Oral lichen planus (OLP) is an ongoing and chronic inflammatory disease affecting the mucous membrane of the oral cavity. Currently, the treatment of choice consists in the direct application into the buccal cavity of semisolid formulations containing a corticosteroid molecule to decrease inflammatory signs and symptoms. However, this administration route has shown various disadvantages limiting its clinical use and efficacy. Indeed, the frequency of application and the incorrect use of the preparation may lead to a poor efficacy and limit the treatment compliance. Furthermore, the saliva clearance and the mechanical stress present in the buccal cavity also involve a decrease in the mucosal exposure to the drug. In this context, the design of a new pharmaceutical formulation, containing a steroidal anti-inflammatory, mucoadhesive, sprayable and exhibiting a sustained and controlled release seems to be suitable to overcome the main limitations of the existing pharmaceutical dosage forms. The present work reports the formulation, optimization and evaluation of the mucoadhesive and release properties of a poloxamer 407 thermosensitive hydrogel containing a poorly water-soluble corticosteroid, dexamethasone acetate (DMA), threaded into hydroxypropyl-beta-cyclodextrin (HP-β-CD) molecules. Firstly, physicochemical properties were assessed to ensure suitable complexation of DMA into HP-β-CD cavities. Then, rheological properties, in the presence and absence of various mucoadhesive agents, were determined and optimized. The hydration ratio (0.218–0.191), the poloxamer 407 (15–17 wt%) percentage and liquid-cyclodextrin state were optimized as a function of the gelation transition temperature, viscoelastic behavior and dynamic flow viscosity. Deformation and resistance properties were evaluated in the presence of various mucoadhesive compounds, being the sodium alginate and xanthan gum the most suitable to improve adhesion and mucoadhesion properties. Xanthan gum was shown as the best agent prolonging the hydrogel retention time up to 45 min. Furthermore, xanthan gum has been found as a relevant polymer matrix controlling drug release by diffusion and swelling processes in order to achieve therapeutic concentration for prolonged periods of time.

Glaucoma is a wide-spread eye disease caused by elevated intraocular pressure. Uncontrolled, this pressure may lead to damages to the optic nerve. Prostaglandin analogues, such as latanoprost and travoprost (which are water-insoluble active substances), are the most used class of active pharmaceutical ingredient. To administer them as eye drops, preservatives, such as benzalkonium chloride, are used as solubilizers. The latter is known to cause a local inflammation when used chronically and is not recommended for patients with ocular surface disorders. In this work, we sought to use polysorbate 80 (PS80) as a solubilizing agent simultaneously with sodium hyaluronate (NaHA) as a thickener and cytoprotective agent for the corneal surface. The first part of this study assessed the compatibility of the excipients with the active substance, using physicochemical methods such as spectra fluorescence and differential scanning calorimetry (DSC), as well as the solubilization mechanism of PS80 regarding prostaglandin analogues using nuclear magnetic resonance (NMR). The second part evaluated the stability of a formula candidate, its viscosity upon instillation, and its pharmacokinetic profile in rabbits as compared to the commercially approved medicine Travatan^®. The results show that sodium hyaluronate is inert with respect to travoprost, while PS80 successfully solubilizes it, meaning that benzalkonium chloride is no longer required. Moreover, the pharmacokinetic profiles of the rabbits showed that the original formula described in the present study enhanced the ocular bioavailability of the drug, making it a promising product to control intraocular pressure with a potential reduced dosage of travoprost, therefore minimizing its related side effects.

Le glaucome à angle ouvert est une maladie chronique dont le traitement symptomatique repose sur la gestion de la pression intra-oculaire. Les analogues de prostaglandine sont les molécules les plus efficaces dans cette indication, cependant, leur faible solubilité et leur instabilité dans l'eau en font un défi de formulation. Pendant longtemps leur formulation reposait donc sur l'utilisation d'agents conservateurs ou de tensioactifs. Les effets délétères de ces agents conservateurs ou tensioactifs sur la surface oculaire au long terme sont de nos jours bien connus. Ainsi, l'objectif du travail a été de développer une nouvelle forme galénique innovante sans conservateurs ni agents tensioactifs afin de limiter les effets indésirables locaux liés au traitement. Dans un premier temps, une stratégie basée sur l'utilisation du hyaluronate de sodium de haut poids moléculaire seul a été envisagée en utilisant différentes techniques de dispersion. Dans un second temps une émulsion de Pickering a été développée. Pour cela, une méthode d'obtention de nanoparticules à base de chitosan et citrate de sodium a été optimisée en suivant une démarche de quality by design à l'aide de plans d'expériences. Ensuite, le choix de la phase huileuse a été guidé par des caractérisation physico-chimiques et biologiques (stabilité de la substance active, mouillabilité des particules, toxicité in vitro). Les nanoparticules formulées précédemment ont ensuite été utilisées afin de stabiliser l'interface huile/eau de l'émulsion comprenant la substance active. Enfin, la rhéologie de l'émulsion a été optimisée grâce à des polymères naturels biodégradables. La stabilité colloïdale de l'émulsion ainsi que les performances in vitro du produit fini ont été étudiées par diffraction laser, essais de libération USP4 , rhéologie et cytotoxicité in vitro.