经鼻脑靶向递药系统的研究进展

鼻腔与脑在解剖生理上的独特联系使得鼻腔给药作为脑内递药途径成为可能.鼻腔给药作为脑靶向的途径之一,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到达脑部,为中枢神经系统疾病的治疗提供了一种极有发展前景的脑内递药途径.就鼻腔给药脑靶向的依据、影响因素、评价方法、剂型等方面对经鼻脑靶向递药系统的研究现状进行总结.     

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。     

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.     

鼻腔给药新剂型研究进展

在鼻腔内使用，经鼻粘膜吸收而发挥全身治疗作用的制剂，称为鼻腔给药系统，鼻腔给药具有生物利用度高，吸收迅速，起效快，无损伤性，使用方便等特点，已成为制剂领域研究的热点之一，本文结合鼻腔的生理和给药的特点,综述了近年来鼻腔给药剂型的研究进展。     

药物的鼻腔黏膜吸收

鼻腔给药具有诸多优点，如能够避免肝脏的首过效应和胃肠道的降解，提高化学药物和肽类药物的生物利用度；增加药物向脑内递释，提高脑部疾病的治疗效果；具有特有的免疫性质等。介绍药物鼻腔黏膜吸收的特点和影响因素，综述鼻腔给药制剂的研究方法和研制情况，旨为该领域研究提供参考。     

鼻腔给药的生物利用度研究进展

目前，鼻腔给药生物利用度的研究主要集中在吸收促进剂、药物性质、剂型和载体等因素的影响。虽然药物通过鼻腔吸收受诸多因素的影响，但由于鼻腔特殊的解剖生理结构，药物吸收迅速；且与其他给药途径相比，尤其对于多肽和蛋白类药物而言，鼻腔给药这种非侵入性给药方法更简单、安全并且节省费用，因此，有望成为未来全身给药的重要途径之一。本文综述了近年来药物经鼻腔给药的生物利用度的研究进展。     

壳聚糖载体对药物鼻腔吸收的促进作用

目的:研究伊文思蓝鼻腔给药壳聚糖载体的促吸收作用及其对鼻腔黏膜的毒性。方法:小鼠鼻腔给伊文思蓝的壳聚糖溶液后,采用荧光显微镜观察脑部伊文思蓝的分布;紫外法测定小鼠脑部其含量;通过鼻腔黏膜切片考察壳聚糖对大鼠鼻腔黏膜毒性。结果:壳聚糖对伊文思蓝经鼻吸收入脑具有促进作用,伊文思蓝在脑前、中、后部均有分布;壳聚糖载体对大鼠鼻黏膜毒性较小。结论:壳聚糖是水溶性药物经鼻吸收入脑的优良载体。     

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。     

鼻腔给药促进盐酸美普他酚在大鼠体内的吸收及脑转运

目的考察大鼠鼻腔给药后血和脑脊液中盐酸美普他酚 (MEP)的浓度，并与口服比较。方法采用连续采集法收集脑脊液样品，用HPLC-荧光检测器测定各生物样品中MEP的浓度。结果鼻腔给药后药物迅速吸收入血，并在血和脑脊液中达到高浓度，而MEP口服后体内药浓很低。鼻腔给药后血和CSF的AUC值分别为口服的7.375和15.6倍。结论MEP鼻腔给药具有起效快、生物利用度高的特点，有望成为口服的替代途径。     

尼莫地平鼻腔给药对犬脑血流动力学的影响

目的观察尼莫地平(NM)鼻腔给药对犬脑血流动力学的影响。方法采用电磁流量计检测犬静注、鼻腔和口服给药后脑血流量(CBF)的改变，并应用MFLab功能学科实验软件进行监测和数据处理。结果鼻腔、静注给药后CBF明显增加，而口服变异大。3种途径给药后CBF平均增长率分别为28.0%，26.4%和8.5%。鼻腔给药后起效稍慢于静注［(5±4) min vs (2.2±1.2) min］，但平均作用持续时间最长［(25±17) min］。结论鼻腔给药有望成为静注或口服NM的替代途径。     

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。     

Evaluation of brain targeting in rats of Salvianolic acid B nasal delivery by the microdialysis technique

The purpose of this study was to investigate the biodistribution of Salvianolic acid B in rats blood and brain after intranasal administration and explore its feasibility and evaluate its brain targeting effect. The concentration of Salvianolic acid B in blood and brain following nasal administration (32?mg?kg^?1) was measured combining with microdialysis sampling and liquid chromatograph-mass spectrometer/MS detection technology. After the microdialysis samples were corrected with in vivo recoveries, the pharmacokinetic parameters were obtained by using non-compartment model and the brain targeting evaluated by the value of drug targeting index (DTI). The C_max in blood and brain by intravenous injection were higher than intranasal administration, but the intranasal administration of MRT_0-∞ significantly prolonged and increased by nearly 2.03 and 1.86 times, respectively. The DTI value of Salvianolic acid B was 5.54 and bioavailability (F) was 43.98%. After nasal administration of Salvianolic acid B, it has a certain brain targeting, which could become a new drug system for the treatment of brain diseases.     

Direct Nose-to-Brain Transfer of Morphine After Nasal Administration to Rats

Purpose The aim of this study was to quantify the olfactory transfer of morphine to the brain hemispheres by comparing brain tissue and plasma morphine levels after nasal administration with those after intravenous administration. Methods Morphine (1.0 mg/kg body weight) was administered via the right nostril or intravenously as a 15-min constant-rate infusion to male rats. The content of morphine and its metabolite morphine-3-glucuronide in samples of the olfactory bulbs, brain hemispheres, and plasma was assessed using high-performance liquid chromatography, and the areas under the concentration–time curves (AUC) were calculated. Results At both 5 and 15 min after administration, brain hemisphere morphine concentrations after nasal administration were similar to those after i.v. administration of the same dose, despite lower plasma concentrations after nasal administration. The brain hemispheres/plasma morphine AUC ratios for the 0–5 min period were thus approximately 3 and 0.1 after nasal and i.v. administration, respectively, demonstrating a statistically significant early distribution advantage of morphine to the brain hemispheres via the nasal route. Conclusion Morphine is transferred via olfactory pathways to the brain hemispheres, and drug transfer via this route significantly contributes to the early high brain concentrations after nasal administration to rats.     

Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents

The aim of this study was to investigate whether morphine can be transferred along the olfactory pathway to the CNS, thereby circumventing the blood–brain barrier, after nasal administration to rodents. Radiolabelled and unlabelled morphine were administered via the right nostril to mice and rats. Olfactory bulbs, brain tissue and blood samples were collected. Morphine-derived radioactivity was measured using liquid scintillation (LS) and the concentrations of morphine and its metabolite morphine-3-glucuronide (M3G) were also assessed with high-performance liquid chromatography. The location of morphine-derived radioactivity in the rat brain was visualised by autoradiography. Overall, the levels of morphine in the right olfactory bulbs (ROBs) significantly exceeded those in the left olfactory bulbs (LOBs) and brain tissue samples 15, 60 and 240 min after right-sided nasal administration. Fifteen minutes after intravenous administration, there were no significant differences between olfactory bulbs and the other brain areas. Five minutes after nasal administration, autoradiography revealed radioactivity surrounding the ROB and reaching one of the ventricles in the brain. After 60 min, radioactivity had reached the peripheral parts of the ROB. All the techniques used in this study demonstrate that morphine was transferred along the olfactory pathway to the CNS after nasal administration to rodents.     

鼻腔给药人体吸收的细胞模型方法学研究进展

经鼻给药具备起效快,生物利用度高,入脑效率高及非侵入性等优点。但复杂的鼻腔微环境,如黏膜屏障、纤毛运动、低pH值的黏液层及酶降解等因素,为鼻腔药物研发带来了诸多挑战。尽管大量动物试验方法已经为鼻腔药物的研发提供了研究手段,但物种间的差异、高额的费用及较长的周期等因素限制了这些方法在研发中的应用,特别是在新药临床前的化合物及处方早期筛选阶段。因此,选择一种具备良好体内外相关性的鼻腔细胞模型用于指导药物的临床前研发成为了关键。基于鼻腔给药途径,无论经鼻入脑或是经鼻入血,上皮细胞的屏障作用均直接决定药物的生物利用度与药效。此外,鼻腔药物黏膜刺激性等毒理评价也是研发成功的关键因素。因此,本文归纳了现阶段基于鼻腔上皮细胞构建的体外鼻腔模型在鼻用制剂研发中的应用现状。     

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。     

Direct nose-brain transport of benzoylecgonine following intranasal administration in rats.

In our previous research, cocaine applied intranasally in rats diffused or was transported directly from the nasal cavity to the brain. However, the direct nose-brain cocaine transport only contributes to an initial increase in the relative cocaine brain exposure. In this study, we have determined the nose-brain transport of a polar metabolite of cocaine, benzoylecgonine, to help understand factors affecting drug transport via this novel pathway. The nasal cavity of male Sprague-Dawley rats was isolated to prevent drainage of nasally applied dosing solution to non-nasal regions. Benzoylecgonine was then administered, either by intranasal administration or by intravenous (iv) injection. At different times postdose, blood and tissues from different regions of the brain were collected from groups of rats (n = 4 for each collection time) and benzoylecgonine concentrations in these samples were analyzed by high-performance liquid chromatography. Benzoylecgonine concentrations in plasma were at maximal levels immediately after iv dosing and declined as a function of time. Following intranasal administration, benzoylecgonine concentrations in plasma reached maximal levels between 15 and 30 min after dosing and declined as a function of time. To allow comparison of brain benzoylecgonine content after iv and intranasal administration, brain benzoylecgonine contents were normalized by plasma benzoylecgonine concentrations. The ratios of the area under the benzoylecgonine concentration-time curve (AUC) between the olfactory bulb and plasma following intranasal administration were 10-100 times higher than those obtained after iv dosing. The olfactory tract-to-plasma benzoylecgonine AUC ratios after intranasal administration were significantly higher than those after iv dosing up to 120 min following dosing. The brain tissue-to-plasma AUC ratios in cerebellum, brain stem, and cerebral cortex after intranasal administration were significantly higher than the corresponding ratios after iv administration up to 30 min following dosing. We conclude than nasally administered benzoylecgonine was transported directly from the nasal cavity to the brain and that the significant increase in brain levels was sustained for a prolonged period of time. Factors contributing to the observed differences in the nose-brain transport of cocaine and benzoylecgonine are discussed.     

Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of β-amyloid and ibotenic acid into the bilateral hippocampus

Basic fibroblast growth factor (bFGF) delivery to the brain of animals appears to be an emerging potential therapeutic approach to neurodegenerative diseases, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracerebroventricular infusion. A nasal spray of bFGF had been developed previously and the objective of the present study was to investigate whether bFGF nasal spray could enhance brain uptake of bFGF and ameliorate memory impairment induced by co-injection of β-amyloid_25-35 and ibotenic acid into bilateral hippocampus of rats. The results of brain uptake study showed that the AUC_0-12 h of bFGF nasal spray in olfactory bulb, cerebrum, cerebellum and hippocampus was respectively 2.47, 2.38, 2.56 and 2.19 times that of intravenous bFGF solution, and 1.11, 1.95, 1.40 and 1.93 times that of intranasal bFGF solution, indicating that intranasal administration of bFGF nasal spray was an effective means of delivering bFGF to the brain, especially to cerebrum and hippocampus. In Morris water maze tasks, intravenous administration of bFGF solution at high dose (40 μg/kg) showed little improvement on spatial memory impairment. In contrast, bFGF solution of the same dose following intranasal administration could significantly ameliorate spatial memory impairment. bFGF nasal spray obviously improved spatial memory impairment even at a dose half (20 μg/kg) of bFGF solution, recovered their acetylcholinesterase and choline acetyltransferase activity to the sham control level, and alleviated neuronal degeneration in rat hippocampus, indicating neuroprotective effects on the central nerve system. In a word, bFGF nasal spray may be a new formulation of great potential for treating AD.