Citation: Kim, M.S.; Ho, M.J.; Joung, M.Y.; Choi,Y.S.; Kang, M.J. Effect of Dispersion Medium on Pharmacokinetic Profile of Rotigotine Crystalline Suspension following Subcutaneous Injection. Pharmaceutics 2022, 14, 2630. https:// doi.org/10.3390/ pharmaceutics14122630 Academic Editor: Luisa Coderch Received: 2 November 2022 Accepted: 24 November 2022 Published: 28 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Article Effect of Dispersion Medium on Pharmacokinetic Profile of Rotigotine Crystalline Suspension following Subcutaneous Injection Min Seop Kim † , Myoung Jin Ho † , Min Yeong Joung, Yong Seok Choi and Myung Joo Kang * College of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan 330-714, Republic of Korea * Correspondence: kangmj@dankook.ac.kr; Tel.: +82-41-550-1446 † These authors contributed equally to this work. 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. Keywords: Rotigotine; parenteral long-acting delivery; crystalline suspension; dispersion medium; pharmacokinetics; local distribution; local inflammation 1. Introduction Rotigotine ([–]2-(N-propyl-N-2-thienylethylamino)5-hydroxytetralin, RTG), a non- ergot dopamine agonist, has been prescribed to manage early Parkinson’s disease (PD) as monotherapy or an adjunct to levodopa [1,2]. Because of its extensive first-pass metabolism in the intestine and liver [3], the lipophilic dopamine agonist was formulated as a once- daily transdermal patch (Neupro ® , Schwarz Pharma, Brussels, Belgium). The transdermal system provides steady absorption of the drug molecule over 24 h, reducing systemic adverse effects, such as motor fluctuations, and dyskinesia [2,4]. However, repeated application of adhesive patches to the skin causes adverse reactions at the application site in patients with PD. In clinical trials, approximately half of RTG patients had application site reactions, including erythema, swelling, and pruritus [4]. Moreover, considering the poor drug compliance by patients with PD, an alternative dosage form offering appropriate therapeutic levels over several weeks following a single administration can provide the benefit of reduced dosing frequency [5,6]. The long-acting injectable (LAI) drug delivery system based on a crystalline suspen- sion is in the spotlight as an effective tool to afford an extended pharmacokinetic profile Pharmaceutics 2022, 14, 2630. https://doi.org/10.3390/pharmaceutics14122630 https://www.mdpi.com/journal/pharmaceutics