A new method based on gastrointestinal transit kinetics has been developed for estimation of the absorption profiles of drugs administered orally as aqueous solutions. The utility of the method was evaluated in rats. The gastrointestinal transit profile for each segment was estimated by in-vivo studies using phenol red, an unabsorbable marker. The gastrointestinal transit profile of phenol red was well explained by a linear gastrointestinal transit kinetic model with eight segments. We also introduced the absorption process into the gastrointestinal transit kinetic model and the plasma profile was predicted by the convolution method. The absorbability of drugs in each segment was assessed by an in-situ absorption study. The validity of the model was evaluated for model drugs with different absorption characteristics. The plasma profiles predicted for ampicillin, theophylline and cephalexin were in good agreement with those observed. The overestimated plasma profile of propranolol suggests that the low bioavailability of propranolol is a result of first-pass metabolism by the intestine wall and the liver, because the calculated absolute absorption is almost perfect. This proposed model is also suitable for estimation of segmental absorption, which is useful for the development of drug delivery systems. We have demonstrated that the plasma profile of orally administered drugs can be predicted by use of gastrointestinal transit and segmental absorbability information and that this method is especially useful for estimating separately the effect of absolute absorption and first-pass metabolism on the bioavailability of drugs.

The effect of gastrointestinal (GI) transit rate on the absorption behavior of orally administered drugs was investigated using rats pretreated with propantheline. The propantheline-treatment reduced the transit rate in all segments to approximately 50%. The absorption behavior was examined for three model drugs with different absorption characteristics: theophylline as a highly absorbable drug without the first-pass elimination, ampicillin as a poorly absorbable one, and cephalexin as a highly absorbable one via carrier-mediated transport system. In the GI transit-retarded state, the Tmax of the plasma concentration-time curve was delayed in all the three drugs. However, the extent of bioavailability was not changed in theophylline and cephalexin. On the other hand, the extent of bioavailability of ampicillin was increased in rats pretreated with propantheline. This might be caused by the increased residence time in the absorption site, i.e., small intestine. These results were generally predicted by use of the convolution method based on the GI-Transit-Absorption Model, which was developed in our previous study, using the GI transit rate parameters in rats pretreated with propantheline. The analysis using this model could clarify that the substantial absorption site of cephalexin moved to the upper region of the small intestine by the reduction of the GI transit rate.

The gastrointestinal (GI) transit and absorption of orally administered theophylline, a highly absorbable drug without presystemic elimination, were investigated under fasted and fed conditions using three rats in a crossover study. To evaluate the GI transit rate for each segment in vivo, a noninvasive technique, gamma scintigraphy, was employed using a nonabsorbable compound, Tc-labeled diethylenetriamine pentaacetic acid (DTPA). Using a gamma scintigraphic technique it is possible to simultaneously evaluate the GI transit and absorption of orally administered drug in the same individual. Theophylline was simultaneously administered along with [ 99m Tc]DTPA to animals in the fasted and fed states. Each GI transit pattern, simulated using the GI transit±kinetic model with a lag time factor, was well ®tted to the experimental data. Gastric emptying rate varied in each study, even under the same experimental condition. The GI transit pattern for each segment was highly variable, especially in animals in the fed state. This inconsistency in transit pattern was mainly due to the variability in gastric emptying, which was much slower in animals in the fed compared with the fasted state. However, in spite of a large variability of GI transit kinetics, the plasma concentration±time curves of theophylline were well predicted by the GI transit±absorption model using the individual GI transit parameters obtained in the study. The absorption rate of theophylline was considerably reduced in animals in the fed state, because of the reduction of gastric emptying rate. Analysis using GI transit±absorption model and gamma scintigraphic technique made it possible to estimate the variable absorption kinetics regulated by GI transit with huge variability. ß

Porous spherical calcium carbonate (PS-CaCO(3)), in contrast to regular calcium carbonate (CaCO(3)), which has a cuboidal particle shape, has a characteristic spherical particle shape with a large number of porous, sliver crystals. The effect of PS-CaCO(3) as a drug carrier on intranasal insulin absorption was investigated in cynomolgus monkeys and healthy human volunteers. Each insulin formulation (powder) containing PS-CaCO(3) or regular CaCO(3) was administered intranasally. Serum insulin and glucose levels after administration were evaluated. The insulin absorption after intranasal administration with each CaCO(3) was found to be much more rapid than that after subcutaneous administration. The serum insulin level after intranasal insulin delivery (16 U per monkey) with PS-CaCO(3) showed a higher C(max) (403.5 microU/mL) and shorter T(max) (0.167 h) when compared with regular CaCO(3). The serum glucose level reduction rate after intranasal delivery using PS-CaCO(3) was faster than that of regular CaCO(3), reflecting the difference in absorption rates. Following repeated intranasal administrations for 4 weeks in monkeys, no toxicity was observed even with a maximum insulin dose level of 25 U. Furthermore, the intranasal insulin absorption rate with PS-CaCO(3) in healthy humans was also observed to be considerably faster than that with regular CaCO(3). Effects of PS-CaCO(3) on a more effective absorption behavior of insulin were considered to be the result of a greater affinity between the nasal mucosa layer and PS-CaCO(3), which is closely related to its structural characteristics. Thus, intranasal insulin delivery using PS-CaCO(3) is thought to be a safe and highly available system enabling more effective insulin absorption behavior with the appearance of endogenous postprandial insulin secretion in healthy humans. We believe that our intranasal insulin delivery system enabling a rapid and short-acting pharmacological effect against postprandial hyperglycemia will be more beneficial than pulmonary insulin delivery systems in the treatment of diabetes.

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The PK and stability data suggests that IN administration of oxytocin formulated in the μco™ carrier may represent a viable option for rapid systemic absorption in humans and a product compatible with resource-scarce regions.

An immune response for a nasal ovalbumin (OVA) powder formulation with an applied nasal delivery platform technology, consisting of a powdery nasal carrier and a device, was evaluated in monkeys with similar upper respiratory tracts and immune systems to those of humans, in order to assess the applicability to a vaccine antigen. Nasal distribution and retention studies using a 3D nasal cavity model and manganese-enhanced MRI were conducted by administering nasal dye and manganese powder formulations with the applied technology. Systemic and mucosal immune responses for the nasal OVA powder formulation were evaluated by determining serum IgG and nasal wash IgA antibody titers. The nasal dye and manganese powder formulations showed wider distribution and longer retention time than did a nasal liquid formulation. The nasal OVA powder formulation also showed comparable and higher antigen-specific IgG antibody titer to an injection and nasal liquid formulation, respectively. Furthermore, antigen-specific IgA antibody response was detected only for the nasal OVA powder formulation. The present study suggests that the technology, originally designed for drug absorption, is promising for nasal vaccines, enabling both a mucosal immunity response as the first line of defense and systemic immunity response as a second line of defense against infection.