Effects of Postprandial Factors and Second Meal Intake Time on Bioequivalence Investigation of Tadalafil-Loaded Orodispersible Films in Human Volunteers

Abstract

Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, although commercial 20 mg TD-loaded tablets (TD-TAB, Cialis^® tablet) may be taken with or without food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936-1.105 and 1.012-1.153, respectively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the C_max T/R of 0.610-0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851-0.998 of TD-TAB and TDF. The predictive diffusion direction model for physical digestion of TD-TAB and TDF in the stomach after the first and second meal intake was successfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions.

Keywords: computational fluid dynamics; drug particle size; in vitro dissolution; in vivo bioequivalence; meal viscosity; orodispersible film; postprandial condition; second meal intake time; tadalafil.

Figure 1

The SEM morphology with different tadalafil (TD) particle sizes (top) and surfaces of TD-filled orodispersible films (TDFs; bottom). (a) TDF-1 TD particles (10,000×), (a′) TDF-1 surface (3000×), (b) TDF-2 TD particles (10,000×), (b′) TDF-2 surface (3000×).

Figure 2

The dissolution rate of tadalafil (TD)-loaded formulations in water containing 0.5% SLS.

Figure 3

The diffusional rate of TD concentrations at the lower region of the dissolution vessel under the fed-simulated conditions to elucidate the diffusional direction of 20 mg TD-TAB (Cialis^®) and 20 mg TDF-1.

Figure 4

The comparative pharmacokinetic profiles of TDF and TD-TAB (Cialis^®) in healthy human volunteers under fasting and fed states. (a) Fasting, (b) Fed I, (c) Fed II, (d) Fed III, (e) Fed IV.

Figure 5

Relative viscosity to simulate postprandial conditions of TD-TAB (150 or 240 mL) and TDF-1 (20 mL) in the stomach according to three different water intake volumes.

Figure 6

The predictive diffusion direction model of TD-TAB (top) and TDF-1 (bottom) in the stomach under a fasting state.

Figure 7

Predictive diffusion direction model in the stomach of TD-TAB (top) and TDF-1 (bottom) under fed state after the first meal intake (breakfast) before drug dosing, followed by the second meal intake (lunch), 4 h or 6 h after drug dosing.