UNIL088 is a water-soluble prodrug of cyclosporine A (CsA) developed for topical eye delivery. Such a prodrug has to fulfil two paradoxical requirements as it must be rapidly hydrolysed under physiological conditions but also retain a long shelf-life in aqueous media. This study has been conducted to explore the stability of UNIL088 formulated as an eyedrop solution. The stability study of the prodrug was performed over a pH range of 5–7 at 20 °C and at various ionic strengths. The molecule was more stable at pH 5 than at pH 7 with conversion rate constant of 3.2 × 10^−3 and 26.0 × 10^−3 days^−1, respectively. The effect of temperature was studied at four different temperatures and activation energy was determined. Conversion of UNIL088 followed a pseudo-first-order kinetic with an activation energy of 79.4 kJ mol^−1. Due to its low solubility, CsA generated precipitated in the solution. The average size of CsA precipitates, determined by photon spectroscopy, was 0.22 and 1.08 μm at 7 and 14 days, respectively. The hydrolysis mechanism was partially elucidated by identification of the intermediate pSer-Sar-CsA.

Electron paramagnetic resonance (EPR) imaging was applied to investigate further the in vitro degradation process of poly(ortho esters) containing 30 mol % lactic acid units in the polymer backbone (POE₇₀LA₃₀) and developed for controlled drug delivery. The objective of this study was the direct and continuous determination of pH values inside the degrading POE₇₀LA₃₀. pH-sensitive nitroxide spin probes 4-amino-2,2,5,5-tetramethyl-3-imidazoline-1-yloxy, 2,2,3,4,5,5-hexamethylimidazolidine-1-yloxy, and 2,2,4,5,5-pentamethyl-3-imidazoline-1-yloxy were calibrated in buffer solutions in order to cover a pH range between 1.0 and 8.0. Nitroxide spin probes were incorporated in POE₇₀LA₃₀, and polymer samples were incubated in 0.1 M phosphate buffer (pH 7.4) at 37 °C. At selected times, polymer samples were removed for the determination of pH values inside the eroding POE₇₀LA₃₀ by EPR at a frequency of 9.4 GHz. EPR imaging showed that the in vitro degradation of POE₇₀LA₃₀ followed a two-phase process:  in the first week of incubation, diffusion of water, and in consequence polymer degradation, were limited to the surface of the hydrophobic POE₇₀LA₃₀ where pH values between 6.0 and 7.4 were measured. After 1 week of incubation, water diffused into the core of the sample, allowing the determination of pH values inside the eroding POE₇₀LA₃₀ until complete erosion. Results indicated the formation of a pH gradient, with the most acidic environment inside the eroding sample where the lowest pH value of 3.8 was measured and higher pH at the surface. It was also possible to observe a polymer erosion front moving down within the polymer matrix in the course of time. The pH value of 3.8 measured inside the degrading POE₇₀LA₃₀ remained constant until polymer samples disintegrated at day 23, where no EPR signal was detectable. In conclusion, EPR imaging allows the noninvasive spatially resolved observation of pH changes within POE₇₀LA₃₀, and results confirmed that the in vitro erosion mechanism of POE₇₀LA₃₀ was neither bulk erosion nor pure surface erosion.