盐酸伊立替康脂质体的制备及体外释药特性研究

目的:制备盐酸伊立替康脂质体并考察其体外释药特性。方法:采用硫酸铵梯度法,通过正交试验进行盐酸伊立替康脂质体处方筛选和制备工艺研究;采用透析法考察体外释放度。结果:制备的盐酸伊立替康脂质体包封率较高,达到75·4%;通过正交设计确定最佳处方为磷脂与胆固醇质量比为2:1,硫酸铵溶液浓度为0·20mol·mL-1,孵育温度为50℃,药脂比为1:10;脂质体中药物1h释放8·09%,9h释放64·2%。结论:制备的盐酸伊立替康脂质体具有较高包封率和缓释特性。     

盐酸伊立替康脂质体制备的影响因素考察

目的:对盐酸伊立替康的脂质体制备方法进行考察。方法:在预实验的基础上初步确定盐酸伊立替康脂质体的制备方法和处方,然后通过单因素考察初步确定影响脂质体制备的因素。结果:硫酸铵梯度法制备的盐酸伊立替康脂质体包封率较高(75.40%),且能保持药物活性。结论:采用硫酸铵梯度法制备脂质体给药系统,制备工艺简单,重现性好,质量稳定,是一种很有前途的靶向给药系统。     

盐酸伊立替康脂质体的制备及体外抗肿瘤活性

采用硫酸铵梯度法制得了平均粒径为(45.3±12.6) nm、包封率为(93.8±0.7)％的盐酸伊立替康脂质体.制品在pH7.4磷酸盐缓冲液中约120 h释放完全,提示其具有缓释作用.体外细胞毒性试验显示,制品在较高浓度(25 μg/ml以上)对人结肠癌细胞株HT-29的抑制作用稍优于游离药物,IC50分别为28.1和33.0 μg/ml.细胞凋亡试验表明,30 μg/ml的脂质体和游离药物均能诱导HT-29细胞的凋亡,与游离药物相比,脂质体具有更强的凋亡诱导效果.     

乙二胺四乙酸铵梯度法制备盐酸伊立替康脂质体

目的制备盐酸伊立替康脂质体,考察包封率及粒径的影响因素。方法采用乙二胺四乙酸铵梯度法制备盐酸伊立替康脂质体,以阳离子交换树脂分离脂质体和游离药物,并以紫外分光光度法和激光粒度仪分别测定盐酸伊立替康脂质体的包封率和粒径;考察不同处方和制备工艺对脂质体包封率及粒径的影响。结果通过处方工艺优化,盐酸伊立替康脂质体包封率达到95.73%,粒径为112.8 nm。结论以乙二胺四乙酸铵梯度法制备的盐酸伊立替康脂质体包封率较高,方法可行。     

乙醇对盐酸伊立替康脂质体粒径及包封率的影响

目的考察乙醇对盐酸伊立替康脂质体粒径及包封率的影响。方法以阳离子交换树脂分离游离药物和脂质体,并以紫外分光光度法和激光粒度仪分别测定脂质体的包封率和粒径;考察24 h内,空白脂质体、梯度脂质体及盐酸伊立替康载药脂质体在体积分数分别为0%、5%、10%、15%、20%、25%的乙醇溶液中粒径及包封率的变化。结果在乙醇体积分数不超过10%范围内,空白脂质体、梯度脂质体及盐酸伊立替康脂质体的粒径与包封率基本无变化;当乙醇体积分数达到15%及以上时,粒径随时间的延长逐渐增大,而包封率逐渐下降,包封率下降最高可达64.51%。结论在盐酸伊立替康脂质体的制备过程中,一定量的乙醇会对脂质体的粒径及包封率产生严重影响,控制乙醇体积分数不大于10%,脂质体的粒径及包封率基本无变化。     

注射用盐酸伊立替康过敏反应2例

患者：女。43岁，因间歇便血半年余，无诉腹痛腹胀等不适症状。近1个月来便血加重，体重下降3～3．5kg。来门诊检后拟“直肠肿块”收住入院。7月12日，充分肠道准备后在全麻下行“肠镜检查”。肠镜检查后提示为“直肠癌”。7月15日，在连续硬膜外麻醉下行“直肠癌根治术”术后予以美士林、氨甲苯酸、脂肪乳剂及乐凡命等抗感染、止血及能量支持疗法。7月22日停输液。7月25日创口愈合良好，予以创口拆线。7月27日主管医师与家属谈话后，家属同意予以盐酸伊立替康、亚叶酸钙、氟尿苷联合化疗，化疗前30min予以昂丹司琼推注。     

复方盐酸伊立替康和氟尿嘧啶脂质体注射液包封率测定方法研究

目的 测定复方脂质体注射液中盐酸伊立替康与氟尿嘧啶包封率。方法 采用凝胶柱层析法,以pH 6.5的磷酸盐缓冲溶液为洗脱剂,柱高400 mm,洗脱流速为1.0 mL·min^-1。在建立的HPLC-DAD色谱条件下同时测定。使用Kromasil C₁₈柱（250 mm×4.6 mm,5 μm）,以甲醇-pH 6.6磷酸缓冲盐（5∶95）为流动相A,以甲醇-pH 6.6磷酸缓冲盐（60∶40）为流动相B,梯度洗脱。柱温35℃,流速1.0 mL·min^-1。检测波长分别为255,268 nm。结果 该方法能有效分离复方脂质体注射液中包封药物和游离药物。3种不同试验水平下,盐酸伊立替康柱回收率分别为98.9%,100.5%,100.4%;氟尿嘧啶柱回收率分别为98.2%,100.5%,100.2%。在液相色谱条件下,复方脂质体注射液中盐酸伊立替康与氟尿嘧啶能很好地分离检出,其线性浓度范围分别为10.7~107.0 μg·mL^-1（r=0.999 9,n=5）,3.9~38.6 μg·mL^-1（r=1.000 0,n=5）,呈良好的线性关系;盐酸伊立替康低、中、高浓度加样回收率分别为99.7%,99.0%,99.8%,RSD分别为0.20%,0.48%,1.38%;氟尿嘧啶低、中、高浓度加样回收率分别为100.3%,100.6%,99.8%,RSD分别为0.72%,0.09%,0.67%。结论 本方法简单,准确,重复性好,可用于测定复方脂质体中盐酸伊立替康、氟尿嘧啶2种药物的包封率。     

盐酸伊立替康脂质体的制备及包封率的测定

目的制备盐酸伊立替康脂质体,建立包封率测定方法。方法采用乙二胺四乙酸铵梯度法制备盐酸伊立替康脂质体;以阳离子交换树脂离心法分离脂质体和游离药物;采用紫外可见分光光度法测定脂质体包封率。结果阳离子交换树脂柱对质量浓度为1.0~2.4 g.L-1伊立替康能够完全吸附,且对空白脂质体无吸附,空白脂质体回收率达99.73%;采用紫外可见分光光度法测定盐酸伊立替康含量,在372 nm波长下,空白辅料对药物测定无干扰,盐酸伊立替康质量浓度在2.5~45.0 mg.L-1内线性关系良好(r=0.999 9),精密度和回收率均符合要求;盐酸伊立替康脂质体包封率为95.4%。结论乙二胺四乙酸铵梯度法适用于制备盐酸伊立替康脂质体,所建立的分析方法简单快速,准确可靠,可用于盐酸伊立替康脂质体包封率的测定。     

盐酸伊立替康脂质体载药方式的研究进展

目的:介绍盐酸伊立替康(CPT-11)脂质体的载药方式,为其进一步研发提供参考。方法:根据文献,综述了硫酸铵梯度法、pH梯度法、二价阳离子载体A23187联合硫酸铜溶液法、金属离子梯度法和六磷酸肌醇作为载入剂等5种CPT-11脂质体的载药方式。结果与结论:利用上述载药方式所制备的CPT-11脂质体的包封率均大于90%。随着脂质体制备和研究技术的不断提高,开发长效、靶向的CPT-11脂质体,进而提高药物的治疗指数、优化药物的给药剂量和降低药物的毒副作用,已成为国内、外学者研究的热点。     

HPLC法测定盐酸伊立替康的有关物质

目的建立盐酸伊立替康中有关物质的分离测定方法。方法十八烷基硅烷键合硅胶为固定相,磷酸盐(pH4.0)-乙腈-甲醇为流动相,检测波长220 nm。结果杂质与伊立替康分离度良好,精密度、重复性、溶液稳定性结果良好。结论本方法可以用于盐酸伊立替康中有关物质的检测。     

盐酸吉西他滨壳聚糖纳米粒的制备及其体外释药特性研究

目的:优化盐酸吉西他滨壳聚糖纳米粒的制备参数,考察纳米粒体外释药特性。方法:以壳聚糖为辅料,采用离子交联法制备盐酸吉西他滨壳聚糖纳米粒,以包封率、载药量、粒径为参考指标设计试验,确定优化制备参数,以透射电镜观察其表观特征,考察纳米粒体外释药程度。结果:以优化参数制备的盐酸吉西他滨壳聚糖纳米粒包封率为(78.93±1.52)%,载药量为(11.71±0.88)%,纳米粒的平均粒径为(169±24)nm,体外释放试验表明纳米粒中盐酸吉西他滨的释放过程符合Higuchi方程。结论:盐酸吉西他滨可以通过离子交联法制备壳聚糖纳米粒,其粒径、包封率、载药量可控,具有缓释效果。     

盐酸环丙沙星壳聚糖纳米粒原位凝胶的制备与评价

目的 制备盐酸环丙沙星壳聚糖纳米粒原位凝胶,并评价其抑菌及创面愈合效果。方法 采用复乳法制备盐酸环丙沙星壳聚糖纳米粒,采用2因素2水平全因子析因实验设计考察了壳聚糖相对分子质量（X₁）和壳聚糖质量浓度（X₂）对壳聚糖纳米粒的药物包封率（Y₁）、粒径分布（Y₂）、多分散系数（Y₃）和Zeta电位（Y₄）的影响;并以泊洛沙姆407作为凝胶基质制备盐酸环丙沙星壳聚糖纳米粒原位凝胶。通过抑菌圈实验比较盐酸环丙沙星乳膏和盐酸环丙沙星壳聚糖纳米粒原位凝胶对金黄色葡萄球菌和铜绿假单胞菌的抑菌活性;使用无菌活检穿刺针在大鼠背部造成直径为5 mm的皮肤全切除的圆形人工创面,并使用金黄色葡萄球菌和铜绿假单胞菌的培养基感染24 h,建立大鼠创面模型,将模型大鼠随机分为模型组、盐酸环丙沙星乳膏组和盐酸环丙沙星壳聚糖纳米粒原位凝胶组,模型组大鼠创面未接受任何处理,给药组大鼠每2天给药1次,每次给药量均约为1 mg,观察并记录每组大鼠创面脱痂时间和愈合时间。结果 选择低相对分子质量壳聚糖、壳聚糖质量浓度为2.0 mg·mL^-1制备盐酸环丙沙星壳聚糖纳米粒,其中盐酸环丙沙星质量浓度为50.0 mg·mL^-1,其包封率为（85.3±0.9）%,平均粒径为（354.7±15.7）nm,PDI为0.357±0.014,Zeta电位为（22.2±0.5）mV,呈球状分布;盐酸环丙沙星壳聚糖纳米粒原位凝胶和盐酸环丙沙星乳膏对金黄色葡萄球菌的抑菌圈直径分别为（38.4±0.2）、（29.2±0.3）mm,对铜绿假单胞菌抗菌圈直径分别为（41.3±0.6）、（32.1±0.1）mm;大鼠创面给予盐酸环丙沙星壳聚糖纳米粒原位凝胶后,其脱痂时间和愈合时间均较模型组和盐酸环丙沙星乳膏组显著缩短（P<0.05）。结论 成功制备盐酸环丙沙星壳聚糖纳米粒原位凝胶,其可以抑制创面细菌繁殖、加速伤口愈合。     

盐酸普萘洛尔凝胶的制备及质量评价

目的 制备用于婴幼儿血管瘤的盐酸普萘洛尔(PPL· HCI)外用凝胶,并对其进行质量评价.方法 以羟丙甲基纤维素(HPMC)为基质,用直接溶胀法制备PPL· HCI凝胶.以体外经皮累积渗透量(Q)为指标,筛选HPMC用量和载药量;并以锥入度、pH值、家兔皮肤刺激性等为指标,对凝胶进行评价.结果 HPMC用量为2.5％,载药量为5％时,PPL·HCl凝胶具有最高的经皮累积渗透量,凝胶外观呈乳白色半固态、细腻均匀,pH约为7.0,40℃恒温条件下保存30 d稳定.单次、多次给予家兔正常及破损皮肤均无刺激性.结论 所制PPL·HCl凝胶性质稳定,质量可控.该制剂为PPL·HCl外用治疗血管瘤的研究开发奠定了基础.     

Preparation and in vitro evaluation of thienorphine-loaded PLGA nanoparticles

Poly (d,l-lactic-co-glycolide) nanoparticles (PLGA-NPs) have attracted considerable interest as new delivery vehicles for small molecules, with the potential to overcome issue such as poor drug solubility and cell permeability. However, their negative surface charge decreases bioavailability under oral administration. Recently, cationically modified PLGA-NPs has been introduced as novel carriers for oral delivery. In this study, our aim was to introduce and evaluate the physiochemical characteristics and bioadhesion of positively charged chitosan-coated PLGA-NPs (CS-PLGA-NPs), using thienorphine as a model drug. These results indicated that both CS-PLGA-NPs and PLGA-NPs had a narrow size distribution, averaging less than 130?nm. CS-PLGA-NPs was positively charged (+42.1?±?0.4?mV), exhibiting the cationic nature of chitosan, whereas PLGA-NPs showed a negative surface charge (?2.01?±?0.3?mV). CS-PLGA-NPs exhibited stronger bioadhesive potency than PLGA-NPs. Furthermore, the transport of thienorphine-CS-PLGA-NPs by Caco-2 cells was higher than thienorphine-PLGA-NPs or thienorphine solution. CS-PLGA-NPs were also found to significantly enhance cellular uptake compared with PLGA-NPs on Caco-2 cells. An evaluation of cytotoxicity showed no increase in toxicity in either kind of nanoparticles during the formulation process. The study proves that CS-PLGA-NPs can be used as a vector in oral drug delivery systems for thienorphine due to its positive surface charge and bioadhesive properties.     

Preparation and in vitro evaluation of bFGF-loaded chitosan nanoparticles

The objective of our study was to prepare and characterize basic fibroblast growth factor (bFGF)-loaded nanoparticles. Protein-loaded chitosan nanoparticles were obtained by ionotropic gelation process based on the interaction between chitosan and tripolyphosphate (TPP). The protein-loading capacity and encapsulation efficiency were 0.021% and 27.388%, respectively. The bFGF-loaded nanoparticles have a mean diameter of 424 nm, a narrow size distribution, spherical shape and positive surface charges. In vitro release showed that the extent of release was 68% at 24 hr. The protein integrity was investigated by SDS-PAGE analysis that confirmed protein integrity was not affected by the encapsulation procedure and release conditions.     

Preparation and in vitro evaluation of heparin-loaded polymeric nanoparticles

Nanoparticles of a highly soluble macromolecular drug, heparin, were formulated with two biodegradable polymers (poly-E-caprolactone [PCL] and poly (D, L-lactic-co-glycolic-acid) 50/50 [PLAGA]) and two nonbiodegradable positively charged polymers (Eudragit RS and RL) by the double emulsion and solvent evaporation method, using a high-pressure homogenization device. The encapsulation efficiency and heparin release profiles were studied as a function of the type of polymers employed (alone or in combination) and the concentration of heparin. Optimal encapsulation efficiency was observed when 5000 IU of heparin were incorporated in the first emulsion. High drug entrapment efficiency was observed in both Eudragit RS and RL nanoparticles (60% and 98%, respectively), compared with PLAGA and PCL nanoparticles (<14%). The use of the two types of Eudragit in combination with PCL and PLAGA increased the encapsulation efficiency compared with these two biodegradable polymers used alone; however, the in vitro drug release was not modified and remained low. On the other hand, the addition of esterase to the dissolution medium resulted in a significant increase in heparin release. The in vitro biological activity of released heparin, evaluated by measuring the anti-Xa activity by a colorimetric assay, was conserved after the encapsulation process.     

Preparation of E-selectin-targeting nanoparticles and preliminary in vitro evaluation

Targeted delivery aims to concentrate therapeutic agents at their site of action and thereby enhance treatment and limit side-effects. E-selectin on endothelial cells is markedly up-regulated by cytokine stimulation of inflamed and some tumoral tissues, promoting the adhesion of leukocytes and metastatic tumor cells, thus making it an interesting molecular target for drug delivery systems. We report here the preparation of targeted nanoparticles from original amphiphilic block copolymers functionalized with an analog of sialyl Lewis X (SLEx), the physiological ligand of E-selectin. Nanoparticles, prepared by nanoprecipitation, caused no significant cytotoxicity. Ligand-functionalized nanoparticles were specifically recognized and internalized better by tumor necrosis factor α (TNF-α)-activated human umbilical vein endothelial cells (HUVECs) than control nanoparticles or HUVECs with low E-selectin expression. These nanoparticles are designed to carry the ligand at the end of a PEG spacer to improve accessibility. This system has potential for the treatment of inflammation, inhibition of tumor metastasis, and for molecular imaging.     

葛根素磷脂复合物纳米粒的制备及体外评价

目的制备葛根素磷脂复合物,以聚氰基丙烯酸正丁酯(PBCA)为载体材料,制备葛根素磷脂复合物纳米粒,并对其进行体外评价。方法采用界面缩合聚法制备纳米粒。以复合率、包封率和载药量为评价指标,通过单因素和正交试验法优选处方和工艺。结果葛根素磷脂复合物的最佳处方及工艺:反应溶剂为无水乙醇,葛根素与磷脂的投料比为1∶2;葛根素磷脂复合物纳米粒的最佳处方及工艺:pH=3.0、α-氰基丙烯酸正丁酯(α-BCA)的浓度为0.8%、V油相∶V水相=1∶60、葛根素磷脂复合物的投药量为1.0 mg。制备的纳米粒平均粒径为(115.1±3.45)nm、包封率为(90.03±1.80)%、载药量为(11.80±0.12)%。体外释药在24 h累积释放量约为80%。结论本研究所制备的葛根素磷脂复合物纳米粒包封率和载药量高、性质稳定、体外释药具有缓释行为。     

川芎嗪固体脂质纳米粒的制备及质量评价

目的制备川芎嗪固体脂质纳米粒并对其制剂性质进行评价。方法采用热熔乳化-高压均质技术制备川芎嗪固体脂质纳米粒,同时利用Box-Behnken效应面法优化其制剂处方,并通过微观形态、粒径分布、多聚分散系数(polydispersity index,Pd I)和Zeta电位、体外释药行为对川芎嗪固体脂质纳米粒的性质进行了评价。结果川芎嗪固体脂质纳米粒的最优处方构成:单硬脂酸甘油酯质量浓度为55 g·L~(-1)、大豆卵磷脂质量浓度为45 g·L~(-1)、脂药质量比为35∶1,制备的川芎嗪固体脂质纳米粒外观澄清透明、略带乳光状;透射电镜照片显示纳米粒大小均一,呈球形或类球形分布,测得平均粒径为(127.4±31.6)nm,Pd I为0.238,Zeta电位为(-11.5±0.9)m V;川芎嗪固体脂质纳米粒在12 h内累积释放度为95.3%。结论该处方可用于川芎嗪固体脂质纳米粒的制备,工艺简单易行,稳定可行。     

Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension

Revaprazan hydrochloride (RH) is a new reversible proton pump inhibitor. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To investigate the particle size reduction effect of RH on dissolution and absorption, three suspensions that containing different sized particles were prepared by high pressure homogenization and in vitro/in vivo evaluations were carried out. DSC and powder X-ray diffraction were used to study crystalline state of freeze dried powder of RH suspensions and the results showed that particles of RH microsuspension and nanosuspension remained in the same crystalline state as coarse suspension, but had lower lattice energy. In the in vitro dissolution test, both microsuspension and nanosuspension showed increased dissolution rate. In the in vivo evaluation, compared to coarse suspension, RH nanosuspension exhibited significant increase in AUC(0-t), C(max) and decrease in T(max), MRT. Nevertheless, RH microsuspension did not display any significant differences in these pharmacokinetic parameters compared to the coarse suspension. The findings revealed that particle size reduction can influence RH absorption in gastrointestinal tract and nanosuspension can enhance oral bioavailability of RH in rats.