Preparation and Characterization of 3D-Printed Dose-Flexible Printlets of Tenofovir Disoproxil Fumarate

Abstract

The aim of this work was to design pediatric-friendly, dose-flexible orally disintegrating drug delivery systems (printlets) of the antiviral drug tenofovir disoproxil fumarate (TDF) by selective laser sintering (SLS) for potential use in hospitals along with other antiviral drugs. In order to obtain a consistent quality of printlets with desired properties, it is important to understand certain critical quality attributes for their main and interactions effect. The printlets were optimized by Box-Behnken's design of the experiment by varying process variables while keeping the composition constant. The composition contained 16.3% TDF, 72.7% polyvinyl pyrrolidone K16-18, 8% magnesium aluminum silicate, 3% Candurin^® NXT Ruby Red, and 0.3% colloidal silicon dioxide. The process variables studied were surface (X₁), chamber temperatures (X₂), and laser scanning speed (X₃). The range of variable levels was 75-85°C for X₁, 50-70°C for X₂, and 200-240 mm/s for X₃, respectively. The responses studied were hardness, disintegration time, dissolution, physiochemical, and pharmacokinetic characterization. X-ray powder diffraction indicated partial or complete conversion of the crystalline drug into amorphous form in the printlets. Comparative pharmacokinetics between Viread^® (generic) and printlets in rats were superimposable. Pharmacokinetic parameters showed statistically insignificant differences between the two formulations in terms of T_max, C_max, and AUC of (p > 0.05). Printlets were bioequivalent to Viread^® as per FDA bioequivalence criteria. Thus, the SLS printing method showed the fabrication of dose-flexible printlets with quality, and in vivo performance equivalent to commercial tablets.

Keywords: Amorphous; Bioequivalence; Critical quality attributes; Pharmacokinetic; Selective laser sintering; Tenofovir disoproxil fumarate.

Fig. 1

a Hardness. b Actual and model-predicted hardness. c Residual of the printlets

Fig. 2

a Disintegration time. b Actual and model-predicted disintegration time. c Residual of the printlets

Fig. 3

Dissolution profiles of the printlets

Fig. 4

a Actual and model predicted disintegration time. b Residual of the printlets

Fig. 5

a Scanning electron microscopy images, tenofovir disoproxil fumarate (a), F3, printlet (b), F5 printlet (c), and F12 printlet (d). a micro-CT images of the printlets

Fig. 6

Fourier transformed infrared spectra of tenofovir disoproxil fumarate, placebo, physical mixture, and printlets

Fig. 7

Near infrared hyperspectral images of F3 printlet (a), F5 printlet (b), F12 printlet (c), PVP K16–18 (d), and tenofovir disoproxil fumarate (e), placebo formulation (f) and physical mixture (g)

Fig. 8

X-ray powder diffractograms of tenofovir disoproxil fumarate, placebo, physical mixture, and delivery system

Fig. 9

Differential scanning calorimetry thermograms of tenofovir disoproxil fumarate, placebo, physical mixture, and delivery system

Fig. 10

Pharmacokinetic profiles of after administration of delivery system and compressed tablet (generic of Viread^®)