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Danilo Aleo, Sergio Mangiafico, Maria Saita, Barbara Melilli, Melina Cro, Sebastiano Mangiafico, Nicola D'Antona, Giovanni Nicolosi; Enantiomeric Separation, Ophthalmic Formulations and Mydriatic Activity Oo Cyclopentolate Hydrochloride. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5417.
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Cyclopentolate Hydrochloride (CYP) is widely used as mydriatic and cycloplegic agent. The product is marketed in the racemic form, an equimolar mixture of the two enantiomers (+) and (-) Cyclopentolate. The aim of our study was the development of an enantio-separation methodology, the preparation of two ophthalmic formulation based on (+) CYP (MDV-D) and (-) CYP (MDV-L) as well as the evaluation of their mydriatic activity in rabbits.
Optical resolution of the racemic mixture was performed via diasteromic salt formation using (2R,3R) O-O’-di-p- toluoyl-tartaric acid (DPTTA) as resolving agent. A microemulsion was used to formulate and to deliver 1% of (+) and 1% of (-) CYP. Nine Albino rabbits were used to control mydriatic effect of MDV-D, MDV-L, and of the commercial Cyclopentolate racemic solution (Ciclolux, Allergan Inc.). The pupils were filmed during 35 minutes with a video camera connected to an operation microscope, and the mean pupil diameters were measured from the video recordings.
A diastereoisomeric salt containing an enantiomeric excess (E.E 90%) of (-) CyP (-) DPTTA has been achieved using (2R,3R) O-O’-di-p- toluoyl-tartaric acid (DPTTA). This salt was then purified by re-crystallization from ethanol (99% purity). (-) CYP (-) DPTTA was dissolved in a 0,4N HCl and extracted with Methyl tert-Butyl Ether (MTBE). Evaporation of aqueous phase gives (-) CyP (100% [α] 20D = -32,8). The mother liquor containing (+)CyP (-)DPTTA was extracted with MTBE and evaporation of aqueous phase gives (+) CYP (100% [α] 20D = +32,8). 1% of (+) CYP (MDV-D) and 1% of (-) CYP (MDV-L) microemulsion were instilled on the ocular surface of rabbits and the mydriatic effect of both formulations was performed. MDV-D and MDV-L showed the same effect on pupil size when compared each other or with Ciclolux.
The comparison between the ophthalmic formulations of the two enantiomers (MDV-D and MDV-L) with one another and in comparison to the commercial formulation of the racemic product (Ciclolux) showed no statistically significant differences in their mydriatic activity. Studies on the known side effects in humans of Cyclopentolate enantiomers (dizziness and mental confusion, impaired coordination of movements, etc…) are in progress.
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