ABSTRACT
Econazole nitrate (EC) is an active, imidazole antifungal agent. However, low aqueous solubility and dissolution rate of EC has discouraged its usage for the treatment of ophthalmic fungal infection. In this study, inclusion complexes of EC with cyclodextrins were prepared to enhance its solubility, dissolution, and ocular bioavailability. To achieve this goal, EC was complexed with ß-CyD/HP-ß-CyD using kneading, co-precipitation, and freeze-drying techniques. Phase-solubility studies were performed to investigate the complexes in the liquid form. Additionally, the complexes in the solid form were characterized with Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and transmission electron microscopy (TEM). Furthermore, different eye drops containing EC-CyD complexes were prepared using different polymers and then characterized regarding their drug contents, pH, viscosity, mucoadhesive strength, and in vitro release characteristics. The results showed that stable EC-CyD complexes were formed in 1:1 molar ratio as designated by BS-type diagram. Econazole nitrate water solubility was significantly increased in about three- and fourfold for ß-CyD and HP-ß-CyD, respectively. The results showed that the prepared complexes were spherical in shape having an average particle diameter from 110 to 288.33 nm with entrapment efficiency ranging from 64.24 to 95.27%. DSC investigations showed the formation of real inclusion complexes obtained with co-precipitation technique. From the in vitro studies, all eye drops containing co-precipitate complexes exhibited higher release rate than that of other complexes and followed the diffusion-controlled mechanism. In vivo study proved that eye drops containing EC-CyD complexes showed higher ocular bioavailability than EC alone which indicated by higher AUC, Cmax, and relative bioavailability values.
Subject(s)
Cyclodextrins/administration & dosage , Cyclodextrins/chemistry , Econazole/administration & dosage , Econazole/chemistry , Administration, Ophthalmic , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/chemistry , Antifungal Agents/metabolism , Biological Availability , Calorimetry, Differential Scanning/methods , Cyclodextrins/metabolism , Econazole/metabolism , Freeze Drying/methods , Male , Rabbits , Spectroscopy, Fourier Transform Infrared/methods , X-Ray Diffraction/methodsABSTRACT
PURPOSE: Preparation of topical ophthalmic formulations containing brimonidine-loaded nanoparticles prepared from various biodegradable polymers-PCL, PLA and PLGA-for sustained release of brimonidine as a once daily regimen for management of glaucoma. METHODS: Nanoparticles were prepared using spontaneous emulsification solvent diffusion method then characterized regarding their particle size, zeta potential, morphology and drug contents. Brimonidine-loaded nanoparticles were incorporated into eye drops, temperature-triggered in situ gelling system and preformed gel and characterized regarding their pH, viscosity, uniformity of drug contents, in vitro release study, in vitro cytotoxicity and in vivo intraocular pressure (IOP) lowering effects. RESULTS: The results of optimized brimonidine-loaded PCL-, PLGA- and PLA-NPs respectively, are: particle sizes of 117.33 ± 4.58 nm, 125.67 ± 5.15 nm and 131.67 ± 3.79 nm; zeta potentials of -18.5 ± 2.87 mV, -21.82 ± 2.7 mV and -28.11 ± 2.21 mV; and encapsulation efficiencies of 77.97 ± 1.38%, 68.65 ± 3.35% and 73.52 ± 2.92%. TEM analyses revealed that all NPs have spherical shapes with dense core and distinct coat. In vitro release data showed a sustained release without any burst effect with Higuchi non-Fickian diffusion mechanism. Cytotoxicity studies revealed that all formulations are non-toxic. Also all formulations possessed a sustained IOP lowering effect compared to Alphagan® P eye drops. CONCLUSIONS: Our formulations showed prolonged management of glaucoma that should meet with better patient compliance as a once-daily formulation.
