Desai S D, Blanchard J
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, USA.
J Pharm Sci. 1998 Oct;87(10):1190-5. doi: 10.1021/js980222j.
The overall objective of this study was to develop Pluronic F127 (PF127)-containing formulations of pilocarpine hydrochloride (PHCL) which can be used for sustained-release ocular delivery of PHCL. The PF127 formulations of PHCL containing methylcellulose (MC) or hydroxypropyl methylcellulose (HPMC) as an additive had previously exhibited the slowest dissolution rates and released the drug the slowest in vitro. This study was performed to assess the in vivo performance of these two formulations using miosis in the albino rabbit eye produced by PHCL as a measure of ocular bioavailability. The PF127MC formulation (20 microL) had a significantly greater intensity of miosis compared to the same volume of an isotonic solution of PHCL. The duration and the intensity of the miotic response increased significantly as the instilled volume of the PF127MC gel formulation increased. The miotic response, expressed as % bioactivity by assigning a value of 100% to the 20 microL PF127MC treatment, was increased as the volume instilled was reduced from 60 to 20 microL. However, no difference in bioactivity between the 60 and 100 microL volumes was observed. In addition, the 100 microL volumes of both the PF127MC and PF127HPMC gel formulations exhibited bioactivity equivalent to 20 microL of an isotonic PHCL solution. Thus, for a given instilled concentration, the larger the volume instilled the greater the amount of drug present in tear fluid and thus the higher the concentration delivered to the iris sphincter muscle and hence the greater the miotic response. However, the fraction of the dose reaching the iris sphincter muscle was greater for the smaller instilled volume. On the basis of these findings and previous in vitro results, the PF127 formulations of PHCL having MC or HPMC as an additive showed considerable potential as sustained-release ocular delivery systems for PHCL. This conclusion was based upon their ability to provide a substantial prolongation of drug action and an improvement in the ocular bioavailability of pilocarpine compared to conventional eye drops and previously utilized PF127 formulations of PHCL. It appears that ocular bioavailability can be increased more readily by altering both the rheological characteristics of the delivery system and by using a smaller dose volume.
本研究的总体目标是开发含泊洛沙姆 F127（PF127）的盐酸毛果芸香碱（PHCL）制剂，该制剂可用于 PHCL 的缓释眼部给药。先前含有甲基纤维素（MC）或羟丙基甲基纤维素（HPMC）作为添加剂的 PHCL 的 PF127 制剂在体外表现出最慢的溶解速率和最慢药物释放速度。本研究旨在以 PHCL 引起的白化兔眼瞳孔缩小作为眼部生物利用度的指标，评估这两种制剂的体内性能。与相同体积的 PHCL 等渗溶液相比，PF127MC 制剂（20 μL）的瞳孔缩小强度明显更大。随着 PF127MC 凝胶制剂滴注体积的增加，缩瞳反应的持续时间和强度显著增加。以 20 μL PF127MC 处理的生物活性值为 100%来表示生物活性百分比，随着滴注体积从 60 μL 减少到 20 μL，缩瞳反应增加。然而，60 μL 和 100 μL 体积之间未观察到生物活性差异。此外，100 μL 体积的 PF127MC 和 PF127HPMC 凝胶制剂均表现出与 20 μL 等渗 PHCL 溶液相当的生物活性。因此，对于给定的滴注浓度，滴注体积越大，泪液中存在的药物量就越大，因此递送至虹膜括约肌的浓度就越高，缩瞳反应也就越大。然而，较小的滴注体积到达虹膜括约肌的剂量分数更大。基于这些发现和先前的体外研究结果，含有 MC 或 HPMC 作为添加剂的 PHCL 的 PF127 制剂作为 PHCL 的缓释眼部给药系统显示出相当大的潜力。这一结论基于它们能够显著延长药物作用时间，并与传统眼药水和先前使用的 PHCL 的 PF127 制剂相比，提高毛果芸香碱的眼部生物利用度。似乎通过改变给药系统的流变学特性和使用较小的剂量体积，可以更容易地提高眼部生物利用度。
