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Globalization of pharmaceutical supply chains has expanded and manufacturers are required to manufacture products in compliance with the pharmacopoeial standards used in all exporting countries/regions to ensure product quality. International harmonization has been facilitated by the Pharmacopoeial Discussion Group consisting of the Japanese Pharmacopoeia, the United States Pharmacopeia, and the European Pharmacopoeia. However, since the pharmacopoeias have been developed individually under the regulatory framework of each country/region, differences exist between these pharmacopoeias. When using pharmacopoeias, an understanding of common pharmacopoeial rules is essential. Clarifying the similarities and differences in the General Notices of the pharmacopoeias widely referenced worldwide is considered valuable for those already using one or two of them to access the remaining pharmacopoeias. In this study, we compared the existence of items and the contents described in the General Notices of the three pharmacopoeias to clarify the differences. Investigation of the existence of items revealed that more than 70% of the 105 items in General Notices in the three pharmacopoeias were in the entire pharmacopoeias (for Japan, including Japanese laws and notifications). Furthermore, investigating contents revealed that approximately 20% of the 105 items have some differences such as numerical values and test conditions. However, it was shown that most of the items did not have major differences. It is expected that the three pharmacopoeias will be utilized simultaneously by understanding the similarities and differences shown in this study.

In line with the recent globalization of the drug supply chain and promotion of the use of generic drugs worldwide, quality assurance is required for drugs globally. In particular, controlling impurities is one of the biggest areas of interest regarding pharmaceutical quality, and it is desirable that the latest scientific standards harmonized in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) are not only implemented in approval applications but also incorporated in pharmacopoeias which are public standards to ensure pharmaceutical quality more widely. However, incorporation into a pharmacopoeia takes time because careful consideration is required owing to the characteristics of a pharmacopoeia that is widely used for drugs, including those already on the market. To consider a smooth approach for the incorporation, we retrospectively examined approaches to incorporate the concepts of the ICH Q3C, Q3D, and M7 guidelines covering residual solvents, elemental impurities, and mutagenic impurities which are particularly toxic impurities into the European Pharmacopoeia, United States Pharmacopeia-National Formulary, and Japanese Pharmacopoeia, with approaches to implement these guidelines into approval processes in Europe, the U.S., and Japan. We also identified barriers and facilitators to this goal via cause and effect analysis. Moreover, we developed a logic model for the smooth incorporation of the concepts of impurity-related ICH guidelines. We expect that our proposed approach will be applied as a framework to smoothly incorporate the results of international harmonization activities for controlling impurities into each pharmacopoeia.

A pharmacopoeia's core mission is to protect public health by creating and making available public standards to help ensure the quality of drugs. In recent years, pharmacopoeias around the world have harmonized their standards in the present context of globalized drug supply chains and markets. For example, the Pharmacopoeial Discussion Group has worked to harmonize excipient monographs and general chapters. In addition, the International Meeting of World Pharmacopoeias has been held by the WHO to discuss information exchange and international collaboration, among other topics. To contribute further to the protection of public health in the globalized drug market, we conducted a comparative study of the pharmacopoeias in Japan, Europe, and the United States. We aimed to examine current differences among the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia-National Formulary and to identify areas that require further collaboration among the three pharmacopoeias. In this study, we analyzed monographs and general chapters listed in the three pharmacopoeias. We identified the features of the monographs and general chapters listed in each pharmacopoeia, as well as differences across the pharmacopoeias. Moreover, on the basis of our findings, we suggest standards that require further collaboration among the pharmacopoeias in certain preferred areas. The comparison data produced by this study are expected to be used to develop strategies for future revisions of pharmacopoeias around the world.

Chiral phosphine oxide sequentially activates silicon tetrachloride and trichlorosilyl enol ethers to facilitate asymmetric aldol/vinylogous aldol reaction of 4-methoxy-3-penten-2-one and conjugated aldehydes in a highly enantioselective fashion, and the subsequent cyclization produced optically active 2,6-disubstituted 2,3-dihydro-4-pyranones bearing stereogenic centers at a remote position in a single operation.

2,3-Dihydro-4-pyranones were synthesized stereoselectively using a chiral phosphine oxide as the catalyst. The phosphine oxide sequentially activated silicon tetrachloride and promoted the double aldol reaction of 4-methoxy-3-buten-2-one with aldehydes. Subsequent stereoselective cyclization afforded the corresponding highly functionalized 2,3-dihydro-4-pyranones bearing three contiguous chiral centers in good yields and with high diastereo- and enantioselectivities.

The aim of this study was to examine the effect of D-sorbitol on the gelation characteristics of methylcellulose in aqueous solution. The addition of D-sorbitol at concentrations of between 25 and 30% (w/v) to 1.0-2.0% (w/v) methylcellulose solutions reduced the gelation temperature from approximately 53 degrees Celsius to values between ambient and 37 degrees Celsius and increased the strength of the gel. The in vitro release of acetaminophen (paracetamol) from 2.0% (w/v) methylcellulose gels containing 20-30% (w/v) D-sorbitol gel was diffusion-controlled.

The effect of an ultrasound (1 MHz) on transdermal absorption of indomethacin from an ointment was studied in rats. Ultrasound energy was supplied for between 5 and 20 min at a range of intensities (0.25, 0.5, 0.75, and 1 W cm-2), energy levels commonly used for therapeutic purposes. For evaluating skin penetration of indomethacin, the change of plasma concentration was measured. The pronounced effect of ultrasound on the transdermal absorption of indomethacin was observed at all ultrasound energy levels studied. The intensity and the time of application were found to play an important role in the transdermal phonophoretic delivery system of indomethacin; 0.75 W cm-2 appeared to be the most effective intensity in improving the transdermal absorption of indomethacin, while the 10 min ultrasound treatment was the most effective. Although the highest penetration was observed at an intensity of 0.75 W cm-2, 0.5 W cm-2 was preferred because intensities of less than 0.5 W cm-2 of ultrasound for 10 min did not result in any significant skin temperature rise nor did it have any destructive effect on rat skin. Progressively more skin damage was noted as the intensity and the time of application of ultrasound increased. When used at a proper intensity and time of application, ultrasound appears to be a safe technique for enhancing the passage of various drug molecules through human skin.

Pluronic F-127 (PLF-127) gels were evaluated as a sustained-release vehicle for intraperitoneal administration of mitomycin C (MMC) in order to enhance the therapeutic effects of MMC against a Sarcoma-180 ascites tumor in mice. Tumor cell injections were made on day 0 and injections of MMC in 25% (w/w) PLF-127 on day 1, both intraperitoneally. A prolongation of the life span of tumor-bearing mice following injection of therapeutic PLF-127 was noted, and PLF-127 containing MMC was therapeutically more active than free drug. The high chemotherapeutic efficiency of MMC in PLF-127 was striking at high doses, which would be toxic in the case of the drug alone. PLF-127 gels exhibit reverse thermal behavior and are fluid at refrigerator temperature, but are soft gels at body temperature. The in vitro release experiments indicated that Pluronic gel might serve as a rate-controlling barrier and be useful as a vehicle for sustained-release preparations of MMC to be administered intraperitoneally. These results suggest that sustained-release occurs in the peritoneum and that effective drug concentrations can be maintained by the preparation.

Human chorionic gonadotropin (hCG) was extracted and purified by reverse-phase resin (Sepralyte C8 resin) adsorption and Sephadex G-100 column chromatography from urine of pregnant women. Approximately 15000 IU of hCG was recovered from 1000 ml of urine by C8 resin adsorption. hCG from the gel-filtration step stimulated testosterone production in rat Leydig cells and had a specific activity of approximately 8000 IU/mg, a value which was higher than those of commercial hCGs. Furthermore, hCG purified to near-homogeneity was separated effectively into its subunits by reverse-phase high-performance liquid chromatography using an acetonitrile gradient in the presence of 0.1% trifluoroacetic acid with no special pretreatment for dissociation of subunits. The separated subunits were able to re-associate. The techniques used are simple and may be suitable for not only laboratory but also industrial production of hCG and its subunits.

A polymeric system capable of delivering 5-fluorouracil (5-FU) at increased rates on demand by external microwave irradiation was developed. Sustained-release systems were made by incorporating 5-FU into an ethylene-vinyl alcohol copolymer. When exposed to release medium, the delivery systems released the drug slowly and continuously. Upon exposure to microwave irradiation, the drug was released at a much higher rate. Release rates returned to base line levels when the microwave irradiation was discontinued. This study demonstrated that release rates of 5-FU from a polymer matrix can be increased at desired times by external microwave irradiation.