(W1130-09-60) Development and Clinical Evaluation of a Dexmedetomidine Sublingual/Buccal Film Using MicroDep Technology: A Rapid-Absorbing High-Bioavailability Dosage Form

Purpose: This study aimed to develop a fast-acting, low-dose, sublingual / buccal film formulation of Dexmedetomidine (Dex), a selective α2-adrenergic agonist, for managing acute agitation [1]. We formulated transmucosal (sublingual/ buccal) films for rapid oromucosal absorption leveraging MicroDep technology to ensure precise and accurate dosing where localization of low quantities of API at mucosal layer would also aid in rapid absorption [2]. The films were evaluated for their physical characteristics and in-vitro permeation across EpiOral cells. Additionally, the formulation was tested in-vivo in rats and compared to intravenous (IV) injection for its pharmacokinetic performance. The results encouraged us to evaluate the films further in clinical set up where it demonstrated high bioavailability.

Methods: Dexmedetomidine sublingual films were developed using MicroDep technology. The films were microdeposited at different strengths and evaluated for its content uniformity, accuracy, and precision. Further the films were also evaluated for the structure and shape of the deposit. To evaluate its potential to permeate across mucosal membrane, the films were evaluated using EpiOral™ tissue models. Burst strength and muco-adhesion were also assessed using a texture analyzer to ensure mechanical robustness and mucosal retention, which are critical for sublingual / buccal delivery. The optimized formulations were evaluated in vivo in rats at three different strengths to evaluate its ability for transmucosal delivery. Clinical evaluation involved administration of varying film strengths sublingually and buccally. Pharmacokinetic parameters, including time to reach maximum concentration (C_MAX), area under the curve (AUC), and absolute bioavailability, were determined. Pharmacodynamic efficacy was assessed based on reduction in agitation levels using validated behavioral scales and compared against the placebo group.

Results: The manufactured films had high accuracy and precision in terms of assay, content uniformity, deposit placement, shape, and structure at all the doses deposited. The content uniformity ranged between 99 to 105% for all strengths. In muco-adhesion testing, the films demonstrated a detachment force of >0.7 Kg, ensuring sufficient adhesion without tissue damage. Burst strength testing revealed a mean force of >0.3 Kg was required to burst the films. This ensured the film wouldn’t be dislodged from location of application and the film had adequate mechanical strength for patient handling. In vitro studies using EpiOral™ tissues confirmed rapid permeation, with >80% of Dex crossing the mucosal layer, validating the film’s design for transmucosal delivery. In vivo rat studies corroborated fast onset, with detectable systemic Dex levels at 5 minutes post-administration [3]. Clinically, all films at different strengths achieved C_MAX within 2 hours, and AUC was dose-proportional, confirming predictable pharmacokinetics [4]. Bioavailability studies demonstrated that sublingual administration achieved 72% absolute bioavailability, while buccal administration reached 82% bioavailability. [5]. Pharmacodynamic results showed that all patients receiving active treatment achieved a significant reduction in agitation response within 2 hours, while none in the placebo group exhibited such improvement [4].

Conclusion: MicroDep™ technology offers a highly effective, accurate, and precise non-invasive dosing platform for low dose APIs. It demonstrated strong mechanical properties, excellent muco-adhesion, and quick release that results in rapid onset of action, and exceptional bioavailability and dose proportional pharmacokinetic response via the sublingual / buccal route [4]. This platform sets a new benchmark for transmucosal drug delivery, with potential applications across other active moieties.

References: 1. Chen B-S., et al. Br J Anaesth. 2009;103(2):244-54.
2. US Patent No. 11,648,197. “Dispensing method for producing dissolvable unit dose film constructs.” 2023.
3. US Patent No. 11,931,340. “Use of sublingual Dexmedetomidine for the treatment of agitation.” 2019.
4. US Patent No 11,497,711. “Film formulations containing Dexmedetomidine and methods of producing them.” 2022.
5. Product Monograph: IGALMI