用于药物吸收研究的消化道定点释放药丸系统研究进展

消化道定点释放药丸系统是一种典型的微型机械电子系统,通过外部遥控实现消化道感兴趣区域的定点药物释放,是一种无创的人体药物吸收(human drug absorption,HDA)研究手段.本文对该领域的国际研究成果进行了综述,并对重庆大学最新开发的应用于中药药理学研究的消化道定点释放药丸系统进行了细节介绍.     

用于人体药物吸收研究的定点释放药丸系统研制

定点释放药丸系统是一种基于微型机械电子系统(MEMs)的工程药丸，无创地实现了消化道内定点药物释放。人体药物吸收(Human Drug Absorption，HDA)研究是新药开发过程中获得药物吸收路线图的重要手段，定点释放药丸系统是HDA研究的重要工具。本研究开发了一种新型的定点释放药丸系统，并开发了基于磁标记跟踪技术的定位跟踪系统，该定点释放药丸系统具有使用方便、效率高、适应多种药物剂型的优点，该系统也为中药药理学研究提供了一种新的手段，具有良好的应用前景。     

植入式十八甲基炔诺孕酮药物缓释系统的研究

用非药理活性的、人体内所含有的小分子物质作为药物控释载体,可避免合成高分子载体可能带来的毒性问题,并具有工艺简单、成本低、药效可靠的优点.方法:用胆固醇为载体,采用自制药丸成型装置用半熔融共混挤压法制成十八甲基炔诺孕酮的长效理植药丸(直径2.5mm,长4～6mm).在体外研究了该药丸的药物释放行为.结果:用自制药丸成型装置制成的共混药丸大小、重量均匀,重现性好;药丸体外释放实验表明十八甲基炔诺孕酮的释放速率恒定,同时使用4个6mm长的药丸平均每天可释放十八甲基炔诺孕酮82±15μg,预计体内植入4个上述药丸即可达到有效避孕剂量.     

基于磁定位的消化道微型药物释放装置动态跟踪技术研究

对消化道微型药物释放装置在体内的运动进行无创动态跟踪更具有特别重要的意义.本文在分析永磁体空间磁场分布规律的基础上,提出了利用磁定位原理实现动态跟踪微型药物释放装置在消化道运动状态的方法.其基本过程是在微型药物释放装置上固定永磁体,当其通过消化道时在体外检测磁场变化,进而实时计算出微型药物释放装置的空间位置,并描记出运动轨迹,实现动态跟踪.通过在模拟肠道中的实际测试,该技术可较好地跟踪永磁体的运动轨迹.     

粘弹性肠道能动性模型的建立与数值模拟

潜入人体肠道释放药物和进行手术的医用微型机器人的研究是目前的一个研究热点，人体肠道的能动性模型对于机器人的控制甚为重要。在理论分析和动物肠道力学特性实验结果的基础上建立了肠道的能动性模型，与粘性蠕动模型相比，能动性模型考虑肠道的弹性性质和粘性性质，更符合肠道的实际特性。与肠道中的液体方程耦合，利用神经控制模型的机械运动模型，运用Galerkin有限元-有限差分法进行了肠道的运动学仿真。为微型机器人进入人体肠道的控制提供了可能。     

化学阀和化学动力微型泵的官能基在药物释放中的作用

凝胶状交联电解质,能够通过引入化学物质改变其孔径大小和通透性,这一性能可以广泛应用在药物释放领域中。本文介绍了作者在研制以下两种不同类型的闭环药物释放装置所做的工作:(a)负载酶的化学阀:(b)负载酶的微型泵。讨论了有关化学反应和凝胶机械调整相结合的物理—化学模型。阐述了两种装置的设计原理。所用材料是聚乙烯醇/聚丙烯酸凝胶,制备方法是循环多次地冷冻。该制备方法有两个优点,其一是可使酶的内涵物不变性;其二是凝胶的膨胀时间常量比起热交联     

美研制可测胃内酸碱值的磁性“药丸”

美国科学家正在研制一种磁性“药丸”,有望为胃内酸碱值的测定提供一种痛苦少的方法。美国肯塔基大学正在开发的这种磁性“药丸”,由外部涂覆有聚合物材料的微型记录磁带构成。当患者将其吞下后 ,“药丸”外的聚合物涂层能根据胃内酸碱值的大小而产生不同程度的膨胀或收缩 ,促使内部记录磁带形状作出相应改变。磁性“药丸”内的记录磁带会在外部磁场激发下发出无线电波 ,电波频率大小受磁带形状所决定。通过分析其发出无线电波频率的大小 ,即可间接测出胃内的酸碱值。研究人员发现 ,如果在“药丸”外部涂覆不同的陶瓷材料 ,“药丸”还可用来…     

基于永磁体空间磁场检测的体内微型诊疗装置定位系统的研究

在微型诊疗装置的应用中,微型装置的体内空间定位非常重要.作者根据消化道微型诊疗装置研究的需要,设计了一种基于永磁体空间磁场检测的体内微型诊疗装置定位系统,由霍尔传感器阵列检测固定在微型装置上永磁体的空间磁场,经多路信号处理电路和单片机采集数据,再把数据通过串口通信传输给主控计算机,进而对数据分析处理计算出微型诊疗装置在体内的空间位置.实验表明,该系统可实时采集数据并可靠传输,空间磁场强度随距离有特定的变化规律,能满足实验研究的需要.     

基于霍尔传感器阵列的体外磁跟踪定位系统

目的为实现体内微型诊疗装置的无创定位,本文提出一种新的定位方法,并开发了一套基于此方法的实验系统.方法在分析永磁体空间磁场分布特殊规律的基础上,采用基于霍尔原理的磁场检测方法设计一种基于霍尔传感器阵列的体外磁跟踪定位系统.通过设计系统优化实验、系统性能实验以及模拟肠道平面实验验证系统的可行性、准确性及定位的精确性.结果该方法定位精度在 mm级,满足实际应用需求.结论此系统能精确确定永磁体所在空间位置,具有非接触测量、操作简单、精度高等特点,为有效监测人体肠道内的微型诊疗装置提供了基础.     

直流电机驱动仿尺護式微型胃肠道机器人的设计

目的 针对现有胃肠道检测方法的被动运动方式的缺点,设计了在肠道（尤指小肠）内主动运动的微型肠道机器人.方法 机器人采取仿尺護式的运动方式,由以直流电机驱动的3个独立机构组成,其中的中间机构是轴向伸缩机构,两端是径向钳位机构.机器人通过步态的配合,完成机器人在肠道内的前进、后退和停留.组装好的机器人收缩时尺寸为13 mm×80 mm,机器人轴向步距为14 mm,径向步距为4 mm.结果 对机器人结构进行速度和传动效率分析,得到机器人理论速度为0.8 mm/s,最大径向力和轴向推力分别是5 N和9.6 N.组装好机器人并让其在体外肠道内进行爬行实验.结论 该仿尺護式直流电机驱动的微型胃肠道机器人在肠道内可以实现主动运动.     

Iontophoretic drug delivery system: a review.

Among the recent developments in the field of transdermal drug delivery, iontophoresis has emerged as a very promising tool for this purpose. Various studies have been performed on drug delivery through the skin using electric current. Iontophoresis has thereby been found to be effective in particular in transdermal protein and peptide drug delivery. This article reviews the principle, potential benefits, and applications of drug delivery based on iontophoresis. It focuses furthermore on current research and future trends in the field of iontophoretic drug delivery.     

青光眼药物跨角膜输运数学模型及特性分析

为研究青光眼药物跨角膜输运特性,首先,通过实验结果修正了基于菲克第二定律的药物输运数学模型,验证了数学模型的可行性。其次,通过对数学模型的求解,分析了眼表给药浓度恒定、眼药膏以及受泪液清除作用的眼药水3种给药方式对药物进入眼球前房输运通量以及累积量的影响。结果表明,提高扩散系数可以缩短药物累积从非稳态阶段进入伪稳态阶段的时间,提高药物累积量;给出了不同给药方式下药物累积规律和后两种给药方式下药物进入眼球前房药物输运通量达到峰值的时间及峰值量。此结果可为建立更加完善的青光眼药物输运数学模型及青光眼药物设计提供理论分析基础。     

Layer-by-layer assembled milk protein coated magnetic nanoparticle enabled oral drug delivery with high stability in stomach and enzyme-responsive release in small intestine

We report a novel drug delivery system composed of layer-by-layer (LBL) milk protein casein (CN) coated iron oxide nanoparticles. Doxorubicin (DOX) and indocyanine green (ICG) were selected as model drug molecules, which were incorporated into the inner polymeric layer, and subsequently coated with casein. The resulting casein coated iron oxide nanoparticles (CN-DOX/ICG-IO) were stable in the acidic gastric condition with the presence of gastric protease. On the other hand, the loaded drugs were released when the casein outer layer was gradually degraded by the intestinal protease in the simulated intestine condition. Such unique properties enable maintenance of the bioactivity of the drugs and thus enhance the drug delivery efficiency. Ex vivo experiments showed that the LBL CN-DOX-IO improved the translocation of DOX across microvilli and its absorption in the small intestine sacs. In vivo imaging of mice that were orally administered with these LBL CN-ICG-IO nanostructures further confirmed that the reported drug delivery vehicles could pass the stomach without significant degradation, and then accumulated in the small intestine. In addition, the magnetic iron oxide nanoparticle core offered an MRI contrast enhancing capability for in vivo imaging guided drug delivery. Therefore, the reported LBL CN-DOX/ICG-IO is a promising oral drug delivery nanoplatform, especially for drugs that are poorly soluble in water or degradable in the gastric environment.     

Alginate encapsulated bioadhesive chitosan microspheres for intestinal drug delivery.

Sustained intestinal delivery of drugs such as 5-fluorouracil (choice for colon carcinomas) and insulin (for diabetes mellitus) seems to be a feasible alternative to injection therapy. For successful therapy, the drug should be delivered at proper sites (here, the intestine) for long duration, for producing maximum pharmacological activity. We have attempted to develop a formulation that can bypass the acidity of the stomach and release the loaded drug for long periods into the intestine by using the bioadhesiveness of polyacrylic acid, alginate, and chitosan. Bromothymol blue was taken as a model drug. The formulation exhibited bioadhesive property and released the drug for an eight-day period in vitro.     

The use of charge-coupled polymeric microparticles and micromagnets for modulating the bioavailability of orally delivered macromolecules

Protein drugs have low bioavailability after oral administration, which is due in part to fast transit of the drugs or drug delivery vehicles through the gastrointestinal tract. Increasing the time that the drugs spend in the intestine after dosing would allow for greater absorption and increased bioavailability. We developed a formulation strategy that can be used to prolong intestinal retention of drug delivery vehicles without substantial alterations to current polymeric encapsulation strategies. A model drug, insulin, was encapsulated in negatively charged poly(lactic-co-glycolic acid) (PLGA) microparticles, and the microparticles were subsequently mixed with positively charged micromagnets, whose size will prevent them from being absorbed. Stable complexes formed through electrostatic interaction. The complexes were effectively immobilized in vitro in a model of the mouse small intestine by application of an external magnetic field. Mice that were gavaged with radio-labeled complexes and fitted with a magnetic belt retained 32.5% of the (125)I-insulin in the small intestine compared with 5.4% for the control group 6h after administration (p=0.005). Furthermore, mice similarly gavaged with complexes encapsulating insulin (120 Units/kg) exhibited long-term glucose reduction in the groups with magnetic belts. The corresponding bioavailability of insulin was 5.11% compared with 0.87% for the control group (p=0.007).     

Fabrication of a novel pH-sensitive glutaraldehyde cross-linked pectin nanogel for drug delivery

A novel pH-sensitive nanogel based on pectin cross-linked with glutaraldehyde (PT-GA) was designed and synthesized for drug delivery. Transmission electron microscope observation shows that the nano-sized gel particles exhibit a spherical morphology. The optical absorbance study of nanogel suspension reveals its pH sensitivity. Cytotoxicity study shows that the nanogel has no apparent inhibitory effect on cells. The in vitro drug-release behavior of the drug-loaded nanogel particles in three kinds of media, i.e., simulated gastric fluid, simulated intestine fluid and simulated colon fluid, was studied. PT-GA nanogel exhibits a faster release at a high pH, and the release could be further accelerated in the presence of pectinolytic enzyme, indicating that the nanogel may be used for colon-specific drug delivery.     

Multi-anticancer drugs encapsulated in the micelle: a novel chemotherapy to cancer

Micelle is a stable, passively targetable and solubilizing minute particle, and plays a key role to anticancer drug delivery for chemotherapy. With an increasing number of novel polymeric micelles synthesized, many anticancer drugs have been core-encapsulated in the micelles. However, only single drug was studied as the model drug at present researches. It is well known that combined medication is a very important and common method for chemotherapy in the clinic. Therefore, we hypotheses that multi-anticancer drugs encapsulated in the micelle may be proposed based on the cancer cell cycle. Briefly, cell cycle specific agents are chemically conjuncted into the micelles firstly, and then cell cycle non-specific agents are physically loaded in the compound of drugs and micelles. Thus combined administration using micelles as drug carriers is achieved. This hypothesis integrates advantages of the nano-micelles at present researches and drug combination in the clinic. So, it presents many merits for drug delivery, such as high efficiency, convenience and anti-resistance.     

经皮给药系统的研究进展

经皮给药系统作为一种非侵入式药物递送系统,与传统的注射、口服等给药方式相比具有许多优势,非常适用于需要频繁治疗或长期治疗的疾病.根据近年来经皮给药系统的研究进展,对经皮给药机制、影响药物经皮渗透的因素、促进药物经皮吸收的方法进行归纳和评述,并对经皮给药系统的未来发展趋势进行展望.     

Modeling of degradation and drug release from a biodegradable stent coating

Biodegradable polymeric coatings on cardiovascular stents can be used for local delivery of therapeutic agents to diseased coronary arteries after stenting procedures. This can minimize the occurrence of clinically adverse events such as restenosis after stent implantation. A validated mathematical model can be a very important tool in the design and development of such coatings for drug delivery. The model should incorporate the important physicochemical processes responsible for the polymer degradation and drug release. Such a model can be used to study the effect of different coating parameters and configurations on the degradation and the release of the drug from the coating. In this paper, a simultaneous transport-reaction model predicting the degradation and release of the drug Everolimus from a polylactic acid (PLA) based stent coating is presented. The model has been validated using in vitro testing data and was further used to evaluate the influence of various parameters such as partitioning coefficient of water, autocatalytic effect of the lactic acid and structural change of the matrix, on the PLA degradation and drug release. The model can be used as a tool for predicting drug delivery from other coating configurations designed using the same polymer-drug combination. In addition, this modeling methodology has broader applications and can be used to develop mathematical models for predicting the degradation and drug release kinetics for other polymeric drug delivery systems.     

The mucoadhesive and gastroretentive properties of hydrophobin-coated porous silicon nanoparticle oral drug delivery systems

Impediments to intestinal absorption, such as poor solubility and instability in the variable conditions of the gastrointestinal (GI) tract plague many of the current drugs restricting their oral bioavailability. Particulate drug delivery systems hold great promise in solving these problems, but their effectiveness might be limited by their often rapid transit through the GI tract. Here we describe a bioadhesive oral drug delivery system based on thermally-hydrocarbonized porous silicon (THCPSi) functionalized with a self-assembled amphiphilic protein coating consisting of a class II hydrophobin (HFBII) from Trichoderma reesei. The HFBII-THCPSi nanoparticles were found to be non-cytotoxic and mucoadhesive in AGS cells, prompting their use in a biodistribution study in rats after oral administration. The passage of HFBII-THCPSi nanoparticles in the rat GI tract was significantly slower than that of uncoated THCPSi, and the nanoparticles were retained in stomach by gastric mucoadhesion up to 3 h after administration. Upon entry to the small intestine, the mucoadhesive properties were lost, resulting in the rapid transit of the nanoparticles through the remainder of the GI tract. The gastroretentive drug delivery system with a dual function presented here is a viable alternative for improving drug bioavailability in the oral route.