(W0930-11-75) Discovery and Development of Memantine Transdermal Patch

Purpose: Memantine is available orally for the treatment of- Alzheimer’s Disease (AD), however, patient’s compliance is poor due to once- or twice-daily dosing regimen with the oral route. The transdermal delivery of memantine twice a week is advantageous in reducing the dosing frequency by reduced fluctuation of plasma levels, compared to oral route of administration. Therefore, memantine patch currently under development to improve patient’s compliance.

Methods: After selecting pharmaceutical acceptable new salts through screening, acrylate copolymer - based memantine transdermal patch was manufactured by matrix-based fabrication method. Physicochemical properties of the patch were characterized, including drug content, uniformity, residual solvent, and long-term/accelerated stability test. In vitro skin permeation was measured for 72 hours using Franz diffusion cell with human cadaver skins. The cumulative amount of memantine in the receptor phase was analyzed by high-performance liquid chromatography (HPLC). For in vivo pharmacokinetics studies in rabbits, the plasma concentrations of memantine were quantified for 48 hours after single dosing of Ebixa® Tab. 10 mg through the oral route, or for three days after single-application of the memantine patches (60cm²/patch), by LC-MS/MS. To examine the skin irritation of the application site, the memantine patch (2.5 x 2.5 cm) was applied transdermally for 3 days in rabbits.

Results: After synthesizing 31 pharmaceutically acceptable and patentable new salts, one memantine salt was selected through solubility, skin permeability and impurity screening. The memantine patch was manufactured with precise control of drug dose and uniformity. The total impurities of patch were less than 0.2% at 6 months. Memantine patch also showed acceptable stability in long-term (25 °C, 60 %RH) and accelerated condition (40 °C, 75 %RH), revealing more than 97% of the drug unchanged after 6 months of the storage. Memantine permeated through human skin over a period of 3 days. Approximately 50% of memantine in the patch permeated transdermally through the human skin for 3 days at a constant rate. After application of the memantine patch in rabbits, the normalized bioavailability of patch was calculated to be the same level of exposure as the oral Ebixa® at 10 mg. In order to examine the toxicity of application site, memantine patch was transdermally applied for 3 days. As a result of skin irritation analysis on the memantine patch, erythema was observed, but the irritation index was less than 2, and no edema was observed. The recovery of skin irritation recovered within 48 hours after removing the patch. There were no abnormalities or specific adverse events detected during the experiments.

Conclusion: Memantine patch is currently under development as a twice weekly type that can be stored at a room temperature. Sustained transdermal delivery of memantine from nonclinical study were supported the feasibility of a convenient, safe and effective twice a weekly dosing regimen as compared to once- or twice-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)