(W1130-11-74) Pre-clinical and Clinical Evaluation of a Weekly Donepezil Transdermal Patch

Purpose: Donepezil is available orally for the treatment of- Alzheimer’s Disease (AD), however, patient’s compliance is poor due to gastrointestinal adverse effects that may be associated with the oral route. The transdermal delivery of once-weekly donepezil is advantageous in reducing the dosing frequency and improving the tolerability by reduced fluctuation of plasma levels, compared to oral route of administration. Therefore, a weekly donepezil patch currently under development to improve patient’s compliance.

Methods: Styrene–isoprene–styrene (SIS) block copolymer - based donepezil transdermal patch was manufactured by matrix-based fabrication method. Physicochemical properties of the patch were characterized, including drug content, uniformity, residual solvent, dissolution and stability test. In vitro skin permeation was measured for 7-day using Franz diffusion cell with human skin. The cumulative amount of donepezil in the receptor phase was analyzed by high-performance liquid chromatography (HPLC). For in vivo pharmacokinetics studies in rabbits, the plasma concentrations of donepezil were quantified for 48 hours after single dosing of Aricept® Tab. 10 mg through the oral route, or for seven days after single-application of the donepezil patches (80mg/patch or 120mg/patch), by LC-MS/MS. To assess skin sensitization effects of the donepezil patch in guinea pigs, weekly patch and placebo patch were applied to the skin and then skin sensitization was evaluated skin reactions of 24 and 48 hours after removal of the irritation. To examine the toxicity of the application site, the donepezil patches (170 and 340 mg/head/week) were applied transdermally for 14 weeks (7-week cycle x 2) by dividing the male Göttingen A/S minipigs back into two and it was placed on the back in vivo preclinical safety study. The donepezil patch was applied to healthy adults and, its pharmacokinetics compared with Aricept® Tab. 10 mg.

Results: The donepezil patch was manufactured with precise control of drug dose and uniformity. Donepezil permeated through human skin over a period of 7 days. Approximately 60~70% of donepezil in the patch permeated transdermally through the human skin for 7 days at a constant rate. After application of the donepezil patch in rabbits, PK profiles were observed in a dose-dependent manner and the normalized bioavailability of patch was calculated to be the same level of exposure as the oral Aricept® at 10 mg. In order to examine the toxicity of application site, donepezil patch was transdermally applied for 14 weeks. As a result of skin irritation analysis on the donepezil patch, erythema was observed, but the irritation index was less than 2, and no edema was observed. The recovery of skin irritation was time-dependent, and the average recovery time to normal was about 3 days. There were no abnormalities or specific adverse events detected during the 14 weeks. In the human study of donepezil patch after single dosing in healthy subjects, the Cmax and AUC_last of patches was proportional to the dose of donepezil with acceptable skin tolerability.

Conclusion: Donepezil patch is currently under development as a weekly type that can be stored at a room temperature. Sustained transdermal delivery of donepezil from nonclinical and clinical study were supported the feasibility of a convenient, safe and effective once-weekly dosing regimen as compared to daily oral treatment.

Acknowledgements: This research was supported by the Senior-friendly Product R&D program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI16C1960)