温敏凝胶原位植入给药系统：进展与挑战

采用温敏凝胶的原位给药系统是理想的长效给药系统。本文从凝胶材料和给药系统的制备、凝胶的机体反应和体内降解以及药物控释三方面,综述了该给药系统的研究进展,总结了关键技术和科学问题,分析了面临的挑战与解决途径。水凝胶网络的不规则形态和较低的机械轻度,其植入后引起的机体炎性反应、组织融合与水分快速流失及这些反应造成的凝胶网络结构和降解速率的个体差异性变化,是控制药物释放的主要困难。通过提高凝胶表面亲水性,降低其表面正电荷,或在其表面修饰抗炎性多肽,可减轻炎性作用、减缓组织融合;通过与亲水性高分子形成共混凝胶或互穿凝胶网络,以及共价交联等方式,可提高凝胶强度,保持凝胶网络的空间结构和水分;通过在凝胶表面建立扩散屏障、加强药物和凝胶骨架的相互作用、构建微粒/原位凝胶复合释药系统等技术,可进一步改善药物释放特征。     

载药原位凝胶中水份随渗透压的变化及其对释药的影响

原位凝胶是实现注射埋植给药的理想载体,凝胶水是药物存在的主要环境并对维持凝胶骨架形态有重要作用,而释药环境渗透压是影响凝胶水的重要因素.以壳聚糖/甘油磷酸钠温敏凝胶为例,研究了体内外渗透压变化引起的载药原位凝胶中水含量与组成变化,及其对释药的影响.由于生物组织与水中的渗透压差异,凝胶植入SD大鼠皮下后水分(主要是自由水)迅速流失,水含量最终接近周围组织,与其在体外溶胀、溶蚀的过程显著不同.通过在释放介质中加入PEG,对体外试验方法进行了改进,模拟研究了渗透压变化对释药的影响:凝胶自由水快速流失携带药物快速流出而出现突释;水分流失又使凝胶网络更致密、凝胶中剩余药物结晶析出,导致药物后期释放缓慢且不完全.控制凝胶水分变化是控制凝胶释药特征的重要方面.     

适用于经皮给药系统的SIS-g-NPEO热熔压敏胶及其释药性研究

通过原位环氧化反应与开环接枝反应相结合,将亲水性壬基酚聚氧乙烯醚(NPEO)支链引入聚苯乙烯-异戊二烯-苯乙烯(SIS)三嵌段共聚物,制备功能型SIS-g-NPEO热塑弹性体,并以SIS-g-NPEO为骨架,配以增粘树脂、矿物油、氢化松香树脂、抗氧剂等组分,制备了面向经皮给药系统的SIS-g-NPEO热熔压敏胶,以栀子苷为亲水性模型药物,研究SIS-g-NPEO热熔压敏胶中各组分对栀子苷的释放影响。结果显示,C5树脂和增塑剂PEG有利于栀子苷释放;矿物油不利于亲水性成分栀子苷的释放。     

体内植入型药物释放系统研究进展

体内植入型药物释放系统为一类经手术植入体内或皮下,或经穿刺导入皮下的控制释药制剂,适用于靶向给药或长期给药。本文根据系统植入形式和释药机制的不同,将植入型药物释放系统进行了分类,并对各种植入药物体系的特点和存在的问题作了评述。反向温敏型注射式原位凝胶植入系统是一类最具潜力的长期释药系统,可实现药物的长期、安全、有效释放,具有广泛的应用前景。     

常见温度敏感型原位凝胶研究及应用进展

温度敏感型原位凝胶是现在国内外研究新型药物传递系统的一个热点,因具有良好的流动性、较长的滞留时间、高效的生物利用度及良好的控制释药性能等优点成为了新型给药系统的主要研究对象。本文以近年来国内外研究温度敏感型原位凝胶的相关文献,对其基质选择、给药途径及质量控制的研究进行综述,从而为温度敏感型原位凝胶的新型药物研发提供一定的借鉴和参考。     

聚己内酯药物控释材料的研究进展

综述了聚ε-己内酯(PCL)药物控释材料的研究进展,以及PCL微球、PCL纳米微粒、PCL纤维、PCL薄膜、PCL胶束、PCL水凝胶的制备方法及应用。PCL在药物控释领域研究中,可通过与其他聚合物共混或共聚来改善亲水性和控释行为。PCL共聚物也可应用到靶向给药系统中,靶向给药系统不仅能够将药物输送至病灶部位,还能实现定向释放。随着新材料的不断研发,构建新型智能药物控释系统的前景将更加广阔。     

酸敏改性葡聚糖的制备和载药研究

以可生物降解的亲水性天然葡聚糖为反应底物,通过缩醛化反应制备两亲性的缩醛化葡聚糖,核磁共振、傅里叶红外等理化表征手段确定缩醛化葡聚糖成功地合成。利用乳化法制备出载药缩醛化葡聚糖纳米粒子,用动态光散射法测得粒径为501.9±15.8 nm。且具有优异的pH响应性,荧光分光光度计检测载药纳米粒子在pH=5.0的缓冲介质中阿霉素荧光药物的酸敏释放的荧光强度增强5倍,说明所设计的纳米载药系统具有酸敏释药功能。     

注射型原位成型药物传递系统的研究现状

注射型原位成型药物传递系统在近年来得到了广泛关注。注射型原位凝胶植入局部位置并使多聚物以半固体形式贮存药物,这种形式相比其它传统的给药方式具有很多优点。本文重点介绍了原位系统中原位沉淀凝胶的贮药机制,特性及其优缺点。     

微凝胶在药物控制释放系统中的应用

药物控制释放系统能弥补传统给药方式在人体血药浓度、药效等方面的不足,并在控制药物释放速率的同时,保持药物有效浓度、降低毒副作用。本文在介绍该释药系统的基础上,以微凝胶结合具体实例阐述说明系统的应用原理及效果,研究发现微凝胶对模型药物具有控制释放作用。     

天麻素温敏型鼻用原位凝胶的制备研究

以天麻素为主药,泊洛沙姆P407和P188为凝胶材料制备凝胶,考察P407、P188的浓度及药物的加入对胶凝温度和体系黏度的影响,优化处方组成;采用无膜溶出法,扩散池法和透析袋法考察凝胶的体外释药行为。确定天麻素含量为10%,以P407 20%,P188 1. 5%或2%为优化的处方组成,平均凝胶温度分别为31. 5℃和33. 6℃。体外释放结果显示三种方法药物均释放完全,无膜溶出法显示药物的释放量与溶蚀量具有良好的相关性;透析袋法表明药物以扩散和溶蚀相结合的方式释药,且以扩散方式为主。天麻素原位凝胶制备工艺简单,药物释放具有缓释行为,适合鼻腔给药。     

Thermosensitive chitosan hydrogel for implantable drug delivery: Blending PVA to mitigate body response and promote bioavailability

Thermosensitive hydrogels promise to be the injectable implants for long-term controlled drug release; however, body response to the implanted hydrogels and its unpredictable impacts on drug release complicates their applications. In the present study, hydrophilic polymer poly(vinyl alcohol) (PVA) was blended into the thermosensitive hydrogel composed of chitosan and glycerophosphate to mitigate the body responses and promote the drug bioavailability. The effects of PVA on the surface properties of the hydrogel were evaluated by zeta-potential, water contact angle, and cell attachment. Body responses were explored by histological examination via subcutaneously implanting the hydrogels into Sprague-Dawley rats. Drug release in vivo and bioavailability were determined with cyclosporine A (CsA) employed as the model drug. The results showed that, on one hand, the presence of PVA improved the surface hydrophilicity of the hydrogel and inhibited the cell attachment on the hydrogel, which alleviated the further cell infiltration and tissue integration in body; and on the other hand, blending of PVA led to the more rapid gel formation and more compact network, which resisted the dehydration and survived the hydrogel from cell division. These advantages benefited the controlled release and absorption of CsA, and contributed to the higher drug bioavailability. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Synthesis of dual physical self-healing starch-based hydrogels for repairing tissue defects

Hydrogels have the potential to simulate and permeate body tissues. They can be used in many biomedical applications, such as drug delivery, wound dressings, contact lenses, synthetic implants, biosensors, and tissue engineering. Despite recent significant advances in hydrogel fabrication, with the introduction of double network hydrogels, with ionic or hydrogen bonds, there is still the challenge of achieving optimal mechanical properties with appropriate self-healing ability. To solve the above problem, in this study, a new type of starch/chitosan/PVA/borax hydrogel was synthesized by adopting the one-pot method. The effect of concentration and ratio of raw materials on the final properties of hydrogels, such as the degree of hydrophilicity, morphology, degradation, mechanical strength, and drug release rate, was investigated. The properties of hydrogels were examined by scanning electron microscopy, thermogravimetric analysis, Fourier-transform infrared spectroscopy, X-ray diffractometry, and contact angle, which confirmed the composite synthesis and uniform distribution of HNT and curcumin. In addition, the composite hydrogel showed excellent mechanical properties. Drug release studies confirmed that the drug is slowly released from the nanocomposite hydrogels. The results showed that starch-based nanocomposite hydrogels could provide appropriate repairing potential for defects exposed to changeable parameters.     

Strategies toward development of biodegradable hydrogels for biomedical applications

ABSTRACT

Hydrogel is a macromolecular gel constructed of a network of cross-linked polymer chains. Hydrogels are class of materials that can be tuned toward the subjected stimuli and can be modified to imitate the extracellular environment of the body which makes hydrogel worthy of being used in tissue regeneration, drug delivery, and other fields of science. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, and biodegradability. Hydrogels are having various tissue engineering and drug delivery application due to its high loading with ensured molecule efficacy, high encapsulation, variable release profile, stable, and inexpensive.     

Effect of drug loading and laser surface melting on drug release profile from biodegradable polymer

The biodegradable polymer such as poly(l ‐lactic acid) is promising in drug delivery applications because it allows for drug release in a controlled manner. In a polymer‐based drug delivery system, drug release is controlled by polymer degradation and drug loading concentration. In this study, effect of drug concentration on drug release profile is investigated through polymer crystallinity, chain mobility, and polymer degradation, as characterized by the wide‐angle X‐ray diffraction, differential scanning calorimetry, and gel permeation chromatography, respectively. The addition of drug has been shown to accelerate polymer degradation and drug release rate. With a low drug concentration, the slow polymer degradation kinetics results in an induction period of drug release, during which a limited amount of drug is released. The induction period is undesirable because it delays drug release and effectiveness. Since drug release is controlled by polymer degradation, which is a function of polymer crystallinity, laser surface melting is conducted to reduce polymer surface crystallinity and modify its degradation. The effect of laser crystallinity modification on drug release is investigated. A numerical model is also implemented based on hydrolysis and diffusion mechanisms to investigate the effects of drug loading and laser surface melting on polymer degradation and drug release process. It has been demonstrated that laser treatment shortens the induction period of drug release while keeps the release rate unmodified, as desired in drug delivery applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 4147–4156, 2013     

A new model of resorbable device degradation and drug release ‐ part I: zero order model

BACKGROUND: Within the field of resorbable devices, recent years have seen an increased demand for better reliability from drug delivery systems and resorbable polymer degradation control, causing researchers to abandon trial‐and‐error approaches towards model‐based methods. In this context, we developed a lumped‐parameters zero‐order model for the degradation of resorbable polymeric drug release systems. Such a model is thought to be applicable in the design of specific devices based on the expected degradation time and drug delivery rates, as it is based on a ‘shrinking core’ approach and takes into account the main physicochemical parameters involved in polymer degradation, in drug release and in mechanical strength prediction, all independently estimated. RESULTS: The model, based on conservation equations, leads to numerically solved ordinary differential equations, the predictions of which were verified through literature data. Data of different authors and various systems were satisfactorily matched by model predictions, thus confirming the reliability of parameter estimation procedures. CONCLUSION: The present model is among the very few that completely address all aspects involved in device degradation and drug delivery altogether, and thus represents a step ahead with respect to current available solutions, firmly enforcing itself into the ongoing debate on the modelling of degradation and release behaviour. Copyright © 2008 Society of Chemical Industry     

Development of a thermosensitive grafted drug delivery system—synthesis and characterization of NIPAAm‐based grafts and hydrogel structure

A thermosensitive grafted hydrogel was investigated for heating‐activated drug release. The hydrogel was created by grafting oligomers of N‐isopropylacrylamide‐co‐acrylamide (AAm) to a poly(2‐hydroxyethyl methacrylate), or PHEMA, hydrogel. N‐Isopropylacrylamide‐co‐AAm oligomers were synthesized with a range of compositions to raise the lower critical solution temperature (LCST) above physiological temperature. PHEMA hydrogels with these thermosensitive grafts were synthesized by free‐radical solution polymerization, using an acrylated version of the oligomers. The oligomers were characterized for their molecular weight, LCSTs, and rate of response to a change in temperature. With the flexibility in tuning their properties by varying reaction parameters, these oligomers present possibilities in several fields, including drug delivery. The impact of cross‐linking agent type and the amount and presence of grafts on the polymer network structure was found by determining the hydrogel mesh sizes. PHEMA gels cross‐linked with methylenebisacrylamide had larger mesh sizes than those cross‐linked with ethylene glycol dimethacrylate. Increasing amounts of cross‐linking agent decreased mesh sizes. LCSTs exhibited by oligomers were slightly lower than those exhibited by polymer gels of the same composition. The grafting reaction was found to have only a slight impact on the hydrogel mesh size. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

A Tough Composite Hydrogel can Controllably Deliver Hydrophobic Drugs under Ultrasound

Hydrogels are promising materials for biomedical uses, but they usually lack the ability to encapsulate hydrophobic drugs with proper drug‐releasing stimulating method. Here a composite hydrogel with ultrasound controllable hydrophobic drug release behavior is reported, hydrophobic drug‐loaded silicone oil were dispersed in poly(vinyl alcohol) hydrogel as microdroplets, which not only act as drug reservoirs but also notably enhance the toughness of the hydrogel. Ultrasound is used to trigger the hydrophobic drug release from the hydrogel, high on–off drug release ratios are obtained in the surveyed samples. Mechanism of ultrasound controlled drug release is studied, and the results indicate the mechanical effect is the main reason. The facile and general method of encapsulation and controlled release of hydrophobic drugs from hydrogels proposed in this contribution can be readily extended to other hydrogel system and can potentially broaden the application scope of hydrogel drug delivery.     

Electroresponsive and spinnable hydrogels from xanthan gum and gelatin enhanced by Fe3+ ions coordination

Polyelectrolyte hydrogels with spinnability and electroresponsive were prepared from xanthan gum (XG) and gelatin. Oscillatory rheological measurements were utilized to explore mechanical properties and thermal stability of the resultant XG-Gelatin5 hydrogels. The XG-Gelatin5 hydrogels possessed higher strength and larger critical strain than these of the XG hydrogels, demonstrating existence of synergistic interactions. The XG-Gelatin5 hydrogels were stable in temperature range of 20–60°C, and gradually release drug with controlled manner in neutral and acid medium at 37°C. The self-recoverable and thixotropic XG-Gelatin5 hydrogels were extruded to form hydrogel fibers, and the dried hydrogel fibers rapidly bend towards cathode under applied voltage. Long hydrogel fibers were harvested with enhancement by Fe³⁺ ions, and were weaved and braided to obtain hydrogel fiber constructs. The XG-Gelatin5 hydrogel fibers with electroresponsive and controlled drug release possess potential applications in biomaterials, tissue engineering, and drug carrier fields.