Development, Internal and External Validation of Naproxen Sodium Sustained Release Formulation: an Level A In Vitro-In Vivo Correlation

[摘要] Objectives: The aim of the present study was to develop and validate an in vitro-in vivo correlation (IVIVC) for naproxen sodium-sustained release tablets and to compare their plasma concentrations over time with the immediate-release tablets. Materials and Methods: In vitro release rate data were obtained for each tablet by using the USP Apparatus II, paddle stirrer at 50 rpm in pH 7.4 phosphate buffer. A four-way crossover study was conducted in 6 healthy subjects by administering naproxen sodium sustained release 375 mg and 500 mg of immediate release tablets. Series of blood samples were collected over 24 hours and estimated by using the validated liquid chromatography tandem-mass spectrometry method. Results: The similarity factor was calculated and it was found that values between, 50 and 100 indicates similarity of the profiles. Assessment of predicted and observed bioavailability was performed and prediction errors (PE) % calculated, as per the Food Drug Administration guidelines, the average absolute PE% of Cmax and AUC of individual formulation was found below 15% for establishment of IVIVC, based on internal prediction strongly suggesting that the naproxen sodium IVIVC models are valid. During external validation the predicted curve for the naproxen sodium sustained-release tablets was found to be identical to immediate release tablets and considered as valid. Conclusion: IVIVC can serve as a surrogate for in vivo bioavailability study and supports biowaivers, supports and validates the dissolution methods and specification settings and assists in quality control during scale-up and post-approval changes. It may be used to predict the variation in site change, process changes and to predict the absorption performance of naproxen sodium products with different release rates.

[关键词] IVIVC;naproxen sodium;sustained release;dissolution;in vivo bioavailability study;internal and external predictability