We warmed and liquefied 24 kinds of steroid and non-steroid ointments dispensed in tubes used at our hospital, and then chilled the tubes to be rehardened in order to study basis homogeneity throughout the ointment. The results showed that distribusion of the basis stayed within acceptable ranges in 4 out of 19 of the steroid ointments and 2 out of 5 of the non-steroid ointments, but the remaining 18 ointments had problems with consistency, as the liquefied basis tended to pool at a specific part of the tube. We also conducted a number of studies on the ointment base with interesting results.

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The preparation of ethanolamine oleate injections containing 50% of iopamiron 300 (EO-IP 300) in sclerosing treatment (endoscopic embolization) of esophageal varix was tried by 4 kinds of representative methods. Because of difficulty in mixing, the whitening solution of EO-IP300 was often produced by method B, C and D. However, method A always gave the clear solution of that.
The preparation of EO-IP300 using differently graded or degraded reagents (oleic acids, ethanolamines and benzyl alcohols) was tried by method A. No abnormality was observed in appearance of all the samples. Then, the samples of EO-IP300 contained in an ampule with air or N₂ were sterilized and were stored for 4 weeks under different conditions. The changes in appearance, pH, specific gravity, viscosity, osmotic pressure, and contents of iopamidol, oleic acid and benzyl alcohol, and the concentration of iodides (contaminants) were examined at intervals. After sterilization, no change was observed in each test item except increase of the content of iodides in all sterilized samples of EO-IP300. Almost no change was observed in each test item during 4 weeks in a dark place below room temperature, nor was significant difference seen between the samples contained with air and N₂.
These results suggest that the reagent grade, the replaced gas, and sterilization condition are not significant to obtain the clear solution of EO-IP300 but the preparation method is, and that EO-IP300 is stable for at least 4 weeks in a dark place below room temperature.

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The preparation of ethanolamine oleate (EO) injections containing a contrast medium [Iopamiron 300 (IP 300), Omnipaque 300 (OP 300), Isovist 240 (IV 240), Angiografin (AF), Hexabrix 320 (HB 320)] in sclerosing treatment (endoscopic embolization) of esophageal varix was tried by the method described in our previous report.Clear injectable solutions were prepared by mixing EO with the non-ionic contrast medium (IP 300, OP 300, IV 240), while whitening solutions were produced by mixing EO with the ionic contrast medium (AF, HB 320).
Then, the samples of EO injections mixed with the non-ionic contrast medium contained in an ampule with air or N₂ were sterilized and were stored for 4 weeks under different conditions. The changes in appearance, pH, specific gravity, viscosity, osmotic pressure, and contents of the contrast medium, oleic acid and benzyl alcohol, and the concentration of iodide (contaminant) were examined at intervals. After sterilization, no change was observed in each test item except increase of the content of iodide in all sterilezed samples and the content of iodide in EO-OP 300 became the highest under any atomosphere.During the storages EO-OP 300 also showed the highest content of iodide under any conditions and a white turbidity appeared in EO-OP 300 injections under some storage conditions. These results suggest that EO-IP 300 and EO-IV 240 are stable for at least 4 weeks in a dark place below room temperature after sterilization but EO-OP 300 is less stable.

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The kinetics of indomethacin (IM) degradation was examined in alkaline aqueous solutions (pH 7.0-10.0) at various temperatures for the purpose of prediction of IM stability. The pseudo first-order rate constants (k_obs) were evaluated from log absorbance of IM versus time plots at 320nm. The k_obs was independent of borate buffer concentration but the primary salt effect was positive, suggesting the reaction of the same kind of ions plays a role in the mechanism of IM hydrolysis. The reaction was specific base catalyzed. From the data at 40, 50, 60 and 70°C, the microscopic rate constants (k_OH-) for hydrolysis were determined and their thermodynamic parameters were obtained from Arrhenius-type plot at μ=0.5. The effect of organic solvents, propylene glycol, polyethylene glycol 400 (PEG 400) and glycerin on the rate constants were also investigated for the degradation of IM in phosphate buffer solutions (pH 8.0, μ=0.5) at 60°C. Degradation reaction obeyed pseudo first-order kinetics in the presence of the solvents. The values of k_obs were decreased with increase in propylene glycol or PEG 400 concentration. The estimated half-lives at 60°C and pH 8.0 were 5.1, 7.1 and 11.9 hr in water or 20% aqueous solutions of propylene glycol or PEG 400, respectively.
These stabilizing effects could be associated with the decrease in dielectric constant of the reaction medium.In the case of glycerin-water mixtures, unexpectedly, hydrolysis of IM was accelerated by increase in glycerin concentration and the half-life was 1.7 hr in 20% solution. The mechanism of the destructive action of glycerin on IM has not yet known, this result suggests that glycerin may influence the stability of IM pharmaceuticals in which glycerin is contained as a humectant or excipient.

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The analytical method of clindamycin (CLDM) in plasma, bile and urine by high-performance liquid chromatography (HPLC) was investigated. The samples were 0.2 ml of plasma and bile, and 0.1 ml of urine containing a known amount of CLDM. Haloperidol as an internal standard (0.2 ml of 5μg/ml in methanol for plasma and bile, 0.1 ml of 30μg/ml in methanol for urine), and then 0.5 ml of 1 N sodium hydroxide and 1 ml of diethyl ether were added to each sample. The solution was shaken for 10 min and centrifuged for 10 min at 10, 000g. The organic phase was transferred to a test tube and evaporated to dryness under a stream of nitrogen gas at 50°C. The residue was redissolved in methanol (0.1 ml for plasma and bile, 0.25 ml for urine), and then 25μl of the solution was injected into HPLC. The analytical condition was as follows: the column was Nucleosil 5C₁₈ (15cm×4, 6mm I.D.), the mobile phase was 10 mM phosphate buffer (pH 3.0)-acetonitrile (64/36, v/v), the flow rate was 1 ml/min, the column temperature was 50±0.2°C and the wavelength was 210 nm. In the concentration ranges of 0-l00μg/ml (plasma, bile) and 0-500μg/ml (urine), each calibration curve showed a good linear correlation (r=0.999). The coefficient of variationss of within-day and between-day of plasma, bile and urine samples were below 3 and 4%, respectively. The recovery was 94-106%. The present method was found to be applicable for pharmacokinetic study of CLDM in plasma, bile and urine obtained from patients.

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A study was made to find out how admixtures of syrups of Alimezine, Inolin and Leftose become discolored during storage for 5.5 hr at room temperature. As for the discoloration of Alimezine syrup from red (λ_max510nm) to yellow (λ_max445nm), the change of absorbance with new coccine in the Alimezine syrup was read at 510 nm with a spectrophotometer. The degree of discoloration of Alimezine syrup in the admixture depended on the concentration of syrups of Inolin and Leftose. Sodium sulfite in the Inolin syrup was essential for discoloration in the admixture. The discoloration in the admixture was accelerated by the lysozyme chloride contained in Leftose syrup. This discoloration was reconstituted with Alimezine syrup, Inolin syrup and a substitute for Leftose in which lysozyme chloride was replaced by bovine serum albumin. In the admixture of the syrups of Alimezine, lnolin and Leftose, new coccine and the yellow discoloration product (yellow new coccine) were bound to lysozyme chloride. These results suggest that the discoloration of new coccine in the admixture of the three kinds of syrups is produced by sodium sulfite and the binding of new coccine to lysozyme chloride.

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The checking system for dispensing of powder drugs has been developed using the bar code, because of difficulty to discriminate the variety of powder drugs. However, the system for refilling of powder drugs to the stock bottle is not available yet. The re-filling work has been checking by manual work.
In present study, we developed new checking system for re-filling of powder drugs to the stock bottle using bar codes with micro-computer. The system requires the correspondence of the package bar code (JAN code) and stock bottle's bar code (NW7 code).

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It can be presumed that liver function will be influenced by the administration of thiopental in the course of barbiturate therapy.Fof this reason, we established and tested a new method for the therapeutic monitoring of the concentration of thiopental in human serum.
In this method, we employed high-performance liquid chromatography (HPLC) to simplify the pretreatment technique, thereby to shorten the amount of time needed for measurement. As a result, chromatographic data, and the calibration curve (Y=0.249X+0.118, r=0.999) obtained indicated that within-, between-run precision, and recovery rates from the serum are all extremely good. The lowest measurable concentration was found to be 0.1μg/ml (Aufs 0.16). Also, in the cross-reaction tests among drugs mainly used in combination, we did not find any influence on the quantitative analysis of thiopental. We, then measured the serum levels in patients to whom thiopental was administered intravenously. By submitting the results of the t-test, we confirmed a significant rise in the concentration of thiopental in patients with the liver failure, as compared with normal patients (p<0.01). Therefore, we conclude that this assay system can provide measurement as fast as possible, with the added benefit of simplified clinical procedures.

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Many studies on the determination of clonazepam by high-performance, liquid chromatograpy (HPLC method) have been reported. In their reports, however, a large volume of plasma or serum sample was used. Therefore, we developed a high sensitivity microanalytical method of clonazepam determination by HPLC with a small volume of sample, since patients treated with clonazepam were almost pediatric epileptics. A plasma or serum sample (0.2ml), to which 0.1ml of 100ng/ml triazolam was added as an internal standard, was alkalinized with 1 ml of 0.01N sodium hydroxide and then was extracted with 5 ml of diethyl ether. The organic layer was evaporated to dryness. The residue was reconstituted with 70μl of mobile phase and the resulting solution was injected into the HPLC. The HPLC condition was as follows: the column was cosmosil 5CN-R (15cm×4.6mm I.D.), the mobile phase was 5mM phosphate buffer (pH 7.0)-acetonitrile (3/1, v/v), the flow rate was 1ml/min, the column temperature was 40±0.2°C and the wavelength was 221nm. The calibration curve showed a good correlation (n=18, r=0.992); the regression equation was Y=0.0164X+0.189 within the range of 5-100ng/ml. The detection limit was found to be 5ng/ml. The coefficient of variations of the withinday and between-day precisions were less than 5 and 10%, respectively. The recovery was approximately 100%. Analysis of clonazepam in serum by this method was not influenced by other antiepileptic drugs when they were administered simultaneously.

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Tissue distribution and tumor uptake of temperature-sensitive liposomes entrapping doxorubicin (DXR) with local hyperthermia were studied. The liposomes composed of dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine (9: 1, molar ratio) were prepared by reverse-phase evaporation method expecting to release the drug at 41°C by hyperthermia. The liposomes were injected intravenously via the tail vein into BALB/c mice bearing tumors (colon carcinomas 26) implanted in hind foot, and local hyperthermia at 42°C was applied for 20 minutes. Liposomal DXR accumulated in reticuloendothelial system such as liver and spleen, but this uptake was decreased with local hyperthermia. The tumor uptake of liposomal DXR with local hyperthermia was 4 times larger than that of free drug. These results suggest that this thermochemotherapy will be useful for targeting therapy.

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The automatic dispensing system which is connected between the prescription ordering system and automatic tablet counting and packing system (ATC) machine has been developed in recent years. The quality control of tablets and capsules (unsealed) in ATC and the stability of these drugs after ATC package must be considered for packing these drugs in a one dose-package by automatic dispensing system. Therefore, we selected 190 drugs (tablets and capsules) from the drugs adopted in our hospital and stored in a light-resistant or moistureproof place as mentioned in package inserts, and investigated the stability of these tablets and capsules (unsealed condition) with time when they were stored in the ATC tablet cases provided in our dispensary and under the conditions of constant temperature and humidity (in a dark place, at 20°C and 52%RH). In our study, we used a new tablet case devised for improving the light-resistant and maintained appropriate conditions of temperature and humidity in the dispensary by using an air conditioning system continuously. As a result, the quality control of these drugs stored in ATC was greatly improved. The appearance of ASPARA K®, DEPAKENE ®and AUGMENTIN ® were changed markedly under the sealed condition in ATC by temperature and humidity. We judged from our findings that the application of these three drugs to the automatic dispensing system is by far difficult since there are still problems to be solved for the quality control of these drugs.

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The effects of several salts on the in vitro adsorption of paraquat by cation exchange resins and activated carbons were studied in the disintegration test fluids (JP XII) at 37°C. Under the condition of no addition of salts, cation exchange resins showed much greater adsorption capacities for paraquat than activated carbons. However, the adsorbing capacities of cation exchange resins were extremely decreased in the presence of sodium chloride and, saline purgatives such as magnesium sulfate and sodium sulfate, whereas the adsorption of paraquat on activated carbons tended to be enhanced by the addition of salts to the media.

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Pediatric doses cited in package inserts were compared between Japanese formulary “Drugs in Japan, Ethical Drugs 1974” and “Drugs in Japan, Ethical Drugs 1989” in order to compare the extent of citation of pediatric doses in recent package inserts with that of 15 years before. In addition, the information on pediatric doses of drugs, which have been used in Kumamoto University Hospital, was collected by searching the literature. The number of drugs cited the pediatric doses in Japanese formulary '89 was less than that in Japanese formulary '74. The pediatric doses were cited in 608 (21.6%) of 2817 drugs adopted in Japanese formulary '74, whereas they were cited in 301 (13.1%) of 2295 drugs adopted in Japanese formulary '89. Antibiotics was the class of drugs whose pediatric doses were most cited in both formularies. The pediatric doses were described more in terms of age than in terms of body weight or body surface area in Japanese formulary'74. On the other hand, those in Japanese formulary '89 were described more in terms of body weight than in terms of age. Any information on pediatric doses could be collected in approximately 80% of the drugs adopted in Kumamoto University Hospital by searching the literature.

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Effects to improve the quality of medical care have meant that increasingly intravenous hyperalimentation fluids (IVH) are being prepared by hospital pharmacists in clean booth or clean benches. Neverthess, there are still many places where IVH are being prepared in the nurse stations or by hospital workers other than a pharmacist. In this study, we prepared IVH under both conditions and compared the microbial contamination of each solutions. We demonstrated that if the proper methods are followed it is possible to prepare the solution free from contamination even in the ward.

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