Model-Informed drug development of gastroretentive release systems for sildenafil citrate

Authors: Pinheiro de Souza F, Sonego Zimmermann E, Tafet Carminato Silva R, Novaes Borges L, Villa Nova M, Miriam de Souza Lima M, Diniz A
Publication: Eur J Pharm Biopharm
Keywords: ACAT, bioequivalence, biopharmaceutics, gastroplus, mechanistic absorption, pbbm, PBPK modeling, physiologically based pharmacokinetics, vbe
Software: GastroPlus®

Abstract

Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways.

By Fabio Pinheiro de Souza, Estevan Sonego Zimmermann, Raizza Tafet Carminato Silva, Luiza Novaes Borges, Mônica Villa Nova, Marli Miriam de Souza Lima & Andréa Diniza