脑靶向性鼻腔给药的研究进展

鼻腔给药作为脑靶向给药的途径之一,可有效地使通过其他给药途径不易透过血脑屏障的药物绕过血脑屏障,靶向递送到脑部,为中枢神经系统疾病的治疗提供一种极有发展前景的给药途径.现从药物由鼻腔到脑的转运方式、影响因素、剂型、评价方法以及增强脑靶向性的方法等方面,对近年来鼻腔给药脑靶向性的研究进展进行综述.     

经鼻递脑机制及基于EPR效应的脑靶向脂质体的研究进展

鼻腔与脑在解剖生理结构上的独特联系使得鼻腔给药作为脑内递药途径成为可能,而作为特殊给药系统的脂质体具有鼻腔给药的诸多特点,经鼻腔给药并且利用肿瘤的长滞留效应（EPR效应）或"炎症靶向"达到脑靶向作用,可增加药物的脑内递送。近年来经鼻递药结合EPR效应的策略越来越受到关注,本文归纳总结了近些年国内外有关经鼻递脑途径的机制、影响因素,探讨了经鼻给药结合EPR效应的脑靶向脂质体在中枢神经系统疾病方面的相关研究。     

鼻粘膜作为脑内递药途径的研究进展

20世纪 90年代以来 ,药物传输系统尤其是靶向给药体系成为药学研究的热点 ,但目前的研究主要集中在肝、脾和肺等靶向方面 ,对于脑内靶向却较少涉及。脑部是靶向给药的一个重要部位 ,很多药物必须进入脑内才能发挥疗效 ,然而由于血脑屏障(ｂｌｏｏｄ ｂｒａｉｎｂａｒｒｉｅｒ ,ＢＢＢ)的存在 ,常规途径给药后在脑内的药物浓度都比较低 ,限制了对脑部疾病的治疗。由于鼻粘膜在解剖生理上与脑部存在着独特的联系 ,因此有望在脑内递药领域有所突破。本文就鼻粘膜作为脑内递药途径的研究作一综述。1　鼻粘膜作为脑内递药途径的研究进展我国古代…     

经鼻纳米递药系统在中枢神经系统疾病治疗中的研究进展

中枢神经系统疾病治疗药物的脑内递送通常受限于血脑屏障。经鼻给药作为脑靶向递药的一种无创给药方式，可绕开血脑屏障，实现药物至脑部的直接、高效靶向输送，在中枢神经系统疾病治疗中具有极大应用潜力。然而，鼻腔黏液纤毛清除力等屏障限制了经鼻给药递送效果。依托纳米递药技术的发展，经鼻纳米递药系统为中枢神经系统疾病的治疗带来了新的希望。本文综述了经鼻入脑递药通路、常见经鼻纳米递药系统及其特性和治疗应用进展，为基于中枢神经系统疾病治疗的经鼻纳米递药系统设计提供思路和方法。     

跨血脑屏障纳米递药系统的研究进展

血脑屏障是治疗多种中枢神经系统疾病的主要障碍.随着纳米技术的发展,新型脑靶向递药系统的研究取得了较大进展.该类递药系统可通过受体、转运体、吸附等介导的转胞吞作用,以及暂时破坏血脑屏障结构完整性等多种机制跨越血脑屏障并完成脑内药物递释,达到治疗中枢神经系统疾病的目的.本文综述了近年来跨血脑屏障纳米递药系统的研究进展.     

经鼻脑靶向给药系统研究进展

由于血脑屏障的存在,血液中的药物难以进入中枢神经系统.近些年研究表明,经鼻腔给药后,药物可以绕过血脑屏障直接进入脑部,而且其对机体的损伤和副作用都较小,因此经鼻脑靶向给药系统不断受到更多人的关注.首先探讨了药物经鼻入脑的通路及机制,并针对鼻腔给药的不同影响因素提出了相应的优化方案,还介绍了脑靶向性的评价方法,为进一步研究鼻脑靶向制剂提供了参考.     

脑靶向鼻腔给药的研究进展

目的阐述鼻腔的生理特点和药物由鼻黏膜转运入脑的机制及其影响因素。方法依据近年来的29篇中外文文献,对药物的鼻腔脑靶向实验手段、离体在体模型、鼻黏膜的毒性等方面的研究进展进行阐述。结果鼻黏膜给药途径在脑内递药领域具有独特优势,其在脑部疾病治疗方面具有独到之处,值得进一步深入研究。结论药物的鼻腔脑靶向给药将受到越来越多的关注。     

基于双级靶向技术的脑部递药系统研究进展

血脑屏障(blood-brain barrier,BBB)是治疗中枢神经系统疾病所面临的一个重要挑战。载药纳米粒子以其独特优势能够被动靶向BBB,在此基础上结合1个可以靶向于病变部位的特异性配体,或是修饰2个分别靶向BBB和病变部位的配体,得到的双级脑靶向纳米递药系统就能增加药物跨BBB转运和在脑病灶区浓集。为了增强系统的稳定性,通过选择一种具有双重靶向作用的功能基,在递药系统完成双级靶向的同时,实现更精准地药物向脑内的靶向递送。本文重点介绍了双级脑靶向递药系统的分类以及在脑肿瘤、阿尔茨海默病及脑卒中这些脑部疾病治疗中取得的研究进展,对在双级脑靶向给药系统构建中存在的问题进行了讨论及展望。     

透血脑屏障制剂的研究进展

透血脑屏障的研究是药剂学研究中的一个热点和难点，目前研究较多的途径是静脉注射纳米粒和鼻腔给药。综述了纳米粒的载药方法和透血脑 屏障的机制，通过鼻腔给药实现透血脑屏障的途径，影响药物从嗅觉区进入中枢神经系统的因素以及大分子药物利用该途径的可能性。     

Angiopep-2用于脑靶向递药系统的研究进展

随着社会的发展,脑部疾病已成为影响人类生活质量和健康的重要因素。一般给药系统很难穿透血脑屏障抵达病变部位,但靶向递药系统的出现,实现了药物在脑内递释,从而达到治疗的效果。Angiopep是一类能与低密度脂蛋白受体结合介导穿透血脑屏障的相关肽家族,其中angiopep-2可用于药物脑靶向递送,改善药物转运及精准作用于病变部位。简介angiopep-2的生物学性质及转运形式,重点介绍其穿透血脑屏障和靶向递药的治疗作用研究进展。     

鼻腔给药在神经系统疾病治疗中的研究进展

鼻腔给药可以避开血脑屏障、胃肠道降解和肝脏首过效应,经过嗅神经通路直接到达脑部,因而被用于多种神经系统疾病的治疗。本文综述了鼻腔解剖、鼻腔给药治疗中枢神经系统疾病的转运通路、作用机制、临床应用、面临挑战和新技术等方面的研究进展。     

In vitro and ex vivo experimental models for evaluation of intranasal systemic drug delivery as well as direct nose-to-brain drug delivery

The intranasal route of administration provides a noninvasive method to deliver drugs into the systemic circulation and/or directly into the brain. Direct nose-to-brain drug delivery offers the possibility to treat central nervous system diseases more effectively, as it can evade the blood–brain barrier. In vitro and ex vivo intranasal models provide a means to investigate physiological and pharmaceutical factors that could play a role in drug delivery across the nasal epithelium as well as to determine the mechanisms involved in drug absorption from the nose. The development and implementation of cost-effective pharmacokinetic models for intranasal drug delivery with good in vitro-in vivo correlation can accelerate pharmaceutical drug product development and improve economic and ecological aspects by reducing the time and costs spent on animal studies. Special considerations should be made with regard to the purpose of the in vitro/ex vivo study, namely, whether it is intended to predict systemic or brain delivery, source and site of tissue or cell sampling, viability window of selected model, and the experimental setup of diffusion chambers. The type of model implemented should suit the relevant needs and requirements of the project, researcher, and interlaboratory. This review aims to provide an overview of in vitro and ex vivo models that have been developed to study intranasal and direct nose-to-brain drug delivery.     

Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood–brain barrier: an excellent platform for brain targeting

Introduction: The blood–brain barrier (BBB) represents a stringent barrier for delivery of neurotherapeutics in vivo. An attempt to overcome this barrier is represented by the direct transport of drugs from the nose to the brain along the olfactory and trigeminal nerve pathways. These nerve pathways initiate in the nasal cavity at olfactory neuroepithelium and terminate in the brain. An enormous range of neurotherapeutics, both macromolecules and low molecular weight drugs, can be delivered to the central nervous system (CNS) via this route.

Areas covered: Present review highlights the literature on the anatomy-physiology of the nasal cavity, pathways and mechanisms of neurotherapeutic transport across nasal epithelium and their biofate and various strategies to enhance direct nose to brain drug delivery. The authors also emphasize a variety of drug molecules and carrier systems delivered via this route for treating CNS disorders. Patents related to direct nose to brain drug delivery systems have also been listed.

Expert opinion: Direct nose to brain drug delivery system is a practical, safe, non-invasive and convenient form of formulation strategy and could be viewed as an excellent alternative approach to conventional dosage forms. Existence of a direct transport route from the nasal cavity to the brain, bypassing the BBB, would offer an exciting mode of delivering neurotherapeutic agents.     

Nano carriers for drug transport across the blood–brain barrier

Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood–brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug–carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully discussed.     

Prodrug strategies in nasal drug delivery

Nasal delivery offers a promising alternative to parenteral delivery. Prodrug strategies are usually aimed at modifying the parent drug such that favourable physicochemical and biological properties for absorption are obtained. Modulation of the drug hydrophilicity/lipophilicity or linkage of a moiety that will target membrane transporters or receptors may lead to enhanced drug absorption. A sizeable number of prodrug patents awarded in the past few years signal a high commercial potential for this approach. Novel developments include prodrug synthesis for drug delivery to the CNS via the nasal route. Prodrug modification also holds promise for intranasal delivery of anticancer drugs.     

The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery

Mucociliary clearance is an important physiological defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. This process is responsible for the rapid clearance of nasally administered drugs from the nasal cavity to the nasopharynx, thereby interfering with the absorption of drugs following intranasal application. This review describes the mucociliary system and the methods used for its characterization. Examples are given of the effects of drugs and additives on its functioning. Further, possible approaches are presented for increasing the residence time of drugs in the nasal cavity, thereby improving intranasal drug delivery.     

鼻脑递送给药装置技术要点探讨及监管考量

针对越来越迫切的脑部疾病治疗需求,鼻脑递送技术利用鼻腔与脑组织间特殊的生理连接,避开血脑屏障、肝脏首过效应等生理因素,采用非侵入性给药方式将治疗脑部疾病的药物直接递送入脑,发挥治疗作用,为解决日益严重的脑部疾病问题提供了新的可能。本文在分析鼻脑递送生理特点和优势的基础上,重点梳理了近年来鼻脑递送给药装置方面的最新研究进展,探讨此类特殊装置的技术关键点,并结合国内外研发及产业现状提出监管考量,以期为鼻脑递送技术的深入发展和更为广阔的应用提供建议。     

多肽类药物鼻腔给药研究进展

随着生物制药技术的发展,越来越多的多肽类药物在医药领域得到应用。但由于这类药物稳定性不佳、口服易被酶解等问题,临床多采用注射途径给药。鼻腔给药不仅能够克服口服给药的首过效应、注射给药的顺应性差等问题,而且具有脑靶向、低剂量高活性的优点。本文主要就多肽类药物的鼻腔给药进行综述,系统地介绍了鼻腔的组织构造,药物本身性质、制剂的特性和鼻腔内环境对药物鼻腔吸收的影响,以及通过添加吸收促进剂、酶抑制剂和设计成不同药物载体等方法改善药物鼻腔吸收,并叙述了鼻腔给药的研究热点-鼻脑传递,为后续相关制剂研发提供参考。     

脑靶向给药系统的研究进展

介绍了近年来脑靶向给药的研究进展，为研制可透过血－脑屏蔽的治疗中枢神经系统疾病的脑内给药系统提供参考。