Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer’s disease

Donepezil hydrochloride (DPH) is often used in the treatment of Alzheimer’s disease. A new treatment method was developed by encapsulating high DPH content in the tips of dissolving microneedles for rapid, transdermal delivery of a predetermined dose of DPH. The microneedles were prepared by a micromolding method using a hydroxy-propyl-methyl-cellulose (HPMC)-ethanol/water mixture (80:20, v/v) for the tips and carboxy-methyl cellulose (CMC)-water for the base of the needles. The micromolding method involved centrifuging a DPH-HPMC-ethanol/water mixture at 10 °C to obtain tips with sufficient mechanical strength. To test their mechanical strength, microneedles with different DPH content were inserted into porcine skin. Then the amount of DPH encapsulated in the microneedles was measured using high-performance liquid chromatography. The efficiency of administering DPH tip-loaded microneedles was investigated using four administrations of a pharmacokinetic test: (1) two oral administration groups (283 μg/kg and 692 μg/kg) and (2) two microneedle administration groups (283 μg/kg and 692 μg/kg). High DPH content (up to 78%, w/w) was encapsulated in the microneedle tips without serious loss of mechanical strength by using a mixture of hydroxy-propyl-methyl-cellulose (HPMC) and ethanol/water mixture (80:20, v/v). Because of the distribution of DPH in the tips, 95% of the DPH was delivered into porcine skin after 5 min of insertion. As measured by Cmax and AUC, transdermal delivery of DPH tip-loaded microneedles was more effective compared to oral administration of the same dose of DPH. Transdermal delivery could replace oral administration of DPH.

Graphical abstractDescriptive figure of a donepezil hydrochloride (DPH) tip-loaded microneedle for treatment of Alzheimer’s disease (a) after insertion into skin and (b) after dissolution in skin and adsorption of donepezil hydrochloride into blood capillaries for systemic delivery. Because DPH was located only in the microneedle tips, most of the DPH was delivered into the skin within 5 min after insertion. DPH content of 78% in 100 microneedles tips, placed on a 0.49 cm2 plate, provided the possibility for the clinical application of DPH.Figure optionsDownload full-size imageDownload high-quality image (218 K)Download as PowerPoint slide