Novel Water-Soluble Mucoadhesive Carbosilane Dendrimers for Ocular Administration

Abstract

The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. 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. 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. 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.

Mildly Cross-Linked Dendrimer Hydrogel Prepared via Aza-Michael Addition Reaction for Topical Brimonidine Delivery

“…28–32 Also, the cationic dendrimers, for example, polyamidoamine dendrimer (PAMAM), can be preferentially captured at the negatively charged corneal surface and therefore enhance the permeability of the formulations. 33–35 In-situ forming hydrogels are also often used as topical drug delivery systems because of ease of administration. 36, 37 The application of hydrogels can result in prolonged pre-corneal residence time and increased ocular bioavailability.…”

<p>Potential Therapeutic Usage of Nanomedicine for Glaucoma Treatment</p>

“…G3 cationic carbosilane dendrimers (5 μM) demonstrated rapid (1 hour post-instillation) and sustained (up to 7 hour) hypotensive effect, reaching a peak 22.6% IOP reduction in normotensive rabbit eyes. 117 …”

Gelatin Nanoparticles-HPMC Hybrid System for Effective Ocular Topical Administration of Antihypertensive Agents

“…The MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) (Sigma Aldrich) cytotoxicity assay was used [15,60]. MTT technique is widely employed for assessing toxicity in novel developed systems [14,15]. Cells were exposed to gelatin (30 mg/mL), GNP (10 mg/mL and 30 mg/mL) and TM-GNP (10 mg/mL, 20 mg/mL and 30 mg/mL) at different exposure times (1 h, 4 h and 24 h).…”

“…The development of new formulations enhancing drug permeation, bioavailability and safety profile after ocular instillation has become one of the most important challenges in pharmaceutical technology in recent years [14][15][16]. Several novel drug delivery systems have been developed like nanoparticles, microparticles, microemulsions, hydrogels or contact lenses among others, to achieve more effective therapies [17][18][19][20][21].…”