Development of a Novel Soluble Ophthalmic Insert: Evaluation of Ocular Tolerance in Rabbits

Ophthalmic inserts, based on mixtures of three components, are manufactured using an extrusion process. The three selected components are: a hydrophilic polymer (hydroxypropylcellulose), a hydrophobic polymer (ethylcellulose) and a bioadhesive polymer (carbomer). The insert batches are subdivided into two principal binary formulation types: the first one corresponds to inserts composed of hydroxypropylcellulose and ethylcellulose and the second one of hydroxypropylcellulose and carbomer. These two types enable to study the influence of the hydrophobic and of the bioadhesive polymers in animals. The inserts are tested directly in vivo, applying two distinct test protocols for irritation and expulsion, which are both essential characteristics for an insert: an insert must be well tolerated and not be expelled shortly after administration or even later. However, there is no protocol available in the literature for these in vivo determinations, useable for ophthalmic devices and for formulation optimization. The aim of this work is to develop test protocols for the evaluation of eye irritation and expulsion of insert vehicle formulations. Each of these two protocols uses 6 rabbits over a period of 72 and 48 h, in the case of irritation and expulsion evaluations, respectively. In the case of the ocular eye irritancy protocol, the animals are evaluated, by comparison with the control eye, at 0.25, 0.5, 1, 2, 3, 6, 12, 18, 24, 48 and 72 h after deposition of one insert in the inferior lateral conjunctival sulcus of unanaesthetized animals. The ocular physiological effects recorded are the discharge, the iritis, the conjunctiva] chemosis and the conjunctival redness. In the case of the expulsion evaluation, the animals are regularly observed and the expelled inserts are noted. The particularity of the two protocols is rhe rigid classification of the observations; there are two possibilities, namely "non-irritant" or "irritant" and "non-expelled" or "expelled'', for the evaluation of eye irritancy and expulsion, respectively. An added in vitro test is proposed for evaluating the water uptake, simulating the insert deformation, another important parameter which could trigger ocular injury. This test is conducted under a relative humidity of 100% and at a temperature of 37 °C. These assays allow to conclude that inserts composed of hydroxypropylcellulose ( 67-78 % w/w ), ethylcellulose (20-30% w/w) and carbomer (2-3% w/w) are well tolerated and are not expelled