This article is available online at http://dmd.aspetjournals.org ABSTRACT:Clinical studies have revealed that plasma concentrations of midazolam after oral administration are greatly increased by coadministration of erythromycin and clarithromycin, whereas azithromycin has little effect on midazolam concentrations.

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Although localization and retention of the drug to the absorption site are known to improve the bioavailability, there are few reports dealing with bioavailability problems. 3)Recently, we have developed mucoadhesive microspheres (Ad-MS) made of oppositely charged dextran derivatives and cellulose acetate butyrate, used as mucoadhesive polymers 4) and hydrophobic polymer, respectively. We confirmed that they adhered to the rat gastric mucosa by direct observation of the inner GI tract. Moreover, we evaluated GI transit patterns of microspheres after oral administration, and revealed that their gastric residence time was prolonged.2)The objective of this study was to evaluate Ad-MS for their ability to improve the bioavailability of drugs by comparison of the pharmacokinetics in both Ad-MS and non-adhesive microspheres (MS). Theophylline (TH) and thiamine disulfide (TDS) were selected as model drugs, having different absorption sites. TH is absorbable from the entire GI tract, 5) whereas the absorption site of TDS is limited to the upper part of the GI tract. . Sugar ester DK F-10 used as a surfactant was kindly supplied by Daiichi Kougyou Seiyaku Co. Ltd. (Kyoto, Japan). 7-(2-Hydroxyethyl)-theophylline (HETH, Tokyo Kasei Kogyo, Tokyo, Japan) was used as an internal standard for TH assay. Acid phosphatase (EC 31.3.2, Nacalai Tesque, Inc., Kyoto, Japan) was used for hydrolysis of thiamine esters. All other chemicals and solvents were of reagent grade and used as received.Preparation of Microspheres Microspheres were prepared by an emulsion solvent evaporation method, as follows. Drug (TH or TDS), DS and EA were dispersed in 15 ml of acetone containing 1 g of CAB, and then poured into 150 ml of liquid paraffin containing 1% w/v of sugar ester, at 20°C under agitation (300 rpm). The mixture was mechanically stirred under atmospheric pressure to form a w/o emulsion. After 30 min, the solution was heated to 50°C to evaporate acetone. Then the solution was gradually cooled at 20°C and then decanted off. The removal of residual oil was performed by washing the microspheres with 50 ml of n-hexane 3 times. The microspheres were dried under vacuum at room temperature. The microspheres sieved at 425-600 mm were used for further experiments. In the case of MS, DS and EA were not added to acetone. In addition, MS for TH, Lac was added to acetone in order to modulate drug release rate.Drug content of the microspheres was determined as follows. Ten milligrams of microspheres were dissolved (or dispersed) in 50 ml of methylene chloride. The solution was subjected to sonication at room temperature for 10 min. The resultant solution was filtered through a 0.2 mm membrane filter and analyzed spectrophotometrically at 274 nm for TH and 237 nm for TDS. All drug content determinations were Shinagawa-ku, Tokyo 142-8501, Japan. Received July 29, 2003; accepted September 19, 2003 Mucoadhesive microspheres made of oppositely charged dextran derivatives and cellulose acetate butyrate (Ad-MS) were evaluated for their ability to improve...