C.S. Draper Laboratory, Cambridge, MA 02139, USA.
J Control Release. 2011 Jun 10;152(2):270-7. doi: 10.1016/j.jconrel.2011.02.021. Epub 2011 Mar 6.
Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5h) or greater distances (>3mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery.
往复式药物输送是一种通过单一套管将可溶性药物直接输送到体内封闭的流体空间而不伴随流体体积变化的方法。它非常适合于将药物输送到小而敏感和独特的流体空间，如耳蜗。我们通过测量流动参数变化对药物在耳蜗长度内分布的影响，来描述往复式药物输送到耳蜗中的 scala tympani 的药代动力学特征。通过使用往复式流动曲线来监测 DNQX（一种可逆的谷氨酸受体阻滞剂）在豚鼠内耳中的分布来评估分布情况。然后，我们使用迭代曲线拟合方法和计算流体动力学模型来模拟这些参数对分布的影响。我们的研究结果与假设一致，即往复式输送将药物分布到耳蜗基部的一个体积中，并表明药物在耳蜗更远端区域分布的主要决定因素是扩散。流速的增加将药物分布到更大的体积中，并向更顶端延伸。在短时间过程（小于 2 小时）中，尽管顶端延伸很小，但显著增强了药物的顶端方向输送。在较长的时间过程（>5 小时）或更大的距离（>3mm）中，在基底 scala tympani 中维持药物浓度可能比增加流速更有利于延长顶端输送。这些观察结果表明，这种往复式技术能够为耳蜗中的封闭流体空间提供受控的药物输送动力学，并且可能适用于其他应用，如局部脑和视网膜输送。
