SeDeM expert system with I-optimal mixture design for oral multiparticulate drug delivery: An encapsulated floating minitablets of loxoprofen Na and its in silico physiologically based pharmacokinetic modeling

Abstract

Introduction: A SeDeM expert tool-driven I-optimal mixture design has been used to develop a directly compressible multiparticulate based extended release minitablets for gastro-retentive drug delivery systems using loxoprofen sodium as a model drug. Methods: Powder blends were subjected to stress drug-excipient compatibility studies using FTIR, thermogravimetric analysis, and DSC. SeDeM diagram expert tool was utilized to assess the suitability of the drug and excipients for direct compression. The formulations were designed using an I-optimal mixture design with proportions of methocel K100M, ethocel 10P and NaHCO₃ as variables. Powder was compressed into minitablets and encapsulated. After physicochemical evaluation lag-time, floating time, and drug release were studied. Heckel analysis for yield pressure and accelerated stability studies were performed as per ICH guidelines. The in silico PBPK Advanced Compartmental and Transit model of GastroPlus™ was used for predicting in vivo pharmacokinetic parameters. Results: Drug release follows first-order kinetics with fickian diffusion as the main mechanism for most of the formulations; however, a few formulations followed anomalous transport as the mechanism of drug release. The in-silico-based pharmacokinetic revealed relative bioavailability of 97.0%. Discussion: SeDeM expert system effectively used in QbD based development of encapsulated multiparticulates for once daily administration of loxoprofen sodium having predictable in-vivo bioavailability.

Keywords: SeDeM expert tool; extended release minitablets; in silico PBPK; loxoprofen Na; multiparticulate drug delivery system.

FIGURE 1

SeDeM expert tool diagram of loxoprofen sodium, methocel K100M, ethocel 10 premium and sodium bicarbonate.

FIGURE 2

(A) Differential scanning calorimetry (DSC) and (B) thermogravimetric analysis (TGA) graphs for loxoprofen sodium, methocel K100M, ethocel 10P, sodium bicarbonate, and Drug Excipient Mixture (1:1:1:1 ratio incubated for 30 days at 40°C/75% ± 5% RH).

FIGURE 3

Response surface graphs (I-optimal mixture design) of input variables (methocel K100M, ethocel 10P and NaHCO₃) with responses (A) floating lag-time, (B) total floating time, (C) desirability (D) drug release at 1 h, (E) drug release at 12 h and (F) drug release at 24 h.

FIGURE 4

(A–D) erosion (%) studies of minitablet formulations (F1-F16) versus time; (E–H) % swelling studies of minitablet formulations (F1-F16) with respect to time (h); (I–L) % drug release from minitablet formulations (F1-F16) with respect to time (h).

FIGURE 5

Stereomicrographs of loxoprofen sodium gastroretentive minitablet formulations after contacting with water (A) at 0 min, (B) after 1 min, (C) after 3 min and (D) after 5 min of contact with water.

FIGURE 6

(A ,B) Scanning electron microscopic (SEM) images of physical mixture of formulation blend, (C ,D) SEM images of surface morphology of the compressed minitablets, (E) Photographic image of loxoprofen Na gastroretentive minitablets and (F) capsules (size “00”) filled with 20 minitablets (120 mg loxoprofen Na).

FIGURE7

Heckle plot of the optimized formulation-blend (F2) at various pressure values (0–160 MPa).

FIGURE 8

Plasma drug concentration vs. time plot of 60 mg IR loxoprofen sodium administered to healthy Korean volunteers (Kang et al. (2011)) and PBPK based in silico modeling and simulation based plasma drug concentration of 120 mg loxoprofen sodium GRDDS minitablets.