Generation of a Weakly Acidic Amorphous Solid Dispersion of the Weak Base Ritonavir with Equivalent In Vitro and In Vivo Performance to Norvir Tablet

Abstract

Ritonavir is an anti-viral compound that has also been employed extensively as a CYP3A4 and P-glycoprotein (Pgp) inhibitor to boost the pharmacokinetic performance of compounds that undergo first pass metabolism. For use in combination products, there is a desire to minimize the mass contribution of the ritonavir system to reduce patient pill burden in these combination products. In this study, KinetiSol® processing was utilized to produce an amorphous solid dispersion of ritonavir at two times the drug load of the commercially available form of ritonavir, and the composition was subsequently developed into a tablet dosage form. The amorphous intermediate was demonstrated to be amorphous by X-ray powder diffraction and C solid-state nuclear magnetic resonance and an intimately mixed single-phase system by modulated differential scanning calorimetry andH T/H T solid-state nuclear magnetic resonance relaxation. In vitro transmembrane flux analysis showed similar permeation rates for the KinetiSol-made tablet and the reference tablet dosage form, Norvir®. In vivo pharmacokinetic comparison between the two dosage forms resulted in equivalent exposure with approximately 20% Cmax reduction for the KinetiSol tablet. These performance gains were realized with a concurrent reduction in dosage form mass of 45%.

Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution Rate

“…To understand the relevance, Norvir is a marketed product that uses HME to formulate 15% ritonavir and copovidone into an ASD. 29 From the 1 H relaxation behaviors of the laboratory frame, Table 3, both the SLS-3DP and HME systems produced molecularly miscible compositions, attributed to the high agreement between ritonavir and copovidone relaxation times. 33 Previously, the importance of the formation of molecular miscible systems was shown by Hanada et al, where molecularly miscible systems exhibit greater physical stability and were found to be less prone to crystallization.…”

“…Embodying ritonavir, as the model drug within SLS-3DP, highlights the robustness of the process to formulate challenging ASDs successfully. Considering ritonavir's thermal sensitivity, 18,29 minimal exposure of the composition to the SLS laser decreases the probability of RTV degradation from excess exposure to elevated temperature. 53 The total energy absorbed by the composition is a function of the laser density and the composition's ability to absorb the wavelength emitted by the laser (Eq.…”

“…The flow rate was set to 1.5 mL/ min with 5-min run time and a 10 mL injection volume. 29 An ulti-Mate RS Variable Wavelength detector was set to 240 nm. 34 The column used for separation was a 25cmx4.6 mm, 5 mm particle size, stainless steel C-18 column (Nucleosil®100-5C18 (Suppleco series), Millipore Sigma, Burlington, Massachusetts).…”

“…mDSC determined the glass transition temperature (T g ) and melting point (T M ) with a heating rate of 3 C/min from 35 to 180 C, modulation temperature of 0.3 C every 50 s, and nitrogen sample purge flow of 50 mL/ min. 29…”

Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing

“…The KSD vemurafenib ASD has better dissolution and pharmacokinetic performance due to slower drug nucleation, recrystallization, and precipitation than the commercial formulation (160). Another study by Ellenberger et al demonstrated an attempt of using KSD to produce a bioequivalent ASD of ritonavir that is double the drug load of a commercially available form of ritonavir (Norvir®), in which the composition can be made into a tablet dosage form with a mass of around 45% less than Norvir® (162). The KSD produced ritonavir tablets exhibited similar performance characteristics, such as the permeation rate and in vivo pharmacokinetics, to those of Norvir®.…”