Use of In silico Methodologies to Predict the Bioavailability of Oral Suspensions: A Regulatory Approach.

BACKGROUND: Oral suspensions are heterogeneous disperse systems, and the particle size distribution, crystalline form of the dispersed solid, and composition of the formulation can be listed as parameters that control the drug dissolution rate and its bioavailability. OBJECTIVE: The aim of this work was to develop a discriminative dissolution test, which, in association with in silico methodologies, can make it possible to safely anticipate bioavailability problems. METHODS: Nimesulide and ibuprofen (BCS class II) and cephalexin (BCS class I) oral suspensions were studied. Previously, solid-state structure and particle size in active pharmaceutical ingredients were characterized and the impact of differences on solubility was evaluated for the choice of discriminative medium. Afterwards, particle size distribution (0.1 to 360 µm), dissolution profile, and in vitro permeability in Caco-2 cell of commercial suspensions, were determined. These parameters were used as input for the establishment of the in vitro-in vivo correlation (IVIVC) for the suspensions using the GastroPlus™ with Wagner-Nelson and Loo- Riegelmann deconvolution approach. RESULTS: The predicted/observed pharmacokinetic model showed good correlation coefficients (r) of 0.960, 0.950, and 0.901, respectively. The IVIVC was established for one nimesulide and two ibuprofen suspensions with r between 0.956 and 0.932, and the percent prediction error (%PE) did not exceed 15%. CONCLUSION: In this work, we have performed a complete study combining in vitro/in silico approaches with the aim of anticipating the safety and efficacy of oral pharmaceutical suspensions in order to provide a regulatory tool for this category of products in a faster and more economical way.

Determinação das curvas de absorção, perfis de dissolução e estabelecimento de correlação in vitro-in vivo por métodos in silico utilizando o GastroPlusTM e o DDDPlusTM / Determination of absorption curves, dissolution profiles and establishment of in vitro-in vivo correlation by in silico methods using GastroPlusTM and DDDPlusTM

O uso de programas de computador para prever a absorção de fármacos em humanos e simular perfis de dissolução tem se tornado uma ferramenta bastante valiosa na área farmacêutica. O objetivo deste trabalho foi utilizar métodos in silico por meio dos programas de computador GastroPlusTM e DDDPlusTM para simular curvas de absorção de fármacos, perfis de dissolução e estabelecer correlações in vitro-in vivo (CIVIVs). O material aqui apresentado é constituído por cinco capítulos incluindo os fármacos cetoprofeno, pirimetamina, metronidazol, fluconazol, carvedilol e doxazosina. No capítulo 1 são apresentadas curvas plasmáticas simuladas para comprimidos matriciais de cetoprofeno, sendo estabelecida a CIVIV. A utilização de simulações de ensaios de dissolução intrínseca para os fármacos pirimetamina e metronidazol como uma ferramenta para classificação biofarmacêutica é detalhada no capítulo 2. No capítulo 3, a simulação de curvas plasmáticas a partir de cápsulas de fluconazol contendo diferentes perfis de dissolução é demonstrada como uma ferramenta para bioisenção. Estudos de CIVIV foram também realizados para comprimidos de liberação imediata de carvedilol a partir dos perfis de dissolução no capítulo 4. Já o capítulo 5 trata da aplicação de simulações de ensaios de dissolução para o desenvolvimento de formulações de liberação prolongada de doxazosina. As simulações das curvas plasmáticas, assim como a CIVIV, obtidas com o auxílio do programa GastroPlusTM, além dos ensaios de dissolução intrínsica e os perfis de dissolução obtidos por meio do uso do programa DDDPlusTM apresentaram-se como ferramentas de grande aplicação na previsão de características biofarmacêuticas sobre os fármacos e formulações, permitindo redução de tempo e custo com trabalho experimental em laboratório

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work