The oral bioavailability of water-soluble and macromolecular drugs is generally poor because they are impermeable through the intestinal mucosa. Therefore, various approaches have been examined to overcome the delivery problems of these drugs when they administered to the gastrointestinal tract and other mucosal sites. These approaches include (1) to use additives such as absorption enhancers, (2) to modify the molecular structure of these drugs to produce prodrugs and analogues, and (3) to use the dosage forms of these drugs. In addition, (4) the use of an alternative route including pulmonary administration is also promising strategy to improve the absorption of these drugs. In this study, we demonstrated that transmucosal absorption of poorly absorbable drugs could be improved by using these approaches. Therefore, these approaches may give us basic information to improve the transmucosal absorption of poorly absorbable drugs.

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We investigated the action mechanisms of absorption enhancers that improve paracellular and transcellular drug transport. For sodium caprate (C10), the increase in the intracellular calcium level was considered to induce the contraction of calmodulin-dependent actin filaments, followed by expansion of the paracellular route. Although decanoylcarnitine (DC) also increased the intracellular calcium level, the action was independent of calmodulin and thus, the action mechanism of DC was considered to differ from that of C10. DC and Tartaric acid (TA) decreased the intracellular ATP level and the intracellular pH. From these results, it was considered that one of the action mechanisms of DC and TA is that the intracellular acidosis increases the calcium level through decrease in ATP levels, followed by opening the tight junction (TJ). TA and pirotiodecane (PD) also increased the transcellular transport based on the functional changes of P-glycoprotein (P-gp) in addition to TJ opening. In particular, TA increased the absorption of rhodaminel23 (Rho123) and daunorubicin in the ileum without TJ opening and changes of expression level of P-gp. On the other hand, TA significantly inhibited the excretion of Rho123 from blood to lumen. These results suggest that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without changing the expression of P-gp in the rat intestine. PD had enhancing effects on nasal and intestinal absorption of rhodamine123 based on functional changes of P-gp. Consequently, we showed the expansion of TJ and inhibition of P-gp increase intestinal absorption of hydrophilic compounds and P-gp substrates.

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Recently, it became clear that drug transporters are closely related to pharmacokinetics, and it has been recognized that the transporters are the important factor for determining drug bioavailability. On the other hand, in a viewpoint of drug delivery system, drug pharmacokinetics are thought to be controllable by manipulating the function of transporters. This review introduces how intestinal active drug influx or efflux transport system is concerned with drug pharmacokinetics, with a focus on the transporters of intestine. In addition, the possibility to control oral bioavailability by manipulating the function of transporters will be discussed.

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A number of therapeutically important protein and peptide drugs have been actively developed. However, there are considerable hurdles to be overcome before practical use can be made of these drugs due to chemical and enzymatic instability and poor absorption through biological membranes. Many attempts have addressed these problems by chemical modifications or by delivery systems for these drugs. This review outlines the current application of cyclodextrins in enhancement of transmucosal absorption for these drugs.

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The lung is an attractive organ to administer proteins and peptides, which are poorly absorbed from the gastro-intestinal tract. Adding an absorption enhancer is a promising method to increase systemic bioavailability of inhaled peptides and proteins. A combination of insulin powder and citric acid powder showed improved hypoglycemic activity without deteriorating effect of citric acid on insulin stability. Spray drying is a useful and widely applied technique to prepare powders for inhalation. Supercritical fluids have recently been applied for producing powders for inhalation. Selecting operating conditions and adding proper additive such as sugars would produce hollow porous particles, which are easily dispersed and avoid phagocytic clearance in lung, with maximized chemical and physical stability.

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Recently skin has been much attention as a site of administration of systemically active drugs. Transdermal route offers a number of potential advantages, e.g., avoidance of first-pass liver metabolism and continuous and consecutive long term drug therapy. However, the skin permeation of therapeutic drugs was extremely low, so that approaches to appropriate enhancement are necessary to be a useful delivery systems. Physical and chemical technologies are utilized to improve skin permeation of drugs. Recent advanced technologies would enable transdermal delivery of macromolecules such as peptide, protein, and oligonucleotides as well as low organic drugs.

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The present study aimed to evaluate the potential usefulness of nasal route for brain delivery of poorly soluble drug, dexamethasone. Dexamethasone was solubilized using water-soluble cyclodextrin (W-CD), mono-maltosyl-β-cyclodextrin (GCD), and high concentration of dexamethasone (1.57%) was prepared. Nasal absorption study was conducted in rats using an improved in situ nasal deposit method. The serum dexamethasone concentration increased rapidly following nasal administration of GCD based formulation and the bioavailability of dexamethasone was equal to that of intravenous administration. In addition, brain edema caused by a cryogenic brain injury was more significantly improved by nasal administration of the dexamethasone-GCD formulation than by intravenous administration, suggesting that dexamethasone was delivered to the brain via nasal route. The nasal delivery of dexamethasone using a cyclodextrin inclusion formulation may have potential for an alternative therapeutic strategy for the brain edema therapy.

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