Formulation and in vivo evaluation of ocular insert containing phenylephrine and tropicamide

Abstract

A Gelfoam® based ocular device containing 1.7 mg of phenylephrine and 0.6 mg of tropicamide was formulated and evaluated for pupillary dilation in rabbits. The manufacturing procedure is fairly simple and the required excipients are inexpensive. The in vivo results show that the mydriatic response produced by the proposed device is larger and longer lasting than that produced by eyedrops with an equivalent amount of phenylephrine and tropicamide. The results reported in this study, along with those of previous studies, imply that Gelfoam® is a versatile drug carrier for either local or systemic drug delivery via the ophthalmic route.

Introduction

A fully dilated pupil is an important factor which allows for optimal ophthalmic examination of the fundus for disease as well as many ocular surgical procedures (Kergoat et al., 1989, Ho et al., 1992, Paggiarino et al., 1993, Zeise et al., 1996). Ocular instillation of pupil-dilating agent(s) is commonly used to produce mydriasis (Ho et al., 1992). An ideally dilated pupil should be large and stable to the intensive light stimulation encountered during ophthalmoscopic examination (Kergoat et al., 1989, Ho et al., 1992). The co-administration of phenylephrine hydrochloride and tropicamide solutions into the eye has been shown to be an effective combination in producing reliable mydriasis (Apt and Henrick, 1980, Levine, 1982, Kergoat et al., 1989, Ho et al., 1992, Paggiarino et al., 1993, Zeise et al., 1996). Although the co-use of these drugs in eyedrops can produce mydriasis, it has a low local bioavailability due to rapid clearance from the ocular surface by the lachrymal system and requires a high frequency of drug instillation to produce satisfactory results (Durrani et al., 1996).

To produce an adequate pupil size, a patient will receive a total of 4–30 drops of tropicamide (1%) and phenylephrine (10%) solution (Brown and Hanna, 1978). This regimen is inconvenient for both physician and patient. Due to the limited volume that the conjunctival sac can hold, most of the eyedrop solution is either blinked out or drained into the nasal cavity allowing only a small portion of the drugs to reach their site of action. The drainage of both phenylephrine and tropicamide into the nasal mucosa could result in systemic absorption of these two agents and produce many unwanted systemic side effects including tachycardia, hypertension, and headache (Rengstorff and Doughty, 1982). In addition, it is well known that both phenylephrine and tropicamide solutions irritate the eye (Zeise et al., 1996).

Since the contact time is considered the most important factor in ophthalmic drug delivery, many attempts to improve efficacy have focused on prolonging the contact time of the drugs with the anterior surface of eye (Harris and Robinson, 1990, Maitani et al., 1997). Phenylephrine and tropicamide have each been formulated as a viscous solution (Saettone et al., 1984), a rod (Alani, 1978), a gel (Durrani et al., 1996), an oinment (Hendrickson and Hanna, 1977, Saettone et al., 1980) or a polyvinyl alcohol flag (O’Donnell and Gillibrand, 1995). Also, microdrop and dilute solution administration have been investigated for these drugs (Brown and Hanna, 1978, Forman, 1980, Gray et al., 1992, Elibol et al., 1997). The latter regimens are designed to slow the drainage by the lacrymal system and to reduce ocular irritation. Although the strategies described above are reasonable they are not routinely used. A need exists for a formulation of dilation agent(s) that can be administered easily in a single dose with reliable, rapid results and minimal risk of adverse effect to the patient.

Previously, a gelatin based ocular device was introduced by this laboratory for the systemic delivery of peptides such as melanotan II (Pinsuwan et al., 1997) and insulin (Simamora et al., 1996, Lee et al., 1997a, Lee et al., 1997b), as well as for the local delivery of pilocarpine (Simamora et al., 1998). In vivo data from rabbits show that melanotan II has a 67% bioavailability if it is delivered by this device and a 25% bioavailability if it is delivered by eyedrop. The therapeutic efficacy of either insulin or pilocarpine was substantially improved with the device, and the duration of activity of these two drugs was also prolonged up to 10 and 8 h, respectively. Recently, the release rate of a wide variety of chemicals from Gelfoam® has been well documented by Hamalainen et al. (1998). In this study Gelfoam® is utilized as a local drug carrier, for both phenylephrine and tropicamide. Measurement of the change in pupil diameter and area were used to assess the efficacy of the proposed device.