Nose-to-brain delivery of tacrine

ABSTRACT In the treatment of Alzheimer's disease tacrine, a cholinesterase inhibitor, is not the drug of choice due to its low oral bioavailability, extensive hepatic first‐pass effect, rapid clearance from the systemic circulation, pronounced hepatotoxicity, and the availability of drugs better than tacrine in the same pharmacological class. Hence, the aim of this investigation was to ascertain the possibility of direct nose‐to‐brain delivery of tacrine to improve bioavailability, to avoid the first‐pass effect and to minimize hepatotoxicity. Tacrine solution (TS) in propylene glycol was radiolabelled with 99mTc (technetium) and administered in BALB/c mice intranasally (i.n.) and intravenously (i.v.). Drug concentrations in blood and brain were determined at predetermined time intervals post dosing. Drug targeting efficiency (DTE %) and the brain drug direct transport percentage (DTP %) were calculated to evaluate the brain targeting efficiency. Brain scintigraphy imaging in rabbits was performed to ascertain the uptake of the drug into the brain. Tacrine solution was effectively labelled with 99mTc and was found to be stable and suitable for in‐vivo studies. Following intranasal administration tacrine was delivered quickly (Tmax 60 min) to the brain compared with intravenous administration (Tmax 120 min). The brain/blood ratios of the drug were found to be higher for [99mTc]TSi.n. compared with [99mTc]TSi.v. at all time points. The DTE (207.23%) and DTP (51.75%) following intranasal administration suggested that part of tacrine was directly transported to brain from the nasal cavity. Rabbit brain scintigraphy imaging showed higher uptake of the drug into the brain following intranasal administration compared with intravenous administration. The results showed that tacrine could be directly transported into the brain from the nasal cavity and intranasal administration resulted in higher bioavailability of drug with reduced distribution into non‐targeted tissues. This selective localization of tacrine in the brain may be helpful in reducing dose, frequency of dosing and dose‐dependent side effects, and may prove an interesting new approach in delivery of the drug to the brain for the treatment of Alzheimer's disease.