The objective of this study was to examine and compare how hydrophilic beta-cyclodextrin derivatives (beta-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of beta-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-beta-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-beta-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-beta-cyclodextrin with a degree of substitution of the sulphobutyl group of 3.9 (SBE4-beta-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8 h. The bioavailability of the insulin/SBE4-beta-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-beta-CyD may be in part due to the inhibitory effects of SBE4-beta-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-beta-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.
Various solubilizing agents for YM466, a new Factor Xa inhibitor, were investigated to begin designing the aqueous formulation for subcutaneous administration. The tentative target concentration was 5 mg/mL. First, three kinds of buffer solutions (glycine-HCl, citrate, and lactate) were examined for their solubilizing effects. The dissolution rate of YM466 in lactate buffer was the fastest, as determined by visual examination at room temperature. The dissolution rate of YM466 in lactate buffer was enhanced, without degradation, by heating at 40 degrees C, and YM466 solution at a concentration of 1 mg/mL became transparent 10 min after the start of heating. The solubility of YM466 increased along with lactate concentrations ranging from 50 mM to 200 mM and reached a high of 1.3 mg/mL after increasing lactate concentration to 200 mM at 5 degrees C. The addition of cyclodextrins beta-cyclodextrin (beta-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and gamma-cyclodextrin (gamma-CD), but not alpha-cyclodextrin (alpha-CD), had remarkable impact on its solubility, and 7-8 mg/mL of YM466 was dissolved by the addition of HP-beta-CD or gamma-CD. These results demonstrated that YM466 was included in cyclodextrins and that the inclusion formations required a cavity size larger than alpha-CD. Based on the calculation from the linear portion of the phase solubility diagrams, apparent stability constants of alpha-CD, beta-CD, HP-beta-CD, and gamma-CD at 5 degrees C were estimated to be 2M(-1), 206M(-1), 143M(-1), and 276M(-1), respectively. Therefore, we found that gamma-CD has the largest inclusion capacity.
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