Nasal administration has gained much attention by many researchers within the last few decades because of its great potential utility for rapid drug delivery.1-3) It offers an attractive alternative for drugs that have limited oral bioavailability, are destroyed by gastrointestinal (GI) fluid, or are highly susceptible to hepatic first pass or gut-wall metabolism. 4)

The aim of this research is to clarify the influence of the viscosity of the nasal formulation on in vivo nasal drug absorption and its mechanism using an in vitro Caco-2 system. The drug solution was made viscous by the addition of dextran (Dex). The disappearance of FITC-labeled Dextran (FD, a marker of the dosing solution) applied with control solution followed monoexponential kinetics, while FD applied with Dex solution showed biexponential elimination. The mean residence time of FD in the nasal cavity was increased with the increase in Dex concentration. The nasal absorption of acyclovir was similar in the formulation with low viscosity, increased in the formulation with moderate viscosity and markedly decreased in the formulation with high viscosity. The result from the normal Caco-2 transport study could not explain the relation of in vivo drug absorption with viscosity, while the modified Caco-2 system provided data partly reflecting the change in in vivo absorption in rats. In conclusion, the residence of the applied solution in the nasal cavity was enhanced by the addition of Dex in a viscosity-dependent manner. Moderate viscosity of the dosing solution improved the in vivo nasal absorption of acyclovir, while higher viscosity decreased it.

In the last few decades, nasal administration has received a great deal of attention as a rationale for the systemic delivery of many drugs.1) The range of compounds investigated for possible nasal application varies greatly from very lipophilic drugs to polar, hydrophilic molecules including peptides and proteins.2) The relatively high permeability of the nasal epithelium, its high vascularization and the avoidance of hepatic first-pass metabolism makes nasal application a promising alternative, especially for drugs exhibiting high metabolism in the intestine and/or liver.Oral drug absorption can be estimated from in vitro transepithelial transport across the Caco-2 monolayer with various systems.3-5) These systems are responsible for screening of huge number of new drug candidates which are synthesized through combinatorial chemistry and pharmacologically screened with an in vitro high throughput system. Although nasal administration has been considered important as an alternative to oral application, as mentioned above, no prediction system has been developed so far. A prediction system would greatly help the development of nasal medications.Some respiratory epithelial cells possess cilia on their surface. The cilia beat in a coordinated fashion to transport the mucous layer, which covers the surface of the epithelium, to the nasopharynx, where it is swallowed. [6][7][8] The combined action of the mucus layer and cilia is called mucociliary clearance (MC). It is an important nonspecific defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. Due to MC, drugs applied to the nasal cavity are translocated to the nasopharynx and, thereafter, to the gastrointestinal (GI) tract, together with the mucus layer. Some fraction of the nasally-administered drug undergoes absorption from the GI tract. In order to develop a predictive system for fractional drug absorption after nasal application, the kinetic characteristics of mucociliary clearance must be clarified and correctly combined in the kinetic model.In the previous manuscript, 9) five non-degradable drugs were selected as model drugs and their fractional absorption following nasal and oral application, and their permeability to the Caco-2 monolayer (P Caco-2 ) were examined. The methods for the calculation of fractional absorption from the nasal cavity and from the GI tract after nasal application were also described. The relationship between fractional absorption and P Caco-2 was discussed, and the feasibility to predict drug absorption following nasal administration from P Caco-2 was indicated. The first aim of this research is to clarify the details of MC. For this purpose, the surgical operation reported by Hirai et al. 10) was not done on the esophagus and trachea, and the animal was kept conscious for as long as possible during the animal study. Based on the information on MC, the second aim is to propose a kinetic model to predict drug absorption following nasal application to rats from P Caco-2 . Various fractiona...