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Published on: February 8, 2017
Corneal targeted nanoparticles for sustained natamycin delivery and their PK/PD indices: an approach to reduce dose
Hardik Chandasana1, Yarra Durga Prasad2, Yashpal S Chhonker1
1Pharmacokinetics & Metabolism Div., CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, Rafi Marg, New Delhi 110001, India.
Abstract:
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.
Insights
This study developed a novel natamycin nanoformulation for mycotic keratitis, significantly improving drug delivery and reducing dosing frequency. The new formulation offers a more compliant and effective treatment option for patients.
Area of Science:
- Ophthalmology
- Pharmaceutics
- Nanotechnology
Background:
- Natamycin is the sole approved treatment for fungal keratitis.
- Current natamycin eye drops require frequent administration, leading to poor patient compliance.
- There is a need for improved drug delivery systems to enhance efficacy and patient adherence.
Purpose of the Study:
- To design a corneal-targeted natamycin nanoformulation.
- To reduce the dosage and frequency of natamycin administration.
- To evaluate the pharmacokinetic and pharmacodynamic properties of the nanoformulation compared to the marketed preparation.
Main Methods:
- Nanoparticles were prepared using the nanoprecipitation method.
- In vitro release studies and antifungal activity assays were performed.
- Pharmacokinetic parameters were evaluated in rabbit eyes using LC-MS/MS analysis.
Main Results:
- The nanoformulation exhibited nanometer size, high entrapment efficiency, and positive surface charge.
- In vitro studies showed prolonged natamycin release up to 8 hours and comparable antifungal activity.
- Pharmacokinetic analysis revealed significantly higher AUC, t½, and MRT, with lower clearance for the nanoformulation.
- An optimized dosing schedule of one instillation every 5 hours was determined, with a 1/5th dose reduction proving effective.
Conclusions:
- The developed natamycin nanoformulation offers prolonged drug release and improved pharmacokinetic profile.
- This nanoformulation allows for a significant reduction in dosing frequency and overall dose.
- The study suggests a more patient-compliant and potentially more effective treatment for fungal keratitis.
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