The effect of acylation on the intestinal absorption and lymphatic transfer of lysozyme was investigated by an in situ closed loop method and an in vitro Ussing chamber method. The acyl derivatives of lysozyme were synthesized by chemical modification with various fatty acids to the lysine residues. The acyl derivatives of lysozyme were more lipophilic than the native lysozyme by high-performance liquid chromatography (HPLC). The activities and modified percentage of amino groups of acyl derivatives of lysozyme decreased as the carbon number of fatty acids increased. The intestinal absorption of lysozyme and its caproyl derivative was examined by in situ closed loops of rats. A significant increase in the cumulative amount of lymph fluid of caproyl derivatives was observed in comparison with that of the parent lysozyme. Neither compound was detected in plasma, however, which might have been due to the low plasma concentration of these compounds. The permeability of caproyl lysozyme was higher than that of native lysozyme by an in vitro Ussing chamber method, although the stability of these compounds were almost the same in phosphate-buffered saline, lymph fluid, and the homogenates of the small intestine. These findings suggested that acylation might be a useful approach for improving the lymphatic transport of macromolecular drugs, including lysozyme.

The release properties of theophylline (TP) from three different types of tablets were investigated, one using a carboxyvinylpolymer (Carbopol^®: CP) as a matrix material and/or as a coating material. CP-matrix tablets were prepared from TP, lactose, and CP by the direct compression method. CP-coated tablets were prepared by spraying an aqueous solution or dispersion of CP onto core tablets containing TP. CP-coated matrix tablets (CM tablets) were prepared by spraying CP aqueous dispersion onto CP-matrix tablets. TP release profiles from each type of the tablet were studied by the JP 13 paddle method, using JP 1st fluid (pH 1.2), purified water, and JP 2nd fluid (pH 6.8) as the dissolution media. The swelling behaviors of the tablets in each of the dissolution media were observed. When CP was used as a matrix material, TP release was retarded in the JP 2nd fluid. On the other hand, when CP was used as a coating material, the release was slowed in both JP 1st fluid and purified water. TP release from the CP-matrix tablet and CP-coated tablet varied depending on the addition amount and the grade of CP. When CP was used in the combination, TP release was retarded in all dissolution media. Furthermore the difference in TP release, depending on the dissolution medium, was decreased. These results suggest that it is feasible to control drug release in various pH environments by using CP as a matrix material, coating material, or both and by varying the addition amount and the grade of CP.

To clarify the mechanism of the transdermal absorption of ethenzamide ointment, which is used clinically as a hospital preparation for the pain relief of postherpetic neuralgia and chronic rheumatoid arthritis, we analyzed the relation of the amount of N-methyl-2-pyrrolidone (NMP) in the ointment to the absorption of ethenzamide by using hairless rats and human skin. Results in the in vitro experiments suggested that the addition of a small amount of NMP loosened the dermal barrier, thus enhancing the intradermal diffusion of ethenzamide. Furthermore, since NMP enhanced solubility of the ethenzamide in the ointment, it was proved that NMP plays important roles in solubility and absorption. The in vivo analysis of area-under-curve of blood concentration of ethenzamide and mean retention time in rats showed that the addition of NMP increases the absorption of ethenzamide into the body for a long period. The experiment in which ethenzamide ointment was applied to human skin also confirmed an enhanced absorption of ethenzamide. These results showed that NMP may be a clinically useful absorption enhancer and suggested the applicability of NMP to the transdermal absorption of many other drugs.

The performance qualification of prospective validation in the mixing and filling processes of suspensions was investigated for internal use. The drug contents of samples from tank and circulation piping during the mixing process were analyzed. The differences in these contents were within 5%, and the contents were within 90-110% (specifications). The time course of drug content and the filling volumes were measured during the filling process. Mean ± 3 σ calculated from the contents was within 90-110% (specifications). Moreover, the mean ± 3 σ calculated from the filling volumes were within 211-215 mL (specifications). Although the method of validation of manufacturing pharmaceutical preparations is generally invested independently in each manufacturer, the results of this study may offer useful information.