(W1130-12-80) Effect of Particle Size on the In Vitro/In Vivo Evaluation of Long-Acting Injectable Paliperidone Palmitate Suspension

Purpose: Paliperidone palmitate (PP) in crystalline suspension-based long-acting injectable formulation has demonstrated effectiveness and tolerability as a treatment for schizophrenia. The PP suspension consist primarily of pure drug crystals with minimal amounts of excipients. It can provide prolonged drug dissolution, allowing for better patient compliance and ease of medical regiment. The Noyes–Whitney equation establishes that the diameter of drug crystal determines the effective surface area of drug particles, directly affecting the dissolution and absorption in vitro and in vivo. Hence, the particle size distribution of drug crystal becomes the most important critical attribute which significantly impacts the in vitro and in vivo performance of suspension. Any deviation in the particle size distribution may result in duration alteration or concentration fluctuation, ultimately affecting the treatment outcome and potentially leading to serious adverse effects. Consequently, certified products must adhere to the appropriate size distribution range to ensure both efficacy and safety. However, there are limited reports available for the effect of PP suspension particle size on the in vitro characterization and in vivo behavior of the formulation. In this work, we have developed bench-made PP suspensions with varying particle sizes and compared them to marketed commercial PP suspension (Invega Sustenna^® and Invega Trinza^®). The principal aim of this study was to comprehensively assess the influence of particle size on the in vitro characteristics and in vivo performance of injectable paliperidone palmitate suspensions.

Methods: We employed high pressure homogenization (HPH) to make bench made suspensions. The size distribution of aqueous PP suspension was measured by Mastersizer 2000 system with Hydro 2000s accessory. The PP concentrations of different bench-made and commercial suspensions were determined by UPLC. The morphology of aqueous PP suspension was assessed using scanning electron microscope (SEM). Dissolution methods were developed to investigate the in vitro dissolution kinetics. The PP suspension was directly loaded into the simulated muscle fluid (SMF) supplemented with 0.5% Tween 20 at a pH of 5.0. The dissolution test was conducted in a shake incubator at 37°C at 80 rpm. The PP content in release buffer was quantified by LC/MS. For the in vivo pharmacokinetics study, a single intramuscular injection of 20 mg/kg of paliperidone palmitate suspension was administrated to the hind leg of SD rats. Blood samples were collected via the jugular vein at the designated time points and subsequently centrifuged to separate the plasma for further analysis. The drug concentration in rat plasma were detected by LC/MS.

Results: The particle size distributions and drug concentrations were presented in Figure 1A. The median diameters (D₅₀) of drug crystal suspensions prepared by HPH and commercial products were determined to be 9.78, 3.80, 0.92, 0.94, and 6.65 μm, respectively, with SPAN values below 2.2. The SEM analysis revealed that PP suspensions with particle sizes less than 1 μm exhibited an irregular granular shape (Figure 1B), while larger drug crystals appeared plate-like with a rough surface (Figure 1B). The in vitro dissolution profiles of the PP suspensions with different median diameters under sink condition are displayed in Figure 2. The results indicated that the drug release rate was highly dependent on the particle size: the drug crystal with sizes less than 1μm achieve complete dissolution within approximately 12 hours, while the accumulated amounts of released PP after 32 h were 91%, 82% and 70% for suspension with median diameters of 3.80, 6.65 and 9.78 μm, respectively. These dissolution behaviors followed the Noyes–Whitney equation where the smaller particles generally dissolve at a faster rate than larger particles. In vivo plasma concentration-time curves of paliperidone following a single intramuscular injection was displayed in Figure 3, demonstrating distinct in vivo performances for suspensions with different particle diameters. The suspensions with crystal size less than 1μm released drugs gradually, reaching T_max around 7 days, after which plasma concentration started to decline. In contrast, suspensions with larger particles exhibited a slower elevation in plasma drug concentration. The C_max and AUC were significantly decreased and T_max was delayed as the particle size reduced.

Conclusion: Our study aimed to develop and compare the in vitro and in vivo evaluation of PP suspensions with varying drug crystal sizes. Our findings revealed that the size of PP particles significantly influences both the in vitro dissolution behavior and the in vivo pharmacokinetics performance.

Figure 1. (A) Particle size distributions and drug concentrations of PP suspensions with different sizes. (B) SEM images of PP suspensions with different sizes.

Figure 2. In vitro dissolution profiles of PP suspensions with different sizes.

Figure 3. In vivo pharmacokinetic evaluation in rats following IM injection of PP suspensions with different sizes.