Corneal targeted nanoparticles for sustained natamycin delivery and their PK/PD indices: An approach to reduce dose and dosing frequency

• Published in: International journal of pharmaceutics Vol. 477; no. 1-2; pp. 317 - 325
• Main Authors: Chandasana, Hardik, Prasad, Yarra Durga, Chhonker, Yashpal S., Chaitanya, Telaprolu K., Mishra, Nripendra N., Mitra, Kalyan, Shukla, Praveen K., Bhatta, Rabi S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.12.2014
• Subjects: Animals; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Antifungal Agents - pharmacology; Aspergillus fumigatus - drug effects; Candida albicans - drug effects; Cornea - drug effects; Cornea - metabolism; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Compounding; Drug Delivery Systems; Drug Liberation; Drug Stability; Eye Infections, Fungal - drug therapy; Male; Microbial Sensitivity Tests; Models, Biological; Mycotic keratitis; Nanoparticles; Nanoparticles - chemistry; Natamycin; Natamycin - administration & dosage; Natamycin - pharmacokinetics; Natamycin - pharmacology; Ocular drug delivery; Ophthalmic Solutions; Particle Size; Pharmacokinetic/pharmacodynamic indices; Polycaprolactone; Rabbits; Surface Properties; Tissue Distribution; Nanoparticles; Natamycin; Pharmacokinetic/pharmacodynamic indices; Mycotic keratitis; Ocular drug delivery; Polycaprolactone
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2014.10.035

[Display omitted] Natamycin is the only approved medication for the treatment of mycotic keratitis. Current dosage regimen include one drop of natamycin suspension (5% w/v) instilled in the conjunctival sac at hourly or two hourly intervals for several days which has poor patient compliance. The purpose of the present study was to design a corneal targeted nanoformulation in order to reduce dose and dosing frequency of natamycin and evaluate its pharmacokinetic/pharmacodynamic indices in comparison with clinical marketed preparation. The nanoparticles prepared by nanoprecipitation method were in nanometer size range with high entrapment efficiency and positive surface charge. In-vitro release studies indicated prolonged release of natamycin up to 8h. In-vitro antifungal activity was comparable with marketed preparation. The performance of nanoformulations was evaluated in rabbit eyes. The concentration of natamycin in tear fluid was determined by using LC–MS/MS. The pharmacokinetic parameters such as area under the curve, t½ and mean residence time were significantly higher and clearance was significantly lower for nanoformulations with that of marketed preparation. The optimized dosing schedule to maintain natamycin concentration above tenfold of MIC90 was one instillation in every 5h. Moreover, 1/5th dose reduction of nanoformulation was also effective.