(M1530-03-16) Development and Optimization of Oral Dissolving Film Formulation Containing Psilocybin

Purpose: The therapeutic potential of psilocybin, a naturally occurring psychedelic compound found in specific mushrooms, has gained renewed interest. Historically used in various cultures for religious, spiritual, and recreational purposes, psilocybin is now being investigated for its efficacy in treating conditions such as depression, anxiety, and post-traumatic stress disorder (PTSD). This study aimed to develop an optimized novel Oral Dissolving Films (ODFs) containing Psilocybin for clinical use.

Methods: The ODFs were produced by a solvent casting method, employing the Design of Experiments (DOE) for the formulation composition and drug loading. Five responses i.e. weight, thickness, disintegration time, %loss on drying, and folding endurance were monitored. Every experimental run was completed with Poly vinyl alcohol, pullulan, carrageenan, glycerol mono-oleate, and distilled water. The partial least square regression was applied to evaluate the fitting of the model and response surface. The modeling was done with a quadratic model, linear, 2FI, and interaction terms. We evaluated physicochemical properties and stability to identify an optimal formula. A selected group of formulations underwent in vitro studies to assess drug release, drug recovery, and stability.

Results: Box-Behnken-RSM suggested 15 runs composed of 12 experimental runs with 3 centered-point replicates using HPMC, xanthan gum, and propylene glycol (PG) as independent variables. The optimal formulation was calculated by setting up the minimized disintegration time and the %loss on drying in the range of 5 to 8%. 59 conditions were identified by the software and the one containing 100 mg of HPMC, 20 mg of xanthan gum, and 1,572 mg of propylene glycol was chosen due to its highest score of desirability (0.963). The Pearson correlation coefficient between independent variables and responses is shown in Table 1. PG exhibited a dual impact. It was identified as having a positive effect on the moisture content of the films, as indicated by a correlation coefficient of 0.895. This suggests that higher PG concentrations correlate with increased moisture content in the films. However, concurrently, PG exerted a negative influence on the disintegration time, with a correlation coefficient of -0.804. These findings offer insights into the multifaceted role of PG in film properties, balancing moisture content with disintegration time. Five additional experiments processed under the optimal formulation were conducted. The data's mean response aligns closely with the predicted mean, with a difference well within the 95% prediction interval. This suggests that the optimized condition can be used. The weight of the Psilocybin-loaded ODF was precisely measured and recorded. Disintegration times were determined for all formulations, with each film disintegrating within 180 seconds. Table 2 displays the film weight, percentage of Psilocybin content, and percent recovery of Psilocybin for each concentration. The Psilocybin recovery for all formulations fell within the range of 89.78±0.11 to 99.56±0.13%. Notably, Formulation 5, containing 16.05% Psilocybin content, exhibited the highest percent recovery. However, despite its maximum Psilocybin loading, the occurrence of a crystalline drug pattern remained below 11.75%, as depicted in Figure 1. After three months of storage under 25°C±2°C/ 60%RH±5%RH and 40°C±2°C/ 75%RH±5%RH conditions, there were no significant changes in ODF appearance or the drug content.

Conclusion: A novel and stable Psilocybin-loaded ODF formulation was successfully developed. This is a promising delivery system especially for phase one clinical trials because a wide dose range can be clinically tested due to the dose proportionality of the formulation. The optimized ODF is a promising delivery system for Psilocybin, a highly soluble drug.

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4. Turkia M. Self-treatment of depression and complex post-traumatic stress disorder (C-PTSD) with psilocybin–a retrospective case study. ResearchGate URL: https://doi org/1013140/RG. 2022;2(20075.41764).
5. Patil SL, Mahaparale PR, editors. Fast Dissolving Oral Films: An Innovative Drug Delivery System2014.
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Acknowledgements: Financial support for this research was obtained from the research and researchers for industries (RRI) program, National Research Council of Thailand (NRCT) [NRCT5-RRI63010-P11] with GRD Tech Co., Ltd as a co-contributor, the NSRF via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation [grant number B16F640099], Centre of Excellence for Innovation in Chemistry (PERCH-CIC) from the Ministry of Higher Education, Science, Research and Innovation. The Canada-ASEAN Scholarships and Educational Exchanges for Development (SEED) program. The Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, and Drug Development and Innovation Centre (DDIC) for the research facilities allowance.
Conflicts of interest: All authors declare that they have no conflict of interest to disclose.


Table 1 The Pearson correlation coefficient between independent variables and responses in Box-Behnken RSM on the optimized formulation


Table 2 The recovery of Psilocybin-loaded ODF


Figure 1 Microscopic view of ODF without Psilocybin, Psilocybin dispersed in light mineral oil, and ODFs with Psilocybin loading from 6.73% to 24.07%.