Evaluation of Pluronic F127-Based Sustained-Release Ocular Delivery Systems for Pilocarpine using the Albino Rabbit Eye Model

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Abstract
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.