(M1030-03-15) Formulation-Related Influences on the Ex Vivo Permeation of Lidocaine Hydrochloride Films

Purpose: Oral films have gained more popularity over the last years duo to their opportunity for improving drug delivery. Investigating formulation-related influences on drug permeation offers insights into optimizing drug release profiles and improving the overall efficacy of oral film formulations.^1,2 Thus, a comprehensive analysis of permeation behavior from oral films is essential for advancing pharmaceutical research and development. Following a Design of Experiment (DoE) approach allows for systematic exploration of various formulation parameters. This comprehensive evaluation aids in developing more robust oral film formulations. By identifying influencing factors on drug permeation, of the model drug (API) lidocaine hydrochloride prediction of pharmacokinetic profiles is feasible.

Methods: Manufacturing of films - Films were produced via solvent casting using the casting bench Coatmaster (Erichsen, Germany). The wet film thickness was adjusted to 500 µm and the films were dried for six hours at room temperature (25 °C). Permeation studies - Porcine esophagus was selected as a biological membrane due to its high comparability with the porcine buccal membrane and ease of preparation.^3,4 The membranes were sliced to a thickness of 300 µm using a dermatome (Integra® Dermal, Germany). Permeation measurements were conducted using Kerski cells with a permeation area of 0.64 cm².⁵ To simulate physiological conditions, 150 µL phosphate buffer pH 6.9 were used on the donor side, while phosphate buffer pH 7.4 was applied on the acceptor side with constant stirring (350 rpm) at 34 °C. Samples of 500 µl were manually collected according to the following sampling times: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 90, and 120 minutes. The quantification was performed using high-pressure liquid chromatography. To investigate formulation- related influences, the flux (mg/min/cm²) and the permeability coefficient (cm/min) were determined for each experiment (n=3). Design of experiment approach - To identify the influencing factors on permeation, a D-optimal design with 34 different formulations was conducted. The investigated factors included various concentrations of polymer, API, plasticizer, solubilizer, and enhancer. Analysis was carried out using MODDE software. Materials - Hydroxypropyl methylcellulose (HPMC, Hypromellose 606, Shin-Etsu; Japan) was used as a film-forming polymer and glycerol (Glycerol 85 %, Caesar & Loretz, Germany) as a plasticizer. Oleic acid (AppliChem, Germany) served as an enhancer, and polyvinylpyrrolidone (Povidone, Kollidon K90, PVP, BASF, Ludwigshafen, Germany) was utilized as a solubilizer. Lidocaine hydrochloride (Caesar & Loretz, Germany) was used as a model drug. The concentrations of individual components were altered based on the various runs of the DoE.

Results: The measured profiles (Figure 1) reveal that permeation initiates following a lag time. The lag time can be attributed to the drug formulation, as the API needs to dissolve from the matrix before permeating through the membrane. The coefficient plot for the flux (Figure 2) demonstrates that a higher polymer concentration exerts a negative effect on the flux. As anticipated, both, higher concentrations of enhancer and API, exhibit a positive effect on the flux. Surprisingly, the concentration of the solubilizer has a negligible influence in our experimental set up. In contrast to the coefficient plot for the flux, it is observed that the concentrations of the API and the polymer do not have a significant influence on the permeation coefficient (Figure 3). Plasticizer and enhancer also exhibit positive coefficients. The effect of the enhancer is equivalent to that of the plasticizer.

Conclusion: It must be noted that the permeation of lidocaine hydrochloride through the oral mucosa is a multifaceted process influenced by factors such as the molecule's lipophilicity, solution pH, and mucosal thickness. Additionally, variations in enhancer concentrations or alternative formulations of oral films can further impact this permeation. The experiments demonstrate that an increase in the concentration of enhancer and plasticizer yields a positive effect on the permeation of lidocaine hydrochloride in this case. Clear conclusions regarding the concentration of the polymer and the API and their influence on permeation cannot be drawn. However, the investigations revealed that a reliable prediction of permeation (for our experiments and compositions) could be achieved.

References: [1] Dinge, A., Nagarsenker ,M., 2008. Formulation and evaluation of fast dissolving films for delivery of triclosan to the oral cavity. AAPS PharmSciTech.9, 349-56.
[2] Borges, AF., Silva, C., Coelho, JF., Simões, S., 2015. Oral films: Current status and future perspectives: I - Galenical development and quality attributes. J Control Release 206, 1-19.
[3] Diaz-del Consuelo, I., Jacques, Y., Pizzolato, G.-P., Guy, R.H., Falson, F., 2005.
Comparison of the lipid composition of porcine buccal and esophageal permeability
barriers. Arch. Oral Biol. 50, 981–987.
[4] Franz-Montan, M., Serpe, L., Martinelli, C.C.M., da Silva, C.B., Santos, C.P.d., Novaes,
P.D., Volpato, M.C., de Paula, E., Lopez, R.F.V., Groppo, F.C., 2016. Evaluation of
different pig oral mucosa sites as permeability barrier models for drug permeation
studies. Eur. J. Pharm. Sci. 81, 52–59.
[5] Kerski, S., W.R., Stodt G., 2015. Permeation with Isofillkammer, patent, DE 20 2015 004 165 U1, Germany.

Acknowledgements: The authors are grateful to BASF, Sin Etsu and Theo Keinhörster Großschlachterei mit Fleischhandel e.g.. for the supply the raw materials.
We further thank Annkathrin Becker and Kristin Behr for their contribution to parts of this work during their internship at the institute.


Figure 1: Permeation profile of lidocaine hydrochloride (n=3) , permeation calculated for an area of 0.64 cm².


Figure 2: Coefficient plot for the flux.


Figure 3: Coefficient Plot for the permeability.