The concept of “nose-to-brain” drug delivery has attracted considerable attention because intranasally administered drugs can be delivered to the brain while bypassing the blood–brain barrier and using other unique pathways, as mentioned in several reviews [1], [2], [3], [4]. Drugs administered intranasally can be delivered to the brain via the olfactory nerve in the olfactory mucosal epithelium and/or the trigeminal nerve in the respiratory epithelium. It is also thought that administered drug molecules can enter brain tissue by passage through nasal mucosal epithelial cells and intercellular clefts to the cerebrospinal fluid. In addition, intranasal drug administration hold promises for reducing systemic side effects.

In this study, we focused on a nasal powder formulation for drug transfer to brain tissue. Intranasal administration of powder formulations has several potential advantages [5], [6], [7], [8]. For example, liquid formulations rapidly flow out of the nasal cavity, whereas powder formulations exhibit improved drug retention in the nasal cavity and allow drug administration at high doses. Additionally, the incorporation of excipient polymers impedes nasal mucociliary clearance and significantly improves nasal retention [9]. Powder formulations are considered safer than liquid formulations because their high physical stability does not require the addition of preservatives. However, intranasal administration of poorly water-soluble drugs can be limited by low aqueous solubility and low drug dissolution in the nasal cavity, representing a possible barrier to efficient drug delivery to brain tissue. Therefore, improved intranasal formulations for poorly-water soluble drugs are necessary.

Amorphous solid dispersion (ASD) involves dispersion of one or more active pharmaceutical ingredients (APIs) in an inert carrier matrix in the solid state [10]. A number of ASD drug formulations have been studied for improving the solubility and gastrointestinal absorption of water-insoluble drugs. ASD retains drug particles or molecules in a high-energy amorphous state [11]. As such, amorphous drugs exhibit higher aqueous solubility compared with crystalline drugs, resulting in increased drug absorption [12]. In the present study, solvent evaporation and spray-drying methods were utilized to prepare an ASD intranasal formulation. Solvent evaporation is a simple and established method for preparing lab-scale samples of ASD drugs. It is useful for screening small amounts of samples. In contrast, spray-drying is extensively utilized for the preparation of powder-based pharmaceutical products, including ASD drugs. An important advantage of the spray-drying method is its cost-effectiveness and scalability [13]. Another advantage is that it enables facile preparation of microparticles with a narrow particle-size distribution [14]. In addition, spray-drying enables control of the physical properties of powder samples. The rapid preparation afforded by spray-drying not only suppresses the growth of drug crystals but also facilitates the production of amorphous drugs particles [15]. Thus, although intranasal ASD formulations have useful properties with regard to drug delivery, they have not been adequately studied to the best of our knowledge.

The purpose of this study was to evaluate the effect of intranasal administration of ASD-based formulation on the drug transfer into brain tissue and to investigate in vitro and in vivo characteristics of ASD-based formulation. Carbamazepine (CBZ), an antiepilepsy drug, was used as a model of a poorly water-soluble drug. We investigated whether an ASD formulation of CBZ exhibits improved drug dissolution, absorption, and transfer to the brain. In the beginning of this study, six commercially available excipient polymers were examined as water-soluble ASD carriers, and the characteristics and dissolution properties were investigated for the purpose of screening suitable ASD formulations. Selected ASD formulations were surgically administered into the nasal cavity of rats. In this study, intranasal administration was evaluated using 1) a CBZ suspension made by dispersing in PBS an ASD (ASD-1) formulation and 2) a spray-dried ASD powder formulation (ASD-2).