肝动脉栓塞米托蒽醌乙基纤维素微球的制剂学研究

利用正交实验设计法优选适用于肝动脉栓塞的米托蒽醌乙基纤维素微球制备条件和工艺，采用动态透析法模拟体内情况研究了该微球的体外释药规律；根据混悬液的稳定性理论，优选并制备了适于临床肝动脉介导栓塞使用的米托蒽醌乙基纤维素微球混悬注射液。结果表明：在优化工艺条件下制得的米托蒽醌乙基纤维素微球外观圆整，球径在４０～１５０μｍ范围内的占总数的８６．５％，平均球径为１１０．２４±３８．１９μｍ；包封率为５５．６％；载药量为１２．５％，体外释药符合单指数模型，释药方程为ｌｏｇ（Ｙ∞－Ｙ）＝－０．１１６ｔ－１．１９８×１０（－３）（ｒ＝０．９９９２，ｔ（５０）＝２．６ｈ）；其混悬注射液理化性质稳定，可适于临床应用。     

肝靶向米托蒽醌白蛋白微球的研究

用乳化—热固化法制备了米托蒽醌白蛋白微球,并对其形态、大小及其分布、微粉学性质、载药性能、体外释药、稳定性和体内分布进行了研究。结果表明,该载药微球的平均算术径为0.99μm,平均表面径为1.24μm,平均容积径为1.44μm;表观载药量为2.558%±0.101%;有效载药量为1.503%±0.127%;包封率为92.82%±4.60%;体外释药符合双相动力学规律,释药方程为1-Q=0.6428e^-0.2132t+0.3988e^-000150t(γ₁=-0.9951,γ₂=-0.9982);T_1/2α=3.250h,T_1/2β=461.7h;室温放置3个月,微球形态、药物含量等均无明显变化。HPLC测定表明,小鼠尾iv该微球20min内即有77.6%±1.38%的药物浓集于肝脏,具有明显的肝靶向性。提示米托蒽醌白蛋白微球有可能提高米托蒽醌的抗肝癌效果和降低其全身毒副作用。     

米托蒽醌肝动脉栓塞羧甲基淀粉微球的研究

为进一步研究栓塞微球的制备工艺、体外释药规律及药动学与药效学之间的关系,以米托蒽醌为模型药物、羧甲基淀粉钠为载体材料、对苯二甲酰氯为交联剂,经均匀设计法优化了制备空白羧甲基淀粉微球的工艺,用吸附法制备了米托蒽醌载药羧甲基淀粉微球。对载药微球的理化性质进行了研究。并以家兔为模型动物研究了载药微球经肝动脉栓塞给药后的药代动力学情况。结果表明:载药微球的平均算术粒径为75.71μm,含药量为13.21%,吸水膨胀率为71.94%,体外释药符合单指数模型。药动学研究表明,米托蒽醌制成微球经肝动脉栓塞给药后可延长药物驻留于靶位的时间,提示有利于肝癌的治疗。     

莪术油明胶微球用于肝动脉栓塞

目的　制备符合肝动脉栓塞要求的莪术油明胶微球(ZT-GMS)。方法　用正交设计优化了微球的制备工艺,对微球的制备工艺、粉体学性质、体外释药、初步稳定性和初步药效进行了研究。结果　球径在40～160 μm的微球占97.16%,平均产率为89.73%,平均含药量为2.13%,平均包封率为19.36%(均以莪术醇计)。体外释药12 h达80%,符合一级动力学模型,释药机理为溶蚀加扩散。稳定性考察实验结果表明其稳定性较好。肝动脉栓塞荷瘤大鼠实验结果表明大鼠平均生存率显著延长(P<0.01),肿瘤体积显著减小(P<0.01)。结论　微球的制备工艺及粒径分布较好,体外释药有明显的缓释作用,有一定疗效。     

结肠定位释药瓜尔胶/乙基纤维素包衣小丸

体外研究瓜尔胶/乙基纤维素混合包衣小丸的结肠靶向性。以5-氟尿嘧啶为模型药， 采用流化包衣技术以瓜尔胶/乙基纤维素混合物的水/醇混悬液对载药小丸进行喷液包衣。瓜尔胶/乙基纤维素混合包衣小丸的释药行为取决于包衣处方中瓜尔胶与乙基纤维素的比例和包衣厚度。分别以混合包衣液中瓜尔胶与乙基纤维素的比例及包衣增重为自变量， 以T₅和T₉₀（药物释放5%和90%所需要的时间）为效应， 进行3×4析因设计/效应面优化， 筛选较优处方。结果表明随着乙基纤维素在衣层中所占比例的增大及包衣厚度的增加， 药物释放时滞增加。当瓜尔胶与乙基纤维素的比例在0.2~0.7， 并且包衣增重在250%~500%时， T_5%为5.1～7.8 h， T_90%为9.8～16.3 h。并且在释药时滞之后， 进入模拟结肠微菌群酶解作用的释放环境中(pH 6.5)药物释放速度加快， T_90%缩短到9.0～14.5 h。由此可以看出适当的瓜尔胶/乙基纤维素混合衣层既可以保护药物顺利通过上消化道而不释放， 达到结肠后药物开始释放， 并且可在结肠微菌群的酶解作用下加速药物的释放， 实现结肠定位释药的目的。     

胸腺肽α1缓释注射微球的研究

制备胸腺肽α₁(Tα₁)的长效注射微球，并对微球的体外释放特性、体外活性及药效学进行考察。采用复乳法(W/O/W)制备了载Tα₁聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；采用CCK-8法评价微球制备工艺和体外释放过程中Tα₁的生物学活性；体内药效学研究中采用流式细胞仪检测免疫抑制模型大鼠给予Tα₁微球后所产生的CD₄⁺，CD₈⁺因子的量，根据CD₄⁺/CD₈⁺的比值变化评价体内药效。微球球形圆整，分散性好，两个优选处方(外水相中加入5%氯化钠和10%葡萄糖)的微球包封率分别为87.8%和90.2%；Tα₁微球1个月的体外累积释放可达90%以上。使用含10%葡萄糖的PVA溶液作为外水相，较好地保持了制备工艺过程中的Tα₁生物学活性，在体外释放过程中Tα₁的生物学活性略有下降；Tα₁微球可显著提高免疫抑制模型小鼠的免疫力。用可生物降解的聚合物PLGA作为载体材料，可以将Tα₁制备成缓释1个月的注射微球。     

肺靶向利福平聚乳酸微球的研究

在单因素考察的基础上进行正交试验设计,筛选出肺靶向利福平聚乳酸微球的最佳制备工艺条件;利用桨板法研究了微球的体外释药规律;考察了微球在不同温度下的稳定性;用新西兰兔为实验对象,研究了利福平聚乳酸微球的体内药动学及组织药物分布。结果制得的微球形态圆整,粒径在5～15μm范围内的占总体积的86.54%,微球平均粒径为9.00±4.08μm;包封率为31.9%;载药量为16.0%;体外释药方程为Q=20.77+10.12T_1/2(γ=0.9892);微球在冰箱4℃和室温(20～25℃)条件下性质稳定;体内实验表明微球具有长效和肺靶向双重作用。     

盐酸川芎嗪肺靶向微球的研究

用乳化法制备盐酸川芎嗪明肢微球,优化了工艺。对微球的外观、粒径与其分布、含量、体外释药、稳定性及体内分布等进行研究。结果表明平均粒径为12.65μm,粒径范围5.0～24.9μm占总数的87.5%,球内含药量平均为16.49%±0.49%(n=3),冰箱或室温放置稳定,体外释药符合一级动力学规律,释药t_1/2比原药延长约5倍。小鼠静注微球后20 min,在肺内的相对分布百分率明显高于其它组织与血液,与溶液对照组相比,提高近6倍。     

阿霉素羧甲基葡聚糖微球犬肝动脉栓塞后阿霉素的体内过程

研究了阿霉素羧甲基葡聚糖微球经肝动脉栓塞后的体内动力学过程、靶向特征和微球在体内的肝动脉栓塞效果。对犬进行肝动脉栓塞实验,并与肝动脉阿霉素(ADM)溶液灌注组进行对照。用HPLC荧光检测外周静脉和组织中药物浓度。结果表明:微球组峰浓度为0.558μg/ml,溶液组为1.013μg/ml;微球组的T_1/2(α),T_1/2(β)和MRT分别为溶液组的2.82,3.19和1.28倍。栓塞不同部位组织中ADM浓度,微球组分别是溶液组的8.0和9.1倍。动态血管造影表明:肝内外未见侧枝循环形成,栓塞作用持久,16周后微球仍未见完全降解。     

顺铂壳聚糖微球的制备及特性研究

对顺铂壳聚糖微球的制备、载药量、大小及分布、形态及表面状态、体外释放及降解性进行了研究。微球用乳化-化学交联技术制备,平均粒径为74.80μm,顺铂含量为20.83%±0.36%。电镜扫描显示,微球球形圆整,表面粗糙。生理盐水中放置1h微球轻微溶胀,其体外释药符合一级方程,微球经⁶⁰Co辐射灭菌达到无菌要求。犬肝动脉栓塞后一个月,病理切片可见栓塞区仍有壳聚糖微球存在。     

米托蒽醌白蛋白微球和联糖米托蒽醌白蛋白微球肝靶向性比较研究

目的：比较米托蒽醌白蛋白微球和联糖米托蒽醌白蛋白微球肝靶向性的优劣。方法：以小鼠为实验动物,以静脉注射给药后小鼠血浆及各器官中的米托蒽醌含量为指标。结果：联糖米托蒽醌白蛋白微球在肝中的分布高于米托蒽醌白蛋白微球,而且肝中米托蒽醌较高浓度的维持时间也更长。结论：联糖米托蒽醌白蛋白微球肝靶向性比米托蒽醌白蛋白微球好,但无统计学上的显著性差异。     

A novel pH-dependant and double crosslinked polymethacrylate-based polysphere matrix for enteric delivery of isoniazid

This study aimed at developing double crosslinked isoniazid (INH)-loaded polymethyl-methacrylate-ethylcellulose (PMMA-EC) polyspheres for rate-controlled enteric drug delivery. A PMMA solution was manipulated with the addition of EC to produce polyspheres by drop-wise extrusion into a primary crosslinking solution of AlCl₃ (25% w/v), before adding a second crosslinking solution of either 30% w/v BaCl₂ (polysphere Batch A) or 30% w/v MgCl₂ (polysphere Batch B). The polyspheres were then subjected to FTIR spectroscopic analysis, in vitro drug release studies, drug entrapment efficiency (DEE) determination as well as surface area and porositometric investigations. Molecular Mechanics (MM) simulations elucidated the interaction between the cations and the PMMA-EC combination. FTIR spectra revealed an affinity of PMMA for Ba²⁺, Mg²⁺ and Al³⁺. SEM showed smooth robust polyspheres ranging between 4–6 mm. Porositometric analysis established that polysphere Batch A had larger pores (315.314 Å_abs) than Batch B (234.603 Å_abs). Drug release profiles from polysphere Batch A displayed burst release with 50% INH released within 2 h (N = 3) that was attributable to the larger ionic radius of the second crosslinker Ba²⁺ compared Mg²⁺ which was employed for polysphere Batch B. The latter produced polyspheres with superior control in INH release (<25% within 2 h) (N = 3) and a higher DEE with minimal pore formation. The experimental findings were well corroborated by the MM simulations.     

口服布洛芬原位凝胶的制备及其在Beagle犬体内药代动力学研究

本文设计并制备了口服布洛芬原位凝胶(in situ gel systems for the oral delivery of ibuprofen，IBU-ISG)， 并对其在Beagle犬上药代动力学进行了研究。以去乙酰结冷胶和海藻酸钠为凝胶材料， 分别对此两种凝胶材料进行了单因素考察， 初步确定了辅料的用量。以成胶前的复合黏度值、 体外释放度等参数为评价指标， 采用正交设计法进行处方优化。优化的制剂处方为： 1.0%海藻酸钠、 0.5%去乙酰结冷胶、 0.21%枸橼酸钠和0.056%氯化钙。采用RP-HPLC法测定6只Beagle犬口服IBU-ISG和参比制剂(市售布洛芬混悬液)后不同时间血浆中布洛芬的浓度， 所得药代动力学参数T_max分别为(1.8±0.6)和(0.4±0.1) h， C_max分别为(29.2±7.6)和(37.8±2.2)μg·mL^-1， T_1/2分别为(2.3±0.5)和(2.0±0.9) h， AUC_0-t分别为(131.0±38.6)和(117.3±23.1)μg·mL^-1·h。结果表明， 采用去乙酰结冷胶和海藻酸钠二元骨架制备IBU-ISG可行。     

莲子心总碱缓释片体外释放度试验

目的 考察莲子心总碱缓释片体外释放度。方法 模拟人体体内环境,用紫外分光光度法测定莲子心总碱的体外释放度。结果 莲子心总碱释药方程:log(100-R_n)=2.112-0.128t(F=219.310,P<0.001),r=-0.982(P<0.001),T₅₀=3.233h,T_d=4.274h,K_r=0.128h^-1。结论 莲子心总碱缓释片体外释药符合一级释药模式,具有缓释特点。     

Schisandra lignans-loaded enteric nanoparticles: preparation,characterization, and in vitro–in vivo evaluation

Schisandrae lignans (SL) have been well proven to possess hepatoprotective effect against the hepatic dysfunction induced by various chemical hepatotoxins. Deoxyschisandrin (DA) and schisantherin A (SA) are both considered as the major active components in SL. The objective of the study was to prepare and evaluate Schisandra lignans (composed of DA and SA)-loaded enteric nanoparticles produced by a novel toxic solvent-free modified spontaneous emulsification solvent diffusion (SESD) method. An organic Schisandra lignans/Eudragit^® S100 solution was injected into an aqueous poloxamer 188 solution under a agitation. The nanoparticles were characterized with respect to particle size distribution, morphology, encapsulation efficiency (EE) and physical stability of the drug, wettability, in vitro release and in vivo bioavailability. Nanoparticles with a smooth surface and dense structure were obtained with high EE (EE_DA >90%; EE_SA >85%). The drug was in a noncrystalline state in the matrix and physically stable for 120 days at room temperature. In vitro drug release study, the drug dissolution rate from the nanoparticles was significantly enhanced compared to the physical mixture and to the pure drug; the release profile of the nanoparticles was stable after 120 days. The appropriate size of nanoparticles (~93?nm), the solubilization of the surfactant, the noncrystalline state of the drug in the matrix and the fast dissolution rate contributed to a significantly enhanced oral bioavailability from the nanoparticles when compared to pure drug suspension.     

Characterization of drug release from diltiazem-loaded polylactide microspheres prepared using sodium caseinate and whey protein as emulsifying agents

The influence of milk protein emulsifying agents on the characteristics, particularly drug release, of polylactide microspheres was investigated. Diltiazem loaded polylactide (PL) microspheres were successfully prepared using the dairy proteins, sodium casinate (SC) and whey protein isolate (WPI) as the emulsifying agents. Microspheres were characerized in terms of microsphere yield, electron microscopy, particle size, drug loading, DSC and XRD analysis and drug release. The yields of microspheres obtained were 53-63% and were independent of the emulsifying agent used. SEM revealed that, regardless of the emulsifying agent employed, the microspheres were of good sphericity, but the surface appearance of the microspheres was not the same in all cases. The milk proteins resulted in microspheres approximately half the size of those obtained with methylcellulose (MC). Significant differences in drug loading were observed between the three emulgents, the MC systems giving the highest values. Release profiles were sigmoidal in shape and were well fitted to the equation ln (x/1-x) = k·t - k·t_max, reflecting degradation controlled drug release. The parameter k increased with drug loading, while t_max decreased. The relationships between the release parameters [P(k and t_max)] and loading (L) could be quantified by equations of the form P = a·L^N, N being negative in the case of t_max. Apart from the effect on loading efficiency, neither SC nor WPI appeared to significantly alter drug release. The quantitative relationships observed in this study may have more general application in quantifying drug release from drug polymer composites at low loadings where polymer degradation controls drug release.     

Liver-targeting self-assembled hyaluronic acid-glycyrrhetinic acid micelles enhance hepato-protective effect of silybin after oral administration

Abstract

In order to enhance oral bioavailability and liver targeting delivery of silybin, two amphiphilic hyaluronic acid derivatives, hyaluronic acid-deoxycholic acid (HA-adh-DOCA) and hyaluronic acid-glycyrrhetinic acid (HA-adh-GA) conjugates, were designed and synthesized. Silybin was successfully loaded in HA-adh-DOCA and HA-adh-GA micelles with high drug-loading capacities (20.3%?±?0.5% and 20.6%?±?0.6%, respectively). The silybin-loaded micelles were spherical in shape with the average size around 130?nm. In vitro release study showed that two silybin-loaded micelles displayed similar steady continued-release pattern in simulated gastrointestinal fluids and PBS. Single-pass intestinal perfusion studies indicated that silybin-loaded micelles were absorbed in the whole intestine and transported via a passive diffusion mechanism. Compared with suspension formulation, silybin-loaded HA-adh-DOCA and HA-adh-GA micelles achieved significantly higher AUC and C_max level. Moreover, liver targeting drug delivery of micelles was confirmed by in vivo imaging analysis. In comparison between the two micellar formulations, HA-adh-GA micelles possessed higher targeting capacity than HA-adh-DOCA micelles, owing to the active hepatic targeting properties of glycyrrhetinic acid. In the treatment of acute liver injury induced by CCl₄, silybin-loaded HA-adh-GA micelles displayed better effects over suspension control and silybin-loaded HA-adh-DOCA micelles. Overall, pharmaceutical and pharmacological indicators suggested that the HA-adh-GA conjugates can be successfully utilized for liver targeting of orally administered therapeutics.     

肝靶向氟尿嘧啶类脂纳米粒的研究

目的　为了提高氟尿嘧啶(5-Fu)的疗效,降低其毒副作用,制备具肝靶向的5-Fu类脂纳米粒。方法　利用氟尿嘧啶与硬脂酰氯进行反应,制备了5-Fu前体药物N₁-硬脂酰-5-Fu,通过红外光谱及核磁共振谱对合成的目标化合物进行结构确认。同时研究了前体药物的性质及稳定性。采用物理凝聚法制备类脂纳米粒,并研究其形态、粒径及粒径分布、载药量、体外释药特征、动物体内分布与药代动力学参数等。结果　平均粒径d_av=240.19 nm,载药量为20.53%。体外释药速率符合一级动力学模型。与5-Fu水针剂比较,类脂纳米粒组在肝脏中药物含量平均增加了一倍以上。家兔体内主要药动学参数为：V_c=0.04336 L.kg^-1,T_1/2β=1.2834 h,CL=0.1632 L.h^-1。结论　利用前体药物可提高药物的脂溶性,首次以物理凝聚法制备类脂纳米粒,小鼠体内分布研究表明类脂纳米粒有明显的肝靶向,有一定的优越性和参考价值。     

Bioequivalence Comparison of Pediatric Dasatinib Formulations and Elucidation of Absorption Mechanisms Through Integrated PBPK Modeling

SPRYCEL^® (Dasatinib) is a Biopharmaceutical Classification System II weakly basic drug that exhibits strong pH-dependent solubility. Dasatinib is currently presented in 2 drug product formulations as an adult immediate release tablet and a pediatric powder for oral suspension. A bioequivalence study comparing the formulations in adult healthy subjects found that overall exposure (AUC_0-24) from suspension treatments was ～9% to 13% lower, Cmax was similar, and median Tmax from powder for oral suspension was ～30 min earlier. To understand the mechanism contributing to this behavior, a combination of biorelevant dissolution studies and physiologically based pharmacokinetic modeling was used to simulate in vivo performance. In vitro biorelevant dissolution confirmed that the rate and extent of release was similar between tablet and suspension formulations (>90% release within first 15 min). Physiologically based pharmacokinetic parameter sensitivity analysis demonstrated particular sensitivity to dosage form gastric residence time. A 12% higher AUC_0-24 was simulated for tablet dosage forms with 10 to 15 min longer gastric transit relative to solutions or suspensions of small particulates (rapid gastric emptying). The corresponding narrow simulated Cmax range also agreed with observed tablet and suspension bioequivalence data. The unique physicochemical properties, absorption characteristics, and inherent differences in dosage form transit behavior are attributed to influence the dasatinib bioequivalence.