Effect of pH and Formulation Variables on In Vitro Transcorneal Permeability of Flurbiprofen: A Technical Note

Most of the topically applied drugs have to enter the eye through the corneal route and therefore epithelial and stromal layer of the cornea act as barrier to transcorneal permeability of both hydrophilic and lipophilic drugs respectively. Paracellular and transcellular pathways are the main two routes for corneal drug transport. Lipophilic drugs cross the cornea through transcellular pathway while the hydrophilic drugs cross through paracellular pathway (1,2). It has been reported based on studies involving different series of compounds that the fraction absorbed through corneal route varies from less than 1% for hydrophilic drugs to 7% for lipophilic drugs (1–3). Corneal epithelium and stroma exert varying degree of resistance to penetration depending on the nature of the drug (4). A corneal permeability coefficient of the order of 0.1 × 10−5 to 4.0 × 10−5 cm/s can be considered a measure of efficient corneal drug permeation (5). Corneal permeability increases when the corneal integrity is compromised by the usage of high concentration of certain formulation excipients like, preservatives and chelating agents (5). Rabbit cornea or eye is most commonly used for in vitro and in vivo studies on ocular drug delivery. An investigation on the mammalian corneal epithelium in different species including human, rabbit and pig revealed morphological similarity of corneal cell layers (6). Nevertheless dissimilarities do exist between these species in terms of response of the eye to irritation and trauma (7). Rabbit eyes were found to be more sensitive to irritant than other species. Reer and his coworkers have suggested that rabbit cornea is not always the model of choice and the great morphological uniformity of mammalian cornea allow a different model like goat cornea to be chosen for in vitro permeation studies (8). Goat corneal membrane has been used for in vitro transcorneal permeability studies of ketrolac tromethamine from aqueous drops, (9) oil based drops and ointments (10). Effect of preservatives on in vitro transcorneal permeability of ibuprofen and flurbiprofen across goat cornea has also been reported (11). Taking the above reports in view, goat cornea was chosen for in vitro permeation studies. A practical advantage of goat cornea is its easy availability so that larger number of experiments could be performed in a shorter time period. The present study was aimed to investigate the effect of various formulation variables in ophthalmic formulation on the in vitro transcorneal permeability of flurbiprofen in excised goat cornea using modified Franz diffusion cell. Effect of pH of the buffer, pH of the unbuffered solution and formulation excipients like, preservatives and chelating agents on the trans-corneal permeability of the drug was investigated. To support transcorneal permeability data, solubility studied were carried out in buffered and unbuffered systems. Also investigated was the transcorneal permeability of flurbiprofen from various 5% w/v gels made of viscosity enhancing polymers and from various vegetable oil vehicles like, olive oil, linseed oil and sesame oil. All the animal experiment protocols were approved by Institutional Animal Ethics Committee, BITS, Pilani, India.