For the purpose of replacement therapy using progesterone, the mixed suppository consisting of Witepsol and ethylene-vinyl acetate copolymer (EVA) was investigated using a computer optimization technique. Witepsol-W35, EVA40Y and EVA250 were employed as the suppository base. Nine formulations were prepared according to a composite experimental designfor two factors; the rate of Witepsol-W35 (X1) and the rate of EVA250 in the EVA phase (X2). Characteristics such as the penetration (Y1), the strength (Y2), DSC peak temperature (Y3), heat of fusion (Y4), the amount dissolved (ADT, Y5) and mean dissolution time (MDT, Y6) were measured. As absorption parameters of progesterone, AUC (Y7) and MRT (Y8) were estimated after vaginal administration of suppositories in rabbits.
After application of multiple regression analysis for each of the characteristics, optimum regression equations were obtained. The best formulation to maximize AUC was sought under the restriction of experimental region. Experimental results obtained for the optimum formulation agreed well with the predictions.
When the mixed suppository which contained 100mg progesterone was administered to voluntary patients, the efficient blood level was maintained for 24 hours.
These results suggested that the progesterone-mixed suppository was quite useful for the treatment of the luteal phase defect.

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The relationships of the serum concentration with daily dose/body weight (Dw) or daily dose/body surface area (Ds) of sodium valproate, phenobarbital and carbamazepine were investigated in epileptic children. The serum concentrations of these drugs significantly correlated with both Dw or Ds. The correlation coefficients (r) of the serum concentrations of sodium valproate (VPA), phenobarbital (PB), and carbamazepine (CBZ) to daily dose were 0.472, 0.638, and 0.812, respectively, using the body weight as a normalizing factor. While those were 0.602, 0.731, and 0.870, respectively, using the body surface area as a normalizing factor. In all drugs, r was higher with using Ds, rather than Dw. These results indicate that it would be better to use Ds than Dw in adjustments of the dosages of these drugs. We also examined the influence of patient age on the ratio of the serum level to the daily dose (L/Dw or L/Ds) for each drug. We found no significant correlation between age and the L/Ds ratio for all antiepileptic drugs studied. However, significant positive correlations were observed between age and the L/Dw ratio.
The serum concentrations of the drugs studied well correlated with Ds, and the L/Ds ratio showed no significant difference among all age groups. These results indicate that dosage regimens based on a body surface area more reliable than those on a body weight basis.

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Quantitative analysis of the relationship between the burden on care-givers while administering medicine to the elderly and the factors which affect this burden were carried out at six longterm facilities in Japan. For grading the burden of administering drugs, we used the method developed by Tsutsui, in which the burden of 128 kinds of care services are quantitatively standardized from 1 point (turning on the TV) to 100 points (contending with violence by confused elderly). According to the method, caregivers graded the burden of every resident when administering the drugs. At the same time, various factors of every resident which influenced to some extent the burden of administering the drugs, were investigated.
The results of this study led us to two important conclusions.
1) As for the distribution of the burden score, most cases received around 20 points (equivalent to the preparation of a meal). The pattern of the score distribution differed widely among institutions.
2) To analyze the relationship between the burden score and some other factors, a multiple regression model was constructed. The dependent variable of the model was the burden score and the explanatory variables comprised several kinds of functional levels of aged people, the disparities among institutes. The model indicated that the factors which strongly affect the burden score are difficulty in swallowing, mental function level, physical activity level, the number of medicines prescribed, and malfunctioning of the hands. The R-square of this model was 0.60.

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The aqueous solubility of cyclosporin (CYA) was remarkably increased by the 2, 6-di-methyl-α-cyclodextrin (DM-α-CD) complex, forming a higher order complex. Analysis of the phase solubility diagram at 37°C estimated the stoichiometric ratio of the main complex to be 1: 3 (CYA: DM-α-CD) with a stability constant of 18600M^-1. Kneading mixtures of CYA with DM-α-CD in various molar ratios (1: 3 to 1: 200) were prepared. The effects of DM-α-CD on the gastrointestinal absorption of CYA was then investigated in the rat. The mean absorption time and the mean residence time of CYA was shortened with the increase in the molar ratio of DM-α-CD to CYA. The maximal AUC was obtained after the administration of the 1: 30 kneading mixture. A further increase in the molar ratio of DM-α-CD showed insignificant changes with regard to the extent of bioavailability. The bioavailability of each mixture was almost the same as or slightly higher than that of Sandimmun^®.

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The compatibility of menatetrenone (VK₂) emulsion stabilized with lecithine in the infusion fluids containing divalent electrolytes and heparin injections was studied. The visual extent of opalescence in the admixtures was inspected, and the hydrodynamic diameter of the lipid droplets in the emulsion was measured using NICOMP photon correlation spectrometer. Samples showing the opalescence or precipitation were subjected to particle counting and sizing. Admixtures of VK₂ emulsion with plasma expanders containing divalent cations showed opalescence or precipitation, but did not containing glucose in place of the divalent cations. The opalescence also occurred in the admixture of VK₂ emulsion with heparin injections in electrolyte solutions containing the divalent cations. These results suggest that the change in the lecithine charge brought on by the divalent cations produces the formation of a bridge of high-molecular compounds such as dextran, gellation and heparin among emulsions.

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Carmofur-loaded microspheres composed of polylactic acid (PLA) with a molecular weight of 20, 000 were prepared as a parenteral dosage form applicable as a sustained release preparation for cancer chemotherapy by a solvent evaporation method on a clean bench in a biological clean room. The amount of residual organic solvent in the microspheres was determined, and the physicochemical characteristics including the release of the drug from the microspheres were also investigated. The periods required to evaporate the methylene chloride remained in the microspheres below 100 ppm at 30, 35 and 40°C were 35, 9 and 5 days, respectively. The shape of microspheres was completely spherical and the surface was found to be quite smooth by scanning electron microscopic observation. Particles with diameter of 20 to 100 μm occupied about 85% of all microspheres, and the mean diameter of the microspheres dried at 35 and 40°C was about 60-80 μm. The release of the drug from the microspheres was relatively sustained, and it took 14 days to release more than 90%. In the sterility test, no growth of microorganism was not observed and thus the microspheres prepared under the biologically clean condition were confirmed to be aseptic. These findings suggest that the present PLA microspheres containing carmofur may be applicable as sustained-release preparation for the cancer chemotherapy.

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We found that an impurity was formed in the 1% dibucaine injection solution following ordinal treatment using the high-pressure steam method. The impurity was isolated and characterized to be 2-hydroxy-N-[2-(diethylamino) ethy1-4-quinolinecarboxamine (debutyl-dibucaine)], which was caused from the thermal degradation of dibucaine brought about by the sterilization process. The degradation of dibucaine with dealkylation was found to be affected under the thermal treatment, time and temperature conditions. In addition, suitable sterilization conditions were established to maintain the purity of the 1% dibucaine injection solution at more than 99.5%.

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A solution comprising sodium azulene sulfonate, lidocaine hydrochloride and Elase (fibrinolysin and DNase) is used as a gargle to relieve the pain after the operation of malignant tumor of the head and neck and to remove exudata from the inflammed part.
Azulene sufonate and lidocaine in Azunol·Elase·Xylocaine gargle (AEXG) were stable when kept at 5°±1, 20°±1 and 30°±1 over a 14-day period. However, the activities of fibrinolysin and DNase in AEXG rapidly decreased even at 5°. These results demonstrated that AEXG is unstable and should be prepared just prior to use. However, AEXG produced a remarkable pain relieving effect with few adverse reactions. And AEXG is clinically evaluated highly in spite of its unstability.

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The discriminative factors of ampules utilized for injection were investigated statistically by quanti fication theory type II, using the data collected from to administration of 216 ampules. A criterion variable was taken to be the answer given from 10 pharmacists to the question as to whether or not an ampule was easily discriminating, and the explanatory variables were taken as the categorical data regarding 10 items characterizing the ampules, such as the material.
The most significant factor was found to be the method of printing, followed by the number of colors in the printing and the physical properties of contents. The conclusion this study produced was that for discriminative improvement of ampules employed for injection, it was important that printing be done on a paper label, to increase the number of colors in the printing, and to design the label so that the product name can be easily read.

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The quartz-crystal microbalance (QCM) used in our experiments showed that a frequency change of 1 Hz corresponded to a mass increase of 1.05±0.01ng on the QCM electrode. The copolyamino acids adsorbed fenitrothion by as much as half of the mass. These results indicated that copolyamino acids had a high affinity for agricultural chemicals. And the adsorption to copolyamino acids was not only high but also rapid. The QCM method is required ouly for determining the microgram quantity of the adsorbents.

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A new double-chambered plastic bag for total parenteral nutrition (TPN) solution, PN-twin^®, has become commercially available. One PN-twin^® chamber termed layer I, contains dextrose and electrolytes while the other chamber, layer II, consists of amino acids. Test samples were prepared by adding vitamins and trace minerals to the mixtures of layers I and II solutions, and only to a layer 11 solution. The stabilities of vitamins A, B₁, B₂, B₆, C, E, folic acid (FA) and K₁ were studied under three different conditions: room temperature in a dark place, room temperature with light exposure, and cold in a dark place.
The residual rates of vitamins B₂, C and K₁ in the layers I and II solution mixture stored at room temperature with light exposure for 48 hours dropped to under 63%. With the addition of trace minerals into the test samples in a cold, dark place, the residual rate of vitamin C decreased significantly. Also, the residual rates of vitamin B₁ in the layer II solution decreased rapidly. After storing at room temperature for 48 hours and/or in a cold, dark place for 7 days, the residual rates of vitamin B₁ fell to below 6%. These findings suggested that the addition of vitamins to PN-twine^® should be avoided before the two separate chambers and connected.

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Miconazole (MCZ) serum concentration was measured by high-performance liquid chromatography (HPLC). We assessed whether the internal standard method produced on intra-assay error, and found that the method gave more precise and more reproducible results than absolute calibration curve method. With 0.5μg/ml of MCZ, the coefficient of variation produced by that method was 3.41%, whereas that of the absolute calibration curve method was 5.20%. The concentrations of absolute calibration curve method showed higher values than the internal standard method. This indicated that the internal standard method was far more precise in measuring the MCZ serum concentrations than was the absolute calibration curve method.

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