Toxicity of ocular formulations

P. Rat Laboratoire de Toxicologie, Faculté de Pharmacie (Université Paris Descartes), Paris, France

Hospital activity in ophthalmology requires the use of specific hospital ocular formulations to increase the efficacy of an antibiotic to obtain better distribution in the eye (fortified eye drops) or to boost an existing formulation on the market to adapt it to the relevant ophthalmologic specificities. These hospital ocular formulations are generally designed starting from the basic active principle but often derive from oral or injectable formulations already on the market and that are adapted to the specific ocular case.
Unfortunately, these hospital formulations cause numerous toxic side effects which give rise to numerous cases of pharmaco-vigilance of ophthalmologic drugs.

These phenomena of toxicity are due to various criteria.
Ocular cells are among the most sensitive cells to toxic iatrogenic substances. In particular, they over express certain death and inflammation receptors, for example the P2X7 receptor, which can trigger sudden cytolytic mechanisms or delayed toxicity phenomena (apoptosis).
Certain substances in injectable or oral formulations, without toxic effects, will provoke extensive inflammatory mechanisms or even phenomena of degenerescence or ocular perforations. Eye drops with fluoroquinolones are an example. Ocular formulations must therefore restrict or eliminate these potentially toxic substances (for example, benzalkonium chloride, ethanol, cyclosporine eye drops) for ocular cells, even at very low concentrations.
For intraocular formulations, the choice of solvents is important so as not to upset the ionic homeostasis which is essential for the lens or trabecula cells. Preference should be given to solvents rich in cations (Mg/ Ca/ Zinc – e.g. BSS) in comparison to classic solvents (Nacl 0.9 %, phosphate buffer) to avoid causing inflammatory mechanisms in reaction. Furthermore, the packaging must be verified because stoppers in elastomer chorobutyl, approved for injectable formulations, can trigger inflammatory mechanisms with ocular formulations.

Ocular formulations therefore comply with particular and specific production rules. Do not hesitate to contact the centres specialised in ophthalmology (for example, CHNO of the 15/20 – Paris) which have the necessary experience with these formulations.
Each ocular formulation is thus a particular case which requires a toxicological assessment of its components and of the complete formulation so as to limit the risk of toxic side effects..

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