Development and Evaluation of Chitosan Nanoparticles for Ocular Delivery of Tedizolid Phosphate

Abstract

This study investigates the development of topically applied non-invasive chitosan-nanoparticles (CSNPs) for ocular delivery of tedizolid phosphate (TZP) for the treatment of MRSA-related ocular and orbital infections. An ionic-gelation method was used to prepare TZP-encapsulated CSNPs using tripolyphosphate-sodium (TPP) as cross-linker. Particle characterization was performed by the DLS technique (Zeta-Sizer), structural morphology was observed by SEM. The drug encapsulation and loading were determined by the indirect method. In-vitro release was conducted through dialysis bags in simulated tear fluid (pH 7) with 0.25% Tween-80. Physicochemical characterizations were performed for ocular suitability of CSNPS. An antimicrobial assay was conducted on different strains of Gram-positive bacteria. Eye-irritation from CSNPs was checked in rabbits. Transcorneal flux and apparent permeability of TZP from CSNPs was estimated through excised rabbit cornea. Ionic interaction between the anionic and cationic functional groups of TPP and CS, respectively, resulted in the formation of CSNPs at varying weight ratios of CS/TPP with magnetic stirring (700 rpm) for 4 h. The CS/TPP weight ratio of 3.11:1 with 10 mg of TZP resulted in optimal-sized CSNPs (129.13 nm) with high encapsulation (82%) and better drug loading (7%). Release profiles indicated 82% of the drug was released from the TZP aqueous suspension (TZP-AqS) within 1 h, while it took 12 h from F2 to release 78% of the drug. Sustained release of TZP from F2 was confirmed by applying different release kinetics models. Linearity in the profile (suggested by Higuchi’s model) indicated the sustained release property CSNPs. F2 has shown significantly increased (p < 0.05) antibacterial activity against some Gram-positive strains including one MRSA strain (SA-6538). F2 exhibited a 2.4-fold increased transcorneal flux and apparent permeation of TZP as compared to TZP-AqS, indicating the better corneal retention. No sign or symptoms of discomfort in the rabbits’ eyes were noted during the irritation test with F2 and blank CSNPs, indicating the non-irritant property of the TZP-CSNPs. Thus, the TZP-loaded CSNPs have strong potential for topical use in the treatment of ocular MRSA infections and related inflammatory conditions.

Fabrication and Characterization of Tedizolid Phosphate Nanocrystals for Topical Ocular Application: Improved Solubilization and In Vitro Drug Release

“…Some conventional formulations for ODD including the eye drops (solutions, suspensions, emulsions, etc.) containing poorly soluble or low permeable drugs have shown low ocular availability (approximately 1-5% of the applied dose) of the drugs [7,8]. Due to normal physiology of eyes (blinking, precorneal loss, nasolacrimal drainage), the conventional formulations are not fully successful to attain effective therapeutic drug concentrations in the eyes [9,10].…”

“…Application of ointments, to some extent, could resolve the poor ocular bioavailability issues though they cause blurring of vision [ 11 ]. Due to the unique anatomical structure and natural defense mechanism of eyes, the permeation of applied drugs is hindered and leads to poor ocular bioavailability [ 8 , 12 , 13 ].…”

“…Despite having some drawbacks, the nanocarriers in ODD have been explored well. The perspective of nanocrystals (NCs) for ocular use has been comparatively unnoticed because of the availability of numerous established bioadhesive polymeric NPs [ 8 , 29 ]. Therefore, we developed the NCs of tedizolid phosphate (BCS Class-IV) for topical ocular application.…”

“…The NCs as ODDS can increase ocular retention, transcorneal permeation and hence bioavailability [ 7 , 9 ]. The positively charged formulations may interact electrostatically with the ocular mucin layer which can prolong the retention of the formulation that facilitates the increased transcorneal permeation and improve the ocular bioavailability of the drug [ 8 ]. Also, the high absolute zeta-potentials provide potential stability to any colloidal systems.…”

“…Above finding encouraged us to develop the NCs for topical ocular application of a highly lipophilic and poorly aqueous soluble drug (TZP). The TZP is a novel 5-Hydroxymethyl-Oxazolidinone class of antibiotic [ 40 ] having excellent antibacterial activity against Mycobacterium tuberculosis [ 41 ], methicillin-resistant Staphylococcus aureus (MRSA) and many other Gram-positive bacteria [ 42 ] including their infections in the eyes [ 8 ]. TZP is a prodrug and converted into tedizolid (TDZ) in vivo by alkaline and acid phosphatases, hence either TZP or TDZ can be chosen for its ocular uses [ 43 ].…”