Design and Evaluation of Two-Step Biorelevant Dissolution Methods for Docetaxel Oral Formulations

Abstract

Dissolution is a pivotal tool for oral formulations. Dissolution could be used to either reduce the risk of product failure through quality control or predict and understand in vivo performance of drug formulations. The latter is always challenging because multiple factors such as selection of media, gastrointestinal components, physiological factors, consideration of fasted and fed state are involved. Previously published dissolution methods such as one-step dissolution in individual simulated gastric fluid, simulated intestinal fluid, or phosphate buffer saline did not signify the realistic gastrointestinal transit effect. Docetaxel (DTX), a poorly water-soluble drug, is commercially available only as injectable dosage forms, and thus many publications studied the development of oral DTX formulations. In our previous report, we developed oral lipid-based DTX granules that showed higher oral absorption in rats compared to DTX powder. However, one-step dissolution in simulated gastric fluid showed no difference between DTX granules and DTX powder. Therefore, the present study aimed to develop new two-step biorelevant dissolution methods for DTX oral formulations. In the study, new two-step biorelevant dissolution methods in fasted or fed states with pancreatin were developed and compared with other previously reported dissolution methods. The new two-step biorelevant dissolution methods successfully discriminated the difference of dissolution between DTX granules and DTX powder, which reflected the in vivo difference of absorption of these two formulations. Moreover, food effects were confirmed for DTX. The new dissolution methods have the potential to be used to predict and understand in vivo performance of oral solid dosage forms.

Keywords: biorelevant media; dissolution; docetaxel; oral delivery; poorly water-soluble drugs.

Fig. 1

In vitro lipolysis of DTX granules in FaSIF (pH 7.4). A Particle size in the medium with DTX granules at 10 min before the addition of pancreatin and at 60 min at the end of lipolysis. B The amount of free fatty acid produced during the lipolysis of DTX granules in the presence of pancreatin (n=3)

Fig. 2

One-step dissolution of DTX granules and DTX powder in PBS (pH 7.4) with 0.5% Tween-80. A Particle size in the medium with DTX granules at 10 min, 60 min, 180 min and 240 min (n=3). B One-step dissolution profiles of DTX granules and DTX powder in PBS with 0.5% Tween-80 over 4 h (n=3)

Fig. 3

One-step dissolution of DTX granules and DTX powder in SGF (pH 1.2). A Particle size in the medium with DTX granules at 10 min, 30 min, 60 min, and 120 min (n=3). B One-step dissolution profiles of DTX granules and DTX powder measured over 2 h (n=3)

Fig. 4

Two-step dissolution of DTX granules and DTX powder in SGF (pH 1.2) for 30 min and in SIF (pH 6.8) with pancreatin for 4.5 h. A Particle size in the medium with DTX granules at 30 min, 45 min, 120 min, and 270 min. B Two-step dissolution profiles of DTX granules and DTX powder measured over 4.5 h (n=3)

Fig. 5

Two-step dissolution of DTX granules and DTX powder in FaSGF (pH 1.6) for 30 min and in FaSIF (pH 6.5) for 4.5 h with pancreatin. A Particle size in the medium with DTX granules at 30 min, 45 min, 120 min, and 270 min. B Two-step dissolution profiles of DTX granules and DTX powder measured over 4.5 h (n=3)

Fig. 6

Two-step dissolution of DTX granules and DTX powder in FeSGF (pH 5.0) for 30 min and in FeSIF (pH 5.8) with pancreatin for 4.5 h. A Particle size in the medium with DTX granules at 30 min, 45 min, 120 min, and 270 min. B Two-step dissolution profiles of DTX granules and DTX powder measured over 4.5 h (n=3)