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Développement et élaboration de systèmes innovants pour la voie ophtalmique

Abstract : The therapeutic management of ophthalmic inflammation must be rapid and effective in order to avoid deleterious effects for the eye and vision. Generally, it includes steroidal (SAID) and non-steroidal (NSAID) anti-inflammatory drugs used by topical ocular administration. Unfortunately, their low bioavailability (1 to 5 % of the instilled dose) implies frequent instillations in patients. Among anti-inflammatory drugs, dexamethasone (DXM) is one of the most powerful and is considered as a reference molecule. DXM acetate (DXMa) is a lipophilic derivative, potentially interesting for topical ophthalmic use, but not marketed to date. This ester would be better absorbed without increasing the risk of ocular hypertension, a frequent adverse effect encountered with SAID. However, DXMa has a major disadvantage: a very low solubility in water (0.021 g / mL at 25 ° C).In this work, we developed a formulation strategy combining the means of improving apparent solubility and prolonging the drug’s residence time at the ocular surface. We used water-soluble cyclodextrins (HPβCD and HPγCD), polysaccharides (CELLUVISC® - Carmellose sodium and VISMED®-sodium hyaluronate) and cationic nanoparticles. Three main formulations emerged from our pharmaceutical development: Gel A (HPβCD / DXMa / VISMED®), Gel B (HPγCD / DXMa / VISMED® / CELLUVISC®) and Nano-Gel B (DXMa-γCD-C10 / MAP 103a nanoparticles / HPγCD / DXMa / VISMED® / CELLUVISC®). They achieved the following objectives: i) a significant increase in the apparent solubility of DXMa 300 times in Gel A, 950 in Gel B and 1000 in Nano-Gel B, ii) an increase in the time residence of the formulations on the ocular surface, 2.9 times for Gel A, 4.9 for Gel B and 5.9 for cationic nanoparticles, iii) an enhancement in DXMa transcorneal penetration, 1.8 -3.8 and 2.5-5.2 times higher than DEXAFREE® and MAXIDEX®. Taking into account the route of administration, the pH, osmolality and viscosity values of the various formulations were found compatible with the eye.In addition, Gels A and B were stable over a period of 12 months at 25 ° C. Although the cytotoxicity and tolerance results would need to be completed by in vivo eye irritation tests, this work sets solid milestones for considering a topical ocular form of DXMa.
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Roseline Mazet. Développement et élaboration de systèmes innovants pour la voie ophtalmique. Médecine humaine et pathologie. Université Grenoble Alpes, 2019. Français. ⟨NNT : 2019GREAV057⟩. ⟨tel-02957683⟩

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