.

    [12]R.K.Kankala,Y.S.Zhang,S.B.Wang,et al.,Supercritical fluid technology∶an emphasis on drug delivery and related biomedical applications advanced healthcare,Materials 6(2017)1700433.

    [13]Y.Choudhari,U.Reddy,F.Monsuur,et al.,Comparative evaluation of porous silica based carriers for lipids and liquid drug formulations,Mesoporous Biomater.1(2014)61–74.

    [14]F.Monsuur,Y.Choudhari,U.Reddy,et al.,Solvent free amorphisation for pediatric formulations(minitablets)using mesoporous silica,Int.J.Pharm.511(2016)1135–1136.

    [15]L.J.Waters,T.Hussain,G.Parkes,et al.,Inclusion of fenofibrate in a series of mesoporous silicas using microwave irradiation,Eur.J.Pharm.Biopharm.85(2013)936–941.

    [16]C.A.McCarthy,W.Faisal,J.P.O'Shea,et al.,In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation,J.Control.Release 250(2017)86–95.

    [17]R.K.Kankala,C.G.Liu,A.Z.Chen,et al.,Overcoming multidrug resistance through the synergistic effects of hierarchical pH-sensitive,ROS-generating nanoreactors,ACS Biomater.Sci.Eng.3(2017)2431–2442.

    [18]R.K.Kankala,Y.Kuthati,C.L.Liu,et al.,Killing cancer cells by delivering a nanoreactor for inhibition of catalase and catalytically enhancing intracellular levels of ROS,RSC Adv.5(2015)86072–86081.

    [19]T.Limnell,H.A.Santos,E.M?kil?,et al.,Drug delivery formulations of ordered and nonordered mesoporous silica∶comparison of three drug loading methods,J.Pharm.Sci.100(2011)3294–3306.

    [20]P.Kinnari,E.M?kil?,T.Heikkil?,et al.,Comparison of mesoporous silicon and non-ordered mesoporous silica materials as drug carriers for itraconazole,Int.J.Pharm.414(2011)148–156.

    [21]W.Xu,J.Riikonen,V.P.Lehto,Mesoporous systems for poorly soluble drugs,Int.J.Pharm.453(2013)181–197.

    [22]L.R.Soma,C.E.Uboh,G.M.Maylin,The use of phenylbutazone in the horse,J.Vet.Pharmacol.Ther.35(2012)1–12.

    [23]C.Castagnetti,J.Mariella,Anti-inflammatory drugs in equine neonatal medicine.Part I∶nonsteroidal anti-inflammatory drugs,J.Equine Vet.Sci.35(2015)475–480.

    [24]L.C.Sanchez,S.A.Robertson,Pain control in horses∶what do we really know?Equine Vet.J.46(2014)517–523.

    [25]J.C.De Grauw,J.P.A.M.van Loon,C.H.A.van de Lest,et al.,In vivo effects of phenylbutazone on inflammation and cartilage-derived biomarkers in equine joints with acute synovitis,Vet.J.201(2014)51–56.

    [26]U.Domańska,A.Pobudkowska,A.Pelczarska,et al.,Modelling,solubility and pKa of five sparingly soluble drugs,Int.J.Pharm.403(2011)115–122.

    [27]S.Khan,H.Batchelor,P.Hanson,et al.,Physicochemical characterisation,drug polymer dissolution and in vitro evaluation of phenacetin and phenylbutazone solid dispersions with polyethylene glycol 8000,J.Pharm.Sci.100(2011)4281–4294.

    [28]M.Van Speybroeck,V.Barillaro,T.D.Thi,et al.,Ordered mesoporous silica material SBA-15∶a broad-spectrum formulation platform for poorly soluble drugs,J.Pharm.Sci.98(2009)2648–2658.

    [29]S.L.Longhofer,C.R.Reinemeyer,S.V.Radecki,Evaluation of the palatability of three nonsteroidal anti inflammatory top-dress formulations in horses,Vet.Ther.9(2008)122–127.

    [30]Y.Hu,J.Wang,Z.Zhi,et al.,Facile synthesis of 3D cubic mesoporous silica microspheres with a controllable pore size and their application for improved delivery of a water-insoluble drug,J.Colloid Interface Sci.363(2011)410–417.

    [31]Z.Guo,X.M.Liu,L.Ma,et al.,Effects of particle morphology,pore size and surface coating of mesoporous silica on Naproxen dissolution rate enhancement,Colloids Surf.B∶Biointerfaces 101(2013)228–235.

    [32]R.Al-Oweini,H.El-Rassy,Synthesis and characterization by FTIR spectroscopy of silica aerogels prepared using several Si(OR)4 and R′′Si(OR′)3 precursors,J.Mol.Struct.919(2009)140–145.

    [33]A.Martín,R.A.García,D.S.Karaman,et al.,Polyethyleneimine-functionalized large pore ordered silica materials for poorly water-soluble drug delivery,J.Mater.Sci.49(2014)1437–1447.

    欧美成人午夜精品| 亚洲精品国产精品久久久不卡| 日日干狠狠操夜夜爽| 久99久视频精品免费| 亚洲天堂国产精品一区在线| 白带黄色成豆腐渣| 亚洲国产精品sss在线观看| АⅤ资源中文在线天堂| 青草久久国产| 亚洲第一电影网av| 国产精品一区二区精品视频观看| 国产又色又爽无遮挡免费看| 极品教师在线免费播放| 在线看三级毛片| 麻豆一二三区av精品| 亚洲精品中文字幕在线视频| 老汉色av国产亚洲站长工具| 成年人黄色毛片网站| 国产人伦9x9x在线观看| 在线a可以看的网站| 欧美在线黄色| 国产高清有码在线观看视频 | 中文亚洲av片在线观看爽| www日本黄色视频网| 免费观看人在逋| 亚洲欧美激情综合另类| 国产熟女xx| 嫩草影视91久久| 久久久水蜜桃国产精品网| 两性夫妻黄色片| 国产高清videossex| 亚洲av五月六月丁香网| 午夜a级毛片| 免费人成视频x8x8入口观看| 熟女少妇亚洲综合色aaa.| 老司机深夜福利视频在线观看| 久久欧美精品欧美久久欧美| 舔av片在线| 99热6这里只有精品| 国产av麻豆久久久久久久| 免费在线观看影片大全网站| 国产午夜精品久久久久久| 一本一本综合久久| 国产探花在线观看一区二区| 国产精品综合久久久久久久免费| 国产黄a三级三级三级人| 香蕉国产在线看| 两个人看的免费小视频| 三级国产精品欧美在线观看 | 欧美乱妇无乱码| 日韩欧美国产在线观看| 动漫黄色视频在线观看| 变态另类丝袜制服| 热99re8久久精品国产| 国产激情偷乱视频一区二区| 久久久久久九九精品二区国产 | 国产精品亚洲美女久久久| 婷婷精品国产亚洲av在线| videosex国产| 很黄的视频免费| 人人妻人人看人人澡| 久久精品人妻少妇| 嫩草影院精品99| 黄色片一级片一级黄色片| 久久 成人 亚洲| 亚洲全国av大片| 久久久久久国产a免费观看| 别揉我奶头~嗯~啊~动态视频| 啦啦啦观看免费观看视频高清| 欧美日韩黄片免| 国产精品一区二区三区四区久久| 精品熟女少妇八av免费久了| 一区二区三区国产精品乱码| 日韩精品青青久久久久久| 九九热线精品视视频播放| 99久久国产精品久久久| 一本综合久久免费| 少妇人妻一区二区三区视频| 色播亚洲综合网| 美女扒开内裤让男人捅视频| 国产精品免费视频内射| 亚洲国产欧洲综合997久久,| 日韩有码中文字幕| 国产亚洲精品av在线| 欧美日本亚洲视频在线播放| 日本免费a在线| 久久久久国产一级毛片高清牌| 天天一区二区日本电影三级| 国产精品久久久久久精品电影| 99riav亚洲国产免费| 制服人妻中文乱码| 黄色 视频免费看| 国产午夜精品久久久久久| 国产成人av教育| 亚洲av成人一区二区三| 美女大奶头视频| 亚洲一码二码三码区别大吗| 国产成人啪精品午夜网站| 午夜激情av网站| 国产免费av片在线观看野外av| 欧美成人一区二区免费高清观看 | 亚洲精品在线美女| videosex国产| 亚洲一区高清亚洲精品| 国内精品一区二区在线观看| 久久精品国产亚洲av香蕉五月| a级毛片在线看网站| 黄色丝袜av网址大全| 亚洲人成网站在线播放欧美日韩| 麻豆国产97在线/欧美 | 国产爱豆传媒在线观看 | 精品福利观看| 亚洲男人天堂网一区| 后天国语完整版免费观看| 国产激情偷乱视频一区二区| 国产三级在线视频| 一级片免费观看大全| 久久婷婷人人爽人人干人人爱| 久久精品成人免费网站| 日日夜夜操网爽| 婷婷精品国产亚洲av在线| 日本免费a在线| 欧洲精品卡2卡3卡4卡5卡区| 久久久久久免费高清国产稀缺| 麻豆国产97在线/欧美 | 99国产极品粉嫩在线观看| 亚洲九九香蕉| 国内久久婷婷六月综合欲色啪| 亚洲熟女毛片儿| 中文字幕人妻丝袜一区二区| av片东京热男人的天堂| 欧美精品啪啪一区二区三区| 美女高潮喷水抽搐中文字幕| 免费在线观看亚洲国产| 婷婷精品国产亚洲av| 免费电影在线观看免费观看| 美女 人体艺术 gogo| 国产亚洲精品一区二区www| 五月伊人婷婷丁香| 青草久久国产| 欧美日韩国产亚洲二区| 国产精品久久久人人做人人爽| 后天国语完整版免费观看| 99久久99久久久精品蜜桃| 国产成人系列免费观看| 俺也久久电影网| 免费观看精品视频网站| 久久人人精品亚洲av| 99国产精品一区二区蜜桃av| 高潮久久久久久久久久久不卡| 久久欧美精品欧美久久欧美| 精品久久久久久久末码| 亚洲在线自拍视频| 亚洲乱码一区二区免费版| 亚洲aⅴ乱码一区二区在线播放 | 我要搜黄色片| 中文字幕最新亚洲高清| 国产精品久久久久久亚洲av鲁大| 久久亚洲真实| 波多野结衣巨乳人妻| 国产三级在线视频| 黄片大片在线免费观看| 午夜日韩欧美国产| 亚洲国产看品久久| 好男人在线观看高清免费视频| 91九色精品人成在线观看| 男女下面进入的视频免费午夜| 久久久久九九精品影院| 久久精品国产综合久久久| 男女下面进入的视频免费午夜| 毛片女人毛片| 亚洲成av人片在线播放无| 日韩精品免费视频一区二区三区| 亚洲欧美日韩高清专用| 日韩国内少妇激情av| 宅男免费午夜| 最新在线观看一区二区三区| 久久久久久免费高清国产稀缺| 舔av片在线| 色尼玛亚洲综合影院| 一区二区三区高清视频在线| 岛国在线免费视频观看| 成人欧美大片| 色噜噜av男人的天堂激情| 亚洲欧美日韩高清专用| 又黄又粗又硬又大视频| 中文字幕人妻丝袜一区二区| 成人三级做爰电影| 国产高清视频在线播放一区| 亚洲欧美一区二区三区黑人| 91老司机精品| av国产免费在线观看| 亚洲五月婷婷丁香| 两性午夜刺激爽爽歪歪视频在线观看 | 18禁黄网站禁片午夜丰满| 亚洲最大成人中文| 十八禁网站免费在线| 亚洲免费av在线视频| 小说图片视频综合网站| 国产精品精品国产色婷婷| 久久伊人香网站| 老熟妇仑乱视频hdxx| 亚洲av第一区精品v没综合| 久久久久久久久免费视频了| 村上凉子中文字幕在线| 成年人黄色毛片网站| 特级一级黄色大片| 变态另类丝袜制服| 在线播放国产精品三级| 欧美日本亚洲视频在线播放| 香蕉国产在线看| 一本大道久久a久久精品| 久久精品aⅴ一区二区三区四区| 精品熟女少妇八av免费久了| 日本成人三级电影网站| 丝袜美腿诱惑在线| 久久午夜综合久久蜜桃| 97人妻精品一区二区三区麻豆| 亚洲五月婷婷丁香| 国产精品一区二区三区四区免费观看 | 动漫黄色视频在线观看| 久久精品国产亚洲av高清一级| 亚洲在线自拍视频| 久久这里只有精品中国| 精品一区二区三区四区五区乱码| 夜夜看夜夜爽夜夜摸| 亚洲性夜色夜夜综合| 久久久久精品国产欧美久久久| 97碰自拍视频| 久久九九热精品免费| 国产午夜精品论理片| 岛国视频午夜一区免费看| 狂野欧美激情性xxxx| 亚洲中文字幕一区二区三区有码在线看 | 免费人成视频x8x8入口观看| 黑人操中国人逼视频| 国产私拍福利视频在线观看| 国产亚洲欧美98| 日韩中文字幕欧美一区二区| 免费搜索国产男女视频| 久久精品亚洲精品国产色婷小说| 国产三级黄色录像| 国产aⅴ精品一区二区三区波| 日本五十路高清| 91国产中文字幕| 欧美 亚洲 国产 日韩一| 99精品欧美一区二区三区四区| 亚洲第一欧美日韩一区二区三区| 亚洲专区中文字幕在线| 男人的好看免费观看在线视频 | 俺也久久电影网| 欧美 亚洲 国产 日韩一| 变态另类丝袜制服| 丰满人妻熟妇乱又伦精品不卡| 久久久久久人人人人人| 国产精品久久视频播放| 两性午夜刺激爽爽歪歪视频在线观看 | 色尼玛亚洲综合影院| 亚洲真实伦在线观看| 亚洲成av人片免费观看| 久久久久国产精品人妻aⅴ院| 免费高清视频大片| 精品第一国产精品| 亚洲精品久久成人aⅴ小说| 精品熟女少妇八av免费久了| 久久久久久免费高清国产稀缺| 久久久久久久精品吃奶| 五月玫瑰六月丁香| 午夜成年电影在线免费观看| 巨乳人妻的诱惑在线观看| 国产精品美女特级片免费视频播放器 | 亚洲精品在线美女| 日本免费a在线| 国产av麻豆久久久久久久| 亚洲激情在线av| 国产成人欧美在线观看| 国产精品久久久久久亚洲av鲁大| 日韩有码中文字幕| 身体一侧抽搐| 两性夫妻黄色片| 国语自产精品视频在线第100页| 欧美一区二区国产精品久久精品 | 日韩精品免费视频一区二区三区| 少妇的丰满在线观看| 日本免费一区二区三区高清不卡| 香蕉国产在线看| 婷婷亚洲欧美| 男女之事视频高清在线观看| 9191精品国产免费久久| 哪里可以看免费的av片| 50天的宝宝边吃奶边哭怎么回事| 国产又色又爽无遮挡免费看| 精品久久蜜臀av无| 久久久久久免费高清国产稀缺| 在线观看美女被高潮喷水网站 | 美女免费视频网站| x7x7x7水蜜桃| 12—13女人毛片做爰片一| 99riav亚洲国产免费| 国产精品国产高清国产av| 国产一区二区三区在线臀色熟女| 黄色毛片三级朝国网站| 麻豆国产97在线/欧美 | 久久中文看片网| 午夜福利成人在线免费观看| 国产成人系列免费观看| 免费看日本二区| 日韩精品青青久久久久久| 真人一进一出gif抽搐免费| 国产精品一区二区精品视频观看| 人成视频在线观看免费观看| 欧美性长视频在线观看| 亚洲av第一区精品v没综合| 久久精品国产综合久久久| 久久香蕉国产精品| 国产99久久九九免费精品| 国产91精品成人一区二区三区| 精品久久久久久成人av| 97人妻精品一区二区三区麻豆| 操出白浆在线播放| 亚洲国产高清在线一区二区三| 国产精品av久久久久免费| 在线看三级毛片| 全区人妻精品视频| 啪啪无遮挡十八禁网站| 不卡av一区二区三区| 亚洲无线在线观看| 一级毛片高清免费大全| 国产精品日韩av在线免费观看| 久久久精品大字幕| 五月玫瑰六月丁香| 欧美最黄视频在线播放免费| 久久精品影院6| 99热这里只有是精品50| 免费在线观看完整版高清| 法律面前人人平等表现在哪些方面| 亚洲欧美日韩无卡精品| 精品久久蜜臀av无| 国产不卡一卡二| 狂野欧美激情性xxxx| 2021天堂中文幕一二区在线观| 18禁黄网站禁片午夜丰满| 99久久久亚洲精品蜜臀av| 18禁裸乳无遮挡免费网站照片| 好看av亚洲va欧美ⅴa在| 久久久久久大精品| 人人妻人人看人人澡| 琪琪午夜伦伦电影理论片6080| 成人一区二区视频在线观看| 亚洲国产欧洲综合997久久,| 国产精品电影一区二区三区| 精品乱码久久久久久99久播| 日本一本二区三区精品| 免费看a级黄色片| 99热6这里只有精品| 又粗又爽又猛毛片免费看| 一级作爱视频免费观看| 亚洲专区中文字幕在线| 久9热在线精品视频| 熟女电影av网| 嫁个100分男人电影在线观看| 久热爱精品视频在线9| 老鸭窝网址在线观看| 欧美日韩瑟瑟在线播放| 男女视频在线观看网站免费 | 久久精品成人免费网站| 夜夜看夜夜爽夜夜摸| 日本一二三区视频观看| 人妻夜夜爽99麻豆av| 男人的好看免费观看在线视频 | 欧美日韩福利视频一区二区| 精品电影一区二区在线| 好男人在线观看高清免费视频| 亚洲国产高清在线一区二区三| 黄片大片在线免费观看| 黄色 视频免费看| 一级作爱视频免费观看| 久久欧美精品欧美久久欧美| 欧美色欧美亚洲另类二区| 97碰自拍视频| a在线观看视频网站| 精品少妇一区二区三区视频日本电影| 国产成人影院久久av| 在线a可以看的网站| 亚洲黑人精品在线| 亚洲色图av天堂| 一级片免费观看大全| 亚洲色图av天堂| 久久精品91无色码中文字幕| 精品国产亚洲在线| 久久精品成人免费网站| 不卡一级毛片| 中亚洲国语对白在线视频| 国产精品一区二区三区四区免费观看 | 精品一区二区三区av网在线观看| 国产成年人精品一区二区| 亚洲在线自拍视频| 国产黄a三级三级三级人| 精品久久久久久久人妻蜜臀av| av有码第一页| 精品久久久久久久人妻蜜臀av| 亚洲av电影在线进入| 午夜日韩欧美国产| 精品免费久久久久久久清纯| 国产精品98久久久久久宅男小说| 日韩大码丰满熟妇| 国产高清视频在线播放一区| xxxwww97欧美| 欧美在线黄色| 日韩欧美国产在线观看| 99在线人妻在线中文字幕| 久久 成人 亚洲| 舔av片在线| 熟妇人妻久久中文字幕3abv| 免费搜索国产男女视频| 久久精品91蜜桃| 久9热在线精品视频| 久久精品人妻少妇| 久久草成人影院| 男人舔女人下体高潮全视频| 成人18禁高潮啪啪吃奶动态图| 免费在线观看完整版高清| 国产探花在线观看一区二区| 成在线人永久免费视频| 国产精品国产高清国产av| 国产成人精品久久二区二区91| 亚洲欧美日韩东京热| 母亲3免费完整高清在线观看| 一边摸一边做爽爽视频免费| 亚洲人成电影免费在线| 女人高潮潮喷娇喘18禁视频| 精品久久久久久成人av| 岛国视频午夜一区免费看| 国产激情欧美一区二区| 俄罗斯特黄特色一大片| 日韩精品中文字幕看吧| 国产成人影院久久av| 每晚都被弄得嗷嗷叫到高潮| 99久久精品国产亚洲精品| av中文乱码字幕在线| 国产成人欧美在线观看| 一进一出好大好爽视频| 一级毛片精品| 国产亚洲精品久久久久5区| 欧美激情久久久久久爽电影| 人妻夜夜爽99麻豆av| 成人av在线播放网站| 婷婷精品国产亚洲av在线| 久久草成人影院| 99久久精品热视频| 99精品在免费线老司机午夜| 精品国产乱码久久久久久男人| www日本在线高清视频| a级毛片在线看网站| 妹子高潮喷水视频| 免费在线观看亚洲国产| 久久精品夜夜夜夜夜久久蜜豆 | 少妇人妻一区二区三区视频| 正在播放国产对白刺激| 国产精品日韩av在线免费观看| 国产精品亚洲美女久久久| 老鸭窝网址在线观看| 999久久久精品免费观看国产| 欧美日韩福利视频一区二区| 丁香欧美五月| 久久热在线av| 90打野战视频偷拍视频| 老熟妇乱子伦视频在线观看| 后天国语完整版免费观看| 午夜免费成人在线视频| svipshipincom国产片| 99精品欧美一区二区三区四区| 看黄色毛片网站| 日日干狠狠操夜夜爽| 中文亚洲av片在线观看爽| 国产成人aa在线观看| 丁香欧美五月| 天堂影院成人在线观看| 99在线人妻在线中文字幕| 国产伦在线观看视频一区| 日本 欧美在线| 每晚都被弄得嗷嗷叫到高潮| 国产成人av教育| 日韩 欧美 亚洲 中文字幕| 黑人欧美特级aaaaaa片| 精品久久久久久久毛片微露脸| 久久久久免费精品人妻一区二区| 亚洲国产欧美一区二区综合| ponron亚洲| 精品欧美一区二区三区在线| 88av欧美| 久久精品亚洲精品国产色婷小说| 国产成人影院久久av| 久久精品人妻少妇| 蜜桃久久精品国产亚洲av| 亚洲av成人av| 久久精品亚洲精品国产色婷小说| a在线观看视频网站| 伊人久久大香线蕉亚洲五| 精品欧美一区二区三区在线| 日本精品一区二区三区蜜桃| 中文资源天堂在线| 免费看十八禁软件| 久久久久亚洲av毛片大全| 一卡2卡三卡四卡精品乱码亚洲| 五月玫瑰六月丁香| 欧美日韩国产亚洲二区| 国产精品 国内视频| 每晚都被弄得嗷嗷叫到高潮| 91麻豆av在线| 国产欧美日韩精品亚洲av| 一本综合久久免费| 在线观看免费日韩欧美大片| 午夜影院日韩av| 天堂影院成人在线观看| 久久久精品欧美日韩精品| 婷婷精品国产亚洲av| 久99久视频精品免费| 亚洲国产看品久久| 可以在线观看毛片的网站| 亚洲av第一区精品v没综合| 国产午夜福利久久久久久| 亚洲一区高清亚洲精品| 亚洲男人天堂网一区| 国产伦一二天堂av在线观看| 午夜福利视频1000在线观看| 日韩成人在线观看一区二区三区| 最新美女视频免费是黄的| 国产精品自产拍在线观看55亚洲| 亚洲精品一卡2卡三卡4卡5卡| 18禁黄网站禁片午夜丰满| 亚洲片人在线观看| 黄色毛片三级朝国网站| 久久亚洲真实| 日韩精品青青久久久久久| 国内久久婷婷六月综合欲色啪| 久久久国产精品麻豆| 亚洲精品一卡2卡三卡4卡5卡| 国产麻豆成人av免费视频| 草草在线视频免费看| 久久久久久人人人人人| 少妇的丰满在线观看| 亚洲国产欧洲综合997久久,| 欧美日韩瑟瑟在线播放| 在线观看免费午夜福利视频| 男女做爰动态图高潮gif福利片| 国产精品电影一区二区三区| 啪啪无遮挡十八禁网站| 国产三级中文精品| 人妻久久中文字幕网| 国产精品久久久人人做人人爽| 亚洲天堂国产精品一区在线| 天堂动漫精品| 国产蜜桃级精品一区二区三区| 亚洲黑人精品在线| 好看av亚洲va欧美ⅴa在| 日本黄大片高清| a级毛片在线看网站| 午夜日韩欧美国产| 久久久国产精品麻豆| 亚洲av成人一区二区三| 亚洲av成人av| 精品久久久久久久久久免费视频| 午夜a级毛片| 熟女少妇亚洲综合色aaa.| 美女午夜性视频免费| 国产成人一区二区三区免费视频网站| 动漫黄色视频在线观看| 男人的好看免费观看在线视频 | 小说图片视频综合网站| 又大又爽又粗| 全区人妻精品视频| 中亚洲国语对白在线视频| av免费在线观看网站| 最近最新中文字幕大全免费视频| 两性午夜刺激爽爽歪歪视频在线观看 | or卡值多少钱| 中文字幕高清在线视频| 黄色视频,在线免费观看| 99国产精品一区二区三区| 亚洲aⅴ乱码一区二区在线播放 | 男女视频在线观看网站免费 | 日本一二三区视频观看| 人妻夜夜爽99麻豆av| 十八禁人妻一区二区| 精品国产超薄肉色丝袜足j| 国产成人影院久久av| 久久精品91蜜桃| 一本一本综合久久| 免费在线观看影片大全网站| 亚洲一卡2卡3卡4卡5卡精品中文| 日韩免费av在线播放| 午夜老司机福利片| 久久久国产欧美日韩av| 欧美极品一区二区三区四区| 两个人免费观看高清视频| 高清在线国产一区| 中文字幕人妻丝袜一区二区| 黄色毛片三级朝国网站| 在线观看美女被高潮喷水网站 | 国产黄片美女视频| 十八禁人妻一区二区| 老熟妇仑乱视频hdxx| 97超级碰碰碰精品色视频在线观看| 国产成人系列免费观看| 熟女少妇亚洲综合色aaa.| 日本精品一区二区三区蜜桃| 亚洲自偷自拍图片 自拍| 午夜精品久久久久久毛片777| 少妇人妻一区二区三区视频| 亚洲avbb在线观看| 宅男免费午夜| 欧美最黄视频在线播放免费| 90打野战视频偷拍视频| 在线观看舔阴道视频|