(W1130-12-70) Development of a Donepezil Dry Powder Formulation for Enhanced Nasal Mucosa Permeation

Purpose: The dosage forms of donepezil (DPZ) on the market are immediate-release tablets, sustained-release tablets, and orally disintegrating tablets. [1] However, a problem with such administration is that the presence of the blood-brain barrier BBB limits the entry of drugs from the blood to the brain, resulting in low brain bioavailability. [2] Nasal drug administration allows drugs delivered via the nasal route to be delivered directly to the brain and bypass the blood-brain barrier. Thus, the purpose of this study is the development of a donepezil dry powder formulation for nose-to-brain delivery via nasal improvement of drug mucosa permeation.

Methods: Phase solubility test was performed using HP-Beta-CD solution to find the solubilizer. The sample was diluted with methanol and analyzed by HPLC-UV method. Solid particles with a selected formulation were prepared using the solvent evaporator (SE) and supercritical antisolvent technique (SAS). Donepezil, HP-Beta-CD and DSPC(1,2-distearoyl-sn-glycero-3-phosphocholine) were dissolved in Ethanol/Dichloromethane mixed solvent. The SE samples were solidified using rotary vacuum evaporator at 45 degree. SAS process was performed as reported earlier [4]. Phospholipid screening was performed by parallel artificial membrane permeability assay (PAMPA) and porcine mucosa permeability test to determine suitable permeation enhancer. For the PAMPA permeability test, a 24-well cell culture plate was used as the permeation donor compartment and a cell culture insert was used as the acceptor. SNF was used as the donor medium, and Phosphate Buffered Saline (PBS) was used as the acceptor medium. Lipoid S100/n-Dodecane solution (1 g/50 mL) was prepared as an artificial lipid membrane solution and coated on the insert. Ex vivo permeability test was conducted in Franz cells using porcine mucosa as previously reported [3]. The samples were collected at predetermined time points, then diluted with methanol for HPLC-UV analysis. In addition, particle size analysis, scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were performed for solid state characterization.

Results: The Phase solubility study showed that HP-Beta-CD can be a solubilizer of poorly water soluble donepezil [Fig.1A]. In the PAMPA and porcine mucosal permeability study, the solubilized Donepezil + HPBCD formulation containing a solubilizer has better permeability than raw donepezil. In addition, DSPC showed the highest permeability enhancement effect, so that it was selected as a suitable permeation enhancer [Table 1 and Fig.1B]. Among the formulations prepared by the SE method [Fig.1C], only samples obtained in the solid state were selected for the evaluation of drug permeability using PAMPA system. As a result, PS-5 formulation of showed higher permeability than that of other formulation screening samples.  In the results of PAMPA permeability test [Table 1 and Fig.1C], the J and Kp values of SAS-5 were higher than that of FS-5, suggesting that the formulation made with SAS showed higher permeability than the formulation made with SE. DSC showed that raw donepezil was crystalline, whereas the particles prepared with SE and SAS were amorphous with no peak for the drug. Looking at the SEM and PSD results [Fig.2A and 2C], the volume mean diameters (VMD) of raw donepezil, FS-5 and SAS-5 particles were 16.61um, 15.96um and 0.74um, respectively. The main reason that FS-5 has a higher permeability than that of raw donepezil is probably due to its amorphous state unlike the crystalline state of raw donepezil [Fig.2B]. Furthermore, the higher permeability of SAS-5 than FS-5 can be explained by the relatively reduced particle size down to nanometers despite being the same amorphous state of two different samples [Fig.2C].

Conclusion: It was revealed that donepezil solid particle formulation containing HPBCD and PSPC as a solubilizer and permeation enhancer, respectively, has a effect of nasal mucosa permeability enhancement of donepezil. In addition, decreased particle size and formation of amorphous state also can increased the permeability of donepezil. Consequently, it is suggested that SAS processed dry powder formulation with HPBCD and DSPC can be an effect way to improve the nasal mucosal permeability of donepezil,, which shows that it can be used for nose-to-brain delivery. As a further study, it is planned to perform the comparative evaluation of the nasal cavity deposition of SAS and SE processed nano/microparticles and stability study of amorphous solid particle.

References: 1. Al Harthi, S., Alavi, S. E., Radwan, M. A., El Khatib, M. M., & AlSarra, I. A. (2019). Nasal delivery of donepezil HCl-loaded hydrogels for the treatment of Alzheimer’s disease. Scientific Reports, 9(1).
2. Hong, S.-S., Oh, K. T., Choi, H.-G., & Lim, S.-J. (2019). Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives. Pharmaceutics, 11(10), 540.
3. Carvalho, F. C., Campos, M. L., Peccinini, R. G., & Gremião, M. P. D. (2013). Nasal administration of liquid crystal precursor mucoadhesive vehicle as an alternative antiretroviral therapy. European Journal of Pharmaceutics and Biopharmaceutics, 84(1), 219–227.
4. Abuzar, S. M., Hyun, S.-M., Kim, J.-H., Park, H. J., Kim, M.-S., Park, J.-S., & Hwang, S.-J. (2018). Enhancing the solubility and bioavailability of poorly water-soluble drugs using supercritical antisolvent (SAS) process. International Journal of Pharmaceutics, 538(1-2), 1–13.

Acknowledgments: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (2016R1A6A1A03007648). This work was also supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (2022R1C1C1010130).

Fig.1 (A) Phase solubility diagram of donepezil as a function of HP-Beta-CD concentrations at different temperatures, 298.15, 310.15 and 318.15 K (n = 3). (B) Permeability test results using ex vivo Porcine Nasal Mucosal and PAMPA Model for phospholipid screening(PS) samples. (C) Permeability test results using PAMPA Model for formulation screening(FS) samples



Fig.2 (A) SEM images of Raw donepezil, SE(FS-5), SAS(SAS-5) samples. (B) DSC thermograms of Raw donepezil, Raw HPBCD(HP-Beta-CD), SE(FS-5), SAS(SAS-5) samples. (C) Particle size distribution (PSD) of Raw donepezil, SE(FS-5), SAS(SAS-5) samples.



Table.1