Lerner Eduard N, van Zanten Elske H, Stewart Gregory R
Lerner Medical Technology Ltd., Amsterdam, The Netherlands.
J Drug Target. 2004 Jun;12(5):273-80. doi: 10.1080/10611860400000938.
Transnasal drug delivery affords an opportunity to circumvent the blood-brain barrier and gain direct access to the brain. To date, this approach has used a relatively passive process relying on drug instillation high into the nasal cavity, formulation and gravity for drug delivery. The present study examined the use of an applied electrical field (transnasal iontophoresis or electrotransport) to actively drive a charged peptide, octreotide, into the rabbit brain. A simply designed electrode containing a reservoir of octreotide was placed deep into the nasal cavity on both sides. A return electrode was applied to the back of the head and a current strength of 3.0 mA was applied for 60 min. In control rabbits, electrodes were placed into the nasal cavity, but no current was applied (passive delivery). Additional control animals were given a bolus intra-arterial injection of octreotide. At the conclusion of drug delivery, animals were sacrificed and samples of brain, spinal cord, cerebrospinal fluid (CSF) and plasma were taken for measurement of octreotide levels by radioimmunoassay (RIA). In a second experiment, rabbits were exsanguinated prior to drug delivery to measure the ability of iontophoresis to transport octreotide into the brain in the absence of blood or CSF circulation. In both experiments, transnasal iontophoresis resulted in significantly elevated levels of octreotide in the brain, although results varied considerably due to electrode and tissue damage related to problems with electrode insertion into the rabbit's nasal cavity. Octreotide was present in samples extending from the olfactory bulb to the cerebellum with 2- to 13-fold increases in active compared to control/passive animals. High and sustained levels of octreotide were also present in the blood following transnasal delivery, but there were negligible amounts of octreotide in the brain following systemic administration indicating that the blood was not a significant route for drug redistribution. The results demonstrate that transnasal electrotransport is a unique, minimally invasive approach for enhancing drug delivery to the brain.
经鼻给药提供了一个绕过血脑屏障并直接进入大脑的机会。迄今为止，这种方法采用的是相对被动的过程，依靠将药物滴入鼻腔深处，利用制剂和重力进行药物递送。本研究考察了应用电场（经鼻离子电渗疗法或电转运）来主动驱动一种带电肽——奥曲肽进入兔脑。一个设计简单、装有奥曲肽储库的电极被置于双侧鼻腔深处。一个回路电极贴于头部后方，并施加3.0 mA的电流强度，持续60分钟。在对照兔中，电极被置于鼻腔内，但不施加电流（被动递送）。另外的对照动物接受奥曲肽动脉推注。在药物递送结束时，处死动物，采集脑、脊髓、脑脊液（CSF）和血浆样本，通过放射免疫测定法（RIA）测量奥曲肽水平。在第二个实验中，在药物递送前对兔放血，以测量在没有血液或脑脊液循环的情况下离子电渗疗法将奥曲肽转运至脑内的能力。在两个实验中，经鼻离子电渗疗法均使脑内奥曲肽水平显著升高，尽管由于电极和与电极插入兔鼻腔相关的组织损伤问题，结果差异很大。奥曲肽存在于从嗅球到小脑的样本中，与对照/被动给药的动物相比，活性样本中的奥曲肽增加了2至13倍。经鼻递送后血液中也存在高且持续的奥曲肽水平，但全身给药后脑内奥曲肽含量可忽略不计，这表明血液不是药物再分布的重要途径。结果表明，经鼻电转运是一种独特的、微创的增强药物向脑内递送的方法。
