Fumiyoshi Ishii

Effect of phospholipid emulsifiers on physicochemical properties of intravenous fat emulsions and/or drug carrier emulsions

Abstract— The physicochemical properties of soybean oil emulsions stabilized with purified egg lecithins (phosphatides) of various concentrations have been examined. The zeta potential of the emulsion droplets and the mean particle size of oil droplets in 10% (w/w) o/w‐type emulsion decreased with increasing emulsifier concentration and then levelled off at more than 1.2% (w/w). In rheological measurements, at the initial stage, the viscosity of 10% (w/w) o/w‐type emulsion gradually increased with increasing purified egg lecithin concentration, at the next stage, a plateau was reached at about 1.0–1.4% (w/w), and at the final stage, the viscosity curve showed a dramatic increase. These results indicate that emulsions stabilized by purified egg lecithin at more than 1.2% (w/w) are likely to be sufficiently stable.

Drug release from poly(vinyl alcohol) gel prepared by freeze-thaw procedure

Abstract Poly(vinyl alcohol) (PVA) gel was prepared by a freeze-thaw cycle method. Sodium alginate or Pluronic L-62 was added for the control of drug release from PVA gel. The concentration dependence of sodium alginate or Fluronic L-62 on the drug release from PVA gel was evaluated according to the in vitro drug release procedure. The rheological strength of the PVA gel was measured with a rheometer. The morphological surface of PVA gel was observed by scanning electron microscopy. The physical strength of the gel increases with increasing sudium alginate concentration, while the drug release from the gel decreased with increasing sodium alginate or Pluronic L-62 concentration. It is apparent that these bases are available for a topical drug delivery system if the physical strength and the drug release from the gel can be controlled by adding sodium alginate or Pluronic L-62.

Physicochemical properties and controlled drug release of microcapsules prepared by simple coacervation.

Ternary phase diagrams of gelatin-water-methanol, gelatin-water-ethanol, and gelatin-water-propanol systems were prepared to evaluate optimal coacervation. The results of their evaluation suggested that the optimal coacervation region expands with the hydrophobicity of the added poor solvent (methanol, ethanol, 1-propanol, and 2-propanol). Microcapsules prepared based on the optimal coacervation region differed in controlled drug release among poor solvents used even when the concentration of gelatin, a membrane component, is the same. Compared with microcapsules prepared using the gelatin-water-ethanol system, those prepared using the gelatin-water-propanol system showed a 34% decrease in the drug release rate 24h after the initiation of the drug release test. These results suggested that microcapsules prepared using gelatin-water-various lower alcohol systems can readily control drug release and can be a useful drug delivery system (DDS).

Factors affecting physicochemical properties of liposomes prepared with hydrogenated purified egg yolk lecithins by the microencapsulation vesicle method

We examined hydrogenated purified egg yolk lecithins, having practical advantages over non-hydrogenated ones, as liposomal membrane materials. Liposomes were prepared by the microencapsulation vesicle (MCV) method in which liposomes are formed through two-step emulsification and dispersion. Three types of purified egg yolk lecithins with different iodine values were examined after being dissolved in one of three lipid solvents. The liposome size increased as the temperature during the second emulsification increased, being closer to the boiling temperature of the solvent. The preparation temperature in relation to the transition temperature of each lecithin was also a factor affecting liposome sizes. As for the encapsulation efficiencies of the model compound calcein in liposomes, they differed mainly depending on the solubility of each lecithin in a lipid solvent and it was more obvious in hydrogenated lecithins. A high preparation temperature resulted in lower encapsulation efficiencies, suggesting that leakage of encapsulated calcein was facilitated at high temperature in the MCV methods. There was a significant correlation between liposome sizes and encapsulation efficiencies in non-hydrogenated purified egg yolk lecithin but not in hydrogenated ones. When using hydrogenated purified egg yolk lecithins as liposomal membrane materials, it was suggested that a lipid solvent should be chosen so that a lecithin completely dissolves under the preparation condition in order to achieve a higher encapsulation efficiency. Smaller liposome particles were obtained when the second emulsification was performed at a lower temperature compared with the boiling point of the lipid solvent. These findings can be applied to control encapsulation efficiencies and particle sizes in each particular liposome preparation enclosing therapeutic agents.

PREPARATION CONDITIONS AND EVALUATION OF THE STABILITY OF LIPID VESICLES (LIPOSOMES) USING THE MICROENCAPSULATION TECHNIQUE

Abstract The conditions for the preparation of lipid vesicles ((liposomes) by the in-water drying method, one of the microencapsulation techniques, were described in detail. This process consists of the following steps: (I) dispersion of an aqueous solution of the drug to be encapsulated into an organic solvent to yield a water-in-oil emulsion, (II) dispersion of this w/o-type emulsion into an aqueous phase (distilled water), (III) formation of a lipid membrane on the surface of droplets by evaporation of the organic solvent from the oil phase, and (IV) removal of the free marker (drug) by ultracentrifugation or gel filtration through a Sephadex column. In this process, the mean diameter of the vesicles was dependent on the mechanical revolution number necessary for dispersing the w/o-type emulsion into the distilled water. Moreover, the percentage encapsulation of the lipid vesicles increased with the decrease in mechanical revolution number necessary for dispersing the w/o-type emulsion into the distill...

The most appropriate storage method in unit-dose package and correlation between color change and decomposition rate of aspirin tablets.

The most appropriate method to preserve Bufferin 81-mg tablets dispensed for unit-dose packaging in the hospital pharmacy was examined. The surface color change of the tablets was investigated over time by spectrophotometry, and the decomposition rate of aspirin was measured by high-performance liquid chromatography (HPLC). To overcome these, it was found that we can effectively prevent color changes and preserve the quality by maintaining the humidity as 55% or less, storage with drying agent in a plastic or aluminum pack. It was revealed that the color changes became greater and the decomposition rate became higher as time passed. Color changes markedly affect the patients compliance, and are found to be a very important factor. It was considered that the clarity of the correlation between the color change and decomposition rate may contribute to a decrease in the number of tablets discarded before the expiration date.

Interaction between erythrocytes from three different animals and emulsions prepared with various lecithins and oils.

The hemolysis of various animal erythrocytes in emulsions prepared with various emulsifying agents (lecithins) and oils was examined. In the emulsions stabilized with different emulsifying agents, the degree of hemolysis increased in the order soybean lecithin<egg yolk lecithin<hydrogenated egg yolk lecithin<hydrogenated soybean lecithin. In the emulsions stabilized with phospholipids with different iodine values that describe the degree of unsaturation in the fatty acyl groups of phospholipids, the percentage hemolysis decreased with increasing iodine value. In addition, in emulsions prepared with various triglycerides as the oil phase the percentage hemolysis increased with increasing triglyceride acyl chain length. The percentage hemolysis of the different animal erythrocytes increased in the order sheep<rabbit<guinea pig according to phosphatidylcholine contents in erythrocyte membrane of each animal. These results suggested that hemolysis caused by the interaction between erythrocytes and emulsions was involved in phospholipid dispersal such as liposome-like vesicles in the water phase, and was dependent on the phosphatidylcholine contents in both the emulsions and the erythrocyte membrane. Moreover, sphingomyelin in the erythrocyte membrane was found to be an important component for stabilization of erythrocyte membranes against hemolysis induced by intravenous fat or lipid emulsions.

Simple and Convenient Method for Estimation of Marker Entrapped in Liposomes

We have developed a new method to determine the marker calcein encapsulated in liposomes using ethanol or propanol instead of Triton X-100. Calcein in ethanol solution was estimated by fluorophotometry with excitation and emission wavelengths of 490 nm and 520 nm, respectively. The fluorescence intensity of calcein solubilized by ethanol was linear in the range of 10 −6−10 −4 mol/L with a correlation coefficient of 0.999. The proposed method, which was accurate and reproducible, was successfully applied to determine the amounts of ethanol-soluble drugs in liposomes.

A Novel Administration Route of Edaravone – II: Mucosal Absorption of Edaravone from Edaravone/Hydroxypropyl-Beta-Cyclodextrin Complex Solution Including L-Cysteine and Sodium Hydrogen Sulfite

We examined the pharmacokinetics of edaravone when edaravone/hydroxypropyl-β-cyclodextrin (HPβCD) complex solution, including L-cysteine (L-Cys) and sodium hydrogen sulfite (SHS), was administered intravenously, rectally and via the oral mucosa. In oral mucosal administration, atomized edaravone/HPβCD complex solution that contained L-Cys and SHS was sprayed into the mouth of Wistar rats. Oral mucosal and rectal administration of edaravone/HPβCD complex solution that contained L-Cys and SHS was compared with that for edaravone/HPβCD complex solution without L-Cys and SHS. When edaravone 0.25–1.0 mg was administered intravenously, C₀ and AUC0–60 were linear. In oral mucosal and rectal administration, Cmax and AUC0–60 of edaravone/HPβCD with L-Cys and SHS were significantly higher than those of edaravone/HPβCD without L-Cys and SHS. On the other hand, bioavailability of oral mucosal, rectal and oral administration was about 100, 63.5 and 26.6%, respectively. This study suggested that L-Cys and SHS were useful for the oral mucosal and rectal administration of edaravone.

Adsorption of various antimicrobial agents to endotoxin removal polymyxin-B immobilized fiber (Toraymyxin®).

The presence/absence of adsorption of 9 representative types of antimicrobial agent used in combination with a polymyxin-B immobilized fiber (PMX-F) were determined and the degree of adsorption to PMX-F was quantitatively evaluated. Various antimicrobial agents were dissolved at appropriate concentrations, and PMX-F was added to each solution and incubated at 37°C. Antimicrobial solutions without PMX-F were also similarly incubated as controls. After 2 and 4h, the concentration of each antimicrobial agent was determined using HPLC. To produce an environment closer to the in vivo state, albumin or serum was added, and similar evaluation was performed. In the presence of albumin, the rate of adsorption to PMX-F was relatively high for Cefmetazon(®), Pentcillin(®), Ciproxan(®) and Zyvox(®). In the presence of serum, the adsorption rate was 4.02±2.83% for Pentcillin(®), 5.59±1.00% for Ciproxan(®), and 22.12±3.23% for Zyvox(®). The results of this study suggest that adequate caution is necessary on the clinical use of Zyvox(®), which was adsorbed in the presence of serum as an environment close to the in vivo environment, but the use of other antimicrobial agents in combination with PMX-F may have only slight influences on adsorption to PMX-F.