Novel water-soluble mucoadhesive carbosilane dendrimers for ocular administration



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Bravo-Osuna, Irene and Vicario-de-la-Torre, Marta and Andrés-Guerrero, Vanessa and Sánchez-Nieves, Javier and Guzmán-Navarro, Manuel and de la Matad, F. Javier and Gómez, Rafael and de las Heras, Beatriz and Argüesoh, Pablo and Poncheli, Gilles and Herrero-Vanrell, Rocío and Molina-Martínez, Irene Teresa (2016) Novel water-soluble mucoadhesive carbosilane dendrimers for ocular administration. Molecular Pharmaceutics, 13 (9). pp. 2966-2976. ISSN 1543-8384

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Purpose: To determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (Generations 1-3) as mucoadhesive polymers in eyedrop formulations.
Methods: Cationic carbosilane dendrimers decorated with ammonium –NH3 + groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits.
Results: The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral –NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 μM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 μM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0 8h and maximal intraocular pressure reduction.
Conclusion: This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these polymers. Our results indicate that low amounts of cationic carbosilane dendrimers are well tolerated and able to improve the hypotensive effect of an acetazolamide solution. Our results suggest that carbosilane dendrimers can be used in a safe range of concentrations to enhance the bioavailability of drugs topically administered in the eye.

Item Type:Article
Uncontrolled Keywords:Carbosilane dendrimers, Ocular transmembrane mucins, Mucoadhesion, Surface plasmon resonance (SPR), Hypotensive activity.
Subjects:Medical sciences > Medicine > Ophtalmology
Medical sciences > Pharmacy
Medical sciences > Pharmacy > Pharmaceutical technology
ID Code:54782
Deposited On:01 Apr 2019 15:40
Last Modified:02 Apr 2019 10:48

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