Effective nose-to-brain drug delivery using a combination system targeting the olfactory region in monkeys

The nose-to-brain (N2B) pathway has garnered attention because it transports drugs directly into the brain. Although recent studies have suggested the necessity of selective drug administration to the olfactory region for effective N2B drug delivery, the importance of delivering the formulation to the olfactory region and the detailed pathway involved in drug uptake in primates brain remain unclear. Here, we developed a combination system for N2B drug delivery comprising a proprietary mucoadhesive powder formulation and a dedicated nasal device (N2B-system) and evaluated it for nasal drug delivery to the brain in cynomolgus monkeys.

Highlights

• An effective combination system for nose-to-brain (N2B) drug delivery was developed.

• Monkeys were tested for N2B-system due to their similarity in human nasal anatomy.

• N2B-system achieved efficient formulation delivery to the olfactory region.

• Olfactory region is a suitable target for efficient N2B drug delivery.

This N2B-system demonstrated a much greater formulation distribution ratio in the olfactory region in an in vitro experiment using a 3D-printed nasal cast and in vivo experiment using cynomolgus monkeys, as compared to that in other nasal drug delivery systems that comprise of a proprietary nasal powder device developed for nasal absorption and vaccination and a commercially available liquid spray. Additionally, Texas Red-labeled dextran (TR-DEX, 3 kDa) was administered using the N2B-system to estimate the drug transition pathway from the nasal cavity to the brain. TR-DEX preferentially localized to the olfactory epithelium and reached the olfactory bulb through the cribriform foramina. Moreover, domperidone, a model drug with poor blood-brain barrier permeability, was administered to assess the brain uptake of medicine after olfactory region-selective administration by using the N2B-system. Domperidone accumulation in the brain was evaluated using positron emission tomography with intravenously administered [¹⁸F]fallypride based on competitive inhibition of the dopamine D2 receptor (D2R). Compared to other systems, the N2B-system significantly increased D2R occupancy and domperidone uptake in the D2R-expressing brain regions. The current study reveals that the olfactory region of the nasal cavity is a suitable target for efficient nasal drug delivery to the brain in cynomolgus monkeys. Thus, the N2B-system, which targets the olfactory region, provides an efficient approach for developing effective technology for nasal drug delivery to the brain in humans.

2.2. Formulations

The yellow dye tartrazine was purchased from FUJIFILM Wako Pure Chemical Corp. (Osaka, Japan). Manganese chloride tetrahydrate (MnCl₂·4H₂O) was purchased from Sigma-Aldrich (MO, USA). Texas Red-labeled 3 kDa dextran and lysine fixable (TR-DEX) were purchased from Thermo Fisher Scientific (Waltham, MA, USA). Domperidone maleate was purchased from Toronto Research Chemicals Inc. (Toronto, Canada). Powder formulations were prepared by mortar mixing each of the above substances with a proprietary carrier that included a specific type of microcrystalline cellulose as the main component (Ceolus® PH grade, Asahi Kasei Corp., Tokyo, Japan). The powder formulations used in the in vitro nasal distribution trial with a 3D-printed nasal model contained the yellow dye and had the following composition (yellow dye/carrier): 1.0 mg/24.0 mg, 1.5 mg/36.0 mg, 2.0 mg/48.0 mg and 3.0 mg/72.0 mg. The powder formulation with manganese used in the in vivo nasal distribution trial using living monkeys was composed of 1.0 mg of MnCl₂·4H₂O/24.0 mg of the carrier. For the immunohistological assessment of the nasal cavity, the powder formulation with TR-DEX had the following composition: 10.0 mg of TR-DEX/15.0 mg of the carrier. For PET imaging in living monkeys, the powder formulation with domperidone (domperidone maleate [an equivalent dose of domperidone-free base]/the carrier) used had the following composition: 2.1 mg (1.6 mg)/22.9 mg, 6.6 mg (5.0 mg)/18.4 mg, and 19.8 mg (15.0 mg)/17.7 mg. For delivery characteristics, nasal deposition, and PET imaging studies, the powder formulation without any substances (placebo powder formulation) had the following composition: 25 mg of the carrier. Liquid formulations were prepared by dissolving each of the mentioned substances in 1% (w/v) carboxymethyl cellulose (CMC) saline solvent, which was composed of sodium carboxymethyl cellulose (Cat No. 039–01335, Lot No. LEE6873, FUJIFILM Wako Pure Chemical Corp., Osaka, Japan) and physiological saline (Otsuka Pharmaceutical Factory, Tokushima, Japan). The liquid formulation with the yellow dye contained 1.0 mg of the yellow dye per 100 μL of the solvent. The liquid formulation with manganese contained 1.0 mg of MnCl₂·4H₂O per 100 μL of the solvent. The liquid formulation with TR-DEX contained 10.0 mg of TR-DEX per 100 μL of solvent. The liquid formulation with domperidone contained 6.6 mg (5.0 mg) of domperidone maleate (an equivalent dose of domperidone-free base) per 100 μL of the solvent. The liquid formulation with 100 μL of the solvent and without any of the above substances (placebo liquid formulation) was used for studying the delivery characteristics.

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Keita Sasaki, Shota Fukakusa, Yusuke Torikai, Chie Suzuki, Ikumi Sonohata, Takuto Kawahata, Yasuhiro Magata, Keiichi Kawai, Shunji Haruta, Effective nose-to-brain drug delivery using a combination system targeting the olfactory region in monkeys, Journal of Controlled Release, Volume 359, 2023, Pages 384-399, ISSN 0168-3659,
https://doi.org/10.1016/j.jconrel.2023.06.005.