无针粉末注射给药技术研究进展

本文对无针粉末注射给药技术在药物研究及应用方面进行综述。从无针粉末注射给药的概念、器械设计原理、透皮给药深度到给药效果研究，详细介绍了这一新型给药系统的国内外研究进展。     

无针注射给药系统及应用

长期以来,为尽量避免传统注射剂固有的缺陷,药剂学家们一方面致力于开展非注射途径给药系统和微针注射给药技术的研究,另一方面积极开展无针注射剂（或称为无针注射给药系统）的研究.国外无针注射剂的研究已经全面展开,国内则刚刚起步.本文初步定义了无针注射剂的广义内涵,按无针注射器动力源差异和药物存在形式不同,用综合的分类方法对无针注射剂进行综述,系统介绍了无针注射剂作用机理、发展现状和不同型号研究产品的优缺点,并就存在的关键技术问题提出可能的解决方案.我们认为,随着无针注射给药系统研究的深入,无针注射药物品种将可能有更大的选择空间,蛋白质组学研究的推进将发掘更多适于无针注射给药的蛋白-多肽类药物,很多中药药效成分将可能适合于无针注射给药,大量基因治疗药物将以无针注射剂形式出现.对无针注射给药系统进行广泛深入的研究将是国内药剂学者共同面对的挑战和责任.     

粉末无针注射给药系统试验性研究

目的获得粉末无针注射的优化技术参数,初步建立粉末无针注射给药系统技术平台。方法利用国产化SSP型无针注射器,以离体人皮,离体猪皮和模拟人皮凝胶为注射靶标,对钨,氧化铝,硅胶和蛋白-壳聚糖微粒等材料进行粉末无针注射研究;筛分控制各种粉末的粒径和粒度分布;测量各种粉末的密度;采用显微镜法观测粉末注射深度,利用SAS统计软件分析试验数据。在优化条件下,利用荧光素进行体内无针注射试验研究。结果经筛选,无针注射用粉末的粒径分布范围在1.0~75.0μm,密度分布范围在1.10~19.3g·ml-1;显微镜观测结果表明:在同种注射靶标中,随着粉末密度和粉末粒径增大,最大注射深度增加;在不同靶标中的注射深度符合不同的规律。荧光素体内注射研究表明,生物利用度达到10%~40%。结论本文涉及的粉末无针注射器是实现无针注射的关键,是自主研制的新型器具。以模拟人皮凝胶作为实用、便捷的注射靶标,可大大简化实验步骤,并得出具有参考价值的结果。本文考察了不同微粒的无针粉末注射最大注射深度,微粒的粒径和密度对无针注射效果具有显著影响。初步建立粉末无针注射给药系统技术平台。     

自制无针粉末注射给药系统药物导入率的体外评价

目的 建立体外吸收评价方法,考察自制无针粉末注射给药系统的给药性能。方法 以人体皮肤为研究材料,荧光素钠作为模型药物,高效液相-荧光法检测,以透皮吸收率为指标,采用正交试验设计优选无针粉末注射的载药喷射参数。结果 建立的方法分析时间小于3min,在0．2304-9．216ng范围内呈线性关系,绝对回收率大于99．8％,RSD〈0．8％;自制无针粉末注射给药系统的最高透皮吸收率可达到40％,超过普通透皮途经400倍以上,与国外同类产品的药物导入效率（33％）相当;正交试验分析表明气源压力、喷管型号、药物剂量、药粉粒径均对无针粉末注射的效果有影响。结论 建立的研究方法简便、快速、准确、可靠,可用于无针粉末注射系统的体外研究;自制无针粉末注射给药系统的药物导入效率较高,值得进一步推广应用。     

胰岛素非注射给药途径的研究进展

本综述近年来国内外关于胰岛素经口、鼻腔、眼部及肺部等非注射给药的研究动态。说明只要采用一定的制剂技术和给药途径，并辅之于吸收促进剂，胰岛素非注射给药可达到３０％以上的生物利用度。     

叶酸放射免疫测定对不同给药途径房水浓度的实验研究

为了更加接近于临床实际和评价球结膜下注射这一给药途径的作用,作者应用放射免疫分析法(RIA),以~(125)I—叶酸(Folic acid FA)为标记抗原,定量观察不同时间血清及房水FA浓度变化,比较这两种途径一次性给药对房水浓度的影响。     

中药直肠给药概况

目的：通过对中药灌肠剂应用研究情况的综述,以期对该中药剂型的临床应用及开发借鉴。方法：在复习有关中药灌肠剂的临床应用、生产及新型型微型灌肠剂在中药方面的应用研究献的基础上,中中药灌肠剂的现状及发展进行概括。结果：中药直脾性给药可作为中药常用的用药途径,不仅适于中医辨证论治随症加减的治疗策略,且可用于急慢性疾病的局部及全身用药,是中医治疗急症的有效途径。结论：固体形态的灌肠剂及微型灌肠剂是灌肠剂发     

胰岛素无针粉末注射给药的降糖效果考察

目的考察胰岛素无针粉末注射给药对糖尿病家兔的降血糖效果,为研制开发胰岛素无针粉末注射剂提供参考。方法36只四氧嘧啶致糖尿病家兔被随机分成6组,每组6只,空白粉末无针注射组、胰岛素无针粉末注射低剂量组（0.2mg·kg^-1）,中剂量组（0.4mg·kg^-1）,高剂量组（0.6mg·kg^-1）;皮下注射胰岛素溶液组（0.2mg·kg^-1）,作为阳性对照;皮下注射生理氯化钠溶液组,作为阴性对照。另外,6只正常家兔作为正常对照组。分别测定用药前后家兔的血糖值,并做组间分析比较。结果胰岛素无针粉末注射给药后,低剂量组血糖值下降到给药前的63.3%：中剂量组下降到给药前的43.8%;高剂量组下降到给药前的38.8%。皮下注射胰岛素后,血糖值下降到给药前的23.9%。胰岛素无针粉末注射给药的药理相对生物利用度低剂量组为42.1%,中剂量组为39.3%,高剂量组为34.3%。结论胰岛素无针粉末注射给药可有效降低糖尿病家兔的血糖。     

The role of ultrasound and magnetic resonance in local drug delivery

Local drug delivery has recently attracted much attention since it represents a strategy to increase the drug concentration at the target location and decrease systemic toxicity effects. Ultrasound can be used in different ways to trigger regional drug delivery. It can cause the local drug release from a carrier vehicle and the local increase of cell membrane permeability either by a mechanical action or by a temperature increase. Ultrasound contrast agents may enhance these effects by means of cavitation. Ultrasound can be focused deep inside the body into a small region with dimensions on the order of 1 mm. Several types of drug microcarriers have been proposed, from nano- to micrometer sized particles. The objective of real-time imaging of local drug delivery is to assure that the delivery takes place in the target region, that the drug concentration and the resulting physiological reaction are sufficient, and to intervene if necessary. Ultrasound and nuclear imaging techniques play an important role. MRI is rather insensitive but allows precise targeting of (focused) ultrasound, can provide real-time temperature maps, and gives access to a variety of imaging biomarkers that may be used to assess drug action. Examples from recent articles illustrate the potential of the principles of ultrasound-triggered local drug delivery.     

Targeted drug delivery under MRI guidance

The main goal of local drug delivery is to increase the concentration of a specific therapeutic agent in a target tissue with minimal nontarget distribution. Compared to systemic therapy, local drug delivery provides a high level of therapeutic efficacy with minimal systemic effects. The current primary imaging modality for drug delivery has been x-ray angiography, but it has major limitations including anatomical ambiguity and inability to visualize the targeted tissues. Due to these inherent problems, MR guidance has been explored as an alternative imaging modality for guiding and monitoring of drug therapy. Recently, interventional MR (XMR) systems have been implemented that have both dual x-ray and MRI capabilities in a single suite and allow for real-time interventional procedures to be performed in a clinical setting. In cases where drug delivery is required, this system provides a significant leap for catheter-based therapies. Although clinical drug delivery procedures utilizing MR guidance are still in the early stages of development and application, recent technological advances should help further promote the adoption of such procedures. This review covers the emerging techniques of drug delivery using MR guidance.     

抗生素/磷酸钙骨水泥载药缓释系统研究进展

抗生素/磷酸钙骨水泥(CPC)载药缓释系统在修复骨缺损的同时持续释放抗生素发挥局部抗感染作用,是骨髓炎理想的治疗手段。载入的抗生素能影响CPC的固化时间、机械强度等理化性质,而抗生素的释放与CPC的孔隙率、微孔直径等显微结构参数相关。随着抗生素/CPC载药缓释系统相关的实验研究不断深入,距离广泛临床治疗将为期不远。     

Fully MR-guided hepatic artery catheterization for selective drug delivery: a feasibility study in pigs

PURPOSE: To demonstrate the feasibility of hepatic catheterization for selective delivery of therapeutic agents using a clinical MRI scanner for real-time image guidance. MATERIALS AND METHODS: Experiments were performed in three domestic pigs (70-80 kg) using a clinical 1.5-T MR scanner. After abdominal three-dimensional contrast-enhanced MR angiography (3D-CE-MRA) was performed, endovascular devices with susceptibility markers were tracked with passive tracking techniques. Catheters were maneuvered into the primary and secondary hepatic arteries. Selective catheterization was verified using selective time-resolved CE angiography. Paramagnetic microspheres were administered to a different region for each liver. The resulting biodistributions were investigated using MR images. RESULTS: Successful selective hepatic catheterization was repeatedly demonstrated using passive tracking techniques. 3D-CE-MRA significantly aided the interventional procedure by showing the vascular anatomy, and maximum-intensity projections (MIPs) were used as roadmaps during the interventions. In all cases, microspheres were successfully delivered to the selected regions. The catheters were visualized at a maximum frame rate of five frames per second, allowing a good depiction of the devices and a reliable catheterization of the hepatic arteries. CONCLUSION: Fully MR-guided real-time navigation of endovascular devices permits complex procedures such as selective intra-arterial delivery of therapeutic agents to parts of the liver.     

Measurement of tumor interstitial volume fraction: method and implication for drug delivery.

It is important to evaluate the tumor interstitial volume fraction that is accessible for drug accumulation during the distribution phase in order to determine the potential efficacy of cancer chemotherapy. In this study, we performed simulations of magnetic resonance imaging (MRI) signal intensity using a two-compartment tissue model for quantitative analyses of absolute interstitial volume measurements while we experimentally characterized a mouse tumor model with a dual MR contrast-agent method. Previously, consecutive intravenous injections of a strictly intravascular T1 contrast agent followed by an extravasating agent were used as a strategy for the quantification of both relative blood volume (Rel_BV) and relative interstitial volume (Rel_ITST) (Weissleder et al. Eur J Cancer 1998;34:1448-1454; Bogdanov et al. Neoplasia 1991;1:438-435). In the current study, we demonstrate that this approach can be further improved, and that it enables one to accurately evaluate both relative and absolute interstitial volumes. The animal data indicated that a significant difference exists between the absolute interstitial volume fractions of subcutaneously implanted MDA PCa 2b tumor and skeletal muscle tissue (27.5 +/- 9.1% and 15.9 +/- 0.7%, respectively (P < 0.05)), while only a minor difference was found for the absolute blood volumes (Abs_BV) (Kim et al. Magn Reson Med 2002;47:1110-1120) of these tissues.     

MR imaging of biodegradable polymeric microparticles: a potential method of monitoring local drug delivery.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) was encapsulated into biodegradable, bioadhesive polymeric microparticles to enable noninvasive monitoring of their local intravesical delivery with MRI. The microparticles were characterized by contrast agent encapsulation and release kinetics, T(1) relaxation rates, and contrast enhancement in vivo. The level of Gd-DTPA loading into microparticles was 14.3 +/- 0.6 mug/mg polymer. The measured T(1) relaxation rates of the microparticles showed a direct dependence on Gd-DPTA content. Both 1.5T and 4.7T MR scanners were used to image murine bladders instilled intravesically with Gd-DTPA-loaded particles in vivo. MR images showed ring-shaped regions of enhancement inscribing the bladder wall, which were attributed to the microparticles that were preferentially adherent to the mucosa lining the urothelium. The images of controls exhibited no such enhancement. The normalized signal intensities measured from post-instillation images were significantly greater (P < 0.05) than those in the pre-instillation images. Contrast enhancement was observed for at least 5 days after the initial instillation, although the enhancement decreased due to microparticle degradation or mucosa renewal. The localized distribution of biodegradable, bioadhesive microparticles encapsulating Gd-DTPA was successfully visualized with MRI in vivo, allowing particle-mediated delivery to be temporally and spatially monitored noninvasively.     

Simultaneous monitoring of temperature and T1: methods and preliminary results of application to drug delivery using thermosensitive liposomes.

A method is presented to obtain temperature and longitudinal relaxivity measurements simultaneously and in near real-time. Quantitative relaxivity values are obtained from the signal magnitude from fast Look-Locker EPI data, whereas phase information from all signal samples on the recovery curve is combined to provide temperature values using the proton resonance frequency method. The utility of this technique is illustrated in an in vitro experiment with thermosensitive liposomes, which are studied as potential micro vehicles for local drug delivery. The method allowed measuring the evolution of relaxivity during RF-heating of liposomes containing a paramagnetic contrast agent, demonstrating increase of liposome permeability near the phase transition temperature. Potential applications are monitoring of local drug delivery using thermosensitive liposomes, and confirmation of reaching the liposomes' threshold temperature during thermal therapy.     

介入分期开通症状性颈内动脉闭塞可行性临床研究

目的 探讨介入分期开通症状性颈内动脉闭塞(ICAO)的可行性和安全性,以及影响开通成功的因素.方法 回顾性分析43例接受介入分期开通支架成形术治疗的症状性ICAO患者,系统分析手术成功率、围术期并发症发生率及影响血管开通的因素.结果 43例患者中36例完成介入分期开通支架成形术,手术成功率为83.7％(36/43).1个月内新发脑梗死患者手术成功率高于半年内短暂性脑缺血发作患者(P＜0.05),ICAO侧眼动脉逆向血流在颈内动脉有反流患者手术成功率高于无眼动脉逆向血流反流患者(P＜0.05).1例患者二期术后3d出现同侧脑组织少量出血,1例二期术后出现脑过度灌注综合征,另1例一期术后出现同侧脑卒中新发梗死,围术期并发症发生率为6.9％ (3/43).结论 介入分期开通症状性ICAO技术上可行,有着较高的安全性.1个月内新发脑梗死、ICAO侧眼动脉逆向血流反流为开通成功的有利因素.     

血管腔内治疗注射毒品所致股动脉假性动脉瘤破裂出血

目的 探讨血管腔内覆膜支架成形及弹簧圈栓塞治疗注射毒品所致股动脉假性动脉瘤(FAP)破裂出血的可行性、安全性、有效性.方法 回顾性分析2012年7月至2015年12月收治的32例注射毒品所致FAP破裂出血患者临床资料.患者平均年龄36.5岁,其中男性25例(78.1％).结果 32例患者均成功止血,血管腔内治疗技术成功率100％,围手术期无死亡患者.其中覆膜支架血管腔内修复术25例(78.1％),弹簧圈栓塞股深动脉3例(9.4％),覆膜支架+股深动脉栓塞4例(12.5％).平均随访(17.5±11.6)个月,随访率93.8％(30/32),3年血管支架累积通畅率为90.9％,3年总体生存率为91.3％.结论 血管腔内治疗注射毒品所致FAP破裂出血安全、快速,近中期疗效良好,为急危重症患者赢得二期外科清创修复时间,二期彻底清创是控制感染的重要手段.