综述——纳米材料与药物输递：经皮给药中纳米制剂与皮肤的质构效关系

皮肤是人体最大的器官,也为药物的递送提供了重要途径。经皮给药是药物以皮肤为媒介,透过皮肤吸收的途径。因此,皮肤角质层是经皮给药的最大限速障碍。纳米经皮给药系统,具有提高透皮效率、缓释性、避免药物肝首过效应、减少副作用等优点,是通过纳米制剂与皮肤组织之间的相互作用实现的。其中,纳米制剂的结构和组分与其发挥皮肤促渗效用密切相关。对纳米制剂与皮肤质构效关系深入透彻的了解,有助于新型透皮纳米制剂的设计,并利用综合手段构建安全、高效、实用的经皮给药系统。     

微针用于生物大分子及纳米药物透皮给药的尝试与挑战

生物大分子及纳米药物,比如,亚单位疫苗、DNA疫苗、以及针对真皮层的治疗药物,作为近年来新兴的治疗药物,在有些治疗领域有着透皮给药的需求。由于具有靶向性高,疗效显著等特点,生物大分子及纳米药物逐渐成为新的研究热点。微针作为一种新型的给药技术,不仅具有无痛、给药方便等优点,而且运用物理手段可大幅提高大分子甚至纳米药物的透皮吸收及皮层靶向,能够避过胃肠道消化作用以及肝脏首过效用。将微针技术与生物大分子药物相结合,能够同时发挥两者的优势,实现高靶向生物药物的无痛给药。本文简述微针透皮给药技术、以及生物大分子给药的研究进展,对微针技术用于生物大分子及纳米药物透皮给药的尝试研究做了介绍和总结,对存在的技术挑战进行了分析和展望。     

中药透皮吸收促进剂的研究进展

经皮给药系统(transdermal drug delivery system,TDDS)由于具有超越一般给药方式的独特优点,其研究已经成为第3代药物制剂开发研究的中心内容之一。然而在经皮给药的临床应用中,人们发现,药物的经皮吸收存在着各种障碍,使得药物很难达到预期的有效的治疗效果。近年来,透皮吸收促进剂(penetration enhancers,PE)的应用为经皮给药系统的研究与应用带来了契机,而天然的中药PE以其具有起效快、效果好、副作用小等优点,正日益引起人们的重视,显示出广阔的发展前景。     

经皮给药载体载MD-CPT透明质酸纳米乳的细胞吞噬与体内药代动力学研究

本文在研究制备了包载10,11-亚甲二氧基喜树碱(MD-CPT)的透明质酸纳米乳(HANs)经皮给药系统的基础上,进一步研究了载MD-CPT透明质酸纳米乳的细胞吞噬,并进行了体内药代动力学分析.通过优化制备条件,得到了皮肤渗透性良好的缓释剂型.从CLSM观察到药物被细胞摄入并传递入细胞核,同时,载药纳米乳的细胞吞噬效率呈时间依赖性,不同细胞株HSF、HUVES、MCF-7、KF的细胞吞噬率略有不同.用Rhodanmine B标记HANs,通过荧光显微镜观察到载药纳米乳透过角质层到达真皮层的拟动态过程.利用HPLC检测MD-CPT血药浓度,测得经皮给药半衰期T1/2是静脉注射的3.6倍,肌肉注射的1.6倍,体内药物滞留时间显著增加;血药浓度峰谷值差异小,曲线平缓,说明经皮给药能保证血药浓度呈现可控的持续性.最终通过活体成像系统和组织切片荧光显微镜,直观地反映出经皮给药后药物在大鼠体内的分布情况和各组织器官药物含量,确定载药纳米乳主要采取胞间渗透的扩散方式,在局部给药的区域滞留时间较长,有利于对浅表性的病灶区持续给药,延长药效,而剩余的MD-CPT和解离的HANs都进入了血液循环,最终通过新陈代谢被排出体外.为无创型HANs经皮给药系统应用于浅表性肿瘤治疗提供了理论基础.     

微针阵列用于生物大分子药物的递送

生物大分子药物难以跨过皮肤的角质层屏障,而微针作为一种微创、无痛、高效的经皮给药方式,能有效破解大分子药物透皮速率和吸收量低下的难题.本文详细综述了微针阵列技术在各类生物大分子药物经皮递送中的应用进展,包括单独微针阵列(固体实心微针、空心微针、涂层微针和可溶性微针)以及微针与其他制剂技术(如微粒给药系统)、医疗器械和智能释药系统等结合对大分子药物的促渗作用和控释作用.同时对微针用于大分子药物递送领域目前面临的问题、发展前景等作出分析.     

生物相容透皮给药微针治疗浅表肿瘤

复杂的肿瘤微环境导致抗肿瘤药物在肿瘤组织内递送效率低下，严重阻碍了药物对浅表肿瘤的治疗效果。生物相容透皮给药微针凭借较高的机械强度，刺穿皮肤角质层，将微针内的药物递送至浅表肿瘤组织内，提高生物利用度，改善静脉注射、口服给药的肝肾毒性等问题。本文介绍了生物相容透皮给药微针的设计及其在癌症化疗、光动力治疗、光热治疗、免疫治疗、基因治疗等领域的研究进展，对浅表肿瘤的微创、局部递药和精准、高效治疗具有重要指导意义。     

项目推介

重组人复合干扰素α（优福金）;透皮给药微针阵列药物芯片系统项目;抗乙肝病毒人单克隆抗体靶向制剂项目;分枝杆菌多糖注射液     

尖端载药气泡可溶性微针的制备与透皮效果分析北大核心CSCD

气泡微针作为一种新型的经皮递药技术,可以实现无痛精确给药,引起了研究者极大的关注。为了提高微针携带药物的利用率,本文提出了一种尖端载药气泡可溶性微针的制备方法。在微针成型过程中将气泡形成于针体内,药物集中到微针顶端。重点研究了气泡微针的制备优化工艺,并探究了起泡剂浓度、干燥温度、溶液黏度对气泡微针成型效果的影响,同时对其透皮效果进行了分析。实验结果表明,气泡微针成型工艺稳定,成型率在90%以上,同时将成型周期缩短至4 h左右。药物主要集中在微针针尖,高度在180μm,气泡的高度在250μm,且该微针阵列能够在小鼠皮肤上打出微通道,微针的针体能够在5min内迅速溶解。透皮扩散实验表明,气泡微针能够在1 min内迅速释放约48%的药物,5 min内共释放约91%的药物。微针阵列的气泡微结构能够阻碍药物向基底的扩散,有效提高了药物的利用率,为微针透皮给药的实际应用提供了一定技术依据。     

新型纳米靶向给药系统载体材料的设计

新型纳米靶向给药系统的研究与开发对于难治愈性疾病（尤其是肿瘤）的治疗具有重大意义,而其发展很大程度上取决于载体材料 的设计。构思巧妙、设计合理的载体材料能使载体实现靶向功能,将药物定位浓集于病灶部位,并最大限度地发挥高效低毒的作用。基于 不同的靶向策略,包括被动靶向、主动靶向和响应肿瘤微环境的靶向,综述了近年来一些新型纳米载体材料的设计,为新型纳米靶向给药 系统的研究提供参考。     

载MD-CPT透明质酸纳米微乳经皮给药作用于瘢痕修复的研究

喜树碱衍生物对瘢痕疙瘩成纤维细胞的增殖有明显的抑制作用,为提高药物利用度,提供透皮给药的治疗途径,本文采用微乳法制备了一种新的O/W型透明质酸纳米载体(HA-GMS),包载药物10,11-亚甲二氧基喜树碱(MD-CPT),制备过程中无酒精,且没有使用化学增强剂,经透射电镜和激光粒度仪分别测得HA-GMS纳米乳粒径为(177.33±27.11)nm,zeta电位为-15.6±1.7,多分散系数为0.55±0.01,纳米微乳对MD-CPT药物的包封率为(77.85±1.29)%,且稳定性良好.用MTT法检测HA-GMS对人正常细胞HSF、HUVECs的作用,细胞相对存活率为75%~95%,生物相容性良好,用HA-GMS对瘢痕疙瘩成纤维细胞培养48 h,其生长抑制率为28.2%.HA-GMS纳米乳运载的MD-CPT皮肤渗透量明显高于对照组MD-CPT乙醇溶液对皮肤的渗透量,作用4 h的累积渗透量分别为(660.72±20.54)μg/cm2和(102.73±13.81)μg/cm2,HA-GMS纳米乳明显增加了MD-CPT的透皮效率,本研究结果为透皮给药治疗瘢痕疾病提供了基础.     

蛋白质和多肽药物长效性研究进展

基于分子生物学和重组技术的发展,蛋白质和多肽已经成为一类重要的药物,但是其稳定性差,生物利用率低,半衰期短等问题也日益受到关注。本文重点介绍了一些新的给药途径和给药系统,例如鼻腔、颊等给药途径以及黏膜给药系统、透皮给药系统、缓控释技术等给药系统的进展。综述了对于蛋白质和多肽药物进行定点突变和化学修饰,以达到增加其长效性的一些新方法。     

Bioresponsive matrices in drug delivery

For years, the field of drug delivery has focused on (1) controlling the release of a therapeutic and (2) targeting the therapeutic to a specific cell type. These research endeavors have concentrated mainly on the development of new degradable polymers and molecule-labeled drug delivery vehicles. Recent interest in biomaterials that respond to their environment have opened new methods to trigger the release of drugs and localize the therapeutic within a particular site. These novel biomaterials, usually termed "smart" or "intelligent", are able to deliver a therapeutic agent based on either environmental cues or a remote stimulus. Stimuli-responsive materials could potentially elicit a therapeutically effective dose without adverse side effects. Polymers responding to different stimuli, such as pH, light, temperature, ultrasound, magnetism, or biomolecules have been investigated as potential drug delivery vehicles. This review describes the most recent advances in "smart" drug delivery systems that respond to one or multiple stimuli.     

Perspectives on transdermal ultrasound mediated drug delivery

The use of needles for multiple injection of drugs, such as insulin for diabetes, can be painful. As a result, prescribed drug noncompliance can result in severe medical complications. Several noninvasive methods exist for transdermal drug delivery. These include chemical mediation using liposomes and chemical enhancers or physical mechanisms such as microneedles, iontophoresis, electroporation, and ultrasound. Ultrasound enhanced transdermal drug delivery offers advantages over traditional drug delivery methods which are often invasive and painful. A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration. From a clinical perspective, few drugs, proteins or peptides have been successfully administered transdermally because of the low skin permeability to these relatively large molecules, although much work is underway to resolve this problem. The proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound. For low frequencies, potential transducers which can be used for drug delivery are discussed, along with cautions regarding ultrasound safety versus efficacy.     

Transdermal drug delivery

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase its impact on medicine.     

经皮给药系统产业化开发的关键问题探讨

以经皮给药系统的开发及产业化为主体思路,在对经皮给药系统发展现状认识的基础上,重点对经皮给药产品研发中的吸收模型 及体内外相关性评价研究、产业化设备、国内外研发模式等进行初步探讨,分析经皮给药系统开发中存在的问题和挑战并提出相应的解 决方案,以期为今后国内经皮给药制剂的发展提供思路。     

超声介导镇痛药物透皮吸收研究进展

现阶段,临床中常用的镇痛药物多采用口服或注射给药的方式,具全身不良反应多,患者依从性差等缺点,透皮给药作为一种非侵入性给药方式,相对于这些有很多显著的优势,如使用方便,患者痛苦少等。但是,如何克服皮肤的低渗透性一直是该种给药方式发展的瓶颈。近年来,使用超声能量增强镇痛药物在皮肤上的的渗透性成为新的研究热点,各项研究发现,低频超声对药物的增透效果尤为显著。本文通过检索各国文献,对超声介导镇痛药物透皮吸收的原理,临床前试验和临床试验进行综述。     

The Experimental Evaluation and Molecular Dynamics Simulation of a Heat-Enhanced Transdermal Delivery System

Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.     

Applications of carbon nanotubes in drug delivery

The development of new and efficient drug delivery systems is of fundamental importance to improve the pharmacological profiles of many classes of therapeutic molecules. Many different types of drug delivery systems are currently available. Within the family of nanomaterials, carbon nanotubes (CNT) have emerged as a new alternative and efficient tool for transporting and translocating therapeutic molecules. CNT can be functionalised with bioactive peptides, proteins, nucleic acids and drugs, and used to deliver their cargos to cells and organs. Because functionalised CNT display low toxicity and are not immunogenic, such systems hold great potential in the field of nanobiotechnology and nanomedicine.     

Nanocarrier for Poorly Water-Soluble Anticancer Drugs—Barriers of Translation and Solutions

Many existing chemotherapeutic drugs, repurposed drugs and newly developed small-molecule anticancer compounds have high lipophilicity and low water-solubility. Currently, these poorly water-soluble anticancer drugs (PWSAD) are generally solubilized using high concentrations of surfactants and co-solvents, which frequently lead to adverse side effects. In recent years, researchers have been actively exploring the use of nanotechnology as an alternative to the solvent-based drug solubilization approach. Several classes of nanocarrier systems (lipid-based, polymer-based and albumin-based) are widely studied for encapsulation and delivery of the existing and new PWSAD. These nanocarriers were also shown to offer several additional advantages such as enhanced tumour accumulation, reduced systemic toxicity and improved therapeutic effectiveness. In this article, the recent nanotechnological advances in PWSAD delivery will be reviewed. The barriers commonly encountered in the development of PWSAD nanoformulations (e.g. formulation issues and nanotoxicity issues) and the strategies to overcome these barriers will also be discussed. It is our goal to provide the pharmaceutical scientists and clinicians with more in-depth information about the nanodelivery approach, thus, more efficacious and safe PWSAD nanoformulations can be developed with improved translational success.