(T1230-08-51) Establish a Mucosa-Mimicking In Vitro Permeation Model for Evaluating Mucoadhesive Formulations

Purpose: Mucosal drug delivery offers a promising alternative to traditional enteral and parenteral routes, providing advantages such as enhanced bioavailability, rapid onset of action, and avoidance of first-pass hepatic metabolism. The mucosal surfaces—such as buccal, nasal, and rectal—are highly vascularized and allow for both localized and systemic drug delivery. Mucoadhesive polymers extend residence time at the site of absorption and improve therapeutic efficacy by maintaining close contact with the mucosal tissue. This property enables reduced dosing frequency and targeted delivery, particularly beneficial for drugs with poor oral bioavailability [1,2]. This study aims to develop and establish a high-throughput in vitro permeation model that mimics mucosal environments and enables comparative assessment of mucoadhesive formulations. Two dosage forms—nasal sprays and gels—formulated with various commonly used mucoadhesive polymers were evaluated to determine their effect on drug permeation across mucosal membranes.

Methods: To evaluate the influence of mucoadhesive polymers on mucosal drug permeation, two dosage forms—nasal sprays and gels—were formulated using commonly used mucoadhesive polymers: Carbomer, hydroxypropyl cellulose (Klucel), and hydroxyethyl cellulose (Natrosol). For the nasal spray formulations, six-hour in vitro permeation studies were performed using the MatTek 3D human respiratory epithelial tissue model mounted in its proprietary permeation device. Dulbecco's phosphate-buffered saline (DPBS) with glucose was used as the receptor medium and pre-warmed to 37°C prior to the experiment. Using sterile technique, 10 µL of each spray formulation was applied to the surface of the tissue inserts. Each insert was placed in a well containing 0.3 mL of receptor medium, and the system was incubated at 37°C. Samples were withdrawn from the receptor medium at 0.5, 1.0, 2.0, 3.0, 4.0, and 6.0 hours and immediately replaced with an equal volume of fresh, pre-warmed medium [3]. For the gel formulations, six-hour in vitro permeation studies were conducted using excised porcine intestine mounted in vertical diffusion cells (VDCs) with a diffusion area of 1.767 cm² and a receptor chamber volume of 5.0 mL. Phosphate-buffered saline (PBS, pH 7.4) served as the receptor medium. A 100 µL aliquot of each gel formulation was evenly applied to the mucosal surface in the donor compartment. The receptor compartment was maintained at 37°C with continuous stirring. Samples were automatically collected at 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 hours and immediately replaced with fresh buffer. This dual-model approach allowed for direct comparison of drug permeation profiles across both synthetic and biological mucosal tissues under controlled conditions.

Results: For nasal spray formulations containing 0.25% polymer, the hydroxyethyl cellulose (HEC)-based formulation exhibited a higher initial permeation rate compared to the hydroxypropyl cellulose (HPC)-based formulation. However, by the 1-hour mark, the permeation rate of the HPC formulation increased, surpassing that of the HEC formulation. After 2 hours, both formulations showed a gradual decline in permeation, suggesting that while HEC facilitated a faster initial drug release, HPC provided a more sustained permeation profile over time (Figure 1). In the gel formulations containing 2% polymer, the HEC-based formulation reached a peak permeation rate of 32.13 µg/cm²/hr at 2 hours post-application, whereas the HPC-based formulation peaked at 27.29 µg/cm²/hr at 3 hours. Although the HEC formulation demonstrated higher permeability during the early phase, the HPC formulation exhibited a more consistent and prolonged release profile, ultimately surpassing the HEC formulation in permeation rate after the 4-hour mark. Both formulations showed similar declining trends following their respective peaks (Figure 2).

Conclusion: This study demonstrates that hydroxypropyl cellulose (HPC)-based mucoadhesive formulations provide more sustained and prolonged drug release compared to hydroxyethyl cellulose (HEC)-based formulations. These differences were effectively characterized using a mucosa-mimicking in vitro permeation model employing either MatTek 3D human respiratory epithelial tissues or porcine intestinal membranes. These findings support hydroxypropyl cellulose’s potential advantage for controlled mucosal drug delivery application.

References: [1] https://www.researchgate.net/publication/385382834_Oral_mucoadhesive_drug_delivery_system_Formulation_strategies_and_evaluation_techniques; Accessed on Sep, 2024
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC3255397/ ; Mucoadhesive drug delivery system: An overview; Accessed on Oct, 2010
[3] https://www.mattek.com/wp-content/uploads/EpiAirway-Drug-Delivery-Protocol.pdf;


Figure 1 Diclofenac Nasal Spray 2.5% w/v permeation test on MatTek 3D Human Respiratory Epithelial Tissue


Figure 1 Diclofenac Gel 1% w/v permeation test on Porcine Intestinal Membrane