新型聚（醚—酐）凝胶纳米粒用于难溶性药物增溶的研究
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摘要
对一些难溶性药物而言,它们在胃肠液中较低的溶解性严重影响了其口服吸收和生物利用度。目前,多种制剂方法包括用固体分散方法抑制药物结晶,利用表面活性剂体系增溶,形成包合物等可以提高药物溶出速率及其水溶性,但都各有优缺点。本课题通过对固体分散材料聚乙二醇(PEG)结构改造,形成可交联的大分子单体,以制备可载难溶性药物的凝胶纳米粒,从而达到药物增溶的目的。本课题首先运用各种合成方法和FT-IR,1H-NMR等分析技术,对构筑凝胶纳米粒的聚乙二醇大分子单体(macromer)及其原料甲基丙烯酸酐(MA)和聚乙二醇丁二酸半酯(PEGDA)进行了合成和表征。
然后采用乳化交联法,制备出了形态为球形或椭圆形,具有200-800nm粒径范围的凝胶纳米粒,并对其溶胀和降解等各种性能进行了表征。结果表明凝胶纳米粒的性能与交联密度和亲水/疏水性有关,随交联密度的增加和亲水性的增强,溶胀度增加,降解速率增大。为了改善凝胶纳米粒的性能,本课题还通过硬脂酸单丙烯酸酐(MSA)与聚乙二醇大分子单体在乳滴内共聚,制备出了具有核-壳结构的凝胶纳米粒,并且运用TEM和染色法对其结构进行了表征。
最后,分别以采用原位聚合和后包合的方法,将难溶性模型药物吲哚美辛和紫杉醇,载入凝胶纳米粒和具有核壳结构的凝胶纳米粒中,研究了凝胶纳米粒对难溶性药物的包载能力,并且用HPLC测定了载药粒子的药物含量和包封率,X-射线衍射和DSC分析检测了药物在凝胶纳米粒内的形态分布,并考察了凝胶纳米粒对药物的增溶效果。结果表明凝胶纳米粒对吲哚美辛和紫杉醇的包封与粒子的疏水性和交联密度有关,具有核-壳结构的凝胶纳米粒由于交联密度低和疏水性好,对两种药物具有最好的包封能力,包封率分别达到90%和85%以上。X-射线衍射和DSC分析表明吲哚美辛在凝胶纳米粒中呈无定型状态,并且可保持这种状态至少8个月,体外溶出实验表明凝胶纳米粒可明显提高药物的溶出速率,其中包封在具有核壳结构的凝胶纳米粒的吲哚美辛和紫杉醇的溶解度分别至少是原料药物的5倍和47倍。
For some poorly water-soluble drugs, their low dissolution rate in theenvironmental lumen limits their bioavailability via absorption into thegastrointestinaltract.Nowadays,severalformulationapproachesincludinginhibitingcrystallization to form amorphous particles by solid dispersion, decreasing thediffusion layer through improved wettability by, e.g., addition of surfactants, andcomplexation et al. have been used to increase the drug dissolution rate and therebyoral absorption and bioavailabilitywith various advantages and disadvantages. In thisthesis, the crosslinkable PEG-based macromer and starting materials-methacrylicanhydride and PEG disuccinate were successfully synthesized and characterized byvarious methods and FT-IR, 1H-NMR et al. The gel nanoparticles which werespherical or elliptoid in shape with nano-sized range, were formulated by in situphotocrosslinking of the two synthesized PEG-based macromers with differentmolecular weight in the oil/water microemulsion. The degradation and swellingperformance were investigated. The results inidicated that the prepared particlesexhibited various swelling capabilities in water and in vitro degradation rates underthe experimental conditions, depending on crosslinking density (molecular weight ofmacromer)andthehydrophilicsusceptibility(containingornotadditive).
Improve the capability of particles, the gel nanoparticles with core-shell structurewerepreparedbycopolymerizingmethacrylatedstearicacidandPEG-basedmacro-mer in the emulsion droplet, whose structure was characterzed by TEM andphosphotungsticaciddying.
Indomethacin and paclitaxel as two poorly water-soluble drugs were respectivelyembedded in the gel nanoparticles and the nanogel with core-shell structure and theentrapment efficiency was determined by HPLC method. The physical state ofindomethacin in the gel nanoparticles was detected by X-ray and DSC analysis. Thein vitro dissolution behavior of indomethacin from the gel particles was studied bydialysis method and water solubility determination. It was found that the drug wasstable in the fabrication process and high drug entrapment efficiencycan be achievedforthecore-shellnanogel,above92%forindomethacinand85%forpaclitaxel.X-rayand DSC analysis showed that indomethacin was amorphously or molecularlydistributed in the gel particles and no recrystallization of indomethacin at room temperaturewas observedintherepresentative gel particles overa period ofat least 8months. The in vitro dissolution experiment indicated that the dissolution rate ofindomethacin from gel nanopartilces was obviously improved and the solubility ofindomethacin and paclitaxel were respectively enhanced by5-fold and 47-fold by thecore-shellnanogel.
然后采用乳化交联法,制备出了形态为球形或椭圆形,具有200-800nm粒径范围的凝胶纳米粒,并对其溶胀和降解等各种性能进行了表征。结果表明凝胶纳米粒的性能与交联密度和亲水/疏水性有关,随交联密度的增加和亲水性的增强,溶胀度增加,降解速率增大。为了改善凝胶纳米粒的性能,本课题还通过硬脂酸单丙烯酸酐(MSA)与聚乙二醇大分子单体在乳滴内共聚,制备出了具有核-壳结构的凝胶纳米粒,并且运用TEM和染色法对其结构进行了表征。
最后,分别以采用原位聚合和后包合的方法,将难溶性模型药物吲哚美辛和紫杉醇,载入凝胶纳米粒和具有核壳结构的凝胶纳米粒中,研究了凝胶纳米粒对难溶性药物的包载能力,并且用HPLC测定了载药粒子的药物含量和包封率,X-射线衍射和DSC分析检测了药物在凝胶纳米粒内的形态分布,并考察了凝胶纳米粒对药物的增溶效果。结果表明凝胶纳米粒对吲哚美辛和紫杉醇的包封与粒子的疏水性和交联密度有关,具有核-壳结构的凝胶纳米粒由于交联密度低和疏水性好,对两种药物具有最好的包封能力,包封率分别达到90%和85%以上。X-射线衍射和DSC分析表明吲哚美辛在凝胶纳米粒中呈无定型状态,并且可保持这种状态至少8个月,体外溶出实验表明凝胶纳米粒可明显提高药物的溶出速率,其中包封在具有核壳结构的凝胶纳米粒的吲哚美辛和紫杉醇的溶解度分别至少是原料药物的5倍和47倍。
For some poorly water-soluble drugs, their low dissolution rate in theenvironmental lumen limits their bioavailability via absorption into thegastrointestinaltract.Nowadays,severalformulationapproachesincludinginhibitingcrystallization to form amorphous particles by solid dispersion, decreasing thediffusion layer through improved wettability by, e.g., addition of surfactants, andcomplexation et al. have been used to increase the drug dissolution rate and therebyoral absorption and bioavailabilitywith various advantages and disadvantages. In thisthesis, the crosslinkable PEG-based macromer and starting materials-methacrylicanhydride and PEG disuccinate were successfully synthesized and characterized byvarious methods and FT-IR, 1H-NMR et al. The gel nanoparticles which werespherical or elliptoid in shape with nano-sized range, were formulated by in situphotocrosslinking of the two synthesized PEG-based macromers with differentmolecular weight in the oil/water microemulsion. The degradation and swellingperformance were investigated. The results inidicated that the prepared particlesexhibited various swelling capabilities in water and in vitro degradation rates underthe experimental conditions, depending on crosslinking density (molecular weight ofmacromer)andthehydrophilicsusceptibility(containingornotadditive).
Improve the capability of particles, the gel nanoparticles with core-shell structurewerepreparedbycopolymerizingmethacrylatedstearicacidandPEG-basedmacro-mer in the emulsion droplet, whose structure was characterzed by TEM andphosphotungsticaciddying.
Indomethacin and paclitaxel as two poorly water-soluble drugs were respectivelyembedded in the gel nanoparticles and the nanogel with core-shell structure and theentrapment efficiency was determined by HPLC method. The physical state ofindomethacin in the gel nanoparticles was detected by X-ray and DSC analysis. Thein vitro dissolution behavior of indomethacin from the gel particles was studied bydialysis method and water solubility determination. It was found that the drug wasstable in the fabrication process and high drug entrapment efficiencycan be achievedforthecore-shellnanogel,above92%forindomethacinand85%forpaclitaxel.X-rayand DSC analysis showed that indomethacin was amorphously or molecularlydistributed in the gel particles and no recrystallization of indomethacin at room temperaturewas observedintherepresentative gel particles overa period ofat least 8months. The in vitro dissolution experiment indicated that the dissolution rate ofindomethacin from gel nanopartilces was obviously improved and the solubility ofindomethacin and paclitaxel were respectively enhanced by5-fold and 47-fold by thecore-shellnanogel.
引文
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[3] Ni N, Sanghvi T, Yalkowsky S H, Solubilization and preformulation ofcarbendazim,Int.J.Pharm.,2002,244(2):99~104.
[4] Sweetana S, Akers J M, Solubility principles and practices for parenteral drugdosageformdevelopment,PDAJ.Pharm.Sci.Technol.,1996,50(5):130~142.
[5] Li P, Solubilization of flurbiprofen in pH2-surfactant solutions, J Pharm Sci,2003,92(5):951~956.
[6] Yokoyama M, Sugiyama T, Okano T, et al., Analysis of micelle formation of anadriamycin conjugated poly (ethylene glycol)-poly(aspartic acid) block copoly-merbygelpermeationchromatography,Pharm.Res.,1993,10:895~899.
[7] Ahn K J, Him K M, Choi J S et al., Effects of cyclodextrin derivatives onbioavailabilityofketioprofen,DrugDev.Ind.Pharm.,1997,23(4):397~401.
[8] Serajuddin A T, Solid dispersion of poorly water-soluble drugs: early promises,subsequentproblemsandrecentbreakthroughs,J.Pharm.Sci.,1999,88:1058~1066.
[9] Hancock B C, Parks M, What is the true solubility advantage for amorphouspharmaceuticals,Pharm.Res.,2000,74:397~404.
[10] Chaw C S, Chooia K W, Liu X M, et al., Thermally responsive core-shellnanoparticles self-assembled from cholesteryl end-capped and graftedpolyacrylamides: drug incorporation and in vitro release, Biomaterials, 2004,25(18):4297~4308.
[11] Takeuchi H, Nagira S, Yamamoto H et al., Solid dispersion particles ofamorphous indomethacin with fine porous silica particles by using spray-dryingmethod,Int.J.Pharm.,2005,293:155~164.
[12] Singla A K, Garg A, Aggarwal D,et al., Paclitaxel and its formulation, Int. J.Pharm.,2002,235(1-2):179-184.
[13]CrocassoP,CerutiM,BrusaP,etal.Preparation,characterizationandproperitiesof stericallystabilized paclitaxel-containingliposomes, J. Control. Release, 2005,63(1-2):19-23.
[14]ShamaD,ChelviTP,kaurJ,et al.Thermosensitiveliposomal taxol formulation:heat-mediatedtargeteddrugdeliveryinmurinemelanoma,MelanomaRes.,1993,8(3):240-247.
[15] He L, Wang GL, Zhang Q, et al., An alternative paclitaxel mieroemulsionformulation:hypersensitivityevalutionandpharmeokinefieprofile.Int.J.Pharm.,2003,250(1):45-52.
[16] Zhang X C, Jackson J K, Burt H M, Development of amphiphilie diblock-copolymersasmicellarcarriersofTaxol,Int.J.Pharm.,1996,132(1-2):195-200.
[17] Kim S C, Kim D W, Shim Y H et a1., Nv/Vo evaluation of polymeric micellarpaclitaxel formulation: toxicityand efficacy, J. Control. Re1ease, 2001, 72(1-3):191-195.
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[19] Benee, L, Snowden, M J, Chowdhry B Z, Encyclopedia of Advanced Materials,NewYork:Wiley,2000.
[20] Lynch I, Dawson K A, Release of model compounds from “plum-pudding”-typegels composed of microgel particles randomlydispersed in a gel matrix, J. Phys.Chem.B,2004,108:10893~10898.
[21] Chan Y, Bulmus V, Zareie M H et al., Acid-cleavable polymeric core-shellparticles for delivery of hydrophobic drugs, J. Control. Release, doi:10.1016/j.jconrel.,2006.07.25.
[22] Lin S Y, Chen K S, Run C L, Design and evaluation of drug-loaded wounddressing having thermoresponsive, adhesive, absorptive and easy peelingproperties,Biomaterials2001,22:2999~3004.
[23] Lee W C, LiY C, Chu I M, Amphiphilic poly(D, L-lactic acid)/poly(ethyleneglycol)/poly(D, L-lactic acid) nanogels for controlled release of hydrophobicdrugs,Macromol.Biosci.,2006,6:846~854.
[24] Zhang Y, Zhu W, Wang B B et al., A novel microgel and associated post-fabrication encapsulation technique of proteins, J. Control. Release, 2005, 105:260~268.
[25] Kim Y H, Bae T O, Hydrogels: swelling, drug loading and release, Pharm. Res.,1992,9:283~290.
[26] Bromberg L, Temchenko M, Hatton T A. Dually responsive microgels frompolyether-modified poly(acrylic acid): swelling and drug Loading, Langmuir2002,18:4944~4952.
[27] Michael B M, Katherine S, Michael V P, Release of protein from highlycross-linked hydrogels of poly(ethylene glycol) diacrylate fabricated by UVpolymerization,Biomaterials,2001,22:929~941.
[28] Nguyen K T, West J L. Photopolymerizable hydrogels for tissue engineeringapplications,Biomaterials,2002,239:4307~4314.
[29] Muggli D S, Burkoth A K, Anseth K S. Crosslinked polyanhydrides for use inorthopedic applications: degradation behavior and mechanics, J. Biomed. Mater.Res.,1998,46:271~278.
[30] Kristi S A, Deborah J Q, Polymerizations of multifunctional anhydridemonomers to form highly crosslinked degradable network, Macromol. RapidCommun.,2001,22:564~572.
[31] Young J S, Gonzales K D, Anseth Kristi S, Photopolymers in orthopedics:characterization of novel crosslinked polyanhydrides, Biomaterials, 2000, 21:1181~1188.
[32] Sawhney A S, Pathak C P, Hubbell J A. Bioerodible hydrogels based onphotopoly-merized poly(ethylene glycol)-co-poly(α-hydroxy acid) diacrylatemacromers,Macromolecules,1993,26:581~587.
[33] Hill W J L, Dunn R C, Local release of fibrinolytic agents for adhesion preven-tion,J.Surg.Res.,1995,59:759~763.
[34] Fife W K, Zhang Z D, Polymer catalyzed synthesis of acid anhydride. UnitedStatesPatent,4874558,1989-10-17.
[35] Ptrice H,Denis L, Joseph R et al. Process for the synthesis of (meth) acrylicanhy-dride,UnitedStatesPatent,4857239,1989-08-15.
[36] Bardo S, Joachim K, Wolfgang K et al., Process for manufacturing unsaturatedcarboxylicacidanhydrides,UnitedStatesPatent,20020161260,2002-10-31.
[37] Burkoth A K, Anseth K S, A review of photocrosslinked polyanhydrides:in situformingdegradablenetworks,Biomaterials,2000,21(23):2395~2404.
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