[Pharmaceutical Properties of Rikkunshito Extract Suppository and Bioequivalence by Pharmacokinetic Parameters and Effectiveness against Nausea and Vomiting and Anorexia in Rats].

　In patients with cancer, it is difficult to continue medical treatment owing to nausea and vomiting (NV). Therefore, it is important to avoid these problems for improving the patient's QOL. Rikkunshito extract (RK) possesses antiemetic effects and is used in combination in cancer therapy. However, patients with cancer find it difficult to take the medicine orally for the treatment of NV and anorexia owing to the characteristic smell and taste of traditional Chinese medicine. We examined the pharmaceutical properties of RK suppository for hospital use, assessed bioequivalence by using pharmacokinetic parameters, and determined its effectiveness against NV and anorexia in rats. In this study, RK suppository was prepared by using RK formulation (A, B, and C) and Witepsol (H and S) (AH, BH, CH, AS, BS, and CS). Pharmaceutical properties, namely, hardness, dispersibility, long-term stability, and drug (hesperidin and glycyrrhizic acid) release were measured for AH, BH, AH, and AS. The pharmacokinetic parameters, effectiveness of substance P against NV and anorexia, and serotonin-activated ghrelin levels were assessed for BH only. AH, BH, AS, and AS demonstrated uniform and sufficient hardness. The release rate of oleaginous components, such as glycyrrhizic acid, did not change significantly, while that of water soluble components, such as hesperidin, decreased when compared with that in powder formulations A and B. NV and anorexia improved in rats administered BH compared with the control group. BH suppository showed effectiveness in terms of both physicochemical property and bioequivalence for hospital use.

Safety evaluation of dermal exposure to phthalates: Metabolism-dependent percutaneous absorption.

Phthalates, known as reproductive toxicants and endocrine disruptors, are widely used as plasticizers in polyvinyl chloride products. The present study was conducted for risk identification of dermal exposure to phthalates. When dibutyl phthalate was applied to the skin of hairless rats and humans, only monobutyl phthalate appeared through the skin, and the permeability of the skin was higher than that after the application of the monoester directly. The inhibition of skin esterases made the skin impermeable to the metabolite following dermal exposure to dibutyl ester, whereas removal of the stratum corneum from the skin did not change the skin permeation behavior. Similar phenomena were observed for benzyl butyl phthalate. The skin permeability of monobenzyl phthalate was higher than that of monobutyl phthalate in humans, although the reverse was observed in rats. Species difference in skin permeation profile corresponded to the esterase activity of the skin homogenate. Di(2-ethylhexyl) phthalate, which was not metabolized by esterases in the skin, was not transported across the skin. These results suggest that highly lipophilic phthalates may be transported easily across the stratum corneum lipids. The water-rich viable layer may become permeable to these phthalates by their metabolism into monoesters, which are relatively hydrophilic. Skin metabolism is essential to the percutaneous absorption of phthalates. Because esterase activity has large inter-individual differences, further study will be needed for individual risk identification of dermal exposure to phthalates.

[Effect of Adhesives on the Properties of Adhesion, Drug Release and Skin Permeation of Lidocaine Tapes].

A generic drug is defined as a drug product that is comparable to a brand name drug in terms of dosage, form, strength, route of administration, quality, performance characteristics, and indicated use. Generic drugs for topical use, in the case of sheet-like products, are required to be the same as the original drug in terms of application area and dosage form. The composition of such generic drug formulations may differ from that of the original product. The adhesive of any pharmaceutically-active tape that directly contacts the skin plays a role in delivering the active ingredient into the skin, and affects the sensation and ease of handling. Therefore, adhesives are an important ingredient in these products. Thus, the aim of this study was to characterize original and generic lidocaine tape products, and to evaluate the adhesive properties of each. The tack force, peel strength and shear adhesion were measured as adhesive properties. In addition, in vitro drug releasing profiles and skin permeation profiles of the products were evaluated. In vivo transdermal absorption was also evaluated to predict the possibility of adverse effects. Adhesive properties differed among the three analyzed products. These differences may have been caused by differences in the adhesives. Drug-releasing profiles and skin permeation profiles also differed among the three products, even though the pharmacokinetics were not significantly different. By obtaining an adequate understanding of the characteristics of original and generic products, we will be able to provide better tailor-made medications for drug therapies for patients.

Evaluation of bilirubin displacement effect by acetaminophen in vitro.

BACKGROUND: The use of acetaminophen as a drug for pain control is expected to increase in the neonatal field. The displacement factor of acetaminophen in the reaction in the glucose oxidase peroxidase method is very high, but is also considered to be inaccurate based on physicochemical properties. METHOD: Unbound bilirubin was measured using the erythrocyte-bound bilirubin measurement method and glucose oxidase peroxidase method by the addition of acetaminophen or sulfisoxazole. The displacement factor was measured using glucose oxidase peroxidase method with the addition of tert-butyl-p-hydroxyanisole. RESULTS: Acetaminophen did not increase erythrocyte-bound bilirubin, and the addition of tert-butyl-p-hydroxyanisole lowered its displacement factor. On the other hand, sulfisoxazole increased erythrocyte-bound bilirubin, while tert-butyl-p-hydroxyanisole did not change its displacement factor. CONCLUSION: Acetaminophen is an accelerator of the reaction in the glucose oxidase peroxidase method and does not displace bilirubin from human serum albumin.

Preparation of polypseudorotaxanes composed of cyclodextrin and polymers in microspheres.

We prepared polypseudorotaxanes (PPRXs) composed of cyclodextrin (CyD) and polyethylene glycol (PEG) inside microspheres (MSs) by an emulsifying process using polypropylene glycol (PPG) that shows temperature-dependent hydrophilicity changes; PPG is hydrophobic at high temperatures but hydrophilic at low temperatures. An aqueous solution of CyD and PEG was dispersed as droplets in PPG at 60°C then cooled to 0°C to allow water of droplets to transfer into PPG. On removal of water in the droplets, CyD and PEG were left behind as a CyD/PEG PPRX inside the solid-state MSs. Examination of α-, ß-, and γ-CyD revealed that α-CyD was suitable for the formation of PPRX containing PEG in this MS preparation procedure. Interestingly, a new PPRX composed of α-CyD and PPG was formed in the α-CyD MSs when they were prepared in the absence of PEG from the aqueous solution of α-CyD. This MS fabrication procedure can control the size and shape of PPRX particles, and will contribute to the production of new types of CyD inclusion complexes.

Safety prediction of topically exposed biocides using permeability coefficients and the desquamation rate at the stratum corneum.

Advances in the synthesis and utilization of new chemical compounds have led to improvements in our daily lives. However, new chemicals may be both beneficial and toxic. Thus, exposure to these new compounds should be restricted in an attempt to limit their potential toxicities. We predicted the safety of three biocides (p-cresol, diazinon and resmethrin) by comparing their skin permeability coefficients and desquamation rate (the counter flux of permeability coefficient for chemical compounds induced by skin turnover) following skin exposure. In vitro skin permeation experiments revealed that the permeability coefficients of diazinon and resmethrin were smaller than the desquamation rate; therefore, these biocides could not permeate the skin, which resulted in very low skin concentrations of these compounds. On the other hand, the skin concentration of p-cresol was high because of its higher permeability coefficient than the desquamation rate. Furthermore, low in vitro cell viability was reported for skin exposed to p-cresol. These results in the present study indicate that the method described herein is useful for predicting the toxicities of chemicals following their topical exposure.

[Skin permeation and transdermal delivery systems of drugs: history to overcome barrier function in the stratum corneum].

Transdermal Drug Delivery Systems (TDDS), where active drugs must be absorbed into the systemic circulation after penetrating the skin barrier, were first launched in 1979, and about 10 TDDS containing different kinds of drugs were developed during the initial decade. Interestingly, a developmental rush has come again in the present century. Various penetration-enhancing approaches to improve drug permeation of the skin (stratum corneum) have been attempted. These approaches are of two types: chemical and physical. Examples of the chemical approach are enhancers such as alcohol, monoterpenes and fatty acid esters, as well as chemical modification of prodrugs. In contrast, physical approaches include the use of electrical-, thermal- and mechanical-energy, as well as microneedles, needle-free injectors or electroporation to completely or partially evade the barrier function in the stratum corneum. The chemical approaches are mainly effective in increasing the skin permeation of low-molecular chemicals, whereas physical means are effective for these chemicals but also high-molecules like peptides, proteins and nucleotides (DNA or RNA). Marked development has been observed in these physical means in the past decade. In addition, recent developments in tissue engineering technologies enables the use of cultured skin containing keratinocytes and fibroblasts as a TDDS. An effective "cell delivery system" may be a reality in the near future. This paper will look back on the 30-year history of TDDS and evaluate the feasibility of a new generation of these systems.