Maleylated bovine serum albumin (Mal-BSA), an anionic modified BSA, is known to inhibit fractionated heparin (FH) uptake mediated by scavenger receptors and similar in Kupffer cells and parenchymal cells isolated from the liver, the major distribution organ of FH. In the present study we therefore examined if it would modulate FH disposition in vivo by administering FH to rats intravenously with or without Mal-BSA. The elimination of FH (0.55 nmol/kg) from plasma was found to be significantly delayed by 30 nmol/kg of Mal-BSA and slightly further by 300 nmol/kg of Mal-BSA. The delay in FH elimination was mainly due to a decrease in the total clearance, though a slight increase in the volume of distribution was also observed. Consistent with the earlier findings in vitro, we found that the clearance of unidirectional hepatic uptake, which accounted for a significant part of the total clearance, was extensively reduced by Mal-BSA. It was also suggested that Mal-BSA inhibited FH uptake not only in the liver, but also in some other tissues, which would mean a significant contribution of scavenger receptors or similar in the distribution of FH to those extrahepatic tissues. Thus the present study demonstrated that Mal-BSA could modulate FH disposition in vivo, presumably by inhibiting unidirectional tissue uptake by scavenger receptors and the like. The information obtained in this study is helpful for an understanding of the disposition mechanism of FH and of anionic macromolecules and for the development of delivery strategies.

We examined the physical properties of tablets prepared by the direct compression of a mixture of surface-modified ibuprofen with light anhydrous silicic acid (200FAD) by the method established in our previous paper (Y. Kato, et al., J. Pharm. Sci. Technol., Jpn., 61 (3), 109-118 (2001)), a disintegrant, and other excipients. The disintegrants were chosen from derivatives of starch, of a synthetic polymer of polyvinylpyrrolidone, and of cellulose. The disintegration mechanism, disintegration time, and hardness of tablets were greatly affected by the kind and amount of disintegrant, the physical properties of the drug, and the formulation. The effect of compression force differed with the kind of disintegrant. Tablets containing some disintegrant swelled under humidity when stored in a nonpackaged state. Therefore it was found that rapidly disintegrating tablets could be designed to suit the needs of individual patients to improve compliance, by a choice of a suitable disintegrant for the properties of the desired tablets or by a combination of disintegrants with different properties.

In dissolution testing for the formulations of low-solubility drugs, generally surfactants are added to dissolution test media to obtain “sink conditions” where all amounts of the drug should dissolve. In Japan, polysorbate 80 (PS80) is recommended as a surfactant, but we experienced such inconsistency that the dissolution behavior of formulations was contrary to their absorbability (AUC values) when administered to beagle dogs. It was thought that surfactants not only solubilized low-solubility drugs, but also influenced the disintegration/dissolution behavior of formulations. Therefore, we examined the effect of PS80 on physical properties of the formulation and investigated the condition of dissolution test media that decreased the effect of PS80. Formulations created with HPC and HPMC were found to be affected by PS80. This phenomenon was caused by interaction between water-soluble celluloses and PS80. Further study was done by the use of HPC, a widely used excipient, the interaction was caused by a conformation of the side chain of PS80, especially, oleic acid residue. From these results, we suggested that the addition of sodium oleate or the use of surfactants having no oleate was an effective way to reduce the interaction between formulations and surfactants.

We measured the current perception threshold (CPT) before and 2 h after an application of 9% lidocaine ointment on healthy subjects and investigated the effect of this ointment on sensory nerve function. The application of 9% lidocaine ointment significantly decreased the CPT within site ratios: 2 kHz/5 Hz (11.20±2.07 (0 h), 3.54±0.26 (2 h); p<0.01), 2 kHz/250 Hz (4.39±0.36 (0 h), 2.64±0.14 (2 h); p<0.01), and 250 Hz/5 Hz (2.71±0.56 (0 h), 1.36±0.11 (2 h); p<0.05), compared with those immediately before the application (0 h). The rate of change in CPT was highest at 5 Hz (4.36±1.04); the rate then decreased in the order of 250 Hz (2.25±0.27) and 2 kHz (1.31±0.09). These findings showed that an application of 9% lidocaine ointment decreased the sensory nerve function and that the A δ fiber and C fiber rather than the A β fiber may be closely involved in this reduction of the sensory nerve function. The experiment was also performed with 10% lidocaine cream, which is clinically used for postherpetic neuralgia, and this concentration reduced the sensory nerve function to a degree similar to that caused by 9% lidocaine ointment. The 9% lidocaine ointment may be an effective topical agent indicated for postherpetic neuralgia.

Highly functional excipients including cellulose derivatives have been developed recently, and it has been reported that the use of these materials may make tablets show excellent workability as well as disintegration. Microcrystalline cellulose and powdered cellulose, in general, are representative excipients using cellulose as the raw material. In this study, powdered cellulose in particular was examined. The workability and disintegration of powdered cellulose were measured to examine its usefulness as an excipient. A standard formulation (prepared by mixing and granulating lactose and corn starch in a ratio of 7:3) was used as the control material. As a result, the addition of powdered cellulose made it possible to obtain functionally excellent tablets. In other words, tablets containing powdered cellulose showed higher hardness and faster disintegration in comparison with the standard formulation. Based on these results, it was found that powdered cellulose is a useful and functional excipient if added to the formulation in proper quantities.

An injectable formulation of E5880, a novel platelet activating factor receptor antagonist, was designated from the study of pH-stability, the selection of excipient, and the relationship between moisture and stability. The physicochemical properties of E5880 micelles in the optimized formulation (0.6 mg/ml of E5880, 0.1% citric acid, 10% lactose, pH 2.8) were characterized. The critical micelle concentration of E5880 in the formulation was 0.09 mg/ml, and the structure was spherical. The micellar size was approximately 5 nm and did not change before or after lyophilization and storage. The number of molecules per micelle was 40. The micropolarity around the hydrocarbon region of the micelle was similar to that of butanol.