In the production of pharmaceuticals, magnesium stearate is used widely as a useful lubricant for tableting because it is inexpensive and has outstanding lubrication properties. However, the addition of magnesium stearate to tablets causes a decrease in tablet hardness and increases the disintegration time because of its poor affinity to water. These properties will affect the pharmacokinetics of the medicinal substance. Furthermore, there is some concern recently that magnesium stearate coming from animals has been contaminated by BSE. Therefore, sugar fatty acid esters have attracted much attention as a substitute for magnesium stearate, and are being used widely as an additive agent for food materials. In this paper, the applicability of sugar fatty acid ester and glycerol ester (compritol) as lubricants in the produciton of pharmaceuticals was discussed and a comparison of properties was made with magnesium stearate. Consequently, when sugar fatty acid ester was used as a lubricant, the optimal concentration range was about 1.0-2.0%. It was also found that sugar fatty acid ester and glycerol ester have only a slight influence on both tablet hardness and dissolution time as compared to magnesium stearate.

The present study investigated leaching mechanisms of di-(2-ethylhexyl) phthalate (DEHP) from polyvinyl chloride (PVC) tube during the administration of enteral nutrition, an Ensure Liquid^® (EL) solution. The leaching amount of DEHP was found to be proportional to both the area and the time in which the PVC membrane and EL solution are in contact. The apparent dissolution rate constant, k (μg/h/cm²), was affected by the concentration of the EL solution, DEHP content of the tube and temperature. Leaching of DEHP was assumed to involve the following mechanisms: (a) DEHP on the surface of the PVC membrane dissolves into the EL solution; (b) Dissolved DEHP distributes among corn-oil particles in the EL solution; and (c) DEHP diffuses in the PVC membrane (PVC/DEHP). Repetition of steps (a), (b) and (c) results in further leaching of DEHP for a long period. In addition, this study indicated that process (a) is the rate-determining step for the ranges of 26-37% DEHP and 0.5-1.0 kcal/ml EL solution.

Acid-treated yeast cell wall (AYC) was produced via a novel approach involving acidification of brewers` yeast cell wall. We investigated the utility of AYC as a novel binder for pharmaceutical preparations. Granulation of calcium hydrogenphosphate dihydrate with hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), pullulan (PUL) and AYC was attempted. Like the granules of HPC, PVP and PUL, the diameter and hardness of the granules of AYC increased as AYC concentration increased and plate-like calcium hydrogenphosphate dihydrate was granulated by AYC, showing that AYC has the function of a binder. The tensile strength of AYC-tablets produced by compressing AYC-granules increased as AYC concentration increased. The dissolution time of AYC-tablets was extremely short, within 2 min at all AYC concentrations. These results indicate that AYC has high utility as a novel binder, giving granules and tablets sufficient binding force but maintaining a rapid dissolution rate.

Powder and liquid dosage treatments for allergic rhinitis are on the market. However, these formulations require frequent administration for the treatment of grave rhinitis. Novel ointment formulations, including a hydrogel base, a hydrophilic ointment, an absorptive ointment and a white petrolatum, were investigated for prolonged drug action. Flunisolide was used as an active ingredient for the treatment of allergic rhinitis. Release behaviors of flunisolide in vitro from each ointment base were determined employing a newly designed release apparatus. The extent of release was greatly affected by the type of ointment base, and the release rate was extremely slow with the use of white petrolatum. Therefore, white petrolatum was thought to be a suitable base for the application of flunisolide into the nasal cavity. To ensure the sustained release phenomena as well as prolonged action, the amount of flunisolide transferred from the base to nasal mucosa was determined in Japanese white rabbits. When the white petrolatum was applied into the nostril of rabbit, a sufficient amount of the drug remained in the nasal mucosa more than 8 h after application, while no drug was observed on application of the hydrogel. From the time course of flunisolide concentration in the nasal mucosa, area under the concentration-time curve (AUC) and variance of residence time (VRT) were estimated. A pharmacokinetic analysis revealed that white petrolatum ointment could retain flunisolide in the nasal mucosa much longer than the hydrogel.

A high-performance size-exclusion chromatographic process, using a TSKgel G4000PWXL column, for the quantitative analysis of FITC-labeled poly(vinyl alcohol) in biological specimens was developed. FITC-labeled poly (vinyl alcohol) of various molecular masses (MW = 10,560 - 116,600) was successfully synthesized by the modified method of de Belder. The derivatives showed a very low degree of substitution where the labeling of the parent poly (vinyl alcohol) with FITC did not affect chromatographic behavior. Linear calibration curves were obtained at concentrations down to 1.5 μg/ml when the derivatives were monitored fluorometrically. The applicability of the method was demonstrated by measuring the biodisposition of the FITC-labeled poly (vinyl alcohol) following injection into rats. In addition to quantitation, the molecular weight distribution of the derivatives could be estimated simultaneously from the chromatograms. As the fraction of the smaller molecular weight of the FITC-labeled poly (vinyl alcohol) was predominantly excreted to urine, the weighted-average molecular weight of the compound in the blood circulation shifted continuously in the high molecular weight direction. Furthermore, the FITC-labeled poly (vinyl alcohol) was found to be stable in the body because no breakdown was detected chromatographically in all biological media under investigation.

Interactions between novel cationic liposomes (TRX-liposomes) and the components of blood such as bovine serum albumin, three kinds of plasma obtained from rat, rabbit, and human, and bovine serum and rat erythrocytes were investigated under in vitro conditions. TRX-liposomes containing 8 mole % of TRX-20 (3,5-dipentadecyloxy-benzamidine hydrochloride) and different contents of two types of polyethylene glycol were prepared by the extrusion method. A distinct increase in the mean diameters of the liposomes was observed in the range of PEG contents from 0.25 to 2.0 mole %, and then the mean diameter tended to approach a constant size up to the PEG content of 4 mole %. On the other hand, the zeta potential of TRX-liposomes decreased in proportion to the increase of PEG content over the experimental range. These results were supposed to be strongly dependent upon the steric form of PEG (mushroom or brush form). From the results of the interaction study, it was discovered that TRX-liposomes interacted with human plasma containing apolipoprotein under physiological ionic conditions but did not interact with animal plasma. Furthermore, this interaction was inhibited by increasing the PEG content. The results obtained here indicat that not electric charge due to cationic lipid (TRX-20), but the steric form of PEG on the liposomal surface is essential for controlling the interactions between TRX-liposomes and the components in blood. In particular, the brush form and the long chain length of PEG would be quite effective for inhibiting interaction. This conclusion will be useful for designing cationic liposomal formulation.

Safety and efficacy information is necessary for drug delivery systems that use particulate systems prepared with copoly (DL-lactic/glycolic acid) (PLGA). To investigate the size-effect of PLGA particulate systems, the present study first evaluated the in vitro cytotoxicity, and then assessed the prolonged efficiency of lidocaine-loaded PLGA nanospheres. PLGA and fluoresceinamine-bound PLGA (FA-PLGA) nanospheres and microspheres were prepared by the modified emulsion solvent diffusion method. Comparative in vitro cytotoxicity studies of PLGA nanospheres and microspheres were evaluated by the direct contact method using the L929 cell culture model; WST-1(2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazollum-Na) assay and LDH (lactate dehydrogenase) release. The fluorescence microscopy method was used to identify the phagocytosed PLGA particulate systems by cultured L929 cells. These in vitro cytotoxicity tests showed that PLGA microspheres were safer than PLGA nanospheres. The PLGA nanospheres were phagocytosed into the L929 cells. To confirm the pharmacological effect of lidocaine-loaded PLGA particulate systems, localized pain-responses were assessed using the subcutaneously administered anesthetic guinea pig model. Lidocaine-loaded PLGA nanospheres were found to provide remarkably prolonged local anesthetic effects compared with lidocaine solution.