Effect of Dispersion Medium on Pharmacokinetic Profile of Rotigotine Crystalline Suspension following Subcutaneous Injection

Abstract

Rotigotine (RTG) is prescribed as a once-daily transdermal patch for managing early Parkinson’s disease (PD), which presents issues such as skin irritation and poor patient adherence. Therefore, the aims of the present study were to formulate aqueous and oily vehicle-based RTG crystalline suspensions for prolonged delivery and to compare their pharmacokinetic profiles and the local behaviors of RTG crystals. RTG-loaded aqueous (AS) and oil suspensions (OS) were fabricated using bead-milling technology (100 mg/mL as RTG), employing carboxymethyl cellulose and sesame oil as suspending agent and oily vehicle, respectively. RTG AS and OS exhibited comparable physical properties in terms of particle size (about 800–900 nm), crystallinity, and dissolution profile, despite higher drug solubility in OS than AS (19.6 and 0.07 mg/mL, respectively). However, AS and OS exhibited markedly distinctive local distribution and inflammatory responses at the injection site, which further promoted different pharmacokinetic patterns following subcutaneous injection in rats. With OS, no drug aggregates were observed with prolonged persistence of the Sudan III-stained oily vehicle at the injection site. In contrast, with AS injection, drug clusters > 7 mm were formed, followed by an enclosure with macrophages and a fibroblastic band. Accordingly, AS exhibited a protracted pharmacokinetic profile over 3 weeks, with prolonged elimination half-life. The local inflammatory response caused by AS injection was almost alleviated after 3 weeks post-dosing. Based on these findings, we conclude that RTG AS system can be a platform to design sophisticated long-acting delivery systems with extended dosing intervals to manage PD.

Early Stage Preclinical Formulation Strategies to Alter the Pharmacokinetic Profile of Two Small Molecule Therapeutics

“…Subcutaneous oil formulations have demonstrated their ability to function as depots, with absorption dictated by factors like solubility, diffusion, and entry into the bloodstream [ 21 ]. The release profile can be optimized by manipulating various parameters, such as particle size, surface properties, and the dosing dispersion medium [ 22 ]. The optimization of long-acting injectables for subcutaneous delivery confers several advantages over oral and intraperitoneal routes of delivery.…”

Design of High-Payload Ascorbyl Palmitate Nanosuspensions for Enhanced Skin Delivery

“…Compared to conventional emulsion or oily formulas, the NS system has the advantages of a high drug payload, improved stability, and lower use of surfactant or organic solvent, which can cause skin irritability [ 31 ]. The NSs were fabricated using a wet-milling technique, a top-down process that relies on mechanical attrition to convert large crystalline particles into submicron particles [ 21 ]. The wet-milling technique employing beads as a collision catalyst was adopted to formulate an AP-loaded NS system.…”

“…AP-loaded NSs were prepared with a lab-scale wet-milling machine using dual centrifuging principles (Zentrimix ® 380 R; Andreas Hettich GmbH & Co KG, Tuttlingen, Germany), as previously described [ 21 ]. Approximately 5–15 mg of the suspending agent was dissolved in 1 mL of 50 mM citrate buffer (pH 4.5), and 25–75 mg of AP powder (average particle size of 5–10 μm) was subsequently added.…”