口服脉冲控释给药系统的释药机制及其应用

口服脉冲控释给药系统因具有定时或定位释放的特点而成为当前药剂研究领域的热点.本文介绍了其释药机制,包括有机酸诱导、渗透压调节、pH依赖、时间依赖、酶依赖、pH-时间依赖及各释药机制应用实例.提出了该给药系统在应用中,尤其是对中药复方制剂所存在的一些问题,期望为口服中药脉冲控释给药系统的研究提供思路.     

脉冲给药系统

本文介绍了一种新型的控释给药系统－脉冲给药系统,并通过其在口服,注射,埋植,透皮,眼用等给药途径中的应用,阐明了脉冲给药系统的释药原理及其按时辰药理学原理适时提供药物的特点,该系统是剂型研究中的一个新领域。     

脉冲给药系统的研究进展

脉冲给药系统是根据时辰药理学与时辰治疗学特点研究而设计的一种新型迟释给药制剂。文章查阅了近几年国内外相关文献,阐述了脉冲给药系统的释药机制,包括生物化学刺激(胃肠道酸碱度、酶敏感度、葡萄糖敏感度等),物理化学刺激(声波、磁场、电场、温度等),膨胀爆破释药机制以及定时脉冲塞胶囊释药机制,并总结了基于各类释药机制的脉冲释药系统在药剂学中的应用研究进展。     

时辰药理学与新型药物开发

目的：介绍根据时辰药理学和疾病发作的时间节律点而研究开发的新型药物。方法：参考国内外文献，从时辰药理学角度来阐述脉冲给药系统、智能给药系统。结果：脉冲给药系统能按最佳给药时间来释放药物，既可提高药效、减少用药量，又可减少不良反应的发生。结论：研究开发新型智能型药物具有较高的临床应用价值和广阔的发展前景。     

蛋白质及多肽药物的药剂学研究进展

蛋白质及多肽类药物的体内过程存在的特殊情况，因而为制剂与生物药剂学研究提出了新课题，新给药途径的研究，本文重点介绍了鼻腔给给与肺部给药，长效脂质本，蛋白质及多肽类药物的吸收促进剂以及一些符合时辰节律的药物释放系统如按需给药系统，脉冲释药系统与自我调节系统等。     

脉冲式释药系统及脂质体的研究进展

脉冲式释药系统是基于时辰药理学的理论,以制剂手段控制药物释放的时间及给药剂量以配合生理节律的变化,达到最佳的疗效。现简要讨论脉冲释药的特点及机制,并介绍了近年来脉冲技术的进展。另外,将脂质体研究中存在问题及解决办法作一简单分析。     

药物制剂技术的发展

随着制剂理论的发展,制剂技术已由经典的被动载体技术向主动控制药物作用方向发展。给药系统的研究开发技术是制剂工业的主导方向。控缓释、靶和、透皮、粘膜给药是当前研究的重点。计算机辅助药物制剂开发系统、脉冲式、自调式给药等新兴技术正在发展。生物制药、中药制剂技术也有很大发展。本文综述了热点、新兴制剂技术及生物制药和中药制剂技术所与现状。     

应答式释药系统

随着时辰药理学研究的深入 ,人们发现某些药物的作用和某些疾病的发作与时间过程有密切关系［１］,这对药物制剂的开发提出了更高的要求 ,即希望开发出适应人体生理、病理时间节律变化的释药剂型———应答式释药系统 (ｒｅｓｐｏｎｓｉｂｌｅｓｙｓ ｔｅｍ )。目前的应答式释药系统有开环和闭环两种体系 ,开环体系是利用外部的变化因素来控制药物释放 ,称为脉冲给药系统 ;闭环体系是通过自身的信息反馈来控制药物的释放 ,称为自调式给药系统。１脉冲给药系统脉冲给药系统不同于按零级释药的控释制剂 ,其目的不是维持稳定的血药浓度 ,而是按…     

基于时辰治疗学的给药技术研究进展

随着时间生物学、时辰药理学及时辰治疗学的不断进步,传统的给药模式已不能满足人体-疾病-药物之间的时效关系,临床需要能依据疾病特点定时释药的符合时辰节律的药物传递系统,而时辰递药系统的发展瓶颈主要在于相应给药技术的应用。本文分别从口服与非口服两方面介绍了现有的时辰给药技术,并对时辰给药系统的发展前景及其局限性进行了客观评价。     

新型给药系统及其在中药制剂中的研究进展

本文综述了2000年以来的新型给药系统-缓控释给药系统、靶向给药系统、透皮给药系统、粘附给药系统,无针粉末喷射给药系统、自乳化药物传递系统等在中药制剂中的研究应用,并扼要介绍了一些国际上应用前景良好的最新给药系统-药物涂层支架、基因治疗载体系统、生物芯片、分子马达、纳米陷阱等,希望能对中药剂型改革与中药现代化提供参考。在中医药现代化的进程中,我们认为中药新型给药系统的研究与开发是中药剂型改革与中药现代化一条有效途径。     

Use of scoring to induce reproducible drug delivery from osmotic pulsatile tablets

An osmotic-controlled pulsatile delivery technology was developed for targeted drug delivery. This novel system consists of a tablet core surrounded by an osmotic coating that has been mechanically compromised in strategic locations to facilitate reliable drug release at a given time point after administration. The tablet core contains a high drug load in addition to several osmotic agents and swellable polymers, and the surrounding mechanically-compromised osmotic coating consists of a semipermeable membrane that has been scored with a razor blade in several key locations. The components in the tablet core attract water into the core, causing it to swell and propagate the scores in the coating along the length of the tablet. After the scores have fully propagated, the coating bursts open, releasing the tablet core’s contents, including the drug, into the surrounding media. The variables that were investigated in this study included the configuration of the scores in the coating, the length of the scores, and the distance between the scores. The delivery system developed in this work is able to generate a reproducible dissolution profile consisting of a specific targeted lag time, between five minutes and two hours, followed by immediate release of the drug from the core. The performance of the system was validated in vitro using the drug salicylic acid. Unlike previously developed osmotic pulsatile delivery systems, the present system is able to accommodate higher drug loading levels, it is easier to manufacture, and has demonstrated more reproducible burst times (i.e. burst time) than several other pulsatile systems.     

Evaluation of an Enzyme-Containing Capsular Shaped Pulsatile Drug Delivery System

Purpose. To develop an enzymatically-controlled pulsatile drug release system based on an impermeable capsule body, which contains the drug and is closed by an erodible pectin/pectinase-plug. Methods. The plug was prepared by direct compression of pectin and pectinase in different ratios. In addition to the disintegration times of the plugs, the lag times and the release profiles of the pulsatile system were determined as a function of pectin:enzyme ratio, the pH of the surrounding medium, and the addition of buffering or chelating agents. Results. The disintegration time of the plug, respectively the lag time prior to the drug release was controlled by the pectin:enzyme ratio and the plug weight. The inclusion of a buffering agent within the plug lead to a plug disintegration independent of the surrounding pH. The addition of Na-EDTA hindered the formation of non-soluble calcium pectinate in the presence of calcium ions in the environment. The addition of effervescent agents to the capsule content resulted in a rapid emptying of the capsule content after plug degradation. Conclusions. A pulsatile drug delivery system based on an erodible pectin plug containing a pectinolytic enzyme was developed. The drug release was controlled by the enzymatic degradation and dissolution of pectin.     

A mathematical model for pulsatile release: controlled release of rhodamine B from UV-crosslinked thermoresponsive thin films

A controlled drug delivery system fabricated from a thermoresponsive polymer was designed to obtain a pulsatile release profile which was triggered by altering the temperature of the dissolution medium. Two stages of release behaviour were found: fast release for a swollen state and slow (yet significant and non-negligible) release for a collapsed state. Six cycles of pulsatile release between 4 °C and 40 °C were obtained. The dosage of drug (rhodamine B) released in these cycles could be controlled to deliver approximately equal doses by altering the release time in the swollen state. However, for the first cycle, the swollen release rate was found to be large, and the release time could not be made short enough to prevent a larger dose than desired being delivered. A model was developed based on Fick's law which describes pulsatile release mathematically for the first time, and diffusion coefficients at different temperatures (including temperatures corresponding to both the fully swollen and collapsed states) were estimated by fitting the experimental data with the theoretical release profile given by this model. The effect of temperature on the diffusion coefficient was studied and it was found that in the range of the lower critical solution temperature (LCST), the diffusion coefficient increased with decreasing temperature. The model predicts that the effective lifetime of the system lies in the approximate range of 1-42 h (95% of drug released), depending on how long the system was kept at low temperature (below the LCST). Therefore this system can be used to obtain a controllable pulsatile release profile for small molecule drugs thereby enabling optimum therapeutic effects.     

盐酸维拉帕米脉冲胶囊的制备及其体外释药考察

目的:制备一种新型脉冲式胶囊给药系统,探索影响药物在一定的时滞后脉冲释放的因素。方法:以蘸胶工艺制备不溶性半透膜囊体,灌装药物粉末或药物与渗透促进剂混合物,以果胶直接压片制备胶塞,塞入囊体后,套上胃溶性囊帽和囊体后外包肠溶衣,进行体外释放试验。结果:该给药系统在人工胃液中不变形,药物不释放,在pH7.4人工肠液中药物的脉冲释放受肠溶包衣厚度、不溶性囊体中致孔剂含量和填充物渗透促进剂比例的影响。结论:胶囊系统设计原理简单,各组成部分可单独制备,药物释放可根据要求来设计调节,可应用于多种药物,有望开发成一种新型药物脉冲释放系统。     

Programmable Drug Delivery from an Erodible Association Polymer System

An erodible association polymer system based on blends of cellulose acetate phthalate (CAP) and Pluronic F127, a block copolymer of poly(ethylene oxide) and poly(propylene oxide), has been investigated for its applicability to rate-programmed drug delivery. The compatibility and thermal properties were characterized by DSC and FTIR. Results from the thermal analysis indicate that the blends are compatible above 50% CAP, as revealed by a single composition-dependent glass transition temperature (T _g). The existence of molecular association through intermolecular hydrogen bonding between the carboxylic acid and the ether oxygen groups is supported by the observation of an upward shift in the IR carbonyl stretching frequency at increasing Pluronic F127 concentrations. Using theophylline as a model drug, the in vitro polymer erosion and drug release characteristics of the present polymer system were evaluated at different buffer pH's on a rotating-disk apparatus. The results show that the rates of both polymer erosion and drug release increase with the Pluronic F127 concentration in the blend. Further, at pH 4, the polymer erosion is minimal and the theophylline release appears to be governed mainly by diffusion through the polymer matrix. In contrast, at pH 7.4, the theophylline release is controlled primarily by the polymer surface erosion. To demonstrate the unique approach to programmed drug release based on the concept of non-uniform initial drug distribution, pulsatile patterns of drug release have been achieved successfully from the present surface-erodible polymer system using a multilaminate sample design with alternating drug-loaded layers. The results suggest that the pulsing frequency and peak rate of such pulsatile drug delivery are pH dependent; however, they can be modulated by varying the thickness, drug loading, and erosion rate of the constituent layers in the multilaminate.     

脉冲给药系统的释药机理及研究进展

脉冲给药是基于时辰药理学的理论，以制剂手段控制药物释放的时间及给药剂量以配合生理节律的变化，达到最佳的疗效。本文简要讨论了脉冲给药的特点及机理，并介绍了近年来脉冲技术的进展。     

脉冲释药系统的新进展

综述近年来脉冲释药系统的新进展。脉冲释药系统是一种按照生理节律设计、定时定量脉冲式释放有效治疗量药物的剂型。根据剂型设计原理和药物释药机制,将脉冲释药系统分为预设药物传递系统、闭环反馈型传递系统和开环传递系统三大类。     

Pulsatile Drug Release from an Insoluble Capsule Body Controlled by an Erodible Plug

Purpose. The objective of this study was to develop and evaluate a pulsatile drug delivery system based on an impermeable capsule body filled with drug and an erodible plug placed in the opening of the capsule body. Methods. The erodible plugs were either prepared by direct compression followed by placing the tablets in the capsule opening or by congealing a meltable plug material directly within the capsule opening. The disintegration/erosion properties of these plugs were determined and optimized for the final delivery system. In order to assure rapid drug release of the capsule content after erosion of the plug, various excipients (fillers, effervescent agents) and drugs with different solubilities were evaluated. The lag time prior to drug release and the subsequent drug release were investigated as function of capsule content, plug composition, plug preparation technique, plug hardness, weight, and thickness. Results. The erosion time of the compressed plugs increased with increasing molecular weight of the hydrophilic polymer (e.g. hydroxypropyl methylcellulose, polyethylene oxide), decreasing filler (lactose) content and decreased with congealable lipidic plugs with increasing HLB-value and inclusion of surfactants. For complete and rapid release of the drug from the capsule body, effervescent agents had to be included in the capsule content. The drug delivery system showed typical pulsatile release profiles with a lag time followed by a rapid release phase. The lag time prior to the pulsatile drug release correlated well with the erosion properties of the plugs and, besides the composition of the plug, could be controlled by the thickness (weight) of the plug. Conclusions. A single-unit, capsular-shaped pulsatile drug delivery system was developed wherein the pulsatile release was controlled by the erosion properties of a compressed or congealed plug placed within the opening of the capsule opening.     

尼莫地平三次脉冲释药系统的研制

目的:制备尼莫地平三次脉冲释药系统并考察其体外释药性。方法:利用固体分散体技术制备尼莫地平的速释小片,采用干包衣法制备时滞4h和8h的脉冲小片,将此3种小片装入胶囊制成尼莫地平三次脉冲释药系统,并对小片和脉冲释药系统均进行体外释药研究。差示扫描量热(DSC)分析鉴别药物在固体分散体载体中的状态。结果:速释小片在30min内释药95%以上,脉冲小片在4h或8h的时滞期内释药<10%,时滞期过后的3h内释药完全;脉冲释药系统分别在5min、4h、8h时实现三次脉冲释药。药物均匀分散于载体中,并以无定型状态存在。结论:成功制备了尼莫地平三次脉冲释药系统。     

Gastrointestinal Transit and Systemic Absorption of Captopril from a Pulsed-Release Formulation

Captopril has been administered to eight healthy male subjects by means of a pulsatile delivery system that was designed to release the drug in the colonic region of the intestine. The gastrointestinal transit and pulsatile release were followed using gamma scintigraphy. A pulsatile capsule system with release after a nominal 5-hr period was found to perform reproducibly in vitro and in vivo. In six of the eight subjects, the drug was delivered to the colon, and in the remaining two subjects, to the terminal ileum. Measurable blood levels of free captopril were found in three subjects. Variable instability of the drug in the distal intestine is suggested as a possible reason for the lack of absorption of the drug in the majority of subjects.